A Case of Kaposi's Sarcoma Following Treatment of Membranoproliferative Glomerulonephritis and a Review of the Literature

Kaposi's sarcoma (KS) is an unusual tumor principally affecting the skin of the lower extremities. Although the association between KS and renal transplant has been well documented, there are a few KS cases in the literature associated with membranoproliferative glomerulonephritis or other glomerular diseases. This report presents a patient with membranoproliferative glomerulonephritis (MPGN) who developed KS following treatment with long-term medium dose glucocorticoid and short-term additional immunosuppressives. The KS cases associated with glomerulonephritis are also reviewed. KS is a rare complication in glomerular diseases that may (or may not) be related to immunosuppression. Hence, immunosuppression treatment should be carefully planned in glomerulonephritis treatment and avoided if they are not essentially necessary.     

Recurrence of glomerulonephritis after renal transplantation

Recurrence of glomerulonephritis following renal transplantation is considered an important cause of allograft failure. The incidence of recurrence of glomerulonephritis varies widely depending on the definition of recurrence (pathologic recurrence or clinicopathologic recurrence) and the original glomerular disease. Moreover the impact of recurrence of glomerular disease on allograft outcome varies widely between different forms of glomerulonephritis. Whereas IgA nephritis recurs in up to one third of transplanted patients, this is not associated with adverse effects on graft survival. In contrast, recurrent focal segmental glomerulosclerosis and membranoproliferative glomerulopathy have an unfavorable prognosis. Overall, long-term graft survival in patients transplanted for glomerulonephritis is comparable to survival in patients with other causes of ESRD. In recent years, several mechanisms for recurrent disease after transplantation (e.g. PLA2R antibodies in membranous nephropathy and suPAR in FSGS) have been identified, and these findings have helped to elucidate the pathogenesis of glomerular diseases. Although renal transplantation is the treatment of choice for end-stage renal disease as a consequence of glomerulonephritis, further studies are required to develop optimal strategies to prevent, diagnose and treat recurrent glomerular diseases.     

Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies

Dense deposit disease and glomerulonephritis with isolated C3 deposits are glomerulopathies characterized by deposits of C3 within or along the glomerular basement membrane. Previous studies found a link between dysregulation of the complement alternative pathway and the pathogenesis of these diseases. We analyzed the role of acquired and genetic complement abnormalities in a cohort of 134 patients, of whom 29 have dense deposit disease, 56 have glomerulonephritis with isolated C3 deposits, and 49 have primary membranoproliferative glomerulonephritis type I, with adult and pediatric onset. A total of 53 patients presented with a low C3 level, and 65 were positive for C3 nephritic factor that was significantly more frequently detected in patients with dense deposit disease than in other histological types. Mutations in CFH and CFI genes were identified in 24 patients associated with a C3 nephritic factor in half the cases. We found evidence for complement alternative pathway dysregulation in 26 patients with membranoproliferative glomerulonephritis type I. The complement factor H Y402H variant was significantly increased in dense deposit disease. We identified one at-risk membrane cofactor protein (MCP) haplotype for glomerulonephritis with isolated C3 deposits and membranoproliferative glomerulonephritis type I. Thus, our results suggest a critical role of fluid-phase alternative pathway dysregulation in the pathogenesis of C3 glomerulopathies as well as in immune complex-mediated glomerular diseases. The localization of the C3 deposits may be under the influence of MCP expression.     

Incidence and prognostic importance of glomerular crescents in renal diseases of childhood

The renal biopsies of 372 children with various glomerular disorders were reviewed and crescent formation was seen in 56 cases (15%). Four disorders, i.e. systemic lupus erythematosus, membranoproliferative glomerulonephritis (MPGN) types I and II and Henoch-Sch?nlein disease accounted for 74% of 10 diagnostic categories. Idiopathic rapidly progressive glomerulonephritis (RPGN) was seen in only 2 cases. Crescents associated with MPGN types I or II or idiopathic RPGN had a bad renal prognosis, whereas the presence of crescents in other disorders did not necessarily affect the renal outcome. Immunofluorescent and electron microscopic findings are essential to distinguish many conditions which may be associated with crescent formation in childhood renal disease.     

Hepatitis C virus-related kidney disease: an overview

Hepatitis C virus (HCV)-infection leads to chronic liver disease, but also to extra-hepatic manifestations, including kidney disease. We provide an overview of HCV-related kidney diseases in non-transplanted and in kidney transplant patients, and their therapies. Membranoproliferative glomerulonephritis, associated with Type 2 cryoglobulinemia, is the predominant Type of HCV-related glomerulonephritis. Membranous glomerulonephritis and focal segmental glomerular sclerosis are less commonly described. HCV infection seems to be linked to Type 2 diabetes mellitus, and might alter the progression of diabetic-related nephropathy. Patients infected by HCV should be annually screened for markers of kidney disease and, similarly, patients with membranoproliferative or membranous glomerulonephritis should be screened for HCV infection. After transplantation, cryoglobulinemia is frequent and is associated with HCV markers. HCV-related kidney disease requires specific treatment. In non-kidney-transplant patients, treatment relies on either only anti-HCV therapy in cases of moderate renal disease, or combined anti-viral and immunosuppressive therapies in cases of severe renal disease, i.e., nephrotic syndrome and/or progressive renal failure, and in diseases that are refractory to anti-HCV therapy. In kidney transplant patients, ribavirin monotherapy could be used cautiously, whereas rituximab might be a treatment of choice in the presence of cryoglobulinemia. In liver-transplant patients, in addition to anti-HCV therapy, rituximab might be also used.     

Membranoproliferative glomerulonephritis associated with small cell lung carcinoma

An association between nephropathy and malignant solid tumours or with lymphoproliferative disorders was repeatedly reported. This association is mainly manifested by a nephrotic syndrome. In Lee's study [14], 11% of the adult nephrotics whom they had seen over a ten-year period developed a carcinoma. Membranous glomerulonephritis (MGN) is the most common glomerular disease associated with malignant solid tumour; the association of membranoproliferative glomerulonephritis (MPGN) with solid tumour is still uncommon. Although lung carcinoma is relatively common, the incidence of glomerular involvement with this tumour is quite rare. To date, only a few cases of lung cancer associated with nephrotic syndrome or glomerulonephritis have been reported by various authors. MGN is the most common glomerular lesion associated with these cases; however, MPGN has not been reported to be associated with lung cancer before. We report on a 45-year old man with nephrotic syndrome due to MPGN which in this case seemed to be a component of the paraneoplastic syndrome.     

Immunotactoid glomerulopathy with microtubular deposits, with reference to the characteristics of Japanese cases

We present the case of a 69-year-old man with nephrotic syndrome and renal insufficiency, who developed lobular glomerulonephritis. An electron microscopy examination of a renal biopsy showed microtubular structures of 24 nm in diameter in the subendothelial space and the paramesangial area. These deposits were PAS-positive and Congo red-negative, and revealed predominantly positive staining for kappa light chain. There was no evidence of diseases with highly organized glomerular deposits, such as amyloidosis, cryoglobulinemia, systemic lupus erythematosus or paraproteinemia. Therefore, the patient was diagnosed to have immunotactoid glomerulopathy (ITG). During a seven-year course he has not developed any disease known to be associated with organized glomerular immune deposits. Hence, we believe ITG occurred as a primary glomerular disease in this case. We also highlight cases of ITG with microtubular deposits that have been reported in Japan, compare these cases to previous reports, and show that the characteristics of the Japanese cases are male predominance; a high incidence of membranoproliferative glomerulonephritis (MPGN); a low incidence of monoclonal gammopathy and hematological malignancies and a higher incidence of hypocomplementemia.     

Cryoglobulinemic membranoproliferative glomerulonephritis: beyond conventional therapy

Membranoproliferative glomerulonephritis associated with Type II cryoglobulinemia is the predominant type of HCV-related glomerulonephritis. Immunosuppressive and anti-viral therapy is alternately used to treat it, but the results are not always satisfactory or lasting. In this paper we report 3 cases of cryoglobulinemic membranoproliferative glomerulonephritis, treated with different and personalized therapeutic approaches by using conventional therapy and new drugs such as mycophenolate mofetil and rituximab. Our case series report emphasizes the importance of choosing the treatment for each patient, taking into account many factors: age, severity of liver and renal involvement, extra-renal manifestations, any previous treatment, contraindications or adverse events and last but not least the balance between immunosuppression and virus activity.     

Pathogenic mechanisms in membranoproliferative glomerulonephritis

PURPOSE OF REVIEW: This review considers new information on the pathogenesis of a long recognized and poorly understood form of glomerular injury, membranoproliferative glomerulonephritis. This disease has received growing attention as it is the principal renal manifestation of hepatitis C virus infection, which has become pandemic worldwide. RECENT FINDINGS: This review briefly describes three murine models of membranoproliferative glomerulonephritis suitable for pathogenesis studies. We consider recent evidence implicating innate immune mechanisms in immune and autoimmune-mediated glomerulonephritis, and recent data pointing to the alternative pathway of complement activation in the amplification of glomerulonephritic injury. SUMMARY: Understanding the contribution of complement activation and innate immunity to the evolution of membranoproliferative glomerulonephritis promises to provide new therapeutic targets for this disease. Inhibitors of the complement cascade are already being tested in clinical trials as therapeutic interventions for some human glomerular diseases. Successful tests of this approach in membranoproliferative glomerulonephritis are still awaited. Our understanding of how the innate immune system modulates glomerulonephritis is still in an early stage, and future studies should be directed at identifying targets and specific interventions that may also benefit patients with this disease.     

Angiotensin blockade in children with chronic glomerulonephritis and heavy proteinuria

Patients with chronic proteinuric nephropathies are at high risk of developing progressive renal insufficiency. There are limited controlled data on the efficacy of potentially toxic immunosuppressive therapies for many of these diseases such as immunoglobulin A nephropathy and idiopathic membranoproliferative glomerulonephritis. This limitation has not deterred healthcare providers from using such agents based on anecdotal experience. We report our experience taking care of three children with heavy proteinuria from chronic glomerular diseases. All were treated with a combination of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers without concomitant immunosuppression. All went into complete remission soon after starting therapy, allowing corticosteroid avoidance. The purpose of this report is to make healthcare professionals more aware of the potential success that can be achieved with this relatively nontoxic drug regimen. Larger controlled clinical trials using this strategy are needed to better evaluate the efficacy and safety of this approach in children with glomerular diseases.     

Efficacy of mycophenolate mofetil on recurrent glomerulonephritis after renal transplantation

Recurrent glomerulonephritis in transplanted kidneys is not rare despite classical immunosuppressive drugs and depends on the etiology of nephropathy. Treatment of recurrence of renal disease on graft remains controversial. We report 6 cases of patients with recurrent glomerulonephritis after renal transplantation treated with mycophenolate mofetil (MMF). The glomerular diseases were Wegener's granulomatosis (n = 1), membranoproliferative glomerulonephritis type I (n = 1), focal and segmental glomerular sclerosis (n = 1), membranous glomerulonephritis (idiopathic membranous nephropathy (n = 1) and systemic lupus erythematous) (n = 1)) and immunoglobulin A nephropathy (n = 1). MMF was introduced because of intolerance of classical immunosuppressive treatment in 2 cases and because of its inefficiency in the other cases. MMF was introduced between 3 months and 36 months (13.5 +/- 7 months) after recurrence of the primitive glomerulonephritis. During combined MMF/cyclosporine/prednisone therapy, only 3 patients responded to MMF. MMF was disrupted precociously in 1 out of 3 patients who stabilized renal function because of discovery of lung cancer and in 2 out of the 3 other patients because of gastrointestinal intolerance and severe anemia. We supposed that MMF could represent a new effective alternative therapy of recurrent glomerulonephritis on renal graft in some cases.     

Biologic agents in the treatment of glomerulonephritides

Current immunosuppression strategies in the treatment of glomerulonephritides remain unsatisfactory, especially in glomerular diseases that are frequently relapsing or are resistant to treatment. Toxicities associated with the use of drugs with non‐specific targets for the immune response result in treatment non‐compliance, and increase morbidity and mortality in these patients. Advances in our understanding of the immunopathogenesis of glomerulonephritis and the availability of biologics have led to their successful use in the treatment of immune‐mediated glomerular diseases. Biologics are usually very large complex molecules, often produced using recombinant DNA technology and manufactured in a living system such as a microorganism, or plant or animal cells. They are novel agents that can target specific immune cell types, cytokines or immune pathways involved in the pathogenesis of these disorders. It is attractive to consider that, given their specific mode of action, these agents can potentially offer a more directed and effective immunosuppression, with side‐effect profiles that are much more desirable. However, there have been few randomized controlled trials comparing biologic agents to conventional immunosuppression, and in many of these studies the side‐effect profiles have been disappointingly similar. In this review, we will examine the rationale, efficacy and safety of some commonly used biologics in the treatment of primary and secondary glomerulonephritides. We will also discuss some of the key challenges that may be encountered with the use of biologics in treating glomerulonephritis in the future.     

Minimal-change nephropathy and chronic hepatitis C infection: coincidental or associated?

Sir, Hepatitis C virus (HCV) infection is among the known main causesof glomerulonephritis. Membranoproliferative glomerulonephritisassociated with cryoglobulinaemia is the predominant form inHCV-infected patients. Less common glomerular diseases, i.e.membranoproliferative glomerulonephritis without cryoglobulinaemia,membranous glomerulonephritis, focal segmental glomerular sclerosis,proliferative glomerulonephritis, renal thrombotic microangiopathyassociated with anti-cardiolipin antibodies and fibrillary andimmunotacoid glomerulopathies, have also occurred in these patients.We encountered a patient with chronic     

Serum hepatocyte growth factor levels in patients with renal diseases.

The serum levels of hepatocyte growth factor (HGF) were determined in patients with various renal diseases. In patients with acute-phase acute renal failure (ARF) and chronic tubulointerstitial nephritis (chronic TIN), the serum HGF levels were 0.55 +/- 0.24 and 0.44 +/- 0.37 ng/ml (mean +/- SD), respectively, and were significantly higher than that in the control group (0.12 +/- 0.12 ng/ml). The serum HGF level tended to be high also in patients with active-phase steroid-sensitive nephrotic syndrome (SSNS). The serum levels of HGF were not elevated in patients with IgA nephropathy (IgAN), Henoch-Sch?nlein purpura nephritis (HSPN), membranoproliferative glomerulonephritis (MPGN), poststreptococcal acute glomerulonephritis (PSAGN), unilateral renal atrophy, unilateral nephrectomy, or proximal tubular dysfunction. These observations suggest that glomerular disorders cause no apparent elevation of the serum HGF level, and that elevation of the serum HGF level may be associated with tubulointerstitial damage in renal diseases.     

C1q nephropathy with asymptomatic urine abnormalities

We found four cases of C1q nephropathy (C1qN) among a total of 193 pediatric series of first renal biopsies. Among them, 94 biopsies were performed because of asymptomatic urine abnormalities detected by school urinary screening program in Japan; three cases out of these 94 biopsies (3.2%) met the criteria of C1qN. One case out of the remaining 99 biopsies with symptomatic renal diseases (1%) also met the criteria of C1qN. Three cases with asymptomatic onset presenting with mild proteinuria with or without hematuria equally showed histologic features of membranoproliferative glomerulonephritis and showed improvements in urinalysis without corticosteroid treatment. Our data suggest that membranoproliferative glomerulonephritis may be a common histological feature of asymptomatic pediatric C1qN in Japan and that this type of glomerulopathy may follow a relatively good clinical course without steroid therapy.     

Resolution of cirrhotic glomerulonephritis following successful liver transplantation

A 38-year-old man with liver failure due to Laennec's cirrhosis developed nephrotic range proteinuria and hematuria. Renal biopsy showed membranoproliferative glomerulonephritis with 2+ staining for IgA and complement consistent with cirrhotic glomerulonephritis. After orthotopic liver transplantation, proteinuria and hematuria rapidly resolved. This case indicates that glomerulonephritis associated with cirrhosis may be successfully treated with hepatic transplantation. Whether the improvement in glomerular abnormalities resulted from immunosuppression therapy or from restoration of normal hepatic function is unknown.     

A case of acute renal failure caused by Hodgkin's lymphoma: concurrent membranous glomerulonephritis and interstitial HL-CD 20 lymphoid infiltration

Although acute renal failure developing due to malignancies is a frequent condition, malignant renal infiltration is rarely observed among these causes. Among all malignant diseases, the hematolymphoid malignancies are the most prone to renal infiltration. Other types involved in cases with lymphoma are glomerulopathies, including immune-complex glomerular diseases such as minimal change disease, membranous glomerulonephritis, membranoproliferative glomerulonephritis, and focal segmental glomerulosclerosis. We present herein the rare case of a 22-year-old male with both membranous glomerulonephritis and CD20 (+) lymphoid infiltration related to Hodgkin's lymphoma in the renal interstitial tissue, as detected on biopsy. The patient was treated with adriamycin, bleomycin, vinblastine, and dacarbazine protocol after pulse corticosteroid treatment, and a dramatic improvement in renal function was observed after 2 days of treatment. In this article, an exceptional renal involvement of Hodgkin's lymphoma is discussed in light of the related literature.     

Hepatitis B virus associated focal and segmental glomerular sclerosis: report of two cases and review of literature

The hepatitis B virus (HBV) is estimated to have infected about 350 million people worldwide, making it one of the most common human pathogens. Renal involvement is among its most common extra hepatic manifestations and usually manifests in the form of immune complex mediated glomerulopathy, such as membranous glomerulonephritis (MGN), membranoproliferative glomerulonephritis (MPGN), mesangioproliferative glomerulonephritis and immunoglobulin A (IgA) nephropathy. Occurrence of focal and segmental glomerular sclerosis (FSGS) with HBV infection is rare and only five cases have been reported earlier. We report two cases of hepatitis B associated FSGS. In both the cases, HBsAg was demonstrated in the renal tissue and both the cases showed response to treatment with lamivudine, thus indicating a possible causal association between the viral infection and occurrence of nephrotic syndrome.     

Pathogenesis of hepatitis C virus-associated glomerulonephritis

Summary: Hepatitis C virus (HCV), in addition to causing both acute and chronic liver disease, may also be associated with several immunologically-mediated syndromes, particularly cryoglobulinaemia and membranoproliferative glomerulonephritis. Although the glomerulonephritis may be a feature of a systemic cryoglobulinaemic syndrome, it may also present as a primary renal disease without evidence of vasculitis or liver disease. Most of these latter patients, however, will have detectable cryoglobulinaemia either at the time of presentation or with continued observation. In this review, we discuss the pathogenesis of the glomerular disease. Most evidence supports the hypothesis that HCV associated glomerular disease results from the deposition of circulating immune complexes that are usually cryoprecipitable and which contain HCV, anti-HCV IgG, and rheumatoid factors. However, HCV antigens have yet to be identified in glomerular biopsies. This has raised the possibility that other pathogenic mechanisms may be involved, including auto-antibodies directed against glomerular antigens and factors related to chronic liver disease. Further studies are necessary to fully elucidate the pathogenesis of this recently recognized disease.     

Hypercholesterolemia and glomerular diseases in urinary screening of school children

 Although hypercholesterolemia frequently accompanies nephrotic syndrome, high serum total cholesterol (TC) levels are occasionally seen in children with non-nephrotic glomerular diseases. However, little is known of the significance, if any, of these elevated serum TC levels in non-nephrotic glomerular diseases. During the past 5 years, a total of 256,179 school children received yearly urinary screening at school for renal diseases and 1,702 children (0.66% of the total, although 174 children dropped out) had proteinuria and/or hematuria. Using the data obtained from the 1,528 children, we studied whether there is any association between serum TC levels and the presence of glomerular diseases. The detection rate of glomerular diseases (IgA nephropathy, membranoproliferative glomerulonephritis, focal segmental glomerular sclerosis, etc.) in the subjects with high serum TC levels (≥200 mg/dl) was significantly higher (16 of 161, 9.94%, P<0.001) than in those with normal serum TC levels (<200 mg/dl) (10 of 1,367, 0.73%). There were no significant differences in serum albumin and blood urea nitrogen levels between the two groups. We conclude that children with chance proteinuria and/or hematuria may be at higher risk for glomerulonephritis of various types when they have unexplained hypercholesterolemia, and that measurement of serum cholesterol levels may be useful in urinary screening for renal diseases. Received: 21 August 1997 / Revised: 16 July 1998 / Accepted: 20 July 1998