CALCINEURIN INHIBITORS AND HYPERKALEMIA Sheena Surindran, MD 3/22/2011
DISTAL TUBULE K SECRETION
EFFECTS OF CYCLOSPORINE ON RAS AND POTASSIUM EXCRETION 10 pts on CsA and prednisone / 10 on AZT and prednisone Pts hospitalized and given 120meq Na and 80meq K diet for 3 days Cr clearance determined by 24hr collection Day 4 pts got 0.75meq/ kg KCl po at 9am Serum K and aldosterone measured 1hr prior, 1,3,5hrs after Urine K excretion by timed 2hrs collection before and after for 6hrs Pts had no po intake during k study- then recived 15meq Na diet and two 40mg lasix doses Day 5 plasma Renin and Aldo measured supine overnight and 2 hrs after upright posture. Archives of internal medicine, 1985
CONCLUSIONS Cyclosporine use was associated with hyporeninemic state but aldo levels lower but not statistically significant Lower U osm in CsA pts and urine K per unit plama aldo conc was less in CsA suggested a distal tubular defect causing NaCl reabsorption, suppress Renin and cause HTN Archives of Internal medicine 1985
BASIS FOR HYPERKALEMIA IN RENAL TRANSPLANTS ON CYCLOSPORINE 12 patients on CsA (creat 1.5-1.6, no rejection, no toxicity) and 14 healthy volunteers 50meq KCl load given to normals and study pts had k>5- urine electrolytes and blood tests drawn 200mcg Fludrocortisone given to both grp- 2hr urine discarded and then 1hr urine collected Po 250mg Azetazolamide, another dose given if urine ph<7.5 and 1hr urine and blood drawn JASN-1991
EFFECT OF FLUDROCORTISONE ON TTKG
RESULTS Relative low aldo level in the presence of hyperkalemia 295pmol/l (111-860) Low renin 0.5+-0.2 (0.6-0.8ng/l/s) Appropriate increase in TTKG in normal post K load, low in study pts (4.3+- 0.2) Response to Fludrocortisone- TTKG in control- 12, and in pts rose to 5.6, rate of excretion k 0.06 in CsA, 0.1 mol/min in control Post bicarb load TTKG in control increased to 17, pts increase to 11 JASN 1991
CONCLUSIONS Hyperkalemia in transplant recipients is due to tubular insensitivity to Aldosterone which can be overcome by bicarbonaturia
COMPARING FK506 AND CYCLOSPORINE 8 patients in either grp randomized Na sulphate and Na bicarbonate loading Studies were performed 6mths post txp Fractional excretion of bicarb unchanged in either Plasma renin and aldo levels were significantly decreased in FK506 grp (p<0.05) Hyperkalemia was more in FK506 grp vs CsA grp Distal hydrogen secretion was impaired in pt on FK506 causing distal tubular acidosis Clinical transplantation Oct, 1998
EFFECTS OF FK506 AND CYCLOSPORINE ON K TRANSPORT IN MDCK CELLS Animal and human studies have shown decrease kaliuresis and impaired urinary acidification by affecting distal ion transport. MDCK cells to study the toxic and antiproliferative effect of FK506 and CsA Effect on Na+/K-ATPase and Na+/K+/2Cl co transporter Role on aldosterone in this system Exp nephrology 2001
Exp nephrology 2001
Exp nephrology 2001
Exp nephrology 2001
RESULTS Cell viability and membrane integrity Both reduced number of viable cells in a dose dependent manner (CsA caused effect at lower dose) Cell proliferation Both reduced proliferation but FK506 at lower doses than CsA- dose dependent effect
EFFECT ON POTASSIUM CHANNELS
EFFECT OF ALDOSTERONE
CONCLUSIONS CsA significantly reduced the activity of Na+/K+- ATPase and of Na+/K+/2Cl co transporter In contrast to CsA, FK506 at the same concentration had no significant effect on Na+/K+-ATPase transport activity but significantly stimulated the Na+/K+/2Cl co transporter activity
ALDOSTERONE RESISTANCE IN KIDNEY TRANSPLANT Cyclosporin binds to cyclophillin and FK506 binds to FKBP52 Hypothesis that CsA and FK506 are able to induce resistance of distal tubule to action of aldosterone in txp pts Effects of immunophillin ligand and CsA on ion transport and expression of MR in renal txp recepients Influence of fludrocotisone on electrolyte homeostasis and MR expression in pts with and without metabolic acidosis Clinical transplantation 2004:18:186-192
METHODS 21 patients, 7 had metabolic acidosis 12 healthy patients were controls Studies carried out 2-12mths post txp PRA, aldo were measured supine Quantitative reverse phase polymerase chain reaction was used to determine hmr
MR EXPRESSION
ALDOSTERONE RESPONSE TO FLUDROCORTISONE
MR EXPRESSION BEFORE AND AFTER TREATMENT
CONCLUSIONS Patients treated with CsA experienced a down regulation in MR in peripheral leucocytes inspite of normal aldo levels with no difference in pts with and without acidosis. Aldo resistance might be partly responsible for hyperkalemia / metabolic acidosis Patients may benefit from treatment with fludrocortisone
SUMMARY EFFECTS OF CALCINEURIN INHIBITORS Hyporeninemic hypoaldosterone state Aldo resistant state in the setting of normal or near normal aldosterone levels by down regulating MR expression Cyclosporine interferes with Na gradient in CD by affecting Na/K-ATPase and possible NKCC2 channels FK506 can also causes a distal tubular defect and more significant hyperkalemia Some patients may respond to Fludrocortisone Thiazide diuretic can be used as initial therapy
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