The glomerular microvasculature is particularly susceptible to injury in thrombotic microangiopathy, but the mechanisms by which this occurs are unclear. We report the cases of six patients who were treated with bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), in whom glomerular disease characteristic of thrombotic microangiopathy developed. To show that local reduction of VEGF within the kidney is sufficient to trigger the pathogenesis of thrombotic microangiopathy, we used conditional gene targeting to delete VEGF from renal podocytes in adult mice; this resulted in a profound thrombotic glomerular injury. These observations provide evidence that glomerular injury in patients who are treated with bevacizumab is probably due to direct targeting of VEGF by antiangiogenic therapy.

Chronic kidney disease (CKD) affects 8 to 16% people worldwide, with an increasing incidence and prevalence of end-stage kidney disease (ESKD). The effective management of CKD is confounded by the inability to identify patients at high risk of progression while in early stages of CKD. To address this challenge, a renal biopsy transcriptome-driven approach was applied to develop noninvasive prognostic biomarkers for CKD progression. Expression of intrarenal transcripts was correlated with the baseline estimated glomerular filtration rate (eGFR) in 261 patients. Proteins encoded by eGFR-associated transcripts were tested in urine for association with renal tissue injury and baseline eGFR. The ability to predict CKD progression, defined as the composite of ESKD or 40% reduction of baseline eGFR, was then determined in three independent CKD cohorts. A panel of intrarenal transcripts, including epidermal growth factor (EGF), a tubule-specific protein critical for cell differentiation and regeneration, predicted eGFR. The amount of EGF protein in urine (uEGF) showed significant correlation (P < 0.001) with intrarenal EGF mRNA, interstitial fibrosis/tubular atrophy, eGFR, and rate of eGFR loss. Prediction of the composite renal end point by age, gender, eGFR, and albuminuria was significantly (P < 0.001) improved by addition of uEGF, with an increase of the C-statistic from 0.75 to 0.87. Outcome predictions were replicated in two independent CKD cohorts. Our approach identified uEGF as an independent risk predictor of CKD progression. Addition of uEGF to standard clinical parameters improved the prediction of disease events in diverse CKD populations with a wide spectrum of causes and stages.

Dendritic cells (DCs) interface innate and adaptive immunity in nonlymphoid organs; however, the exact distribution and types of DC within the kidney are not known. We utilized CX3CR1GFP/+ mice to characterize the anatomy and phenotype of tissue-resident CX3CR1+ DCs within normal kidney. Laser-scanning confocal microscopy revealed an extensive, contiguous network of stellate-shaped CX3CR1+ DCs throughout the interstitial and mesangial spaces of the entire kidney. Intravital microscopy of the superficial cortex showed stationary interstitial CX3CR1+ DCs that continually probe the surrounding tissue environment through dendrite extensions. Flow cytometry of renal CX3CR1+ DCs showed significant coexpression of CD11c and F4/80, high major histocompatibility complex class II and FcR expression, and immature costimulatory but competent phagocytic ability indicative of tissue-resident, immature DCs ready to respond to environment cues. Thus, within the renal parenchyma, there exists little immunological privilege from the surveillance provided by renal CX3CR1+ DCs, a major constituent of the heterogeneous mononuclear phagocyte system populating normal kidney.

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. Morphologic features of visceral epithelial cell hypertrophy and hyperplasia, tubular microcysts, tubular epithelial degenerative and regenerative features and interstitial edema were more prevalent and severe in collapsing FSGS. Median time to ESRD was rapid in collapsing FSGS versus controls (13.0 months vs. 62.5 months, P < 0.05). Correlates of progression to ESRD included a higher initial serum creatinine and failure to undergo remission of proteinuria. Both glomerulosclerosis and certain features of tubular damage were independent predictors of the level of renal function at time of biopsy, but not of the rate of progression of renal insufficiency. Although three patients had partial or complete spontaneous remissions, none of 26 patients treated with steroids alone responded. Idiopathic collapsing FSGS is a variant of FSGS with increasing incidence, distinct clinicopathologic features, black racial predominance, a rapidly progressive course and relative steroid resistance.

Primary coenzyme Q 10 (CoQ 10 ) deficiency includes a group of rare autosomal recessive disorders primarily characterized by neurological and muscular symptoms. Rarely, glomerular involvement has been reported. The COQ2 gene encodes the para-hydroxybenzoate-polyprenyl-transferase enzyme of the CoQ 10 synthesis pathway. We identified two patients with early-onset glomerular lesions that harbored mutations in the COQ2 gene. The first patient presented with steroid-resistant nephrotic syndrome at the age of 18 months as a result of collapsing glomerulopathy, with no extrarenal symptoms. The second patient presented at five days of life with oliguria, had severe extracapillary proliferation on renal biopsy, rapidly developed end-stage renal disease, and died at the age of 6 months after a course complicated by progressive epileptic encephalopathy. Ultrastructural examination of renal specimens from these cases, as well as from two previously reported patients, showed an increased number of dysmorphic mitochondria in glomerular cells. Biochemical analyses demonstrated decreased activities of respiratory chain complexes [IIϩIII] and decreased CoQ 10 concentrations in skeletal muscle and renal cortex. In conclusion, we suggest that inherited COQ2 mutations cause a primary glomerular disease with renal lesions that vary in severity and are not necessarily associated with neurological signs. COQ2 nephropathy should be suspected when electron microscopy shows an increased number of abnormal mitochondria in podocytes and other glomerular cells.

The Nephrotic Syndrome Study Network (NEPTUNE) is a North American multi-center collaborative consortium established to develop a translational research infrastructure for Nephrotic Syndrome. This includes a longitudinal observational cohort study, a pilot and ancillary studies program, a training program, and a patient contact registry. NEPTUNE will enroll 450 adults and children with minimal change disease, focal segmental glomerulosclerosis and membranous nephropathy for detailed clinical, histopathologic, and molecular phenotyping at the time of clinically-indicated renal biopsy. Initial visits will include an extensive clinical history, physical examination, collection of urine, blood and renal tissue samples, and assessments of quality of life and patient-reported outcomes. Follow-up history, physical measures, urine and blood samples, and questionnaires will be obtained every 4 months in the first year and bi-annually, thereafter. Molecular profiles and gene expression data will be linked to phenotypic, genetic, and digitalized histologic data for comprehensive analyses using systems biology approaches. Analytical strategies were designed to transform descriptive information to mechanistic disease classification for Nephrotic Syndrome and to identify clinical, histological, and genomic disease predictors. Thus, understanding the complexity of the disease pathogenesis will guide further investigation for targeted therapeutic strategies.

A spectrum of proteinuric glomerular diseases results from podocyte abnormalities. The understanding of these podocytopathies has greatly expanded in recent years, particularly with the discovery of more than a dozen genetic mutations that are associated with loss of podocyte functional integrity. It is apparent that classification of the podocytopathies on the basis of morphology alone is inadequate to capture fully the complexity of these disorders. Herein is proposed a taxonomy for the podocytopathies that classifies along two dimensions: Histopathology, including podocyte phenotype and glomerular morphology (minimal-change nephropathy, focal segmental glomerulosclerosis, diffuse mesangial sclerosis, and collapsing glomerulopathy), and etiology (idiopathic, genetic, and reactive forms). A more complete understanding of the similarities and differences among podocyte diseases will help the renal pathologist and the nephrologist communicate more effectively about the diagnosis; this in turn will help the nephrologist provide more accurate prognostic information and select the optimal therapy for these often problematic diseases. It is proposed that final diagnosis of the podocytopathies should result from close collaboration between renal pathologists and nephrologists and should whenever possible include three elements: Morphologic entity, etiologic form, and specific pathogenic mechanism or association.Clin J Am Soc Nephrol 2: 529-542, 2007. doi: 10.2215/CJN.04121206 T he spectrum of primary nephrotic syndrome includes a variety of causes, presentations, histopathologic findings, and outcomes. These disorders may appear at any age, may be exquisitely sensitive or highly resistant to therapy, and have varied implications for long-term renal function. Past efforts to develop an organized approach to these diseases have largely centered on histopathology. Although these approaches were helpful in defining lesions, for each morphologic entity there is a wide range in response to treatment and outcome. This observation suggests that traditional pathologic description alone is insufficient to classify these disorders.Here, we propose a new taxonomy for podocyte diseases. The word "taxonomy" was coined by Carl Linnaeus, the 18th century Swedish scientist who proposed the system for naming and classifying organisms that remains in use today. A taxonomy is organized into multiple levels, each of which represents a taxon with one or more elements. The ideal taxonomy separates the elements of each taxon (the taxa) into mutually exclusive, unambiguous, and all-encompassing categories. In practice, a good taxonomy should be simple, easy to remember, and easy to use. Taxonomies provide classification and frequently more: A conceptual framework for analysis, discussion, and hypothesis generation. Our proposed podocyte taxonomy has two dimensions-histopathology and etiology-and includes additional modifiers related to biomarkers that have been identified through recent progress in the genetics, cell biology, and pathophysiol...

Collapsing glomerulopathy (CG) has become an important cause of ESRD. First delineated from other proteinuric glomerular lesions in the 1980s, CG is now recognized as a common, distinct pattern of proliferative parenchymal injury that portends a rapid loss of renal function and poor responses to empiric therapy. Notwithstanding, the rise in disorders that are associated with CG, the identification of the first susceptibility genes for CG, the remarkable increase in murine modeling of CG, and promising preclinical testing of new therapeutic strategies suggest that the outlook for CG as a poorly understood and therapeutically resistant renal disease is set to change in the future. This focused review highlights recent advances in research into the pathogenesis and treatment of CG.