Meclofenamate Treatment of Recurrent Idiopathic Nephrotic Syndrome With Focal Segmental Glomerulosclerosis After Renal Transplantation VICENTE E. TORRES, M.D. , JORGE A. VELOSA, M.D. , KEITH E. HOLLEY, M.D. , PETER P. FROHNERT, M.D., Division of Nephrology and Internal Medicine; HORST ZINCKE, M.D. , SYLVESTER STERIOFF, M.D. , Organ and Tissue Transplantation Program, Department of Surgery

Recurrent corticosteroid-resistant nephrotic syndrome with focal segmental glomerulosclerosis (FSGS) caused the failure of a first renal allograft in a 41 -year-old man. Recurrence of the nephrotic syndrome in the second renal allograft was successfully controlled by the administration of meclofenamate, and the renal function has remained stable for 2'Λ years. No accepted treatment is available for corticosteroid-resistant nephrotic syndrome with FSGS. This report suggests that administration of meclofenamate might be beneficial in some patients with corticosteroid-resistant nephrotic syndrome and FSGS. Because of the potential side effects, however, careful supervision of this therapy is of the utmost importance.

Focal segmental glomerulosclerosis (FSGS) can result from a variety of glomerular injuries and is a rather nonspecific finding on renal biopsy. In the clinical setting of idiopathic nephrotic syndrome, however, this lesion indicates a poor prognosis because resistance to cortico-steroid therapy and progression to renal failure are likely.1 Idiopathic nephrotic syndrome with FSGS fre­quently recurs after renal transplantation and can result in failure of the renal allograft.2,3 We report the case of a patient in whom the first renal allograft failed because of recurrent FSGS and in whom recurrent disease in the second renal allograft has been successfully treated with meclofenamate. The published experience on recurrent FSGS in first and second renal allografts is also reviewed.

REPORT OF CASE A 40-year-old man was admitted to a hospital in his home­town on Apr. 24,1975, with a history of increasing edema of the lower extremities for several weeks. On examination, the blood pressure was 140/90 mm Hg, and edema of the lower extremities to the level of the thighs was noted. The serum blood urea nitrogen was 25 mg/dl, serum albumin was 1.7 g/dl, and 24-hour urine protein excretion was 9.8 g. Institution of treatment with prednisone, 80 mg daily, caused subsidence of the edema but had an undetermined effect on the urine protein excretion. The dosage of pred­nisone was slowly tapered to 5 mg daily and then increased again to 30 mg daily by June 23 because of worsening edema. At that time, the serum creatinine was 4 mg/dl. A percutaneous renal biopsy revealed FSGS (Fig. 1 A). The serum creatinine continued to increase to 8.1 mg/dl, and anasarca developed despite use of diuretics.

Hemodialysis was started in July 1975, mainly in an effort to control the edema. Renal function deteriorated further after the onset of hemodialysis, and by the time the patient was transferred to our institution on June 23,1976, to be evaluated for renal transplantation, he was virtually anuric. The clinical course after this initial evaluation is summa­rized in Figure 2.

On Sept. 10,1976, splenectomy and renal transplantation from a one-haplotype-matched living related donor were performed. Recurrence of proteinuria (2.6 g/24 h) was noted within the first month after transplantation in the absence of clinically detectable episodes of rejection. Dramatic manifestations of the nephrotic syndrome, how­ever, did not become clinically evident until June 1978, at which time a biopsy specimen of the renal allograft showed swelling of visceral epithelial cells with fusion of podocytes and recurrent FSGS (Fig. 1 B) in addition to a modest tubulointerstitial cell infiltrate.

Massive nephrotic syndrome persisted, and treatment with antiplatelet drugs did not prevent progressive deterio­ration of renal function during the following year. Allograft nephrectomy was performed on July 24,1979, and histo-logic examination of the kidney confirmed the diagnosis of FSGS with hyalinosis (Fig. 1 Q.

A second renal transplantation, with a kidney from a cadaveric donor (B matched, HLA-A and B identical, no apparent HLA-DR mismatch), was performed on Feb. 23, 1980. Nephrotic-range proteinuria (3.8 g/24 h) recurred within the first month after renal transplantation without clinical episodes of acute rejection. Despite development of clinical nephrotic syndrome and grade 2 to 3+ micro-hematuria, the renal function remained stable during the first year after transplantation.

In February 1981, clinical aggravation of the nephrotic syndrome (urine protein excretion 9.9 g/24 h, serum albu-

Mayo Clin Proc 59:146-152, 1984 146

Mayo Clin Proc, March 1984, Vol 59 TREATMENT OF RECURRENT FSGS AFTER TRANSPLANTATION 147

Fig. 1. Segmental glomerulosclerosis in biopsy specimens of the native kidney (A) and first renal allograft (6), in the first allograft after nephrectomy (C), and in biopsy specimen of second renal allograft (D).

min 1.8 g/dl) and mild deterioration of renal function (se­rum creatinine 1.6 mg/dl) led to renal allograft biopsy, which again showed recurrent FSCS and hyalinosis (Fig. 1 D). We then decided to attempt to ameliorate the severity of the proteinuria by administration of meclofenamate, a nonsteroidal anti-inflammatory drug.

Before the meclofenamate therapy was instituted, the effects of a single oral dose of 50 mg of the drug on urine output, urine protein excretion, and creatinine clearance were studied. A 55% reduction in urine flow, a 30% de­crease in urine protein, and a 27% reduction in creatinine clearance were noted. At 9 hours after the administration of the meclofenamate, the creatinine clearance and particu­larly the urine protein excretion had increased to above the baseline values (Fig. 3).

The patient was consuming a low-sodium diet (60 to 90 meq daily). The initial dosage of meclofenamate was 50 mg orally every 6 hours. This regimen resulted in an elevation of the serum creatinine (2.1 mg/dl), a decrease in urine

output, and a worsening of the edema, despite the admin­istration of furosemide. Consequently, use of meclofen­amate was discontinued for 2 days and reinstituted at a dosage of 25 mg every 12 hours. The regimen was then progressively increased to 300 mg daily divided into six doses. The result was an 80% overall reduction of the protein excretion in the urine and normalization of the serum albumin concentration. The hypercholesterolemia that had been noted while the patient was nephrotic sub­sided, whereas hypertriglyceridemia persisted.

During the Th years after the initiation of treatment with meclofenamate, the renal function of this patient has re­mained stable (Fig. 2). Furthermore, microhematuria has disappeared. On four occasions, the administration of meclofenamate was temporarily discontinued (2 to 5 days), and each time the urine protein excretion increased sub­stantially (Fig. 4). Interestingly, these increases have be­come progressively milder with each of the consecutive attempts (13.1,12.4,6.0, and 5.4 g/24 h). Temporary discon-

148 TREATMENT OF RECURRENT FSGS AFTER TRANSPLANTATION Mayo Clin Proc, March 1984, Vol 59

1UU ■ 50 -

T

TX BX TX

X TX NX TX BX

300 -r 200 -100 -300 200 100 300 -r 200 -100 -

3.50 -2.50 -1.50 -19.7

1.1 40 0 -30.0 -20.0 4 5.0 3.0 H 1.0 1 1 1 1 1 1 r

1976 1977 1978 1979 1980 1981 1982 1983

Prednisone, mg/day

Azathioprine, mg/day

Furosemide, mg/day

Meclofenamate, mg/day

S. Albumin, gm/dl

Proteinuria, gm/24 hr lothalamate Cl., ml/min/1.73M2

Creatinine, mg/dl

Fig. 2. Summary of clinical course and treatment of our patient, 1976 through 1983. TX = transplantation; TX BX = renal allograft biopsy; TX NX = renal allograft nephrectomy. Dose of corticosteroid is expressed as prednisone equivalent.

tinuation of the use of meclofenamate also resulted in prompt return of the serum creatinine to the level ob­served before the institution of meclofenamate therapy (1.6 mg/dl). While the patient has been taking meclofena­mate, the dosage of methylprednisolone has been steadily tapered from 20 to 8 mg daily without difficulty.

REVIEW OF THE LITERATURE Since the initial description by Hoyer and associates,4 the recurrence of FSGS in a renal allograft has often been reported5"7 and has been the subject of clinicopathologic conferences.8,9 Recently, several medical centers and national surveys10"22 reported their experience with large numbers of patients and thereby allow the statistical estimation of the recurrence rate. Thus, the mean rate of recurrence of idiopathic nephrotic syndrome with FSGS

is 33% (75 of 229 reported cases) in first renal allografts and 73% (8 of 11 reported cases) in second renal allo­grafts. The prognosis of patients with recurrent FSGS after renal transplantation is poor because failure of the renal allograft (not necessarily related to recurrent disease) had already occurred in 62% of the reported cases at the time of reporting.10"22

The Mayo Clinic experience with recurrence of idio­pathic nephrotic syndrome with FSGS in the renal allo­graft has been published previously.20 Of 541 patients who underwent renal transplantation between 1966 and July 1981, 8 had had idiopathic nephrotic syndrome with FSGS as their primary renal disease. Of these eight pa­tients, two had rejection of the allograft within 1 month after transplantation and three have stable transplant

Mayo Clin Proc, March 1984, Vol 59 TREATMENT OF RECURRENT FSGS AFTER TRANSPLANTATION 149

C (D O k_ a> a .

150

> a> c (0 (0 100 13

Protein excretion V

Creatinine clearance

J L 1

Urine flow

J I I L 1 0 2 4 6 8 10

Hours after administration of meclofenamate (50 mg po.)

Fig. 3. Graph depicting percent change in protein excretion, creatinine clearance, and urine flow after oral administration of a single 50-mg dose of meclofenamate.

function without evidence of recurrent disease. The re­maining three patients had immediate recurrence of pro-teinuria and biopsy-proven recurrent FSGS in five of six primary and secondary renal allografts. In one patient, two renal allografts, the first from a living related donor and the second from a cadaveric donor, had failed be­cause of recurrent disease. The second patient had failure of her first allograft (from a living related donor) due to recurrent disease, but the second renal transplant (from a cadaveric donor), which was implanted at another insti­tution, has been successful without evidence of recur­rence. The third patient is the subject of our case report.

Several investigators have attempted to identify risk factors that might predict the likelihood of recurrence of FSGS in the renal allograft, such as childhood onset of the nephrotic syndrome, mesangial cell hypercellularity in the native kidneys, rapid evolution of the primary FSGS to end-stage renal failure, and recipient-donor HLA iden­

tity, 9,13,17-19,22 but no general agreement prevails. Nev­ertheless, an overall correlation between the severity of the primary renal disease and the frequency of recurrence seems to exist.

Thus far, no satisfactory treatment has been formulated for corticosteroid-resistant idiopathic nephrotic syn­drome with FSGS in native or allografted kidneys.1"22

DISCUSSION The patient described herein had well-substantiated idio­pathic nephrotic syndrome with FSGS and recurrent disease in two renal allografts. Before renal transplanta­tion, several risk factors that indicated the likelihood of recurrence of the primary renal disease in the renal allograft had been noted—namely, severe nephrotic syndrome and rapid evolution to end-stage renal failure. Mesangial cell hypercellularity was not noted.

The early recurrence of proteinuria after renal trans­plantation in some patients with idiopathic nephrotic syndrome with FSGS has been thought to support the existence of a responsible humoral factor—possibly a vascular permeability factor or a lymphokine produced by the host T-lymphocyte.23 Such a factor might induce glomerular injury and FSGS through a direct toxic effect on glomerular cells or indirectly by increasing glomerular permeability to macromolecules and thus resulting in

150 TREATMENT OF RECURRENT FSGS AFTER TRANSPLANTATION Mayo Clin Proc, March 1984, Vol 59

300 -f 200 -100 - ÜT I 13LZ £L JL

I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I J F M A M J J A S O N D ' J F M A M J J A S O N D ' J F M A M J J A S

1981 1982 1983

Meclofenamate, mg/day

Proteinuria, gm/24 hr

S. Albumin, gm/dl

Fig. 4. Graph showing recurrence of proteinuria after temporary discontinuation of administration of meclofenamate.

mesangial overload and dysfunction.24 Whether pro­teinuria is simply a marker of glomerular injury or is an important pathogenetic mechanism, the severity of the proteinuria correlates with the rate of progression to renal failure.25

If an increased traffic of protein through the capillary wall and the mesangium, rather than a direct glomerular injury by a humoral factor, is responsible for the devel­opment of glomerulosclerosis, the course of the disease might be altered by measures aimed at reducing glomeru­lar permeability to macromolecules—as, for instance, with the use of nonsteroidal anti-inflammatory drugs. The complex mechanisms by which nonsteroidal anti-inflam­matory drugs result in a reduction of proteinuria are possibly mediated by their inhibitory effect on synthesis of prostaglandins. A recent review by Michielsen and Varenterghem26 suggested that nonsteroidal anti-inflam­matory drugs can influence proteinuria by modifying glomerular hemodynamics, decreasing the glomerular filtration rate, altering the capillary wall permeability, and attenuating the inflammatory reaction. Indometha-cin has been successfully used to reduce proteinuria in patients with FSGS.27,28 We decided to use meclofena­mate because this nonsteroidal anti-inflammatory drug not only inhibits the synthesis of prostaglandins but also reduces their action, possibly by blocking prostaglandin receptors in cells.29 Furthermore, meclofenamate has an antikinin action and has been shown to be the only nonsteroidal anti-inflammatory drug able to prevent an increase in dermal capillary permeability in the guinea pig after administration of a vascular permeability factor

that had been isolated from patients with idiopathic nephrotic syndrome.23 Finally, some evidence has sug­gested that meclofenamate has less potential for hepato-toxicity than does indomethacin.30

After the administration of a single oral dose of 50 mg of meclofenamate to our patient, a reduction in urine flow, proteinuria, and glomerular filtration rate was noted at 1V2 hours and persisted during the subsequent 6 hours. At 9 and 10V2 hours after administration of meclo­fenamate, the values of the glomerular filtration rate and proteinuria had increased to above the baseline levels. On the basis of these results, the dose intervals were planned to avoid rebound effects on urine protein excre­tion. Administration of furosemide (Lasix) was necessary to avoid retention of salt and fluids. It is well known that the administration of nonsteroidal anti-inflammatory drugs blunts but does not completely block the diuretic action of furosemide. This inhibitor effect can be over­come by the use of higher than usual doses of furo­semide.31 In fact, the administration of furosemide to maintain a negative sodium balance is probably essential to obtain the desired antiproteinuric effect.27

With use of this therapeutic approach in our patient, the proteinuria was substantially reduced, the nephrotic syndrome remitted, and the renal function has remained stable for 2V2 years. Spontaneous remission of recurrent idiopathic nephrotic syndrome in a patient who has undergone renal transplantation would be extremely unusual1"22 and can almost be disregarded in this case because on four occasions discontinuation of the admin­istration of meclofenamate resulted in a rapid recurrence

Mayo Clin Proc, March 1984, Vol 59 TREATMENT OF RECURRENT FSCS AFTER TRANSPLANTATION 151

of nephrotic-range proteinuria. Whether administration of meclofenamate and the consequent reduction of pro­teinuria have been responsible for the stability of the function of the second renal allograft is more difficult to prove. When the malignant course of the primary renal disease and of the recurrent disease in the first renal allograft after the appearance of massive proteinuria, the development of microhematuria, and the early deteriora­tion of renal function are considered, the possibility that the stabilization of renal function and the disappearance of microhematuria in the second renal allograft were unrelated to the administration of meclofenamate seems quite unlikely. The possibility that the interaction be­tween meclofenamate and the immunosuppressive drugs given for renal transplantation (methylprednisolone and azathioprine) was responsible for the reduction in pro­teinuria and the stability of renal function, rather than the effect of meclofenamate alone, cannot be ruled out.

In summary, this case suggests that the use of nonste-roidal anti-inflammatory drugs in idiopathic nephrotic syndrome associated with FSGS not only is helpful in controlling the manifestations of the nephrotic syndrome but also may influence the natural history of the disease. Preliminary results on the use of nonsteroidal anti-inflam­matory drugs in patients with idiopathic nephrotic syn­drome with FSGS who have not undergone transplanta­tion are consistent with this impression, although indi­vidual variability and nonresponding patients have also been noted.32 These observations suggest that the patho-genesis of proteinuria might not necessarily be the same in all of the patients with nephrotic syndrome and FSGS. Further studies on the use of meclofenamate in the treat­ment of corticosteroid-resistant nephrotic syndrome should be conducted and should take into consideration that use of nonsteroidal anti-inflammatory drugs is not without risks, that interstitial nephritis can cause deterio­ration of renal function in some patients, and that careful and close follow-up is imperative.33

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Velosa JA, Torres VE, Donadio JV Jr, Wochos DN, Wagoner RD: Unpublished data Torres VE: Present and future of the nonsteroidal anti-inflamma­tory drugs in nephrology (editorial). Mayo Clin Proc 57:389-393, 1982