Nephrology

For many years, the medical community speculated about the possibility of organ transplantation. The first successful transplant of any kind involving humans was a corneal transplant in 1905.¹

It wasn’t until 1954 that the first successful organ transplant, a kidney transplant between identical twins, occurred.² Several new concepts emerged: organ rejection plays a major role in the failure or success of a transplant; and donors and recipients must be matched based on blood group.

Today, about 169,000 people in the US live with a donated kidney. Each year, some 10,500 cadaveric organs are transplanted, and 6,400 donors are living donors.³ The National Kidney Foundation’s recent 10-year initiative, End the Wait!,⁴ seeks to close the gap between the more than 50,000 people on the transplant waiting list³ and the number of available donor organs.

Since many patients live for years with their transplanted organs, the primary care clinician is likely to see transplant recipients in a family practice or internal medicine setting. While each patient has unique needs, there are commonalities among them.

Renal Consult welcomes any additional comments or questions regarding care of the renal patient. Please address them to [email protected].
Jane S. Davis, CRNP, DNP

Q: I have a 70-year-old male patient who is losing kidney function. He asked me about transplantation, but I really don’t know whether he is eligible to get on the list. Who is eligible? Is there an age limit? Are patients with chronic illnesses (hepatitis B, hepatitis C, HIV) eligible? How long is the list? Where can I find these answers?

There are no specific guidelines regarding eligibility or age restrictions for kidney transplantation in the United States. Most transplant centers look at patients older than 65 a little more carefully than younger patients—they have to be in good health apart from their renal disease. Some centers will not transplant patients older than 70, while others transplant patients who are 80 or older.¹⁵ The best thing to do is to refer the patient to the local center or call and find out. Again, the Organ Procurement and Transplantation Network,⁷ which lists transplant centers and contact information, can be accessed at optn.transplant.hrsa.gov/mem bers/search.asp

Chronic illnesses are not automatic rule-outs for the most part. Very few centers transplant HIV-positive patients, but this does occur, especially in major cities with a large population of persons with HIV (eg, Washington, DC; San Francisco, New York City, Cincinnati). An infectious disease specialist must follow these patients after transplantation and adjust their HAART (highly active antiretroviral therapy) medications to compensate for both the decreased renal function and anti-rejection medications.  Hepatitis B and C patients are often accepted as long as liver biopsy shows no cirrhosis and the viral load is low or manageable. If the patient is found to have cirrhosis or decompensation, a combined liver-kidney transplant can be planned, although the success rate of this procedure is low.^16,17

Patients with certain types of hepatitis C may be eligible to receive a kidney from a donor with hepatitis C¹⁸ in order to shorten the wait time and make use of a kidney that cannot be transplanted into a person not infected with hepatitis C.

Transplant waiting lists vary by region across the country. There is a centralized electronic list managed by UNOS, on which eligible recipients are placed once they have been approved by the transplant center, following the medical work-up and acceptance by the transplant committee at each center. This is referred to as “being listed” or “on the list.” Patients begin to accrue waiting time as soon as they are added, and this list is precise to the second! There is a list for each blood type, with its own set of waiting times in each region.²⁰ Average waiting times, by blood type (ie, ABO), can be searched at www.ustransplant.org/Calcula tors/KidneyWaitTime.aspx

When a donor organ becomes available and has been evaluated by the procurement team, the donor’s information is entered into the system and the computer generates a list of eligible candidates, based on a variety of factors. This is called a “match-run.”

Waiting time is the most important factor, but consideration is given to patients younger than 18, those who have previously donated an organ, and those with high antibody levels (ie, panel-reactive antibodies, or PRAs). Patients in the latter group may find it more difficult to locate a compatible donor, as these patients have been sensitized as a result of prior transplantation, pregnancy, or blood transfusions. It is very rare for a patient to be a perfect match (0 mismatch), but should the right organ become available, the matched patient receives priority consideration.

Besides the ABO match, human leukocyte antigen (HLA) matching of six main HLA antibodies is done.  Within each of these six antibodies (HLA-A, B, C, DP, DR, DQ), subgroup matching is also done because some HLA subgroups are more highly correlated with rejection than others.^21,22 A more complete explanation of organ matching and allocation can be found on the “Transplant Living” Web site: www.transplantliving.org/beforethetransplant/allocation/matchingorgans.aspx.

Patients should be encouraged to access “Transplant Living” (www.transplantliving.org) and UNOS for information and links. Additional information about transplantation, eligibility, performance statistics, policies, procedures, and other questions and answers, for both clinicians and patients, can be found on the Organ Procurement and Transplantation Network Web site (optn.transplant.hrsa.gov).
Annette Needham, MSN, ARNP, NP-C, CNN-NP, CCTC, Florida Hospital Transplant Center, Orlando

References
1. Armitage WJ, Tullo AB, Larkin DFP. The first successful full-thickness corneal transplant: a commentary on Eduard Zirm’s landmark paper of 1906. Br J Ophthalmol. 2006;90(10):1222-1223.

2. Kidney transplantation: past, present, and future. www.stanford.edu/dept/HPS/transplant/html/history.html. Accessed September 16, 2011.

3. United States Renal Data System. Atlas. www .usrds.org/atlas.htm. Accessed September 16, 2011.

4. National Kidney Foundation. End the wait! www.kidney.org/news/end_the_wait/index.cfm. Accessed September 16, 2011.

5. National Kidney Foundation. Kidney transplant (2011). www.kidney.org/atoz/content/kidneytransnewlease.cfm. Accessed September 16, 2011.

6. United States Renal Data Systems. Presentations and posters (2000-2011). www.usrds.org/presentations.htm. Accessed September 16, 2011.

7. Organ Procurement and Transplantation Network. Members: member directory. optn.transplant.hrsa.gov/members/search.asp. Accessed September 16, 2011.

8. Jensen P, Møller B, Hansen S. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol. 2000;42(2 pt 1):307.

9. Wong G, Chapman JR, Craig JC. Cancer screening in renal transplant recipients: what is the evidence? Clin J Am Soc Nephrol. 2008;3 suppl 2:S87-S100.

10. Parker A, Bowles K, Bradley JA, et al; Haemato-oncology subgroup of the British Committee for Standards in Haematology and the British Transplantation Society. Diagnosis of post-transplant lymphoproliferative disorder in solid organ transplant patients. Br J Haematol. 2010;149(5):675-692.

11. Transplant Living. After the transplant (2011). www.transplantliving.org/afterthetransplant/default.aspx. Accessed September 16, 2011.

12. United Network for Organ Sharing. www.unos.org. Accessed September 16, 2011.

13. Kidney Disease Improving Global Outcomes. Managing your adult patients who have a kidney transplant (2010). www.kidney.org/professionals/tools/pdf/02-50-4079_ABB_ManagingTransRecip Bk_PC.pdf. Accessed September 16, 2011.

14. Abbud-Filho M, Adams P, Alberu J, et al. A report of the Lisbon Conference on the care of the kidney transplant recipient. Transplantation. 2007; (Suppl 8):83:1-22.

15. Heldal K, Hartmann A, Leivestad T, et al. Risk variables associated with the outcome of kidney recipients >70 years of age in the new millennium. Nephrol Dial Transplant. 2011;26(8):2706-2711.

16. Chava SP, Singh B, Stangou A, et al. Simultaneous combined liver and kidney transplantation: a single center experience. Clin Transplant. 2010; 24(3):E62-E68.

17. Ruiz R, Kunitake H, Wilkinson AH, et al. Long-term analysis of combined liver and kidney transplantation at a single center. Arch Surg. 2006;141 (8):735-741.

18. Veroux P, Veroux M, Puliatti C, et al. Kidney transplantation from hepatitis C virus-positive donors into hepatitis C virus-positive recipients: a safe way to expand the donor pool? Transplant Proc. 2005;37(6):2571-2573.

19. United States Renal Data Systems, Annual Data Reports. National Kidney and Urologic Disease Information Clearinghouse. Figure 6ii. Transplant (kidney only) wait list and wait times. www.usrds.org/2010/pdf/v2_07.pdf. Accessed September 16, 2011.

20. Arbor Research Collaborative for Health. Kidney waiting time calculator. www.ustransplant.org/Calculators/KidneyWaitTime.aspx. Accessed September 16, 2011.

21. Karakayali FY, Ozdemir H, Kivrakdal S, et al. Recurrent glomerular diseases after renal transplantation. Transplant Proc. 2006;38(2):470-472.

22. Nojima M, Ichikawa Y, Ihara H, et al. Significant effect of HLA-DRB1 matching on acute rejection of kidney transplants within 3 months. Transplant Proc. 2001;33(1-2):1182-1184.

For many years, the medical community speculated about the possibility of organ transplantation. The first successful transplant of any kind involving humans was a corneal transplant in 1905.¹

It wasn’t until 1954 that the first successful organ transplant, a kidney transplant between identical twins, occurred.² Several new concepts emerged: organ rejection plays a major role in the failure or success of a transplant; and donors and recipients must be matched based on blood group.

Today, about 169,000 people in the US live with a donated kidney. Each year, some 10,500 cadaveric organs are transplanted, and 6,400 donors are living donors.³ The National Kidney Foundation’s recent 10-year initiative, End the Wait!,⁴ seeks to close the gap between the more than 50,000 people on the transplant waiting list³ and the number of available donor organs.

Since many patients live for years with their transplanted organs, the primary care clinician is likely to see transplant recipients in a family practice or internal medicine setting. While each patient has unique needs, there are commonalities among them.

Renal Consult welcomes any additional comments or questions regarding care of the renal patient. Please address them to [email protected].
Jane S. Davis, CRNP, DNP

Q: I have a 70-year-old male patient who is losing kidney function. He asked me about transplantation, but I really don’t know whether he is eligible to get on the list. Who is eligible? Is there an age limit? Are patients with chronic illnesses (hepatitis B, hepatitis C, HIV) eligible? How long is the list? Where can I find these answers?

There are no specific guidelines regarding eligibility or age restrictions for kidney transplantation in the United States. Most transplant centers look at patients older than 65 a little more carefully than younger patients—they have to be in good health apart from their renal disease. Some centers will not transplant patients older than 70, while others transplant patients who are 80 or older.¹⁵ The best thing to do is to refer the patient to the local center or call and find out. Again, the Organ Procurement and Transplantation Network,⁷ which lists transplant centers and contact information, can be accessed at optn.transplant.hrsa.gov/mem bers/search.asp

Chronic illnesses are not automatic rule-outs for the most part. Very few centers transplant HIV-positive patients, but this does occur, especially in major cities with a large population of persons with HIV (eg, Washington, DC; San Francisco, New York City, Cincinnati). An infectious disease specialist must follow these patients after transplantation and adjust their HAART (highly active antiretroviral therapy) medications to compensate for both the decreased renal function and anti-rejection medications.  Hepatitis B and C patients are often accepted as long as liver biopsy shows no cirrhosis and the viral load is low or manageable. If the patient is found to have cirrhosis or decompensation, a combined liver-kidney transplant can be planned, although the success rate of this procedure is low.^16,17

Patients with certain types of hepatitis C may be eligible to receive a kidney from a donor with hepatitis C¹⁸ in order to shorten the wait time and make use of a kidney that cannot be transplanted into a person not infected with hepatitis C.

Transplant waiting lists vary by region across the country. There is a centralized electronic list managed by UNOS, on which eligible recipients are placed once they have been approved by the transplant center, following the medical work-up and acceptance by the transplant committee at each center. This is referred to as “being listed” or “on the list.” Patients begin to accrue waiting time as soon as they are added, and this list is precise to the second! There is a list for each blood type, with its own set of waiting times in each region.²⁰ Average waiting times, by blood type (ie, ABO), can be searched at www.ustransplant.org/Calcula tors/KidneyWaitTime.aspx

When a donor organ becomes available and has been evaluated by the procurement team, the donor’s information is entered into the system and the computer generates a list of eligible candidates, based on a variety of factors. This is called a “match-run.”

Waiting time is the most important factor, but consideration is given to patients younger than 18, those who have previously donated an organ, and those with high antibody levels (ie, panel-reactive antibodies, or PRAs). Patients in the latter group may find it more difficult to locate a compatible donor, as these patients have been sensitized as a result of prior transplantation, pregnancy, or blood transfusions. It is very rare for a patient to be a perfect match (0 mismatch), but should the right organ become available, the matched patient receives priority consideration.

Besides the ABO match, human leukocyte antigen (HLA) matching of six main HLA antibodies is done.  Within each of these six antibodies (HLA-A, B, C, DP, DR, DQ), subgroup matching is also done because some HLA subgroups are more highly correlated with rejection than others.^21,22 A more complete explanation of organ matching and allocation can be found on the “Transplant Living” Web site: www.transplantliving.org/beforethetransplant/allocation/matchingorgans.aspx.

Patients should be encouraged to access “Transplant Living” (www.transplantliving.org) and UNOS for information and links. Additional information about transplantation, eligibility, performance statistics, policies, procedures, and other questions and answers, for both clinicians and patients, can be found on the Organ Procurement and Transplantation Network Web site (optn.transplant.hrsa.gov).
Annette Needham, MSN, ARNP, NP-C, CNN-NP, CCTC, Florida Hospital Transplant Center, Orlando

References
1. Armitage WJ, Tullo AB, Larkin DFP. The first successful full-thickness corneal transplant: a commentary on Eduard Zirm’s landmark paper of 1906. Br J Ophthalmol. 2006;90(10):1222-1223.

2. Kidney transplantation: past, present, and future. www.stanford.edu/dept/HPS/transplant/html/history.html. Accessed September 16, 2011.

3. United States Renal Data System. Atlas. www .usrds.org/atlas.htm. Accessed September 16, 2011.

4. National Kidney Foundation. End the wait! www.kidney.org/news/end_the_wait/index.cfm. Accessed September 16, 2011.

5. National Kidney Foundation. Kidney transplant (2011). www.kidney.org/atoz/content/kidneytransnewlease.cfm. Accessed September 16, 2011.

6. United States Renal Data Systems. Presentations and posters (2000-2011). www.usrds.org/presentations.htm. Accessed September 16, 2011.

7. Organ Procurement and Transplantation Network. Members: member directory. optn.transplant.hrsa.gov/members/search.asp. Accessed September 16, 2011.

8. Jensen P, Møller B, Hansen S. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol. 2000;42(2 pt 1):307.

9. Wong G, Chapman JR, Craig JC. Cancer screening in renal transplant recipients: what is the evidence? Clin J Am Soc Nephrol. 2008;3 suppl 2:S87-S100.

10. Parker A, Bowles K, Bradley JA, et al; Haemato-oncology subgroup of the British Committee for Standards in Haematology and the British Transplantation Society. Diagnosis of post-transplant lymphoproliferative disorder in solid organ transplant patients. Br J Haematol. 2010;149(5):675-692.

11. Transplant Living. After the transplant (2011). www.transplantliving.org/afterthetransplant/default.aspx. Accessed September 16, 2011.

12. United Network for Organ Sharing. www.unos.org. Accessed September 16, 2011.

13. Kidney Disease Improving Global Outcomes. Managing your adult patients who have a kidney transplant (2010). www.kidney.org/professionals/tools/pdf/02-50-4079_ABB_ManagingTransRecip Bk_PC.pdf. Accessed September 16, 2011.

14. Abbud-Filho M, Adams P, Alberu J, et al. A report of the Lisbon Conference on the care of the kidney transplant recipient. Transplantation. 2007; (Suppl 8):83:1-22.

15. Heldal K, Hartmann A, Leivestad T, et al. Risk variables associated with the outcome of kidney recipients >70 years of age in the new millennium. Nephrol Dial Transplant. 2011;26(8):2706-2711.

16. Chava SP, Singh B, Stangou A, et al. Simultaneous combined liver and kidney transplantation: a single center experience. Clin Transplant. 2010; 24(3):E62-E68.

17. Ruiz R, Kunitake H, Wilkinson AH, et al. Long-term analysis of combined liver and kidney transplantation at a single center. Arch Surg. 2006;141 (8):735-741.

18. Veroux P, Veroux M, Puliatti C, et al. Kidney transplantation from hepatitis C virus-positive donors into hepatitis C virus-positive recipients: a safe way to expand the donor pool? Transplant Proc. 2005;37(6):2571-2573.

19. United States Renal Data Systems, Annual Data Reports. National Kidney and Urologic Disease Information Clearinghouse. Figure 6ii. Transplant (kidney only) wait list and wait times. www.usrds.org/2010/pdf/v2_07.pdf. Accessed September 16, 2011.

20. Arbor Research Collaborative for Health. Kidney waiting time calculator. www.ustransplant.org/Calculators/KidneyWaitTime.aspx. Accessed September 16, 2011.

21. Karakayali FY, Ozdemir H, Kivrakdal S, et al. Recurrent glomerular diseases after renal transplantation. Transplant Proc. 2006;38(2):470-472.

22. Nojima M, Ichikawa Y, Ihara H, et al. Significant effect of HLA-DRB1 matching on acute rejection of kidney transplants within 3 months. Transplant Proc. 2001;33(1-2):1182-1184.

For many years, the medical community speculated about the possibility of organ transplantation. The first successful transplant of any kind involving humans was a corneal transplant in 1905.¹

It wasn’t until 1954 that the first successful organ transplant, a kidney transplant between identical twins, occurred.² Several new concepts emerged: organ rejection plays a major role in the failure or success of a transplant; and donors and recipients must be matched based on blood group.

Today, about 169,000 people in the US live with a donated kidney. Each year, some 10,500 cadaveric organs are transplanted, and 6,400 donors are living donors.³ The National Kidney Foundation’s recent 10-year initiative, End the Wait!,⁴ seeks to close the gap between the more than 50,000 people on the transplant waiting list³ and the number of available donor organs.

Since many patients live for years with their transplanted organs, the primary care clinician is likely to see transplant recipients in a family practice or internal medicine setting. While each patient has unique needs, there are commonalities among them.

Renal Consult welcomes any additional comments or questions regarding care of the renal patient. Please address them to [email protected].
Jane S. Davis, CRNP, DNP

Q: I have a 70-year-old male patient who is losing kidney function. He asked me about transplantation, but I really don’t know whether he is eligible to get on the list. Who is eligible? Is there an age limit? Are patients with chronic illnesses (hepatitis B, hepatitis C, HIV) eligible? How long is the list? Where can I find these answers?

There are no specific guidelines regarding eligibility or age restrictions for kidney transplantation in the United States. Most transplant centers look at patients older than 65 a little more carefully than younger patients—they have to be in good health apart from their renal disease. Some centers will not transplant patients older than 70, while others transplant patients who are 80 or older.¹⁵ The best thing to do is to refer the patient to the local center or call and find out. Again, the Organ Procurement and Transplantation Network,⁷ which lists transplant centers and contact information, can be accessed at optn.transplant.hrsa.gov/mem bers/search.asp

Chronic illnesses are not automatic rule-outs for the most part. Very few centers transplant HIV-positive patients, but this does occur, especially in major cities with a large population of persons with HIV (eg, Washington, DC; San Francisco, New York City, Cincinnati). An infectious disease specialist must follow these patients after transplantation and adjust their HAART (highly active antiretroviral therapy) medications to compensate for both the decreased renal function and anti-rejection medications.  Hepatitis B and C patients are often accepted as long as liver biopsy shows no cirrhosis and the viral load is low or manageable. If the patient is found to have cirrhosis or decompensation, a combined liver-kidney transplant can be planned, although the success rate of this procedure is low.^16,17

Patients with certain types of hepatitis C may be eligible to receive a kidney from a donor with hepatitis C¹⁸ in order to shorten the wait time and make use of a kidney that cannot be transplanted into a person not infected with hepatitis C.

Transplant waiting lists vary by region across the country. There is a centralized electronic list managed by UNOS, on which eligible recipients are placed once they have been approved by the transplant center, following the medical work-up and acceptance by the transplant committee at each center. This is referred to as “being listed” or “on the list.” Patients begin to accrue waiting time as soon as they are added, and this list is precise to the second! There is a list for each blood type, with its own set of waiting times in each region.²⁰ Average waiting times, by blood type (ie, ABO), can be searched at www.ustransplant.org/Calcula tors/KidneyWaitTime.aspx

When a donor organ becomes available and has been evaluated by the procurement team, the donor’s information is entered into the system and the computer generates a list of eligible candidates, based on a variety of factors. This is called a “match-run.”

Waiting time is the most important factor, but consideration is given to patients younger than 18, those who have previously donated an organ, and those with high antibody levels (ie, panel-reactive antibodies, or PRAs). Patients in the latter group may find it more difficult to locate a compatible donor, as these patients have been sensitized as a result of prior transplantation, pregnancy, or blood transfusions. It is very rare for a patient to be a perfect match (0 mismatch), but should the right organ become available, the matched patient receives priority consideration.

Besides the ABO match, human leukocyte antigen (HLA) matching of six main HLA antibodies is done.  Within each of these six antibodies (HLA-A, B, C, DP, DR, DQ), subgroup matching is also done because some HLA subgroups are more highly correlated with rejection than others.^21,22 A more complete explanation of organ matching and allocation can be found on the “Transplant Living” Web site: www.transplantliving.org/beforethetransplant/allocation/matchingorgans.aspx.

Patients should be encouraged to access “Transplant Living” (www.transplantliving.org) and UNOS for information and links. Additional information about transplantation, eligibility, performance statistics, policies, procedures, and other questions and answers, for both clinicians and patients, can be found on the Organ Procurement and Transplantation Network Web site (optn.transplant.hrsa.gov).
Annette Needham, MSN, ARNP, NP-C, CNN-NP, CCTC, Florida Hospital Transplant Center, Orlando

References
1. Armitage WJ, Tullo AB, Larkin DFP. The first successful full-thickness corneal transplant: a commentary on Eduard Zirm’s landmark paper of 1906. Br J Ophthalmol. 2006;90(10):1222-1223.

2. Kidney transplantation: past, present, and future. www.stanford.edu/dept/HPS/transplant/html/history.html. Accessed September 16, 2011.

3. United States Renal Data System. Atlas. www .usrds.org/atlas.htm. Accessed September 16, 2011.

4. National Kidney Foundation. End the wait! www.kidney.org/news/end_the_wait/index.cfm. Accessed September 16, 2011.

5. National Kidney Foundation. Kidney transplant (2011). www.kidney.org/atoz/content/kidneytransnewlease.cfm. Accessed September 16, 2011.

6. United States Renal Data Systems. Presentations and posters (2000-2011). www.usrds.org/presentations.htm. Accessed September 16, 2011.

7. Organ Procurement and Transplantation Network. Members: member directory. optn.transplant.hrsa.gov/members/search.asp. Accessed September 16, 2011.

8. Jensen P, Møller B, Hansen S. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol. 2000;42(2 pt 1):307.

9. Wong G, Chapman JR, Craig JC. Cancer screening in renal transplant recipients: what is the evidence? Clin J Am Soc Nephrol. 2008;3 suppl 2:S87-S100.

10. Parker A, Bowles K, Bradley JA, et al; Haemato-oncology subgroup of the British Committee for Standards in Haematology and the British Transplantation Society. Diagnosis of post-transplant lymphoproliferative disorder in solid organ transplant patients. Br J Haematol. 2010;149(5):675-692.

11. Transplant Living. After the transplant (2011). www.transplantliving.org/afterthetransplant/default.aspx. Accessed September 16, 2011.

12. United Network for Organ Sharing. www.unos.org. Accessed September 16, 2011.

13. Kidney Disease Improving Global Outcomes. Managing your adult patients who have a kidney transplant (2010). www.kidney.org/professionals/tools/pdf/02-50-4079_ABB_ManagingTransRecip Bk_PC.pdf. Accessed September 16, 2011.

14. Abbud-Filho M, Adams P, Alberu J, et al. A report of the Lisbon Conference on the care of the kidney transplant recipient. Transplantation. 2007; (Suppl 8):83:1-22.

15. Heldal K, Hartmann A, Leivestad T, et al. Risk variables associated with the outcome of kidney recipients >70 years of age in the new millennium. Nephrol Dial Transplant. 2011;26(8):2706-2711.

16. Chava SP, Singh B, Stangou A, et al. Simultaneous combined liver and kidney transplantation: a single center experience. Clin Transplant. 2010; 24(3):E62-E68.

17. Ruiz R, Kunitake H, Wilkinson AH, et al. Long-term analysis of combined liver and kidney transplantation at a single center. Arch Surg. 2006;141 (8):735-741.

18. Veroux P, Veroux M, Puliatti C, et al. Kidney transplantation from hepatitis C virus-positive donors into hepatitis C virus-positive recipients: a safe way to expand the donor pool? Transplant Proc. 2005;37(6):2571-2573.

19. United States Renal Data Systems, Annual Data Reports. National Kidney and Urologic Disease Information Clearinghouse. Figure 6ii. Transplant (kidney only) wait list and wait times. www.usrds.org/2010/pdf/v2_07.pdf. Accessed September 16, 2011.

20. Arbor Research Collaborative for Health. Kidney waiting time calculator. www.ustransplant.org/Calculators/KidneyWaitTime.aspx. Accessed September 16, 2011.

21. Karakayali FY, Ozdemir H, Kivrakdal S, et al. Recurrent glomerular diseases after renal transplantation. Transplant Proc. 2006;38(2):470-472.

22. Nojima M, Ichikawa Y, Ihara H, et al. Significant effect of HLA-DRB1 matching on acute rejection of kidney transplants within 3 months. Transplant Proc. 2001;33(1-2):1182-1184.

For many years, the medical community speculated about the possibility of organ transplantation. The first successful transplant of any kind involving humans was a corneal transplant in 1905.¹

It wasn’t until 1954 that the first successful organ transplant, a kidney transplant between identical twins, occurred.² Several new concepts emerged: organ rejection plays a major role in the failure or success of a transplant; and donors and recipients must be matched based on blood group.

Today, about 169,000 people in the US live with a donated kidney. Each year, some 10,500 cadaveric organs are transplanted, and 6,400 donors are living donors.³ The National Kidney Foundation’s recent 10-year initiative, End the Wait!,⁴ seeks to close the gap between the more than 50,000 people on the transplant waiting list³ and the number of available donor organs.

Since many patients live for years with their transplanted organs, the primary care clinician is likely to see transplant recipients in a family practice or internal medicine setting. While each patient has unique needs, there are commonalities among them.

Renal Consult welcomes any additional comments or questions regarding care of the renal patient. Please address them to [email protected].
Jane S. Davis, CRNP, DNP

Q: I am in primary care and have a kidney transplant patient that I see annually for her Pap test and pelvic exam. Is there anything in particular that I am supposed to look for? I feel out of my comfort zone.

As with most people, preventive care is vital and posttransplant patients are no different. However, there are a few “special circumstances” to keep in mind.

Besides ascertaining that posttransplant patients are taking their medications every day, determine whether they have recently had a generic substituted for their regular anti-rejection meds. Many transplant medications have generic equivalents now; while we want changes made only with the approval of a transplant center, it is legal for a pharmacy to substitute a generic without notifying the transplant nephrologist. We have seen rejection, toxicities, or changes in creatinine levels due to substitution of generics—or even substitution from one generic equivalent to another. These medications have a small effective window and have to be closely monitored whenever different manufacturers are used.

In addition, some patients will stop taking their immunosuppressive drug, either because they “feel better” and don’t believe they need it anymore, or because they can no longer afford it. Medicare will only pay for 36 months of these medications, and patients often halve the dose or stop taking the medication altogether when the cost becomes too high.⁵

There is a very useful Web site on transplant medications from the United States Renal Data System.⁶ The site, which also offers a wealth of information on chronic kidney disease (CKD), is www.usrds.org/presentations.htm

Dosing for any medication is based on the patient’s glomerular filtration rate (GFR). Your transplant patients have been taught their baseline creatinine level, but some do forget. Even after transplant (whether of a kidney, a pancreas, a liver, lungs, or a heart), the immunosuppressive medications will affect the GFR, and the patient is a CKD patient.

If a patient’s creatinine level is 1.9 mg/dL (normal range, 0.6 to 1.2), but it has varied between 1.8 and 2.0 ever since the transplant and they are not having any other issues, this is “normal” for them and no cause for alarm. On the other hand, if the creatinine level is 1.9 mg/dL and the patient reports that it is always 1.2, they need immediate referral. If the patient is new to the area, you can find a local transplant center on the Organ Procurement and Transplantation Network directory⁷:  optn.transplant.hrsa.gov/mem bers/search.asp

Screening for infections and malignancies is another important aspect of posttransplant care. I advise all patients to see a dermatologist at least once annually, as the risk for skin cancer is increased sevenfold in a transplant patient, compared with the general population.⁸ Annual Pap test, pelvic exam, and mammogram are important for female posttransplant patients, as is annual prostate-specific antigen testing for male posttransplant patients older than 45 with a life expectancy of at least 10 years.⁹

During the physical exam, the clinician should always check for lymphadenopathy or any other “lumps and bumps,” as posttransplant lymphoproliferative disorder is also a risk associated with long-term immunosuppression.¹⁰ A wonderful online resource for patients and providers, “Transplant Living,”¹¹ has an excellent section on posttransplant care: www.transplantliving.org/af terthetransplant/default.aspx. This Web site is managed by the United Network of Organ Sharing¹² (UNOS; www.unos.org), the organization that manages organ transplantation and donation under contract with the federal government.

Routine vaccinations are recommended—especially pneumococcal vaccine and an annual flu shot. Diphtheria-pertussis-tetanus, hepatitis A, hepatitis B, inactivated polio, and typhoid are also acceptable vaccines for a transplant patient. Vaccines that are contraindicated after transplantation include varicella, bacillus Calmette-Guérin, smallpox, intranasal influenza, live oral typhoid, measles, mumps, rubella, oral polio, live Japanese B encephalitis, and yellow fever.^13,14

References
1. Armitage WJ, Tullo AB, Larkin DFP. The first successful full-thickness corneal transplant: a commentary on Eduard Zirm’s landmark paper of 1906. Br J Ophthalmol. 2006;90(10):1222-1223.

2. Kidney transplantation: past, present, and future. www.stanford.edu/dept/HPS/transplant/html/history.html. Accessed September 16, 2011.

3. United States Renal Data System. Atlas. www .usrds.org/atlas.htm. Accessed September 16, 2011.

4. National Kidney Foundation. End the wait! www.kidney.org/news/end_the_wait/index.cfm. Accessed September 16, 2011.

5. National Kidney Foundation. Kidney transplant (2011). www.kidney.org/atoz/content/kidneytransnewlease.cfm. Accessed September 16, 2011.

6. United States Renal Data Systems. Presentations and posters (2000-2011). www.usrds.org/presentations.htm. Accessed September 16, 2011.

7. Organ Procurement and Transplantation Network. Members: member directory. optn.transplant.hrsa.gov/members/search.asp. Accessed September 16, 2011.

8. Jensen P, Møller B, Hansen S. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol. 2000;42(2 pt 1):307.

9. Wong G, Chapman JR, Craig JC. Cancer screening in renal transplant recipients: what is the evidence? Clin J Am Soc Nephrol. 2008;3 suppl 2:S87-S100.

10. Parker A, Bowles K, Bradley JA, et al; Haemato-oncology subgroup of the British Committee for Standards in Haematology and the British Transplantation Society. Diagnosis of post-transplant lymphoproliferative disorder in solid organ transplant patients. Br J Haematol. 2010;149(5):675-692.

11. Transplant Living. After the transplant (2011). www.transplantliving.org/afterthetransplant/default.aspx. Accessed September 16, 2011.

12. United Network for Organ Sharing. www.unos.org. Accessed September 16, 2011.

13. Kidney Disease Improving Global Outcomes. Managing your adult patients who have a kidney transplant (2010). www.kidney.org/professionals/tools/pdf/02-50-4079_ABB_ManagingTransRecip Bk_PC.pdf. Accessed September 16, 2011.

14. Abbud-Filho M, Adams P, Alberu J, et al. A report of the Lisbon Conference on the care of the kidney transplant recipient. Transplantation. 2007; (Suppl 8):83:1-22.

15. Heldal K, Hartmann A, Leivestad T, et al. Risk variables associated with the outcome of kidney recipients >70 years of age in the new millennium. Nephrol Dial Transplant. 2011;26(8):2706-2711.

16. Chava SP, Singh B, Stangou A, et al. Simultaneous combined liver and kidney transplantation: a single center experience. Clin Transplant. 2010; 24(3):E62-E68.

17. Ruiz R, Kunitake H, Wilkinson AH, et al. Long-term analysis of combined liver and kidney transplantation at a single center. Arch Surg. 2006;141 (8):735-741.

18. Veroux P, Veroux M, Puliatti C, et al. Kidney transplantation from hepatitis C virus-positive donors into hepatitis C virus-positive recipients: a safe way to expand the donor pool? Transplant Proc. 2005;37(6):2571-2573.

19. United States Renal Data Systems, Annual Data Reports. National Kidney and Urologic Disease Information Clearinghouse. Figure 6ii. Transplant (kidney only) wait list and wait times. www.usrds.org/2010/pdf/v2_07.pdf. Accessed September 16, 2011.

20. Arbor Research Collaborative for Health. Kidney waiting time calculator. www.ustransplant.org/Calculators/KidneyWaitTime.aspx. Accessed September 16, 2011.

21. Karakayali FY, Ozdemir H, Kivrakdal S, et al. Recurrent glomerular diseases after renal transplantation. Transplant Proc. 2006;38(2):470-472.

22. Nojima M, Ichikawa Y, Ihara H, et al. Significant effect of HLA-DRB1 matching on acute rejection of kidney transplants within 3 months. Transplant Proc. 2001;33(1-2):1182-1184.

For many years, the medical community speculated about the possibility of organ transplantation. The first successful transplant of any kind involving humans was a corneal transplant in 1905.¹

It wasn’t until 1954 that the first successful organ transplant, a kidney transplant between identical twins, occurred.² Several new concepts emerged: organ rejection plays a major role in the failure or success of a transplant; and donors and recipients must be matched based on blood group.

Today, about 169,000 people in the US live with a donated kidney. Each year, some 10,500 cadaveric organs are transplanted, and 6,400 donors are living donors.³ The National Kidney Foundation’s recent 10-year initiative, End the Wait!,⁴ seeks to close the gap between the more than 50,000 people on the transplant waiting list³ and the number of available donor organs.

Since many patients live for years with their transplanted organs, the primary care clinician is likely to see transplant recipients in a family practice or internal medicine setting. While each patient has unique needs, there are commonalities among them.

Renal Consult welcomes any additional comments or questions regarding care of the renal patient. Please address them to [email protected].
Jane S. Davis, CRNP, DNP

Q: I am in primary care and have a kidney transplant patient that I see annually for her Pap test and pelvic exam. Is there anything in particular that I am supposed to look for? I feel out of my comfort zone.

As with most people, preventive care is vital and posttransplant patients are no different. However, there are a few “special circumstances” to keep in mind.

Besides ascertaining that posttransplant patients are taking their medications every day, determine whether they have recently had a generic substituted for their regular anti-rejection meds. Many transplant medications have generic equivalents now; while we want changes made only with the approval of a transplant center, it is legal for a pharmacy to substitute a generic without notifying the transplant nephrologist. We have seen rejection, toxicities, or changes in creatinine levels due to substitution of generics—or even substitution from one generic equivalent to another. These medications have a small effective window and have to be closely monitored whenever different manufacturers are used.

In addition, some patients will stop taking their immunosuppressive drug, either because they “feel better” and don’t believe they need it anymore, or because they can no longer afford it. Medicare will only pay for 36 months of these medications, and patients often halve the dose or stop taking the medication altogether when the cost becomes too high.⁵

There is a very useful Web site on transplant medications from the United States Renal Data System.⁶ The site, which also offers a wealth of information on chronic kidney disease (CKD), is www.usrds.org/presentations.htm

Dosing for any medication is based on the patient’s glomerular filtration rate (GFR). Your transplant patients have been taught their baseline creatinine level, but some do forget. Even after transplant (whether of a kidney, a pancreas, a liver, lungs, or a heart), the immunosuppressive medications will affect the GFR, and the patient is a CKD patient.

If a patient’s creatinine level is 1.9 mg/dL (normal range, 0.6 to 1.2), but it has varied between 1.8 and 2.0 ever since the transplant and they are not having any other issues, this is “normal” for them and no cause for alarm. On the other hand, if the creatinine level is 1.9 mg/dL and the patient reports that it is always 1.2, they need immediate referral. If the patient is new to the area, you can find a local transplant center on the Organ Procurement and Transplantation Network directory⁷:  optn.transplant.hrsa.gov/mem bers/search.asp

Screening for infections and malignancies is another important aspect of posttransplant care. I advise all patients to see a dermatologist at least once annually, as the risk for skin cancer is increased sevenfold in a transplant patient, compared with the general population.⁸ Annual Pap test, pelvic exam, and mammogram are important for female posttransplant patients, as is annual prostate-specific antigen testing for male posttransplant patients older than 45 with a life expectancy of at least 10 years.⁹

During the physical exam, the clinician should always check for lymphadenopathy or any other “lumps and bumps,” as posttransplant lymphoproliferative disorder is also a risk associated with long-term immunosuppression.¹⁰ A wonderful online resource for patients and providers, “Transplant Living,”¹¹ has an excellent section on posttransplant care: www.transplantliving.org/af terthetransplant/default.aspx. This Web site is managed by the United Network of Organ Sharing¹² (UNOS; www.unos.org), the organization that manages organ transplantation and donation under contract with the federal government.

Routine vaccinations are recommended—especially pneumococcal vaccine and an annual flu shot. Diphtheria-pertussis-tetanus, hepatitis A, hepatitis B, inactivated polio, and typhoid are also acceptable vaccines for a transplant patient. Vaccines that are contraindicated after transplantation include varicella, bacillus Calmette-Guérin, smallpox, intranasal influenza, live oral typhoid, measles, mumps, rubella, oral polio, live Japanese B encephalitis, and yellow fever.^13,14

References
1. Armitage WJ, Tullo AB, Larkin DFP. The first successful full-thickness corneal transplant: a commentary on Eduard Zirm’s landmark paper of 1906. Br J Ophthalmol. 2006;90(10):1222-1223.

2. Kidney transplantation: past, present, and future. www.stanford.edu/dept/HPS/transplant/html/history.html. Accessed September 16, 2011.

3. United States Renal Data System. Atlas. www .usrds.org/atlas.htm. Accessed September 16, 2011.

4. National Kidney Foundation. End the wait! www.kidney.org/news/end_the_wait/index.cfm. Accessed September 16, 2011.

5. National Kidney Foundation. Kidney transplant (2011). www.kidney.org/atoz/content/kidneytransnewlease.cfm. Accessed September 16, 2011.

6. United States Renal Data Systems. Presentations and posters (2000-2011). www.usrds.org/presentations.htm. Accessed September 16, 2011.

7. Organ Procurement and Transplantation Network. Members: member directory. optn.transplant.hrsa.gov/members/search.asp. Accessed September 16, 2011.

8. Jensen P, Møller B, Hansen S. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol. 2000;42(2 pt 1):307.

9. Wong G, Chapman JR, Craig JC. Cancer screening in renal transplant recipients: what is the evidence? Clin J Am Soc Nephrol. 2008;3 suppl 2:S87-S100.

10. Parker A, Bowles K, Bradley JA, et al; Haemato-oncology subgroup of the British Committee for Standards in Haematology and the British Transplantation Society. Diagnosis of post-transplant lymphoproliferative disorder in solid organ transplant patients. Br J Haematol. 2010;149(5):675-692.

11. Transplant Living. After the transplant (2011). www.transplantliving.org/afterthetransplant/default.aspx. Accessed September 16, 2011.

12. United Network for Organ Sharing. www.unos.org. Accessed September 16, 2011.

13. Kidney Disease Improving Global Outcomes. Managing your adult patients who have a kidney transplant (2010). www.kidney.org/professionals/tools/pdf/02-50-4079_ABB_ManagingTransRecip Bk_PC.pdf. Accessed September 16, 2011.

14. Abbud-Filho M, Adams P, Alberu J, et al. A report of the Lisbon Conference on the care of the kidney transplant recipient. Transplantation. 2007; (Suppl 8):83:1-22.

15. Heldal K, Hartmann A, Leivestad T, et al. Risk variables associated with the outcome of kidney recipients >70 years of age in the new millennium. Nephrol Dial Transplant. 2011;26(8):2706-2711.

16. Chava SP, Singh B, Stangou A, et al. Simultaneous combined liver and kidney transplantation: a single center experience. Clin Transplant. 2010; 24(3):E62-E68.

17. Ruiz R, Kunitake H, Wilkinson AH, et al. Long-term analysis of combined liver and kidney transplantation at a single center. Arch Surg. 2006;141 (8):735-741.

18. Veroux P, Veroux M, Puliatti C, et al. Kidney transplantation from hepatitis C virus-positive donors into hepatitis C virus-positive recipients: a safe way to expand the donor pool? Transplant Proc. 2005;37(6):2571-2573.

19. United States Renal Data Systems, Annual Data Reports. National Kidney and Urologic Disease Information Clearinghouse. Figure 6ii. Transplant (kidney only) wait list and wait times. www.usrds.org/2010/pdf/v2_07.pdf. Accessed September 16, 2011.

20. Arbor Research Collaborative for Health. Kidney waiting time calculator. www.ustransplant.org/Calculators/KidneyWaitTime.aspx. Accessed September 16, 2011.

21. Karakayali FY, Ozdemir H, Kivrakdal S, et al. Recurrent glomerular diseases after renal transplantation. Transplant Proc. 2006;38(2):470-472.

22. Nojima M, Ichikawa Y, Ihara H, et al. Significant effect of HLA-DRB1 matching on acute rejection of kidney transplants within 3 months. Transplant Proc. 2001;33(1-2):1182-1184.

For many years, the medical community speculated about the possibility of organ transplantation. The first successful transplant of any kind involving humans was a corneal transplant in 1905.¹

It wasn’t until 1954 that the first successful organ transplant, a kidney transplant between identical twins, occurred.² Several new concepts emerged: organ rejection plays a major role in the failure or success of a transplant; and donors and recipients must be matched based on blood group.

Today, about 169,000 people in the US live with a donated kidney. Each year, some 10,500 cadaveric organs are transplanted, and 6,400 donors are living donors.³ The National Kidney Foundation’s recent 10-year initiative, End the Wait!,⁴ seeks to close the gap between the more than 50,000 people on the transplant waiting list³ and the number of available donor organs.

Since many patients live for years with their transplanted organs, the primary care clinician is likely to see transplant recipients in a family practice or internal medicine setting. While each patient has unique needs, there are commonalities among them.

Renal Consult welcomes any additional comments or questions regarding care of the renal patient. Please address them to [email protected].
Jane S. Davis, CRNP, DNP

Q: I am in primary care and have a kidney transplant patient that I see annually for her Pap test and pelvic exam. Is there anything in particular that I am supposed to look for? I feel out of my comfort zone.

As with most people, preventive care is vital and posttransplant patients are no different. However, there are a few “special circumstances” to keep in mind.

Besides ascertaining that posttransplant patients are taking their medications every day, determine whether they have recently had a generic substituted for their regular anti-rejection meds. Many transplant medications have generic equivalents now; while we want changes made only with the approval of a transplant center, it is legal for a pharmacy to substitute a generic without notifying the transplant nephrologist. We have seen rejection, toxicities, or changes in creatinine levels due to substitution of generics—or even substitution from one generic equivalent to another. These medications have a small effective window and have to be closely monitored whenever different manufacturers are used.

In addition, some patients will stop taking their immunosuppressive drug, either because they “feel better” and don’t believe they need it anymore, or because they can no longer afford it. Medicare will only pay for 36 months of these medications, and patients often halve the dose or stop taking the medication altogether when the cost becomes too high.⁵

There is a very useful Web site on transplant medications from the United States Renal Data System.⁶ The site, which also offers a wealth of information on chronic kidney disease (CKD), is www.usrds.org/presentations.htm

Dosing for any medication is based on the patient’s glomerular filtration rate (GFR). Your transplant patients have been taught their baseline creatinine level, but some do forget. Even after transplant (whether of a kidney, a pancreas, a liver, lungs, or a heart), the immunosuppressive medications will affect the GFR, and the patient is a CKD patient.

If a patient’s creatinine level is 1.9 mg/dL (normal range, 0.6 to 1.2), but it has varied between 1.8 and 2.0 ever since the transplant and they are not having any other issues, this is “normal” for them and no cause for alarm. On the other hand, if the creatinine level is 1.9 mg/dL and the patient reports that it is always 1.2, they need immediate referral. If the patient is new to the area, you can find a local transplant center on the Organ Procurement and Transplantation Network directory⁷:  optn.transplant.hrsa.gov/mem bers/search.asp

Screening for infections and malignancies is another important aspect of posttransplant care. I advise all patients to see a dermatologist at least once annually, as the risk for skin cancer is increased sevenfold in a transplant patient, compared with the general population.⁸ Annual Pap test, pelvic exam, and mammogram are important for female posttransplant patients, as is annual prostate-specific antigen testing for male posttransplant patients older than 45 with a life expectancy of at least 10 years.⁹

During the physical exam, the clinician should always check for lymphadenopathy or any other “lumps and bumps,” as posttransplant lymphoproliferative disorder is also a risk associated with long-term immunosuppression.¹⁰ A wonderful online resource for patients and providers, “Transplant Living,”¹¹ has an excellent section on posttransplant care: www.transplantliving.org/af terthetransplant/default.aspx. This Web site is managed by the United Network of Organ Sharing¹² (UNOS; www.unos.org), the organization that manages organ transplantation and donation under contract with the federal government.

Routine vaccinations are recommended—especially pneumococcal vaccine and an annual flu shot. Diphtheria-pertussis-tetanus, hepatitis A, hepatitis B, inactivated polio, and typhoid are also acceptable vaccines for a transplant patient. Vaccines that are contraindicated after transplantation include varicella, bacillus Calmette-Guérin, smallpox, intranasal influenza, live oral typhoid, measles, mumps, rubella, oral polio, live Japanese B encephalitis, and yellow fever.^13,14

References
1. Armitage WJ, Tullo AB, Larkin DFP. The first successful full-thickness corneal transplant: a commentary on Eduard Zirm’s landmark paper of 1906. Br J Ophthalmol. 2006;90(10):1222-1223.

2. Kidney transplantation: past, present, and future. www.stanford.edu/dept/HPS/transplant/html/history.html. Accessed September 16, 2011.

3. United States Renal Data System. Atlas. www .usrds.org/atlas.htm. Accessed September 16, 2011.

4. National Kidney Foundation. End the wait! www.kidney.org/news/end_the_wait/index.cfm. Accessed September 16, 2011.

5. National Kidney Foundation. Kidney transplant (2011). www.kidney.org/atoz/content/kidneytransnewlease.cfm. Accessed September 16, 2011.

6. United States Renal Data Systems. Presentations and posters (2000-2011). www.usrds.org/presentations.htm. Accessed September 16, 2011.

7. Organ Procurement and Transplantation Network. Members: member directory. optn.transplant.hrsa.gov/members/search.asp. Accessed September 16, 2011.

8. Jensen P, Møller B, Hansen S. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol. 2000;42(2 pt 1):307.

9. Wong G, Chapman JR, Craig JC. Cancer screening in renal transplant recipients: what is the evidence? Clin J Am Soc Nephrol. 2008;3 suppl 2:S87-S100.

10. Parker A, Bowles K, Bradley JA, et al; Haemato-oncology subgroup of the British Committee for Standards in Haematology and the British Transplantation Society. Diagnosis of post-transplant lymphoproliferative disorder in solid organ transplant patients. Br J Haematol. 2010;149(5):675-692.

11. Transplant Living. After the transplant (2011). www.transplantliving.org/afterthetransplant/default.aspx. Accessed September 16, 2011.

12. United Network for Organ Sharing. www.unos.org. Accessed September 16, 2011.

13. Kidney Disease Improving Global Outcomes. Managing your adult patients who have a kidney transplant (2010). www.kidney.org/professionals/tools/pdf/02-50-4079_ABB_ManagingTransRecip Bk_PC.pdf. Accessed September 16, 2011.

14. Abbud-Filho M, Adams P, Alberu J, et al. A report of the Lisbon Conference on the care of the kidney transplant recipient. Transplantation. 2007; (Suppl 8):83:1-22.

15. Heldal K, Hartmann A, Leivestad T, et al. Risk variables associated with the outcome of kidney recipients >70 years of age in the new millennium. Nephrol Dial Transplant. 2011;26(8):2706-2711.

16. Chava SP, Singh B, Stangou A, et al. Simultaneous combined liver and kidney transplantation: a single center experience. Clin Transplant. 2010; 24(3):E62-E68.

17. Ruiz R, Kunitake H, Wilkinson AH, et al. Long-term analysis of combined liver and kidney transplantation at a single center. Arch Surg. 2006;141 (8):735-741.

18. Veroux P, Veroux M, Puliatti C, et al. Kidney transplantation from hepatitis C virus-positive donors into hepatitis C virus-positive recipients: a safe way to expand the donor pool? Transplant Proc. 2005;37(6):2571-2573.

19. United States Renal Data Systems, Annual Data Reports. National Kidney and Urologic Disease Information Clearinghouse. Figure 6ii. Transplant (kidney only) wait list and wait times. www.usrds.org/2010/pdf/v2_07.pdf. Accessed September 16, 2011.

20. Arbor Research Collaborative for Health. Kidney waiting time calculator. www.ustransplant.org/Calculators/KidneyWaitTime.aspx. Accessed September 16, 2011.

21. Karakayali FY, Ozdemir H, Kivrakdal S, et al. Recurrent glomerular diseases after renal transplantation. Transplant Proc. 2006;38(2):470-472.

22. Nojima M, Ichikawa Y, Ihara H, et al. Significant effect of HLA-DRB1 matching on acute rejection of kidney transplants within 3 months. Transplant Proc. 2001;33(1-2):1182-1184.

Evidence summary

Six studies have evaluated SUA levels in patients with acute gout. Despite variations in diagnostic approach (clinical criteria vs synovial crystal analysis) and definitions of normal SUA (based on laboratory methods and sex), all 6 studies found normal levels in 11% to 49% of patients with acute gout (TABLE 1).

TABLE 1
Serum uric acid and acute gout: The evidence

Elevated SUA can be an indicator of gout—or not
A prospective cohort study of 82 patients at a Veterans Administration rheumatology clinic found elevated SUA to be the most sensitive indicator among various clinical criteria for diagnosing acute gout. However, 3 (11%) of the 28 patients who had crystal-proven gout also had a normal SUA.¹

A second prospective cohort study that evaluated 38 patients during 42 episodes of acute gout in various clinical settings reported a normal SUA in 43% of patients diagnosed on clinical grounds or by joint aspiration.²

Some patients become hyperuricemic after diagnosis
The largest retrospective cohort study evaluated 226 Korean inpatients with acute gout diagnosed either by synovial crystals or American College of Rheumatology (ACR) criteria (TABLE 2). It found that 12% (27) had a normal SUA at diagnosis. Interestingly, 81% became hyperuricemic some time after diagnosis.³

TABLE 2
American College of Rheumatology criteria for classifying acute gouty arthritis

What is a normal SUA value?
Another study reviewed SUA levels in a cohort derived from 2 large prospective RCTs of etoricoxib in patients diagnosed with acute gout by crystal analysis. The proportion of patients with a normal SUA varied substantially according to the definition of a normal value: 32% were normal using a value of 0.48 mmol/L; 11% had normal SUA levels when 0.36 mmol/L was used as the cutoff.⁴

A secondary analysis evaluated the effect of allopurinol on SUA. The proportion of patients on allopurinol with a normal SUA level compared with patients not taking allopurinol was 49% vs 29% using the higher normal cutoff value, and 29% vs 11% using the lower normal value (P<.001).⁴

Two studies find many gout patients with a normal SUA
A Japanese retrospective cohort study using ACR criteria found that nearly half of patients diagnosed with acute gout had a normal SUA level.⁵ A 1967 retrospective examination of Framingham Heart Study data found that one-third of patients clinically diagnosed with gout had a normal level. Some of the patients hadn’t been diagnosed at the time their SUA was measured, however.⁶

Recommendations

The ACR’s 1977 criteria for diagnosing gout include hyperuricemia as one potential indicator.⁷ The European League Against Rheumatism advises that normal SUA levels may accompany crystal-proven gout because uric acid either acts as a negative acute-phase reactant or increases in renal excretion during acute episodes. They conclude that SUA has “limited diagnostic value,” especially during acute gout.⁸

Evidence summary

Six studies have evaluated SUA levels in patients with acute gout. Despite variations in diagnostic approach (clinical criteria vs synovial crystal analysis) and definitions of normal SUA (based on laboratory methods and sex), all 6 studies found normal levels in 11% to 49% of patients with acute gout (TABLE 1).

TABLE 1
Serum uric acid and acute gout: The evidence

Elevated SUA can be an indicator of gout—or not
A prospective cohort study of 82 patients at a Veterans Administration rheumatology clinic found elevated SUA to be the most sensitive indicator among various clinical criteria for diagnosing acute gout. However, 3 (11%) of the 28 patients who had crystal-proven gout also had a normal SUA.¹

A second prospective cohort study that evaluated 38 patients during 42 episodes of acute gout in various clinical settings reported a normal SUA in 43% of patients diagnosed on clinical grounds or by joint aspiration.²

Some patients become hyperuricemic after diagnosis
The largest retrospective cohort study evaluated 226 Korean inpatients with acute gout diagnosed either by synovial crystals or American College of Rheumatology (ACR) criteria (TABLE 2). It found that 12% (27) had a normal SUA at diagnosis. Interestingly, 81% became hyperuricemic some time after diagnosis.³

TABLE 2
American College of Rheumatology criteria for classifying acute gouty arthritis

What is a normal SUA value?
Another study reviewed SUA levels in a cohort derived from 2 large prospective RCTs of etoricoxib in patients diagnosed with acute gout by crystal analysis. The proportion of patients with a normal SUA varied substantially according to the definition of a normal value: 32% were normal using a value of 0.48 mmol/L; 11% had normal SUA levels when 0.36 mmol/L was used as the cutoff.⁴

A secondary analysis evaluated the effect of allopurinol on SUA. The proportion of patients on allopurinol with a normal SUA level compared with patients not taking allopurinol was 49% vs 29% using the higher normal cutoff value, and 29% vs 11% using the lower normal value (P<.001).⁴

Two studies find many gout patients with a normal SUA
A Japanese retrospective cohort study using ACR criteria found that nearly half of patients diagnosed with acute gout had a normal SUA level.⁵ A 1967 retrospective examination of Framingham Heart Study data found that one-third of patients clinically diagnosed with gout had a normal level. Some of the patients hadn’t been diagnosed at the time their SUA was measured, however.⁶

Recommendations

The ACR’s 1977 criteria for diagnosing gout include hyperuricemia as one potential indicator.⁷ The European League Against Rheumatism advises that normal SUA levels may accompany crystal-proven gout because uric acid either acts as a negative acute-phase reactant or increases in renal excretion during acute episodes. They conclude that SUA has “limited diagnostic value,” especially during acute gout.⁸

Evidence summary

Six studies have evaluated SUA levels in patients with acute gout. Despite variations in diagnostic approach (clinical criteria vs synovial crystal analysis) and definitions of normal SUA (based on laboratory methods and sex), all 6 studies found normal levels in 11% to 49% of patients with acute gout (TABLE 1).

TABLE 1
Serum uric acid and acute gout: The evidence

Elevated SUA can be an indicator of gout—or not
A prospective cohort study of 82 patients at a Veterans Administration rheumatology clinic found elevated SUA to be the most sensitive indicator among various clinical criteria for diagnosing acute gout. However, 3 (11%) of the 28 patients who had crystal-proven gout also had a normal SUA.¹

A second prospective cohort study that evaluated 38 patients during 42 episodes of acute gout in various clinical settings reported a normal SUA in 43% of patients diagnosed on clinical grounds or by joint aspiration.²

Some patients become hyperuricemic after diagnosis
The largest retrospective cohort study evaluated 226 Korean inpatients with acute gout diagnosed either by synovial crystals or American College of Rheumatology (ACR) criteria (TABLE 2). It found that 12% (27) had a normal SUA at diagnosis. Interestingly, 81% became hyperuricemic some time after diagnosis.³

TABLE 2
American College of Rheumatology criteria for classifying acute gouty arthritis

What is a normal SUA value?
Another study reviewed SUA levels in a cohort derived from 2 large prospective RCTs of etoricoxib in patients diagnosed with acute gout by crystal analysis. The proportion of patients with a normal SUA varied substantially according to the definition of a normal value: 32% were normal using a value of 0.48 mmol/L; 11% had normal SUA levels when 0.36 mmol/L was used as the cutoff.⁴

A secondary analysis evaluated the effect of allopurinol on SUA. The proportion of patients on allopurinol with a normal SUA level compared with patients not taking allopurinol was 49% vs 29% using the higher normal cutoff value, and 29% vs 11% using the lower normal value (P<.001).⁴

Two studies find many gout patients with a normal SUA
A Japanese retrospective cohort study using ACR criteria found that nearly half of patients diagnosed with acute gout had a normal SUA level.⁵ A 1967 retrospective examination of Framingham Heart Study data found that one-third of patients clinically diagnosed with gout had a normal level. Some of the patients hadn’t been diagnosed at the time their SUA was measured, however.⁶

Recommendations

The ACR’s 1977 criteria for diagnosing gout include hyperuricemia as one potential indicator.⁷ The European League Against Rheumatism advises that normal SUA levels may accompany crystal-proven gout because uric acid either acts as a negative acute-phase reactant or increases in renal excretion during acute episodes. They conclude that SUA has “limited diagnostic value,” especially during acute gout.⁸

Even at doses three times higher than usual, saw palmetto extract was no better than placebo at improving lower urinary tract symptoms attributed to benign prostatic hyperplasia in a study in the Sept. 28 issue of JAMA.

Extracts from the fruit of the saw palmetto dwarf palm tree are the most widely used plant extracts in the United States and Europe for urinary symptoms. They are purported to have anti-androgenic, anti-inflammatory, and antiproliferative effects, but none of these properties have been proved.

A meta-analysis from approximately 10 years ago showed that, compared with placebo, saw palmetto significantly reduced nocturia and improved peak uroflow, as well as being rated by study subjects as more beneficial. But more recent clinical trials and reviews of the literature have had more negative findings.

"We conducted a randomized clinical trial to determine if a standard daily dose of saw palmetto extract increased to a double and then a triple daily dose over 72 weeks would improve lower urinary tract symptoms attributed to benign prostatic hypertrophy," said Dr. Michael J. Barry of Massachusetts General Hospital, Boston, and his associates in the Complementary and Alternative Medicine for Urological Symptoms (CAMUS) study group.

This study design allowed an adequate duration of treatment – 24 weeks at each dose level – to assess outcomes, they noted.

The double-blind trial included 369 men aged 45 years and older who had a peak uroflow rate of at least 4 mL per second and a score of 8-24 on the American Urological Association Symptom Index (AUASI) at baseline. They were treated at 11 sites across North America with a standard dose (320 mg/day) of gelcaps containing saw palmetto extract or placebo, which was escalated to 640 mg/day at 24 weeks and 960 mg/day at 48 weeks.

The primary outcome measure was the change in AUASI score at 72 weeks. This decreased only slightly, and to nearly the same degree, in both groups: The reduction was 2.20 points with saw palmetto and 2.99 points with placebo, the investigators said (JAMA 2011;306:1344-51).

The result was the same in a per-protocol analysis of the 151 subjects who received saw palmetto and the 155 who received placebo for the entire duration of the study.

Similarly, the proportion of men who achieved a minimal (3-point) decrease in AUASI score over time was 42.6% with saw palmetto and 44.2% with placebo, slightly favoring placebo. A dose-response analysis showed that saw palmetto was no better than placebo at any dose level.

Further analyses also showed that the active treatment was no better than placebo for a wide range of secondary outcomes including change in BPH Index scores and change in measures of nocturia, peak uroflow, postvoiding residual volume, and incontinence.

The trial also did not reveal any subgroup of patients, such as men with higher PSA levels or men with lower peak uroflow, who showed "a clinically important differential response" to saw palmetto, compared with placebo.

At the conclusion of the study, two measures of patient satisfaction with treatment did not differ between the two groups. Both men who received saw palmetto and men who received placebo rated their symptoms as "between ‘a little better’ and ‘about the same.’ "

This study was supported by the National Institutes of Health, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Center for Complementary and Alternative Medicine, and the NIH Office of Dietary Supplements. Saw palmetto extract and matching placebo gelcaps were donated by Rottapharm/Madaus, Cologne, Germany. This study was conducted under an Investigational New Drug Application from the Food and Drug Administration. Dr. Barry’s associates reported ties to numerous industry sources.

Even at doses three times higher than usual, saw palmetto extract was no better than placebo at improving lower urinary tract symptoms attributed to benign prostatic hyperplasia in a study in the Sept. 28 issue of JAMA.

Extracts from the fruit of the saw palmetto dwarf palm tree are the most widely used plant extracts in the United States and Europe for urinary symptoms. They are purported to have anti-androgenic, anti-inflammatory, and antiproliferative effects, but none of these properties have been proved.

A meta-analysis from approximately 10 years ago showed that, compared with placebo, saw palmetto significantly reduced nocturia and improved peak uroflow, as well as being rated by study subjects as more beneficial. But more recent clinical trials and reviews of the literature have had more negative findings.

"We conducted a randomized clinical trial to determine if a standard daily dose of saw palmetto extract increased to a double and then a triple daily dose over 72 weeks would improve lower urinary tract symptoms attributed to benign prostatic hypertrophy," said Dr. Michael J. Barry of Massachusetts General Hospital, Boston, and his associates in the Complementary and Alternative Medicine for Urological Symptoms (CAMUS) study group.

This study design allowed an adequate duration of treatment – 24 weeks at each dose level – to assess outcomes, they noted.

The double-blind trial included 369 men aged 45 years and older who had a peak uroflow rate of at least 4 mL per second and a score of 8-24 on the American Urological Association Symptom Index (AUASI) at baseline. They were treated at 11 sites across North America with a standard dose (320 mg/day) of gelcaps containing saw palmetto extract or placebo, which was escalated to 640 mg/day at 24 weeks and 960 mg/day at 48 weeks.

The primary outcome measure was the change in AUASI score at 72 weeks. This decreased only slightly, and to nearly the same degree, in both groups: The reduction was 2.20 points with saw palmetto and 2.99 points with placebo, the investigators said (JAMA 2011;306:1344-51).

The result was the same in a per-protocol analysis of the 151 subjects who received saw palmetto and the 155 who received placebo for the entire duration of the study.

Similarly, the proportion of men who achieved a minimal (3-point) decrease in AUASI score over time was 42.6% with saw palmetto and 44.2% with placebo, slightly favoring placebo. A dose-response analysis showed that saw palmetto was no better than placebo at any dose level.

Further analyses also showed that the active treatment was no better than placebo for a wide range of secondary outcomes including change in BPH Index scores and change in measures of nocturia, peak uroflow, postvoiding residual volume, and incontinence.

The trial also did not reveal any subgroup of patients, such as men with higher PSA levels or men with lower peak uroflow, who showed "a clinically important differential response" to saw palmetto, compared with placebo.

At the conclusion of the study, two measures of patient satisfaction with treatment did not differ between the two groups. Both men who received saw palmetto and men who received placebo rated their symptoms as "between ‘a little better’ and ‘about the same.’ "

This study was supported by the National Institutes of Health, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Center for Complementary and Alternative Medicine, and the NIH Office of Dietary Supplements. Saw palmetto extract and matching placebo gelcaps were donated by Rottapharm/Madaus, Cologne, Germany. This study was conducted under an Investigational New Drug Application from the Food and Drug Administration. Dr. Barry’s associates reported ties to numerous industry sources.

Even at doses three times higher than usual, saw palmetto extract was no better than placebo at improving lower urinary tract symptoms attributed to benign prostatic hyperplasia in a study in the Sept. 28 issue of JAMA.

Extracts from the fruit of the saw palmetto dwarf palm tree are the most widely used plant extracts in the United States and Europe for urinary symptoms. They are purported to have anti-androgenic, anti-inflammatory, and antiproliferative effects, but none of these properties have been proved.

A meta-analysis from approximately 10 years ago showed that, compared with placebo, saw palmetto significantly reduced nocturia and improved peak uroflow, as well as being rated by study subjects as more beneficial. But more recent clinical trials and reviews of the literature have had more negative findings.

"We conducted a randomized clinical trial to determine if a standard daily dose of saw palmetto extract increased to a double and then a triple daily dose over 72 weeks would improve lower urinary tract symptoms attributed to benign prostatic hypertrophy," said Dr. Michael J. Barry of Massachusetts General Hospital, Boston, and his associates in the Complementary and Alternative Medicine for Urological Symptoms (CAMUS) study group.

This study design allowed an adequate duration of treatment – 24 weeks at each dose level – to assess outcomes, they noted.

The double-blind trial included 369 men aged 45 years and older who had a peak uroflow rate of at least 4 mL per second and a score of 8-24 on the American Urological Association Symptom Index (AUASI) at baseline. They were treated at 11 sites across North America with a standard dose (320 mg/day) of gelcaps containing saw palmetto extract or placebo, which was escalated to 640 mg/day at 24 weeks and 960 mg/day at 48 weeks.

The primary outcome measure was the change in AUASI score at 72 weeks. This decreased only slightly, and to nearly the same degree, in both groups: The reduction was 2.20 points with saw palmetto and 2.99 points with placebo, the investigators said (JAMA 2011;306:1344-51).

The result was the same in a per-protocol analysis of the 151 subjects who received saw palmetto and the 155 who received placebo for the entire duration of the study.

Similarly, the proportion of men who achieved a minimal (3-point) decrease in AUASI score over time was 42.6% with saw palmetto and 44.2% with placebo, slightly favoring placebo. A dose-response analysis showed that saw palmetto was no better than placebo at any dose level.

Further analyses also showed that the active treatment was no better than placebo for a wide range of secondary outcomes including change in BPH Index scores and change in measures of nocturia, peak uroflow, postvoiding residual volume, and incontinence.

The trial also did not reveal any subgroup of patients, such as men with higher PSA levels or men with lower peak uroflow, who showed "a clinically important differential response" to saw palmetto, compared with placebo.

At the conclusion of the study, two measures of patient satisfaction with treatment did not differ between the two groups. Both men who received saw palmetto and men who received placebo rated their symptoms as "between ‘a little better’ and ‘about the same.’ "

This study was supported by the National Institutes of Health, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Center for Complementary and Alternative Medicine, and the NIH Office of Dietary Supplements. Saw palmetto extract and matching placebo gelcaps were donated by Rottapharm/Madaus, Cologne, Germany. This study was conducted under an Investigational New Drug Application from the Food and Drug Administration. Dr. Barry’s associates reported ties to numerous industry sources.

CHICAGO – Patients with end-stage renal disease have sharply elevated rates of hospitalization for pneumonia throughout the renal transplantation trajectory, researchers reported at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

The findings underscore the importance of vaccinating this group against pneumococcal and other diseases, lead investigator Lise Haubjerg Nielsen recommended in an interview. Pneumonia "is a big economic burden for society and it is a huge [source of] mortality for these patients."

In a Danish nationwide population-based cohort study among more than 90,000 individuals, those with end-stage renal disease (ESRD) had an 8- to 14-fold higher incidence of such hospitalization, depending on whether they were wait-listed, posttransplant, or post–graft failure, when compared with their counterparts in the general population.

About one-third of the posttransplant group was hospitalized for pneumonia. Male sex and older age were among the significant risk factors for pneumonia hospitalization at this stage. On the other hand, risk fell after the first year posttransplant.

The marked increase in posttransplant risk was expected, given patients’ use of immunosuppressants, according to Ms. Nielsen, who is a medical student undertaking a research year in the department of infectious diseases at Aarhus University Hospital, Skejby. However, the fact that the elevations seen before and after transplantation were even greater was surprising, she said at the meeting, which was sponsored by the American Society for Microbiology.

The increase in pretransplant risk was probably caused by patients’ uremic state, while that post–graft failure "could also be just [a reflection of] these patients being more sick than the general population," she speculated.

The investigators analyzed data from the Danish National Hospital Registry, identifying all hospitalizations since 1977 having a discharge diagnosis of pneumonia, regardless of whether the infection was community or hospital acquired.

They assessed first hospitalizations for pneumonia (excluding those caused by Pneumocystis jiroveci) occurring during 1990-2009. Patients with ESRD who were wait-listed for and/or underwent transplantation were matched by age and sex with up to 19 unaffected individuals from the general population. Analyses were based on 4,973 individuals with and 85,899 individuals without ESRD.

The incidence of first pneumonia hospitalization was 46, 32, and 63 per 1,000 person-years among wait-listed patients, renal transplant recipients, and patients who experienced graft loss, respectively.

These groups had corresponding 10-, 9, and 14-fold increases in the incidence of such hospitalization compared with the general population, according to Ms. Nielsen.

In an analysis of risk factors among the renal transplant recipients, the adjusted incidence rate of pneumonia hospitalization was significantly higher for men; patients aged 50 years or older; those who underwent 1-3 years of dialysis pretransplantation versus none; and those whose renal disease was associated with diabetes, chronic interstitial nephritis, or polycystic kidney disease as compared with glomerulonephritis. The risk of pneumonia hospitalization was significantly lower for those who were at least 1 year out from transplantation.

Ms. Nielsen reported having no conflicts of interest.

CHICAGO – Patients with end-stage renal disease have sharply elevated rates of hospitalization for pneumonia throughout the renal transplantation trajectory, researchers reported at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

The findings underscore the importance of vaccinating this group against pneumococcal and other diseases, lead investigator Lise Haubjerg Nielsen recommended in an interview. Pneumonia "is a big economic burden for society and it is a huge [source of] mortality for these patients."

In a Danish nationwide population-based cohort study among more than 90,000 individuals, those with end-stage renal disease (ESRD) had an 8- to 14-fold higher incidence of such hospitalization, depending on whether they were wait-listed, posttransplant, or post–graft failure, when compared with their counterparts in the general population.

About one-third of the posttransplant group was hospitalized for pneumonia. Male sex and older age were among the significant risk factors for pneumonia hospitalization at this stage. On the other hand, risk fell after the first year posttransplant.

The marked increase in posttransplant risk was expected, given patients’ use of immunosuppressants, according to Ms. Nielsen, who is a medical student undertaking a research year in the department of infectious diseases at Aarhus University Hospital, Skejby. However, the fact that the elevations seen before and after transplantation were even greater was surprising, she said at the meeting, which was sponsored by the American Society for Microbiology.

The increase in pretransplant risk was probably caused by patients’ uremic state, while that post–graft failure "could also be just [a reflection of] these patients being more sick than the general population," she speculated.

The investigators analyzed data from the Danish National Hospital Registry, identifying all hospitalizations since 1977 having a discharge diagnosis of pneumonia, regardless of whether the infection was community or hospital acquired.

They assessed first hospitalizations for pneumonia (excluding those caused by Pneumocystis jiroveci) occurring during 1990-2009. Patients with ESRD who were wait-listed for and/or underwent transplantation were matched by age and sex with up to 19 unaffected individuals from the general population. Analyses were based on 4,973 individuals with and 85,899 individuals without ESRD.

The incidence of first pneumonia hospitalization was 46, 32, and 63 per 1,000 person-years among wait-listed patients, renal transplant recipients, and patients who experienced graft loss, respectively.

These groups had corresponding 10-, 9, and 14-fold increases in the incidence of such hospitalization compared with the general population, according to Ms. Nielsen.

In an analysis of risk factors among the renal transplant recipients, the adjusted incidence rate of pneumonia hospitalization was significantly higher for men; patients aged 50 years or older; those who underwent 1-3 years of dialysis pretransplantation versus none; and those whose renal disease was associated with diabetes, chronic interstitial nephritis, or polycystic kidney disease as compared with glomerulonephritis. The risk of pneumonia hospitalization was significantly lower for those who were at least 1 year out from transplantation.

Ms. Nielsen reported having no conflicts of interest.

CHICAGO – Patients with end-stage renal disease have sharply elevated rates of hospitalization for pneumonia throughout the renal transplantation trajectory, researchers reported at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

The findings underscore the importance of vaccinating this group against pneumococcal and other diseases, lead investigator Lise Haubjerg Nielsen recommended in an interview. Pneumonia "is a big economic burden for society and it is a huge [source of] mortality for these patients."

In a Danish nationwide population-based cohort study among more than 90,000 individuals, those with end-stage renal disease (ESRD) had an 8- to 14-fold higher incidence of such hospitalization, depending on whether they were wait-listed, posttransplant, or post–graft failure, when compared with their counterparts in the general population.

About one-third of the posttransplant group was hospitalized for pneumonia. Male sex and older age were among the significant risk factors for pneumonia hospitalization at this stage. On the other hand, risk fell after the first year posttransplant.

The marked increase in posttransplant risk was expected, given patients’ use of immunosuppressants, according to Ms. Nielsen, who is a medical student undertaking a research year in the department of infectious diseases at Aarhus University Hospital, Skejby. However, the fact that the elevations seen before and after transplantation were even greater was surprising, she said at the meeting, which was sponsored by the American Society for Microbiology.

The increase in pretransplant risk was probably caused by patients’ uremic state, while that post–graft failure "could also be just [a reflection of] these patients being more sick than the general population," she speculated.

The investigators analyzed data from the Danish National Hospital Registry, identifying all hospitalizations since 1977 having a discharge diagnosis of pneumonia, regardless of whether the infection was community or hospital acquired.

They assessed first hospitalizations for pneumonia (excluding those caused by Pneumocystis jiroveci) occurring during 1990-2009. Patients with ESRD who were wait-listed for and/or underwent transplantation were matched by age and sex with up to 19 unaffected individuals from the general population. Analyses were based on 4,973 individuals with and 85,899 individuals without ESRD.

The incidence of first pneumonia hospitalization was 46, 32, and 63 per 1,000 person-years among wait-listed patients, renal transplant recipients, and patients who experienced graft loss, respectively.

These groups had corresponding 10-, 9, and 14-fold increases in the incidence of such hospitalization compared with the general population, according to Ms. Nielsen.

In an analysis of risk factors among the renal transplant recipients, the adjusted incidence rate of pneumonia hospitalization was significantly higher for men; patients aged 50 years or older; those who underwent 1-3 years of dialysis pretransplantation versus none; and those whose renal disease was associated with diabetes, chronic interstitial nephritis, or polycystic kidney disease as compared with glomerulonephritis. The risk of pneumonia hospitalization was significantly lower for those who were at least 1 year out from transplantation.

Ms. Nielsen reported having no conflicts of interest.

Lifestyle modifications and pharmacotherapy to reduce the risk of cardiovascular disease can also improve sexual function in men who have erectile dysfunction, according to findings from a meta-analysis first posted online Sept. 12 in Archives of Internal Medicine.

Erectile dysfunction (ED), with a prevalence ranging from 12% of men younger than 59 years of age to 42% of men aged 40-70, shares modifiable risks factors with atherosclerosis and coronary artery disease. These factors include hypertension, diabetes, dyslipidemia, cigarette smoking, obesity, metabolic syndrome, and sedentary behavior. ED has a high prevalence in individuals with multiple risk factors for cardiovascular (CV) disease, and its presence may be an early predictor or marker for cardiovascular events.

While clinical trials have shown that modifying lifestyle risks led to improvement in ED, many are limited by a small sample size and single geographic location and have not studied both lifestyle modifications and pharmacotherapy on ED.

So, Dr. Bhanu P. Gupta and colleagues with the Mayo Clinic, Rochester, Minn., conducted a meta-analysis of six previous randomized controlled trials from four countries to evaluate the relationship between lifestyle intervention and pharmaceutical treatment of cardiovascular risk factors and the severity of ED (Arch. Intern. Med. 2011 Sept 12 [doi:10.1001/archinternmed.2011.440]). The six trials, published between 2004 and 2010 examined in the meta-analysis, included a total of 740 participants (374 who received intervention and 366 control subjects), with the number of participants per trial ranging from 12 to 372. Average age of the participants was 55.4 years, and the study duration ranged from 12 to 104 weeks. All studies included in the analysis showed lessening of ED with adoption of a more healthful lifestyle and improvement in blood lipid parameters.

The meta-analysis showed that improvement in CV risk factors was associated with statistically significant improvement in sexual function, as measured by the Internal Index of Erectile Function, or IIEF-5 score, in which a score of 22- 25 points indicates normal erectile function, 17-21 indicates mild ED, 12-16 indicates mild to moderate ED, 8-11 indicates moderate ED, and 7 and below indicates severe ED.

Meta-analysis of all six trials showed a 2.7-point improvement in mean IIEF-5 score. When excluding studies that included use of statin medications, there was a 2.4-point improvement on the IIEF-5 score. Pharmacotherapy targeting CV risk factors demonstrated improvement of 3.1 points.

Typically, a 4-point improvement in the IIEF-5 score is considered the minimal clinically important difference (MCID). However, the MCID varies significantly according to baseline ED severity, ranging from 2.0 for mild ED to 7.0 for severe ED. "Therefore, the results of this analysis regarding the pooled IIEF-5 score improvement of 2.7 points might not translate into clinically important differences for moderate and severe ED," the researchers say. "Nevertheless, the overall weighted mean difference of 2.7 in IIEF-5 score improvement is consistent with significant improvement in mild ED and lesser improvement in more advanced ED."

"The results of the present meta-analysis add to and strengthen existing knowledge that healthy dietary habits and increased physical activity are important components of health to improve quality of life in men by improving sexual health," the researchers say.

The authors had no financial disclosures to report.

Lifestyle modifications and pharmacotherapy to reduce the risk of cardiovascular disease can also improve sexual function in men who have erectile dysfunction, according to findings from a meta-analysis first posted online Sept. 12 in Archives of Internal Medicine.

Erectile dysfunction (ED), with a prevalence ranging from 12% of men younger than 59 years of age to 42% of men aged 40-70, shares modifiable risks factors with atherosclerosis and coronary artery disease. These factors include hypertension, diabetes, dyslipidemia, cigarette smoking, obesity, metabolic syndrome, and sedentary behavior. ED has a high prevalence in individuals with multiple risk factors for cardiovascular (CV) disease, and its presence may be an early predictor or marker for cardiovascular events.

While clinical trials have shown that modifying lifestyle risks led to improvement in ED, many are limited by a small sample size and single geographic location and have not studied both lifestyle modifications and pharmacotherapy on ED.

So, Dr. Bhanu P. Gupta and colleagues with the Mayo Clinic, Rochester, Minn., conducted a meta-analysis of six previous randomized controlled trials from four countries to evaluate the relationship between lifestyle intervention and pharmaceutical treatment of cardiovascular risk factors and the severity of ED (Arch. Intern. Med. 2011 Sept 12 [doi:10.1001/archinternmed.2011.440]). The six trials, published between 2004 and 2010 examined in the meta-analysis, included a total of 740 participants (374 who received intervention and 366 control subjects), with the number of participants per trial ranging from 12 to 372. Average age of the participants was 55.4 years, and the study duration ranged from 12 to 104 weeks. All studies included in the analysis showed lessening of ED with adoption of a more healthful lifestyle and improvement in blood lipid parameters.

The meta-analysis showed that improvement in CV risk factors was associated with statistically significant improvement in sexual function, as measured by the Internal Index of Erectile Function, or IIEF-5 score, in which a score of 22- 25 points indicates normal erectile function, 17-21 indicates mild ED, 12-16 indicates mild to moderate ED, 8-11 indicates moderate ED, and 7 and below indicates severe ED.

Meta-analysis of all six trials showed a 2.7-point improvement in mean IIEF-5 score. When excluding studies that included use of statin medications, there was a 2.4-point improvement on the IIEF-5 score. Pharmacotherapy targeting CV risk factors demonstrated improvement of 3.1 points.

Typically, a 4-point improvement in the IIEF-5 score is considered the minimal clinically important difference (MCID). However, the MCID varies significantly according to baseline ED severity, ranging from 2.0 for mild ED to 7.0 for severe ED. "Therefore, the results of this analysis regarding the pooled IIEF-5 score improvement of 2.7 points might not translate into clinically important differences for moderate and severe ED," the researchers say. "Nevertheless, the overall weighted mean difference of 2.7 in IIEF-5 score improvement is consistent with significant improvement in mild ED and lesser improvement in more advanced ED."

"The results of the present meta-analysis add to and strengthen existing knowledge that healthy dietary habits and increased physical activity are important components of health to improve quality of life in men by improving sexual health," the researchers say.

The authors had no financial disclosures to report.

Lifestyle modifications and pharmacotherapy to reduce the risk of cardiovascular disease can also improve sexual function in men who have erectile dysfunction, according to findings from a meta-analysis first posted online Sept. 12 in Archives of Internal Medicine.

Erectile dysfunction (ED), with a prevalence ranging from 12% of men younger than 59 years of age to 42% of men aged 40-70, shares modifiable risks factors with atherosclerosis and coronary artery disease. These factors include hypertension, diabetes, dyslipidemia, cigarette smoking, obesity, metabolic syndrome, and sedentary behavior. ED has a high prevalence in individuals with multiple risk factors for cardiovascular (CV) disease, and its presence may be an early predictor or marker for cardiovascular events.

While clinical trials have shown that modifying lifestyle risks led to improvement in ED, many are limited by a small sample size and single geographic location and have not studied both lifestyle modifications and pharmacotherapy on ED.

So, Dr. Bhanu P. Gupta and colleagues with the Mayo Clinic, Rochester, Minn., conducted a meta-analysis of six previous randomized controlled trials from four countries to evaluate the relationship between lifestyle intervention and pharmaceutical treatment of cardiovascular risk factors and the severity of ED (Arch. Intern. Med. 2011 Sept 12 [doi:10.1001/archinternmed.2011.440]). The six trials, published between 2004 and 2010 examined in the meta-analysis, included a total of 740 participants (374 who received intervention and 366 control subjects), with the number of participants per trial ranging from 12 to 372. Average age of the participants was 55.4 years, and the study duration ranged from 12 to 104 weeks. All studies included in the analysis showed lessening of ED with adoption of a more healthful lifestyle and improvement in blood lipid parameters.

The meta-analysis showed that improvement in CV risk factors was associated with statistically significant improvement in sexual function, as measured by the Internal Index of Erectile Function, or IIEF-5 score, in which a score of 22- 25 points indicates normal erectile function, 17-21 indicates mild ED, 12-16 indicates mild to moderate ED, 8-11 indicates moderate ED, and 7 and below indicates severe ED.

Meta-analysis of all six trials showed a 2.7-point improvement in mean IIEF-5 score. When excluding studies that included use of statin medications, there was a 2.4-point improvement on the IIEF-5 score. Pharmacotherapy targeting CV risk factors demonstrated improvement of 3.1 points.

Typically, a 4-point improvement in the IIEF-5 score is considered the minimal clinically important difference (MCID). However, the MCID varies significantly according to baseline ED severity, ranging from 2.0 for mild ED to 7.0 for severe ED. "Therefore, the results of this analysis regarding the pooled IIEF-5 score improvement of 2.7 points might not translate into clinically important differences for moderate and severe ED," the researchers say. "Nevertheless, the overall weighted mean difference of 2.7 in IIEF-5 score improvement is consistent with significant improvement in mild ED and lesser improvement in more advanced ED."

"The results of the present meta-analysis add to and strengthen existing knowledge that healthy dietary habits and increased physical activity are important components of health to improve quality of life in men by improving sexual health," the researchers say.

The authors had no financial disclosures to report.

BOSTON – The recent identification of two gene mutations in a cohort of African Americans with nondiabetic kidney disease helps explain the disproportionately higher rates of kidney disease in this population and represents a disease-mechanism pathway that could lead to new treatments and possibly a cure, Dr. David J. Friedman said at the annual meeting of the International Society on Hypertension in Blacks.

Dr. Friedman of Beth-Israel Deaconess Medical Center, Boston, and his colleagues recently reported the association between two independent variants in the apolipoprotein L1 (APOL1) gene on chromosome 22 and focal segmental glomerulosclerosis (FSGS) and hypertension-attributed end-stage kidney disease in blacks (Science 2010;329:841-5). Not only do the investigators believe that APOL1 is very important to the understanding of nondiabetic renal disease in blacks, "we think the variants in the gene are among the most powerful that have been discovered to date," Dr. Friedman stressed.

The disparity between the rates of end-stage renal disease (ESRD) in blacks and whites in the United States is "incredible," Dr. Friedman stated, noting that the incidence rate is four to five times higher in blacks, according to the 2010 United States Renal Data System annual report. "People have been debating for decades whether the major cause of this disparity is genes or environment. No doubt both are important, but given how strongly this phenotype travels in families, I think we can say with certainty that genes play an important role."

The APOL1 discovery came on the heels of an earlier association linking FSGS, nondiabetic ESRD, and HIV nephropathy in blacks with the MYH9 gene located on the same chromosome, Dr. Friedman explained. "This was quite striking, because we used to think of the three conditions as entirely different diseases, yet each one had exactly the same locus."

Despite the strong association and several years spent looking for causal mutations using fine mapping sequences, the causal variants remained elusive until Dr. Friedman and his colleagues approached the problem from a different perspective.

"We asked, ‘How could any disease gene that’s this deleterious become so common in a population?’ We assumed there was something in this [genetic region] that was beneficial once upon a time to human evolution in Africa," he said. Using mathematical techniques, "we realized that because of the effects of natural selection, the disease gene interval was much larger than anyone thought and probably contained at least five genes." Consequently, the investigators tested new variants in other genes for association with renal disease in African Americans, looking specifically for variants that had not yet been documented, he said.

In a cohort of 205 African Americans with biopsy-proven FSGS and no family history of the disease and 180 African American control subjects, "we saw that variants in the neighboring APOL1 gene were much more strongly associated with renal disease, and unlike the MYH9 variants, which were located in regions of the gene that did not encode for protein, the APOL1 variants were protein-coding sequences."

The investigators determined that the top two variants almost always co-occurred on the same chromosome and each changed an amino acid somewhere on the protein. "We called this the g1 risk allele, and when we controlled for it, a new variant popped up, which we called the g2 allele," he said. Controlling for both the g1 and g2 alleles, "the entire association of this region disappeared and there was no signal left for MYH9."

The investigators also tested the genetic variants in hypertension-associated ESRD in a larger cohort of 1,030 African Americans with the disease and 1,025 geographically matched control subjects and found that the same two variants had a tremendous impact on the development of the disease.

"When combined together, the P value was on the order of 10 to the minus 60, or 35 orders of magnitude greater than the very best MYH9 [result]," Dr. Friedman said. Surprisingly, he noted, we found that these disease variants follow a recessive pattern and together the odds ratio was on the order of 7-10, while the very largest effect sizes of the common variants that affect hypertension or diabetes will confer odds ratios of about 1.4-1.5."

The APOL1 gene and these variants "tend to fall into a different category that we’ve all been familiar with in the past," Dr. Friedman explained. "Most disease variants are either very rare with powerful effects or common with relatively modest effects. The APOL1 variants have a surprising combination of effect size and frequency such that 50%-60% of African Americans carry g1 and/or g2 risk alleles, and 50% are risk homozygous, meaning they are in the highest risk for kidney disease: That translates into about 3.5 million individuals."

Further, while the odds ratios for the more common forms of nondiabetic kidney disease in this population range from 7 to 10, "we’re starting to see odds ratios in the range of 30 for diseases like HIV nephropathy."

Comparing Kidney Disease Rates Between Races

To determine how much of nondiabetic kidney disease can be explained by the genetic variants, the investigators reviewed data from the prospective population-based Dallas Heart Study and compared the outcomes of European American and Caucasian patients, in whom the renal risk alleles are essentially nonexistent, with those of African Americans with zero or one risk allele and those with both risk alleles. Looking at urine protein levels, an indicator of renal microvascular disease, "we found that black individuals with zero or one copy of the risk allele had rates more similar to whites than to blacks with two alleles," Dr. Friedman reported.

The results were even more striking for actual hard measures of renal function, he said. "Rates of chronic kidney disease or impaired renal function, indicated by glomerular filtration rates less than 60 mL/min per 1.73 m2, were essentially the same among blacks with zero or one allele and whites, whereas individuals with a risk genotype had a fourfold increase in impaired renal function." Although the study does not include many individuals with ESRD, the investigators hope to look more closely into such patients in future studies, he said.

In their preliminary review of the data, "we can’t tell any difference between African Americans with zero or one copy of the allele and Caucasians, but African Americans with two renal risk alleles have at least 10-fold increase in kidney failure," Dr. Friedman stated. "To our surprise, this really only applies to nondiabetic kidney disease. The alleles have essentially no effect that we can detect on diabetic renal disease."

This realization led the investigators to revisit the issue of natural selection. It turns out, according to Dr. Friedman, "APOL1 is the genetic source for the immunity factor that protected people from African sleeping sickness, a parasitic infection caused by Trypanosoma brucei gambiense." Similar to selection for the gene variants associated with sickle cell anemia, he explained, "inheriting one copy of the APOL1 gene risk variant provides protection from the parasite, while two copies seems to render individuals increases the risk of kidney disease up to 10-fold." Through natural selection, as more people survived African sleeping sickness, the percentage of the population with kidney disease risk variants increased, he said.

The investigators are currently studying the risk variants intensively to figure out how they work. "We think they may differentially regulate processes such as apoptosis and cell repair may function as a chloride channel in mammalian systems in the same way it doses in lysosomes and may affect biological function," Dr. Friedman hypothesized.

In addition to exploring the underlying mechanisms, the potential clinical value of the genetic discovery is also being considered. "This may help us improve risk stratification," Dr. Friedman said. "It’s one thing to say that African Americans have a fourfold increased risk of kidney disease. It’s better to find the tag SNP [single nucleotide polymorphism] that will tell if an individual might have an increased risk. If you can actually find the causal variant, then you can potentially predict with much higher success who is and is not at risk for kidney failure," he stated. "The problem is that it works pretty well in Western African populations, such as Nigerians, but not as well in East Africans, such as Ethiopians."

One of the main questions that Dr. Friedman and his colleagues currently are pursuing is whether hypertension causes kidney disease in these at-risk individuals or whether hypertension is the result of primary renal vascular disease.

"To us, the fact that the very same genetic variants cause hypertension-associated ESRD and FSGS, a primary renal microvascular disease, suggests that these may be the same disease process that we are either catching at different stages or that have different modifiers, and that hypertension in these patients may just be a symptom and not a cause of kidney failure," Dr. Friedman said. Additionally, the investigators are trying to determine why only some people with two risk alleles develop kidney disease and why APOL1 risk variants have little to no effect on diabetic nephropathy, which may offer some clues to how the molecules work, he said.

A cure for nondiabetic kidney disease, which accounts for more than $8.2 billion annually in dialysis coasts, may directly result from the APOL1 finding, Dr. Friedman said. "It’s that important."

Dr. Friedman reported no financial conflicts of interested related to his presentation.

BOSTON – The recent identification of two gene mutations in a cohort of African Americans with nondiabetic kidney disease helps explain the disproportionately higher rates of kidney disease in this population and represents a disease-mechanism pathway that could lead to new treatments and possibly a cure, Dr. David J. Friedman said at the annual meeting of the International Society on Hypertension in Blacks.

Dr. Friedman of Beth-Israel Deaconess Medical Center, Boston, and his colleagues recently reported the association between two independent variants in the apolipoprotein L1 (APOL1) gene on chromosome 22 and focal segmental glomerulosclerosis (FSGS) and hypertension-attributed end-stage kidney disease in blacks (Science 2010;329:841-5). Not only do the investigators believe that APOL1 is very important to the understanding of nondiabetic renal disease in blacks, "we think the variants in the gene are among the most powerful that have been discovered to date," Dr. Friedman stressed.

The disparity between the rates of end-stage renal disease (ESRD) in blacks and whites in the United States is "incredible," Dr. Friedman stated, noting that the incidence rate is four to five times higher in blacks, according to the 2010 United States Renal Data System annual report. "People have been debating for decades whether the major cause of this disparity is genes or environment. No doubt both are important, but given how strongly this phenotype travels in families, I think we can say with certainty that genes play an important role."

The APOL1 discovery came on the heels of an earlier association linking FSGS, nondiabetic ESRD, and HIV nephropathy in blacks with the MYH9 gene located on the same chromosome, Dr. Friedman explained. "This was quite striking, because we used to think of the three conditions as entirely different diseases, yet each one had exactly the same locus."

Despite the strong association and several years spent looking for causal mutations using fine mapping sequences, the causal variants remained elusive until Dr. Friedman and his colleagues approached the problem from a different perspective.

"We asked, ‘How could any disease gene that’s this deleterious become so common in a population?’ We assumed there was something in this [genetic region] that was beneficial once upon a time to human evolution in Africa," he said. Using mathematical techniques, "we realized that because of the effects of natural selection, the disease gene interval was much larger than anyone thought and probably contained at least five genes." Consequently, the investigators tested new variants in other genes for association with renal disease in African Americans, looking specifically for variants that had not yet been documented, he said.

In a cohort of 205 African Americans with biopsy-proven FSGS and no family history of the disease and 180 African American control subjects, "we saw that variants in the neighboring APOL1 gene were much more strongly associated with renal disease, and unlike the MYH9 variants, which were located in regions of the gene that did not encode for protein, the APOL1 variants were protein-coding sequences."

The investigators determined that the top two variants almost always co-occurred on the same chromosome and each changed an amino acid somewhere on the protein. "We called this the g1 risk allele, and when we controlled for it, a new variant popped up, which we called the g2 allele," he said. Controlling for both the g1 and g2 alleles, "the entire association of this region disappeared and there was no signal left for MYH9."

The investigators also tested the genetic variants in hypertension-associated ESRD in a larger cohort of 1,030 African Americans with the disease and 1,025 geographically matched control subjects and found that the same two variants had a tremendous impact on the development of the disease.

"When combined together, the P value was on the order of 10 to the minus 60, or 35 orders of magnitude greater than the very best MYH9 [result]," Dr. Friedman said. Surprisingly, he noted, we found that these disease variants follow a recessive pattern and together the odds ratio was on the order of 7-10, while the very largest effect sizes of the common variants that affect hypertension or diabetes will confer odds ratios of about 1.4-1.5."

The APOL1 gene and these variants "tend to fall into a different category that we’ve all been familiar with in the past," Dr. Friedman explained. "Most disease variants are either very rare with powerful effects or common with relatively modest effects. The APOL1 variants have a surprising combination of effect size and frequency such that 50%-60% of African Americans carry g1 and/or g2 risk alleles, and 50% are risk homozygous, meaning they are in the highest risk for kidney disease: That translates into about 3.5 million individuals."

Further, while the odds ratios for the more common forms of nondiabetic kidney disease in this population range from 7 to 10, "we’re starting to see odds ratios in the range of 30 for diseases like HIV nephropathy."

Comparing Kidney Disease Rates Between Races

To determine how much of nondiabetic kidney disease can be explained by the genetic variants, the investigators reviewed data from the prospective population-based Dallas Heart Study and compared the outcomes of European American and Caucasian patients, in whom the renal risk alleles are essentially nonexistent, with those of African Americans with zero or one risk allele and those with both risk alleles. Looking at urine protein levels, an indicator of renal microvascular disease, "we found that black individuals with zero or one copy of the risk allele had rates more similar to whites than to blacks with two alleles," Dr. Friedman reported.

The results were even more striking for actual hard measures of renal function, he said. "Rates of chronic kidney disease or impaired renal function, indicated by glomerular filtration rates less than 60 mL/min per 1.73 m2, were essentially the same among blacks with zero or one allele and whites, whereas individuals with a risk genotype had a fourfold increase in impaired renal function." Although the study does not include many individuals with ESRD, the investigators hope to look more closely into such patients in future studies, he said.

In their preliminary review of the data, "we can’t tell any difference between African Americans with zero or one copy of the allele and Caucasians, but African Americans with two renal risk alleles have at least 10-fold increase in kidney failure," Dr. Friedman stated. "To our surprise, this really only applies to nondiabetic kidney disease. The alleles have essentially no effect that we can detect on diabetic renal disease."

This realization led the investigators to revisit the issue of natural selection. It turns out, according to Dr. Friedman, "APOL1 is the genetic source for the immunity factor that protected people from African sleeping sickness, a parasitic infection caused by Trypanosoma brucei gambiense." Similar to selection for the gene variants associated with sickle cell anemia, he explained, "inheriting one copy of the APOL1 gene risk variant provides protection from the parasite, while two copies seems to render individuals increases the risk of kidney disease up to 10-fold." Through natural selection, as more people survived African sleeping sickness, the percentage of the population with kidney disease risk variants increased, he said.

The investigators are currently studying the risk variants intensively to figure out how they work. "We think they may differentially regulate processes such as apoptosis and cell repair may function as a chloride channel in mammalian systems in the same way it doses in lysosomes and may affect biological function," Dr. Friedman hypothesized.

In addition to exploring the underlying mechanisms, the potential clinical value of the genetic discovery is also being considered. "This may help us improve risk stratification," Dr. Friedman said. "It’s one thing to say that African Americans have a fourfold increased risk of kidney disease. It’s better to find the tag SNP [single nucleotide polymorphism] that will tell if an individual might have an increased risk. If you can actually find the causal variant, then you can potentially predict with much higher success who is and is not at risk for kidney failure," he stated. "The problem is that it works pretty well in Western African populations, such as Nigerians, but not as well in East Africans, such as Ethiopians."

One of the main questions that Dr. Friedman and his colleagues currently are pursuing is whether hypertension causes kidney disease in these at-risk individuals or whether hypertension is the result of primary renal vascular disease.

"To us, the fact that the very same genetic variants cause hypertension-associated ESRD and FSGS, a primary renal microvascular disease, suggests that these may be the same disease process that we are either catching at different stages or that have different modifiers, and that hypertension in these patients may just be a symptom and not a cause of kidney failure," Dr. Friedman said. Additionally, the investigators are trying to determine why only some people with two risk alleles develop kidney disease and why APOL1 risk variants have little to no effect on diabetic nephropathy, which may offer some clues to how the molecules work, he said.

A cure for nondiabetic kidney disease, which accounts for more than $8.2 billion annually in dialysis coasts, may directly result from the APOL1 finding, Dr. Friedman said. "It’s that important."

Dr. Friedman reported no financial conflicts of interested related to his presentation.

BOSTON – The recent identification of two gene mutations in a cohort of African Americans with nondiabetic kidney disease helps explain the disproportionately higher rates of kidney disease in this population and represents a disease-mechanism pathway that could lead to new treatments and possibly a cure, Dr. David J. Friedman said at the annual meeting of the International Society on Hypertension in Blacks.

Dr. Friedman of Beth-Israel Deaconess Medical Center, Boston, and his colleagues recently reported the association between two independent variants in the apolipoprotein L1 (APOL1) gene on chromosome 22 and focal segmental glomerulosclerosis (FSGS) and hypertension-attributed end-stage kidney disease in blacks (Science 2010;329:841-5). Not only do the investigators believe that APOL1 is very important to the understanding of nondiabetic renal disease in blacks, "we think the variants in the gene are among the most powerful that have been discovered to date," Dr. Friedman stressed.

The disparity between the rates of end-stage renal disease (ESRD) in blacks and whites in the United States is "incredible," Dr. Friedman stated, noting that the incidence rate is four to five times higher in blacks, according to the 2010 United States Renal Data System annual report. "People have been debating for decades whether the major cause of this disparity is genes or environment. No doubt both are important, but given how strongly this phenotype travels in families, I think we can say with certainty that genes play an important role."

The APOL1 discovery came on the heels of an earlier association linking FSGS, nondiabetic ESRD, and HIV nephropathy in blacks with the MYH9 gene located on the same chromosome, Dr. Friedman explained. "This was quite striking, because we used to think of the three conditions as entirely different diseases, yet each one had exactly the same locus."

Despite the strong association and several years spent looking for causal mutations using fine mapping sequences, the causal variants remained elusive until Dr. Friedman and his colleagues approached the problem from a different perspective.

"We asked, ‘How could any disease gene that’s this deleterious become so common in a population?’ We assumed there was something in this [genetic region] that was beneficial once upon a time to human evolution in Africa," he said. Using mathematical techniques, "we realized that because of the effects of natural selection, the disease gene interval was much larger than anyone thought and probably contained at least five genes." Consequently, the investigators tested new variants in other genes for association with renal disease in African Americans, looking specifically for variants that had not yet been documented, he said.

In a cohort of 205 African Americans with biopsy-proven FSGS and no family history of the disease and 180 African American control subjects, "we saw that variants in the neighboring APOL1 gene were much more strongly associated with renal disease, and unlike the MYH9 variants, which were located in regions of the gene that did not encode for protein, the APOL1 variants were protein-coding sequences."

The investigators determined that the top two variants almost always co-occurred on the same chromosome and each changed an amino acid somewhere on the protein. "We called this the g1 risk allele, and when we controlled for it, a new variant popped up, which we called the g2 allele," he said. Controlling for both the g1 and g2 alleles, "the entire association of this region disappeared and there was no signal left for MYH9."

The investigators also tested the genetic variants in hypertension-associated ESRD in a larger cohort of 1,030 African Americans with the disease and 1,025 geographically matched control subjects and found that the same two variants had a tremendous impact on the development of the disease.

"When combined together, the P value was on the order of 10 to the minus 60, or 35 orders of magnitude greater than the very best MYH9 [result]," Dr. Friedman said. Surprisingly, he noted, we found that these disease variants follow a recessive pattern and together the odds ratio was on the order of 7-10, while the very largest effect sizes of the common variants that affect hypertension or diabetes will confer odds ratios of about 1.4-1.5."

The APOL1 gene and these variants "tend to fall into a different category that we’ve all been familiar with in the past," Dr. Friedman explained. "Most disease variants are either very rare with powerful effects or common with relatively modest effects. The APOL1 variants have a surprising combination of effect size and frequency such that 50%-60% of African Americans carry g1 and/or g2 risk alleles, and 50% are risk homozygous, meaning they are in the highest risk for kidney disease: That translates into about 3.5 million individuals."

Further, while the odds ratios for the more common forms of nondiabetic kidney disease in this population range from 7 to 10, "we’re starting to see odds ratios in the range of 30 for diseases like HIV nephropathy."

Comparing Kidney Disease Rates Between Races

To determine how much of nondiabetic kidney disease can be explained by the genetic variants, the investigators reviewed data from the prospective population-based Dallas Heart Study and compared the outcomes of European American and Caucasian patients, in whom the renal risk alleles are essentially nonexistent, with those of African Americans with zero or one risk allele and those with both risk alleles. Looking at urine protein levels, an indicator of renal microvascular disease, "we found that black individuals with zero or one copy of the risk allele had rates more similar to whites than to blacks with two alleles," Dr. Friedman reported.

The results were even more striking for actual hard measures of renal function, he said. "Rates of chronic kidney disease or impaired renal function, indicated by glomerular filtration rates less than 60 mL/min per 1.73 m2, were essentially the same among blacks with zero or one allele and whites, whereas individuals with a risk genotype had a fourfold increase in impaired renal function." Although the study does not include many individuals with ESRD, the investigators hope to look more closely into such patients in future studies, he said.

In their preliminary review of the data, "we can’t tell any difference between African Americans with zero or one copy of the allele and Caucasians, but African Americans with two renal risk alleles have at least 10-fold increase in kidney failure," Dr. Friedman stated. "To our surprise, this really only applies to nondiabetic kidney disease. The alleles have essentially no effect that we can detect on diabetic renal disease."

This realization led the investigators to revisit the issue of natural selection. It turns out, according to Dr. Friedman, "APOL1 is the genetic source for the immunity factor that protected people from African sleeping sickness, a parasitic infection caused by Trypanosoma brucei gambiense." Similar to selection for the gene variants associated with sickle cell anemia, he explained, "inheriting one copy of the APOL1 gene risk variant provides protection from the parasite, while two copies seems to render individuals increases the risk of kidney disease up to 10-fold." Through natural selection, as more people survived African sleeping sickness, the percentage of the population with kidney disease risk variants increased, he said.

The investigators are currently studying the risk variants intensively to figure out how they work. "We think they may differentially regulate processes such as apoptosis and cell repair may function as a chloride channel in mammalian systems in the same way it doses in lysosomes and may affect biological function," Dr. Friedman hypothesized.

In addition to exploring the underlying mechanisms, the potential clinical value of the genetic discovery is also being considered. "This may help us improve risk stratification," Dr. Friedman said. "It’s one thing to say that African Americans have a fourfold increased risk of kidney disease. It’s better to find the tag SNP [single nucleotide polymorphism] that will tell if an individual might have an increased risk. If you can actually find the causal variant, then you can potentially predict with much higher success who is and is not at risk for kidney failure," he stated. "The problem is that it works pretty well in Western African populations, such as Nigerians, but not as well in East Africans, such as Ethiopians."

One of the main questions that Dr. Friedman and his colleagues currently are pursuing is whether hypertension causes kidney disease in these at-risk individuals or whether hypertension is the result of primary renal vascular disease.

"To us, the fact that the very same genetic variants cause hypertension-associated ESRD and FSGS, a primary renal microvascular disease, suggests that these may be the same disease process that we are either catching at different stages or that have different modifiers, and that hypertension in these patients may just be a symptom and not a cause of kidney failure," Dr. Friedman said. Additionally, the investigators are trying to determine why only some people with two risk alleles develop kidney disease and why APOL1 risk variants have little to no effect on diabetic nephropathy, which may offer some clues to how the molecules work, he said.

A cure for nondiabetic kidney disease, which accounts for more than $8.2 billion annually in dialysis coasts, may directly result from the APOL1 finding, Dr. Friedman said. "It’s that important."

Dr. Friedman reported no financial conflicts of interested related to his presentation.

Persistent asymptomatic isolated microscopic hematuria in adolescence and young adulthood appears to be a strong predictor of end-stage renal disease in later adulthood, independent of other risk factors, according to a report in the Aug. 17 JAMA.

Such hematuria is frequently an incidental finding on routine examination in this age group, but its significance has been unclear. Short-term prognosis is favorable, and the condition is generally considered benign. But long-term data are lacking, and uncertainty about the implications has prompted "considerable controversy over appropriate evaluation, management, and prognosis," said Dr. Asaf Vivante of the Israeli Defense Forces Medical Corps and the Edmond and Lily Safra Children’s Hospital, Tel Hashomer, Israel, and his associates.

"The most recent American Academy of Pediatrics guidelines rescinded the recommendation for urine screening during the second decade of life," they noted.

They conducted a nationwide retrospective cohort study to assess the long-term outcomes of persistent asymptomatic isolated microscopic hematuria, which by definition is unaccompanied by proteinuria or kidney abnormalities and unrelated to any systemic condition. By using mandatory military service records, the researchers assessed medical data on over 1.2 million Israelis who were aged 16-25 years at induction in 1975-1997 and who were followed for about 22 years.

Study subjects were initially screened by urinary dipstick test. In those with positive results for hematuria, urinary sediment was examined by microscopy. A total of 3,690 of these young men and women (0.3% of the cohort) were found to have persistent asymptomatic isolated hematuria.

The investigators then used a national end-stage renal disease (ESRD) database to identify all patients receiving any form of renal replacement therapy from 1980 through 2010. During follow-up, 565 members of the study cohort were treated for ESRD.

The incidence of ESRD was 34 per 100,000 person-years for subjects who had had hematuria in adolescence and young adulthood, a strikingly higher rate than the 2.05 cases per 100,000 person-years for subjects who had not had hematuria, Dr. Vivante and his associates said (JAMA 2011;306:729-36).

A total of 0.7% of subjects with hematuria in adolescence developed ESRD, compared with 0.04% of those without hematuria, yielding an unadjusted hazard ratio of 19.5. When the data were adjusted to account for factors that might influence kidney function, such as subject age, sex, BMI, and blood pressure, there was no significant change in the estimated HR (18.5).

In addition, study subjects who had hematuria in adolescence were considerably younger at the onset of ESRD (34 years) than were subjects without hematuria during their youth (38 years).

When the cases of ESRD were categorized by nine possible causes – diabetes, hypertension, glomerulonephritis, hereditary nephritis, interstitial nephritis, cystic kidney disease, secondary glomerulonephritis, drug-induced, and other causes – the clear majority of cases among subjects who had hematuria in adolescence were found to be due to glomerular disease.

"Our findings suggest that persistent asymptomatic isolated microscopic hematuria detected during adolescence and young adulthood is an early marker for primary glomerular injury and may be the first sign of an occult renal disease," the researchers said.

They added that follow-up in this study ended well before subjects reached the age at which ESRD incidence peaks, so their calculations likely underestimate the true significance of hematuria as a predictor for the disease.

Since this study involved only Jewish subjects, the results may not be generalizable to other racial/ethnic groups, and confirmation of these results should be sought in other populations.

"Future studies [also] are warranted to evaluate the utility of population screening in improving clinical outcomes," they noted.

This study was supported by the Israel Defense Forces Medical Corps and the Israeli Ministry of Health. No financial conflicts of interest were reported.

Persistent asymptomatic isolated microscopic hematuria in adolescence and young adulthood appears to be a strong predictor of end-stage renal disease in later adulthood, independent of other risk factors, according to a report in the Aug. 17 JAMA.

Such hematuria is frequently an incidental finding on routine examination in this age group, but its significance has been unclear. Short-term prognosis is favorable, and the condition is generally considered benign. But long-term data are lacking, and uncertainty about the implications has prompted "considerable controversy over appropriate evaluation, management, and prognosis," said Dr. Asaf Vivante of the Israeli Defense Forces Medical Corps and the Edmond and Lily Safra Children’s Hospital, Tel Hashomer, Israel, and his associates.

"The most recent American Academy of Pediatrics guidelines rescinded the recommendation for urine screening during the second decade of life," they noted.

They conducted a nationwide retrospective cohort study to assess the long-term outcomes of persistent asymptomatic isolated microscopic hematuria, which by definition is unaccompanied by proteinuria or kidney abnormalities and unrelated to any systemic condition. By using mandatory military service records, the researchers assessed medical data on over 1.2 million Israelis who were aged 16-25 years at induction in 1975-1997 and who were followed for about 22 years.

Study subjects were initially screened by urinary dipstick test. In those with positive results for hematuria, urinary sediment was examined by microscopy. A total of 3,690 of these young men and women (0.3% of the cohort) were found to have persistent asymptomatic isolated hematuria.

The investigators then used a national end-stage renal disease (ESRD) database to identify all patients receiving any form of renal replacement therapy from 1980 through 2010. During follow-up, 565 members of the study cohort were treated for ESRD.

The incidence of ESRD was 34 per 100,000 person-years for subjects who had had hematuria in adolescence and young adulthood, a strikingly higher rate than the 2.05 cases per 100,000 person-years for subjects who had not had hematuria, Dr. Vivante and his associates said (JAMA 2011;306:729-36).

A total of 0.7% of subjects with hematuria in adolescence developed ESRD, compared with 0.04% of those without hematuria, yielding an unadjusted hazard ratio of 19.5. When the data were adjusted to account for factors that might influence kidney function, such as subject age, sex, BMI, and blood pressure, there was no significant change in the estimated HR (18.5).

In addition, study subjects who had hematuria in adolescence were considerably younger at the onset of ESRD (34 years) than were subjects without hematuria during their youth (38 years).

When the cases of ESRD were categorized by nine possible causes – diabetes, hypertension, glomerulonephritis, hereditary nephritis, interstitial nephritis, cystic kidney disease, secondary glomerulonephritis, drug-induced, and other causes – the clear majority of cases among subjects who had hematuria in adolescence were found to be due to glomerular disease.

"Our findings suggest that persistent asymptomatic isolated microscopic hematuria detected during adolescence and young adulthood is an early marker for primary glomerular injury and may be the first sign of an occult renal disease," the researchers said.

They added that follow-up in this study ended well before subjects reached the age at which ESRD incidence peaks, so their calculations likely underestimate the true significance of hematuria as a predictor for the disease.

Since this study involved only Jewish subjects, the results may not be generalizable to other racial/ethnic groups, and confirmation of these results should be sought in other populations.

"Future studies [also] are warranted to evaluate the utility of population screening in improving clinical outcomes," they noted.

This study was supported by the Israel Defense Forces Medical Corps and the Israeli Ministry of Health. No financial conflicts of interest were reported.

Persistent asymptomatic isolated microscopic hematuria in adolescence and young adulthood appears to be a strong predictor of end-stage renal disease in later adulthood, independent of other risk factors, according to a report in the Aug. 17 JAMA.

Such hematuria is frequently an incidental finding on routine examination in this age group, but its significance has been unclear. Short-term prognosis is favorable, and the condition is generally considered benign. But long-term data are lacking, and uncertainty about the implications has prompted "considerable controversy over appropriate evaluation, management, and prognosis," said Dr. Asaf Vivante of the Israeli Defense Forces Medical Corps and the Edmond and Lily Safra Children’s Hospital, Tel Hashomer, Israel, and his associates.

"The most recent American Academy of Pediatrics guidelines rescinded the recommendation for urine screening during the second decade of life," they noted.

They conducted a nationwide retrospective cohort study to assess the long-term outcomes of persistent asymptomatic isolated microscopic hematuria, which by definition is unaccompanied by proteinuria or kidney abnormalities and unrelated to any systemic condition. By using mandatory military service records, the researchers assessed medical data on over 1.2 million Israelis who were aged 16-25 years at induction in 1975-1997 and who were followed for about 22 years.

Study subjects were initially screened by urinary dipstick test. In those with positive results for hematuria, urinary sediment was examined by microscopy. A total of 3,690 of these young men and women (0.3% of the cohort) were found to have persistent asymptomatic isolated hematuria.

The investigators then used a national end-stage renal disease (ESRD) database to identify all patients receiving any form of renal replacement therapy from 1980 through 2010. During follow-up, 565 members of the study cohort were treated for ESRD.

The incidence of ESRD was 34 per 100,000 person-years for subjects who had had hematuria in adolescence and young adulthood, a strikingly higher rate than the 2.05 cases per 100,000 person-years for subjects who had not had hematuria, Dr. Vivante and his associates said (JAMA 2011;306:729-36).

A total of 0.7% of subjects with hematuria in adolescence developed ESRD, compared with 0.04% of those without hematuria, yielding an unadjusted hazard ratio of 19.5. When the data were adjusted to account for factors that might influence kidney function, such as subject age, sex, BMI, and blood pressure, there was no significant change in the estimated HR (18.5).

In addition, study subjects who had hematuria in adolescence were considerably younger at the onset of ESRD (34 years) than were subjects without hematuria during their youth (38 years).

When the cases of ESRD were categorized by nine possible causes – diabetes, hypertension, glomerulonephritis, hereditary nephritis, interstitial nephritis, cystic kidney disease, secondary glomerulonephritis, drug-induced, and other causes – the clear majority of cases among subjects who had hematuria in adolescence were found to be due to glomerular disease.

"Our findings suggest that persistent asymptomatic isolated microscopic hematuria detected during adolescence and young adulthood is an early marker for primary glomerular injury and may be the first sign of an occult renal disease," the researchers said.

They added that follow-up in this study ended well before subjects reached the age at which ESRD incidence peaks, so their calculations likely underestimate the true significance of hematuria as a predictor for the disease.

Since this study involved only Jewish subjects, the results may not be generalizable to other racial/ethnic groups, and confirmation of these results should be sought in other populations.

"Future studies [also] are warranted to evaluate the utility of population screening in improving clinical outcomes," they noted.

This study was supported by the Israel Defense Forces Medical Corps and the Israeli Ministry of Health. No financial conflicts of interest were reported.

WASHINGTON – Research has documented a strong association between the formation of kidney stones and the presence or development of cardiovascular disease, metabolic syndrome, and a number of components of the metabolic syndrome, said Dr. Dean G. Assimos.

"There is increasing evidence" of this link, he noted at the annual meeting of the American Urological Association. "We need to be cognizant of these associations."

Most recently, an analysis of data from the Coronary Artery Risk Development in Young Adults (CARDIA) study showed that individuals who developed kidney stones had a 1.6-fold increased risk of developing subclinical carotid artery atherosclerosis, even after adjustments for major cardiovascular risk factors were made, said Dr. Assimos, professor of urology at Wake Forest University, Winston-Salem, N.C.

The longitudinal cohort study followed 5,115 white and black men and women who were 18-30 years old at the time of recruitment in 1985-1986. Carotid artery intima-media thickness was measured with serial ultrasound periodically throughout the observation period. By 20 years, almost 4% had reported having kidney stones, and kidney stones were associated with a 60% increased risk of carotid atherosclerosis (J. Urol. 2011;185:920-5). Kidney stones were associated with myocardial infarction (MI) in another recent study aimed specifically at assessing "the risk of a kidney stone former developing an MI," Dr. Assimos said. Investigators of this case-controlled study matched almost 4,600 stone formers on age and sex with almost 11,000 control subjects among residents of Olmstead County, Minn.

During a mean follow-up of 9 years, "despite controlling for other medical comorbidities," investigators found that "stone formers had a 31% increased risk of sustaining an MI," he said.

Chronic kidney disease, which itself is a risk factor for MI, was one of the comorbidities adjusted for (J. Am. Soc. Nephrol. 2010;21:1641-4).

Numerous studies published since 2005 have demonstrated positive associations between kidney stone formation and specific components of the metabolic syndrome, as well as with the full constellation of disorders, Dr. Assimos said.

An analysis of National Health and Nutrition Examination Survey III data published in 2008, for instance, showed that individuals with four traits of the metabolic syndrome had two times the risk of having a history of kidney stones (Am. J. Kidney Dis. 2008;51:741-7). The prevalence of self-reported history of kidney stones, moreover, increased as the number of traits or component disorders of the metabolic syndrome increased, from 3% with no disorders to 7.5% with three disorders, and to almost 10% with five disorders. (An individual must have at least three of the five component disorders to qualify as having the metabolic syndrome.)

Similarly, in an Italian study of hospitalized adults, more than 10% of 725 patients with metabolic syndrome had evidence of nephrolithiasis on renal ultrasound (Nephrol. Dial. Transplant 2009;24:900-6). "This is 10 times higher than [rates reported from] renal ultrasound screening studies done in the general population," Dr. Assimos said.

Data from three large cohorts – the Nurses’ Health Study (NHS) I of older women, the NHS II of younger women, and the Health Professionals Follow-Up Study (HPFS) of men aged 40-75 years – have been crucial in elucidating the associations between kidney stones and specific components of the metabolic syndrome.

In one prospective study of the cohorts that looked at the incidence of symptomatic kidney stones, for instance, investigators documented that the relative risk of an obese individual (body mass index, 30 kg/m² or greater) for kidney stone formation, compared with individuals with a BMI of 21-23, was 1.9 in the NHS I cohort, 2.09 in the NHS II cohort, and 1.33 in the HPFS cohort (JAMA 2005;293:455-62).

"There was also a positive correlation in all these cohorts with waist circumference," Dr. Assimos said.

Other analyses of these cohorts have documented positive associations between type 2 diabetes or hypertension, and incident kidney stone formation, as well as associations between a history of kidney stone formation and the diagnosis of diabetes or development of hypertension.

The causative factors underlying the associations between stone formation and cardiovascular disease and the metabolic syndrome include low urinary pH levels. At lower urinary pH levels, "more [of the body’s] uric acid is in its undissociated form and is insoluble in urine," for instance, which increases the risk of uric acid stone formation, Dr. Assimos said.

Studies have demonstrated a negative correlation between BMI and urinary pH, he noted. The reasons are not fully known, but "it is hypothesized that individuals [with higher BMI] do not produce ammonium effectively in the proximal tubule," he said.

Individuals with obesity and low urinary pH also excrete greater amounts of calcium and oxalate, and this increases the risk of calcium oxalate stone formation, he said.

Dr. Assimos’s own research team has identified a possible new pathway for the endogenous synthesis of oxalate. It involves the metabolism of glyoxal, which is stimulated by oxidative stress. The glyoxal metabolism "may explain the increased oxalate excretion in those with obesity as well as diabetes," he said.

The associations between kidney stone formation and cardiovascular risk have hit home for Dr. Assimos, he said at the end of his presentation. At age 39, he developed his first kidney stone. By 3 years later, he developed hypertension. "And 3 years ago. I started having symptoms of gastroesophageal reflux when exercising ... I had a stress test ... and here is my coronary arteriogram," he told the audience. The end result, he said, was successful coronary artery bypass grafting.

Dr. Assimos reported that he is an investigator for the National Institutes of Health and a partner at Piedmont Stone, a facility in Winston-Salem that provides lithotripsy procedures.

WASHINGTON – Research has documented a strong association between the formation of kidney stones and the presence or development of cardiovascular disease, metabolic syndrome, and a number of components of the metabolic syndrome, said Dr. Dean G. Assimos.

"There is increasing evidence" of this link, he noted at the annual meeting of the American Urological Association. "We need to be cognizant of these associations."

Most recently, an analysis of data from the Coronary Artery Risk Development in Young Adults (CARDIA) study showed that individuals who developed kidney stones had a 1.6-fold increased risk of developing subclinical carotid artery atherosclerosis, even after adjustments for major cardiovascular risk factors were made, said Dr. Assimos, professor of urology at Wake Forest University, Winston-Salem, N.C.

The longitudinal cohort study followed 5,115 white and black men and women who were 18-30 years old at the time of recruitment in 1985-1986. Carotid artery intima-media thickness was measured with serial ultrasound periodically throughout the observation period. By 20 years, almost 4% had reported having kidney stones, and kidney stones were associated with a 60% increased risk of carotid atherosclerosis (J. Urol. 2011;185:920-5). Kidney stones were associated with myocardial infarction (MI) in another recent study aimed specifically at assessing "the risk of a kidney stone former developing an MI," Dr. Assimos said. Investigators of this case-controlled study matched almost 4,600 stone formers on age and sex with almost 11,000 control subjects among residents of Olmstead County, Minn.

During a mean follow-up of 9 years, "despite controlling for other medical comorbidities," investigators found that "stone formers had a 31% increased risk of sustaining an MI," he said.

Chronic kidney disease, which itself is a risk factor for MI, was one of the comorbidities adjusted for (J. Am. Soc. Nephrol. 2010;21:1641-4).

Numerous studies published since 2005 have demonstrated positive associations between kidney stone formation and specific components of the metabolic syndrome, as well as with the full constellation of disorders, Dr. Assimos said.

An analysis of National Health and Nutrition Examination Survey III data published in 2008, for instance, showed that individuals with four traits of the metabolic syndrome had two times the risk of having a history of kidney stones (Am. J. Kidney Dis. 2008;51:741-7). The prevalence of self-reported history of kidney stones, moreover, increased as the number of traits or component disorders of the metabolic syndrome increased, from 3% with no disorders to 7.5% with three disorders, and to almost 10% with five disorders. (An individual must have at least three of the five component disorders to qualify as having the metabolic syndrome.)

Similarly, in an Italian study of hospitalized adults, more than 10% of 725 patients with metabolic syndrome had evidence of nephrolithiasis on renal ultrasound (Nephrol. Dial. Transplant 2009;24:900-6). "This is 10 times higher than [rates reported from] renal ultrasound screening studies done in the general population," Dr. Assimos said.

Data from three large cohorts – the Nurses’ Health Study (NHS) I of older women, the NHS II of younger women, and the Health Professionals Follow-Up Study (HPFS) of men aged 40-75 years – have been crucial in elucidating the associations between kidney stones and specific components of the metabolic syndrome.

In one prospective study of the cohorts that looked at the incidence of symptomatic kidney stones, for instance, investigators documented that the relative risk of an obese individual (body mass index, 30 kg/m² or greater) for kidney stone formation, compared with individuals with a BMI of 21-23, was 1.9 in the NHS I cohort, 2.09 in the NHS II cohort, and 1.33 in the HPFS cohort (JAMA 2005;293:455-62).

"There was also a positive correlation in all these cohorts with waist circumference," Dr. Assimos said.

Other analyses of these cohorts have documented positive associations between type 2 diabetes or hypertension, and incident kidney stone formation, as well as associations between a history of kidney stone formation and the diagnosis of diabetes or development of hypertension.

The causative factors underlying the associations between stone formation and cardiovascular disease and the metabolic syndrome include low urinary pH levels. At lower urinary pH levels, "more [of the body’s] uric acid is in its undissociated form and is insoluble in urine," for instance, which increases the risk of uric acid stone formation, Dr. Assimos said.

Studies have demonstrated a negative correlation between BMI and urinary pH, he noted. The reasons are not fully known, but "it is hypothesized that individuals [with higher BMI] do not produce ammonium effectively in the proximal tubule," he said.

Individuals with obesity and low urinary pH also excrete greater amounts of calcium and oxalate, and this increases the risk of calcium oxalate stone formation, he said.

Dr. Assimos’s own research team has identified a possible new pathway for the endogenous synthesis of oxalate. It involves the metabolism of glyoxal, which is stimulated by oxidative stress. The glyoxal metabolism "may explain the increased oxalate excretion in those with obesity as well as diabetes," he said.

The associations between kidney stone formation and cardiovascular risk have hit home for Dr. Assimos, he said at the end of his presentation. At age 39, he developed his first kidney stone. By 3 years later, he developed hypertension. "And 3 years ago. I started having symptoms of gastroesophageal reflux when exercising ... I had a stress test ... and here is my coronary arteriogram," he told the audience. The end result, he said, was successful coronary artery bypass grafting.

Dr. Assimos reported that he is an investigator for the National Institutes of Health and a partner at Piedmont Stone, a facility in Winston-Salem that provides lithotripsy procedures.

WASHINGTON – Research has documented a strong association between the formation of kidney stones and the presence or development of cardiovascular disease, metabolic syndrome, and a number of components of the metabolic syndrome, said Dr. Dean G. Assimos.

"There is increasing evidence" of this link, he noted at the annual meeting of the American Urological Association. "We need to be cognizant of these associations."

Most recently, an analysis of data from the Coronary Artery Risk Development in Young Adults (CARDIA) study showed that individuals who developed kidney stones had a 1.6-fold increased risk of developing subclinical carotid artery atherosclerosis, even after adjustments for major cardiovascular risk factors were made, said Dr. Assimos, professor of urology at Wake Forest University, Winston-Salem, N.C.

The longitudinal cohort study followed 5,115 white and black men and women who were 18-30 years old at the time of recruitment in 1985-1986. Carotid artery intima-media thickness was measured with serial ultrasound periodically throughout the observation period. By 20 years, almost 4% had reported having kidney stones, and kidney stones were associated with a 60% increased risk of carotid atherosclerosis (J. Urol. 2011;185:920-5). Kidney stones were associated with myocardial infarction (MI) in another recent study aimed specifically at assessing "the risk of a kidney stone former developing an MI," Dr. Assimos said. Investigators of this case-controlled study matched almost 4,600 stone formers on age and sex with almost 11,000 control subjects among residents of Olmstead County, Minn.

During a mean follow-up of 9 years, "despite controlling for other medical comorbidities," investigators found that "stone formers had a 31% increased risk of sustaining an MI," he said.

Chronic kidney disease, which itself is a risk factor for MI, was one of the comorbidities adjusted for (J. Am. Soc. Nephrol. 2010;21:1641-4).

Numerous studies published since 2005 have demonstrated positive associations between kidney stone formation and specific components of the metabolic syndrome, as well as with the full constellation of disorders, Dr. Assimos said.

An analysis of National Health and Nutrition Examination Survey III data published in 2008, for instance, showed that individuals with four traits of the metabolic syndrome had two times the risk of having a history of kidney stones (Am. J. Kidney Dis. 2008;51:741-7). The prevalence of self-reported history of kidney stones, moreover, increased as the number of traits or component disorders of the metabolic syndrome increased, from 3% with no disorders to 7.5% with three disorders, and to almost 10% with five disorders. (An individual must have at least three of the five component disorders to qualify as having the metabolic syndrome.)

Similarly, in an Italian study of hospitalized adults, more than 10% of 725 patients with metabolic syndrome had evidence of nephrolithiasis on renal ultrasound (Nephrol. Dial. Transplant 2009;24:900-6). "This is 10 times higher than [rates reported from] renal ultrasound screening studies done in the general population," Dr. Assimos said.

Data from three large cohorts – the Nurses’ Health Study (NHS) I of older women, the NHS II of younger women, and the Health Professionals Follow-Up Study (HPFS) of men aged 40-75 years – have been crucial in elucidating the associations between kidney stones and specific components of the metabolic syndrome.

In one prospective study of the cohorts that looked at the incidence of symptomatic kidney stones, for instance, investigators documented that the relative risk of an obese individual (body mass index, 30 kg/m² or greater) for kidney stone formation, compared with individuals with a BMI of 21-23, was 1.9 in the NHS I cohort, 2.09 in the NHS II cohort, and 1.33 in the HPFS cohort (JAMA 2005;293:455-62).

"There was also a positive correlation in all these cohorts with waist circumference," Dr. Assimos said.

Other analyses of these cohorts have documented positive associations between type 2 diabetes or hypertension, and incident kidney stone formation, as well as associations between a history of kidney stone formation and the diagnosis of diabetes or development of hypertension.

The causative factors underlying the associations between stone formation and cardiovascular disease and the metabolic syndrome include low urinary pH levels. At lower urinary pH levels, "more [of the body’s] uric acid is in its undissociated form and is insoluble in urine," for instance, which increases the risk of uric acid stone formation, Dr. Assimos said.

Studies have demonstrated a negative correlation between BMI and urinary pH, he noted. The reasons are not fully known, but "it is hypothesized that individuals [with higher BMI] do not produce ammonium effectively in the proximal tubule," he said.

Individuals with obesity and low urinary pH also excrete greater amounts of calcium and oxalate, and this increases the risk of calcium oxalate stone formation, he said.

Dr. Assimos’s own research team has identified a possible new pathway for the endogenous synthesis of oxalate. It involves the metabolism of glyoxal, which is stimulated by oxidative stress. The glyoxal metabolism "may explain the increased oxalate excretion in those with obesity as well as diabetes," he said.

The associations between kidney stone formation and cardiovascular risk have hit home for Dr. Assimos, he said at the end of his presentation. At age 39, he developed his first kidney stone. By 3 years later, he developed hypertension. "And 3 years ago. I started having symptoms of gastroesophageal reflux when exercising ... I had a stress test ... and here is my coronary arteriogram," he told the audience. The end result, he said, was successful coronary artery bypass grafting.

Dr. Assimos reported that he is an investigator for the National Institutes of Health and a partner at Piedmont Stone, a facility in Winston-Salem that provides lithotripsy procedures.

Twice as common as autism and half as well-known,¹ autosomal polycystic kidney disease (ADPKD) occurs in one in 400 to one in 1,000 people.² It is an inherited progressive genetic disorder that causes hypertension and decreased renal function and, over time, can lead to kidney failure. Two polycstin genes that code for ADPKD, PKD1 and PKD2, were identified in 1994 and 1996, respectively.^3,4 Awareness and understanding of the genes responsible for ADPKD have increased clinicians’ ability to identify at-risk patients and to slow or alter the course of the ­disease.

Case Presentation

A 45-year-old black man presents to your office with severe, nonradiating back pain and new-onset hypertension. Regarding the pain, he stated, “I turned around to see who kicked me, but no one was there.” When the pain began, he went to see the nurse at the school where he is employed, and she found that his blood pressure was high at 162/90 mm Hg. Although the patient’s back pain is resolving, he is very concerned about his blood pressure, since he has never had a high reading before.

He is the baseball coach and physical education teacher at the local high school and is in excellent physical condition as a result of his professional interaction with teenagers every day. He does not smoke or use any illicit drugs but does admit to occasional alcohol consumption. His medical history is significant only for occasional broken fingers and twisted ankles, all occurring while he was engaged in sports.

His family history includes one brother without medical problems, a brother and a sister with hypertension, a sister with diabetes and obesity, and a brother with a congenital abnormality that required a living donor kidney transplant at age 17 (the father served as donor). No family-wide workup has ever been done because no one practitioner has ever made a connection among these conditions and considered a diagnosis of ADPKD.

The patient’s blood pressure in the office is 172/92 mm Hg while sitting and 166/88 mm Hg while standing. He is somewhat sore with a localized spasm in the lumbar-sacral area but no radiation of pain. The patient has trouble touching his toes but reports that he can never touch his toes. His straight leg lift is negative. The rest of his physical exam is noncontributory.

What should be the next step in this patient’s workup?

PATHOPHYSIOLOGY

ADPKD is a progressive expansion of numerous fluid-filled cysts that result in massive enlargement of the kidneys.⁵ Less than 5% of all nephrons become cystic; however, the average volume of a polycystic kidney is 1,000 mL (normal, 300 mL), that is, the volume of a standard-sized pineapple. Even with this significant enlargement, a decline in the glomerular filtration rate (GFR) is not usually seen initially. Each cyst is derived from a single hyperproliferative epithelial cell. Increased cellular proliferation, followed by fluid secretion and alterations in the extracellular matrix, cause an outpouching from the parent nephron, which eventually detaches from the parent nephron and continues to enlarge and autonomously secrete fluid.^6,7

PKD1 and PKD2 are two genes responsible for ADPKD that have been isolated so far. Since there are families carrying neither the PKD1 nor the PKD2 gene that still have an inherited type of ADPKD, there is suspicion that at least one more PKD gene, not yet isolated, exists.⁸ It is also possible that other genetic or environmental factors may be at play.^9,10

In 1994, the PKD1 gene was isolated on chromosome 16,³ and it was found to code for polycystin 1. A lack of polycystin 1 causes an abnormality in the Na+/K(+)-ATPase pumps, leading to abnormal sodium reabsorption.¹¹ How and why this happens is not quite clear. However, the hypertension that is a key objective finding in patients with ADPKD is thought to result from this pump abnormality.

PKD2 is found on the long arm of chromosome 4 and codes for polycystin 2.⁴ Polycystin 2 is an amino acid that is responsible for voltage-activated cellular calcium channels,⁵ again explaining the hypertension so commonly seen in the course of ADPKD. ADPKD-associated hypertension may be present as early as the teenage years.¹²

EPIDEMIOLOGY

More than 85% of ADPKD cases are associated with PKD1, and this form is called polycystic kidney disease 1 (PKD 1), the more aggressive form of the disease.^13,14 PKD 2 (the form associated with the gene PKD2), though less common, is also likely to progress to end-stage renal disease (ESRD), but at a later age (median age of 74 years, compared with 54 in patients with PKD 1).¹⁴ ADPKD accounts for about 5% of cases of ESRD in North America,⁹ but for most patients, presentation and decreased renal function do not occur until the 40s.¹⁵ However, patients with the risk factors listed in Table 1^5,16-19 are likely to experience a more rapid and aggressive form of the disease.

Even with the same germline mutation in a family with this inherited disease, the severity of ADPKD among family members is quite variable; this is true even in the case of twins.^9,10,20 Since the age and symptoms at presentation can vary so greatly, a uniform method of identifying patients with ADPKD, along with staging, was needed. Most patients do not undergo genetic testing (ie, DNA linkage or gene-based direct sequencing⁹) for a diagnosis of ADPKD or to differentiate between the PKD 1 and PKD 2 disease forms unless they are participating in a research study. Diagnostic criteria were needed that were applicable for any type of ADPKD.

In 2009, the University of Toronto’s Division of Nephrology convened experts in the fields of nephrology and radiology to reach a consensus on standardized ultrasonographic diagnostic criteria.²¹ They formulated definitions based on a study of 948 individuals who were at risk for either PKD 1 or PKD 2 (see Table 2²¹). The specificity and sensitivity of the resulting criteria range from 82% to 100%, making it possible to standardize the care and classification of renal patients worldwide.

Since family members with the same genotypes can experience very divergent disease manifestations, the two-hit hypothesis has been developed.²² In simple terms, it proposes that after the germline mutation (PKD1 or PKD2), there is a second somatic mutation that leads to progressive cyst formation; when the number and size of cysts increase, the patient starts to experience symptoms of ADPKD.²²

Age at presentation can be quite variable, as can the presenting symptoms. Most patients with PKD 1 present in their 50s, with 54 being the average age in US patients.¹⁴ The most common presenting symptom is flank or back pain.^2,5 The pain is due to the massive enlargement of the kidneys, causing a stretching of the kidney capsule and leading to a chronic, dull and persistent pain in the low back. Severe pain, sharp and cutting, occurs when one of the cysts hemorrhages; to some patients, the pain resembles a quick, powerful “kick in the back.” Hematuria can occur following cyst hemorrhage; depending on the location of the cyst that burst within the kidney (ie, how close it is to the collecting system) and how large it is, the amount and color of the hematuria can be impressive.

ADPKD is more common in men than women, and cyst rupture can be precipitated by trauma or lifting heavy objects. Cyst hemorrhage can turn the urine bright red, which is especially frightening to the male patient. Hematuria is often the key presenting symptom in patients who will be diagnosed with ­ADPKD-induced hypertension.

Besides hematuria, other common manifestations of ­ADPKD include:

• Hypertension (60% of affected patients, which increases to 100% by the time ESRD develops)

• Extrarenal cysts (100% of affected patients)

• Urinary tract infections

• Nephrolithiasis (20% of affected patients)

• Proteinuria, occasionally (18% of affected patients).^2,5,23

Among these manifestations, those most commonly attributed to a diagnosis of ADPKD are hypertension, kidney stones, and urinary tract or kidney infections. Since isolated proteinuria is unusual in patients with ­ADPKD, it is recommended that another cause of kidney disease be explored in patients with this presentation.²⁴

Extrarenal manifestations of cyst development are common, eventually occurring in all patients as they age. Hepatic cysts are universal in patients with ADPKD by age 30, although hepatic function is preserved. There may be a mild elevation in the alkaline phosphatase level in patients with ADPKD, resulting from the presence of hepatic cysts. Cysts may also be found in the pancreas, spleen, thyroid, and epididymis.^5,25 Some patients may complain of dyspnea, pain, early satiety, or lower extremity edema as a result of enlarged cyst.

The Case Patient

Because you recently attended a lecture about ADPKD, you are aware that flank pain in men with hypertension is indicative of ADPKD until proven otherwise. Believing that this patient’s hypertension is renal in origin, you order an abdominal ultrasound. You also order a comprehensive metabolic panel and a complete blood count. The patient’s GFR is measured at 89 mL/min (indicative of stage 2 kidney disease). Other results are shown in Table 3.

The very broad differential includes essential hypertension, hypertension resulting from intake of “power drinks” or salt in an athlete, illicit use of medications (including steroids), herniated disc leading to transient hypertension, and urinary tract infection or sexually transmitted disease. All of this is moot when the ultrasound shows both kidneys measuring greater than 15 cm, with four distinct cysts on the right kidney and three distinct cysts on the left.

You explain to the patient that ADPKD is a genetic disease and that he and his siblings each had a certain chance of inheriting it. Although different presentations may occur (“congenital” polycystic kidney disease, hypertension, or obesity), they all must undergo ultrasonographic screening for ADPKD. You add that although ADPKD is a genetic disease, it can also be diagnosed in different members of the same family at different ages.

TREATMENT

The goal of treatment for the patient with ADPKD is to slow cyst development and the natural course of the disease. If this can be achieved, the need for dialysis or kidney transplantation may be postponed for a number of years. Because cyst growth causes an elevation in renin and activates the angiotensin II renin system²⁶ (see figure,²⁴), an ACE inhibitor is the most effective treatment to lower blood pressure and thus slow the progression of ADPKD. Most patients with ADPKD are started on an ACE inhibitor at an early age to slow the rate of disease progression.^27,28 Several studies are under way to determine the best antihypertensive medication and the optimal age for initiating treatment.^29,30

Lipid screening and treatment for dyslipidemia are important²³ because ADPKD can lead to a reduction in kidney function, resulting in chronic kidney disease (CKD). CKD is considered a coronary heart disease risk equivalent, and most professionals will treat the patient with ADPKD for hyperlipidemia.^23,31 While there are no data showing that statin use will reduce the incidence of ESRD or delay the need for dialysis or kidney transplantation in patients with ADPKD, the beneficial effects of good renal blood flow and endothelial function have been noted.^32,33

One of the most common and significant complications in ADPKD is intracranial hemorrhage resulting from a ruptured cerebral aneurysm. In the younger adult, the incidence of cerebral aneurysm is 4%, but incidence increases to 10% in patients older than 65.^34-36 Family clusters of aneurysms have been reported.³⁷ If an intracranial aneurysm is found in the family history, the risk of an aneurysm in another family member increases to 22%.³⁸

Since rupture of an intracranial hemorrhage is associated with a 30-day mortality rate of 50% and 80% morbidity,^5,38 standard of care for patients with ADPKD includes CT or magnetic resonance angiographic (MRA) screening in the asymptomatic patient with a positive family history.^34,38 If an aneurysm is found, the lifetime chance of rupture is 50%, although the risk is greater in the case of an aneurysm larger than 10 mm.⁵

As in all patients with kidney disease, left ventricular hypertrophy is common among patients with ADPKD.^23,28,39

The Case Patient

The patient is started on an ACE inhibitor, scheduled for fasting lipid screening, and referred to a nephrology practice for disease management. As research and investigation of possible treatment options for ADPKD are ongoing, the patient may benefit from participating in a new research protocol.

Because the patient’s family has no history of cerebral aneurysm, CT/MRA screening is not required. A discussion of the pros and cons of genetic testing for the entire family, including nieces and nephews, is initiated. The patient and his family are referred to a genetic counselor to decide whether the benefit of early treatment for hypertension outweighs the risk of carrying a diagnosis of ADPKD for his younger relatives, who may later seek health insurance coverage.

NATURAL PROGRESSION OF ADPKD

Hypertension and cyst formation will continue as the patient ages. The natural progression of ADPKD is to renal failure with renal replacement therapy (dialysis or organ transplantation) as treatment options. If the progression of ­ADPKD can be slowed through pharmacotherapy, the patient may live for many years without needing dialysis. This ideal can be accomplished only through aggressive hypertension control, which should be started in the teenage years.^23,30,31

Suggestions to increase fluid consumption and to limit the use of NSAIDs, contrast dye, and MRI with gadolinium are appropriate. It is rare for hypertension to be diagnosed before some organ damage has already occurred.¹² Often the patient’s renal function, as determined by measuring the GFR, remains stable until the patient reaches his or her 40s.⁴⁰ However, kidney damage often begins before any detectable change in GFR. Once the GFR does start to decline, the average decrease is 4.4 to 5.9 mL/min/1.73m² each year.⁴¹

MANAGEMENT CONSIDERATIONS
For ESRD Organ Transplantation

Kidney transplantation—the only curative treatment for ­ADPKD—can be offered to patients once the GFR falls below 20 mL/min. However, the patient with ADPKD can experience kidney enlargement to such an extent that introducing a third kidney into the limited abdominal space becomes technically difficult. Although nephrectomy is avoided whenever possible, there are cases in which there is no alternative.⁴²

In addition to space concerns, recurrent urinary tract infections, chronic pain, renal cell carcinoma, chronic hematuria, or chronic cyst infections can necessitate a nephrectomy.^43,44 A laparoscopic approach with decompression of cysts or removal of only one kidney is preferred.^43,45 If removal of both kidneys is required before a transplant, the patient must be maintained on dialysis until after transplantation. Since the transplant waiting list can exceed seven years in some areas, most patients arrange for a willing live donor before agreeing to a bilateral nephrectomy.^46,47

Dialysis

Either peritoneal dialysis (PD) or hemodialysis (HD) can be offered to patients with severe ADPKD. Depending on the size of the native kidneys and the history of previous abdominal surgery, PD often offers a better chance of survival in these patients, particularly compared with patients who have ESRD associated with other causes.⁴⁸

For management of the patient with ADPKD who receives PD, it can be difficult to differentiate between the pain of a cyst and the pain of a peritoneal infection. Generally, cyst rupture is accompanied by hematuria; and peritonitis, by cloudy fluid.⁵ Management provided by an experienced nephrologist and PD nurse is vital.

In ADPKD patients who undergo HD, too, survival is better than in patients who have ESRD with other causes^49,50; five-year survival can be as high as 10% to 15%.⁵¹ This is likely due to the lower incidence of coronary artery disease in the ADPKD population, compared with patients who have ESRD associated with other chronic diseases.⁴⁹

FUTURE TRENDS AND ONGOING TRIALS

HALT PKD^29,30 is an NIH-funded, double-blind study to determine whether adding an angiotensin receptor blocker (ARB) to standard ACE inhibitor therapy results in a more significant decrease in the progression of renal cysts. The rationale for this is that the ARB is expected to block the renin-angiotensin-aldosterone system in the kidney. Use of ACE inhibitor monotherapy versus ARB/ACE inhibitor therapy is being compared in two study arms: patients between ages 15 and 49 with a GFR of 60 mL/min or greater; and patients between ages 18 and 64 with a GFR of 25 to 60 mL/min.²⁹ To date, preliminary results indicate no benefit in adding the second medication.⁴⁹

The TEMPO Trial⁵² is a multicenter, double-blind study looking at the effect of tolvaptan on renal cyst growth. Tolvaptan is a potent vasopressin receptor antagonist, and in vitro evidence has shown that intracellular cyclic adenosine monophosphate (cAMP) plays a large role in the development of cysts in patients with ADPKD. If it is possible to block the cAMP that is causing cyst growth, progression of ­ADPKD should slow.^53,54 Only short-term effects of tolvaptan use are currently known.⁵⁵

High Water Intake to Slow Progression of Polycystic Kidney Disease⁵⁶ is an open-label, nonrandomized trial in which patients drink a minimum of
3 L of water. Previously, a small study showed that an increase in fluid intake partially suppresses the urine osmolality and the serum antidiuretic hormone (ADH) levels.⁵⁷ According to this theory, increasing water intake to greater than 3 L/d may result in complete suppression of ADH and cAMP. This is a small study (n = 20),⁵⁶ since patients with ADPKD are likely to have urinary concentrating defects, and hyponatremia is a concern is in these patients.⁵⁸

Sirolimus and ADPKD⁵⁹ is an open-label randomized study to see whether sirolimus (also known as rapamycin) can reduce cyst growth. Originally, it was noted that posttransplant ADPKD patients underwent a regression of both liver and kidney cysts when they were taking sirolimus, and a preliminary crossover study was done.⁶⁰ However, preliminary results at 18 months showed no difference in renal growth or cyst growth but did show kidney damage as determined by an increase of proteinuria in the treatment group.⁵⁹ The study is still in progress.

Somatostatin in Polycystic Kidney⁶¹ is a long-term (three-year) study following patients who agreed to participate in a randomized, double-blind protocol; in it, an intramuscular injection of either an octreotide (ie, somatastatin) or placebo was administered every four weeks for one year in an effort to reduce the size of kidney and liver cysts.⁶² At one year, the quality of life in the treatment group was rated better, as measured by pain reduction and improved physical activity. Cyst growth in the treatment group was smaller for both the kidney and liver. However, the GFR decreased to the same degree in both groups.⁶²

CONCLUSION

ADPKD is a common, often overlooked genetic disease that is a cause of hypertension. ­ADPKD’s presenting symptoms of flank pain, back pain, and/or hematuria often bring the patient to the provider, but a high index of suspicion must be maintained to diagnose these patients at an early age. Due to the variable presentation even within affected families, many patients do not realize that their family carries the PKD gene.

While genetic testing is available, ultrasound is a quick, relatively inexpensive, and easy method to screen for this diagnosis. The progression of ADPKD to ESRD, requiring dialysis or organ transplantation, can be slowed with early and aggressive treatment of hypertension. As with all patients affected by renal impairment, suggestions for ­patients with ADPKD to avoid  use of NSAIDs, contrast dye, and gadolinium-enhanced MRI are appropriate. The primary care PA or NP is in an appropriate position to see to this.  

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13. Davies F, Coles GA, Harper PS, et al. Polycystic kidney disease re-evaluated: a population-based study. Q J Med. 1991;79(290):477-485.

14. Hateboer N, v Dijk MA, Bogdanova N, et al; European PKD1-PKD2 Study Group. Comparison of phenotypes of polycystic kidney disease types 1 and 2. Lancet. 1999;353(9147):103-107.

15. Peters DJ, Breuning MH. Autosomal dominant polycystic kidney disease: modification of disease progression. Lancet. 2001;358(9291):1439-1444.

16. Dicks E, Ravani P, Langman D, et al. Incident renal events and risk factors in autosomal dominant polycystic kidney disease: a population- and family-based cohort followed for 22 years. Clin J Am Soc Nephrol. 2006;1(4):710-717.

17. Fick-Brosnahan GM, Belz MM, McFann KK, etc. Relationship between renal volume growth and renal function in autosomal dominant polycystic kidney disease: a longitudinal study. Am J Kidney Dis. 2002;39(6):1127-1134.

18. Fick-Brosnahan GM, Tran ZV, Johnson AM, et al. Progression of autosomal-dominant polycystic kidney disease in children. Kidney Int. 2001;59(5):1654-1662.

19. Johnson AM, Gabow PA. Identification of patients with autosomal dominant polycystic kidney disease at highest risk for end-stage renal disease. J Am Soc Nephrol. 1997;8(10): 1560-1567.

20. Risk D. Autosomal dominant polycystic kidney disease. Presented at: National Kidney Foundation, Spring Clinical Meetings; April 28, 2011; Las Vegas, NV.

21. Pei Y, Obaji J, Dupuis A, et al. Unified criteria for ultrasonographic diagnosis of ADPKD. J Am Soc Nephrol. 2009;20(1):205-212.

22. Watnick T, Germino GG. Molecular basis of autosomal dominant polycystic kidney disease. Semin Nephrol. 1999;19(4):327-343.

23. Ecder T, Schrier RW. Cardiovascular abnormalities in autosomal-dominant polycystic kidney disease. Nat Rev Nephrol. 2009;5(4):221-228.

24. Patch C, Charlton J, Roderick PJ, Gulliford MC. Use of antihypertensive medications and mortality of patients with autosomal dominant polycystic kidney disease: a population-based study. Am J Kidney Dis. 2011;57(6):856-862.

25. Pirson Y. Extrarenal manifestations of autosomal dominant polycystic kidney disease. Adv Chronic Kidney Dis. 2010;17(2):173-180.

26. Chapman AB, Johnson A, Gabow PA, Schrier RW. The renin-angiotensin-aldosterone system and autosomal dominant polycystic kidney disease. N Engl J Med. 1990;323(16):1091-1096.

27. Jafar TH, Stark PC, Schmid CH, et al. The effect of angiotensin-converting-enzyme inhibitors on progression of advanced polycystic kidney disease. Kidney Int. 2005;67(1):265-271.

28. Schrier RW. Renal volume, renin-angiotensin-aldosterone system, hypertension, and left ventricular hypertrophy in patients with autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2009;20(9):1888-1893.

29. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, sponsor. HALT PKD (Halt Progression of Polycystic Kidney Disease): Efficacy of Aggressive Renin-Angiotensin-Aldosterone Axis Blockade in Preventing/Slowing Renal Function Decline in ADPKD. www2.niddk.nih.gov/NR/rdonlyres/175578F6-62B4-429A-9BBF-96CCEC2FFB3A/0/KUHHALT PKDPROTOCOL9107.pdf. Accessed July 22, 2011.

30. Chapman AB, Torres VE, Perrone RD, et al. The HALT polycystic kidney disease trials: design and implementation. Clin J Am Soc Nephrol. 2010;5(1):102-109.

31. Taylor M, Johnson AM, Tison M, et al. Earlier diagnosis of autosomal dominant polycystic kidney disease: importance of family history and implications for cardiovascular and renal complications. Am J Kidney Dis. 2005;46(3):415-423.

32. Namli S, Oflaz H, Turgut F, et al. Improvement of endothelial dysfunction with simvastatin in patients with autosomal dominant polycystic kidney disease. Ren Fail. 2007;29(1):55-59.

33. Bremmer MS, Jacobs SC. Renal artery embolization for the symptomatic treatment of adult polycystic kidney disease. Nat Clin Pract Nephrol. 2008;4(5):236-237.

34. Chapman AB, Rubinstein D, Hughes R, et al. Intracranial aneurysms in autosomal dominant polycystic kidney disease. N Engl J Med. 1992; 327(13):916-920.

35. Schievink WI, Torres VE, Piepgras DG, Wiebers DO. Saccular intracranial aneurysms in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 1992;3(1):88-95.

36. Fick GM, Gabow PA. Hereditary and acquired cystic disease of the kidney. Kidney Int. 1994;46(4):951-964.

37. Watson ML. Complications of polycystic kidney disease. Kidney Int. 1997;51(1):353-365.

38. Huston J 3rd, Torres VE, Sulivan PP, et al. Value of magnetic resonance angiography for the detection of intracranial aneurysms in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 1993;3(12):1871-1877. 

39. Longenecker JC, Coresh J, Powe NR, et al. Traditional cardiovascular disease risk factors in dialysis patients compared with the general population: the CHOICE Study. J Am Soc Nephrol. 2002;13(7):1918-1927.

40. Meijer E, Rook M, Tent H, et al. Early renal abnormalities in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol. 2010; 5(6):1091-1098.

41. Torres VE, Harris PC. Autosomal dominant polycystic kidney disease: the last 3 years. Kidney Int. 2009;76(2):149-168.

42. Tabibi A, Simforoosh N, Abadpour P, et al. Concomitant nephrectomy of massively enlarged kidneys and renal transplantation in autosomal dominant polycystic kidney disease. Transplant Proc. 2005;37(7):2939-2940.

43. Dunn MD, Portis AJ, Elbahnasy AM, et al. Laparoscopic nephrectomy in patients with end-stage renal disease and autosomal dominant polycystic kidney disease. Am J Kidney Dis. 2000;35(4):720-725.

44. Sulikowski T, Tejchman K, Zietek Z, et al. Experience with autosomal dominant polycystic kidney disease in patients before and after renal transplantation: a 7-year observation. Transplant Proc. 2009;41(1):177-180.

45. Desai MR, Nandkishore SK, Ganpule A, Thimmegowda M. Pretransplant laparoscopic nephrectomy in adult polycystic kidney disease: a single centre experience. BJU Int. 2008;101 (1):94-97.

46. Glassman DT, Nipkow L, Bartlett ST, Jacobs SC. Bilateral nephrectomy with concomitant renal graft transplantation for autosomal dominant polycystic kidney disease. J Urol. 2000;164 (3 pt 1):661-664.

47. Fuller TF, Brennan TV, Feng S, et al. End stage polycystic kidney disease: indications and timing of native nephrectomy relative to kidney transplantation. J Urol. 2005;174(6):2284-2288.

48. Abbott KC, Agodoa LY. Polycystic kidney disease at end-stage renal disease in the United States: patient characteristics and survival. Clin Nephrol. 2002;57(3):208-214.

49. Perrone RD, Ruthazer R, Terrin NC. Survival after end-stage renal disease in autosomal dominant polycystic kidney disease: contribution of extrarenal complications to mortality. Am J Kidney Dis. 2001;38(4):777-784.

50. Batista PB, Lopes AA, Costa FA. Association between attributed cause of end-stage renal disease and risk of death in Brazilian patients receiving renal replacement therapy. Ren Fail. 2005;27(6):651-656.

51. Pirson Y, Christophe JL, Goffin E. Outcome of renal replacement therapy in autosomal dominant polycystic kidney disease. Nephrol Dial Transplant. 1996;11 suppl 6:24-28.

52. Torres VE, Meijer E, Bae KT, et al. Rationale and design of the TEMPO (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes) 3-4 Study. Am J Kidney Dis. 2011;57(5):692-699.

53. Calvet JP. Strategies to inhibit cyst formation in ADPKD. Clin J Am Soc Nephrol. 2008;3 (4):1205-1211.

54. Grantham JJ. Lillian Jean Kaplan International Prize for advancement in the understanding of polycystic kidney disease. Understanding polycystic kidney disease: a systems biology approach. Kidney Int. 2003;64(4):1157-1162.

55. Irazabal MV, Torres VE, Hogan MC, et al. Short-term effects of tolvaptan on renal function and volume in patients with Autosomal Dominant Polycystic Kidney Disease. Kidney Int. 2011 May 4 [Epub ahead of print].

56. New York University, sponsor. High Water Intake to Slow Progression of Polycystic Kidney Disease. http://clinicaltrials.gov/ct2/show/NCT00784030. Accessed July 22, 2011.

57. Wang CJ, Creed C, Winklhofer FT, Grantham JJ. Water prescription in autosomal dominant polycystic kidney disease: a pilot study. Clin J Am Soc Nephrol. 2011;6(1):192-197.

58. Grampsas SA, Chandhoke Ps, Fan J, et al. Anatomic and metabolic risk factors for nephrolithiasis in patients with autosomal dominant polycystic kidney disease. Am J Kidney Dis. 2000;36(1):53-57.

59. Serra AL, Poster D, Kistler AD, et al. Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N Engl J Med. 2010; 363(9):820-829.

60. Perico N, Antiga L, Caroli A, et al. Sirolimus therapy to halt the progression of ADPKD. J Am Soc Nephrol. 2010;21(6):1031-1040.

61. Mario Negri Institute for Pharmacological Research, sponsor. Somatostatin in Polycystic Kidney: a Long-term Three Year Follow up Study. http://clinicaltrials.gov/ct2/show/NCT00309283. Accessed July 22, 2011.

62. Hogan MC, Masyuk TV, Page LJ, et al. Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease. J Am Soc Nephrol. 2010; 21(6):1052-1061. 

Twice as common as autism and half as well-known,¹ autosomal polycystic kidney disease (ADPKD) occurs in one in 400 to one in 1,000 people.² It is an inherited progressive genetic disorder that causes hypertension and decreased renal function and, over time, can lead to kidney failure. Two polycstin genes that code for ADPKD, PKD1 and PKD2, were identified in 1994 and 1996, respectively.^3,4 Awareness and understanding of the genes responsible for ADPKD have increased clinicians’ ability to identify at-risk patients and to slow or alter the course of the ­disease.

Case Presentation

A 45-year-old black man presents to your office with severe, nonradiating back pain and new-onset hypertension. Regarding the pain, he stated, “I turned around to see who kicked me, but no one was there.” When the pain began, he went to see the nurse at the school where he is employed, and she found that his blood pressure was high at 162/90 mm Hg. Although the patient’s back pain is resolving, he is very concerned about his blood pressure, since he has never had a high reading before.

He is the baseball coach and physical education teacher at the local high school and is in excellent physical condition as a result of his professional interaction with teenagers every day. He does not smoke or use any illicit drugs but does admit to occasional alcohol consumption. His medical history is significant only for occasional broken fingers and twisted ankles, all occurring while he was engaged in sports.

His family history includes one brother without medical problems, a brother and a sister with hypertension, a sister with diabetes and obesity, and a brother with a congenital abnormality that required a living donor kidney transplant at age 17 (the father served as donor). No family-wide workup has ever been done because no one practitioner has ever made a connection among these conditions and considered a diagnosis of ADPKD.

The patient’s blood pressure in the office is 172/92 mm Hg while sitting and 166/88 mm Hg while standing. He is somewhat sore with a localized spasm in the lumbar-sacral area but no radiation of pain. The patient has trouble touching his toes but reports that he can never touch his toes. His straight leg lift is negative. The rest of his physical exam is noncontributory.

What should be the next step in this patient’s workup?

PATHOPHYSIOLOGY

ADPKD is a progressive expansion of numerous fluid-filled cysts that result in massive enlargement of the kidneys.⁵ Less than 5% of all nephrons become cystic; however, the average volume of a polycystic kidney is 1,000 mL (normal, 300 mL), that is, the volume of a standard-sized pineapple. Even with this significant enlargement, a decline in the glomerular filtration rate (GFR) is not usually seen initially. Each cyst is derived from a single hyperproliferative epithelial cell. Increased cellular proliferation, followed by fluid secretion and alterations in the extracellular matrix, cause an outpouching from the parent nephron, which eventually detaches from the parent nephron and continues to enlarge and autonomously secrete fluid.^6,7

PKD1 and PKD2 are two genes responsible for ADPKD that have been isolated so far. Since there are families carrying neither the PKD1 nor the PKD2 gene that still have an inherited type of ADPKD, there is suspicion that at least one more PKD gene, not yet isolated, exists.⁸ It is also possible that other genetic or environmental factors may be at play.^9,10

In 1994, the PKD1 gene was isolated on chromosome 16,³ and it was found to code for polycystin 1. A lack of polycystin 1 causes an abnormality in the Na+/K(+)-ATPase pumps, leading to abnormal sodium reabsorption.¹¹ How and why this happens is not quite clear. However, the hypertension that is a key objective finding in patients with ADPKD is thought to result from this pump abnormality.

PKD2 is found on the long arm of chromosome 4 and codes for polycystin 2.⁴ Polycystin 2 is an amino acid that is responsible for voltage-activated cellular calcium channels,⁵ again explaining the hypertension so commonly seen in the course of ADPKD. ADPKD-associated hypertension may be present as early as the teenage years.¹²

EPIDEMIOLOGY

More than 85% of ADPKD cases are associated with PKD1, and this form is called polycystic kidney disease 1 (PKD 1), the more aggressive form of the disease.^13,14 PKD 2 (the form associated with the gene PKD2), though less common, is also likely to progress to end-stage renal disease (ESRD), but at a later age (median age of 74 years, compared with 54 in patients with PKD 1).¹⁴ ADPKD accounts for about 5% of cases of ESRD in North America,⁹ but for most patients, presentation and decreased renal function do not occur until the 40s.¹⁵ However, patients with the risk factors listed in Table 1^5,16-19 are likely to experience a more rapid and aggressive form of the disease.

Even with the same germline mutation in a family with this inherited disease, the severity of ADPKD among family members is quite variable; this is true even in the case of twins.^9,10,20 Since the age and symptoms at presentation can vary so greatly, a uniform method of identifying patients with ADPKD, along with staging, was needed. Most patients do not undergo genetic testing (ie, DNA linkage or gene-based direct sequencing⁹) for a diagnosis of ADPKD or to differentiate between the PKD 1 and PKD 2 disease forms unless they are participating in a research study. Diagnostic criteria were needed that were applicable for any type of ADPKD.

In 2009, the University of Toronto’s Division of Nephrology convened experts in the fields of nephrology and radiology to reach a consensus on standardized ultrasonographic diagnostic criteria.²¹ They formulated definitions based on a study of 948 individuals who were at risk for either PKD 1 or PKD 2 (see Table 2²¹). The specificity and sensitivity of the resulting criteria range from 82% to 100%, making it possible to standardize the care and classification of renal patients worldwide.

Since family members with the same genotypes can experience very divergent disease manifestations, the two-hit hypothesis has been developed.²² In simple terms, it proposes that after the germline mutation (PKD1 or PKD2), there is a second somatic mutation that leads to progressive cyst formation; when the number and size of cysts increase, the patient starts to experience symptoms of ADPKD.²²

Age at presentation can be quite variable, as can the presenting symptoms. Most patients with PKD 1 present in their 50s, with 54 being the average age in US patients.¹⁴ The most common presenting symptom is flank or back pain.^2,5 The pain is due to the massive enlargement of the kidneys, causing a stretching of the kidney capsule and leading to a chronic, dull and persistent pain in the low back. Severe pain, sharp and cutting, occurs when one of the cysts hemorrhages; to some patients, the pain resembles a quick, powerful “kick in the back.” Hematuria can occur following cyst hemorrhage; depending on the location of the cyst that burst within the kidney (ie, how close it is to the collecting system) and how large it is, the amount and color of the hematuria can be impressive.

ADPKD is more common in men than women, and cyst rupture can be precipitated by trauma or lifting heavy objects. Cyst hemorrhage can turn the urine bright red, which is especially frightening to the male patient. Hematuria is often the key presenting symptom in patients who will be diagnosed with ­ADPKD-induced hypertension.

Besides hematuria, other common manifestations of ­ADPKD include:

• Hypertension (60% of affected patients, which increases to 100% by the time ESRD develops)

• Extrarenal cysts (100% of affected patients)

• Urinary tract infections

• Nephrolithiasis (20% of affected patients)

• Proteinuria, occasionally (18% of affected patients).^2,5,23

Among these manifestations, those most commonly attributed to a diagnosis of ADPKD are hypertension, kidney stones, and urinary tract or kidney infections. Since isolated proteinuria is unusual in patients with ­ADPKD, it is recommended that another cause of kidney disease be explored in patients with this presentation.²⁴

Extrarenal manifestations of cyst development are common, eventually occurring in all patients as they age. Hepatic cysts are universal in patients with ADPKD by age 30, although hepatic function is preserved. There may be a mild elevation in the alkaline phosphatase level in patients with ADPKD, resulting from the presence of hepatic cysts. Cysts may also be found in the pancreas, spleen, thyroid, and epididymis.^5,25 Some patients may complain of dyspnea, pain, early satiety, or lower extremity edema as a result of enlarged cyst.

The Case Patient

Because you recently attended a lecture about ADPKD, you are aware that flank pain in men with hypertension is indicative of ADPKD until proven otherwise. Believing that this patient’s hypertension is renal in origin, you order an abdominal ultrasound. You also order a comprehensive metabolic panel and a complete blood count. The patient’s GFR is measured at 89 mL/min (indicative of stage 2 kidney disease). Other results are shown in Table 3.

The very broad differential includes essential hypertension, hypertension resulting from intake of “power drinks” or salt in an athlete, illicit use of medications (including steroids), herniated disc leading to transient hypertension, and urinary tract infection or sexually transmitted disease. All of this is moot when the ultrasound shows both kidneys measuring greater than 15 cm, with four distinct cysts on the right kidney and three distinct cysts on the left.

You explain to the patient that ADPKD is a genetic disease and that he and his siblings each had a certain chance of inheriting it. Although different presentations may occur (“congenital” polycystic kidney disease, hypertension, or obesity), they all must undergo ultrasonographic screening for ADPKD. You add that although ADPKD is a genetic disease, it can also be diagnosed in different members of the same family at different ages.

TREATMENT

The goal of treatment for the patient with ADPKD is to slow cyst development and the natural course of the disease. If this can be achieved, the need for dialysis or kidney transplantation may be postponed for a number of years. Because cyst growth causes an elevation in renin and activates the angiotensin II renin system²⁶ (see figure,²⁴), an ACE inhibitor is the most effective treatment to lower blood pressure and thus slow the progression of ADPKD. Most patients with ADPKD are started on an ACE inhibitor at an early age to slow the rate of disease progression.^27,28 Several studies are under way to determine the best antihypertensive medication and the optimal age for initiating treatment.^29,30

Lipid screening and treatment for dyslipidemia are important²³ because ADPKD can lead to a reduction in kidney function, resulting in chronic kidney disease (CKD). CKD is considered a coronary heart disease risk equivalent, and most professionals will treat the patient with ADPKD for hyperlipidemia.^23,31 While there are no data showing that statin use will reduce the incidence of ESRD or delay the need for dialysis or kidney transplantation in patients with ADPKD, the beneficial effects of good renal blood flow and endothelial function have been noted.^32,33

One of the most common and significant complications in ADPKD is intracranial hemorrhage resulting from a ruptured cerebral aneurysm. In the younger adult, the incidence of cerebral aneurysm is 4%, but incidence increases to 10% in patients older than 65.^34-36 Family clusters of aneurysms have been reported.³⁷ If an intracranial aneurysm is found in the family history, the risk of an aneurysm in another family member increases to 22%.³⁸

Since rupture of an intracranial hemorrhage is associated with a 30-day mortality rate of 50% and 80% morbidity,^5,38 standard of care for patients with ADPKD includes CT or magnetic resonance angiographic (MRA) screening in the asymptomatic patient with a positive family history.^34,38 If an aneurysm is found, the lifetime chance of rupture is 50%, although the risk is greater in the case of an aneurysm larger than 10 mm.⁵

As in all patients with kidney disease, left ventricular hypertrophy is common among patients with ADPKD.^23,28,39

The Case Patient

The patient is started on an ACE inhibitor, scheduled for fasting lipid screening, and referred to a nephrology practice for disease management. As research and investigation of possible treatment options for ADPKD are ongoing, the patient may benefit from participating in a new research protocol.

Because the patient’s family has no history of cerebral aneurysm, CT/MRA screening is not required. A discussion of the pros and cons of genetic testing for the entire family, including nieces and nephews, is initiated. The patient and his family are referred to a genetic counselor to decide whether the benefit of early treatment for hypertension outweighs the risk of carrying a diagnosis of ADPKD for his younger relatives, who may later seek health insurance coverage.

NATURAL PROGRESSION OF ADPKD

Hypertension and cyst formation will continue as the patient ages. The natural progression of ADPKD is to renal failure with renal replacement therapy (dialysis or organ transplantation) as treatment options. If the progression of ­ADPKD can be slowed through pharmacotherapy, the patient may live for many years without needing dialysis. This ideal can be accomplished only through aggressive hypertension control, which should be started in the teenage years.^23,30,31

Suggestions to increase fluid consumption and to limit the use of NSAIDs, contrast dye, and MRI with gadolinium are appropriate. It is rare for hypertension to be diagnosed before some organ damage has already occurred.¹² Often the patient’s renal function, as determined by measuring the GFR, remains stable until the patient reaches his or her 40s.⁴⁰ However, kidney damage often begins before any detectable change in GFR. Once the GFR does start to decline, the average decrease is 4.4 to 5.9 mL/min/1.73m² each year.⁴¹

MANAGEMENT CONSIDERATIONS
For ESRD Organ Transplantation

Kidney transplantation—the only curative treatment for ­ADPKD—can be offered to patients once the GFR falls below 20 mL/min. However, the patient with ADPKD can experience kidney enlargement to such an extent that introducing a third kidney into the limited abdominal space becomes technically difficult. Although nephrectomy is avoided whenever possible, there are cases in which there is no alternative.⁴²

In addition to space concerns, recurrent urinary tract infections, chronic pain, renal cell carcinoma, chronic hematuria, or chronic cyst infections can necessitate a nephrectomy.^43,44 A laparoscopic approach with decompression of cysts or removal of only one kidney is preferred.^43,45 If removal of both kidneys is required before a transplant, the patient must be maintained on dialysis until after transplantation. Since the transplant waiting list can exceed seven years in some areas, most patients arrange for a willing live donor before agreeing to a bilateral nephrectomy.^46,47

Dialysis

Either peritoneal dialysis (PD) or hemodialysis (HD) can be offered to patients with severe ADPKD. Depending on the size of the native kidneys and the history of previous abdominal surgery, PD often offers a better chance of survival in these patients, particularly compared with patients who have ESRD associated with other causes.⁴⁸

For management of the patient with ADPKD who receives PD, it can be difficult to differentiate between the pain of a cyst and the pain of a peritoneal infection. Generally, cyst rupture is accompanied by hematuria; and peritonitis, by cloudy fluid.⁵ Management provided by an experienced nephrologist and PD nurse is vital.

In ADPKD patients who undergo HD, too, survival is better than in patients who have ESRD with other causes^49,50; five-year survival can be as high as 10% to 15%.⁵¹ This is likely due to the lower incidence of coronary artery disease in the ADPKD population, compared with patients who have ESRD associated with other chronic diseases.⁴⁹

FUTURE TRENDS AND ONGOING TRIALS

HALT PKD^29,30 is an NIH-funded, double-blind study to determine whether adding an angiotensin receptor blocker (ARB) to standard ACE inhibitor therapy results in a more significant decrease in the progression of renal cysts. The rationale for this is that the ARB is expected to block the renin-angiotensin-aldosterone system in the kidney. Use of ACE inhibitor monotherapy versus ARB/ACE inhibitor therapy is being compared in two study arms: patients between ages 15 and 49 with a GFR of 60 mL/min or greater; and patients between ages 18 and 64 with a GFR of 25 to 60 mL/min.²⁹ To date, preliminary results indicate no benefit in adding the second medication.⁴⁹

The TEMPO Trial⁵² is a multicenter, double-blind study looking at the effect of tolvaptan on renal cyst growth. Tolvaptan is a potent vasopressin receptor antagonist, and in vitro evidence has shown that intracellular cyclic adenosine monophosphate (cAMP) plays a large role in the development of cysts in patients with ADPKD. If it is possible to block the cAMP that is causing cyst growth, progression of ­ADPKD should slow.^53,54 Only short-term effects of tolvaptan use are currently known.⁵⁵

High Water Intake to Slow Progression of Polycystic Kidney Disease⁵⁶ is an open-label, nonrandomized trial in which patients drink a minimum of
3 L of water. Previously, a small study showed that an increase in fluid intake partially suppresses the urine osmolality and the serum antidiuretic hormone (ADH) levels.⁵⁷ According to this theory, increasing water intake to greater than 3 L/d may result in complete suppression of ADH and cAMP. This is a small study (n = 20),⁵⁶ since patients with ADPKD are likely to have urinary concentrating defects, and hyponatremia is a concern is in these patients.⁵⁸

Sirolimus and ADPKD⁵⁹ is an open-label randomized study to see whether sirolimus (also known as rapamycin) can reduce cyst growth. Originally, it was noted that posttransplant ADPKD patients underwent a regression of both liver and kidney cysts when they were taking sirolimus, and a preliminary crossover study was done.⁶⁰ However, preliminary results at 18 months showed no difference in renal growth or cyst growth but did show kidney damage as determined by an increase of proteinuria in the treatment group.⁵⁹ The study is still in progress.

Somatostatin in Polycystic Kidney⁶¹ is a long-term (three-year) study following patients who agreed to participate in a randomized, double-blind protocol; in it, an intramuscular injection of either an octreotide (ie, somatastatin) or placebo was administered every four weeks for one year in an effort to reduce the size of kidney and liver cysts.⁶² At one year, the quality of life in the treatment group was rated better, as measured by pain reduction and improved physical activity. Cyst growth in the treatment group was smaller for both the kidney and liver. However, the GFR decreased to the same degree in both groups.⁶²

CONCLUSION

ADPKD is a common, often overlooked genetic disease that is a cause of hypertension. ­ADPKD’s presenting symptoms of flank pain, back pain, and/or hematuria often bring the patient to the provider, but a high index of suspicion must be maintained to diagnose these patients at an early age. Due to the variable presentation even within affected families, many patients do not realize that their family carries the PKD gene.

While genetic testing is available, ultrasound is a quick, relatively inexpensive, and easy method to screen for this diagnosis. The progression of ADPKD to ESRD, requiring dialysis or organ transplantation, can be slowed with early and aggressive treatment of hypertension. As with all patients affected by renal impairment, suggestions for ­patients with ADPKD to avoid  use of NSAIDs, contrast dye, and gadolinium-enhanced MRI are appropriate. The primary care PA or NP is in an appropriate position to see to this.  

REFERENCES

1. Newschaffer CJ, Falb MD, Gurney JG. National autism prevalence trends from United States special education data. Pediatrics. 2005;115 (3):e277-e282.

2. Torres VE, Harris PC, Pirson Y. Autosomal dominant polycystic kidney disease. Lancet. 2007;369(9569):1287-1301.

3. The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16: European Polycystic Kidney Disease Consortium. Cell. 1994;77(6):881-894.

4. Mochizuki T, Wu G, Hayashi T, et al. PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science. 1996; 272(5266):1339-1342.

5. Chapman AB. Polycystic and other cystic kidney diseases. In: Greenberg A, ed. Primer on Kidney Diseases: Expert Consult. 5th ed. National Kidney Foundation; 2009:345-353.

6. Fischer E, Legue E, Doyen A, et al. Defective planar cell polarity in polycystic kidney disease. Nat Genet. 2006;38(1):21-23.

7. Murcia NS, Sweeney WE Jr, Avner ED. New insights into the molecular pathophysiology of polycystic kidney disease. Kidney Int. 1999;55 (4):1187-1197.

8. Paterson AD, Pei Y. Is there a third gene for autosomal dominant polycystic kidney disease? Kidney Int. 1998;54(5):1759-1761.

9. Pei Y. Practical genetics for autosomal dominant polycystic kidney disease. Nephron Clin Pract. 2011;118(1):c19-c30.

10. Tan YC, Blumenfeld J, Rennert H. Autosomal dominant polycystic kidney disease: genetics, mutations and microRNAs.
Biochim Biophys Acta. 2011 Mar 16 [Epub ahead of print].

11. Avner ED, Sweeney WE Jr, Nelson WJ. Abnormal sodium pump distribution during renal tubulogenesis in congenital murine polycystic kidney disease. Proc Natl Acad Sci U S A. 1992;89(16):7447-7451.

12. Torra R, Badenas C, Darnell A, et al. Linkage, clinical features, and prognosis of autosomal dominant polycystic kidney disease types 1 and 2. J Am Soc Nephrol. 1996;7(10):2142-2151.

13. Davies F, Coles GA, Harper PS, et al. Polycystic kidney disease re-evaluated: a population-based study. Q J Med. 1991;79(290):477-485.

14. Hateboer N, v Dijk MA, Bogdanova N, et al; European PKD1-PKD2 Study Group. Comparison of phenotypes of polycystic kidney disease types 1 and 2. Lancet. 1999;353(9147):103-107.

15. Peters DJ, Breuning MH. Autosomal dominant polycystic kidney disease: modification of disease progression. Lancet. 2001;358(9291):1439-1444.

16. Dicks E, Ravani P, Langman D, et al. Incident renal events and risk factors in autosomal dominant polycystic kidney disease: a population- and family-based cohort followed for 22 years. Clin J Am Soc Nephrol. 2006;1(4):710-717.

17. Fick-Brosnahan GM, Belz MM, McFann KK, etc. Relationship between renal volume growth and renal function in autosomal dominant polycystic kidney disease: a longitudinal study. Am J Kidney Dis. 2002;39(6):1127-1134.

18. Fick-Brosnahan GM, Tran ZV, Johnson AM, et al. Progression of autosomal-dominant polycystic kidney disease in children. Kidney Int. 2001;59(5):1654-1662.

19. Johnson AM, Gabow PA. Identification of patients with autosomal dominant polycystic kidney disease at highest risk for end-stage renal disease. J Am Soc Nephrol. 1997;8(10): 1560-1567.

20. Risk D. Autosomal dominant polycystic kidney disease. Presented at: National Kidney Foundation, Spring Clinical Meetings; April 28, 2011; Las Vegas, NV.

21. Pei Y, Obaji J, Dupuis A, et al. Unified criteria for ultrasonographic diagnosis of ADPKD. J Am Soc Nephrol. 2009;20(1):205-212.

22. Watnick T, Germino GG. Molecular basis of autosomal dominant polycystic kidney disease. Semin Nephrol. 1999;19(4):327-343.

23. Ecder T, Schrier RW. Cardiovascular abnormalities in autosomal-dominant polycystic kidney disease. Nat Rev Nephrol. 2009;5(4):221-228.

24. Patch C, Charlton J, Roderick PJ, Gulliford MC. Use of antihypertensive medications and mortality of patients with autosomal dominant polycystic kidney disease: a population-based study. Am J Kidney Dis. 2011;57(6):856-862.

25. Pirson Y. Extrarenal manifestations of autosomal dominant polycystic kidney disease. Adv Chronic Kidney Dis. 2010;17(2):173-180.

26. Chapman AB, Johnson A, Gabow PA, Schrier RW. The renin-angiotensin-aldosterone system and autosomal dominant polycystic kidney disease. N Engl J Med. 1990;323(16):1091-1096.

27. Jafar TH, Stark PC, Schmid CH, et al. The effect of angiotensin-converting-enzyme inhibitors on progression of advanced polycystic kidney disease. Kidney Int. 2005;67(1):265-271.

28. Schrier RW. Renal volume, renin-angiotensin-aldosterone system, hypertension, and left ventricular hypertrophy in patients with autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2009;20(9):1888-1893.

29. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, sponsor. HALT PKD (Halt Progression of Polycystic Kidney Disease): Efficacy of Aggressive Renin-Angiotensin-Aldosterone Axis Blockade in Preventing/Slowing Renal Function Decline in ADPKD. www2.niddk.nih.gov/NR/rdonlyres/175578F6-62B4-429A-9BBF-96CCEC2FFB3A/0/KUHHALT PKDPROTOCOL9107.pdf. Accessed July 22, 2011.

30. Chapman AB, Torres VE, Perrone RD, et al. The HALT polycystic kidney disease trials: design and implementation. Clin J Am Soc Nephrol. 2010;5(1):102-109.

31. Taylor M, Johnson AM, Tison M, et al. Earlier diagnosis of autosomal dominant polycystic kidney disease: importance of family history and implications for cardiovascular and renal complications. Am J Kidney Dis. 2005;46(3):415-423.

32. Namli S, Oflaz H, Turgut F, et al. Improvement of endothelial dysfunction with simvastatin in patients with autosomal dominant polycystic kidney disease. Ren Fail. 2007;29(1):55-59.

33. Bremmer MS, Jacobs SC. Renal artery embolization for the symptomatic treatment of adult polycystic kidney disease. Nat Clin Pract Nephrol. 2008;4(5):236-237.

34. Chapman AB, Rubinstein D, Hughes R, et al. Intracranial aneurysms in autosomal dominant polycystic kidney disease. N Engl J Med. 1992; 327(13):916-920.

35. Schievink WI, Torres VE, Piepgras DG, Wiebers DO. Saccular intracranial aneurysms in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 1992;3(1):88-95.

36. Fick GM, Gabow PA. Hereditary and acquired cystic disease of the kidney. Kidney Int. 1994;46(4):951-964.

37. Watson ML. Complications of polycystic kidney disease. Kidney Int. 1997;51(1):353-365.

38. Huston J 3rd, Torres VE, Sulivan PP, et al. Value of magnetic resonance angiography for the detection of intracranial aneurysms in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 1993;3(12):1871-1877. 

39. Longenecker JC, Coresh J, Powe NR, et al. Traditional cardiovascular disease risk factors in dialysis patients compared with the general population: the CHOICE Study. J Am Soc Nephrol. 2002;13(7):1918-1927.

40. Meijer E, Rook M, Tent H, et al. Early renal abnormalities in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol. 2010; 5(6):1091-1098.

41. Torres VE, Harris PC. Autosomal dominant polycystic kidney disease: the last 3 years. Kidney Int. 2009;76(2):149-168.

42. Tabibi A, Simforoosh N, Abadpour P, et al. Concomitant nephrectomy of massively enlarged kidneys and renal transplantation in autosomal dominant polycystic kidney disease. Transplant Proc. 2005;37(7):2939-2940.

43. Dunn MD, Portis AJ, Elbahnasy AM, et al. Laparoscopic nephrectomy in patients with end-stage renal disease and autosomal dominant polycystic kidney disease. Am J Kidney Dis. 2000;35(4):720-725.

44. Sulikowski T, Tejchman K, Zietek Z, et al. Experience with autosomal dominant polycystic kidney disease in patients before and after renal transplantation: a 7-year observation. Transplant Proc. 2009;41(1):177-180.

45. Desai MR, Nandkishore SK, Ganpule A, Thimmegowda M. Pretransplant laparoscopic nephrectomy in adult polycystic kidney disease: a single centre experience. BJU Int. 2008;101 (1):94-97.

46. Glassman DT, Nipkow L, Bartlett ST, Jacobs SC. Bilateral nephrectomy with concomitant renal graft transplantation for autosomal dominant polycystic kidney disease. J Urol. 2000;164 (3 pt 1):661-664.

47. Fuller TF, Brennan TV, Feng S, et al. End stage polycystic kidney disease: indications and timing of native nephrectomy relative to kidney transplantation. J Urol. 2005;174(6):2284-2288.

48. Abbott KC, Agodoa LY. Polycystic kidney disease at end-stage renal disease in the United States: patient characteristics and survival. Clin Nephrol. 2002;57(3):208-214.

49. Perrone RD, Ruthazer R, Terrin NC. Survival after end-stage renal disease in autosomal dominant polycystic kidney disease: contribution of extrarenal complications to mortality. Am J Kidney Dis. 2001;38(4):777-784.

50. Batista PB, Lopes AA, Costa FA. Association between attributed cause of end-stage renal disease and risk of death in Brazilian patients receiving renal replacement therapy. Ren Fail. 2005;27(6):651-656.

51. Pirson Y, Christophe JL, Goffin E. Outcome of renal replacement therapy in autosomal dominant polycystic kidney disease. Nephrol Dial Transplant. 1996;11 suppl 6:24-28.

52. Torres VE, Meijer E, Bae KT, et al. Rationale and design of the TEMPO (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes) 3-4 Study. Am J Kidney Dis. 2011;57(5):692-699.

53. Calvet JP. Strategies to inhibit cyst formation in ADPKD. Clin J Am Soc Nephrol. 2008;3 (4):1205-1211.

54. Grantham JJ. Lillian Jean Kaplan International Prize for advancement in the understanding of polycystic kidney disease. Understanding polycystic kidney disease: a systems biology approach. Kidney Int. 2003;64(4):1157-1162.

55. Irazabal MV, Torres VE, Hogan MC, et al. Short-term effects of tolvaptan on renal function and volume in patients with Autosomal Dominant Polycystic Kidney Disease. Kidney Int. 2011 May 4 [Epub ahead of print].

56. New York University, sponsor. High Water Intake to Slow Progression of Polycystic Kidney Disease. http://clinicaltrials.gov/ct2/show/NCT00784030. Accessed July 22, 2011.

57. Wang CJ, Creed C, Winklhofer FT, Grantham JJ. Water prescription in autosomal dominant polycystic kidney disease: a pilot study. Clin J Am Soc Nephrol. 2011;6(1):192-197.

58. Grampsas SA, Chandhoke Ps, Fan J, et al. Anatomic and metabolic risk factors for nephrolithiasis in patients with autosomal dominant polycystic kidney disease. Am J Kidney Dis. 2000;36(1):53-57.

59. Serra AL, Poster D, Kistler AD, et al. Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N Engl J Med. 2010; 363(9):820-829.

60. Perico N, Antiga L, Caroli A, et al. Sirolimus therapy to halt the progression of ADPKD. J Am Soc Nephrol. 2010;21(6):1031-1040.

61. Mario Negri Institute for Pharmacological Research, sponsor. Somatostatin in Polycystic Kidney: a Long-term Three Year Follow up Study. http://clinicaltrials.gov/ct2/show/NCT00309283. Accessed July 22, 2011.

62. Hogan MC, Masyuk TV, Page LJ, et al. Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease. J Am Soc Nephrol. 2010; 21(6):1052-1061. 

Twice as common as autism and half as well-known,¹ autosomal polycystic kidney disease (ADPKD) occurs in one in 400 to one in 1,000 people.² It is an inherited progressive genetic disorder that causes hypertension and decreased renal function and, over time, can lead to kidney failure. Two polycstin genes that code for ADPKD, PKD1 and PKD2, were identified in 1994 and 1996, respectively.^3,4 Awareness and understanding of the genes responsible for ADPKD have increased clinicians’ ability to identify at-risk patients and to slow or alter the course of the ­disease.

Case Presentation

A 45-year-old black man presents to your office with severe, nonradiating back pain and new-onset hypertension. Regarding the pain, he stated, “I turned around to see who kicked me, but no one was there.” When the pain began, he went to see the nurse at the school where he is employed, and she found that his blood pressure was high at 162/90 mm Hg. Although the patient’s back pain is resolving, he is very concerned about his blood pressure, since he has never had a high reading before.

He is the baseball coach and physical education teacher at the local high school and is in excellent physical condition as a result of his professional interaction with teenagers every day. He does not smoke or use any illicit drugs but does admit to occasional alcohol consumption. His medical history is significant only for occasional broken fingers and twisted ankles, all occurring while he was engaged in sports.

His family history includes one brother without medical problems, a brother and a sister with hypertension, a sister with diabetes and obesity, and a brother with a congenital abnormality that required a living donor kidney transplant at age 17 (the father served as donor). No family-wide workup has ever been done because no one practitioner has ever made a connection among these conditions and considered a diagnosis of ADPKD.

The patient’s blood pressure in the office is 172/92 mm Hg while sitting and 166/88 mm Hg while standing. He is somewhat sore with a localized spasm in the lumbar-sacral area but no radiation of pain. The patient has trouble touching his toes but reports that he can never touch his toes. His straight leg lift is negative. The rest of his physical exam is noncontributory.

What should be the next step in this patient’s workup?

PATHOPHYSIOLOGY

ADPKD is a progressive expansion of numerous fluid-filled cysts that result in massive enlargement of the kidneys.⁵ Less than 5% of all nephrons become cystic; however, the average volume of a polycystic kidney is 1,000 mL (normal, 300 mL), that is, the volume of a standard-sized pineapple. Even with this significant enlargement, a decline in the glomerular filtration rate (GFR) is not usually seen initially. Each cyst is derived from a single hyperproliferative epithelial cell. Increased cellular proliferation, followed by fluid secretion and alterations in the extracellular matrix, cause an outpouching from the parent nephron, which eventually detaches from the parent nephron and continues to enlarge and autonomously secrete fluid.^6,7

PKD1 and PKD2 are two genes responsible for ADPKD that have been isolated so far. Since there are families carrying neither the PKD1 nor the PKD2 gene that still have an inherited type of ADPKD, there is suspicion that at least one more PKD gene, not yet isolated, exists.⁸ It is also possible that other genetic or environmental factors may be at play.^9,10

In 1994, the PKD1 gene was isolated on chromosome 16,³ and it was found to code for polycystin 1. A lack of polycystin 1 causes an abnormality in the Na+/K(+)-ATPase pumps, leading to abnormal sodium reabsorption.¹¹ How and why this happens is not quite clear. However, the hypertension that is a key objective finding in patients with ADPKD is thought to result from this pump abnormality.

PKD2 is found on the long arm of chromosome 4 and codes for polycystin 2.⁴ Polycystin 2 is an amino acid that is responsible for voltage-activated cellular calcium channels,⁵ again explaining the hypertension so commonly seen in the course of ADPKD. ADPKD-associated hypertension may be present as early as the teenage years.¹²

EPIDEMIOLOGY

More than 85% of ADPKD cases are associated with PKD1, and this form is called polycystic kidney disease 1 (PKD 1), the more aggressive form of the disease.^13,14 PKD 2 (the form associated with the gene PKD2), though less common, is also likely to progress to end-stage renal disease (ESRD), but at a later age (median age of 74 years, compared with 54 in patients with PKD 1).¹⁴ ADPKD accounts for about 5% of cases of ESRD in North America,⁹ but for most patients, presentation and decreased renal function do not occur until the 40s.¹⁵ However, patients with the risk factors listed in Table 1^5,16-19 are likely to experience a more rapid and aggressive form of the disease.

Even with the same germline mutation in a family with this inherited disease, the severity of ADPKD among family members is quite variable; this is true even in the case of twins.^9,10,20 Since the age and symptoms at presentation can vary so greatly, a uniform method of identifying patients with ADPKD, along with staging, was needed. Most patients do not undergo genetic testing (ie, DNA linkage or gene-based direct sequencing⁹) for a diagnosis of ADPKD or to differentiate between the PKD 1 and PKD 2 disease forms unless they are participating in a research study. Diagnostic criteria were needed that were applicable for any type of ADPKD.

In 2009, the University of Toronto’s Division of Nephrology convened experts in the fields of nephrology and radiology to reach a consensus on standardized ultrasonographic diagnostic criteria.²¹ They formulated definitions based on a study of 948 individuals who were at risk for either PKD 1 or PKD 2 (see Table 2²¹). The specificity and sensitivity of the resulting criteria range from 82% to 100%, making it possible to standardize the care and classification of renal patients worldwide.

Since family members with the same genotypes can experience very divergent disease manifestations, the two-hit hypothesis has been developed.²² In simple terms, it proposes that after the germline mutation (PKD1 or PKD2), there is a second somatic mutation that leads to progressive cyst formation; when the number and size of cysts increase, the patient starts to experience symptoms of ADPKD.²²

Age at presentation can be quite variable, as can the presenting symptoms. Most patients with PKD 1 present in their 50s, with 54 being the average age in US patients.¹⁴ The most common presenting symptom is flank or back pain.^2,5 The pain is due to the massive enlargement of the kidneys, causing a stretching of the kidney capsule and leading to a chronic, dull and persistent pain in the low back. Severe pain, sharp and cutting, occurs when one of the cysts hemorrhages; to some patients, the pain resembles a quick, powerful “kick in the back.” Hematuria can occur following cyst hemorrhage; depending on the location of the cyst that burst within the kidney (ie, how close it is to the collecting system) and how large it is, the amount and color of the hematuria can be impressive.

ADPKD is more common in men than women, and cyst rupture can be precipitated by trauma or lifting heavy objects. Cyst hemorrhage can turn the urine bright red, which is especially frightening to the male patient. Hematuria is often the key presenting symptom in patients who will be diagnosed with ­ADPKD-induced hypertension.

Besides hematuria, other common manifestations of ­ADPKD include:

• Hypertension (60% of affected patients, which increases to 100% by the time ESRD develops)

• Extrarenal cysts (100% of affected patients)

• Urinary tract infections

• Nephrolithiasis (20% of affected patients)

• Proteinuria, occasionally (18% of affected patients).^2,5,23

Among these manifestations, those most commonly attributed to a diagnosis of ADPKD are hypertension, kidney stones, and urinary tract or kidney infections. Since isolated proteinuria is unusual in patients with ­ADPKD, it is recommended that another cause of kidney disease be explored in patients with this presentation.²⁴

Extrarenal manifestations of cyst development are common, eventually occurring in all patients as they age. Hepatic cysts are universal in patients with ADPKD by age 30, although hepatic function is preserved. There may be a mild elevation in the alkaline phosphatase level in patients with ADPKD, resulting from the presence of hepatic cysts. Cysts may also be found in the pancreas, spleen, thyroid, and epididymis.^5,25 Some patients may complain of dyspnea, pain, early satiety, or lower extremity edema as a result of enlarged cyst.

The Case Patient

Because you recently attended a lecture about ADPKD, you are aware that flank pain in men with hypertension is indicative of ADPKD until proven otherwise. Believing that this patient’s hypertension is renal in origin, you order an abdominal ultrasound. You also order a comprehensive metabolic panel and a complete blood count. The patient’s GFR is measured at 89 mL/min (indicative of stage 2 kidney disease). Other results are shown in Table 3.

The very broad differential includes essential hypertension, hypertension resulting from intake of “power drinks” or salt in an athlete, illicit use of medications (including steroids), herniated disc leading to transient hypertension, and urinary tract infection or sexually transmitted disease. All of this is moot when the ultrasound shows both kidneys measuring greater than 15 cm, with four distinct cysts on the right kidney and three distinct cysts on the left.

You explain to the patient that ADPKD is a genetic disease and that he and his siblings each had a certain chance of inheriting it. Although different presentations may occur (“congenital” polycystic kidney disease, hypertension, or obesity), they all must undergo ultrasonographic screening for ADPKD. You add that although ADPKD is a genetic disease, it can also be diagnosed in different members of the same family at different ages.

TREATMENT

The goal of treatment for the patient with ADPKD is to slow cyst development and the natural course of the disease. If this can be achieved, the need for dialysis or kidney transplantation may be postponed for a number of years. Because cyst growth causes an elevation in renin and activates the angiotensin II renin system²⁶ (see figure,²⁴), an ACE inhibitor is the most effective treatment to lower blood pressure and thus slow the progression of ADPKD. Most patients with ADPKD are started on an ACE inhibitor at an early age to slow the rate of disease progression.^27,28 Several studies are under way to determine the best antihypertensive medication and the optimal age for initiating treatment.^29,30

Lipid screening and treatment for dyslipidemia are important²³ because ADPKD can lead to a reduction in kidney function, resulting in chronic kidney disease (CKD). CKD is considered a coronary heart disease risk equivalent, and most professionals will treat the patient with ADPKD for hyperlipidemia.^23,31 While there are no data showing that statin use will reduce the incidence of ESRD or delay the need for dialysis or kidney transplantation in patients with ADPKD, the beneficial effects of good renal blood flow and endothelial function have been noted.^32,33

One of the most common and significant complications in ADPKD is intracranial hemorrhage resulting from a ruptured cerebral aneurysm. In the younger adult, the incidence of cerebral aneurysm is 4%, but incidence increases to 10% in patients older than 65.^34-36 Family clusters of aneurysms have been reported.³⁷ If an intracranial aneurysm is found in the family history, the risk of an aneurysm in another family member increases to 22%.³⁸

Since rupture of an intracranial hemorrhage is associated with a 30-day mortality rate of 50% and 80% morbidity,^5,38 standard of care for patients with ADPKD includes CT or magnetic resonance angiographic (MRA) screening in the asymptomatic patient with a positive family history.^34,38 If an aneurysm is found, the lifetime chance of rupture is 50%, although the risk is greater in the case of an aneurysm larger than 10 mm.⁵

As in all patients with kidney disease, left ventricular hypertrophy is common among patients with ADPKD.^23,28,39

The Case Patient

The patient is started on an ACE inhibitor, scheduled for fasting lipid screening, and referred to a nephrology practice for disease management. As research and investigation of possible treatment options for ADPKD are ongoing, the patient may benefit from participating in a new research protocol.

Because the patient’s family has no history of cerebral aneurysm, CT/MRA screening is not required. A discussion of the pros and cons of genetic testing for the entire family, including nieces and nephews, is initiated. The patient and his family are referred to a genetic counselor to decide whether the benefit of early treatment for hypertension outweighs the risk of carrying a diagnosis of ADPKD for his younger relatives, who may later seek health insurance coverage.

NATURAL PROGRESSION OF ADPKD

Hypertension and cyst formation will continue as the patient ages. The natural progression of ADPKD is to renal failure with renal replacement therapy (dialysis or organ transplantation) as treatment options. If the progression of ­ADPKD can be slowed through pharmacotherapy, the patient may live for many years without needing dialysis. This ideal can be accomplished only through aggressive hypertension control, which should be started in the teenage years.^23,30,31

Suggestions to increase fluid consumption and to limit the use of NSAIDs, contrast dye, and MRI with gadolinium are appropriate. It is rare for hypertension to be diagnosed before some organ damage has already occurred.¹² Often the patient’s renal function, as determined by measuring the GFR, remains stable until the patient reaches his or her 40s.⁴⁰ However, kidney damage often begins before any detectable change in GFR. Once the GFR does start to decline, the average decrease is 4.4 to 5.9 mL/min/1.73m² each year.⁴¹

MANAGEMENT CONSIDERATIONS
For ESRD Organ Transplantation

Kidney transplantation—the only curative treatment for ­ADPKD—can be offered to patients once the GFR falls below 20 mL/min. However, the patient with ADPKD can experience kidney enlargement to such an extent that introducing a third kidney into the limited abdominal space becomes technically difficult. Although nephrectomy is avoided whenever possible, there are cases in which there is no alternative.⁴²

In addition to space concerns, recurrent urinary tract infections, chronic pain, renal cell carcinoma, chronic hematuria, or chronic cyst infections can necessitate a nephrectomy.^43,44 A laparoscopic approach with decompression of cysts or removal of only one kidney is preferred.^43,45 If removal of both kidneys is required before a transplant, the patient must be maintained on dialysis until after transplantation. Since the transplant waiting list can exceed seven years in some areas, most patients arrange for a willing live donor before agreeing to a bilateral nephrectomy.^46,47

Dialysis

Either peritoneal dialysis (PD) or hemodialysis (HD) can be offered to patients with severe ADPKD. Depending on the size of the native kidneys and the history of previous abdominal surgery, PD often offers a better chance of survival in these patients, particularly compared with patients who have ESRD associated with other causes.⁴⁸

For management of the patient with ADPKD who receives PD, it can be difficult to differentiate between the pain of a cyst and the pain of a peritoneal infection. Generally, cyst rupture is accompanied by hematuria; and peritonitis, by cloudy fluid.⁵ Management provided by an experienced nephrologist and PD nurse is vital.

In ADPKD patients who undergo HD, too, survival is better than in patients who have ESRD with other causes^49,50; five-year survival can be as high as 10% to 15%.⁵¹ This is likely due to the lower incidence of coronary artery disease in the ADPKD population, compared with patients who have ESRD associated with other chronic diseases.⁴⁹

FUTURE TRENDS AND ONGOING TRIALS

HALT PKD^29,30 is an NIH-funded, double-blind study to determine whether adding an angiotensin receptor blocker (ARB) to standard ACE inhibitor therapy results in a more significant decrease in the progression of renal cysts. The rationale for this is that the ARB is expected to block the renin-angiotensin-aldosterone system in the kidney. Use of ACE inhibitor monotherapy versus ARB/ACE inhibitor therapy is being compared in two study arms: patients between ages 15 and 49 with a GFR of 60 mL/min or greater; and patients between ages 18 and 64 with a GFR of 25 to 60 mL/min.²⁹ To date, preliminary results indicate no benefit in adding the second medication.⁴⁹

The TEMPO Trial⁵² is a multicenter, double-blind study looking at the effect of tolvaptan on renal cyst growth. Tolvaptan is a potent vasopressin receptor antagonist, and in vitro evidence has shown that intracellular cyclic adenosine monophosphate (cAMP) plays a large role in the development of cysts in patients with ADPKD. If it is possible to block the cAMP that is causing cyst growth, progression of ­ADPKD should slow.^53,54 Only short-term effects of tolvaptan use are currently known.⁵⁵

High Water Intake to Slow Progression of Polycystic Kidney Disease⁵⁶ is an open-label, nonrandomized trial in which patients drink a minimum of
3 L of water. Previously, a small study showed that an increase in fluid intake partially suppresses the urine osmolality and the serum antidiuretic hormone (ADH) levels.⁵⁷ According to this theory, increasing water intake to greater than 3 L/d may result in complete suppression of ADH and cAMP. This is a small study (n = 20),⁵⁶ since patients with ADPKD are likely to have urinary concentrating defects, and hyponatremia is a concern is in these patients.⁵⁸

Sirolimus and ADPKD⁵⁹ is an open-label randomized study to see whether sirolimus (also known as rapamycin) can reduce cyst growth. Originally, it was noted that posttransplant ADPKD patients underwent a regression of both liver and kidney cysts when they were taking sirolimus, and a preliminary crossover study was done.⁶⁰ However, preliminary results at 18 months showed no difference in renal growth or cyst growth but did show kidney damage as determined by an increase of proteinuria in the treatment group.⁵⁹ The study is still in progress.

Somatostatin in Polycystic Kidney⁶¹ is a long-term (three-year) study following patients who agreed to participate in a randomized, double-blind protocol; in it, an intramuscular injection of either an octreotide (ie, somatastatin) or placebo was administered every four weeks for one year in an effort to reduce the size of kidney and liver cysts.⁶² At one year, the quality of life in the treatment group was rated better, as measured by pain reduction and improved physical activity. Cyst growth in the treatment group was smaller for both the kidney and liver. However, the GFR decreased to the same degree in both groups.⁶²

CONCLUSION

ADPKD is a common, often overlooked genetic disease that is a cause of hypertension. ­ADPKD’s presenting symptoms of flank pain, back pain, and/or hematuria often bring the patient to the provider, but a high index of suspicion must be maintained to diagnose these patients at an early age. Due to the variable presentation even within affected families, many patients do not realize that their family carries the PKD gene.

While genetic testing is available, ultrasound is a quick, relatively inexpensive, and easy method to screen for this diagnosis. The progression of ADPKD to ESRD, requiring dialysis or organ transplantation, can be slowed with early and aggressive treatment of hypertension. As with all patients affected by renal impairment, suggestions for ­patients with ADPKD to avoid  use of NSAIDs, contrast dye, and gadolinium-enhanced MRI are appropriate. The primary care PA or NP is in an appropriate position to see to this.  

REFERENCES

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2. Torres VE, Harris PC, Pirson Y. Autosomal dominant polycystic kidney disease. Lancet. 2007;369(9569):1287-1301.

3. The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16: European Polycystic Kidney Disease Consortium. Cell. 1994;77(6):881-894.

4. Mochizuki T, Wu G, Hayashi T, et al. PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science. 1996; 272(5266):1339-1342.

5. Chapman AB. Polycystic and other cystic kidney diseases. In: Greenberg A, ed. Primer on Kidney Diseases: Expert Consult. 5th ed. National Kidney Foundation; 2009:345-353.

6. Fischer E, Legue E, Doyen A, et al. Defective planar cell polarity in polycystic kidney disease. Nat Genet. 2006;38(1):21-23.

7. Murcia NS, Sweeney WE Jr, Avner ED. New insights into the molecular pathophysiology of polycystic kidney disease. Kidney Int. 1999;55 (4):1187-1197.

8. Paterson AD, Pei Y. Is there a third gene for autosomal dominant polycystic kidney disease? Kidney Int. 1998;54(5):1759-1761.

9. Pei Y. Practical genetics for autosomal dominant polycystic kidney disease. Nephron Clin Pract. 2011;118(1):c19-c30.

10. Tan YC, Blumenfeld J, Rennert H. Autosomal dominant polycystic kidney disease: genetics, mutations and microRNAs.
Biochim Biophys Acta. 2011 Mar 16 [Epub ahead of print].

11. Avner ED, Sweeney WE Jr, Nelson WJ. Abnormal sodium pump distribution during renal tubulogenesis in congenital murine polycystic kidney disease. Proc Natl Acad Sci U S A. 1992;89(16):7447-7451.

12. Torra R, Badenas C, Darnell A, et al. Linkage, clinical features, and prognosis of autosomal dominant polycystic kidney disease types 1 and 2. J Am Soc Nephrol. 1996;7(10):2142-2151.

13. Davies F, Coles GA, Harper PS, et al. Polycystic kidney disease re-evaluated: a population-based study. Q J Med. 1991;79(290):477-485.

14. Hateboer N, v Dijk MA, Bogdanova N, et al; European PKD1-PKD2 Study Group. Comparison of phenotypes of polycystic kidney disease types 1 and 2. Lancet. 1999;353(9147):103-107.

15. Peters DJ, Breuning MH. Autosomal dominant polycystic kidney disease: modification of disease progression. Lancet. 2001;358(9291):1439-1444.

16. Dicks E, Ravani P, Langman D, et al. Incident renal events and risk factors in autosomal dominant polycystic kidney disease: a population- and family-based cohort followed for 22 years. Clin J Am Soc Nephrol. 2006;1(4):710-717.

17. Fick-Brosnahan GM, Belz MM, McFann KK, etc. Relationship between renal volume growth and renal function in autosomal dominant polycystic kidney disease: a longitudinal study. Am J Kidney Dis. 2002;39(6):1127-1134.

18. Fick-Brosnahan GM, Tran ZV, Johnson AM, et al. Progression of autosomal-dominant polycystic kidney disease in children. Kidney Int. 2001;59(5):1654-1662.

19. Johnson AM, Gabow PA. Identification of patients with autosomal dominant polycystic kidney disease at highest risk for end-stage renal disease. J Am Soc Nephrol. 1997;8(10): 1560-1567.

20. Risk D. Autosomal dominant polycystic kidney disease. Presented at: National Kidney Foundation, Spring Clinical Meetings; April 28, 2011; Las Vegas, NV.

21. Pei Y, Obaji J, Dupuis A, et al. Unified criteria for ultrasonographic diagnosis of ADPKD. J Am Soc Nephrol. 2009;20(1):205-212.

22. Watnick T, Germino GG. Molecular basis of autosomal dominant polycystic kidney disease. Semin Nephrol. 1999;19(4):327-343.

23. Ecder T, Schrier RW. Cardiovascular abnormalities in autosomal-dominant polycystic kidney disease. Nat Rev Nephrol. 2009;5(4):221-228.

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53. Calvet JP. Strategies to inhibit cyst formation in ADPKD. Clin J Am Soc Nephrol. 2008;3 (4):1205-1211.

54. Grantham JJ. Lillian Jean Kaplan International Prize for advancement in the understanding of polycystic kidney disease. Understanding polycystic kidney disease: a systems biology approach. Kidney Int. 2003;64(4):1157-1162.

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