The dysregulated podocyte phenotype: a novel concept in the pathogenesis of collapsing idiopathic focal segmental glomerulosclerosis and HIV-associated nephropathy.

Podocytes are highly differentiated, postmitotic cells, whose function is largely based on their complex cytoarchitecture. The differentiation of podocytes coincides with progressive expression of maturity markers, including WT-1, CALLA, C3b receptor, GLEPP-1, podocalyxin, and synaptopodin. In collapsing forms of focal segmental glomerulosclerosis (FSGS), including idiopathic FSGS and HIV-associated nephropathy, podocytes undergo characteristic, irreversible ultrastructural changes.

Hepatitis C viral infection is associated with fibrillary glomerulonephritis and immunotactoid glomerulopathy.

The most common form of glomerular disease seen in association with hepatitis C virus (HCV) infection is membranoproliferative glomerulonephritis, with or without associated cryoglobulinemia. This study examines four cases of fibrillary glomerulonephritis and two cases of immunotactoid glomerulopathy in association with HCV infection. Findings at presentation included proteinuria, renal insufficiency, and hematuria.

Acute interstitial nephritis following treatment with anorectic agents phentermine and phendimetrazine.

A 47-year-old mildly obese female began a weight reduction program that included anorectic therapy with phentermine and phendimetrazine. A normal urinalysis and serum creatinine were documented at the start of therapy. After three weeks of treatment, the patient felt ill and discontinued her treatment.

De novo minimal change disease.

Beyond the acute posttransplantation period, glomerular causes of proteinuria in the renal allograft include recurrent glomerulopathy, transplant-associated entities, and de novo disease. We present a case of de novo minimal change disease with reversible acute renal failure occurring 2.5 years posttransplantation in a 56-year-old man.

Polyclonal immunoglobulin G deposition disease: a unique entity.

We report a unique case of tubular polyclonal immunoglobulin G (IgG) deposition disease (PIDD) superimposed on diabetic nephropathy in an 84-year-old man presenting with subacute renal failure and proteinuria. The deposits were located exclusively between the tubular epithelial cells and the tubular basement membranes (TBMs) and stained intensely with antisera to IgG heavy chain and both kappa and lambda light chains. Electron microscopy revealed large predominantly extracellular electron-dense deposits with a distinctive curvilinear substructure.

Renal pathology of human immunodeficiency virus infection.

Renal complications of HIV infection are clinically and morphologically diverse. These may affect the glomerular, tubulointerstitial, and vascular compartments. Tubulointerstitial injury predominates in most autopsy-based studies, whereas glomerular disease is most frequently identified in biopsy-based studies.

Somatic inactivation of Pkd2 results in polycystic kidney disease.

Germline mutations in PKD2 cause autosomal dominant polycystic kidney disease. We have introduced a mutant exon 1 in tandem with the wild-type exon 1 at the mouse Pkd2 locus. This is an unstable allele that undergoes somatic inactivation by intragenic homologous recombination to produce a true null allele.

Polycystic kidney disease in SBM transgenic mice: role of c-myc in disease induction and progression.

SBM mouse is a unique transgenic model of polycystic kidney disease (PKD) produced by dysregulation of c-myc in the kidneys. Our previous demonstration that c-myc is overexpressed in human autosomal polycystic kidney disease (ADPKD) prompted us to investigate the pathogenetic role of c-myc in the induction and progression of the cystogenic phenotype in our mouse model. In young SBM kidneys, c-myc was two- to threefold increased with persistent expression levels into adulthood, an age when c-myc is normally undetectable.

C-myc-induced apoptosis in polycystic kidney disease is Bcl-2 and p53 independent.

The SBM mouse is a unique transgenic model of polycystic kidney disease (PKD) induced by the dysregulated expression of c-myc in renal tissue. In situ hybridization analysis demonstrated intense signal for the c-myc transgene overlying tubular cystic epithelium in SBM mice. Renal proliferation index in SBM kidneys was 10-fold increased over nontransgenic controls correlating with the presence of epithelial hyperplasia.

Epidermal growth factor suppresses renal tubular apoptosis following ureteral obstruction.

Objectives: Acute unilateral ureteral obstruction (UUO) results in ipsilateral hydronephrosis characterized by a decrease in epidermal growth factor (EGF) mRNA expression and EGF protein levels in the distal renal tubules. UUO results in programmed cell death with increases in the characteristic markers of apoptosis. To suppress the apoptotic response during UUO, recombinant EGF was administered during renal obstruction and the ensuing molecular and histologic changes were studied.

Polycystin expression is temporally and spatially regulated during renal development.

Mutations in PKD1 cause autosomal dominant polycystic kidney disease (ADPKD), a common genetic disease in which cysts form from kidney tubules. The predicted product of this gene is a novel protein with cell-adhesive and membrane-spanning domains. To test the hypothesis that polycystin, the product of the PKD1 gene, is a cell adhesion molecule, we raised antibodies against peptides derived from the unduplicated, membrane-spanning portion of the predicted amino acid sequence.

Spatial and temporal expression of cell surface molecules during nephrogenesis.

Cell-to-cell interaction is fundamental to the development of the kidney. Ureteric bud cells, through cell contact or short-distance interactions, induce the metanephric mesenchyme to convert, to epithelia and begin the process of tubulogenesis. To identify new molecules that are involved in these processes, we generated a panel of monoclonal antibodies (MAbs) to the surface of induced mesenchymal cells taken from a day 15 rat embryonic kidney rudiment.

HIV infection and the kidney.

HIV-infected patients may present with a variety of patterns of renal involvement. Acute renal failure is common and most often a result of sepsis, hypotension, and nephrotoxic agents. It is potentially avoidable, and support through the period of renal failure may lead to resolution of the renal dysfunction.

Immunohistologic analysis of renal CD40 and CD40L expression in lupus nephritis and other glomerulonephritides.

Objective: To investigate potential mechanisms by which CD40L-mediated signals may be involved in the pathogenesis of lupus glomerulonephritis (GN).

Methods: Renal in situ CD40L and CD40 expression was examined in patient biopsy specimens. Immunohistochemical studies were performed on frozen sections utilizing anti-CD40L monoclonal antibody (MAb), anti-CD40 MAb, or control MAb.

Membranous lupus nephritis with antineutrophil cytoplasmic antibody-associated segmental necrotizing and crescentic glomerulonephritis.

Focal segmental necrotizing and crescentic lupus nephritis accompanied by perinuclear antineutrophil cytoplasmic antibody (P-ANCA) seropositivity is an unusual occurrence. We report the first biopsy-documented cases of membranous lupus nephritis class V with associated "pauci-immune" segmental necrotizing glomerulonephritis and P-ANCA seropositivity. The absence of subendothelial electron-dense deposits favored a manifestation of superimposed ANCA-associated glomerulonephritis rather than class III lupus nephritis.

Idiopathic collapsing focal segmental glomerulosclerosis: a clinicopathologic study.

A review of all native kidney biopsies at our center from 1974 to 1993 identified 43 cases of idiopathic focal segmental glomerulosclerosis (FSGS) with predominantly collapsing features and lacking evidence of HIV-1 infection or intravenous drug use. No case was identified before 1979 and the incidence of this entity has progressively increased over the past two decades. Compared to 50 age-matched controls of idiopathic FSGS with typical perihilar scars, the group of idiopathic collapsing FSGS displayed black racial predominance, a higher serum creatinine and more severe features of nephrotic syndrome at biopsy.

Apoptosis in renal cell carcinoma: detection by in situ end-labeling of fragmented DNA and correlation with other prognostic factors.

Because stage and grade of renal cell carcinoma (RCC) sometimes fail to predict the patient's outcome, additional prognostic predictors are needed. Apoptosis is a process of programmed cell death seen in both normal and neoplastic tissues, which has been shown to have prognostic significance in some tumor types. Forty-seven RCCs were studied for size, grade, stage, apoptosis, and proliferation.

Dysregulation of cellular proliferation and apoptosis mediates human autosomal dominant polycystic kidney disease (ADPKD).

The proto-oncogene c-myc has been implicated in both cellular proliferation and apoptosis, and we have shown that overexpression of c-myc can induce polycystic kidney disease in transgenic mice. To elucidate the molecular and cellular defects underlying cystogenesis, we have investigated the potential roles of cell proliferation and apoptosis as they relate to c-myc and modulators of c-myc function in human autosomal dominant polycystic kidney disease (ADPKD). Renal c-myc expression was consistently elevated, up to 15-fold, in ADPKD.

Does aspirin cause acute or chronic renal failure in experimental animals and in humans?

There are conflicting reports on the ability of aspirin as a single agent to cause acute or chronic renal failure in experimental animals. Chronic administration of aspirin alone over 18 to 68 weeks in doses of 120 to 500 mg/kg/d has been reported to cause renal papillary necrosis in rats. However, some investigators have been unable to produce renal papillary necrosis in other species or in rats given lower divided doses comparable to therapeutic doses used in humans.

Renal agenesis and hypodysplasia in ret-k- mutant mice result from defects in ureteric bud development.

The c-ret gene encodes a receptor tyrosine kinase that is expressed in the Wolffian duct and ureteric bud of the developing excretory system. Newborn mice homozygous for a mutation in c-ret displayed renal agenesis or severe hypodysplasia, suggesting a critical role for this gene in metanephric kidney development. To investigate the embryological basis of these defects, we characterized the early development of the excretory system in mutant homozygotes, and observed a range of defects in the formation, growth and branching of the ureteric bud, which account for the spectrum of renal defects seen at birth.

IgA multiple myeloma presenting as Henoch-Schönlein purpura/polyarteritis nodosa overlap syndrome.

We report the unusual case of a man with a 5-year history of relapsing Henoch-Schonlein purpura (HSP) and macroscopic polyarteritis nodosa (PAN) as early manifestations of IgA kappa multiple myeloma. The glomeruli contained monoclonal IgA kappa deposits, without other immunoglobulins or lambda light chains. Glomerular deposits lacked the usual electron density but could be demonstrated by immunoelectron microscopy.

Differential effects of an erythropoietin receptor gene disruption on primitive and definitive erythropoiesis.

Although the hormone erythropoietin (Epo) and its receptor (EpoR) are known to play important roles in the regulation of erythropoiesis, several questions remain concerning the developmental role of Epo/EpoR signaling. As the functions of Epo have been defined primarily through studies of definitive erythroid cells, its importance for primitive, embryonic erythropoiesis remains uncertain, as does the significance of EpoR expression in several nonerythroid cell types. To address these questions, mouse embryonic stem cells and embryos lacking a functional EpoR gene were produced by gene targeting.

Tenascin is an ubiquitous extracellular matrix protein of human renal interstitium in normal and pathologic conditions.

Tenascin, a large oligomeric glycoprotein, is a recent addition to a list of increasing extracellular matrix proteins. Previous studies have documented the strong expression of tenascin in embryonic kidney and in both normal and abnormal mature glomeruli implicating an important role of this extracellular matrix protein in nephrogenesis and glomerular scarring. Whether tenascin plays any role in interstitial fibrosis, a common final pathway of tubulointerstitial nephritis, is no known; on the other hand, a detailed knowledge of the structural components of interstitial fibrosis is essential for further studies on other fundamental aspects of this biologically and clinically important process.