Authors: Hengameh Abdi- M.D. Shahrzad Ossareh- M.D.

The patient was a 62 year old man with 15 years history of diabetes mellitus and 8 years history of hypertension. He had been diagnosed to have diabetic kidney disease since about 4 years ago. He told about the history of coronary artery(two-vessels) disease documented by coronary arteriography.
He was under hemodialysis via arterio-venous fistula for one year till 3 weeks before his admission, when he underwent renal transplantation from a living unrelated donor. He had been discharged from transplantation ward after 2 weeks with serum cratinine level of 1.1 mg/dl.
He returned to the hospital after 1 week of discharge from transplantation wad, because of severe asthenia since four days ago. His discharge medications were as follows: CellCept 1000 mg bid, Cyclosporine 150 mg bid, Prednisolone 15 mg bid, Metoprolol 50 mg daily, Omeprazole 20 mg daily, trimetoprime- sulfomethoxazole, 400/80 mg bid, and NPH insulin.
His physical examination was normal on admission, except for cushingoid face and generalized weakness, with normal vital signs.

Lab data:
WBC=13200 (PMN=85%), Hb=14, Plt=119000
ESR=8 mm, CRP: negative, PT and PTT: Normal
BUN=62 mg/dl, Cr=1.8 62 mg/dl, Na=129 meq/L, K=8.5 meq/L, Cl=108 meq/L, Ca=8.9 62 mg/dl, P=3.4 62 mg/dl
BS= 369 mg/dl, AST=93 U/L, ALT=109 U/L, Alk.P=174 U/L,
TG=178 mg/dl, Cholestrol=238 mg/dl, LDL=159 mg/dl, HDL=43 mg/dl,
Albumin=4.4 g/dl, CPK=43
Serum iron=135 μg/dl, TIBC=279 μg/dl, Ferritin> 800 ng/ml
HBsAg & HCV-Ab: Negative.
ABG: pH=6.83, PCO2=18 mmHg, HCO3=2.9 meq/L, PO2=92.6
U/A: pH=5, Pr(-), WBC=2-3, RBC=2-3, U/C: Negative
Cyclosporine level: C0=329 (307), C2=907
CMV Ag (PP65): Negative
CMV DNA PCR: Positive

Abdominal ultrasonography:
Mild fatty liver, Normal spleen, Transplanted kidney: 112 x 54 x 43 mm with volume of 138 ml & parenchymal thickness of 16 mm & normal echogenicity, Prostate: 38 ml

Treatment of hyperkalemia and metabolic acidosis was started with optimal hydration, intravenous and then oral NaHCO3, IV insulin and glucose and oral Kayexalate and sorbitol. Cellcept was continued and cyclosporine was switched to sirolimus, 2 mg daily after a loading dose, with suspicion to cyclosporine induced hyperkalemia and renal tubular acidosis.
Prednisolone dose was decreased to 10 mg bid, Ganciclovir was started with a dose of 300mg IV bid.
His general condition improved significantly after several days of admission. Urine output was about 3L/d.Serum Cr level decreased to 1 mg/dl and serum potassium level to 4.3
Serial VBGs after treatment:
pH =7.22, PCO2=32 mmHg, HCO3=13 meq/L
pH =7.35, PCO2=27 mmHg, HCO3=15 meq/L

An elevation in the plasma potassium concentration due to reduced efficiency of urinary potassium excretion is common in cyclosporine-treated patients; it may be severe and potentially life-threatening with concurrent administration of an angiotensin converting enzyme inhibitor, which diminishes aldosterone release. Cyclosporine may reduce potassium excretion both by decreasing the activity of the renin-angiotensin-aldosterone system and by impairing tubular responsiveness to aldosterone (1,2).
In vitro studies suggest that cyclosporine may directly impair the function of the potassium secreting cells in the cortical collecting tubule by affecting each of these steps: reduced activity of the Na-K-ATPase pump (3), inhibition of the luminal potassium channel (4), and increased chloride reabsorption, which prevents generation of lumen-negative potential that drives potassium secretion (2).
Cyclosporine may also have a second effect on potassium homeostasis in patients concurrently treated with a ß-blocker. In this setting, there is often a modest (less than 1 meq/L) and transient elevation in the plasma potassium concentration due to the movement of potassium out of the cells into the extracellular fluid (5).
Tubular injury induced by cyclosporine can also impair acid excretion. This may be manifested as a hyperchloremic (normal anion gap) metabolic acidosis that may also reflect decreased aldosterone activity and suppression of ammonium excretion by hyperkalemia (6).
Our patient is a case of metabolic acidosis with severe hyperkalemia as a result of cyclosporine effect. Ratio of changes in anion gap to bicarbonate (∆AG/∆HCO3) was 18/21, or 0.85 which implies a mixed normal- and high anion gap metabolic acidosis. Normal anion-gap metabolic acidosis may be explained by renal tubular acidosis caused by cyclosporine. The explanation for high anion gap metabolic acidosis is not quite clear for us, because the patient had no clinical cause of lactic acidosis such as hypotension or septicemia or any kind of intoxication or significant renal failure. We only suspect diabetic ketoacidosis, with a blood sugar level of 369 mg/dl, although no ketones were detected in urinalysis (blood ketones were not measured).
After 9 months of follow-up he has normal kidney function electrolyte levels.

References:
1. Deray, G, et al. Renal function & blood pressure in patients receiving long-term, low-dose cyclosporine therapy for idiopathic autoimmune uveitis. Ann Intern Med 1992; 117:578
2. Kamel, KS, Ethier, JH, Quaggin, S, et al. Studies to determine the basis for hyperkalemia in recipients of a renal transplant who are treated with cyclosporine. J Am Soc Nephrol 1992; 2:1279.
3. Tumlin, JA, Sands, JM. Nephron segment-specific inhibition of Na-K-ATPase activity by Cyclosporine. Kidney Int 1993; 43: 246
4. Ling, BN, Eaton DC. Cyclosporine A inhibits apical secretory K channels in rabbit cortical collecting tubule principal cells. Kidney Int 1993; 44: 974
5. Pei, Y, et al. Extrarenal effect of Cyclosporine A on potassium homeostasis in renal transplant recipients. Am J Kidney Dis 1993; 22: 314
6. Kahan, BD. Drug therapy: Cyclosporine. N Engl J Med 1989; 321: 1725