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The adverse effects of vasopressin (AVP) in diverse forms of chronic kidney disease have been well described. They depend on the antidiuretic action of AVP mediated by V2 receptors (V2R). Tolvaptan, a selective V2R antagonist, is now largely used for the treatment of patients with autosomal dominant polycystic kidney disease. Another way to reduce the adverse effects of AVP is to reduce endogenous AVP secretion by a voluntary increase in fluid intake. These two approaches differ in several ways, including the level of thirst and AVP. With voluntary increased drinking, plasma osmolality will decline and so will AVP secretion. Thus, not only will V2R-mediated effects be reduced, but also those mediated by V1a and V1b receptors (V1aR and V1bR). In contrast, selective V2R antagonism will induce a loss of fluid that will stimulate AVP secretion and thus increase AVP's influence on V1a and V1b receptors. V1aR is expressed in the luminal side of the collecting duct (CD) and in inner medullary interstitial cells, and their activation induces the production of prostaglandins, mostly prostaglandin E2 (PGE2). Intrarenal PGE2 has been shown to reduce sodium and water reabsorption in the CD and increase blood flow in the renal medulla, both effects contributing to increase sodium and water excretion and reduce urine-concentrating activity. Conversely, non-steroidal anti-inflammatory drugs have been shown to induce significant water and sodium retention and potentiate the antidiuretic effects of AVP. Thus, during V2R antagonism, V1aR-mediated actions may be responsible for part of the diuresis observed with this drug. These V1aR-dependent effects do not take place with a voluntary increase in fluid intake. In summary, while both strategies may have beneficial effects, the information reviewed here leads us to assume that pharmacological V2R antagonism, with resulting stimulation of V1aR and increased PGE2 production, may provide greater benefit than voluntary high water intake. The influence of tolvaptan on the PGE2 excretion rate and the possibility to use somewhat lower tolvaptan doses than presently prescribed remain to be evaluated., (© The Author(s) 2021. Published by Oxford University Press on behalf of the ERA.)

Contrast medium administration is classically considered to cause or worsen kidney failure, but recent data may moderate this assertion. The European Society of Urogenital Radiology recently published guidelines re-evaluating the precautions before administering contrast media. Kidney injury does not constitute a contra-indication to the administration of iodinated contrast medium, as long as the benefit-risk ratio justifies it. Intravenous hydration with 0.9% NaCl or 1.4% sodium bicarbonate is the only validated measure for the prevention of post-iodine contrast nephropathy. This is necessary for intravenous or intra-arterial administration of iodinated contrast agent without first renal pass when the glomerular filtration rate is less than 30mL/min/1.73m 2 , for intra-arterial administration of iodinated contrast agent with first renal passage when the glomerular filtration rate is less than 45mL/min/1.73m 2 , or in patients with acute renal failure. The use of iodinated contrast medium should allow the carrying out of relevant examinations based on an analysis of the benefit-risk ratio and the implementation of measures to prevent toxicity when necessary., (Copyright © 2021 Société française de radiologie. Published by Elsevier Masson SAS. All rights reserved.)

Experimental models of cardiovascular diseases largely depend on the genetic background. Subtotal 5/6 nephrectomy (5/6 Nx) is the most frequently used model of chronic kidney disease (CKD) in rodents. However, in mice, cardiovascular consequences of 5/6 Nx are rarely reported in details and comparative results between strains are scarce. The present study detailed and compared the outcomes of 5/6 Nx in the 2 main strains of mice used in cardiovascular and kidney research, 129/Sv and C57BL/6JRj. Twelve weeks after 5/6 Nx, CKD was demonstrated by a significant increase in plasma creatinine in both 129/Sv and C57BL/6JRj male mice. Polyuria and kidney histological lesions were more pronounced in 129/Sv than in C57BL/6JRj mice. Increase in albuminuria was significant in 129/Sv but not in C57BL/6JRj mice. Both strains exhibited an increase in systolic blood pressure after 8 weeks associated with decreases in cardiac systolic and diastolic function. Heart weight increased significantly only in 129/Sv mice. Endothelium-dependent mesenteric artery relaxation to acetylcholine was altered after 5/6 Nx in C57BL/6JRj mice. Marked reduction of endothelium-dependent vasodilation to increased intraluminal flow was demonstrated in both strains after 5/6 Nx. Cardiovascular and kidney consequences of 5/6 Nx were more pronounced in 129/Sv than in C57BL/6JRj mice.

The kidney harbours different types of endothelia, each with specific structural and functional characteristics. The glomerular endothelium, which is highly fenestrated and covered by a rich glycocalyx, participates in the sieving properties of the glomerular filtration barrier and in the maintenance of podocyte structure. The microvascular endothelium in peritubular capillaries, which is also fenestrated, transports reabsorbed components and participates in epithelial cell function. The endothelium of large and small vessels supports the renal vasculature. These renal endothelia are protected by regulators of thrombosis, inflammation and complement, but endothelial injury (for example, induced by toxins, antibodies, immune cells or inflammatory cytokines) or defects in factors that provide endothelial protection (for example, regulators of complement or angiogenesis) can lead to acute or chronic renal injury. Moreover, renal endothelial cells can transition towards a mesenchymal phenotype, favouring renal fibrosis and the development of chronic kidney disease. Thus, the renal endothelium is both a target and a driver of kidney and systemic cardiovascular complications. Emerging therapeutic strategies that target the renal endothelium may lead to improved outcomes for both rare and common renal diseases.

This study addressed the hypothesis that inhibition of the EETs degrading enzyme soluble epoxide hydrolase affords renal protection in the early stage of diabetic nephropathy. The renal effects of the sEH inhibitor t-AUCB (10mg/l in drinking water) were compared to those of the sulfonylurea glibenclamide (80mg/l), both administered for 8 weeks in FVB mice subjected to a high-fat diet (HFD, 60% fat) for 16 weeks. Mice on control chow diet (10% fat) and non-treated HFD mice served as controls. Compared with non-treated HFD mice, HFD mice treated with t-AUCB had a decreased EET degradation, as shown by their higher plasma EETs-to-DHETs ratio, and an increased EET production, as shown by the increase in EETs+DHETs levels, which was associated with induction of CYP450 epoxygenase expression. Both agents similarly reduced fasting glycemia but only t-AUCB prevented the increase in the urinary albumine-to-creatinine ratio in HFD mice. Histopathological analysis showed that t-AUCB reduced renal inflammation, which was associated with an increased mRNA expression of the NFκB inhibitor Iκ≡ and related decrease in MCP-1, COX2 and VCAM-1 expressions. Finally, there was a marginally significant increase in reactive oxygen species production in HFD mice, together with an enhanced NOX2 expression. Both agents did not modify these parameters but t-AUCB increased the expression of the antioxidant enzyme superoxide dismutase 1. These results demonstrate that, independently from its glucose-lowering effect, sEH inhibition prevents microalbuminuria and renal inflammation in overweight hyperglycemic mice, suggesting that this pharmacological strategy could be useful in the management of diabetic nephropathy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Chronic lymphocytic leukemia and small lymphocytic lymphoma are 2 different presentations of the most common B-cell neoplasm in western countries (CLL/SLL). In this disease, kidney involvement is usually silent, and is rarely reported in the literature. This study provides a clinicopathological analysis of all-cause kidney disease in CLL/SLL patients., Methods: Fifteen CLL/SLL patients with kidney biopsy were identified retrospectively. Demographic, clinical, pathological and laboratory data were assessed at biopsy, and during follow-up., Results: At biopsy 11 patients presented impaired renal function, 7 patients nephrotic syndrome, 6 patients dysproteinemia, and 3 patients cryoglobulinemia. Kidney pathology revealed CLL/SLL-specific monoclonal infiltrate in 10 biopsies, glomerulopathy in 9 biopsies (5 membranoproliferative glomerulonephritis, 2 minimal change disease, 1 glomerulonephritis with organized microtubular monoclonal immunoglobulin deposits, 1 AHL amyloidosis). Five patients presented interstitial granulomas attributed to CLL/SLL. After treatment of the hematological disease, improvement of renal function was observed in 7/11 patients, and remission of nephrotic syndrome in 5/7 patients. During follow-up, aggravation of the kidney disease systematically occurred in the absence of favorable response to hematological treatment., Conclusions: A broad spectrum of kidney diseases is associated with CLL/SLL. In this setting, kidney biopsy can provide important information for diagnosis and therapeutic guidance.

Kidney diseases impart a vast burden on affected individuals and the overall health care system. Progressive loss of renal parenchymal cells and functional decline following injury are often observed. Notch-1 and -2 receptors are crucially involved in nephron development and contribute to inflammatory kidney diseases. We specifically determined the participation of receptor Notch-3 following tubulointerstitial injury and in inflammatory responses. Here we show by heat map analyses that Notch-3 transcripts are up-regulated in human kidney diseases. A similar response was corroborated with kidney cells following TGF-β exposure in vitro. The murine unilateral ureteral obstruction (UUO) model mirrors hallmarks of tubulointerstitial injury and damage. A subset of tubular and interstitial cells demonstrated up-regulated Notch-3 receptor expression in diseased animals. We hypothesized a relevance of Notch-3 receptors for the chemotactic response. To address this question, animals with genetic ablation of receptor Notch-3 were analysed following UUO. As a result, we found that Notch-3-deficient animals are protected from tubular injury and cell loss with significantly reduced interstitial collagen deposition. Monocytic cell infiltration was significantly reduced and retarded, likely due to abrogated chemokine synthesis. A cell model was set up that mimics enhanced receptor Notch-3 expression and activation. Here a pro-mitogenic response was seen with activated signalling in tubular cells and fibroblasts. In conclusion, Notch-3 receptor fulfils non-redundant roles in the inflamed kidney that may not be replaced by other Notch receptor family members. Thus, specific blockade of this receptor may be suitable as therapeutic option to delay progression of kidney disease., (Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

The Notch3 receptor participates in the development and maturation of vessels. Mutations of Notch3 in humans are associated with defective regulation of cerebral blood flow. To investigate the role of Notch3 in the regulation of renal hemodynamics, we used mice lacking expression of the Notch3 gene (Notch3-/- mice). Bolus injections of norepinephrine and angiotensin II increased renal vascular resistance and decreased renal blood flow in a dose-dependent manner in wild-type mice. In sharp contrast, renal vascular resistance of Notch3-/- mice varied little after boluses of norepinephrine and angiotensin II. Inversely, bradykinin and prostacyclin relaxed renal vasculature in wild-type mice. Both vasodilators had a negligible effect on renal vascular resistance of Notch3-/- mice. Afferent arterioles freshly isolated from Notch3-/- mice displayed decreased thickness of vascular wall compared with wild -type mice and showed a deficient contractile response to angiotensin II. To examine the physiopathological consequences of the above-described deficiency, hypertension was induced by continuous infusion of angiotensin II. Angiotensin II gradually increased blood pressure in both strains, but this increase was lesser in the Notch3-/- mice. Despite this blunted systemic effect, Notch3-/- mice displayed high mortality rates (65%) attributed to heart failure. In the kidney, the surviving Notch3-/- mice showed focal structural alterations characteristic of nephroangiosclerosis. These data show that Notch3 is necessary for the adaptive response of the renal vasculature to vasoactive systems. A deficiency in the expression of Notch3 could have important physiopathological consequences in the adaptation of the cardiac and renal function to chronic increase of blood pressure.

The need for novel insights into the mechanisms of progression of renal disease has become urgent during the last several years because of the increasing incidence of chronic renal disease worldwide. Independent of the underlying disease, the subsequent progression of renal fibrosis is characterized mainly by both an exaggerated synthesis and abnormal accumulation of extracellular matrix proteins produced by mesenchymal cells within the kidney. These cells are mainly myofibroblasts deriving from a variety of renal cells such as vascular smooth muscle, mesangial, resident stem, tubular epithelial, vascular endothelial cells or pericytes. The appearance of myofibroblasts is a reversible process, as suggested by studies in experimental models showing regression of renal fibrosis during therapy with antagonists and/or blockers of the renin-angiotensin system. An additional factor that can also affect the mechanisms of progression/regression of fibrosis is the plasticity of podocytes controlling glomerular filtration., (© 2011 The Authors. International Journal of Experimental Pathology © 2011 International Journal of Experimental Pathology.)

With the increasing incidence of chronic renal diseases worldwide, there is an urgent need to understand the mechanisms involved in progression of renalfibrosis. Independently of the underlying cause or trigger, progression of renalfibrosis is mainly characterized by excessive synthesis and abnormal accumulation of extracellular matrix proteins in renal mesenchymal cells. These cells are mainly myofibroblasts deriving from phenotypic transformation of a variety of renal cells, including vascular smooth muscle cells, mesangial cells, tubular epithelial cells, endothelial cells, and pericytes. Recent animal studies showing the regression of renal fibrosis during curative therapy suggest that this phenotypic "transition" is reversible. The plasticity of podocytes controlling glomerular filtration may also play a role in the progression/regression of fibrosis in this setting

The present study investigated mechanisms of regression of renal disease after severe proteinuria by focusing on the interaction among EGF receptors, renal hemodynamics, and structural lesions. The nitric oxide (NO) inhibitor N(G)-nitro-l-arginine-methyl ester (l-NAME) was administered chronically in Sprague-Dawley rats. When proteinuria exceeded 2 g/mmol creatinine, animals were divided into three groups for an experimental period of therapy of 2 wk; in one group, l-NAME was removed to allow reactivation of endogenous NO synthesis; in the two other groups, l-NAME removal was combined with EGF or angiotensin receptor type 1 (AT(1)) antagonism. l-NAME removal partially reduced mean arterial pressure and proteinuria and increased renal blood flow (RBF), but not microvascular hypertrophy. Progression of structural damage was stopped, but not reversed. The administration of an EGF receptor antagonist did not have an additional effect on lowering blood pressure or on renal inflammation but did normalize RBF and afferent arteriole hypertrophy; the administration of an AT(1) antagonist normalized all measured functional and structural parameters. Staining with a specific marker of endothelial integrity indicated loss of functional endothelial cells in the l-NAME removal group; in contrast, in the animals treated with an EGF or AT(1) receptor antagonist, functional endothelial cells reappeared at levels equal to control animals. In addition, afferent arterioles freshly isolated from the l-NAME removal group showed an exaggerated constrictor response to endothelin; this response was blunted in the vessels isolated from the EGF or AT(1) receptor antagonist groups. The EGF receptor is an important mediator of endothelial dysfunction and contributes to the decline of RBF in the chronic kidney disease induced by NO deficiency. The EGF receptor antagonist-induced improvement of RBF is important but not sufficient for a complete reversal of renal disease, because it has little effect on renal inflammation. To achieve full recovery, it is necessary to apply AT(1) receptor antagonism.