Jane S. Davis, CRNP

Kidney stones (nephrolithiasis), seen in 11% of all Americans, may increase patients’ risk for chronic kidney disease (CKD), although current research findings are insufficient to support a well-established relationship.^1,2 Actually, CKD may have a protective effect against the formation of calcium-based stones (which account for about 80% of all stones), since the CKD-affected kidney may fail to concentrate and excrete calcium. However, this effect is often offset by metabolic syndrome, diabetes, and hypertension—all of which increase the risk for calcium-based stones.^4,5 Heredity is also a factor.

After calcium-based stones, the most common types are struvite, uric acid, cysteine, and “mixed” stones. Not so common are the hereditary stones associated with four relatively rare conditions: primary hyperoxaluria (PH), adenine phosphoribosyltransferase (APRT) deficiency, cystinuria, and Dent’s disease. According to the NIH Rare Diseases Clinical Research Network, only 524 patients with these conditions are enrolled in the Mayo Clinic–based Rare Kidney Stone Consortium, indicating the orphan status of these illnesses.⁶

Patients with PH are born with an autosomal recessive error of glyoxylate metabolism that results in an overproduction of calcium oxalate.⁷ The oxalate is deposited in various organs—most often the kidneys, in the form of kidney stones. PH can occur in infants; parents are often alerted by rust spots in diapers, caused by passage of small stones.

There are three types of PH: PH1, PH2, and PH3. PH1 and PH2 account for approximately 90% of cases.⁸ In PH1, the genetic error is linked to an insufficient or absent liver enzyme. About 50% of children with PH1 will develop end-stage renal disease by young adulthood.⁹ One of the suggested treatments is liver transplantation, because replacing the diseased kidney alone would not spare the newly transplanted kidney from the same fate: a shower of stones from the liver. For patients with PH2 (which is generally less severe than PH1), kidney transplantation alone is often effective.¹⁰ In patients with any type of PH, high fluid intake is recommended.

Like PH, APRT/2,8-DHA crystalluria is an autosomal recessive disorder, one that researchers consider underrecognized and underdiagnosed. The majority of cases have been reported from Japan, France, and Iceland.¹¹ Often the stones are misidentified as uric acid or xanthine stones. Patients with APRT deficiency present with a range of symptoms—from stone disease to full kidney failure.¹² Treatment components include administration of allopurinol (a purine analog), increased fluid intake, a mildly purine-restricted diet, and extracorporeal shock-wave lithotripsy, when indicated.¹³

Cystinuria is found in 1% to 2% of patients with kidney stones but about 5% of children with stones¹⁴; it most often presents in early childhood. Patients have impaired renal cysteine transport, which leads to stone formation.¹⁵ Before it became possible to identify the genes responsible for cystinuria, patients were classified according to cystine excretion levels. Treatment includes high fluid intake, mild restriction of protein and sodium, alkalinization of urine, and use of medications including penicillamine and captopril.^16,17

The rare stone-producing illness Dent’s disease is an X-linked recessive condition that can lead to hypercalciuria, stones, CKD, and rickets.¹⁸ It usually presents in childhood, often in children who fail to thrive, and is associated with mutations of at least two genes (accounting for different disease types). Low-molecular-weight proteinuria is almost always present, but renal failure is relatively uncommon. Thiazide therapy has been found effective in treating the hypercalciuria associated with Dent’s disease, and addition of an ACE inhibitor may be helpful in patients with cystinosis.¹⁹

Kidney stones should be suspected in children with a family history of stones and symptoms such as hematuria, flank or abdominal pain, and/or urinary symptoms (dysuria, urinary tract infection). Genetic testing and counseling is frequently advised for these children and their families, as the correct diagnosis guides appropriate treatment.

References
1. Scales CD Jr, Smith AC, Hanley JM, Saigal CS. Urologic Diseases in America Project: Prevalence of kidney stones in the United States. Eur Urol. 2012;62:160-165.

2. Worcester EM, Coe FL. Calcium kidney stones. N Engl J Med. 2010;363:954-963.

3. Rule AD, Krambeck AE, Lieske JC. Chronic kidney disease in kidney stone formers. Clin J Am Soc Nephrol. 2011;6(8):2069-2075.

4. Teichman JM. Clinical practice. Acute renal colic from ureteral calculus. N Engl J Med. 2004;350(7):684-693.

5. National Institute of Diabetes and Digestive and Kidney Diseases. Kidney stones in adults: what are the types of kidney stones? http://kidney.niddk.nih.gov/KUDiseases/pubs/stonesadults/index.aspx. Accessed September 29, 2014.

6. Nazzal L. Spotlight on RDCRN consortia: the Rare Kidney Stone Consortium. http://rarediseasesnetwork.org/spotlight/April2013/RKSC. Accessed September 26, 2014.

7. Hoppe B. An update on primary hyperoxaluria. Nat Rev Nephrol. 2012;8(8):467-475.

8. Hoppe B, Langman CB. A United States survey on diagnosis, treatment, and outcome of primary hyperoxaluria. Pediatr Nephrol. 2003;18(10):986-991.

9. Harambat J, Farque S, Acquaviva C. Genotype-phenotype correlation in primary hyperoxaluria type 1: the p.Gly170Arg AGXT mutation is associated with a better outcome. Kidney Int. 2010;77(5):443-449.

10. Bergstralh EJ, Monico CG, Lieske JC. Transplantation outcomes in primary hyperoxaluria. Am J Transplant. 2010;10(11):2493-2501. 

11. Rare Clinical Diseases Research Network. Diseases in depth: adenine phosphoribosyltransferase (APRT) deficiency. www.rarediseasesnetwork.org/RKSC/professional/APRT/index.htm. Accessed September 29, 2014.

12. Edvardsson V, Palsson R. Adenine phosphoribosyltransferase deficiency and 2,8-dihydroxyadeninuria. In: Moriwaki Y, ed. Genetic Errors Associated with Purine and Pyrimidine Metabolism in Humans: Diagnosis and Treatment. Kerala, India: Research Signpost; 2006:79-93.

13. Edvardsson V, Palsson R, Olafsson I, et al. Clinical features and genotype of adenine phosphoribosyltransferase deficiency in Iceland. Am J Kidney Dis. 2001;38(3):473-480.

14. Stapleton FB. Childhood stones. Endocrinol Metab Clin North Am. 2002;31(4):1001-1015.

15. Mattoo A, Goldfarb DS. Cystinuria. Semin Nephrol. 2008;28(2):181-191.

16. Goldfarb DS, Coe FL, Asplin JR. Urinary cystine excretion and capacity in patients with cystinuria. Kidney Int. 2006;69(6):1041-1047.

17. Perazella MA, Buller GK. Successful treatment of cystinuria with captopril. Am J Kidney Dis. 1993;21(5):504-507.

18. Devuyst O, Thakker RV. Dent’s disease. Orphanet J Rare Dis. 2010;5:28.

19. Ludwig M, Utsch B, Monnens LA. Recent advances in understanding the clinical and genetic heterogeneity of Dent’s disease. Nephrol Dial Transplant. 2006;21(10):2708-2717.

Kidney stones (nephrolithiasis), seen in 11% of all Americans, may increase patients’ risk for chronic kidney disease (CKD), although current research findings are insufficient to support a well-established relationship.^1,2 Actually, CKD may have a protective effect against the formation of calcium-based stones (which account for about 80% of all stones), since the CKD-affected kidney may fail to concentrate and excrete calcium. However, this effect is often offset by metabolic syndrome, diabetes, and hypertension—all of which increase the risk for calcium-based stones.^4,5 Heredity is also a factor.

After calcium-based stones, the most common types are struvite, uric acid, cysteine, and “mixed” stones. Not so common are the hereditary stones associated with four relatively rare conditions: primary hyperoxaluria (PH), adenine phosphoribosyltransferase (APRT) deficiency, cystinuria, and Dent’s disease. According to the NIH Rare Diseases Clinical Research Network, only 524 patients with these conditions are enrolled in the Mayo Clinic–based Rare Kidney Stone Consortium, indicating the orphan status of these illnesses.⁶

Patients with PH are born with an autosomal recessive error of glyoxylate metabolism that results in an overproduction of calcium oxalate.⁷ The oxalate is deposited in various organs—most often the kidneys, in the form of kidney stones. PH can occur in infants; parents are often alerted by rust spots in diapers, caused by passage of small stones.

There are three types of PH: PH1, PH2, and PH3. PH1 and PH2 account for approximately 90% of cases.⁸ In PH1, the genetic error is linked to an insufficient or absent liver enzyme. About 50% of children with PH1 will develop end-stage renal disease by young adulthood.⁹ One of the suggested treatments is liver transplantation, because replacing the diseased kidney alone would not spare the newly transplanted kidney from the same fate: a shower of stones from the liver. For patients with PH2 (which is generally less severe than PH1), kidney transplantation alone is often effective.¹⁰ In patients with any type of PH, high fluid intake is recommended.

Like PH, APRT/2,8-DHA crystalluria is an autosomal recessive disorder, one that researchers consider underrecognized and underdiagnosed. The majority of cases have been reported from Japan, France, and Iceland.¹¹ Often the stones are misidentified as uric acid or xanthine stones. Patients with APRT deficiency present with a range of symptoms—from stone disease to full kidney failure.¹² Treatment components include administration of allopurinol (a purine analog), increased fluid intake, a mildly purine-restricted diet, and extracorporeal shock-wave lithotripsy, when indicated.¹³

Cystinuria is found in 1% to 2% of patients with kidney stones but about 5% of children with stones¹⁴; it most often presents in early childhood. Patients have impaired renal cysteine transport, which leads to stone formation.¹⁵ Before it became possible to identify the genes responsible for cystinuria, patients were classified according to cystine excretion levels. Treatment includes high fluid intake, mild restriction of protein and sodium, alkalinization of urine, and use of medications including penicillamine and captopril.^16,17

The rare stone-producing illness Dent’s disease is an X-linked recessive condition that can lead to hypercalciuria, stones, CKD, and rickets.¹⁸ It usually presents in childhood, often in children who fail to thrive, and is associated with mutations of at least two genes (accounting for different disease types). Low-molecular-weight proteinuria is almost always present, but renal failure is relatively uncommon. Thiazide therapy has been found effective in treating the hypercalciuria associated with Dent’s disease, and addition of an ACE inhibitor may be helpful in patients with cystinosis.¹⁹

Kidney stones should be suspected in children with a family history of stones and symptoms such as hematuria, flank or abdominal pain, and/or urinary symptoms (dysuria, urinary tract infection). Genetic testing and counseling is frequently advised for these children and their families, as the correct diagnosis guides appropriate treatment.

References
1. Scales CD Jr, Smith AC, Hanley JM, Saigal CS. Urologic Diseases in America Project: Prevalence of kidney stones in the United States. Eur Urol. 2012;62:160-165.

2. Worcester EM, Coe FL. Calcium kidney stones. N Engl J Med. 2010;363:954-963.

3. Rule AD, Krambeck AE, Lieske JC. Chronic kidney disease in kidney stone formers. Clin J Am Soc Nephrol. 2011;6(8):2069-2075.

4. Teichman JM. Clinical practice. Acute renal colic from ureteral calculus. N Engl J Med. 2004;350(7):684-693.

5. National Institute of Diabetes and Digestive and Kidney Diseases. Kidney stones in adults: what are the types of kidney stones? http://kidney.niddk.nih.gov/KUDiseases/pubs/stonesadults/index.aspx. Accessed September 29, 2014.

6. Nazzal L. Spotlight on RDCRN consortia: the Rare Kidney Stone Consortium. http://rarediseasesnetwork.org/spotlight/April2013/RKSC. Accessed September 26, 2014.

7. Hoppe B. An update on primary hyperoxaluria. Nat Rev Nephrol. 2012;8(8):467-475.

8. Hoppe B, Langman CB. A United States survey on diagnosis, treatment, and outcome of primary hyperoxaluria. Pediatr Nephrol. 2003;18(10):986-991.

9. Harambat J, Farque S, Acquaviva C. Genotype-phenotype correlation in primary hyperoxaluria type 1: the p.Gly170Arg AGXT mutation is associated with a better outcome. Kidney Int. 2010;77(5):443-449.

10. Bergstralh EJ, Monico CG, Lieske JC. Transplantation outcomes in primary hyperoxaluria. Am J Transplant. 2010;10(11):2493-2501. 

11. Rare Clinical Diseases Research Network. Diseases in depth: adenine phosphoribosyltransferase (APRT) deficiency. www.rarediseasesnetwork.org/RKSC/professional/APRT/index.htm. Accessed September 29, 2014.

12. Edvardsson V, Palsson R. Adenine phosphoribosyltransferase deficiency and 2,8-dihydroxyadeninuria. In: Moriwaki Y, ed. Genetic Errors Associated with Purine and Pyrimidine Metabolism in Humans: Diagnosis and Treatment. Kerala, India: Research Signpost; 2006:79-93.

13. Edvardsson V, Palsson R, Olafsson I, et al. Clinical features and genotype of adenine phosphoribosyltransferase deficiency in Iceland. Am J Kidney Dis. 2001;38(3):473-480.

14. Stapleton FB. Childhood stones. Endocrinol Metab Clin North Am. 2002;31(4):1001-1015.

15. Mattoo A, Goldfarb DS. Cystinuria. Semin Nephrol. 2008;28(2):181-191.

16. Goldfarb DS, Coe FL, Asplin JR. Urinary cystine excretion and capacity in patients with cystinuria. Kidney Int. 2006;69(6):1041-1047.

17. Perazella MA, Buller GK. Successful treatment of cystinuria with captopril. Am J Kidney Dis. 1993;21(5):504-507.

18. Devuyst O, Thakker RV. Dent’s disease. Orphanet J Rare Dis. 2010;5:28.

19. Ludwig M, Utsch B, Monnens LA. Recent advances in understanding the clinical and genetic heterogeneity of Dent’s disease. Nephrol Dial Transplant. 2006;21(10):2708-2717.

Kidney stones (nephrolithiasis), seen in 11% of all Americans, may increase patients’ risk for chronic kidney disease (CKD), although current research findings are insufficient to support a well-established relationship.^1,2 Actually, CKD may have a protective effect against the formation of calcium-based stones (which account for about 80% of all stones), since the CKD-affected kidney may fail to concentrate and excrete calcium. However, this effect is often offset by metabolic syndrome, diabetes, and hypertension—all of which increase the risk for calcium-based stones.^4,5 Heredity is also a factor.

After calcium-based stones, the most common types are struvite, uric acid, cysteine, and “mixed” stones. Not so common are the hereditary stones associated with four relatively rare conditions: primary hyperoxaluria (PH), adenine phosphoribosyltransferase (APRT) deficiency, cystinuria, and Dent’s disease. According to the NIH Rare Diseases Clinical Research Network, only 524 patients with these conditions are enrolled in the Mayo Clinic–based Rare Kidney Stone Consortium, indicating the orphan status of these illnesses.⁶

Patients with PH are born with an autosomal recessive error of glyoxylate metabolism that results in an overproduction of calcium oxalate.⁷ The oxalate is deposited in various organs—most often the kidneys, in the form of kidney stones. PH can occur in infants; parents are often alerted by rust spots in diapers, caused by passage of small stones.

There are three types of PH: PH1, PH2, and PH3. PH1 and PH2 account for approximately 90% of cases.⁸ In PH1, the genetic error is linked to an insufficient or absent liver enzyme. About 50% of children with PH1 will develop end-stage renal disease by young adulthood.⁹ One of the suggested treatments is liver transplantation, because replacing the diseased kidney alone would not spare the newly transplanted kidney from the same fate: a shower of stones from the liver. For patients with PH2 (which is generally less severe than PH1), kidney transplantation alone is often effective.¹⁰ In patients with any type of PH, high fluid intake is recommended.

Like PH, APRT/2,8-DHA crystalluria is an autosomal recessive disorder, one that researchers consider underrecognized and underdiagnosed. The majority of cases have been reported from Japan, France, and Iceland.¹¹ Often the stones are misidentified as uric acid or xanthine stones. Patients with APRT deficiency present with a range of symptoms—from stone disease to full kidney failure.¹² Treatment components include administration of allopurinol (a purine analog), increased fluid intake, a mildly purine-restricted diet, and extracorporeal shock-wave lithotripsy, when indicated.¹³

Cystinuria is found in 1% to 2% of patients with kidney stones but about 5% of children with stones¹⁴; it most often presents in early childhood. Patients have impaired renal cysteine transport, which leads to stone formation.¹⁵ Before it became possible to identify the genes responsible for cystinuria, patients were classified according to cystine excretion levels. Treatment includes high fluid intake, mild restriction of protein and sodium, alkalinization of urine, and use of medications including penicillamine and captopril.^16,17

The rare stone-producing illness Dent’s disease is an X-linked recessive condition that can lead to hypercalciuria, stones, CKD, and rickets.¹⁸ It usually presents in childhood, often in children who fail to thrive, and is associated with mutations of at least two genes (accounting for different disease types). Low-molecular-weight proteinuria is almost always present, but renal failure is relatively uncommon. Thiazide therapy has been found effective in treating the hypercalciuria associated with Dent’s disease, and addition of an ACE inhibitor may be helpful in patients with cystinosis.¹⁹

Kidney stones should be suspected in children with a family history of stones and symptoms such as hematuria, flank or abdominal pain, and/or urinary symptoms (dysuria, urinary tract infection). Genetic testing and counseling is frequently advised for these children and their families, as the correct diagnosis guides appropriate treatment.

References
1. Scales CD Jr, Smith AC, Hanley JM, Saigal CS. Urologic Diseases in America Project: Prevalence of kidney stones in the United States. Eur Urol. 2012;62:160-165.

2. Worcester EM, Coe FL. Calcium kidney stones. N Engl J Med. 2010;363:954-963.

3. Rule AD, Krambeck AE, Lieske JC. Chronic kidney disease in kidney stone formers. Clin J Am Soc Nephrol. 2011;6(8):2069-2075.

4. Teichman JM. Clinical practice. Acute renal colic from ureteral calculus. N Engl J Med. 2004;350(7):684-693.

5. National Institute of Diabetes and Digestive and Kidney Diseases. Kidney stones in adults: what are the types of kidney stones? http://kidney.niddk.nih.gov/KUDiseases/pubs/stonesadults/index.aspx. Accessed September 29, 2014.

6. Nazzal L. Spotlight on RDCRN consortia: the Rare Kidney Stone Consortium. http://rarediseasesnetwork.org/spotlight/April2013/RKSC. Accessed September 26, 2014.

7. Hoppe B. An update on primary hyperoxaluria. Nat Rev Nephrol. 2012;8(8):467-475.

8. Hoppe B, Langman CB. A United States survey on diagnosis, treatment, and outcome of primary hyperoxaluria. Pediatr Nephrol. 2003;18(10):986-991.

9. Harambat J, Farque S, Acquaviva C. Genotype-phenotype correlation in primary hyperoxaluria type 1: the p.Gly170Arg AGXT mutation is associated with a better outcome. Kidney Int. 2010;77(5):443-449.

10. Bergstralh EJ, Monico CG, Lieske JC. Transplantation outcomes in primary hyperoxaluria. Am J Transplant. 2010;10(11):2493-2501. 

11. Rare Clinical Diseases Research Network. Diseases in depth: adenine phosphoribosyltransferase (APRT) deficiency. www.rarediseasesnetwork.org/RKSC/professional/APRT/index.htm. Accessed September 29, 2014.

12. Edvardsson V, Palsson R. Adenine phosphoribosyltransferase deficiency and 2,8-dihydroxyadeninuria. In: Moriwaki Y, ed. Genetic Errors Associated with Purine and Pyrimidine Metabolism in Humans: Diagnosis and Treatment. Kerala, India: Research Signpost; 2006:79-93.

13. Edvardsson V, Palsson R, Olafsson I, et al. Clinical features and genotype of adenine phosphoribosyltransferase deficiency in Iceland. Am J Kidney Dis. 2001;38(3):473-480.

14. Stapleton FB. Childhood stones. Endocrinol Metab Clin North Am. 2002;31(4):1001-1015.

15. Mattoo A, Goldfarb DS. Cystinuria. Semin Nephrol. 2008;28(2):181-191.

16. Goldfarb DS, Coe FL, Asplin JR. Urinary cystine excretion and capacity in patients with cystinuria. Kidney Int. 2006;69(6):1041-1047.

17. Perazella MA, Buller GK. Successful treatment of cystinuria with captopril. Am J Kidney Dis. 1993;21(5):504-507.

18. Devuyst O, Thakker RV. Dent’s disease. Orphanet J Rare Dis. 2010;5:28.

19. Ludwig M, Utsch B, Monnens LA. Recent advances in understanding the clinical and genetic heterogeneity of Dent’s disease. Nephrol Dial Transplant. 2006;21(10):2708-2717.