Another case of focal segmental glomerulosclerosis in an acutely uraemic patient following interferon therapy

D. Dressler, J. R. Wright, J. B. Houghton1 and P. A. Kalra

Departments of Nephrology and 1 Haematology, Hope Hospital, Salford, UK

Sir,

Nephrology Dialysis Transplantation has reported two cases of acute tubular necrosis and nephrotic syndrome following {alpha}-Interferon treatment for malignancy. We report another case of acute renal failure and persistent nephrotic syndrome following such therapy. The renal histological lesion was focal segmental glomerulosclerosis (FSGS).

Case. A 46-year-old Afro-Caribbean man with a diagnosis of multiple myeloma (IgG kappa) and sickle-cell trait underwent two autologous bone marrow transplants, in 1997 and 1998. He also received high dose melphalan and peripheral blood stem-cell transplantation (PBSCT). Following treatment with melphalan and PBSCT, in February 1998 he developed septicaemia and multi-organ failure due to a Staphylococcal aureus central line infection. He was admitted to an Intensive Care Unit where he received inotropic, renal and haematological support. Despite being profoundly unwell on admission, he staged a remarkable recovery.

Post-discharge his myeloma appeared to be in remission with no monoclonal bands being demonstrable. Haemopoetic recovery was slow; he received several red blood cell transfusions and remained thrombocytopaenic (platelet count 25x109/l).

Six-months after his last melphalan and PBSCT treatment he was immunized against Hib and influenza. A trace of monoclonal IgG was detected in his serum. As the platelet count was recovering, {alpha}-interferon (Intron A) was commenced at a dose of 3 mega units thrice weekly. His serum creatinine at this stage was 84 µmol/l, and dipstick urinalysis was negative. Symptoms of anorexia, bloating and lethargy developed within 4 weeks of the introduction of interferon. He was found to have acute renal impairment, (urea 21.7 mmol/l, creatinine 332 µmol/l) and he also had nephrotic range proteinuria (24-h urinary protein excretion 7.2 g/l, serum albumin 14 g/l). Interferon therapy was stopped immediately.

Although a bone marrow biopsy was not performed, no evidence of overt myeloma recurrence was found (trace IgG paraprotein in serum, no urinary monoclonal free light chains). Percutaneous renal biopsy was performed and histological examination revealed FSGS. There was no evidence of interstitial nephritis and acute tubular lesions were minimal. Immunoperoxidase showed IgM, C3, C1q present focally within the mesangium, however no immune complexes were seen on electron microscopy.

In view of these renal abnormalities he was commenced on 30 mg of prednisolone daily. Four months later, renal function had almost returned to pre-interferon baseline, (creatinine 111 µmol/l, creatinine clearance 50 ml/min) but nephrotic range proteinuria (13 g/24-h) remained. The myeloma is still in remission.

Comment. Recombinant interferons are increasingly used in the treatment of malignancy and viral illness. Recognized side effects include fever, fatigue, nausea, reversible leucopenia and liver enzyme derangement. Although dipstick positive proteinuria is said to occur in up to 15–25% of interferon-treated patients, the association of interferon with acute renal failure and nephrotic syndrome is uncommon [1,2].

Reversible acute renal failure with the nephrotic syndrome has previously been reported in association with interferon [3] although renal biopsy was not performed in this instance. However, renal histo-pathology has been clarified in a number of patients with renal dysfunction associated with interferon treatment. Dimitrov et al. [4] identified acute tubular necrosis and membranous glomerulonephritis in a patient who was Hep BSAg positive where nephrotic syndrome improved on stopping treatment. Other recorded pathology includes acute interstitial nephritis (following therapy for mycosis fungoides) [5], and minimal change glomerulopathy in a patient who presented with nephrotic range proteinuria and interstitial nephritis. In this case cessation of interferon, (prescribed as treatment for cutaneous T-cell lymphoma) led to improvement but not complete resolution of the proteinuria [6]. There has also been a case of membranoproliferative glomerulonephritis reported associated with proteinuria in a patient treated for HIV infection [7]. Lederer et al. described an unusual lesion in a patient whose renal dysfunction did not improve on stopping interferon. Here the glomerular lesion was characterised by global, diffuse and marked widening of the lamina rara interna, and focal segmental mesangial proliferation [8]. There have been two previous reports of FSGS in association with nephrotic syndrome and acute renal failure in patients who had received interferon. Coroneos et al. [9] report FSGS in a patient receiving interferon for hepatitis C who initially showed slight improvement with steroid therapy before relapsing and progressing to end-stage renal failure. Ault et al. [10] describe FSGS after treatment for acute lymphoblastic leukaemia and this fully resolved with no steroid therapy. Like our case, neither of these had immune deposits on electron microscopy.

As yet the mechanism of interferon-induced renal disease remains unknown. It is postulated that a combination of immuno-modulatory effects and direct nephro-toxicity may be responsible [3].

Here we report another case of FSGS resulting from interferon therapy—the presentation was with acute renal failure and nephrotic syndrome, and the latter has persisted despite steroid therapy. With growing experience of the renal disorders associated with this drug, the necessity for regular evaluation of renal function and urinalysis with its usage is further demonstrated. Unfortunately, the current literature does not help our difficulty in providing our patient with a likely prognosis for his nephrotic syndrome, or indeed, his long-term renal functional outcome.

References

  1. Quesada J, Talpaz M, Rios A, Kurzrock R, Gutterman J. Clinical toxicity of Interferons in cancer patients: a review. J Clin Oncol 1986; 4: 234–243[Abstract]
  2. Kurschel E, Metz-Kurschel V, Nierderle N, Aulberg E. Investigations on the subclinical and clinical nephrotoxicity of IFN{alpha}-2B in patients with myeloprolifrative syndrome. Renal Fail 1991; 13: 87–93[ISI][Medline]
  3. Harbi AA, Al Ghambi S, Subaity Y, Khalil A. Interferon induced acute renal failure in nephrotic syndrome. Nephrology Dialysis Transplant 1998; 13: 1316–1318[Free Full Text]
  4. Dimitrov Y, Heibel F, Marcellin L, Chantrel F, Moulin B, Hannedouche T. Acute renal failure and nephrotic syndrome with alpha interferon therapy. Nephrology Dialysis Transplant1997; 12: 200–203[Abstract]
  5. Averbuch SD, Austin HA, Sherwin SA, Antonovynch T, Bunn P, Longo D. Acute interstitial nephritis with the nephrotic syndrome following recombinant leukocyte interferon therapy for mycosis fungoides. N Engl J Med 1984; 310: 32[ISI][Medline]
  6. Traynor A, Kurzel T, Samuelson E, Kanwar Y. Minimal change glomerulopathy and glomerular visceral epithelial hyperplasia associated with alpha IFN therapy for cutaneous T cell lymphoma. Nephron 1994; 67: 94–100[ISI][Medline]
  7. Kimmel PL, Abraham AA, Philips TM. Membranoproliferative glomerulonephritis in a patient treated with IFN alpha for HIV infection. Am J Kid Dis1994; 24: 858–863[ISI][Medline]
  8. Lederer E, Truong L. Unusual glomerular lesion in a patient receiving long term Interferon alpha. Am J Kid Dis 1992; 20: 516–518[ISI][Medline]
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  10. Ault B, Stapelton F, Gaber L, Martin A, Roy S, Murphy S. Acute renal failure during therapy with recombinant human gamma interferon. N Eng J Med 1988; 319: 1397–1400[ISI][Medline]




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