Pentoxifylline protects against loss of function and renal interstitial fibrosis in chronic experimental partial ureteral obstruction.

Tubulointerstitial fibrosis (TIF) is a hallmark of chronic kidney disease resulting from diverse etiologies and predicts severity and progression of the kidney disease. To investigate the pathogenesis of TIF, complete unilateral ureteral obstruction (UUO) is the most widely used animal model. However, UUO precludes evaluation of renal function. In the present study, we created a rat model of chronic partial ureteral obstruction (PUO), which allowed assessment of renal function at different intervals after obstruction. We examined the effects of pentoxifylline (PTF), a phosphodiesterase inhibitor used clinically to treat peripheral artery disease, on renal function and TIF. Studies were performed in sham-PUO rats and rats with 14-day PUO or 30-day PUO receiving vehicle in drinking water or PTF (400 mg/liter in drinking water). At day-14 PUO, glomerular filtration rate (GFR) was markedly and similarly depressed in rats receiving vehicle or PTF as compared with sham-operated rats. However, at day-30 PUO, GFR in rats receiving PTF was significantly higher than that in rats receiving vehicle, approaching the level seen in the sham-operated rats. At day-30 PUO, histologic studies also revealed a marked reduction of TIF in rats treated with PTF as compared with the rats receiving vehicle in drinking water. Western blot analysis demonstrated that at day-30 the expression of α-smooth muscle actin (an indicator of renal fibrosis) in the medulla was significantly reduced in PUO rats treated with PTF. In conclusion, PTF treatment ameliorated renal fibrosis and helped preserve renal function in a rodent model of PUO.

Atorvastatin ameliorates tubulointerstitial fibrosis and protects renal function in chronic partial ureteral obstruction cases.

PURPOSE: Tubulointerstitial fibrosis, the histological feature of chronic obstructive nephropathy, is delineated in complete unilateral ureteral obstruction models. Histological changes during chronic partial ureteral obstruction are not well studied. We describe changes in a rat model of partial ureteral obstruction. We examined the effects of atorvastatin on histological alterations, fibrosis and function in this model. MATERIALS AND METHODS: All rats underwent right nephrectomy. To create partial ureteral obstruction the left ureter was incorporated into the psoas muscle, which was split and reapproximated. Excretory urogram, histology, Western blot of alpha-smooth muscle actin and renal clearance were examined in rats with sham, 14-day or 30-day partial ureteral obstruction. Obstructed rats received a regular or a diet supplemented with 50 mg/kg body weight atorvastatin per day. RESULTS: At 14 days of partial ureteral obstruction pyelogram showed hydronephrosis, which was more pronounced on obstruction day 30. Histological studies on obstruction days 14 and 30 revealed tubulointerstitial fibrosis in the medulla and cortex. Atorvastatin significantly decreased tubulointerstitial fibrosis seen in alpha-smooth muscle actin expression. On obstruction day 14 or 30 the glomerular filtration rate in rats on a regular diet was significantly lower than in sham PUO rats or rats on atorvastatin. CONCLUSIONS: This model of partial ureteral obstruction enables chronic studies of morphological and histological changes of the obstructed kidney. It showed progressive fibrosis and decreased filtration function. Atorvastatin ameliorated fibrosis and helped preserve kidney filtration function.

Beer Potomania: A View on the Dynamic Process of Developing Hyponatremia.

Poor solute intake has been ascribed to hyponatremia seen in patients with beer potomania, an uncommon etiology of hyponatremia. Our current understanding of how hyponatremia develops in these patients is derived only from individual cases described in the literature. In these case reports, the pathophysiology of beer potomania is explained exclusively by the concept of solute-free water clearance in the kidney. Specifically, low solute intake reduces urinary excretion of osmoles, thereby capping a ceiling on the renal capacity of free water excretion. A positive water balance follows an excess of water intake, causing dilutional hyponatremia. We propose that further inquiry is needed to explain how water is retained by the kidney. From reviewing the clinical data of these case reports, it is evident that there is a broad range of urine osmolality, ranging from levels below to above plasma osmolality. This finding is consistent with a dynamic course of vasopressin secretion during the development of hyponatremia. Vasopressin raises epithelial permeability to water in the collecting duct; the amount of luminal osmoles then determines the osmotic gradient for water transport. At a certain degree of hyponatremia, vasopressin secretion may cease and profound water diuresis ensues. Unfortunately, the status of vasopressin release is rarely investigated. We propose that in patients with beer potomania detailed fluid balance studies, sequential observations of changes in urine and plasma osmolality corresponding to dynamics of vasopressin release would advance our understanding of its pathophysiology.

Left ventricular geometry and renal function in hypertensive patients with diastolic heart failure.

BACKGROUND: The objective is to define the relationship between cardiac geometry and renal function in hypertensive subjects with and without diastolic heart failure (DHF). METHODS: This is a prospective observational study in a tertiary-care teaching institute in a 15-month period of consecutive hospitalized hypertensive patients. Patients on dialysis therapy or with atrial fibrillation, systolic heart failure, gross proteinuria, and glomerular diseases were excluded. Two-dimensional echocardiography was performed and stable glomerular filtration rate (GFR) was calculated by using the Modification of Diet in Renal Disease formula. Patients were classified into stage 1 to 5 chronic kidney disease (CKD). RESULTS: Five hundred forty hypertensive patients were separated into 2 groups: 286 patients with DHF and 254 patients without DHF. Mean age was 69.1 +/- 13.7 (SD) years in general. In patients with DHF, from stages 1 to 5 CKD, there was a significant graded increase in left ventricular mass index (from 117.3 to 162.4 g/m(2)) and relative wall thickness (from 0.42 to 0.52) and a significant graded decrease in aortic cusp separation (from 1.85 to 1.55 cm). Among echocardiographic variables, left ventricular mass index and relative wall thickness were associated inversely and aortic cusp separation was associated directly with GFR. In the absence of DHF, only left ventricular mass index was associated inversely with GFR, suggesting a prominent role of aortic cusp separation and relative wall thickness in the variability in GFR in patients with DHF through a hemodynamic disturbance. CONCLUSION: Hemodynamic alterations have a prominent role in the variability of GFR in patients with CKD with DHF. Adverse cardiac geometry is linked to the severity of CKD in hypertensive patients, raising the possibility of preserving both cardiac and renal function by means of hypertension control.

Risk factors for acute renal insufficiency induced by diuretics in patients with congestive heart failure.

BACKGROUND: In patients with congestive heart failure (CHF), continuous diuretic therapy may result in acute renal insufficiency (ARI). This study examines factors contributing to this complication. METHODS: We analyzed clinical data from 318 consecutive patients who were hospitalized for CHF. All were treated with diuretics and had echocardiography performed within 4 days of hospitalization. Systolic left ventricular (LV) dysfunction is defined as an ejection fraction less than 50%, and diastolic LV dysfunction, as an ejection fraction of 50% or greater in the presence of LV hypertrophy and a reversed E/A ratio. RESULTS: ARI, defined as a 25% increase in serum creatinine level, occurred in 110 patients (35%) after diuretic therapy. Risk factors for ARI on univariate analyses were older age, higher baseline serum creatinine level, lower baseline serum sodium level, lower mean arterial pressure (MAP) during diuretic therapy, and greater doses and longer duration of diuretic therapy. In multivariate analyses, ARI occurred more frequently in patients with systolic (40%) than diastolic dysfunction (28%). The use of digoxin in patients with systolic LV dysfunction was observed to decrease the risk for ARI by 61%, independent of other agents used for the treatment of patients with CHF. CONCLUSION: Age, baseline renal function and serum sodium concentration, MAP, and intensity of diuretic therapy can identify individuals at risk for ARI while receiving diuretic therapy for CHF. This complication is observed more often in individuals with systolic dysfunction, and its risk may be decreased with the use of digoxin.

Resin-Induced Colonic Pseudotumor: Rare Complication from Chronic Use of Potassium Binders in a Hemodialysis Patient.

Potassium-binding resins are widely used in the treatment of hyperkalemia, mostly in the acute setting. Gastrointestinal adverse events, although reported, are not frequently seen due to its short course of use. This report describes a case involving an end-stage renal disease patient on hemodialysis who developed a colonic mass after being on sodium polystyrene sulfonate chronically for persistent hyperkalemia. Gastrointestinal symptoms developed late during the treatment rather than early as reported previously in the literature. This mass was mistaken for a carcinomatous lesion, which initiated an extensive work-up as well as hospitalization that nearly resulted in a subtotal colectomy.

Atorvastatin protects renal function in the rat with acute unilateral ureteral obstruction.

OBJECTIVES: To examine the effects of atorvastatin on renal hemodynamics and urinary microalbumin levels in rats with acute unilateral ureteral obstruction (UUO). Previous studies have demonstrated that treatment with statins attenuated renal structural damages in rodents with chronic UUO. However, it is not known whether statins afford protection of renal function. METHODS: UUO was created by ligation of the left ureter in rats maintained on a regular diet or the same diet but supplemented with atorvastatin (50 mg/kg/d) for 2 weeks. Renal clearance experiments were performed after release of UUO at 1 hour, 6 hours, or 12 hours. RESULTS: Atorvastatin treatment lowered plasma triglyceride but not cholesterol levels. Both glomerular filtration rate and effective renal plasma flow were significantly greater in atorvastatintreated rats after release of UUO at 1 hour, 6 hours, and 12 hours. Significant reduction of urinary microalbumin to creatinine ratios occurred in the atorvastatin-treated group at 12 hours but not earlier. CONCLUSIONS: Atorvastatin treatment affords protection of renal function in acute UUO and reduces urinary microalbumin levels without lowering cholesterol levels. This pleiotropic action of atorvastatin on preservation of renal hemodynamics may be important in attenuating subsequent renal structural injury in chronic UUO.

Atorvastatin preserves renal function in chronic complete unilateral ureteral obstruction.

PURPOSE: The pleiotropic effects of hMG-CoA (3-hydroxy-3-metylglutaryl coenzyme A) reductase inhibitors may provide renal protection in chronic kidney disease. We examined whether atorvastatin administration preserved renal function in rats with chronic unilateral ureteral obstruction. MATERIALS AND METHODS: Renal clearance experiments were performed in sham operated rats and rats subjected to 3 or 12-day unilateral ureteral obstruction. Hemodynamics parameters and urinary microalbumin levels from the obstructed kidney were also measured. The rats were maintained on a regular diet or the same diet but supplemented with atorvastatin (50 mg/kg daily). RESULTS: Atorvastatin administration did not alter plasma total cholesterol but it significantly decreased triglyceride levels. In sham operated and 3-day unilateral ureteral obstruction rats atorvastatin treatment did not have effects on the glomerular filtration rate or effective renal plasma flow and it also did not affect urinary microalbumin levels. In rats with 12-day unilateral ureteral obstruction the glomerular filtration rate but not effective renal plasma flow was significantly higher and urinary microalbumin was significantly lower in atorvastatin treated rats than in those without atorvastatin treatment. CONCLUSIONS: Atorvastatin treatment decreased microalbuminuria and helped preserve filtration function in chronic unilateral ureteral obstruction without altering plasma cholesterol levels, suggesting that pleiotropic renal protection is offered by this statin.

Calcium-sensing receptor gene polymorphism Arg990Gly and its possible effect on response to cinacalcet HCl.

Cinacalcet, a novel calcimimetic compound, is effective in reducing parathyroid hormone (PTH) levels in approximately 70% of patients with secondary hyperparathyroidism. However, interindividual variations in the dose required to achieve the treatment goal have been noted in clinical studies. Our investigation examined the genetic polymorphisms of the calcium-sensing receptor (CaSR) gene as one possible cause of the different responses to cinacalcet. We report data on seven end-stage renal failure patients who were treated with regular haemodialysis and who participated in clinical trials of cinacalcet. All patients had secondary hyperparathyroidism with baseline intact PTH (iPTH) levels greater than 600 pg/ml. Three patients were male and four female with a mean+/-SD age of 60+/-12 years. DNA was extracted from peripheral lymphocytes. An area in exon 7 of the CaSR gene was amplified by the polymerase chain reaction and sequenced. Mean+/-SD baseline iPTH was 1086+/-189 pg/ml. The five patients without Arg990Gly demonstrated a 29.7+/-4.0% (+/-SEM) reduction in iPTH from individual baseline. One patient was found to be homozygous for the Arg990Gly polymorphism and another was heterozygous for both arginine and glycine alleles. The homozygous patient showed a significantly higher sensitivity to cinacalcet compared to the other patients (P=0.003) with a 76.3+/-7.7% reduction in iPTH from baseline. No polymorphisms were noted in codons 986 or 1011. This preliminary study points to the possibility that patients homozygous for glycine at the 990 position in exon 7 of the CaSR may be more sensitive to the calcimimetic drug cinacalcet compared to those who are homozygous for arginine at that location.

Renal responses to atrial natriuretic peptide are preserved in bilateral ureteral obstruction and augmented by neutral endopeptidase inhibition.

PURPOSE: Atrial natriuretic peptide (ANP) contributes to post-obstructive diuresis in bilateral ureteral obstruction (BUO). In this study we examined the activity of neutral endopeptidase (NEP), an enzyme responsible for degradation of ANP, in the kidney in rats subjected to BUO for 24 hours. MATERIALS AND METHODS: Renal function was examined by the clearance method in sham operated rats and BUO rats after obstruction release. Renal responses to an intravenous bolus injection of ANP (5 microg/kg) were studied in sham operated and BUO rats with or without pretreatment with intravenous phosphoramidon (100 microg/kg per minute), a NEP inhibitor. RESULTS: In BUO rats natriuresis and diuresis occurred despite a marked decrease in the glomerular filtration rate (GFR). ANP administration increased GFR and induced marked natriuresis and diuresis in sham operated and BUO rats. Inhibition of ANP degradation by phosphoramidon induced natriuresis and diuresis, and accentuated these renal responses to ANP. CONCLUSIONS: Renal responses to ANP and renal NEP activity were preserved in 24-hour BUO. NEP inhibition to attenuate ANP degradation augmented responses to ANP in increasing GFR, natriuresis and diuresis. These findings provide the theoretical potential for facilitating the recovery of GFR after BUO release by inhibiting ANP degradation by pharmacological means.

Regional expression of cyclooxygenase isoforms in the rat kidney in complete unilateral ureteral obstruction.

PURPOSE: The cyclooxygenase (COX) pathway is activated in unilateral ureteral obstruction (UUO), contributing to renal hemodynamic alterations in different regions of the kidney. After the release of 24-hour UUO cortical vasoconstriction occurs but medullary hyperemia is seen. We examined the expression of the 2 COX isoforms COX-1 and COX-2 in different regions of the kidney in rats subjected to UUO. MATERIALS AND METHODS: Clearance experiments were performed after ureteral obstruction release in rats with 24-hour UUO or sham operated rats. COX-1 and COX-2 expression in the cortex and medulla were examined by Western blot analysis and immunohistochemistry. RESULTS: After UUO release the glomerular filtration rate and renal plasma flow were markedly lower in post-obstructed kidneys than in contralateral kidneys or in kidneys in sham operated rats (p <0.001). Western blot analysis showed that COX-2/beta-actin in the cortex of the obstructed kidney was 0.28 +/- 0.02 densitometry units, significantly lower than 0.67 +/- 0.12 densitometry units in the contralateral unobstructed kidney. In contrast, COX-2/beta-actin in the outer and inner medullae of the obstructed kidney was 7.85 +/- 1.09 and 2.51 +/- 0.14 densitometry units, significantly greater than 3.03 +/- 0.22 and 0.66 +/- 0.14 densitometry units, respectively, in the contralateral unobstructed kidney. The expression of COX-1/beta-actin in the obstructed kidney was similar to that in the contralateral unobstructed kidney in the cortex and medulla. CONCLUSIONS: Renal COX-2 expression is markedly altered in UUO. Decreased cortical expression of COX-2 and markedly increased expression in the medulla may contribute to disparate regional hemodynamic alterations in UUO.

Alterations of renal hemodynamics in unilateral ureteral obstruction mediated by activation of endothelin receptor subtypes.

PURPOSE: Unilateral ureteral obstruction (UUO) for 21 hours causes severe renal vasoconstriction. We examined the role of endothelin (ET)-A receptor in renal hemodynamic alterations induced by UUO. MATERIALS AND METHODS: Hemodynamic and clearance experiments were performed in 3 groups of anesthetized dogs. In group 1, 6 sham operated dogs received intrarenal infusion of the specific ET-A receptor antagonist BQ-610 (Peninsula Laboratories, Inc., Belmont, California), followed by infusion of the nitric oxide synthase substrate L-arginine. In the 7 group 2 dogs release of 21-hour UUO was followed by intrarenal infusion of BQ-610 and L-arginine. In the 5 group 3 dogs release of 21-hour UUO was followed by L-arginine infusion. RESULTS: UUO caused marked decreases in renal blood flow (RBF) and glomerular filtration rate (GFR) in groups 2 and 3 compared with group 1. In group 1 BQ-610 and L-arginine infusion did not alter RBF or GFR. In contrast, BQ-610 infusion in group 2 after UUO release led to a significant increase in RBF and GFR as well as additional increases after L-arginine infusion. After UUO release in group 3 L-arginine infusion alone did not change RBF or GFR. CONCLUSIONS: After UUO release blockade of the ET-A receptor ameliorates renal vasoconstriction. The addition of L-arginine, which is a substrate for nitric oxide synthase, superimposed on ET-A receptor blockade confers a further decrease in renal vascular resistance, suggesting that the ET and L-arginine-nitric oxide systems are involved in renal hemodynamic alterations caused by UUO.