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Case
A 55-year-old woman with diabetes, hypertension, and chronic kidney disease (CKD) stage 4 is admitted to the hospital for treatment of left lower-extremity cellulitis. Laboratory studies on admission show a creatinine level of 2.5 mg/dL (glomerular filtration rate [GFR] is 20 mL/min per 1.73 m2; baseline creatinine is between 2.2 and 2.6 mg/dL), potassium level of 3.0 mEq/L, magnesium level of 1.5 mEq/L, bicarbonate level of 18 mEq/L, phosphate level of 6.5 mg/dL, and calcium level of 7.5 mg/dL.
She is put on renally dosed vancomycin to treat her cellulitis. As the hospitalist, how should you manage her multiple electrolyte abnormalities?
Overview of the issue
CKD is also an important risk factor for acute kidney injury. Additionally, rates of readmission for CKD patients are higher than those without CKD. Given that CKD is a “silent disease” that many patients do not realize they have, it is very possible that the first documentation of CKD could happen during an acute hospitalization.
Among the various manifestations of CKD, electrolyte abnormalities are the most likely ones hospitalists will run into.
Overview of the data
Hypokalemia and Hypomagnesemia
Hypokalemia (potassium levels less than 3.5 mEq/L) is not as common as hyperkalemia (potassium levels greater than 5.0 mEq/L) in CKD, which is the result of impaired renal excretion of potassium. Hypokalemia can occur as a result of GI losses, urinary losses, or decreased intake and can be worsened by the use of certain drugs, such as non–K-sparing diuretics.
In the setting of diuretic use involving thiazides and loop diuretics, hypokalemia is dose and sodium-intake dependent. Potassium deficiency worsens the effects of detrimental sodium excess, which plays a role in hypertension and its associated complications. Potassium also has a protective vascular effect, which is a major reason why potassium should be kept normal in patients with CKD.
Acutely, hypokalemia can cause arrhythmias, ileus, and paralysis, which are all indications for immediate repletion. In these cases, hypokalemia must be repleted carefully in small increments (some suggest 20 mEq doses), and the patient must be monitored frequently to avoid hyperkalemia. If patients are persistently hypokalemic, several options can be considered based on the underlying cause. Dietary modifications with foods rich in potassium (containing 250mg/100g) can be suggested. Daily potassium chloride supplementation can be used in those on diuretic therapy who have hypokalemia and metabolic alkalosis (bicarbonate levels greater than 30 mEq/L). Alkalinizing salts, containing citrate or bicarbonate, can be used in hypokalemia without metabolic alkalosis. Initiation of angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta-adrenergic blockers, and K-sparing diuretics can be used as well.
Potassium supplementation and K-sparing diuretics should be used with extreme caution in CKD 3 and 4 given the risk of overcorrection. If potassium supplements or drugs to raise serum potassium are initiated in house, potassium should be rechecked within a week. These treatments should be avoided in individuals with diabetes, who are at highest risk for hyperkalemia given hyporeninemic hypoaldosteronism (type IV renal tubular acidosis).
There is emerging evidence that hypomagnesemia can play a part in progression to end-stage renal disease. In the setting of cardiovascular disease, which often co-exists with CKD, the risk of hypomagnesemia precipitating arrhythmia necessitates repletion to a normal level. Any of the magnesium salts and antacids can be used for treatment. K-sparing diuretics are also magnesium sparing. An important side effect of magnesium repletion is diarrhea, which can potentiate electrolyte losses and reduce long-term adherence rates.
Metabolic acidosis
Acid-base balance is maintained by the kidney through urinary excretion of hydrogen ions both as titratable acids and ammonium. In CKD, renal excretion of the daily acid load is impaired, primarily from decreased ammonium excretion caused by there being too few functioning nephrons.
Metabolic acidosis in CKD is defined as a serum bicarbonate concentration of persistently less than 22 mEq/L. The overall prevalence of metabolic acidosis in cases of CKD that don’t require dialysis is about 15% and increases linearly with a decline in GFR. In the Chronic Renal Insufficiency Cohort study, 7%, 13%, and 37% of participants with CKD stages 2, 3, and 4 respectively had metabolic acidosis.
Metabolic acidosis has a variety of adverse outcomes, including bone demineralization, increased protein catabolism and muscle wasting, impaired cardiac function, impaired glucose homeostasis, and systemic inflammation. Additionally, multiple studies have shown an association between metabolic acidosis and progression of CKD and increased mortality.
The 2013 Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend maintaining the serum bicarbonate level within the reference range (23-29 mEq/L) with alkali therapy. Options include sodium bicarbonate or sodium citrate (which is rapidly metabolized to bicarbonate) in doses of 0.5-1.0 mEq/kg once per day. Sodium bicarbonate is inexpensive; however, it can lead to gastrointestinal upset as the bicarbonate is converted into CO2 in the stomach. This side effect is usually self-limited and improves with time. Typical starting doses are 650 mg twice a day if the serum bicarbonate level is 19-21 mEq/L or 1300 mg twice a day if the serum bicarbonate level is less than or equal to 18 mEq/L.
Sodium citrate can be used if gastrointestinal upset occurs, although caution should be used in those on aluminum binders or with liver disease. Alkali treatment should be started when bicarbonate levels are persistently low (for weeks or months) or if very low (less than or equal to 18 mEq/L) without an acute reversible cause. After patients have begun therapy, they should be monitored for the development of worsening hypertension or edema caused by sodium-mediated fluid retention, although this rarely occurs.
Hyperphosphatemia and Hypocalcemia
Hyperphosphatemia (phosphate levels greater than 4.6 mg/dL) develops early in CKD because of a reduced filtered-phosphate load. Hypocalcemia and hyperphosphatemia can lead to secondary hyperparathyroidism. Given that hyperphosphatemia has been associated with an increased mortality among patients with CKD, treatment is warranted, but the optimal phosphorus range is unknown. According to the KDIGO guidelines, the goal phosphorus level is less than 4.5 mg/dL in patients with CKD who are not on dialysis.
Treatment includes dietary restriction to 900 mg/day and phosphate binders. There is a high phosphate load in processed foods and colas because of food additives. It is therefore recommended to reduce consumption of these foods while encouraging consumption of meat and eggs, which offer additional nutritional value. Those who have failed dietary restrictions should be put on a phosphate binder, either calcium containing (calcium carbonate, calcium acetate) or non–calcium containing (Sevelamer, lanthanum). Non–calcium-containing binders are recommended for patients with hypercalcemia (levels greater than 9.5 mg/dL). There is some data that suggests that non–calcium-containing binders are superior to calcium-containing binders in terms of vascular disease outcomes, but non–calcium-containing binders are sometimes difficult to obtain because of cost and insurance coverage.
Hypocalcemia (calcium levels below 8.4 mg/dL) occurs in the setting of late stage untreated CKD because of decreased GI uptake of calcium from diet in the context of vitamin D deficiency (less than 30 ng/mL) in addition to hyperphosphatemia. Phosphate and vitamin D correction is preferred to calcium supplementation because hyperphosphatemia and vitamin D deficiency occur earlier in CKD. Phosphate reduction is described above.
Regarding vitamin D deficiency, it is recommended to start supplementation with either vitamin D2 or D3. Doses should be adjusted if GFR is less than 30 mL/min per 1.73 m2. It is important to monitor for hypercalcemia, which can also occur in CKD in this context, because it has also been associated with increased morbidity and mortality. If calcium levels are greater than 10.2 mg/dL, all vitamin D supplementation should be discontinued.
Back to the case
Our patient who was admitted for cellulitis has concomitant hypokalemia, hypomagnesemia, acidosis, and hyperphosphatemia with related hypocalcemia. She revealed that her diet was poor prior to her admission for her infection. She was given 20 mEq of potassium orally and placed on a potassium rich diet until potassium levels normalized. She was also given magnesium oxide orally on the first and second day of admission, with repeat levels that were normal. Her acidosis was treated with sodium bicarbonate – 1,300 mg orally twice daily. For her hyperphosphatemia and hypocalcemia, she was placed on phosphate restriction with nutritional counseling with plans to follow up as an outpatient to determine need for phosphate binders. In addition, vitamin D levels were checked, and she was started on repletion for vitamin D deficiency (27 ng/mL). Daily BMP, magnesium, and phosphorus were checked while in house until they were normal for 2 days, and follow-up lab work was requested with her nephrology appointment, which was scheduled for within 1 week.
Bottom line
Electrolyte abnormalities in CKD are numerous and have multiple adverse clinical outcomes. Early intervention and management, especially of metabolic acidosis and hyperphosphatemia, can have a significant effect, including prevention of progression of CKD and possibly reduced mortality.
Dr. Daya, Dr. Apgar, and Dr. Eniasivam are assistant clinical professors in the division of hospital medicine at the University of California, San Francisco.
References
1. Coresh J et al. Prevalence of chronic kidney disease in the United States. JAMA. 2007 Nov 7;298(17):2038-47.
2. Dhondup T et al. Electrolyte and acid-base disorders in chronic kidney disease and end-stage kidney failure. Blood Purif. 2017;43(1-3):179-188.
3. K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis. 2004 May;43(5 Suppl 1):S1-290.
4. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl (2011). 2013 Jan;3(1):1–150.
5. Sakaguchi Y et al. Hypomagnesemia in type 2 diabetic nephropathy: A novel predictor of end-stage renal disease. Diabetes Care. 2012 Jul;35(7):1591-7.
6. Palmer SC et al. Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: A systematic review and meta-analysis. JAMA. 2011 Mar 16;305(11):1119-27.
7. Patel L et al. Sevelamer versus calcium-based binders for treatment of hyperphosphatemia in CKD: A meta-analysis of randomized controlled trials. Clin J Am Soc Nephrol. 2016 Feb 5;11(2):232-44.
8. Raphael KL. Approach to the treatment of chronic metabolic acidosis in CKD. Am J Kidney Dis. 2016 Apr;67(4):696-702.
9. Raphael KL et al. Prevalence of and risk factors for reduced serum bicarbonate in chronic kidney disease. Nephrology (Carlton). 2014 Oct;19(10):648-54.
Additional reading
1. Chapter 3: Management of Progression and Complications of CKD. Kidney Int Suppl (2011). 2013 Jan:3(1):73-90.
2. Raphael KL. Approach to the treatment of chronic metabolic acidosis in CKD. Am J Kidney Dis. 2016 Apr;67(4):696-702.
Quiz
A 75-year-old male with hypertension and CKD Stage 4 is admitted to the hospital for a hip fracture following a fall. Laboratory studies on admission show a potassium level of 3.2 mEq/L, vitamin D level of 45 ng/mL, bicarbonate level of 17 mEq/L, phosphate level of 5.0 mg/dL, and calcium level of 10.3 mg/dL.
What electrolyte replacements should be initiated?
A. Dietary restriction of phosphate, sodium bicarbonate, potassium chloride, and vitamin D.
B. Non–calcium-containing phosphate binder, vitamin D, and potassium chloride.
C. Calcium-containing phosphate binder and sodium bicarbonate.
D. Non–calcium-containing phosphate binder, sodium bicarbonate, and potassium chloride.
Answer: D. Given the patient’s hypokalemia, potassium supplementation should be considered. Additionally, given his hyperphosphatemia and hypercalcemia, a non–calcium-containing phosphate binder like Sevelamer should be started. His metabolic acidosis should be corrected with sodium bicarbonate. There is no indication to supplement vitamin D based on his current lab values.
Key Points
- Identify and treat underlying causes of hypokalemia and hypomagnesemia.
- Do not hesitate to treat metabolic acidosis in CKD.
- Manage hyperphosphatemia and hypocalcemia by ordering appropriate lab studies and providing nutritional consultation with outpatient nephrology follow-up as indicated.
Case
A 55-year-old woman with diabetes, hypertension, and chronic kidney disease (CKD) stage 4 is admitted to the hospital for treatment of left lower-extremity cellulitis. Laboratory studies on admission show a creatinine level of 2.5 mg/dL (glomerular filtration rate [GFR] is 20 mL/min per 1.73 m2; baseline creatinine is between 2.2 and 2.6 mg/dL), potassium level of 3.0 mEq/L, magnesium level of 1.5 mEq/L, bicarbonate level of 18 mEq/L, phosphate level of 6.5 mg/dL, and calcium level of 7.5 mg/dL.
She is put on renally dosed vancomycin to treat her cellulitis. As the hospitalist, how should you manage her multiple electrolyte abnormalities?
Overview of the issue
CKD is also an important risk factor for acute kidney injury. Additionally, rates of readmission for CKD patients are higher than those without CKD. Given that CKD is a “silent disease” that many patients do not realize they have, it is very possible that the first documentation of CKD could happen during an acute hospitalization.
Among the various manifestations of CKD, electrolyte abnormalities are the most likely ones hospitalists will run into.
Overview of the data
Hypokalemia and Hypomagnesemia
Hypokalemia (potassium levels less than 3.5 mEq/L) is not as common as hyperkalemia (potassium levels greater than 5.0 mEq/L) in CKD, which is the result of impaired renal excretion of potassium. Hypokalemia can occur as a result of GI losses, urinary losses, or decreased intake and can be worsened by the use of certain drugs, such as non–K-sparing diuretics.
In the setting of diuretic use involving thiazides and loop diuretics, hypokalemia is dose and sodium-intake dependent. Potassium deficiency worsens the effects of detrimental sodium excess, which plays a role in hypertension and its associated complications. Potassium also has a protective vascular effect, which is a major reason why potassium should be kept normal in patients with CKD.
Acutely, hypokalemia can cause arrhythmias, ileus, and paralysis, which are all indications for immediate repletion. In these cases, hypokalemia must be repleted carefully in small increments (some suggest 20 mEq doses), and the patient must be monitored frequently to avoid hyperkalemia. If patients are persistently hypokalemic, several options can be considered based on the underlying cause. Dietary modifications with foods rich in potassium (containing 250mg/100g) can be suggested. Daily potassium chloride supplementation can be used in those on diuretic therapy who have hypokalemia and metabolic alkalosis (bicarbonate levels greater than 30 mEq/L). Alkalinizing salts, containing citrate or bicarbonate, can be used in hypokalemia without metabolic alkalosis. Initiation of angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta-adrenergic blockers, and K-sparing diuretics can be used as well.
Potassium supplementation and K-sparing diuretics should be used with extreme caution in CKD 3 and 4 given the risk of overcorrection. If potassium supplements or drugs to raise serum potassium are initiated in house, potassium should be rechecked within a week. These treatments should be avoided in individuals with diabetes, who are at highest risk for hyperkalemia given hyporeninemic hypoaldosteronism (type IV renal tubular acidosis).
There is emerging evidence that hypomagnesemia can play a part in progression to end-stage renal disease. In the setting of cardiovascular disease, which often co-exists with CKD, the risk of hypomagnesemia precipitating arrhythmia necessitates repletion to a normal level. Any of the magnesium salts and antacids can be used for treatment. K-sparing diuretics are also magnesium sparing. An important side effect of magnesium repletion is diarrhea, which can potentiate electrolyte losses and reduce long-term adherence rates.
Metabolic acidosis
Acid-base balance is maintained by the kidney through urinary excretion of hydrogen ions both as titratable acids and ammonium. In CKD, renal excretion of the daily acid load is impaired, primarily from decreased ammonium excretion caused by there being too few functioning nephrons.
Metabolic acidosis in CKD is defined as a serum bicarbonate concentration of persistently less than 22 mEq/L. The overall prevalence of metabolic acidosis in cases of CKD that don’t require dialysis is about 15% and increases linearly with a decline in GFR. In the Chronic Renal Insufficiency Cohort study, 7%, 13%, and 37% of participants with CKD stages 2, 3, and 4 respectively had metabolic acidosis.
Metabolic acidosis has a variety of adverse outcomes, including bone demineralization, increased protein catabolism and muscle wasting, impaired cardiac function, impaired glucose homeostasis, and systemic inflammation. Additionally, multiple studies have shown an association between metabolic acidosis and progression of CKD and increased mortality.
The 2013 Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend maintaining the serum bicarbonate level within the reference range (23-29 mEq/L) with alkali therapy. Options include sodium bicarbonate or sodium citrate (which is rapidly metabolized to bicarbonate) in doses of 0.5-1.0 mEq/kg once per day. Sodium bicarbonate is inexpensive; however, it can lead to gastrointestinal upset as the bicarbonate is converted into CO2 in the stomach. This side effect is usually self-limited and improves with time. Typical starting doses are 650 mg twice a day if the serum bicarbonate level is 19-21 mEq/L or 1300 mg twice a day if the serum bicarbonate level is less than or equal to 18 mEq/L.
Sodium citrate can be used if gastrointestinal upset occurs, although caution should be used in those on aluminum binders or with liver disease. Alkali treatment should be started when bicarbonate levels are persistently low (for weeks or months) or if very low (less than or equal to 18 mEq/L) without an acute reversible cause. After patients have begun therapy, they should be monitored for the development of worsening hypertension or edema caused by sodium-mediated fluid retention, although this rarely occurs.
Hyperphosphatemia and Hypocalcemia
Hyperphosphatemia (phosphate levels greater than 4.6 mg/dL) develops early in CKD because of a reduced filtered-phosphate load. Hypocalcemia and hyperphosphatemia can lead to secondary hyperparathyroidism. Given that hyperphosphatemia has been associated with an increased mortality among patients with CKD, treatment is warranted, but the optimal phosphorus range is unknown. According to the KDIGO guidelines, the goal phosphorus level is less than 4.5 mg/dL in patients with CKD who are not on dialysis.
Treatment includes dietary restriction to 900 mg/day and phosphate binders. There is a high phosphate load in processed foods and colas because of food additives. It is therefore recommended to reduce consumption of these foods while encouraging consumption of meat and eggs, which offer additional nutritional value. Those who have failed dietary restrictions should be put on a phosphate binder, either calcium containing (calcium carbonate, calcium acetate) or non–calcium containing (Sevelamer, lanthanum). Non–calcium-containing binders are recommended for patients with hypercalcemia (levels greater than 9.5 mg/dL). There is some data that suggests that non–calcium-containing binders are superior to calcium-containing binders in terms of vascular disease outcomes, but non–calcium-containing binders are sometimes difficult to obtain because of cost and insurance coverage.
Hypocalcemia (calcium levels below 8.4 mg/dL) occurs in the setting of late stage untreated CKD because of decreased GI uptake of calcium from diet in the context of vitamin D deficiency (less than 30 ng/mL) in addition to hyperphosphatemia. Phosphate and vitamin D correction is preferred to calcium supplementation because hyperphosphatemia and vitamin D deficiency occur earlier in CKD. Phosphate reduction is described above.
Regarding vitamin D deficiency, it is recommended to start supplementation with either vitamin D2 or D3. Doses should be adjusted if GFR is less than 30 mL/min per 1.73 m2. It is important to monitor for hypercalcemia, which can also occur in CKD in this context, because it has also been associated with increased morbidity and mortality. If calcium levels are greater than 10.2 mg/dL, all vitamin D supplementation should be discontinued.
Back to the case
Our patient who was admitted for cellulitis has concomitant hypokalemia, hypomagnesemia, acidosis, and hyperphosphatemia with related hypocalcemia. She revealed that her diet was poor prior to her admission for her infection. She was given 20 mEq of potassium orally and placed on a potassium rich diet until potassium levels normalized. She was also given magnesium oxide orally on the first and second day of admission, with repeat levels that were normal. Her acidosis was treated with sodium bicarbonate – 1,300 mg orally twice daily. For her hyperphosphatemia and hypocalcemia, she was placed on phosphate restriction with nutritional counseling with plans to follow up as an outpatient to determine need for phosphate binders. In addition, vitamin D levels were checked, and she was started on repletion for vitamin D deficiency (27 ng/mL). Daily BMP, magnesium, and phosphorus were checked while in house until they were normal for 2 days, and follow-up lab work was requested with her nephrology appointment, which was scheduled for within 1 week.
Bottom line
Electrolyte abnormalities in CKD are numerous and have multiple adverse clinical outcomes. Early intervention and management, especially of metabolic acidosis and hyperphosphatemia, can have a significant effect, including prevention of progression of CKD and possibly reduced mortality.
Dr. Daya, Dr. Apgar, and Dr. Eniasivam are assistant clinical professors in the division of hospital medicine at the University of California, San Francisco.
References
1. Coresh J et al. Prevalence of chronic kidney disease in the United States. JAMA. 2007 Nov 7;298(17):2038-47.
2. Dhondup T et al. Electrolyte and acid-base disorders in chronic kidney disease and end-stage kidney failure. Blood Purif. 2017;43(1-3):179-188.
3. K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis. 2004 May;43(5 Suppl 1):S1-290.
4. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl (2011). 2013 Jan;3(1):1–150.
5. Sakaguchi Y et al. Hypomagnesemia in type 2 diabetic nephropathy: A novel predictor of end-stage renal disease. Diabetes Care. 2012 Jul;35(7):1591-7.
6. Palmer SC et al. Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: A systematic review and meta-analysis. JAMA. 2011 Mar 16;305(11):1119-27.
7. Patel L et al. Sevelamer versus calcium-based binders for treatment of hyperphosphatemia in CKD: A meta-analysis of randomized controlled trials. Clin J Am Soc Nephrol. 2016 Feb 5;11(2):232-44.
8. Raphael KL. Approach to the treatment of chronic metabolic acidosis in CKD. Am J Kidney Dis. 2016 Apr;67(4):696-702.
9. Raphael KL et al. Prevalence of and risk factors for reduced serum bicarbonate in chronic kidney disease. Nephrology (Carlton). 2014 Oct;19(10):648-54.
Additional reading
1. Chapter 3: Management of Progression and Complications of CKD. Kidney Int Suppl (2011). 2013 Jan:3(1):73-90.
2. Raphael KL. Approach to the treatment of chronic metabolic acidosis in CKD. Am J Kidney Dis. 2016 Apr;67(4):696-702.
Quiz
A 75-year-old male with hypertension and CKD Stage 4 is admitted to the hospital for a hip fracture following a fall. Laboratory studies on admission show a potassium level of 3.2 mEq/L, vitamin D level of 45 ng/mL, bicarbonate level of 17 mEq/L, phosphate level of 5.0 mg/dL, and calcium level of 10.3 mg/dL.
What electrolyte replacements should be initiated?
A. Dietary restriction of phosphate, sodium bicarbonate, potassium chloride, and vitamin D.
B. Non–calcium-containing phosphate binder, vitamin D, and potassium chloride.
C. Calcium-containing phosphate binder and sodium bicarbonate.
D. Non–calcium-containing phosphate binder, sodium bicarbonate, and potassium chloride.
Answer: D. Given the patient’s hypokalemia, potassium supplementation should be considered. Additionally, given his hyperphosphatemia and hypercalcemia, a non–calcium-containing phosphate binder like Sevelamer should be started. His metabolic acidosis should be corrected with sodium bicarbonate. There is no indication to supplement vitamin D based on his current lab values.
Key Points
- Identify and treat underlying causes of hypokalemia and hypomagnesemia.
- Do not hesitate to treat metabolic acidosis in CKD.
- Manage hyperphosphatemia and hypocalcemia by ordering appropriate lab studies and providing nutritional consultation with outpatient nephrology follow-up as indicated.
Case
A 55-year-old woman with diabetes, hypertension, and chronic kidney disease (CKD) stage 4 is admitted to the hospital for treatment of left lower-extremity cellulitis. Laboratory studies on admission show a creatinine level of 2.5 mg/dL (glomerular filtration rate [GFR] is 20 mL/min per 1.73 m2; baseline creatinine is between 2.2 and 2.6 mg/dL), potassium level of 3.0 mEq/L, magnesium level of 1.5 mEq/L, bicarbonate level of 18 mEq/L, phosphate level of 6.5 mg/dL, and calcium level of 7.5 mg/dL.
She is put on renally dosed vancomycin to treat her cellulitis. As the hospitalist, how should you manage her multiple electrolyte abnormalities?
Overview of the issue
CKD is also an important risk factor for acute kidney injury. Additionally, rates of readmission for CKD patients are higher than those without CKD. Given that CKD is a “silent disease” that many patients do not realize they have, it is very possible that the first documentation of CKD could happen during an acute hospitalization.
Among the various manifestations of CKD, electrolyte abnormalities are the most likely ones hospitalists will run into.
Overview of the data
Hypokalemia and Hypomagnesemia
Hypokalemia (potassium levels less than 3.5 mEq/L) is not as common as hyperkalemia (potassium levels greater than 5.0 mEq/L) in CKD, which is the result of impaired renal excretion of potassium. Hypokalemia can occur as a result of GI losses, urinary losses, or decreased intake and can be worsened by the use of certain drugs, such as non–K-sparing diuretics.
In the setting of diuretic use involving thiazides and loop diuretics, hypokalemia is dose and sodium-intake dependent. Potassium deficiency worsens the effects of detrimental sodium excess, which plays a role in hypertension and its associated complications. Potassium also has a protective vascular effect, which is a major reason why potassium should be kept normal in patients with CKD.
Acutely, hypokalemia can cause arrhythmias, ileus, and paralysis, which are all indications for immediate repletion. In these cases, hypokalemia must be repleted carefully in small increments (some suggest 20 mEq doses), and the patient must be monitored frequently to avoid hyperkalemia. If patients are persistently hypokalemic, several options can be considered based on the underlying cause. Dietary modifications with foods rich in potassium (containing 250mg/100g) can be suggested. Daily potassium chloride supplementation can be used in those on diuretic therapy who have hypokalemia and metabolic alkalosis (bicarbonate levels greater than 30 mEq/L). Alkalinizing salts, containing citrate or bicarbonate, can be used in hypokalemia without metabolic alkalosis. Initiation of angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta-adrenergic blockers, and K-sparing diuretics can be used as well.
Potassium supplementation and K-sparing diuretics should be used with extreme caution in CKD 3 and 4 given the risk of overcorrection. If potassium supplements or drugs to raise serum potassium are initiated in house, potassium should be rechecked within a week. These treatments should be avoided in individuals with diabetes, who are at highest risk for hyperkalemia given hyporeninemic hypoaldosteronism (type IV renal tubular acidosis).
There is emerging evidence that hypomagnesemia can play a part in progression to end-stage renal disease. In the setting of cardiovascular disease, which often co-exists with CKD, the risk of hypomagnesemia precipitating arrhythmia necessitates repletion to a normal level. Any of the magnesium salts and antacids can be used for treatment. K-sparing diuretics are also magnesium sparing. An important side effect of magnesium repletion is diarrhea, which can potentiate electrolyte losses and reduce long-term adherence rates.
Metabolic acidosis
Acid-base balance is maintained by the kidney through urinary excretion of hydrogen ions both as titratable acids and ammonium. In CKD, renal excretion of the daily acid load is impaired, primarily from decreased ammonium excretion caused by there being too few functioning nephrons.
Metabolic acidosis in CKD is defined as a serum bicarbonate concentration of persistently less than 22 mEq/L. The overall prevalence of metabolic acidosis in cases of CKD that don’t require dialysis is about 15% and increases linearly with a decline in GFR. In the Chronic Renal Insufficiency Cohort study, 7%, 13%, and 37% of participants with CKD stages 2, 3, and 4 respectively had metabolic acidosis.
Metabolic acidosis has a variety of adverse outcomes, including bone demineralization, increased protein catabolism and muscle wasting, impaired cardiac function, impaired glucose homeostasis, and systemic inflammation. Additionally, multiple studies have shown an association between metabolic acidosis and progression of CKD and increased mortality.
The 2013 Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend maintaining the serum bicarbonate level within the reference range (23-29 mEq/L) with alkali therapy. Options include sodium bicarbonate or sodium citrate (which is rapidly metabolized to bicarbonate) in doses of 0.5-1.0 mEq/kg once per day. Sodium bicarbonate is inexpensive; however, it can lead to gastrointestinal upset as the bicarbonate is converted into CO2 in the stomach. This side effect is usually self-limited and improves with time. Typical starting doses are 650 mg twice a day if the serum bicarbonate level is 19-21 mEq/L or 1300 mg twice a day if the serum bicarbonate level is less than or equal to 18 mEq/L.
Sodium citrate can be used if gastrointestinal upset occurs, although caution should be used in those on aluminum binders or with liver disease. Alkali treatment should be started when bicarbonate levels are persistently low (for weeks or months) or if very low (less than or equal to 18 mEq/L) without an acute reversible cause. After patients have begun therapy, they should be monitored for the development of worsening hypertension or edema caused by sodium-mediated fluid retention, although this rarely occurs.
Hyperphosphatemia and Hypocalcemia
Hyperphosphatemia (phosphate levels greater than 4.6 mg/dL) develops early in CKD because of a reduced filtered-phosphate load. Hypocalcemia and hyperphosphatemia can lead to secondary hyperparathyroidism. Given that hyperphosphatemia has been associated with an increased mortality among patients with CKD, treatment is warranted, but the optimal phosphorus range is unknown. According to the KDIGO guidelines, the goal phosphorus level is less than 4.5 mg/dL in patients with CKD who are not on dialysis.
Treatment includes dietary restriction to 900 mg/day and phosphate binders. There is a high phosphate load in processed foods and colas because of food additives. It is therefore recommended to reduce consumption of these foods while encouraging consumption of meat and eggs, which offer additional nutritional value. Those who have failed dietary restrictions should be put on a phosphate binder, either calcium containing (calcium carbonate, calcium acetate) or non–calcium containing (Sevelamer, lanthanum). Non–calcium-containing binders are recommended for patients with hypercalcemia (levels greater than 9.5 mg/dL). There is some data that suggests that non–calcium-containing binders are superior to calcium-containing binders in terms of vascular disease outcomes, but non–calcium-containing binders are sometimes difficult to obtain because of cost and insurance coverage.
Hypocalcemia (calcium levels below 8.4 mg/dL) occurs in the setting of late stage untreated CKD because of decreased GI uptake of calcium from diet in the context of vitamin D deficiency (less than 30 ng/mL) in addition to hyperphosphatemia. Phosphate and vitamin D correction is preferred to calcium supplementation because hyperphosphatemia and vitamin D deficiency occur earlier in CKD. Phosphate reduction is described above.
Regarding vitamin D deficiency, it is recommended to start supplementation with either vitamin D2 or D3. Doses should be adjusted if GFR is less than 30 mL/min per 1.73 m2. It is important to monitor for hypercalcemia, which can also occur in CKD in this context, because it has also been associated with increased morbidity and mortality. If calcium levels are greater than 10.2 mg/dL, all vitamin D supplementation should be discontinued.
Back to the case
Our patient who was admitted for cellulitis has concomitant hypokalemia, hypomagnesemia, acidosis, and hyperphosphatemia with related hypocalcemia. She revealed that her diet was poor prior to her admission for her infection. She was given 20 mEq of potassium orally and placed on a potassium rich diet until potassium levels normalized. She was also given magnesium oxide orally on the first and second day of admission, with repeat levels that were normal. Her acidosis was treated with sodium bicarbonate – 1,300 mg orally twice daily. For her hyperphosphatemia and hypocalcemia, she was placed on phosphate restriction with nutritional counseling with plans to follow up as an outpatient to determine need for phosphate binders. In addition, vitamin D levels were checked, and she was started on repletion for vitamin D deficiency (27 ng/mL). Daily BMP, magnesium, and phosphorus were checked while in house until they were normal for 2 days, and follow-up lab work was requested with her nephrology appointment, which was scheduled for within 1 week.
Bottom line
Electrolyte abnormalities in CKD are numerous and have multiple adverse clinical outcomes. Early intervention and management, especially of metabolic acidosis and hyperphosphatemia, can have a significant effect, including prevention of progression of CKD and possibly reduced mortality.
Dr. Daya, Dr. Apgar, and Dr. Eniasivam are assistant clinical professors in the division of hospital medicine at the University of California, San Francisco.
References
1. Coresh J et al. Prevalence of chronic kidney disease in the United States. JAMA. 2007 Nov 7;298(17):2038-47.
2. Dhondup T et al. Electrolyte and acid-base disorders in chronic kidney disease and end-stage kidney failure. Blood Purif. 2017;43(1-3):179-188.
3. K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis. 2004 May;43(5 Suppl 1):S1-290.
4. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl (2011). 2013 Jan;3(1):1–150.
5. Sakaguchi Y et al. Hypomagnesemia in type 2 diabetic nephropathy: A novel predictor of end-stage renal disease. Diabetes Care. 2012 Jul;35(7):1591-7.
6. Palmer SC et al. Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: A systematic review and meta-analysis. JAMA. 2011 Mar 16;305(11):1119-27.
7. Patel L et al. Sevelamer versus calcium-based binders for treatment of hyperphosphatemia in CKD: A meta-analysis of randomized controlled trials. Clin J Am Soc Nephrol. 2016 Feb 5;11(2):232-44.
8. Raphael KL. Approach to the treatment of chronic metabolic acidosis in CKD. Am J Kidney Dis. 2016 Apr;67(4):696-702.
9. Raphael KL et al. Prevalence of and risk factors for reduced serum bicarbonate in chronic kidney disease. Nephrology (Carlton). 2014 Oct;19(10):648-54.
Additional reading
1. Chapter 3: Management of Progression and Complications of CKD. Kidney Int Suppl (2011). 2013 Jan:3(1):73-90.
2. Raphael KL. Approach to the treatment of chronic metabolic acidosis in CKD. Am J Kidney Dis. 2016 Apr;67(4):696-702.
Quiz
A 75-year-old male with hypertension and CKD Stage 4 is admitted to the hospital for a hip fracture following a fall. Laboratory studies on admission show a potassium level of 3.2 mEq/L, vitamin D level of 45 ng/mL, bicarbonate level of 17 mEq/L, phosphate level of 5.0 mg/dL, and calcium level of 10.3 mg/dL.
What electrolyte replacements should be initiated?
A. Dietary restriction of phosphate, sodium bicarbonate, potassium chloride, and vitamin D.
B. Non–calcium-containing phosphate binder, vitamin D, and potassium chloride.
C. Calcium-containing phosphate binder and sodium bicarbonate.
D. Non–calcium-containing phosphate binder, sodium bicarbonate, and potassium chloride.
Answer: D. Given the patient’s hypokalemia, potassium supplementation should be considered. Additionally, given his hyperphosphatemia and hypercalcemia, a non–calcium-containing phosphate binder like Sevelamer should be started. His metabolic acidosis should be corrected with sodium bicarbonate. There is no indication to supplement vitamin D based on his current lab values.
Key Points
- Identify and treat underlying causes of hypokalemia and hypomagnesemia.
- Do not hesitate to treat metabolic acidosis in CKD.
- Manage hyperphosphatemia and hypocalcemia by ordering appropriate lab studies and providing nutritional consultation with outpatient nephrology follow-up as indicated.