calcineurin inhibitors and hyperkalemia · calcineurin inhibitors and hyperkalemia sheena...
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CALCINEURIN INHIBITORS AND HYPERKALEMIASheena Surindran, MD3/22/2011
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DISTAL TUBULE K SECRETION
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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
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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
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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
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EFFECT OF FLUDROCORTISONE ON TTKG
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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
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CONCLUSIONS
Hyperkalemia in transplant recipients is due to tubular insensitivity to Aldosterone which can be overcome by bicarbonaturia
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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
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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
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Exp nephrology 2001
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Exp nephrology 2001
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Exp nephrology 2001
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RESULTSCell 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
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EFFECT ON POTASSIUM CHANNELS
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EFFECT OF ALDOSTERONE
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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
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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
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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
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MR EXPRESSION
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ALDOSTERONE RESPONSE TO FLUDROCORTISONE
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MR EXPRESSION BEFORE AND AFTER TREATMENT
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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
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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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