IJ.M.S. June. 1990

The Use of Cyclosporin A in Adult Nephrotic Syndrome : Nine Cases and Literature Review

A. Green, Y. O'Meara, J. Sheehan, M. Carmody, G. Doyle, J. Donohoe

Departments of Nephrology and Pathology, Beaumont Hospital, Dublin 9.

Summary Nine adult patients with resistant

nephrotic syndrome were treated with cyclosporin A (CyA). All had failed to respond to high dose corticosteroids with or without cyclophosphamide. Three patients had minimal change disease, 3 had focal sclerosing glom- erulosclerosis (FSGS), 2 had mesangio- capillary GN, and one had membranous nephropathy. The mean age of the patients was 26.4 years (range 16 to 39 y.ears). CyA was given orally twice daily at a mean dose of 6.7 mg/kg/24 hours (range 6-10 mg/kg/24 hours).

Four patients achieved full remis- sion, two patients went into partial remission, and three failed to respond. Two patients developed clinical neph- rotoxicity, which reversed on dose re- duction or cessation of CyA. All 3 pa- tients with minimal change disease who responded subsequently relapsed after stopping CyA, but remitted rapidly on reintroduction of the drug.

We suggest that the mode of action of CyA in nephrotic syndrome may be related to intra-renal vasoconstriction in addition to its direct immunosuppres- sire effect. In this limited series, we found that CyA can be an effective therapy for otherwise refractory neph- rotic syndrome, although relapse on withdriawal of CyA may well be a sig- nificant clinical problem.

Introduction The management of severe nephrotic

syndrome presents a number of major therapeutic problems. Patients may be steroid dependent and relapse as soon as therapy is reduced or withdrawn. Oth- ers may be steroid resistant, requiring cytotoxic drugs 1. These forms of treat- ment carry both short term risks of in-

Correspondence to : Dr. A. Green, MRC Molecular Genetics Unit, Level 5, Addenbrooke's Hospital, Hills Road, Cambridge CB1 5 HB, U.K.

fection and long term risks of gonadal dysfunction and malignancy. The con- tinuing nephrotic state has its own sig- nificant morbidity, including throm- boembolism, hyperlipidaemia, and spontaneous peritonitis. �9 Animal studies have suggested that

the aetiology of minimal change dis- ease (MCD) and FSGS may be medi- ated by lymphokines 2,3. Interference with the production of lymphokines especially interleukin 2, by CyA has been well documented 4. This fact has prompted several studies of the effec- tiveness of CyA in patients with the nephrotic syndrome~,e.L

P a t i e n t s a n d M e t h o d s Nine adult patients were treated. All

had severe resistant or relapsing neph- rotic syndrome. All required large doses of loop diuretics to control oedema. Three had failed to respond to both cor- ticosteroids and cyclophosphamide ther- apy, and 6 had no or slight response to corticosteroids. Three patients had minimal change disease (MCD), 3 had FSGS (one recurring in a sibling trans- pianO, 2 had mesangiocapillary glom-

erulonephritis (MCGN), and one had membranous nephropathy. The patient with recurring FSGS received a sibling transplant 18 months prior to the onset of nephrotic syndrome, and was im- munosuppressed with prednisone and azathioprine. CyA was substituted for azathioprine, and prednisone was con- tinued at a dose of 10 mg daily. Patient details are summarized in Table I. Both patients with MCGN were hyperten- sive, but no other patient had raised blood pressure.

Patients had baseline clinical exami- nation, full biochemistry, blood pres- sure, weight, and 24 hour urine collec- tion for protein estimation performed. These parameters were checked weekly, along with trough CyA levels, for one month and then monthly thereafter, as long as the patient remained on CyA.

Cyclosporin A was given orally as a twice daily dose. Blood levels meas- tired initially by HPLC to maintain whole blood levels between 300 and 700 ng/ml, and subsequently by mono- clonal RIA (Sandoz) to keep whole blood levels between 150 and 350 ng/ ml. The mean cyclosporin dose was 6.7

TABLE I PATIENT CLINICAL DETAILS

Case Age Sex Urine Protein SE Albumin SE Creatinine Lesion years GM/24 hours GM/L umol/1

1 20 M 7.6 17 59 MCD 2 26 M 7.9 26 80 FSGS 3 26 M 16.3 21 100 FSGS 4 32 F 4.2 26 61 MCD 5 38 M 7.3 31 145 FSGS

(in transplant) 6 19 M 8.5 22 94 MCD 7 16 M 13.5 15 84 MCGN 8 22 M 12.4 20 159 MCGN 9 39 M 9.5 19 105 MEMB

Mean 9.6 22 98

MCD = FSGS = MCGN = MEMB =

Minimal change disease Focal segmental glomerulosclerosis Mesangiocapillary glomerulonephritis Membranous nephropathy

178

Vo1159 Cyclosporin A in adult nephrotic syndrome 179 No. 6

mg/kg/day (range 6-10 mg/kg/day). The maximum duration of initial ther- apy was 12 months. Mean follow up was 13 months (range 3 to 18 months).

Complete remission was defined as a fall in proteinuria to less than 1 gm/24 hours. Partial remission was defined as a significant fall in proteinuria, with a reduction in diuretic requirements, re- turn of the serum albumin to normal, and resolution of oedema.

Results All 3 patients with MCD achieved

full remission after one month's ther- apy, as did the patient with recurrent FSGS. All were able to be weaned off their diuretics, and their serum albumin rose to normal.. Two patients went into partial remission after one month, one having FSGS, and one having membra- nous nephropathy. Their serum albu- min rose to normal, their oedema cleared and their proteinuria fell from 16.3 to 3.8 gm/24 hours, and 9.5 to 4.5 gm/24 hours respectively. Neither patient with MCGN, and one patient with FSGS did not respond at all after 2 months therapy (see Table II).

There was no change in the degree of hypertension in those with raised blood pressure, and no patient developed hypertension. All patients developed varying degrees of hypertfichosis. The female patient stopped therapy on ac- count of this side-effect. Two patients developed overt nephrotoxicity. One patient with MCGN showed a rise in serum creatinine from 160 to 400 umol/ 1, despite therapeutic blood CyA levels. This responded to cessation of therapy. Serum creatinine in the patient with recurrent FSGS rose from 130 to 190 umol/l, with associated high blood CyA levels, nausea and tremor. This re- sponded fully with dose reduction. A third patient developed high blood lev- els with no change in serum creatinine,

when given cimetidine. This resolved on cessation of cimetidine.

The patients that responded have been followed up for a mean of 13 months (range 3 to 18 months), with a gradual weaning of the CyA dose to a mean of 4.4 mg/kg/day (range 2.5 to 6 mg/kg). All three patients with MCD stopped CyA at 3, 6 and 9 months respectively. All relapsed at a time of 1 to 3 months after stopping CyA. All remitted on reintroduction of CyA at a dose of 3 to 5 mg/kg/day. The patient with recur- rent FSGS remains on CyA at a dose of 5 mg/kg/day, along with 10 mg/day of prednisone, as maintenance transplant immunosuppression.

Discussion and Literature Review To date, the majority of experimental

work with CyA has focussed on its immunosuppressive effects. The drug acts to impair T-helper cell response when presented with antigen, it inter- feres with the elaboration ofinterleukin- 2 by T-helper cells, it disrupts the acti- vation of B-cell responses by T-helper cells, and also blocks the proliferation of cytotoxic T-cells 4.s. Abnormalities of T-cell function have been implicated in the pathogenesis of idiopathic neph- rotic syndrome, and a predominance of T-suppressor cells has been reported 2,3. Lymphokines secreted by abnormal T- cells are suggested as potential media- tors of glomerular basement membrane damageL

Animal studies of CyA in experi- mental glomerulonephritis (GN) have all shown significant reduction or abo- lition of proteinuria in rodents 9.1~ This effect was seen in a wide variety of disease models ranging from anti-glom- erular basement antibody GN, to serum sickness. In two studies, GN could be completely suppressedifCyA was given before the onset of the disease, but not after the disease was established 9,~3. One

TABLE II RESULTS OF CYCLOSPORIN THERAPY IN NEPHROT1C SYNDROME

Full Remission 4 patients

Partial Remission 2 patients

No Response 3 patients

3 minimal change disease 1 focal segmental glomerulosclerosis in transplant 1 membranous nephropathy 1 focal segmental glomerulosclerosis 2 mesangiocapillary glomerulonephritis 1 focal segmental glomerulosclerosis

study showed relapse on cessation of CyA, which responded to re-inlxoduc- tion of therapy 11.

Cyclosporin A also has significant non-immunological effects. It has been shown to increase renal vascular resis- tance and reduce renal blood flow in rats 14,1~. These effects were not pre- vented by captopril, suggesting that they were not directly mediated by angioten- sin activation. Denervation of the kid- ney blocked these effects, posing a neu- ral sympathetic role in CyA induced intra-renal vasoconstriction. Human studies have shown reduced plasma renin activity, reduced effective renal plasma flow, and reduced glomerular filtration rate in renal transplant pa- tients on CyA ~6.

We have demonstrated a 66% re- sponse rate to CyA in adult nephrotic syndrome, with a 44% complete remis- sion rate. Patients with minimal change disease appeared to do best, whereas the patients with MCGN did not respond. The drug was overall well tolerated, but with two cases of reversible nephrotox- icity, a close guard must be kept on renal function and CyA levels. Poten- tial drug interactions with CyA as in our study must also be highlighted. A dis- appointing feature in our group was the 100% relapse rate on withdrawal of CyA in patients in remission. If CyA is therefore required long term to main- tain remission, then the serious issue of chronic nephrotoxicity has to be dealt with. /

To date, sixteen previous studies of CyA in adult nephrotic syndrome have been published, totalling 226 patients, the majority of whom had either MCD or FSGS (see Table III) ~7"~3. The largest of these, the French Collaborative Study zs, showed a 65% remission rate for MCD, and a 40% rate for FSGS, a significant difference. Response was also better in those patients who were steroid dependent rather than steroid resistant. However, most patients who remitted became CyA dependent, re- lapsing on withdrawal of CyA. Only minor side-effects were observed. In general, remission rates varied between 66% and 100% in different series, re- missions being more frequent in pa- tients with MCD. Remissions usually occurred within one month of corn-

180 Green et al. I .J.M.S. June, 1990

TABLE III REPORTS ON CYCLOSPORIN A IN ADULT NEPHROTIC SYNDROME

Author (ref.) Pts. MCD FSGS MEMB Other Dose CyA % Remission Follow up mg/kg Months

Lagrue (17) 13 10 3 5 92% 3 Sreepada (18) 5 2 3 7 80% 2 Balcke (19) 5 5 3 80% 12 Desanto (20) 5 5 7 80% 3 Miller (22) 3 3 6 100% 6 Praga (34) 1 1 7 Acute renal failure Zietse (23) 15 1 3 6 3 6 73% 3

Alport's Berthoux (24) 3 3 10 66% 3 Heule (25) 7 3 71% 3 Kuhn (26) 15 10 5 86% 11 Meyrier (28) 56 23 28 5 65% MCD

40% FSGS CSSN (29) 40 10 15 5 3 MCGN 5 55% MCD 6

18% FSGS 5 diffuse prolif GN 2 SLE

"Erbay (27) 18 5 88% Schulz (30) 15 2-6 1000 6-18 Clasen (31) 7 7 3-5 71% 6-18 Maher (32) 15 11 4 7.7 100% MCD

0% FSGS Lai (33) 4 4 IgA 5 75% 6

TOTAL 226 82 62 19

MCD = FSGS = MEMB =

MCGN =

Minimal change disease Focal segmental glomerulosclerosis Membranous nephropathy Mesangiocapillary glomerulonephritis

mencing CyA therapy. In those stud- ies where the drug was withdrawn, re- lapse rates were high, varying from 38% to 100%. The longest reported period of follow up in any patient has been 18 months 3~

Fewer patients with a much. com- moner cause of nephrotic syndrome, membranous nephropathy, have been studied. Nineteen patients have been reported, of which twelve have re- sponded (63%) 2~ The selection criteria for these patients is not clear, and thus exlrapolation o f these results is difficult. The presence o f renal failure with membranous nephropathy may have a negative influence on the effi- cacy of CyA in membranous nephropa- thy. One patient with adult IgM disease did not respond to CyA 32. Three other patients with adult MCGN have been documented , none of whom re- sponded z3'~s. The good response to CyA of three patients with nephrotic syn-

drome due to Alport's syndrome, pre- sumably non-immunologic in origin, would suggest a more haemodynamic than immunological role for CyA in reducing proteinuria z~.

One case of acute renal failure with CyA therapy for nephrotic syndrome resolved on stopping therapy. Interest- ingly, this episode o f renal failure was associated with reduction of urinary 6- keto-PFG, a prostaglandin metabolite. It was suggested that some of the effects of CyA in nephrotic syndrome may be due to impairment o f prostaglandin bal- ance s . Twenty-twopatients (9.7% of the total) in five series had documented reversible nephrotoxic i ty 19,23,~,29,31. Other side-effects such as nausea, tremor, hypertrichosis and gum hy- pertrohy were reported as common.

From these reports and from our own experience, it would appear that CyA is an effective agent in inducing remission in otherwise refractory idiopathic syn-

drome. However, there was a disap- pointingly high rate of relapse in all series where follow up was reported. It would appear that CyA dependence is an emerging problem. The occurrence o f definite reversible nephrotoxicity, and possible irreversible renal effects is also a cause for concern.

We would recommend the use of C y A in severe refractory nephrotic syndrome, despite the risk o f depend- ence and possible damage. We would suggest that the effect o f CyA in idio- pathic nephrotic syndrome is not only by its immunosuppression, but also by intra-renal vasoconstriction. The natu- ral history o f .CyA induced remission requires further evaluation.

R e f e r e n c e s

1. Glassock, R.J.,Cohen, A. H.,Bennett, C.M. and Martinez-Maldonado, M. Primary glom- emlar diseases. In: Brenner, B. M. and Rec- tor, F. C. Jr., eds. The Kidney, 2rid ed. W. B. Saunders, Philadelphia. 1981: p. 349-351.

2. Mallick, N. P. Pathogenesis of minimal change nephropathy. Clin. Nephrol. 1977: 9, 87-95.

3. Shalboub, R. J. Pathogenesis of lipoid neph- rosis: a disorder of T-eeU function. Lancet 1974: ii, 556-560.

4. Borel, J. F. and Lafferty, K. J. Cyclosporin: speculation about its mechanism of action. Transplant Proc. 1983: 15, 1881-1885.

5. Hoyer, P., Kru11, F., Brodehl, J. Cyclosporin in frequently relapsing minimal change syn- drome. Lancet 9 Aug. 1986: 335.

6. Meyrier, A., Simon, P., Perret, G. et al. Remission of idiopathic nephrofic syndrome after treatment with cydosporin A. B.MJ. (Clin. Res.) 1986: 292, 789-792.

7. Tejani, A., Buu, K., Trachtman, T. et al. Cyclosporin induced remission of relapsing nephrotic syndrome in children. Kidney Int. 1988: 33,729-734.

8. Cohen, D. J., Loertscher, R., Rubin, M. F. et al. Cyclosporin: a new immunosuppressive agent for organ transplantation. Ann. Int. Med. 1984: 101,667-682.

9. Baran, D., Vendeville, B., Vial, M. C. et al. Effect of cyclosporin A on mercury-induced autoimmune glomerulonephritis in the Brown Norway rat. Clin. Nephrol. 1986: 25, Suppl. No. 1. S175-S180.

10. Gunn, H. C. and Ryffel, B. Glomemloneph- riffs in NZ B/W mice: therapeutic effect of cyclosporin. Clin. Nephrol. 1986: 25, Suppl. No. 1. S189-S192. Neild, G. H., Ivory, K. and Williams, D. G. Effect of cyclosporin on proteinuria in chronic serum sickness in rats. Clin. Nephrol. 1986: Suppl. No. 1. S186-S188. Thaiss, E., Mihatsch, M. J., Batsford, S. et al. Effect of cyclosporin on in situ immune com- plex glomemlonephfitis. Clin Nephrol. 1986: Suppl. No. 1. S181-S185. Tipping, P. G. and Holdsworth, S. R. Effect of cyclosporin A on antibody induced experi- mental glomemlonephritis. Nephron. 1985: 40, 201-205.

11.

12.

13.

Vo1159 Cyclosporin A in adult nephrotic syndrome 181 No. 6

14. Humes, H. D et al. Pathogenic mechanisms of nephrotoxieity: insights into cydosporin nephrotoxieity. Transplant Proc. Vol XVII No. 4. Suppl. 1 (Aug.) 1985: 51-62.

15. Murray, B.M.,Paller, M.S. andFerris, T. F. Effect of cyclosporin administration on renal haemodynamics in conscious rats. Kidney Int. 1985: 28, 767-774.

16. Banfle, L P., Boudreau, R. J., Ferris, T. F. Suppression of plasma renin activity by cy- closporin. Am. J. Med. 1987: 83, 59-64.

17. Lagrue, G., Lament, J., Belghitti, D. et al. Cyclosporin and idiopathic nephrotic syn- drome. Lancet 1986: ii, 692-693.

18. Sreepada, T. K. et al. Prospective study of cyclosporin in refractory nephrotic syndrome in adults: preliminary results. Kidney Int. 1987: 31,214.

19. Balcke, P. et al. Cyclosporin A treatment of patients with minimal change nephritis. Wien, Klin. Wschr. 1987: 99, 242-245.

20. DeSanto, N. G., Capodicasa, G., Giordano, C. Treatment of idiopathic membranous nephropathy unresponsive to methylpredni- solone and chlorambucfl with eyclosporin.

Am. J. Nephrol. 1987: 7, 74-76.

21. Chan, M.K. andCheng, I.K.P. Cydosporin in steroid-sensitive frequent relapsing neph- rotic syndrome. Postgrad. Med. J. 1987: 63, 757-759.

22. Millet, V. G. et al. Cyclosporin A in minimal change nephrotic syndrome. Kidney Int. 1987: 3,614.

23. Zietse, R. et al. Cyclosporin A in patients with nephrotic syndrome. Kidney Int. 1988: 33, 1035.

24. Berthoux, F. C. et al. Cyclosporin in the treatment of nephrotic syndrome. Nephrol Dial Transplant. 1987: 2, 412.

25. Heule, H. et al. Treatment of severe neph- rotie syndrome with cyclosporin A. Nephrol Dial Transplant. 1987: 2, 415.

26. Kuhn, K. et al. Cydosporin treatment for nephrotic syndrome. Nephrol Dial Trans- plant. 1987: 2, 416.

27. Meyrier, A. Cyclosporin A in the treatment of idiopathic nephrotic syndrome. Springer Semin. Immunopathol, 1987: 441-450.

28. Meyrier, A. et al. Cyclosporin treatment of refractory idiopathic nephrotie syndrome in

adults: resuks of the French Collaborative Study. Transplant Proc. 1988, Suppl. 4 (Book IN), 259-261.

29. The Cooperative Study of the Spanish Soci- ety of Nephrology. Cyclosporin in glomem- lonephritis. Nefrologia 1988: Vol. VIII, Suppl. 1, 15-23.

30. Sehulz, A. W. et al. Treatment of nephrotic syndrome with cyclosporin A. Kidney Int. 1988: 34, 576.

31. Clasen, W. et al. Long-term treatment of nephrotic patients with cydosporin A. Neph- rol Dial Transplant. 1988:3,733-737.

32. Maher, E. R. et al. Cyclosporin A in the treatment of steroid-responsive and steroid- resistant nephrotic syndrome in adults. Neph- rol Dial Transplant. 1988: 3,728-732.

33. Lai, K. N., Lai, F. M. and VaUance-Owen, J. A short-term controlled trial of cyclosporin A in IgA nephropathy. Trans. Proc. 1988: Vol. XX, No. 3, Suppl. 4, 297-303.

34. Praga, M. et al. Cyclosporin A induced acute renal failure in the nephrotic syndrome : a case report. Ann, Int. Meal. 1987: 107, 786- 787.