Single-center experience with renal transplantation in patients with Wegener's granulomatosis

Between 1980 and 1995, 13 patients with end-stage renal disease due to Wegener's granulomatosis received 14 renal transplants (10 cadaveric, 4 living related). The mean follow-up in the 13 successfully transplanted patients was 50 months (4–107 months). One patient had primary nonfunction and received another graft 4 months later. Three episodes of acute rejection occurred in two patients, and one of these patients lost her graft due to severe vascular rejection 4 months after transplantation. Two patients died with well-functioning grafts (one of metastatic cancer and one of sepsis). One patient presented with perisinusitis and had a mild recurrence of Wegener's disease. None of the patients developed recurrent disease in the transplanted organ. At the last follow-up, the mean creatinine ( ± SD) in the 12 patients with functioning grafts was 1.6 ± 0.6 mg/dl. We conclude that renal transplantation is an excellent treatment for renal failure due to Wegener's granulomatosis. Recurrence of the disease is uncommon in patients under immunosuppression, but careful monitoring is extremely important. Received: 1 July 1996 Received after revision: 6 September 1996 Accepted: 23 September 1996     

Clinical observations of mycophenolate mofetil therapy in refractory primary nephrotic syndrome

SUMMARY:   Mycophenolate mofetil (MMF) is an effective immunosuppressive agent in renal transplantation, and preliminary studies suggest that it may also be effective in the treatment of lupus nephritis. This study investigated the efficacy and safety of MMF therapy in patients with refractory primary nephrotic syndrome in a prospective multicentre clinical observation. Nineteen refractory nephrotic patients with minimal change disease or mesangial proliferative glomerulonephritis were enrolled in this study. Combined MMF and prednisone therapy was used for 6 months with an initial MMF dose of 1.0–2.0 g/day and a prednisone dose of 20–60 mg/day; both drugs were tapered gradually. It was found that all patients achieved clinical remission and 11 of 19 responded within 4 weeks, and 12 of 19 patients entered complete clinical remission. The prednisone dose in those patients who were previously steroid dependent could be successfully tapered. During follow up, three patients experienced transient increasing of proteinuria associated with infections and recovered without an adjustment of therapy. One patient was withdrawn from the study because of a fall in haemoglobin levels; other adverse effects did not necessitate withdrawal. Follow-up renal biopsies in two patients found no alteration in renal pathology. Mycophenolate mofetil is an effective and well-tolerated immunosuppressive agent for patients with refractory nephrotic syndrome.     

Autoantibodies to glomerular antigens in patients with Wegener's granulomatosis

Patients with Wegener's granulomatosis have autoantibodies to a neutrophil cytoplasmic antigen. As these patients often present with severe glomerulonephritis we investigated whether the same autoantigen was expressed in glomeruli by using both cultured human glomerular cells and frozen normal human kidney sections. Glomeruli were isolated from normal human kidney cortex by differential sieving and plated on to coverslips in growth medium containing various supplements. Cell types were identified by a series of markers and designated either epithelial, endothelial or mesangial. In single and double staining experiments, glomerular cells were incubated with a monoclonal antibody to the neutrophil cytoplasmic antigen (MCAW8), control mouse monoclonal IgG, sera from patients with Wegener's granulomatosis and control normal human serum. MCAW8 and Wegener's patient sera bound specifically to cultured epithelial and endothelial cells. MCAW8 was also found to bind to the glomerular epithelium in frozen sections. We conclude that autoantibodies to glomerular antigens are present in serum of patients with Wegener's granulomatosis and may be important in the pathogenesis of rapidly progressive glomerulonephritis.     

Prospective controlled study on mycophenolate mofetil and prednisolone in the treatment of membranous nephropathy with nephrotic syndrome

BACKGROUND: Retrospective and anecdotal data suggest that mycophenolate mofetil (MMF) might be effective when given as rescue therapy for membranous nephropathy (MN). Prospective controlled data on MMF and prednisolone as primary therapy are lacking. METHODS: A prospective, randomized, controlled, open-label study was performed to investigate the efficacy and tolerability of MMF and prednisolone as primary treatment in MN with nephrotic syndrome. MMF and prednisolone given for 6 months was compared against a modified Ponticelli regimen in 20 patients, with follow up of 15 months. RESULTS: MMF with prednisolone and the comparative immunosuppressive regimen showed similar efficacy in proteinuria reduction, despite a lower cumulative prednisolone dose in the MMF group (3.80 +/- 0.28 vs 9.93 +/- 0.25 g, P < 0.001). Remission (composite of 'complete' and 'partial') rates were 63.6% and 66.7% in the MMF group and control group, respectively (P = 1.000). Serum creatinine and creatinine clearance remained stable during follow up. Cumulative relapse rate was 23.1% at 2 years. Chlorambucil resulted in more leucopenia compared with MMF. CONCLUSION: Data from this pilot study indicate that more than 60% of patients with MN and nephrotic syndrome respond to combined MMF and prednisolone treatment, and suggest potential benefits of MMF as being steroid-sparing and having less adverse effects compared with other commonly used cytotoxic agents.     

Wegener's granulomatosis of the breast

A 60-year-old woman presented with a painless self-detected breast lump. After wide local excision, the histology of this radiologically suspicious lump turned out to be an inflammatory lesion with granulomatous foci, suggesting a diagnosis of granulomatous mastitis. Prior to the excision biopsy, this woman had suffered from and been treated for anterior uveitis, secretory otitis media, and proximal myopathy. Four weeks later, a skin biopsy of a rapidly developing widespread petechial rash, mainly affecting the lower limbs, confirmed the diagnosis as Wegener's granulomatosis. Treatment with intravenous steroids and later cyclophosphamide produced rapid remission.     

Limited Wegener＇s granulomatosis of the epididymis and testis

A case is presented of Wegener＇s granulomatosis limited to the testis and epididymis, simultaneously, in a 69-year-old man. Orchiectomy was carried out through an inguinal incision under the presumptive diagnosis of a right testicular tumor. A hard, irregular mass occupied the upper testicle and a portion of the epididymal head was visualized. Histopathologic examination of the specimen showed granulomatous inflammation of the testis and epididymis with prominent angiocentric granulomata in the walls of arteries, veins and foci of fibrinoid necrosis, surrounded by palisading inflammatory cells with a few giant cells. The diagnosis of limited Wegener＇s granulomatosis was considered, although antineutrophil cytoplasmic antibody （c-ANCA） test was negative 2 weeks after orchiectomy. The patient showed an excellent response after local complete excision. He remains free of disease 18 months after orchiectomy.     

Limited Wegener's granulomatosis of the epididymis and testis

A case is presented of Wegener's granulomatosis limited to the testis and epididymis,simultaneously,in a 69-year-old man.Orchiectomy was carried out through an inguinal incision under the presumptive diagnosis of a righttesticular tumor.A hard,irregular mass occupied the upper testicle and a portion of the epididymal head was visualized.Histopathologic examination of the specimen showed granulomatous inflammation of the testis and epididymis withprominent angiocentric granulomata in the walls of arteries,veins and foci of fibrinoid necrosis,surrounded bypalisading inflammatory cells with a few giant cells.The diagnosis of limited Wegener's granulomatosis was considered,although antineutrophil cytoplasmic antibody(c-ANCA)test was negative 2 weeks after orchiectomy.The patientshowed an excellent response after local complete excision.He remains free of disease 18 months after orchiectomy.(Asian J Androl 2006 Nov,8:737-739)     

Efficacy of mycophenolate mofetil in pediatric patients with steroid-dependent nephrotic syndrome

Most patients with minimal change nephrotic syndrome are steroid responsive and tolerate this medication. However, a substantial number of patients relapse frequently and become steroid dependent. These patients often require treatment with alternative immunosuppressive drugs to maintain remission and minimize steroid toxicity. Previous studies have suggested that mycophenolate mofetil is effective in treating these patients. However, there are limited data on the effectiveness of this agent in pediatric patients, specifically those with steroid-dependent nephrotic syndrome. The purpose of this study was to assess the efficacy and safety of mycophenolate mofetil therapy in children and adolescents with steroid-dependent nephrotic syndrome who failed other treatments. A retrospective chart review was performed on all patients with steroid-dependent nephrotic syndrome. Clinical characteristics, laboratory data and the relapse rate were assessed prior to and during mycophenolate mofetil treatment. Twenty-one patients, ages 2–17 years, with steroid-dependent nephrotic syndrome who were treated with mycophenolate mofetil between 2001–2005 were included in this review. The indication for mycophenolate mofetil use was steroid dependence in 17 and steroid toxicity in 4 patients. The mean duration of treatment was 1.0±0.5 years (range: 0.2–2.0 years). Patients treated with mycophenolate mofetil had a reduction in relapse rate from 0.80±0.41 to 0.47±0.43 relapses per month ( P <0.02). Side effects were mild and mostly gastrointestinal in nature. In 1 child, mycophenolate mofetil was discontinued due to varicella infection and not restarted. The findings indicate that mycophenolate mofetil is a useful adjunctive therapy in the treatment of patients with steroid-dependent nephrotic syndrome. It lowers the relapse rate by 40% and is well tolerated by patients with steroid-dependent nephrotic syndrome.     

Wegener's granulomatosis: clinical course in 108 patients with renal involvement.

BACKGROUND: The aim of this study was to evaluate the clinical course of patients with Wegener's granulomatosis and renal involvement, with special reference to relapse rate, renal and patient survival and morbidity from serious infections. METHODS: A retrospective analysis was carried out of 108 patients presenting with Wegener's granulomatosis and active renal disease in eight hospitals in Norway between 1988 and 1998. Multivariate analysis was used to investigate whether selected variables predicted relapse, renal and patient survival and serious infections. RESULTS: Median follow-up was 41.5 months. Twenty-two patients (20.4%) were admitted with a need for dialysis. Complete remission was obtained in 81.5% after a median of 4 months, and 54.7% relapsed after a median of 22. 5 months. Two- and five-year renal survival was 86 and 75%, respectively, and 22.8% developed end-stage renal disease (ESRD). Two- and five-year patient survival was 88 and 74%, respectively, and the cumulative mortality was 3.8 times higher than expected. The relative risk of relapse increased with the use of intravenous pulse cyclophosphamide compared with daily oral cyclophosphamide. Initial renal function predicted renal survival, and low serum albumin and high age at treatment start increased the mortality risk. Thirty one per cent of the patients were hospitalized for serious infections during follow-up. Old age increased the risk of having an infection. CONCLUSIONS: The current treatment of Wegener's granulomatosis does not prevent relapse, development of ESRD and serious treatment-induced infections in a considerable fraction of the patients. Alternative strategies for the management of this disease will be an important objective for further studies.     

Treatment of idiopathic membranoproliferative glomerulonephritis with mycophenolate mofetil and steroids.

BACKGROUND: Treatment of adults with idiopathic membranoproliferative glomerulonephritis (IMPGN) is often unrewarding with approximately 60% of patients progressing to end-stage renal failure within 10 years. Although children with IMPGN may respond to steroid therapy, there is no significant benefit to treating adult IMPGN patients with immunosuppression. METHODS: Outcome measures in five patients with IMPGN who were treated with oral prednisolone and mycophenolate mofetil (MMF) (treatment group) were compared with six patients with IMPGN who did not receive immunosuppression (control group). RESULTS: There was no significant difference between either group in baseline clinical characteristics or systolic and diastolic blood pressure during observation. In the treatment group, there was a significant reduction in proteinuria from a baseline of 5.09 to 1.97 g/24 h (P = 0.003) at 6 months, 1.96 g/24 h (P = 0.003) at 12 months and 2.59 g/24 h (P = 0.015) at 18 months. There was no significant change in proteinuria over 18 months in the control group. Serum creatinine concentration and creatinine clearance did not change significantly over 18 months in the treatment group. In the control group, there were significant changes in serum creatinine and creatinine clearance over 18 months [baseline 103 to 159 micromol/l (P = 0.004) and baseline 108 to 67 ml/min (P > 0.001), respectively] when compared to baseline, although the differences were not significant when the two groups were compared directly. CONCLUSIONS: This preliminary study suggests that in the short term, the combination of MMF and prednisolone can significantly reduce proteinuria and may preserve renal function in patients with IMPGN.     

Prolonged treatment of refractory Wegener's granulomatosis with 15-deoxyspergualin: an open study in seven patients.

BACKGROUND: A subset of patients with Wegener's granulomatosis does not respond to daily oral cyclophosphamide (CYC) plus corticosteroids or suffers from intolerable side effects. A 6 month course of the immunosuppressant 15-deoxyspergualin (DSG) has previously been employed successfully in these refractory cases. However, there are no reports on long-term treatment with DSG. METHODS: To document the effects of prolonged DSG treatment, this study reports on seven patients suffering refractory Wegener's granulomatosis, who were successfully treated with DSG over an average of 26.5 months (range: 11-55.5 months). RESULTS: Before administration of DSG, patients had experienced an average of 6.6 relapses (range: 3-12) under an average of 5.4 (range: 2-11) different therapeutic approaches, which included CYC in all cases. All suffered active disease when DSG was initiated. Four were unresponsive to CYC and three did not tolerate it. DSG (0.5 mg/kg/day subcutaneous) was given for 2-3 weeks until the leukocyte count dropped to 3000/microl, followed by a rest until a leukocyte count of 4000/microl was reached again. No other immunosuppressants besides corticosteroids were given. All patients showed a long-lasting, favourable response to DSG with complete (n = 5) or partial (n = 2) remission. Only one case relapsed while being treated with DSG. Termination/interruption of DSG was followed by relapse in four of five occasions. Resumption of DSG led to complete remission. Currently, five of the seven patients are still treated with DSG and are in remission. Infections, mainly of the respiratory tract, were observed in five cases and resolved after treatment. One case developed a third-degree heart block that required pacing. CONCLUSIONS: In patients with refractory Wegener's granulomatosis, prolonged treatment with DSG seems safe and successful.     

Renal histopathology and clinical course in 94 patients with Wegener's granulomatosis.

BACKGROUND: The main purpose of this study was to examine histopathological changes seen in renal biopsies from patients with Wegener's granulomatosis (WG) with varying degrees of renal involvement and to study possible correlations between the morphological variables and the severity of the disease. METHODS: Ninety-four patients with WG and active renal disease were included in this retrospective study. All patients had a percutaneous renal biopsy taken on their first admission to the hospital and 14 patients had a second biopsy. The patients were followed for a median of 42.5 months (range 0.5-184). RESULTS: Segmental necrotizing glomerulonephritis and extracapillary proliferation were present in 85.1 and 91.5% respectively. Of seven patients (7.4%) with normal serum creatinine and urinary protein excretion <0.5 g/day, all had crescents and six had segmental glomerular necrosis. Serum creatinine at biopsy correlated significantly with the percentage of glomeruli with crescents (rho=0.52, P=0.0004), with necrosis (rho=0.36, P=0.002) and with the percentage of normal glomeruli (rho=-0.55, P=0.0003). On a multivariate analysis, only the percentage of normal glomeruli was significantly associated with renal function and development of end-stage renal disease. In 14 second biopsies after a mean of 41.2 (+/-26) months, chronicity scores had increased significantly in 13 biopsies in spite of full immunosuppressive treatment. CONCLUSION: Although renal biopsy is of value in defining renal involvement in WG, it is of limited help in the early stage of the disease in predicting renal outcome for the individual patient. A follow-up biopsy can be useful in revealing the degree of activity and chronicity and hence be of importance for the choice of further therapy.     

Effects of mycophenolate mofetil for patients with crescentic lupus nephritis

Objective: To compare the effects, relapse ratio and outcomes between mycophenolate mofetil (MMF) and pulse intravenous cyclophosphamide (CTX) for the induction therapy in patients with crescentic lupus nephritis. Methodology: This is a retrospective, controlled study. Twenty-seven MMF therapeutic and twenty-five CTX therapeutic lupus patients with ≥50% crescent formation were enrolled in this study. The general conditions, clinicopathological findings, remission and relapse ratio, and outcomes of them were compared. Results: There was no significant difference of general condition and clinicopathological findings between MMF and CTX group. At 12 months, the total remission ratio in MMF and CTX group were 73.1% and 69.6%, while the complete remission ratio in MMF group (53.8%) was significantly higher than that in CTX group (26.1%). The relapse ratio in MMF group (10.5%) was significantly lower than in CTX group (43.8%). Forty per cent of PR patients in CTX group suffered from relapse. Until June 2005, the patients in CTX group received a follow time with 38.5 ± 21.2 (range 10∼80) months, and in MMF group the follow time was 41.1 ± 27.0 (range 12∼90) months. Two patients in MMF group and two in CTX group entered into end stage renal failure. The side effect of infection was more significant in CTX group. Conclusion: Higher complete remission ratio and lower relapse ratio were observed in MMF group than in CTX group. The side effect of infection was more infrequent in MMF group, which showed preferable security of MMF.     

Daclizumab induction and maintenance steroid-free immunosuppression with mycophenolate mofetil and tacrolimus to prevent acute rejection of hepatic allografts

Steroid-free immunosuppressive regimens reduce corticosteroid-related side effects in liver transplant recipients although their efficacy is very variable. We evaluated the efficacy and safety of a steroid-free regimen in a 6-month, open-label, multicenter, pilot study, which involved 102 liver transplant patients treated with daclizumab (2 mg/kg within 6 h following transplant and 1 mg/kg on day 7), mycophenolate mofetil (MMF, 1 g b.i.d) and tacrolimus (trough levels of 5-15 ng/ml in the first month and 5-10 ng/ml thereafter). One intra-operative dose of methylprednisolone was administered. At 6 months, the acute rejection rate was 9.8%, and patient and graft survival rates were 96% and 95%, respectively. Acute rejection rates were similar for hepatitis C-positive patients (8.6%) and hepatitis C-negative patients (10.4%). Infections occurred in 22% of patients; most cases were considered mild or moderate. Post-transplantation hypertension and diabetes mellitus developed in 37% and 14% of patients, respectively, during the study period, but were markedly less frequent (8% and 6%, respectively) at 6 months. Hypercholesterolemia was observed in only 2% of patients. In conclusion, the steroid-free immunosuppressive regimen of daclizumab, MMF, and tacrolimus effectively prevents acute rejection after liver transplantation without decreasing safety.     

Safe conversion of mycophenolate mofetil to azathioprine in kidney transplant recipients with sirolimus-based immunosuppression

Aim:   Mycophenolate mofetil (MMF) is a powerful immunosuppressive drug with established efficacy and safety. The long-term use of MMF may bring increased risk of for infection and malignancy and also increased cost of transplantation. The search for minimization of immunosuppressive protocol has led to an open randomized clinical trial of conversion from MMF to azathioprine (AZA).
Methods:   A total of 50 kidney allograft recipients treated with prednisone, sirolimus and MMF were randomized into two groups: converted (AZA group) and continuing (MMF group). The average duration of MMF therapy prior to conversion was 43 months in each group. Inclusion criteria included: patients with serum creatinine levels of less than 200 µmol/L; no past history of acute vascular rejection or recent acute rejection 6 months before randomization; and normal liver function tests.
Results:   Baseline demographics were similar in the two groups. During the 12 month observation period, there were no acute rejection episodes in either group. There were no significant differences in overall patient or graft survival or function. AZA-treated patients had a lower incidence of gastrointestinal complications ( P  = 0.03). Daily cost reduction in the AZA group was more than $US8.79/day per patient.
Conclusion:   In general, replacing MMF with AZA in stable renal transplant recipients is well tolerated and was cost effective with no increased risk of rejection. As the this study was on relatively small samples, larger and longer follow-up studies will be needed to confirm these expected advantages for the long-term outcome and to assess the long-term safety of this minimization of immunosuppressive therapy.