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IntroductionPrevious studies in Ren-2 transgenic hypertensive rats (TGR) after 5/6 renal ablation (5/6 NX) have shown that besides pharmacological blockade of the renin-angiotensin system (RAS) also increasing kidney tissue epoxyeicosatrienoic acids (EET) levels by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for degradation of EETs, and endothelin type A (ETA) receptor blockade retards chronic kidney disease (CKD) progression. This prompted us to evaluate if this progression will be alleviated by the addition of sEH inhibitor and ETA receptor antagonist to the standard complex blockade of RAS (angiotensin-converting enzyme inhibitor plus angiotensin II type 1 receptor blocker) in rats with established CKD.MethodsThe treatment regimens were initiated 6 weeks after 5/6 NX in TGR, and the follow-up period was 60 weeks.ResultsThe addition of sEH inhibition to RAS blockade improved survival rate, further reduced albuminuria and renal glomerular and kidney tubulointerstitial injury, and attenuated the decline in creatinine clearance - all this as compared with 5/6 NX TGR treated with RAS blockade alone. Addition of ETA receptor antagonist to the combined RAS and sEH blockade not only offered no additional renoprotection but, surprisingly, also abolished the beneficial effects of adding sEH inhibitor to the RAS blockade.ConclusionThese data indicate that pharmacological strategies that combine the blockade of RAS and sEH could be a novel tool to combat the progression of CKD. Any attempts to further extend this therapeutic regimen should be made with extreme caution.

Graphical abstract Abstract Nowadays, chronic kidney disease (CKD) is considered a worldwide public health problem. CKD is a term used to describe a set of pathologies that structurally and functionally affect the kidney, it is mostly characterized by the progressive loss of kidney function. Current therapeutic approaches are insufficient to avoid the development of this disease, which highlights the necessity of developing new strategies to reverse or at least delay CKD progression. Kidney is highly dependent on mitochondrial homeostasis and function, consequently, the idea that mitochondrial pathologies could play a pivotal role in the genesis and development of kidney diseases has risen. Although many research groups have recently published studies of mitochondrial function in acute kidney disease models, the existing information about CKD is still limited, especially in renal mass reduction (RMR) models. This paper focuses on reviewing current experimental information about the bioenergetics, dynamics (fission and fusion processes), turnover (mitophagy and biogenesis) and redox mitochondrial alterations in RMR, to discuss and integrate the mitochondrial changes triggered by nephron loss, as well as its relationship with loss of kidney function in CKD, in these models. Understanding these mechanisms would allow us to design new therapies that target these mitochondrial alterations. [ABSTRACT FROM AUTHOR]

Purpose:The 5/6 nephrectomy, mimics the stages of human chronic renal failure (CRF), but the procedure causes severe renal functional and morphological damage that could interfere with the evaluation of therapies for slowing the progression of the disease. This study summarizes the results of renal function, histology, and immunohistochemical findings in rats undergoing a 2/3 nephrectomy.Methods:The rats were distributed in groups according to the type of nephrectomy: CRF5/6: induced by a 5/6 renal mass reduction and CRF2/3: less severe CRF. The body weight and blood pressure were monitored, and the serum creatinine (SCr), creatinine clearance (CCr), urine osmolality, and 24-h proteinuria (PT24h) were measured. CRF progression was evaluated by the rate of decline of CCr (RCCr). Histology and immunohistochemistry were performed in the remnant kidneys. Statistical analysis was done by unpairedt-test, and aP-value < 0.05 was taken as a statistical significance.Results:Compared to the CRF5/6 group, the CRF2/3 model had a lower SCr, PT24h, CCr, and variations of the SCr from baseline. The disease progression was also significantly slower. The renal histopathological findings revealed fewer chronic lesions in rats with CRF2/3. Similarly, we observed less macrophage accumulation as well as lower proliferative activity and expression of fibronectin and a-smooth muscle-actin in the CRF2/3 model.Conclusions:The CRF2/3 model presented with a pattern of less severe CRF, functionally and morphologically, compared to the classical CRF5/6 model, and the CRF2/3 model may be useful for evaluating therapeutic interventions that target the early stages of CRF. [ABSTRACT FROM PUBLISHER]

The Nω-nitro-L-arginine methyl ester (L-NAME) model is widely employed to investigate the role of nitric oxide (NO) in renal injury. The present studies show that Sprague-Dawley rats from Harlan (H) and Charles River (CR) exhibit strikingly large differences in susceptibility to L-NAME nephropathy. After 4 wk of L-NAME (∼50 mg.kg-1.day-1 in drinking water), H rats (n = 13) exhibited the expected hypertension [average radiotelemetric systolic blood pressure (BP), 180 ± 3 mmHg], proteinuria (136 ± 17 mg/24 h), and glomerular injury (GI) (12 ± 2%). By contrast, CR rats developed less hypertension (142 ± 4), but surprisingly no proteinuria or GI, indicating a lack of glomerular hypertension. Additional studies showed that conscious H, but not CR, rats exhibit dose-dependent renal vasoconstriction after L-NAME. To further investigate these susceptibility differences, L-NAME was given 2 wk after 3/4 normotensive nephrectomy (NX) and comparably impaired renal autoregulation in CR-NX and H-NX rats. CR-NX rats, nevertheless, still failed to develop proteinuria and GI despite moderate hypertension (144 ± 2 mmHg, n = 29). By contrast, despite an 80-90% L-NAME dose reduction and lesser BP increases (169 ± 4 mmHg), H-NX rats (n = 20) developed greater GI (26 ± 3%) compared with intact H rats. Linear regression analysis showed significant (P < 0.01) differences in the slope of the relationship between BP and GI between H-NX (slope 0.56 ± 0.14; r = 0.69; P < 0.008) and CR-NX (slope 0.09 ± 0.06; r = 0.29; P = 0.12) rats. These data indicate that blunted BP responses to L-NAME in the CR rats are associated with BP-independent resistance to nephropathy, possibly mediated by a resistance to the renal (efferent arteriolar) vasoconstrictive effects of NO inhibition. [ABSTRACT FROM AUTHOR]

Background. Children with a solitary functioning kidney (SFK) have an increased risk of developing hypertension, albuminuria and chronic kidney disease in later life. This renal injury is hypothesized to be caused by glomerular hyperfiltration that follows renal mass reduction in animal studies. Furthermore, children with an SFK show a high incidence of congenital anomalies of the kidney and urinary tract (CAKUT), which could further compromise renal function.Methods. A retrospective study of renal injury markers was performed in 206 children, divided into groups based on the origin of SFK [primary (congenital) SFK (n = 116) and secondary SFK (n = 90)]. Data on ipsilateral CAKUT were stratified separately. For blood pressure, albuminuria and glomerular filtration rate, longitudinal models were additionally developed using generalized estimated equation analysis.Results. Renal injury, defined as the presence of hypertension and/or albuminuria and/or the use of renoprotective medication, was present in 32% of all children with an SFK at a mean age of 9.5 (SD 5.6) years. Children with ipsilateral CAKUT had higher proportions of renal injury (48.3 versus 24.6%, P < 0.05). Furthermore, longitudinal models showed a decrease in glomerular filtration rate in both groups from the beginning of puberty onwards.Conclusions. This large cohort study demonstrates that renal injury is present in children with an SFK at a young age, whereas our longitudinal models show an increased risk for chronic kidney disease in adulthood. Renal injury is even more pronounced in the presence of ipsilateral CAKUT. Therefore, we underline that clinical follow-up of all children with an SFK is needed. [ABSTRACT FROM AUTHOR]

ACE (angiotensin-converting enzyme) 2 is expressed in the heart and kidney and metabolizes Ang (angiotensin) II to Ang-(1–7) a peptide that acts via the Ang-(1–7) or mas receptor. The aim of the present study was to assess the effect of Ang-(1–7) on blood pressure and cardiac remodelling in a rat model of renal mass ablation. Male SD (Sprague-Dawley) rats underwent STNx (subtotal nephrectomy) and were treated for 10 days with vehicle, the ACE inhibitor ramipril (oral 1 mg·kg-1 of body weight · day-1) or Ang-(1–7) (subcutaneous 24 μg · kg-1 of body weight · h-1) (all n = 15 per group). A control group (n = 10) of sham-operated rats were also studied. STNx rats were hypertensive (P<0.01) with renal impairment (P<0.001), cardiac hypertrophy (P<0.001) and fibrosis (P<0.05), and increased cardiac ACE (P<0.001) and ACE2 activity (P<0.05). Ramipril reduced blood pressure (P<0.01), improved cardiac hypertrophy (P<0.001) and inhibited cardiac ACE (P<0.001). By contrast, Ang-(1–7) infusion in STNx was associated with further increases in blood pressure (P<0.05), cardiac hypertrophy (P<0.05) and fibrosis (P<0.01). Ang-(1–7) infusion also increased cardiac ACE activity (P<0.001) and reduced cardiac ACE2 activity (P<0.05) compared with STNx-vehicle rats. Our results add to the increasing evidence that Ang-(1–7) may have deleterious cardiovascular effects in kidney failure and highlight the need for further in vivo studies of the ACE2/Ang-(1–7)/mas receptor axis in kidney disease. [ABSTRACT FROM AUTHOR]

Abstract: It is estimated that over 10% of the adult population in developed countries have some degree of chronic kidney disease (CKD). CKD is a progressive and irreversible deterioration of the renal excretory function that results in implementation of renal replacement therapy in the form of dialysis or renal transplant, which may also lead to death. CKD poses a growing problem to society as the incidence of the disease increases at an annual rate of 8%, and consumes up to 2% of the global health expenditure. CKD is caused by a variety of factors including diabetes, hypertension, infection, reduced blood supply to the kidneys, obstruction of the urinary tract and genetic alterations. The nephropathies associated with some of these conditions have been modeled in animals, this being crucial to understanding their pathophysiological mechanism and assessing prospective treatments at the preclinical level. This article reviews and updates the pathophysiological knowledge acquired primarily from experimental models and human studies of CKD. It also highlights the common mechanism(s) underlying the most relevant chronic nephropathies which lead to the appearance of a progressive, common renal phenotype regardless of aetiology. Based on this knowledge, a therapeutic horizon for the treatment of CKD is described. Present therapy primarily based upon renin–angiotensin inhibition, future diagnostics and therapeutic perspectives based upon anti-inflammatory, anti-fibrotic and hemodynamic approaches, new drugs targeting specific signaling pathways, and advances in gene and cell therapies, are all elaborated. [Copyright &y& Elsevier]

Background. In clinical renal transplantation, an increase in proteinuria after conversion from calcineurin inhibitors to rapamycin has been reported. In contrast, there are studies showing a nephro-protective effect of rapamycin in proteinuric diseases characterized by progressive interstitial inflammatory fibrosis. [ABSTRACT FROM PUBLISHER]

Blockade of the renin–angiotensin system (RAS), the standard treatment for chronic proteinuric nephropathy, slows but may not halt progression of the disease, particularly when therapy is started late. Because vasopressin may also play a role in the progression of renal disease, we measured the effect of a dual V1a and V2 vasopressin receptor antagonist (RWJ-676070) alone or combined with angiotensin-converting enzyme inhibition or angiotensin II type 1 receptor blockade on proteinuria and renal disease progression during overt nephropathy. Twenty-one days after renal mass reduction, a time of established injury, rats were given vehicle, RWJ-676070, enalapril, losartan, RWJ-676070 plus enalapril, or losartan in drinking water for an additional 39 days. RWJ-676070 returned the blood pressure to pre-treatment levels, which were significantly lower than those in vehicle-treated rats. Enalapril, losartan, and the combined therapies reduced blood pressure to a greater extent. RWJ-676070 afforded a partial antiproteinuric effect, which was enhanced by the addition of enalapril or losartan. Renal functional impairment, and glomerular and tubular changes were partially ameliorated by RWJ-676070; parameters significantly improved with either enalapril or losartan alone and improved to a greater extent with the combined therapies. Our findings suggest that vasopressin receptor antagonists could be of additional therapeutic value in the treatment of chronic proteinuric nephropathy. [ABSTRACT FROM AUTHOR]

Background. Partial renal ablation is associated with compensatory renal growth, significant azotaemia, a significant increase in fractional excretion of sodium and changes in solute transport. The present study evaluated the occurrence of adaptations in the remnant kidney, especially in renal amino acid transporters and sodium transporters and their putative role in sodium handling in the early stages (24 h and 1 week) after uninephrectomy. [ABSTRACT FROM PUBLISHER]

Background: Dopamine of renal origin exerts natriuretic and diuretic effects by activating D1-like receptors located at various regions in the nephron. Two weeks after uninephrectomy the renal dopaminergic system was suggested to be involved in the adaptative increase of sodium excretion. Aim: The aim of the present study was to evaluate the renal adaptations in sodium handling and renal dopaminergic system activity in uninephrectomized (Unx) rats up to 26 weeks after the surgery. Results: A time-dependent increase in both systolic and diastolic blood pressure was observed in Unx rats up to 26 weeks after uninephrectomy. This was accompanied by a compensatory increase in aromatic L-amino acid decarboxylase at 2 weeks but not 10 and 26 weeks after uninephrectomy. In contrast to what has been found 2 weeks after uninephrectomy, at 10 and 26 weeks after surgery the natriuretic response to volume expansion was reduced in Unx rats and this was accompanied by insensitivity of natriuresis to dopamine D1 receptor selective antagonist (Sch23390). Conclusion: A time-dependent decrease in dopamine sensitive natriuresis is observed in Unx rats throughout the 26 weeks after uninephectomy. It is suggested that this may contribute to compromise sodium excretion and increase blood pressure. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Factors influencing the appearance and progression of renal damage in patients with unilateral renal agenesis and remnant kidney. Background. Although some studies have shown that the risk to develop proteinuria and renal insufficiency is increased in patients with a remnant kidney (RK) or unilateral renal agenesis (URA), other patients maintain normal renal function and negative proteinuria, and the reasons to explain these different outcomes are not known. Methods. We performed a retrospective study of 54 patients with a severe reduction in renal mass (33 patients with URA and 21 with RK). Follow-up was 100± 72 months. Results. Twenty patients (group 1) showed normal renal function at presentation, whereas the 34 remaining (group 2) had proteinuria, and some of them renal insufficiency. Group 2 patients were older and had a higher blood pressure and BMI than group 1 patients. Eleven patients of group 1 remained normal throughout follow-up (group 1A), whereas the remaining 9 developed proteinuria/renal insufficiency (group 1B). BMI at presentation was significantly higher in group 1B: 27± 3.6 kg/m2 versus 21.6± 2.6 kg/m2, and BMI was the only factor statistically associated with the risk to develop proteinuria/renal insufficiency in group 1. Among group 2 patients, renal function remained stable in 20 (group 2A), and deteriorated (>50% increase of baseline serum creatinine) in the remaining 14 patients (group 2B). BMI at presentation and treatment with ACEI during follow-up were the only factors statistically associated with the risk for renal failure progression among group 2 patients. Conclusion. Overweight plays a fundamental role in the appearance of proteinuria and renal damage in patients with severe renal mass reduction. [ABSTRACT FROM AUTHOR]

We investigated the role of endothelin ETB receptor in the remnant kidney model of chronic renal failure, by using the spotting-lethal (sl) rat, which carries a naturally occurring deletion in the endothelin ETB receptor gene. After 5/6 nephrectomy, systolic blood pressure and renal functional parameters were measured for 12 weeks. At the end of the experimental period, arterial blood sample, remnant kidney, heart and aorta were collected and used for biochemical measurements and histopathological studies. The ETB-deficient sl/sl rats exhibited earlier and higher increases in systolic blood pressure, urinary protein excretion, blood urea nitrogen and plasma creatinine concentration, compared with cases in wild-type rats. Histopathologic examination of the kidney revealed glomerular and tubular lesions, alterations of which were more severe in sl/sl than in wild-type rats. While aortic endothelin-1 contents were increased similarly in both groups, the level of renal endothelin-1 content was significantly elevated in sl/sl rats, but not in the wild-type rats. These results suggest that enhanced endothelin-1 production is at least partly responsible for the increased susceptibility to partial ablation-induced chronic renal failure in ETB receptor-deficient rats and that ETB receptor-mediated actions are protective against vascular and renal injuries in this disease. [Copyright &y& Elsevier]

Several factors such as proteinuria and renal fibrosis may be important in the progression of many forms of chronic renal diseases. The purposes of the current study were to investigate the progressive renal failure of the rats with surgical renal mass reduction (RMR) and the effect of the angiotensin-converting enzyme (ACE) inhibitor, lisinopril, and to document correlation of several factors associated with progressive renal failure. Rats were subtotal (5/6) nephrectomized by resection of the renal poles and sham-operated. The functional, histological and haematological changes of the rats were studied for up to 10 weeks. After 2 weeks of RMR, oral administration of lisinopril (10 mg kg−1 per day) was performed for 8 weeks. RMR resulted in progressive renal failure with proteinuria, monocyte/macrophage (ED1+) infiltration, anaemia as assessed by haemoglobin and haematocrit (Htc), renal hypertrophy as assessed by left kidney to body weight ratio (BKW/BW), and renal fibrosis as assessed by glomerular lesions and tubulointerstitial changes. Lisinopril exhibited renoprotection with antiproteinuric effect and inhibition of monocyte/macrophage (ED1+) infiltration. However, beneficial effect of lisinopril on anaemia was not observed. At 10 weeks after surgery, severity of proteinuria positively correlated with plasma creatinine (Pcr), BKW/BW, histological damage, and systolic blood pressure, and negatively correlated with haemoglobin. Severity of tubulointerstitial changes positively correlated with Pcr and blood urea nitrogen, and negatively correlated with haemoglobin and Htc. Moreover, monocyte/macrophage (ED1+) infiltration positively correlated with severity of proteinuria and tubulointerstitial changes. These findings strongly support that proteinuria, monocyte/macrophage infiltration and renal fibrosis appear to play principal roles in the progressive renal failure with anaemia and renoprotection of ACE inhibition may be mediated by multiple actions of ACE inhibitor. The present study confirms that rats with RMR is useful to explore target molecules for renoprotective drugs and evaluate renoprotective effect of new molecular entities. [Copyright &y& Elsevier]

The present study was designed to evaluate, in rats, the effect of varying degrees of reduced renal mass on the disposition of administered cadmium. As part of this evaluation, the intrarenal, hepatic, and hematological disposition of cadmium and the urinary and fecal excretion of cadmium were studied and characterized in control, uninephrectomized (NPX), and 75% nephrectomized (75% NPX) rats 1 d, 2 d, and 7 d after the intravenous injection of a nonnephrotoxic 8.9 mol/kg dose of cadmium chloride. Renal accumulation of cadmium, especially in the cortex and outer stripe of the outer medulla, was reduced significantly in the 75% NPX rats, but not in the NPX rats, between d 2 and 7 after the injection of cadmium. The diminution in the renal accumulation of cadmium in the 75% NPX rats was most likely due to diminished glomerular filtration rate and renal clearance of cadmium induced by 75% nephrectomy. Despite reduced glomerular filtration rate, the cumulative urinary excretion of cadmium in the 75% NPX rats was significantly greater than that in either the NPX rats or the control rats. It should be mentioned, however, that very little of the administered dose of cadmium was excreted in the urine by any of the three groups of rats. Interestingly, the content of cadmium in the liver was significantly greater in 75% NPX rats than in NPX or control rats between d 1 and 7 after the injection of cadmium. Moreover, the 75% NPX rats excreted significantly less cadmium in the feces over the 7 d of study than did the other 2 groups of rats, indicating that 75% nephrectomy causes a significant alteration in one or more of the mechanisms involved in the fecal excretion of cadmium. In summary, the findings from the present study indicate that the renal and hepatic handling of administered cadmium in rats changes significantly when renal mass is reduced by 75% . Further studies are needed to better characterize the effects of reductions of renal mass, which impair renal function significantly, on both the disposition and toxicity of cadmium in renal and hepatic tissues. [ABSTRACT FROM AUTHOR]

Although experiments in the rat suggest that glomerular hemodynamic alterations following a reduction of renal mass may be implicated in the progression of chronic renal failure, we argue that the deleterious effects of similar adaptations in human renal disease are unproven. In the otherwise normal solitary kidney the supranormal glomerular filtration rate (GFR) remains stable over the longterm, and in early diabetic nephropathy which is also accompanied by hyperfiltration, renal deterioration cannot be dissociated from a rise in systemic blood pressure. In patients with miscellaneous renal diseases and a depressed basal GFR there is indirect evidence that hyperfiltration might occur in some of the remnant glomeruli. However, at present there is little conclusive evidence to indicate that therapies which might normalize glomerular hemodynamics, e.g., dietary protein restriction, have any effect on progression of renal disease, or that angiotensin converting-enzyme inhibitors, which lower glomerular capillary pressure, have any advantage over other antihypertensive agents which are equally efficacious in lowering systemic blood pressure. [ABSTRACT FROM AUTHOR]

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Background: Animal models of chronic renal failure have been widely used in the experimental nephrology laboratories. The most common technique used is the 5/6 reduction of renal mass, either by surgical resection or by infarction. Methods: In the present work, we describe a forgotten technique based in the ligation of the renal parenchyma in both renal poles. This technique combines the advantages of the resection model, like the reproducibility and homogeneity, with the ones of the infarction technique, like the absence of bleeding. Results: 8 weeks after the procedure, animals showed a decrease in creatinine clearance together with an increase in plasma creatinine. Furthermore, glomeruli of animals with 5/6 nephrectomy showed a marked hypertrophy, with a glomerular volume significantly higher than control animals. Serum levels of parathyroid hormone were also increased, consistent with the development of secondary hyperparathyroidism. Conclusions: We conclude that the present technique is a valid and improved tool for the study of chronic renal failure. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]