Membranoproliferative glomerulonephritis following allogeneic hematopoietic stem cell transplantation

Nephrotic syndrome after allogeneic hematopoietic stem cell transplantation has been increasingly described as a manifestation of chronic graft-versus-host disease (GVHD); however, GVHD-associated membranoproliferative glomerulonephritis is extremely rare. A 44-year-old man developed nephrotic syndrome 24 months after HSCT for acute lymphoblastic leukemia. The renal biopsy showed type I membranoproliferative glomerulonephritis. Salivary gland biopsy demonstrated mild lymphocytic infiltration, indicating chronic GVHD. Improvement of the proteinuria and recovery of renal function were achieved within 11 months of treatment with oral prednisolone and azathioprine.     

Antineutrophil cytoplasmic antibody-associated glomerulonephritis in chronic graft-versus-host disease after allogenic hematopoietic stem cell transplantation

Graft-versus-host disease (GVHD) is one of the most frequent complications that occur after hematopoietic stem cell transplantation (HSCT). Recently, renal involvement, including membranous nephropathy, focal segmental glomerulosclerosis, and minimal change disease, has been described as a manifestation of chronic GVHD. This case report describes a patient who developed antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis after HSCT. Following preparation with chemotherapy, a 29-year-old man with chronic myeloid leukemia underwent allogenic peripheral blood stem cell (PBSC) transplantation, after which first acute and then chronic GVHD developed. Treatment with prednisone resulted in improvement in the patient's GVHD. After the termination of steroid therapy and about 10 months after PBSC transplantation, nephritic syndrome appeared and the patient's serum creatinine value increased to 1.7 mg/dL. Laboratory evaluation revealed perinuclear antineutrophilic cytoplasmic antibody (p-ANCA) in the serum. Histological examination of renal biopsy tissue showed focal segmental proliferative glomerulonephritis with glomerulosclerosis in 20% of available glomeruli, large cellular crescents in 6% of glomeruli, and no staining of immunoglobulins or complement along the capillary walls. Electron microscopy revealed no immune deposits. After treatment with prednisone 60 mg/d, diltiazem 120 mg/d, and enalapril 10 mg/d, the proteinuria gradually decreased, and p-ANCA was undetectable. These findings suggest that in this patient the ANCA-associated glomerulonephritis was associated with renal involvement that occurred during the course of chronic GVHD.     

Rapid development of diffuse crescents in post-streptococcal glomerulonephritis

A 14-year-old boy presented with 3 days of hematuria and oliguria following impetigo. Renal biopsy showed diffuse endocapillary proliferative glomerulonephritis with subendothelial electron dense deposits but no crescents. Due to recrudescence of clinical abnormalities after initial improvement, the patient was re-biopsied 10 days later. This biopsy showed circumferential crescents in 83% of the glomeruli. Treatment with intensive plasma exchange, prednisolone, cyclophosphamide and dipyridamole was accompanied by prompt improvement in renal function. The need to carefully monitor the course in patients with acute post-streptococcal glomerulonephritis is emphasized.     

Superimposition of poststreptococcal acute glomerulonephritis on the course of IgA nephropathy

A 17-year-old male with poststreptococcal acute glomerulonephritis (PSAGN) superimposed on the course of IgA nephropathy is presented. The histological findings of the first renal biopsy showed mild IgA nephropathy with a mesangial deposition of IgA and C3. Eighteen months later, acute nephritic syndrome with hypocomplementemia and rising antihyaluronidase titer occurred 10 days following the onset of an upper respiratory infection. The second renal biopsy revealed severe diffuse endocapillary proliferative and exudative glomerulonephritis with cellular crescents in 70% of the glomeruli. Immunofluorescence showed granular staining of C3 alone along the capillary walls. The pre-existing IgA deposits had disappeared. Typical 'humps' were observed by electron microscopy. The symptoms were gradually resolved by intensive steroid and anticoagulant therapy. Five months after the episode of acute nephritic syndrome, the patient was clear of symptoms except for mild proteinuria and hematuria. The third renal biopsy at that time showed morphologic changes similar to those of the first renal biopsy with mild mesangial IgA deposits.     

Clinicopathological study of patients with mesangial isolated C3d deposition in various glomerular diseases

The clinicopathological findings of isolated mesangial C3d deposition in the absence of other complement components or immunoglobulins are summarized. 55 out of 242 individual human renal biopsies examined by immunoperoxidase microscopy had isolated C3d deposition. This group consisted of 12 patients with chronic glomerulonephritis, 8 with minimal-change nephrotic syndrome, 32 with benign recurrent hematuria, 2 with Bartter's syndrome and 1 with Raynaud's syndrome. None of these patients had a disorder of the renal function and in all the patients the disease took a benign clinical course. Light-microscopic findings indicated injuries ranging from minor glomerular abnormality to mild diffuse mesangial proliferative glomerulonephritis, and there were no other remarkable findings such as cellular crescents, global sclerosis or interstitial infiltration. By immunoperoxidase microscopy, fine granular deposits of C3d were identified only in the mesangium, and arteriolar C3 staining was seen in 31 of the 55 patients. In 38 of the 42 patients examined by electron microscopy, electron-dense deposits were identified in the mesangial matrix. These findings suggest that isolated C3d deposition is a new entity with benign features both clinically and pathologically.     

Clinical and histological improvement with long-term, low-dose cyclosporin A in a patient with severe IgA nephropathy

We report the case of an 11-year-old girl with nephrotic syndrome with massive proteinuria and microscopic hematuria. Her first renal biopsy specimen (June 1997) showed diffuse/segmental mesangial proliferative glomerulonephritis with capillary wall thickening, crescent, and sclerosis by light microscopy, as well as diffuse/global moderate deposition of IgA, C₃, and fibrinogen predominantly in the mesangium, and partly along the capillary wall, by immunofluorescent microscopy. After the patient failed to show remission with the usual dose of prednisolone and azathioprine, cyclosporin A was administered, in addition to dipyridamole, warfarin, and prednisolone (on alternative days). In consequence, the proteinuria had completely disappeared after 6 weeks of this regimen and microscopic hematuria had disappeared after 8 months of the regimen. A second renal biopsy was performed in August 1998. The epithelial proliferation and crescent seen in the first biopsy specimen had disappeared, and only mesangial proliferation and sclerosis persisted, without histological evidence of cyclosporin-induced nephrotoxicity. A third renal biopsy was performed in March, 2000. IgA deposition in glomeruli had disappeared in this biopsy specimen. Low-dose cyclosporin A therapy resulted in dramatic improvements in both clinical manifestations and renal histological findings, without detrimental effects on renal function. Received: September 4, 2000 / Accepted: December 22, 2000     

Naproxen-induced nephropathy in systemic lupus erythematosus

A 34-year-old female with an 8-month history of systemic lupus erythematosus and intermittent naproxen use presented with acute oliguric renal failure, hypoalbuminemia, 4+ proteinuria, and an active urinary sediment. The clinical picture suggested a rapidly progressive lupus glomerulonephritis. Renal biopsy, however, demonstrated chronic, active interstitial nephritis without evidence of immune deposits by immunofluorescence or electron microscopy. Nonsclerotic glomeruli revealed diffuse foot process fusion without cellular proliferation. These findings were consistent with nonsteroidal anti-inflammatory drug induced nephropathy. Discontinuation of naproxen and institution of corticosteroid therapy was followed by improvement in renal function and remission of nephrotic syndrome. This case represents the first report of nonsteroidal antiinflammatory drug nephropathy associated with systemic lupus erythematosus.     

Immunosuppressive therapy and plasmapheresis in rapidly progressive glomerulonephritis associated with bacterial endocarditis

A 25-year-old male presented with new cardiac murmurs and acute renal insufficiency. Blood cultures grew Streptococcus viridans and appropriate antibiotic therapy was initiated. A renal biopsy revealed diffuse proliferative glomerulonephritis with crescents involving more than 50% of the glomeruli. Treatment with antibiotics, plasmapheresis, and steroids resulted in renal recovery that paralleled reductions in circulating immune complexes. The rationale for this therapeutic approach is discussed, as well as a review of two similar case reports. These experiences suggest a possible role for plasmapheresis and immunosuppressive drugs in patients who develop rapidly progressive glomerulonephritis as a complication of bacterial endocarditis.     

Dense intramembranous deposit disease: new pathologic features

The pathologic and clinical features of 16 patients with dense intramembranous deposit disease are described. By light microscopy nine patients had membranoproliferative glomerulonephritis, five had focal segmental necrotizing glomerulonephritis with segmental epithelial crescents, four of whom also had a prominent tubulointerstitial nephritis, and two had focal segmental mesangial proliferative glomerulonephritis. The patients with membranoproliferative glomerulonephritis and one with focal segmental mesangial proliferative glomerulonephritis had easily recognizable dense intramembranous deposits by optical microscopy. The patients with focal segmental necrotizing glomerulonephritis and one with focal segmental mesangial proliferative glomerulonephritis did not have recognizable peripheral loop dense intramembranous deposits even under oil immersion. In patients with membranoproliferative glomerulonephritis ultrastructural examination revealed extensive capillary wall dense intramembranous deposits. Immunofluorescence revealed diffuse double linear staining along the capillary walls and "mesangial rings" of C3. In the patients with focal segmental necrotizing glomerulonephritis and one with focal segmental mesangial proliferative glomerulonephritis the immunofluorescence study suggested a diagnosis of dense intramembranous deposit disease because of the segmental double linear staining of the capillary walls and "mesangial rings" of C3, but the diagnosis was only established by fine structural analysis where occasional peripheral loop and prominent paramesangial basement membrane dense intramembranous deposits and mesangial nodular deposits were identified. Clinical features prior to biopsy included nephrotic syndrome in eight patients, an acute nephritic syndrome in six patients, and asymptomatic proteinuria and hematuria in two patients. Five of six patients with an acute nephritic presentation had focal segmental necrotizing glomerulonephritis. The acute renal insufficiency in these patients was transitory and appeared to be related to a prominent acute tubulointerstitial nephritis present in four of the biopsy specimens. Depressed serum C3 levels were present in patients with membranoproliferative glomerulonephritis; patients with focal segmental lesions were normocomplementemic. Because of the "atypical" light microscopic features in six of our patients, we support the suggestion that membranoproliferative glomerulonephritis, type II be replaced by the term 'dense intramembranous deposit disease' for this glomerulopathy with variable clinical and histologic features.     

Renal survival rate of IgA nephropathy

In an attempt to identify prognostic indicators in IgA nephropathy, we evaluated the relationship between clinical and histological findings and changes in renal function in 81 patients with IgA nephropathy whose creatinine clearance was more than 80 ml/min at the time of renal biopsy. The incidence of patients whose creatinine clearance decreased to less than 60 ml/min during the follow-up period was calculated with the life table method to designate the renal survival rate. This rate was compared according to the clinical and histological findings at the time of renal biopsy. In conclusion, a statistically significant decrease in the renal survival rate was observed in patients with proteinuria of more than 1.0 g/day, hypertension, severe diffuse proliferative glomerulonephritis, diffuse proliferative glomerulonephritis with focal crescents and glomerular deposition of IgM and/or fibrinogen-related antigen.     

Nephrotic syndrome in patients after successful myeloablative allogeneic hematopoietic stem cell transplantation: clinical findings obtained from four transplanted patients

We experienced four patients who suffered from nephrotic syndrome after a successful allogeneic hematopoietic stem cell transplantation (HSCT). These cases were seen in the nineteen-year period from September, 1986 to June, 2005. Our data showed that the incidence of nephrotic syndrome was 0.51% (3 out of 585 HSCT patients) in our hospital. Pathological findings of their renal biopsy specimens revealed that 3 patients had membranous nephropathy and that one patient had minimal change disease. Three patients were positive for anti nuclear antibody. Administration of prednisolone or cyclosporine improved the nephrotic syndrome, leading all patients to a complete or almost complete remission. The nephrotic syndrome occurred at 17 to 25 months after HSCT and accompanied the relapse of chronic graft-versus-host disease (GVHD), possibly due to the termination or a decrease of immunosuppressant administration in all patients. This suggests that immunological abnormality associated with chronic GVHD may be partly involved.     

High-dose methylprednisolone therapy for nephrotic syndrome in Henoch-Schoenlein nephritis

Twelve patients with nephrotic syndrome (NS) in Henoch-Schoenlein (HS) nephritis were treated with a high dose of intravenous methylprednisolone (MP) on each of nine alternate days followed by oral prednisolone for 4 to 6 months. Renal biopsy was performed on 10 of the 12 patients. The glomerular change in 5 patients, which was accompanied by crescents and/or sclerosis, with NS and acute nephritic syndrome (ANS) at onset, was more severe than that of the other 5 patients with NS and hematuria at onset. The renal insufficiency or hypertension in these 5 patients with NS and ANS improved within 2 weeks on this MP therapy. After a mean follow-up period of 40.5 months, all patients except 2 revealed normal physical findings and renal function as well as urinary findings. Repeated biopsies in the 2 patients with NS and ANS at onset demonstrated an improved renal pathology in comparison with their initial biopsies. No severe side effects related to high-dose intravenous MP followed by oral prednisolone therapy were encountered in any of the patients. Our results suggest that high-dose intravenous MP therapy can lead to a favorable outcome in patients with NS in HS nephritis.     

Superimposition of post-streptococcal acute glomerulonephritis on the course of IgA nephropathy: predominance of Th1 type immune response

A 23-year-old man was admitted with macrohematuria and systemic edema appearing after an acute upper respiratory tract infection. He had been diagnosed 6 years earlier with IgA nephropathy (IgA-N). On admission, hypertension, nephrotic syndrome and hypocomplementemia were evident together with a high titer of anti-streptokinase (ASK). Renal biopsy showed severe glomerular mesangial proliferation, segmental endocapillary proliferation and crescent formation. Immunofluorescence microscopy (IF) showed strong deposition of C3 and reduced deposition of IgA. Electron microscopy showed a so-called "hump" on the epithelial side of the glomerular basement membrane.These features were consistent with post-streptococcal acute glomerulonephritis (PSAGN) superimposed on IgA-N. Following 2 weeks of observation, blood pressure, C3 level and ASK titer returned to normal ranges, although nephrotic syndrome was still evident, which necessitated oral prednisolone (30 mg/day) therapy. Another biopsy taken 2 months later demonstrated regression of endocapillary proliferation and IF showed decreased deposition of C3. Immunohistochemical staining of the specimen taken on admission revealed the presence of numerous T cells and macrophages in the interstitium. Macrophages were also seen in the glomerular tuft. Many interstitial infiltrating cells were positive for interferon-gamma, but their number diminished after treatment. Our findings suggest that PSAGN complicating pre-existing IgA-N activates cellular immunity and augments renal tissue injury.     

Crescentic glomerulonephritis in children: a review of 43 cases.

Forty-three children with crescentic glomerulonephritis (GN), having large crescents in more than 50% of the glomeruli, were observed during a period of 22 years. There were 17 boys and 26 girls between the ages of 3.5 and 14 years (mean 8.7 +/- 2.6). Thirty-one patients (72%) presented with acute nephritic features and increasing renal insufficiency (rapidly progressive GN) whereas 12 had an insidious onset with nephrotic syndrome, or rarely with nonspecific symptoms. Eleven patients had evidence of poststreptococcal GN and 6 an underlying systemic disorder. Renal biopsy showed large crescents in greater than 80% of the glomeruli in 38 cases (100% in 28) which were predominantly fibrocellular or fibrous in 80% of the patients. Nineteen patients (44%) were treated with prednisolone, cyclophosphamide and dipyridamole; in addition, 8 were also given anticoagulants. Six patients received pulse doses of corticosteroids. In 23 patients, there was inexorable progression of renal failure, 14 showed partial improvement but subsequently had varying degrees of renal insufficiency and in 6, there was recovery of renal function with normal levels of serum creatinine. Of the latter, 4 had received immunosuppressive anticoagulant therapy and 2 only supportive care. Of 11 patients with poststreptococcal crescentic GN, 7 progressed to end-stage renal disease and 2 developed chronic renal insufficiency. Our findings confirm the poor outcome of crescentic GN in children, irrespective of the underlying etiology. In a small proportion of cases, the disorder may have an insidious onset and a slowly progressive course, but an equally grave prognosis.     

Methylprednisolone pulse therapy in the treatment of severe forms of Schönlein-Henoch purpura nephritis

 Between 1980 and 1994, 38 children with severe forms of Sch?nlein-Henoch purpura glomerulonephritis were entered into a prospective study to evaluate methylprednisolone pulse therapy on the outcome of nephropathy in terms of clinical symptoms and histopathological changes. The patients were considered at risk of developing chronic renal failure when they presented with a nephrotic syndrome and/or had 50% or more crescentic glomeruli. Initial renal biopsies were obtained from all patients and revealed diffuse proliferative endocapillary glomerulonephritis in 2, focal and segmental glomerulonephritis in 4, and endo- and extracapillary glomerulonephritis in 32, 21 of whom had 50% or more glomeruli with crescents. Patients were treated with intravenous pulse methylprednisolone (3 days) followed by oral prednisone (3.5 months). At the latest follow-up, 1–16 years after initiation of therapy, 27 children had clinically recovered, 3 showed minimal urinary abnormalities, 4 persistent nephropathy, and 4 had progressed to end-stage renal failure. Sequential renal biopsies were obtained from 30 patients, 7–25 months after initiation of therapy. The clinical outcome correlated well with of the activity (hypercellularity, cellular and fibrocellular crescents, and interstitial edema with mononuclear cell infiltrates) and the chronicity (fibrous crescents, glomerular sclerosis, tubular atrophy, and interstitial fibrosis) indexes of post-therapy biopsies. Of particular interest were the post-therapy biopsies of the 18 patients who clinically recovered. They showed a significant decrease of the activity index from 5.1±1.1 to 0.4±0.8 with a decrease or even a disappearance of IgA deposits, while the chronicity index remained low (0.4±0.8 compared with 1.4±1). Although uncontrolled, our study suggests that methylprednisolone pulse therapy is effective in those patients at risk of progression of their nephropathy, especially if started early during the course of the disease before the crescents become fibrous. Received February 26, 1997; received in revised form and accepted June 15, 1997     

Membranous nephropathy with crescents

Membranous nephropathy is a common cause of nephrotic syndrome in adults and can be primary or secondary to systemic lupus erythematosus, chronic infection, or drugs. Rapid decline in renal function in patients with membranous nephropathy may be due to renal vein thrombosis, malignant hypertension, or an additional superimposed destructive process involving the renal parenchyma. Crescents are rare in primary membranous nephropathy and thus suggest another underlying disease process, such as combined membranous and focal or diffuse lupus nephritis. However, in some patients with membranous nephropathy and crescents, the crescentic lesion may be due to a distinct, separate disease process, such as anti-glomerular basement membrane antibodies or anti-neutrophil cytoplasmic antibodies-related pauci-immune glomerulonephritis. Here we describe a case with such renal biopsy findings, review previous reported cases, and discuss possible implications for pathogenesis of the coexistence of these lesions.     

Crescentic post-streptococcal glomerulonephritis with nephrotic syndrome in the adult: is aggressive therapy warranted?

The prognosis for adults with acute post-streptococcal glomerulonephritis (PSGN) who present with crescentic glomerulonephritis and nephrotic proteinuria is not known. We report a patient with rapidly progressive glomerulonephritis and nephrotic-range proteinuria following acute pharyngitis, in whom serologic and kidney biopsy findings led to a diagnosis of PSGN. The patient was treated with corticosteroids and anti-hypertensive medications resulting in improvement in renal function and decrease in proteinuria. These results suggest that aggressive treatment of crescentic PSGN with nephrotic syndrome can result in a favorable outcome.     

Biopsy proven evolution of post streptococcal glomerulonephritis to rapidly progressive glomerulonephritis of a post infectious type

A 15 year old boy with chronic impetigo was admitted with severe acute oliguric renal failure requiring temporary dialytic treatment. Renal biopsy revealed typical diffuse and proliferative glomerulonephritis of the poststreptococcal type. Subsequently high temperature developed with flank pains at the biopsy site, concomitantly with deterioration of renal function. On exploration, a sterile perirenal hematoma was found and a wedge renal biopsy revealed crescentic rapidly progressive glomerulonephritis of the post infectious type. Deterioration to end stage renal failure occurred within a few months. Although universally accepted, biopsy proven evolution from diffuse proliferative and exudative glomerulonephritis to crescentic form of post streptococcal glomerulonephritis has been rarely reported.     

Remission of hepatitis B virus-associated membranoproliferative glomerulonephritis in a cirrhotic patient after lamivudine therapy

We describe a 39-year-old man with hepatitis B virus-(HBV) related chronic hepatitis who presented with nephrotic syndrome and decompensated cirrhosis. A kidney biopsy revealed membranoproliferative glomerulonephritis (MPGN) which was thought to be related to the HBV infection. Because interferon-alpha therapy was generally not recommended in patients with advanced liver disease, we chose lamivudine as an alternate treatment for the HBV-associated glomerulonephritis (GN). After 3-month treatment with oral lamivudine, resolution of the renal disease dramatically occurred together with improvement in liver function. To our knowledge, this is the first case of HBV-associated MPGN successfully treated with oral lamivudine therapy. The possible role of lamivudine in the treatment of HBV-associated GN is discussed.     

Nephrotic syndrome in a child after umbilical-cord-blood transplantation

We report a 12-year-old girl who developed nephrotic syndrome 6 months after umbilical-cord-blood transplantation (UCBT) for acute lymphoblastic leukemia (L2). In addition to nephrotic syndrome, she also showed autoimmune hemolytic anemia, thrombocytopenia and gastrointestinal symptoms. Since these symptoms were manifested during the course of tapering immunosuppressive agents, a diagnosis of chronic graft-versus-host disease (GVHD) was made. Findings from a kidney biopsy were compatible with minimal-change disease (MCD), and focal glomerular capillary thrombosis and mild tubular damage were also noted. She was treated with methylprednisolone pulse therapy followed by oral prednisolone. Proteinuria disappeared in 14 days. Gastrointestinal symptoms, anemia and thrombocytopenia were also corrected. This is a case report of nephrotic syndrome as a manifestation of chronic GVHD developed after stem-cell transplantation. A review of the cases reported in the literature is also made.This case was presented at the 3rd Japan-Korea Pediatric Nephrology Seminar held in Tokyo, Japan, on 28 May 2005.