CALCINEURIN INHIBITORS AND HYPERKALEMIASheena Surindran, MD3/22/2011

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

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

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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