Podocyte foot process effacement is not correlated with the level of proteinuria in human glomerulopathies

BACKGROUND: Nephrotic syndromes result from increased glomerular permeability to proteins and are structurally believed to be associated with podocyte foot process effacement. Despite increasing knowledge of the molecular composition of the glomerular filtration barrier, the relationship between proteinuria and foot process effacement is unclear. METHODS: We conducted a morphologic study on the relationship between podocyte foot process effacement and proteinuria. Electron microscope pictures of glomerular capillaries were randomly taken from 27 cases in various stages of minimal change nephrotic syndrome (MCNS), from six cases of IgA nephropathy (IgAN) with high proteinuria and from seven control kidneys. From each picture, the mean width of the foot processes (FPW) was quantitated. RESULTS: In normal kidney the mean FPW was 580 +/- 40 nm. In biopsies from patients with MCNS without treatment, foot processes were diffusely effaced, reflected by a FPW of 1600 +/- 440 nm. In biopsies from patients with MCNS relapsing under prednisolone treatment, foot processes were significantly less effaced than in untreated MCNS (FPW 920 +/- 200 nm). In biopsies displaying IgAN, effacement was significantly more segmental than in untreated MCNS (FPW 800 +/- 170 nm). Proteinuria did not differ significantly among the groups. Neither in MCNS nor in IgAN was the extent of foot process effacement correlated with the level of proteinuria. CONCLUSION: Podocyte foot process effacement is not correlated with proteinuria. The differences in podocyte effacement between MCNS, MCNS relapsing under prednisolone treatment, and IgAN may point to different mechanisms of podocyte injury in these diseases.     

Late flare-up of nephrotic lupus nephritis transforming histological pattern and autoantibody reactions

A 15-year-old boy developed a nephrotic syndrome. At that time, autoantibodies related to systemic lupus erythematosus (SLE) had been persistently negative, even on repeated evaluation. C1q was normal, but C4, C3 and CH50 were low. Renal biopsy revealed membranous lupus nephritis (LN) based on the new classification of glomerulonephritis in SLE [Weenig et al. 2004]. We did not establish our diagnosis of SLE on the criteria of the American Rheumatism Association (ARA). The patient showed complete remission ofnephrotic syndrome treated with prednisolone and cyclophosphamide. Thereafter, he had no proteinuria and clinical evidence of SLE for 22 years. At the age of 37, however, he developed facial discoid eruption, proteinuria in the nephrotic range, hypocomplementemia and positive reaction to autoantibodies of SLE. Light microscopic findings of renal biopsy indicated mesangial LN, which showed "full-house" immunofluorescence and mesangial dense deposits associated with diffuse epithelial cell foot process effacement in electron microscopy. Steroid therapy was very effective. This case initially showed autoantibody-negative and hypocomplementemic LN with membranous type, and transformed to SLE with mesangial LN after a long interval.     

Proteinuria with and without renal glomerular podocyte effacement

Renal biopsies of patients with proteinuria and kidney disease most often are associated with podocyte foot process effacement. For several decades, nephrologists have wondered whether proteinuria is a result of podocyte foot process effacement or the cause of it. In the past few years, the author's laboratory has addressed this issue using different mouse models of proteinuria. Although in most cases, podocyte effacement is associated with proteinuria and glomerular disease, in three different mouse models, it was demonstrated that proteinuria can be observed without podocyte foot process effacement. The first model is generated by injection of antibodies to vascular endothelial growth factor or soluble vascular endothelial growth factor receptor 1. The second model is a mouse with deletion of type IV collagen alpha3 chain in the glomerular basement membrane. The third model was generated by genetic deletion of a slit diaphragm protein known as nephrin. Collectively, these experiments and the supporting evidence from several human studies demonstrate that severe defects in either the glomerular basement membrane or the glomerular endothelium can lead to proteinuria without foot process effacement.     

Chronic sclerosing glomerulopathy (heroin-associated nephropathy) in intravenous T's and Blues abusers

The intravenous (IV) use of pentazocine (Talwin) and tripelennamine (pyribenzamine) has become a major form of drug abuse seen in the midwestern United States. Complications of this abuse have included psychotic reactions, acute pulmonary insufficiency, convulsions, and various infections. We have observed three patients in whom the IV use of these agents was associated with the nephrotic syndrome and renal histopathologic findings similar to that reported in heroin addicts with the so-called "heroin-associated nephropathy." Percutaneous renal biopsy demonstrated focal to diffuse segmental or global glomerulosclerosis by light microscopy. Electron microscopy revealed glomerular visceral epithelial cell foot process effacement and microvillus formation. Immunofluorescent studies were negative in the two patients studied. One patient presented in renal failure, and two others progressed to renal failure within 3 years of diagnosis. We suggest the term opiate nephropathy for this lesion in narcotics users, indicating its potential occurrence in non-heroin-using drug addicts.     

Acute interstitial nephritis predisposed a six-year-old girl to minimal change nephrotic syndrome

A six-year-old girl was admitted to our hospital with acute renal failure. We made a clinical diagnosis of acute interstitial nephritis and oral corticosteroid therapy was started. Her renal failure soon recovered, and renal biopsy showed acute interstitial nephritis by light microscopy with glomerular foot process effacement by electron microscopy. Although her proteinuria was not heavy at the time of biopsy, her proteinuria subsequently increased to show nephrotic syndrome. We continued to give corticosteroids and her nephrotic syndrome went into remission 13 days after biopsy. Serological and bacteriological examination showed no evidence of known pathogen or drug hypersensitivity. The time changes in proteinuria were monitored by fractional total protein excretion (FETP) and fractional 2 microglobulin excretion (FE2MG) in order to evaluate the severity of proteinuria under different glomerular filtration rates and different proximal tubular functions. The results revealed that nephrotic syndrome had occurred during recovery from acute interstitial nephritis. This is the first case report to show the sequential occurrence of acute interstitial nephritis and nephrotic syndrome based on evidence from fractional protein excretion.     

Recurrent nephrotic syndrome in renal allografts

We describe the clinicopathologic course of two patients with recurrent focal segmental glomerular sclerosis (FSGS). In both patients, FSGS was initially demonstrated during the evaluation of proteinuria. After progressing to end-stage renal disease, each patient received a living-related renal transplant. Shortly after transplantation, proteinuria recurred in both patients, progressing to the nephrotic syndrome. Serial renal biopsies were obtained from each patient. These initially demonstrated focal segmental epithelial proliferation (the "cellular lesion"), but focal segmental scars were observed in subsequent biopsies. None of the biopsies demonstrated immunoglobulin, complement deposition, or diffuse epithelial cell foot process fusion. These findings suggest that the scarring lesion in recurrent FSGS may be the result of a primary process involving damage to a limited number of visceral epithelial cells.     

An unusual case of anti-glomerular basement membrane disease presenting with nephrotic syndrome

Anti-glomerular basement membrane (anti-GBM) disease is a vasculitic disease characterized by acute kidney injury, oliguria, hematuria and proteinuria. Proteinuria is rarely in the nephrotic range. A case of anti-GBM disease with proteinuria of 22.5g/day is discussed. Immunofluorescence showed strong linear IgG deposits while electron microscopy showed widespread visceral epithelial cell foot cell process effacement. No electron dense immune complex-type deposits were identified. Pathology findings were not suggestive of simultaneous presentation of anti-GBM disease and other diseases associated with nephrotic range proteinuria. Anti-GBM disease should be considered in a comprehensive differential diagnosis of severe proteinuria.     

Nephrotic range proteinuria with "minimal change glomerulopathy" in human renal allografts: report of four cases

Four patients who received renal allografts developed nephrotic range proteinuria 2 to 16 months after renal transplantation. Twenty-four-hour urine protein excretion at the time of renal allograft biopsy ranged from 5.9 to 17.0 g/24 hours. The serum creatinine at the time of renal allograft biopsy ranged from 2.0 to 3.9 mg/dl (180 to 350 mumol/L). Biopsies of the allografts demonstrated minimal glomerular abnormalities by light microscopy, immunomicroscopy, and electron microscopy. Two biopsies exhibited severe interstitial fibrosis. These four cases illustrate the unusual finding of "minimal change glomerulopathy" in renal allograft recipients exhibiting nephrotic range proteinuria. All four patients progressed to dialysis 4, 36, 46, and 53 months after transplantation. Transplant nephrectomy was performed in three patients. One showed acute cortical necrosis. Two showed glomerular, vascular, and tubular-interstitial features of chronic rejection.     

Expanding the phenotype of proteinuria in Dent disease. A case series

Background

Dent disease is an X-linked recessive renal tubular disorder characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and progressive renal failure (MIM 300009). A recent case series identified four patients with CLCN5 mutations who presented with nephrotic-range proteinuria, histologic evidence of focal segmental and/or global sclerosis, and low molecular weight proteinuria.

Case-Diagnosis/Treatment

We characterize the clinical, genetic, and histopathological features of seven unrelated adolescent males with nephrotic-range proteinuria and CLCN5 mutations. Six patients underwent renal biopsy prior to assessing tubular proteinuria. All biopsied patients had either segmental sclerosis (3/6) or segmental increase in mesangial matrix (3/6). Five patients revealed some degree of foot process effacement, but only one patient biopsy revealed >50 % foot process effacement. The attenuated foot process effacement suggests the glomerulosclerosis is not due to a primary podocytopathy.

Conclusions

These data suggest that clinicians should consider a diagnostic evaluation for Dent disease in young males presenting with high-grade proteinuria.     

Minimal change nephrotic syndrome developing during postoperative interferon-beta therapy for malignant melanoma

A 64-year-old man presented with proteinuria during postoperative interferon (IFN)-beta therapy against malignant melanoma. Renal pathologic findings were consistent with minimal change nephrotic syndrome (MCNS) showing extensive foot process effacement of visceral glomerular epithelial cells (podocyte). Nephrotic range proteinuria gradually regressed after stoppage of local injection of IFN-beta without glucocorticoid treatment. To our knowledge this is the first report that demonstrates histological abnormalities of the glomerulus associated with postoperative IFN-beta therapy for the malignant melanoma.     

Minimal change disease associated with MALT lymphoma

Low-grade Extranodal Marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, a subtype of non-Hodgkin??s Lymphoma, involving the kidney is a rare clinical entity. Association of Minimal change disease nephrotic range proteinuria with Hodgkin??s lymphoma is well described, however is extremely uncommon with non-Hodgkin??s lymphoma. We describe a patient who presented with nephrotic syndrome and a kidney biopsy revealed marginal zone lymphoma and diffuse epithelial foot process effacement. He showed dramatic response to a combination therapy with cyclophosphamide, corticosteroids, and Rituximab.     

A case of minimal change nephrotic syndrome manifesting acute renal failure in the course of systemic lupus erythematosus

A 51-year-old woman with systematic lupus erythematosus(SLE) associated with minimal change nephrotic syndrome(MCNS) is described. The patient was diagnosed as SLE at 33 years of age. After steroid therapy for two years, the patient's course was uneventful without therapy until June 2000, when facial erythema and facial, pretibial edema developed. On admission, proteinuria and renal dysfunction were detected. Subsequently, oliguric acute renal failure developed and hemodialysis was started. Laboratory examination showed no significant change in complements and anti ds-DNA antibody levels. Renal biopsy revealed minor glomerular abnormalities without the deposition of immune complexes. Electron microscopic examination showed foot process fusion and a vacuolar change in glomerular epithelial cells. The diagnosis of MCNS was made and administration of steroid(40 mg/day) was started. Urine volume and renal function improved after 2 weeks, and nephrotic syndrome remitted completely after 5 weeks. Although the association of SLE and MCNS is rare, the findings suggest that in the course of SLE manifesting acute ranal failure, not only lupus nephritis, but also the complication of MCNS should be considered.     

HIV-associated immune complex glomerulonephritis with "lupus-like" features: a clinicopathologic study of 14 cases

BACKGROUND: While the most common glomerular lesion associated with human immunodeficiency virus (HIV) infection is collapsing focal segmental glomerulosclerosis (FSGS) [HIV-associated nephropathy (HIVAN)], immune complex-mediated forms of glomerulonephritis have been increasingly reported. One form of glomerulonephritis that has been described in the HIV-infected population is immune complex glomerulonephritis with "lupus-like" features, characterized by histologic, immunohistologic, and ultrastructural features resembling lupus nephritis, but occurring in patients without evidence of systemic lupus erythematosus (SLE). Data regarding clinical outcomes in patients with this form of glomerulonephritis are very limited. METHODS: We reviewed pathology reports for all native renal biopsy specimens from HIV-positive patients processed at our center from January 1999 through December 2003. Of 77 total specimens, 14 met the following criteria for lupus-like glomerulonephritis: (1) immunofluorescence microscopy showed granular glomerular staining for IgG, IgA, IgM, C3 and C1q, with > or=1+ (0 to 4+ scale) staining for C1q; and (2) the patient's serum was negative for antinuclear antibodies (ANA), or weakly positive (titer < or =1:80) for ANA and negative for antidouble-stranded DNA. RESULTS: Clinically, ten of the 14 patients with lupus-like glomerulonephritis presented with nephrotic syndrome, all had microscopic hematuria, and nine had serum creatinine >3.0 mg/dL. All but one were African American. Histologically, seven biopsies showed diffuse proliferative glomerulonephritis, six focal proliferative glomerulonephritis, and one membranous nephropathy. All but two biopsies showed moderate or severe chronic change, and three showed concurrent HIVAN. Ten of the 14 patients developed end-stage renal disease (ESRD) within 1 year of the biopsy. Nine of these ten patients presented with proteinuria >5.0 g/24 hours and nephrotic syndrome, while three of four patients who did not develop ESRD had proteinuria < or =3.0 g/24 hours. CONCLUSION: Lupus-like glomerulonephritis, defined by immunohistologic features and absence of serologic evidence of SLE, is not an uncommon form of glomerular disease in HIV-infected patients undergoing a renal biopsy. Renal outcomes in these patients were poor, although this may be due largely to most patients presenting with advanced disease.     

Diagnosis and natural course of membranous nephropathy

Membranous nephropathy is a relatively common glomerular disease found to underlie both nonnephrotic and nephrotic proteinuria. In adults, about 75% of cases are primary (idiopathic) and 25% are secondary to a wide variety of causes, including neoplasia, infections, autoimmunity, and drugs. Presenting features are not distinctive enough to permit a diagnosis without a renal biopsy examination. Serologic studies are normal in the idiopathic disorder. The morphologic features are characteristic and include gradual thickening of the capillary wall caused by the in situ deposition of immune complexes accompanied by new basement membrane synthesis. The natural history of the untreated disorder is variable. Spontaneous remissions (complete and partial) of proteinuria, usually accompanied by stable renal function, eventually occur in 40% to 50% of patients and the remainder slowly progress to end-stage renal disease (ESRD) or die of complications or from unrelated disease after 5 to 15 years. Factors associated with a progressive course include older age at onset, male gender, persisting hypertension, hyperlipidemia and/or hypoalbuminemia, reduced renal function at discovery, persisting nephrotic range glomerular proteinuria, concomitant tubular proteinuria, and advanced glomerular damage with chronic tubulointerstitial fibrosis.     

Adult and paediatric patients with minimal change nephrotic syndrome show no major alterations in glomerular expression of sulphated heparan sulphate domains.

BACKGROUND: Minimal change nephrotic syndrome (MCNS) is the most frequent form of nephrotic syndrome in childhood. In the glomerular basement membrane (GBM) of adult patients with MCNS, a reduced expression of a specific heparan sulphate (HS) domain has been reported. In children with MCNS, urinary activity of the HS-degrading enzyme heparanase was increased. It is, therefore, possible that a decreased GBM HS expression is associated with the pathogenesis of proteinuria in patients with MCNS. METHODS: In this study, HS in glomeruli of five adult and six paediatric patients with MCNS were analysed by immunofluorescence staining using four different antibodies, each defining a specific sulphated HS domain. The pediatric patients were subdivided into three groups depending on the presence or absence of podocyte foot process effacement, the level of proteinuria and prednisone administration at the time of the biopsy. In addition, kidneys of rats with adriamycin nephropathy (ADRN), a model for MCNS, were included in the study. RESULTS: Expression of sulphated HS domains was not aberrant in adult or paediatric patients compared with control subjects. Children with and without proteinuria had the same HS content. In contrast, rats with ADRN showed a decreased glomerular expression of sulphated HS domains. CONCLUSIONS: These results suggest that in patients with MCNS proteinuria is not associated with major changes in glomerular expression of sulphated HS domains.     

Mesangial IgA nephropathy and idiopathic nephrotic syndrome

A 17-year-old male presented with nephrotic syndrome associated with microscopic hematuria. Renal biopsy showed only minor glomerular abnormalities (light microscopy). Immunohistology demonstrated strong mesangial deposition of IgA. Electronmicroscopy disclosed widespread effacement of foot processes in combination with isolated osmiophilic mesangial deposits. The patient responded to standard corticosteroid therapy with complete disappearance of proteinuria. Microscopic hematuria, however, persisted. Five months after steroid therapy was stopped, the nephrotic syndrome relapsed. It was again steroid-responsive with persisting microhematuria. From clinical and morphological data we conclude that the patient has concomitant idiopathic nephrotic syndrome (minimal change glomerulonephritis) and mesangial IgA glomerulonephritis. The simultaneous presence of these two diseases may give some hint as to their pathogenesis. In both, abnormalities in T cell regulation have been found. If these were indeed involved in the pathogenesis of the two glomerular diseases, a higher than expected probability for the two entities to coexist in the same patient is to be expected.     

Prompt remission of post-renal transplant nephrotic syndrome with high-dose cyclosporine

A 2.8-year-old girl with focal segmental glomerulosclerosis had recurrence of nephrotic syndrome within 3 days of renal transplantation and the serum creatinine increased. Renal biopsy showed cellular rejection and also complete effacement of the epithelial cell foot processes. The rejection responded to methylprednisolone therapy but massive proteinuria persisted. An increase in the dose of cyclosporine A to 14 mg/kg per day was followed by immediate remission of the proteinuria. One month later, a second renal biopsy showed only focal fusion of foot processes. She remains free of proteinuria 2 years later. We propose that the higher dose of cyclosporine caused remission of the nephrotic syndrome.     

Minimal change disease in systemic lupus erythematosus

We report the clinical and pathologic findings in 7 patients with systemic lupus erythematosus and minimal change disease. All 7 patients presented with full nephrotic syndrome including peripheral edema, nephrotic range proteinuria (mean 9.6 g/day), and hypoalbuminemia (mean 1.8 g/dl). In all cases, renal biopsy revealed diffuse foot process effacement in the absence of significant peripheral capillary wall immune deposits, findings consistent with minimal-change disease. In addition, 5 cases displayed mesangial electron-dense deposits, with or without associated mesangial proliferation, consistent with underlying lupus nephritis class II. In all cases, steroid therapy induced a rapid remission of nephrotic syndrome. Minimal change disease is an underrecognized and readily reversible form of nephrotic syndrome in systemic lupus erythematosus. Because it may occur superimposed on mild mesangial proliferative lupus nephritis, this entity may be misinterpreted as an atypical presentation of lupus nephritis class II. Proper recognition of this entity requires careful integration of the renal biopsy immunofluorescence and electron microscopic findings.     

Benign persistent asymptomatic proteinuria with incomplete foot process disease in adolescents: a new clinical entity?

A distinct glomerular damage characterized by the following clinical and pathological findings was verified in 20 children with a proteinuria. The clinical features were: 1) glomerular damage was frequent in adolescent males, the male to female ratio being 3:1; 2) the onset was initiated by asymptomatic proteinuria which remitted spontaneously after 3-5 years, with no resulting nephrotic syndrome; 3) there was no apparent cause for the proteinuria such as postural proteinuria, wandering kidney, hypertension or heart disease; 4) in no patient was there a past history of infection or occurrence of other diseases; 5) there were no morphological alterations except for fusion of the epithelial foot processes in about 40% of the glomerular capillary wall; and 6) immunofluorescence microscopy revealed the lack of deposition of immunoglobulins in 20 patients and deposits of complement (C3) or fibrinogen in 4 out of 20. The degree of fusion of epithelial foot processes in incomplete foot process disease was significantly different from that seen in orthostatic proteinuria, thin basement membrane syndrome and minimal change nephrotic syndrome. Compared to the latter, incomplete foot process disease is likely to occur at a higher age with a peak at adolescence, then remit spontaneously without therapy. These events may constitute a distinct entity.     

Anti-cardiolipin antibody and renal disease: a report three cases

Anti-cardiolipin antibodies have been linked to recurrent arterial and venous thrombosis in multiple organs. We present a biopsy-documented report of thrombotic renal disease apparently attributable to circulating anti-cardiolipin antibodies. One patient had primary anti-cardiolipin syndrome, one had mild SLE, and the third had a mild lupus-like syndrome. All three patients had a clinical course dominated by repeated multi-organ system thrombosis. Renal biopsy disclosed thrombosis at the level of the glomerular capillaries, arterioles, and interlobular arteries--similar to that described in other thrombotic microangiopathies. Renal thrombosis was not associated with active endocapillary proliferative lupus nephritis, suggesting a mechanism independent of subendothelial immune deposit injury. Renal presentation was variable, ranging from asymptomatic mild proteinuria to nephrotic-range proteinuria, renal insufficiency, and hypertension.