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

The reversibility of diabetic nephropathy remains controversial. Here, we tested whether replacing leptin could reverse the advanced diabetic nephropathy modeled by the leptin-deficient BTBR ob/ob mouse. Leptin replacement, but not inhibition of the renin-angiotensin-aldosterone system (RAAS), resulted in near-complete reversal of both structural (mesangial matrix expansion, mesangiolysis, basement membrane thickening, podocyte loss) and functional (proteinuria, accumulation of reactive oxygen species) measures of advanced diabetic nephropathy. Immunohistochemical labeling with the podocyte markers Wilms tumor 1 and p57 identified parietal epithelial cells as a possible source of regenerating podocytes. Thus, the leptin-deficient BTBR ob/ob mouse provides a model of advanced but reversible diabetic nephropathy for further study. These results also suggest that restoration of lost podocytes is possible but is not induced by RAAS inhibition, possibly explaining the limited efficacy of RAAS inhibitors in promoting repair of diabetic nephropathy. Diabetic nephropathy (DN) is now the major cause of CKD and ESRD throughout the world and is the largest single cause of ESRD in the United States, accounting for nearly half of the patients entering dialysis each year. [1][2][3][4][5] The mainstays of current therapy for DN are control of hyperglycemia and BP and inhibition of the renin-angiotensin-aldosterone system (RAAS). 6,7 These therapies can be effective in slowing progression but have not been effective in reversing established complications, such as DN. The recently reported Renin-Angiotensin System Study, a prospective 5-year clinical trial in which early and sustained therapy with inhibitors of the RAAS in diabetic patients did not prevent development of DN, was particularly disappointing in this regard. 8 Two of the major obstacles to progress in the treatment of DN are the lack of relevant animal models in which reversal of advanced DN can be tested and uncertainty about whether podocytes, a cell type that has long thought to be nonreplicating and nonrenewable and to be lost during development of DN, can be replaced and hence permit reconstitution of a normal glomerulus. 9 In this study, we show that both of these obstacles can be overcome. We have recently characterized a new murine model of type 2 DN, the BTBR ob/ob leptin-deficient mouse, which better mirrors human DN than do most previous murine models. 10,11 We have extended our previous characterization of this model by administering leptin to mice with advanced DN and demonstrating, uniquely among both experimental models and human DN, that DN can be reversed with pharmacologic therapy.

Evidence-based cinical practice guidelines improve delivery of uniform care to patients with and at risk of developing kidney disease, thereby reducing disease burden and improving outcomes. These guidelines are not well-integrated into care delivery systems in most low- and middle-income countries (LMICs). The KDIGO Controversies Conference on Implementation Strategies in LMIC reviewed the current state of knowledge in order to define a road map to improve the implementation of guideline-based kidney care in LMICs. An international group of multidisciplinary experts in nephrology, epidemiology, health economics, implementation science, health systems, policy, and research identified key issues related to guideline implementation. The issues examined included the current kidney disease burden in the context of health systems in LMIC, arguments for developing policies to implement guideline-based care, innovations to improve kidney care, and the process of guideline adaptation to suit local needs. This executive summary serves as a resource to guide future work, including a pathway for adapting existing guidelines in different geographical regions.

Mice transgenic for thymic stromal lymphopoietin (TSLP), under regulation of the lymphocyte-specific promoter Lck, develop cryoglobulinemia and membranoproliferative glomerulonephritis (MPGN) similar to the disease in patients. To determine whether infiltrating macrophages, a hallmark of this disease, are deleterious or beneficial in the injury process, we developed Lck-TSLP transgenic mice expressing the human diphtheria toxin receptor (DTR) under control of the monocyte/macrophage-restricted CD11b promoter (Lck-TSLP;CD11b-DTR). Treatment with DT resulted in a marked reduction of monocytes/macrophages in the peritoneal cavity of both CD11b-DTR and Lck-TSLP;CD11b-DTR mice and marked reduction of macrophage infiltration in glomeruli of Lck-TSLP;CD11b-DTR mice. Lck-TSLP;CD11b-DTR mice, with or without toxin treatment, had similar levels of cryoglobulinemia and glomerular immunoglobulin deposition as Lck-TSLP mice. Lck-TSLP;CD11b-DTR mice, treated with toxin, had reduced mesangial matrix expansion, glomerular collagen IV accumulation, expression of the activation marker α-smooth muscle actin and transforming growth factor-β1 in mesangial cells, and proteinuria compared with control mice. Thus, macrophage ablation confers protection in this model and indicates a predominately deleterious role for macrophages in the progression of kidney injury in cryoglobulinemic MPGN.

A rterial hypertension is prevalent in chronic kidney disease (CKD) and contributes to its adverse outcomes. 1 The major benefits of lowering blood pressure (BP) for survival and cardiovascular outcomes are well established, as are those of inhibiting the renin angiotensinaldosterone system (RAAS) to slow CKD progression. 2-8 BP control and RAAS inhibitor use are therefore major goals in the management of patients with CKD, 9 although no consensus exists about the ideal BP level. Current guidelines