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.

There remains a need for robust mouse models of diabetic nephropathy (DN) that mimic key features of advanced human DN. The recently developed mouse strain BTBR with the ob/ob leptin-deficiency mutation develops severe type 2 diabetes, hypercholesterolemia, elevated triglycerides, and insulin resistance, but the renal phenotype has not been characterized. Here, we show that these obese, diabetic mice rapidly develop morphologic renal lesions characteristic of both early and advanced human DN. BTBR ob/ob mice developed progressive proteinuria beginning at 4 weeks. Glomerular hypertrophy and accumulation of mesangial matrix, characteristic of early DN, were present by 8 weeks, and glomerular lesions similar to those of advanced human DN were present by 20 weeks. By 22 weeks, we observed an approximately 20% increase in basement membrane thickness and a Ͼ50% increase in mesangial matrix. Diffuse mesangial sclerosis (focally approaching nodular glomerulosclerosis), focal arteriolar hyalinosis, mesangiolysis, and focal mild interstitial fibrosis were present. Loss of podocytes was present early and persisted. In summary, BTBR ob/ob mice develop a constellation of abnormalities that closely resemble advanced human DN more rapidly than most other murine models, making this strain particularly attractive for testing therapeutic interventions. Diabetic nephropathy (DN) is the largest single cause of ESRD in the United States, accounting for nearly half of the patients who enter the dialysis patient population each year and currently accounting for 45% of prevalent kidney failure in the United States. 1-4 Although both type 1 and type 2 diabetes lead to DN, the current epidemic of DN is due to type 2 diabetes; however, understanding the mechanisms that produce the constellation of clinical and pathologic alterations that define DN in humans remains very incomplete, in part because clinical DN is a slowly progressive disease, and relevant animal models that produce this constellation of pathologic and clinical abnormalities have important limitations. Mice rendered hyperglycemic by administration of streptozotocin (STZ) or through genetic predisposition such as the db/db mouse can develop some features of DN, most notably glomerular mesangial expansion, but do so only over prolonged periods and do not progress to ESRD. [5][6][7][8][9] Most murine models to date have failed to develop reliably marked mesangial expansion or the

Pippin JW, Brinkkoetter PT, Cormack-Aboud FC, Durvasula RV, Hauser PV, Kowalewska J, Krofft RD, Logar CM, Marshall CB, Ohse T, Shankland SJ. Inducible rodent models of acquired podocyte diseases. Am J Physiol Renal Physiol 296: F213-F229, 2009. First published September 10, 2008 doi:10.1152/ajprenal.90421.2008.-Glomerular diseases remain the leading cause of chronic and end-stage kidney disease. Significant advances in our understanding of human glomerular diseases have been enabled by the development and better characterization of animal models. Diseases of the glomerular epithelial cells (podocytes) account for the majority of proteinuric diseases. Rodents have been extensively used experimentally to better define mechanisms of disease induction and progression, as well as to identify potential targets and therapies. The development of podocyte-specific genetically modified mice has energized the research field to better understand which animal models are appropriate to study acquired podocyte diseases. In this review we discuss inducible experimental models of acquired nondiabetic podocyte diseases in rodents, namely, passive Heymann nephritis, puromycin aminonucleoside nephrosis, adriamycin nephrosis, liopolysaccharide, crescentic glomerulonephritis, and protein overload nephropathy models. Details are given on the model backgrounds, how to induce each model, the interpretations of the data, and the benefits and shortcomings of each. Genetic rodent models of podocyte injury are excluded.glomerulus; animal models HISTOLOGICAL ANALYSIS is a cornerstone for studying mechanisms of glomerular disease. However, analysis in human disease is limited by a relative paucity of tissue availability. Renal biopsies are only pursued if a presumptive diagnosis cannot be established on clinical grounds. Tissue sampling is typically restricted to the time of disease presentation and is rarely performed in follow-up, providing a mere snapshot of disease course.Animal models have significantly advanced our understanding of the pathogenesis of glomerular disease by overcoming these hurdles. Serial assessment of renal tissue in experimental models affords the opportunity to study development and progression of disease over time. Furthermore, the host response to injury may be deliberately modified, for example, through pharmacological intervention, selective disruption (knockout strategies), or overexpression (transgenic strategies) of a particular gene, allowing for mechanistic evaluations. A variety of animal species have been employed in the study of glomerular disease, but rodent models are preferred due to lower cost, maintenance requirements, and short gestational periods. Although both rats and mice are utilized, there are some important advantages and disadvantages for each (Table 1). The development of transgenic technology has proven an invaluable tool in elucidating the function of individual genes in health and disease. However, they cannot replace experimental models in furthering our understanding of the mechanisms...

The patient was a 48-yr-old man who had a history of hypertension, hyperlipidemia, obesity, and chronic renal insufficiency and was referred for evaluation of proteinuria. The patient's history was notable for a myocardial infarction 5 yr previously.Physical examination revealed an obese man with BP of 168/89 mmHg and no other notable findings. Urinalysis revealed 4ϩ protein and 2ϩ glucose and rare red and white blood cells and no casts. A 24-h urine collection revealed 8 g of protein.Other relevant laboratory data included serum albumin of 2.8 mg/ dl, creatinine of 4.2 mg/dl, and total cholesterol of 204 mg/dl. Liver function tests were within normal limits. Serologic tests for evidence of autoimmune disease were not obtained.A renal biopsy showed cortex containing 16 glomeruli, seven of which were completely sclerosed and three of which were segmentally sclerosed. The remaining glomeruli revealed marked expansion of mesangial stalks and irregular thickening of capillary walls as a result of infiltration and accumulation of silver negative and periodic acid-Schiff-positive acellular material ( Figure 1). There was neither significant increase in mesangial cellularity nor basement membrane "spike" formation. There was a background of patchy interstitial fibrosis and tubular atrophy and associated interstitial inflammation. Arterial vessels showed mild intimal sclerosis. Staining with the Congo Red reagent for amyloidosis was negative.Immunofluorescence microscopy demonstrated confluent mesangial and glomerular capillary wall staining for IgG (3ϩ) and and light chain (each trace). There was no significant staining of the glomeruli for IgA, IgM, C3, C1q, fibrinogen, or albumin. Ultrastructural examination of two glomeruli revealed expansion of the mesangial stalks and capillary walls as a result of extracellular accumulation of haphazardly arranged fibrils measuring approximately 16 nm in thickness. Podocyte foot processes were diffusely effaced. There was no evidence of fibrillary deposits in the tubular basement membranes or interstitium. The diagnosis of fibrillary glomerulonephritis was established on the basis of the ultrastructural findings in conjunction with the negative Congo Red stain and typical histologic and immunohistochemical features. FIBRILLARY GLOMERULONEPHRITISFibrillary glomerulonephritis is a morphologically defined entity characterized by glomerular accumulations of nonbranching, randomly arranged fibrils that are ultrastructurally indistinguishable from amyloid fibrils but differ from amyloid by virtue of their larger size and lack of reactivity with Congo Red and other reagents that are histochemically reactive with amyloid. [1][2][3][4] As in our case, this diagnosis requires electron microscopic identification of characteristic infiltrating fibrils within glomerular structures. It has been identified in approximately 0.5 to 1.0% of native Published online ahead of print. Publication date available at www.jasn.org.Correspondence: Dr. Charles E. Alpers, Department of Pathology, University o...

Background and Objectives: Hematopoietic cell transplantation is a common treatment option for a variety of hematopoietic malignancies. As a result of the use of total body irradiation and/or chemotherapeutic agents, renal dysfunction often ensues. Many pharmacologic agents, such as cyclosporine and high-intensity conditioning regimens, have been linked with thrombotic microangiopathy. In addition, an association between membranous nephropathy and graft-versus-host disease has been reported in this clinical setting.Design, Setting, Participants, and Measurements: A study of autologous and allogeneic hematopoietic cell transplantation patients with renal dysfunction was conducted to document the spectrum of renal manifestations. The pathology files at the University of Washington and University of Chicago Medical Centers were reviewed, and 20 patients with a kidney biopsy after hematopoietic cell transplantation were identified. The histologic findings were correlated with relevant clinical information.Results: A wide spectrum of renal diseases could be classified into four categories: (1) Complications related to hematopoietic cell transplantation (conditioning regimen, immunosuppression, or posttransplantation complications), (2) podocytopathy, (3) membranous nephropathy, or (4) recurrence or persistence of original hematologic disease. Pathologic diagnoses included thrombotic microangiopathy, polyoma virus nephropathy, acute kidney injury/acute tubular necrosis, acute and chronic interstitial nephritis, minimal-change disease, "tip" variant of focal segmental glomerulosclerosis, membranous nephropathy, amyloidosis, and myeloma cast nephropathy. Membranous nephropathy, minimal-change disease, and amyloidosis were common causes of severe proteinuria. Because of the conditioning regimens, posttransplantation complications, and potential nephrotoxic agents used during hematopoietic cell transplantation, it was difficult to attribute the subsequent renal dysfunction to specific factors.Conclusions: The renal biopsy remains essential for diagnosing the underlying injury that can affect one or more compartments of the kidney in this unique clinical setting.