Development Of Chronic Renal Disease Research Articles

Evaluation of differential renal function in children – a comparative study between magnetic resonance urography and dynamic renal scintigraphy

BackgroundUrinary system anomalies, both congenital and acquired, constitute a relatively common clinical problem in children. The main role of diagnostic imaging is to determine early diagnosis and support therapeutic decisions to prevent the development of chronic renal disease. The aim of this study was to evaluate the utility of magnetic resonance urography (MRU) in assessment of urinary system in children, by comparing differential renal function calculated using MRU with dynamic renal scintigraphy (DRS).Materials and methodsThe study group consisted of 46 patients aged 1 week to 17 years (median 7 (0.5; 13) years, 17 (37%) girls, 29 (63%) boys), who underwent dynamic renal scintigraphy due to various clinical reasons. All participants underwent MRU, which was used to measure differential renal function. Functional analysis was performed using dedicated external software (CHOP-fMRU and pMRI without prior knowledge of DRS results. MRU results acquired using pMRI were assessed for inter and intraobserver agreement.ResultsStatistical analysis of the results showed excellent agreement between MRU and DRS in measuring differential renal function with Pearson correlation coefficient 0.987 for CHOP-fMRU and 0.971 for pMRI, p < 0.001. Interclass correlation coefficient (ICC) for these programs was 0.987 (95% CI 0.976–0.993) and 0.969 (95% CI 0.945–0.983) respectively, p < 0.001. The Bland-Altman 95% limits of agreement for CHOP-fMRU results vs. DRS was − 6.29–5.50 p.p. and for pMRI results vs. DRS − 9.15–9.63 p.p. The differential renal function measurements calculated in pMRI showed excellent intraobserver and interobserver agreement with ICC 0.996 (95% CI 0.994–0.998) and 0.992 (95% CI 0.986–0.996) respectively, p < 0.001.ConclusionsThe study showed no significant differences between magnetic resonance urography and dynamic renal scintigraphy in calculating differential renal function. It indicates high utility of MRU in the evaluation of urinary system in children.

UCP1 alleviates renal interstitial fibrosis progression through oxidative stress pathway mediated by SIRT3 protein stability

BackgroundRenal interstitial fibrosis is a common pathway for the progressive development of chronic renal diseases (CKD) with different etiology, and is the main pathological basis leading to end-stage renal disease. Although the current research on renal interstitial fibrosis is gradually deepening, the diagnosis and treatment methods are still very lacking. Uncoupling protein 1 (UCP1) is a nuclear encoded protein in mitochondria inner membrane and plays an important role in regulating energy metabolism and mitochondrial homeostasis. However, the biological significance of UCP1 and potential regulatory mechanisms in the development of CKD remain unclear.MethodsUnilateral ureteral obstruction (UUO) model was used to construct the animal model of renal fibrosis, and TGF-β1 stimulation of HK2 cells was used to construct the vitro model of renal fibrosis. UCP1 expression was detected by Western blot, immunoblot analysis and immunohistochemistry. UCP1 was upregulated by UCP1 overexpressing lentivirus and UCP1 agonist CL316243. Western blot and immunofluorescence were used to detect epithelial mesenchymal transition (EMT)-related markers, such as collagen I, fibronectin, antioxidant enzyme SOD2 and CAT. Reactive oxygen species (ROS) production was detected by ROS detection kit. SIRT3 knockdown was performed by siRNA.ResultsThis study presents that UCP1 is significantly downregulated in patients with renal fibrosis and UUO model. Further studies discover that UCP1 overexpression and CL316243 treatments (UCP1 agonists) reversed EMT and extracellular matrix (ECM) accumulation in renal fibrosis models in vivo and in vitro. Simultaneously, UCP1 reduced the ROS production by increasing the stability of SIRT3. When SIRT3 was knocked down, the production of ROS decreased.ConclusionsElevating the expression of UCP1 can inhibit the occurrence of oxidative stress by stabilizing SIRT3, thereby reducing EMT and ECM accumulation, and ultimately alleviating renal interstitial fibrosis. It will provide new instructions and targets for the treatment of CKD.

CHRONIC RENAL DISEASE AND CEREBROVASCULAR PATHOLOGY (LITERATURE REVIEW)

Introduction. Chronic renal disease is an umbrella term including kidney impairment or impaired renal function for more than 3 months. According to various estimates, chronic renal disease affects 8-16% of the world's population, and this figure is growing steadily. The etiological factors of chronic renal disease the most commonly include diabetic nephropathy, glomerulonephritis, hypertensive nephropathy, tubulointerstitial kidney disease, and polycystic kidney disease. Glomerular filtration rate and albuminuria are the most valuable markers of chronic renal disease that determine the severity of the disease. The objectives of this article is to review and systematize the results of global studies of chronic renal disease as a risk factor for cerebrovascular pathology and a factor, which determines the severity of stroke as well as post-stroke consequences. Results. Decreased glomerular filtration rate is an independent risk factor for chronic renal disease. There is an independent link between proteinuria and the risk of stroke. Chronic renal disease is associated with the clinical severity of strokes and the severity of post-stroke sequelae. Chronic renal disease has significant associations with the severity of neuroimaging markers of cerebral microangiopathy. The mechanisms of the development of cerebrovascular pathology in patients with chronic kidney disease have not been clearly understood, but are thought to be complex, involving a variety of factors, including arterial hypertension, impaired lipid metabolism, diabetes mellitus, and some others. Haemo-cerebral barrier disruptions due to chronic renal disease may contribute to the development of chronic renal disease. Moreover, chronic renal disease is an independent risk factor for atherosclerotic lesions of cerebral arteries. Considerable attention is paid to the genetic factors in the axis "chronic renal disease cerebrovascular pathology". Certain monogenic mutations can simultaneously have a negative impact on the development of chronic renal disease and cerebrovascular pathology. Recently the role of haemodialysis as a factor that mediates the relationship between chronic kidney disease and cerebrovascular pathology has been found out. Conclusion. Chronic renal disease and cerebrovascular pathology have many common pathophysiological mechanisms. Understanding the interaction between renal damage and impaired cerebral blood supply as well as close collaboration between neurologists and nephrologists are important issues to manage cerebrovascular complications effectively in patients with chronic renal disease.

Role of urinary NAG enzyme in early detection of renal impairment in cystic fibrosis patients

BackgroundCystic fibrosis (CF) is the most common life-limiting autosomal recessive disease among people in the USA and Europe with increased prevalence in Egypt. Affected children are in danger of acute kidney injury and the development of chronic renal disease through exposure to multiple nephrotoxic agents. N-acetyl beta-D-glucosaminidase (NAG) is a lysosomal enzyme present in high concentrations in the proximal tubular cells, thus raising urinary NAG levels to reflect tubular dysfunction. The aim of our study is to detect the role of the urinary NAG enzyme in the early detection of renal impairment in CF patients. This cross-sectional study enrolled 40 CF patients diagnosed in the CF Clinic in Children’s Hospital of Cairo University. They were age- and sex-matched to 40 healthy controls. All patients had glomerular filtration rate (GFR), serum creatinine, blood urea nitrogen (BUN), albumin/creatinine (A/C) ratio measured, urine analysis, urinary NAG enzyme using enzyme-linked immunosorbent assay (ELISA), and renal ultrasound (U/S) were done.ResultsOur study showed high levels of urinary NAG in cases with a significant difference between cases and controls (P value < 0.001). There was a significant correlation between urinary NAG enzyme elevation and A/C ratio in urine, nephrotoxic drugs administration, and duration of disease (P value = 0.002, 0.005, 0.019), respectively.ConclusionOur study suggested that the NAG enzyme is a good early detector of renal impairment in CF patients before the conventional laboratory assays become deranged.

Pop-off mechanisms as protective factors against chronic renal disease in children with posterior urethral valves.

To identify whether pop-off mechanisms act as protective factors against chronic or end-stage renal disease in patients with posterior urethral valves. A retrospective cohort study of patients with posterior urethral valves treated at a tertiary care children's hospital was carried out. Demographic, clinical, analytical, and radiological variables were collected. Considered as pop-off mechanisms were: unilateral high-grade vesicoureteral reflux with ipsilateral renal dysplasia and without involvement of the contralateral kidney, urinoma, prenatal urinary ascites, large bladder diverticulum, and persistent urachus. Multiple logistic regression and multivariate Cox regression were used for statistical analysis. 70 patients undergoing posterior urethral valve surgery in our institution from 2010 to August 2020 were included. 14 (20%) had pop-off mechanisms and 56 (80%) did not. Pop-off mechanisms protected against developing chronic renal disease (0% vs. 27%; p=0.03) and could protect against the need for renal replacement therapy (0% vs. 9%; p=0.58). Nadir creatinine values (mg/dl) were predictors for the development of chronic renal disease (0.37 vs. 0.53; p<0.0001) and the need for renal replacement therapy (0.38 vs. 1.21; p<0.001). Pop-off mechanisms act as a protective factor against chronic renal disease in patients with posterior urethral valves. Nadir creatinine is a predictor of chronic renal disease and the need for renal replacement therapy. A larger sample size is needed to determine whether pop-off mechanisms protect against the need for renal replacement therapy.

The role of urinary kidney injury molecule-1 in monitoring the child with idiopathic microscopic hematuria

Background/Aim: Idiopathic microscopic hematuria is common during childhood, and numerous factors play a role with varying degrees in its etiopathogenesis. We aimed to investigate whether urinary kidney injury molecule-1 level could be a new indicator to detect a possible renal injury that may cause idiopathic microscopic hematuria. Methods: This prospective case-control study included 38 children between 1-15 years of age who were followed up due to idiopathic microscopic hematuria without hypertension and/or edema and 39 healthy individuals with similar gender distribution. Kidney injury molecule-1, urine culture, microalbumin, calcium, magnesium, uric acid, and creatinine levels in spot urine were measured in both groups. A throat culture and abdominal ultrasound were performed on all those included. Results: No significant differences were found between the patient and control groups in terms of age, gender, weight, and height (P>0.05). Microalbumin, microalbumin to creatinine ratio in spot urine, urinary kidney injury molecule-1 levels, and kidney injury molecule-1 to creatinine ratio were higher among the patients than the controls (P=0.016, P=0.013, P=0.001, and P=0.001, respectively). Conclusion: Urinary microalbumin and kidney injury molecule-1 levels, as well as rates of these two markers to creatinine, may be higher in the children with idiopathic microscopic hematuria. Our findings show that children with microscopic hematuria should be monitored for renal tubular injury and the development of chronic renal disease.

Silencing of keratin 1 inactivates the Notch signaling pathway to inhibit renal interstitial fibrosis and glomerular sclerosis in uremia.

Renal interstitial fibrosis is a key factor in the development of chronic renal diseases, possibly leading to uremia. The present study conducted aimed to assess the hypothesis whether keratin 1 (KRT1) silencing could suppress kidney interstitial fibrosis and glomerular sclerosis via the Notch pathway to alleviate uremic symptoms. Differentially expressed genes associated with uremia were identified using the gene expression omnibus (GEO) database. Uremic rat models were established, in which short hairpin-RNA against KRT1, activators, and inhibitors of the Notch pathway were transfected. To further validate the mechanism of KRT1 in uremia, KRT1 expression, cell apoptosis, glomerular area (GA), and glomerular capillary volume (GV), the score of glomerular sclerosis, and tubulointerstitial injury were assayed and investigated. GEO database revealed that KRT1 was upregulated in uremia and regulated the Notch pathway. GA, GV, cell apoptosis, glomerular sclerosis, and tubulointerstitial injury were typically located in more elevated levels of uremia in rats. KRT1 silencing and Notch pathway inhibition decreased the expression of Jagged1, Notch1, NICD1, Hey1, Hes1, α-SMA, and FN, which further resulted in decreased cell apoptosis, GA, GV, the score of glomerular sclerosis, and tubulointerstitial injury. Subsequently, the effect of KRT1 silencing on uremia was no longer evident once the Notch pathway was activated. The co-localization of high expression KRT1 and Notch1 was found in uremia. In summary, the results identified KRT1 as a key regulator in uremia progression, and KRT1 silencing can suppress glomerular sclerosis and tubulointerstitial injury via inactivation of the Notch pathway in uremic rats.

Primary vesicoureteral reflux; what have we learnt from the recently published randomized, controlled trials?

In recent years, progress has been made on understanding the relationship between vesicoureteral reflux (VUR) and urinary tract infection (UTI). The findings on recent prospective, randomized, controlled studies have questioned the conventional VUR clinical significance and, therefore, have challenged the traditional diagnostic and therapeutic recommendations. These new studies have redefined the pathogenic role of vesicoureteral reflux in UTI as well as have disputed the routine use of urinary antibiotic prophylaxis to prevent UTI and renal damage in VUR patients. The time to overinvestigate and treat the vast majority of otherwise healthy children who have an uncomplicated UTI with long-term antibiotic prophylaxis seems to be over. Is there a role of severe VUR in the development of chronic renal disease and renal failure? New ideas are needed to answer these questions with the goal to avoid repeating past mistakes when therapeutic choices were based on expert opinions rather than facts.

Obesity and kidney disease - renal consequences of an "epidemic"

Overweight and obesity are widespread in the German population, affecting not only adults but also a significant number of children and adolescents. The risk to develop chronic kidney disease is markedly increased in overweight or adipose children, adolescents and adults.Overweight and obesity induced risk factors have a direct impact on the development of chronic renal disease (obesity-associated focal segmental glomerulosclerosis). They accelerate the progression of coexistent nephropathies (diabetic or hypertensive nephropathy, primary glomerulonephritides) and are independent risk factors for the development of acute kidney injury in critically ill patients.Obesity induced nephropathies are basically preventible. Marked weight reduction, normoglycemia and control of hypertension may contribute to an improved glomerular filtration rate and/or reduced proteinuria in early stages of renal damage.The prevalence of kidney diseases in Germany is 13 % and estimated 80 000 patients need renal replacement therapy. In order to avoid a further rapid increase in numbers, preventive measures should be enforced more rigorously.It is necessary to raise the awareness of the negative consequences of obesity in the general public, to motivate the public to adopt a healthier lifestyle and to install nephrological surveillance to contain the obesity "epidemic".

A targeted approach toward more accurate assessment of hypertension

There is neither a unifying concept nor a sufficient multivariable approach to apply the use of laboratory markers to clinical practice with respect to the metabolic syndrome. The relationship of metabolic syndrome to the development of hypertension and the concurrent development of chronic renal disease has become evident. We have shown biomarkers to have significant value in combination for assessing heart failure and pulmonary hypertension. The pathogenesis of hypertension and cardiovascular and renal diseases is tightly linked to increased oxidative stress and reduced nitric oxide bioavailability. This review addresses the mathematical foundation for such an evaluation of the biological markers and the computational tools and the interest in outcomes research for improved healthcare practice. The review also addresses the heavy investment in health information systems intended to improve a rapidly consolidating patient health network. This has become important to enable a suitable method of assessing drug efficacy and of lifestyle changes to improve the population health, the pharmaceutical industry, and allied health sciences.

Sulfotransferase-1A1-dependent bioactivation of aristolochic acid I and N-hydroxyaristolactam I in human cells.

Aristolochic acids (AA) are implicated in the development of chronic renal disease and upper urinary tract carcinoma in humans. Using in vitro approaches, we demonstrated that N-hydroxyaristolactams, metabolites derived from partial nitroreduction of AA, require sulfotransferase (SULT)-catalyzed conjugation with a sulfonyl group to form aristolactam-DNA adducts. Following up on this observation, bioactivation of AA-I and N-hydroxyaristolactam I (AL-I-NOH) was studied in human kidney (HK-2) and skin fibroblast (GM00637) cell lines. Pentachlorophenol, a known SULT inhibitor, significantly reduced cell death and aristolactam-DNA adduct levels in HK-2 cells following exposure to AA-I and AL-I-NOH, suggesting a role for Phase II metabolism in AA activation. A gene knockdown, siRNA approach was employed to establish the involvement of selected SULTs and nitroreductases in AA-I bioactivation. Silencing of SULT1A1 and PAPSS2 led to a significant decrease in aristolactam-DNA levels in both cell lines following exposure to AA-I, indicating the critical role for sulfonation in the activation of AA-I in vivo Since HK-2 cells proved relatively resistant to knockdown with siRNAs, gene silencing of xanthine oxidoreductase, cytochrome P450 oxidoreductase and NADPH:quinone oxidoreductase was conducted in GM00637 cells, showing a significant increase, decrease and no effect on aristolactam-DNA levels, respectively. In GM00637 cells exposed to AL-I-NOH, suppressing the SULT pathway led to a significant decrease in aristolactam-DNA formation, mirroring data obtained for AA-I. We conclude from these studies that SULT1A1 is involved in the bioactivation of AA-I through the sulfonation of AL-I-NOH, contributing significantly to the toxicities of AA observed in vivo.

CONTRIBUTION OF ATRIAL FIBRILLATION TO FORMATION OF CARDIORENAL CORRELATION IN HYPERTENSIVE PATIENTS

Aim. The aim of the study was to evaluate the contribution of atrial fibrillation into development of chronic renal disease in patients with hypertension. Materials and methods. Eighty patients divided into 3 groups were examined. Group 1 included patients with sinus cardiac rhythm ( n = 30), group 2 - patients with persisting form of atrial fibrillation ( n = 30), and group 3 - patients with constant one ( n = 20). Results. Presence of atrial fibrillation was revealed to contribute to development of chronic renal disease. Decrease in glomerular filtration rate progresses when a patient is moving (by the stages of natural atrial fibrillation course) and correlates with patient’s age, left atrium size and cardiac output fraction. Conclusions. Patients with atrial fibrillation should be considered as patients with a threat of development of chronic renal disease.

-572 G/C single nucleotide polymorphism of interleukin-6 and sepsis predisposition in chronic renal disease

Single nucleotide polymorphisms (SNPs) of interleukin (IL)-6 are associated with the development of chronic renal disease (CRD). Their impact for sepsis in the field of CRD was investigated. One control cohort of 115 patients with CRD without infection and another case cohort of 198 patients with CRD and sepsis were enrolled. Genotyping at the −174 (rs1800795) and −572 positions of IL-6 (rs1800796) was done by restriction fragment length polymorphism. Circulating IL-6 was measured by an enzyme immunoassay. The GG genotype of rs1800796 was more frequent among cases (78.3 %) than controls (62.6 %). No difference in the genotype frequencies of rs1800795 between cases and controls were found. Odds ratio for sepsis was 2.07 (95%CI 1.24–3.44, p = 0.005) with the GG genotype of rs1800796, which was confirmed by logistic regression analysis taking into consideration the presence of chronic comorbidities. All-cause mortality until day 28 was similar between patients with the GG genotype and the GC/CC genotypes of rs1800796, but death caused from cardiovascular events not-related with infection was more frequent with the GG genotype (14.6 % vs 2.4 %, p = 0.031). Circulating IL-6 was greater among patients of the GC/CC genotypes of rs1800796 and multiple organ dysfunction (p = 0.013). The GG genotype of rs1800796 predisposes to sepsis in CRD and to 28-day mortality by sepsis-unrelated cardiovascular phenomena.

Hypoxia-induced Bmi1 promotes renal tubular epithelial cell-mesenchymal transition and renal fibrosis via PI3K/Akt signal.

Hypoxia is an important microenvironmental factor in the development of renal fibrosis; however, the underlying mechanisms are not well elucidated. Here we show that hypoxia induces Bmi1 mRNA and protein expression in human tubular epithelial cells. We further demonstrate that Bmi1 expression might be directly regulated by hypoxia-inducible factor-1a (HIF-1a) under low oxygen. Moreover, chromatin immunoprecipitation and reporter gene assay studies reveal cooperative transactivation of Bmi1 by HIF-1α and Twist. Enforced Bmi1 expression induces epithelial-mesenchymal transition (EMT), whereas silencing endogenous Bmi-1 expression reverses hypoxia-induced EMT. Up-regulation of Bmi1 leads to stabilization of Snail via modulation of PI3K/Akt signaling, whereas ablation of PI3K/Akt signaling partially rescues the phenotype of Bmi1-overexpressing cells, indicating that PI3K/Akt signaling might be a major mediator of Bmi1-induced EMT. In a rat model of obstructive nephropathy, Bmi1 expression increases in a time-dependent manner. Furthermore, we demonstrate that increased levels of Bmi1, correlated with HIF-1α and Twist, are associated with patients with chronic kidney disease. We provide in vitro and in vivo evidence that activation of HIF-1a/Twist-Bmi1 signaling in renal epithelial cells is associated with the development of chronic renal disease and may promote fibrogenesis via modulation of PI3K/Akt/Snail signaling by facilitating EMT.

Combined effect of hyperfiltration and renin angiotensin system activation on development of chronic kidney disease in diabetic db/db mice

BackgroundHypertension is a major risk factor for renal disease progression. However, the mechanisms by which hypertension aggravates the effects of diabetes on the kidney are incompletely understood. We tested the hypothesis that renovascular hypertension accelerates angiotensin-II-dependent kidney damage and inflammation in the db/db mouse, a model of type II diabetes.MethodsRenovascular hypertension was established in db/db and wild-type control mice through unilateral renal artery stenosis (RAS); the non-stenotic contralateral kidneys evaluated 2, 4 and 6 weeks later. Angiotensin-II infusion (1000 ng/kg/min), unilateral nephrectomy, or both were also performed in db/db mice to discern the contributions of hypertension versus hyperfiltration to development of chronic renal injury in db/db mice with RAS. The effect of blood pressure reduction in db/db mice with RAS was assessed using angiotensin-receptor-blocker (ARB) or hydralazine treatment.ResultsDb/db mice with renovascular hypertension developed greater and more prolonged elevation of renin activity than all other groups studied. Stenotic kidneys of db/db mice developed progressive interstitial fibrosis, tubular atrophy, and interstitial inflammation. Contralateral kidneys of wild type mice with RAS showed minimal histopathologic abnormalities, whereas db/db mice with RAS developed severe diffuse mesangial sclerosis, interstitial fibrosis, tubular atrophy, and interstitial inflammation. Db/db mice with Angiotensin II-induced hypertension developed interstitial lesions and albuminuria but not mesangial matrix expansion, while nephrectomized db/db mice exhibited modest mesangial expansion and interstitial fibrosis, but not significant albuminuria. The combination of unilateral nephrectomy and angiotensin II infusion reproduced all the features of the injury albeit in a less severe manner. ARB and hydralazine were equally effective in attenuating the development of mesangial expansion in the contralateral kidneys of db/db mice with RAS. However, only ARB prevented elevation of urinary albumin/creatinine in db/db mice with RAS.ConclusionRenovascular hypertension superimposed on diabetes exacerbates development of chronic renal disease in db/db mice at least in part through interaction with the renin-angiotensin system. Both ARB and hydralazine were equally effective in reducing systolic blood pressure and in preventing renal injury in the contralateral kidney of db/db mice with renal artery stenosis. ARB but not hydralazine prevented elevation of urinary albumin/creatinine in the db/db RAS model.

CCR2 deficiency fails to protect mice with renal artery stenosis from chronic renal injury (278.7)

Recent studies have implicated CCR2 ‐ CCL2 signaling in macrophage influx and development of chronic renal disease in human and experimental renal artery stenosis (RAS). We sought to test the hypothesis that development of chronic renal disease would be abrogated in CCR2 knockout (KO) mice. We established RAS in CCR2 KO and WT mice (n=10) through placement of a cuff on the right renal artery We have shown that the cuff reproducibly reduces blood flow by 65% to the kidney. Sham mice underwent manipulation of the right renal artery without cuff placement. Both CCR2 KO and WT mice developed hypertension, which persisted throughout the 4 week study. There was no difference in renal atrophy between CCR2 KO (53+//‐14.6% cortical surface area) and WT (61.2%+/‐14%) mice. Furthermore, there were no significant differences in F4/80+ macrophage infiltration (12.78+/‐4.9% surface area for CCR2 KO mice and 13.13+/‐ 3.1% for WT mice) or CD3+ T cell infiltration. Infiltrating macrophages were predominantly iNOS+ M1 phenotype; few arginase+ cells were observed in any group. Urine protein excretion was similar in CCR2 KO and WT mice. CCL was induced to a similar extent in CCR2 KO and WT mice. Furthermore, no differences in CCL5, CCL7, CCR5, CCR1, or iNOS expression was observed between CCR2 KO and WT mice. We conclude that macrophage infiltration and chronic renal damage occurs in mice with deletion of CCR2. Future studies will identify signaling pathway(s) responsible for macrophage influx and chronic renal damage in this model.Grant Funding Source: AI‐100911

Management of renal artery stenosis: What does the experimental evidence tell us?

Optimal management of patients with renal artery stenosis (RAS) is a subject of considerable controversy. There is incontrovertible evidence that renal artery stenosis has profound effects on the heart and cardiovascular system in addition to the kidney. Recent evidence indicates that restoration of blood flow alone does not improve renal or cardiovascular outcomes in patients with renal artery stenosis. A number of human and experimental studies have documented the clinical, hemodynamic, and histopathologic features in renal artery stenosis. New approaches to the treatment of renovascular hypertension due to RAS depend on better understanding of basic mechanisms underlying the development of chronic renal disease in these patients. Several groups have employed the two kidney one clip model of renovascular hypertension to define basic signaling mechanisms responsible for the development of chronic renal disease. Recent studies have underscored the importance of inflammation in the development and progression of renal damage in renal artery stenosis. In particular, interactions between the renin-angiotensin system, oxidative stress, and inflammation appear to play a critical role in this process. In this overview, results of recent studies to define basic pathways responsible for renal disease progression will be highlighted. These studies may provide the rationale for novel therapeutic approaches to treat patients with renovascular hypertension.

Passive Immunization Against Marinobufagenin Attenuates Renal Fibrosis and Improves Renal Function in Experimental Renal Disease

We have shown that the cardiotonic steroid marinobufagenin (MBG) is elevated in clinical and experimental renal disease, and significantly contributes to the development of experimental uremic cardiomyopathy induced by removal of five-sixths of the kidney (5/6 nephrectomy; PNx) in the rat. We have demonstrated that both active and passive immunization against MBG with an anti-MBG monoclonal antibody (mAb 3E9) significantly attenuated cardiac fibrosis following PNx. In the present study we sought to determine whether the use of mAb 3E9 could improve renal function following PNx. Sprague-Dawley rats were treated with either mAb 3E9 or with DigiFab (an affinity-purified anti-digoxin antibody formerly named Digibind) during the fourth week after PNx. Sham-operated animals and PNx animals treated with an IgG antibody served as controls. Plasma, urine, and renal tissue were collected at the completion of the study to determine the effects of antibody treatment on renal function. In PNx rats, treatments with mAb 3E9 and DigiFab, respectively, significantly reduced plasma creatinine, improved creatinine clearance, and reduced proteinuria below the values of these three measures in IgG-treated PNx controls. Additionally, treatment with mAb 3E9 and DigiFab significantly reduced renal fibrosis as measured with Western blotting and Sirius red/Fast green staining. Passive immunization against MBG significantly improved renal function and markedly reduced renal fibrosis following the experimental induction of renal disease. The work in the study reported here adds to a growing body of knowledge implicating MBG in the development of chronic renal disease. Passive immunization against cardiotonic steroids may serve as a promising treatment for chronic renal disease.

GW24-e2192 NK-1 Receptor-mediated Renal Injury during DOCA-salt Hypertension

ObjectivesSalt-sensitive hypertension is a leading risk factor contributing to the development of chronic renal disease. We found that high-salt intake activated sensory nerves, leading to release of sensory neuropeptides including...

Effects of hydrophilic statins on renal tubular lipid accumulation in diet-induced obese mice

Animal models of obesity show that lipid deposits can injure the kidneys,and there is evidence for the role of lipids in the development of chronic renal dis-ease (CKD). Statins exhibit a lipid-lowering effect that acts on both total cholesterol and triglyceride (TG) levels and pleiotropic effects including their ability to reduce inflammation and fibrosis. The purpose of the present study was to confirm whether obesity induced by a high-fat diet (HFD, 60% fat) promotes lipid accumulation in the tubulointerstitial and/or glomerular areas in the kidney, and whether treatment of several statins, pravastatin (30 mg/kg, p.o.), rosuvastatin (3 mg/kg, p.o.),pitavastatin (1 mg/kg, p.o.) and atorvastatin (10 mg/kg, p.o.), suppresses obesity-induced lipid accumulation. Using male C57Bl/6J mice, we examined parameters related to energy metabolism, lipid accumulation as well as macrophage infiltration in glomeruli and the tubulointerstitial area, and glomerular injury using nephrin and desmin expression. None of the statins affected body weight, glucose metabolism,serum TG and adiponectin levels, or serum inflammatory cytokine levels. However,all statins improved lipid accumulation in the proximal tubules, improved glomerular hypertrophy, increased nephrin expression and decreased desmin expression, compared to non-treated obese animals. Moreover, the reduction of proximal tubular lipid accumulation was greater with pravastatin and rosuvastatin treatment than with pitavastatin and atorvastatin treatment. We concluded that hydrophilic statins may be more effective for preventing lipid accumulation in renal tubules than lipophilic statins.