Search PubMed⌕ Search

Biomedical subjects

S Klahr

Publications and source records attributed to S Klahr.

At least 55 records · Page 3Linked to original sources
PubMed1996

Delayed treatment with enalapril halts tubulointerstitial fibrosis in rats with obstructive nephropathy.

Tubulointerstitial fibrosis in unilateral ureteral obstruction (UUO) is driven by increased levels of angiotensin II (Ang II). In this study, we examined the time course of the fibrotic process in rats with UUO and explored the effect of delayed administration of an angiotensin converting enzyme (ACE) inhibitor, enalapril, on the tubulo-interstitial fibrosis of obstructive uropathy. Rats were sacrificed at 3, 5, 8, or 10 days after UUO was initiated. Some rats did not receive treatment, whereas others were treated with enalapril from day 4 to day 8 or from day 6 to day 10 after the onset of UUO. The levels of mRNA for transforming growth factor beta 1 (TGF-beta 1), collagen type IV (collagen IV), and tissue inhibitor of metalloproteinase (TIMP-1) were measured at each time point by reverse transcription-polymerase chain reaction (RT-PCR). The relative volume of the tubulointerstitium (Vv) was measured by a point-counting method. Monocyte/macrophage infiltration and collagen IV protein deposition were examined histologically using specific antibodies. There were significant increases in TGF-beta 1, TIMP-1, and collagen IV mRNAs in the obstructed kidney. Treatment with enalapril on day 4 through day 8 or on day 6 through day 10 significantly reduced the elevated mRNA levels of these compounds in the obstructed kidney. Histological studies showed augmented Vv, monocyte/macrophage infiltration, interstitial alpha-smooth muscle actin expression, and collagen IV protein deposition on days 3, 5, 8, or 10 of UUO; enalapril treatment from day 4 to 8 or from day 6 to 10 halted and to an extent reversed these increases. These data suggest that enalapril administration after several days of UUO is an effective means of preventing the progression of tubulointerstitial fibrosis of obstructive uropathy.

Actins↗
PubMed1996

Role of dietary protein and blood pressure in the progression of renal disease.

The Modification of Diet in Renal Disease (MDRD) Study examined the effect of two interventions, reduction of dietary protein and control of blood pressure below the usual recommended level, on the progression of chronic renal disease. Patients in Study A (N = 585), GFR of 25 to 55 ml/min, were randomized to a group following a usual or low protein diet (1.3 or 0.58 g/kg body wt/day) and maintained at a usual (107 mm Hg) or low (92 mm Hg) mean arterial pressure. Patients in Study B (N = 255), GFR 13 to 24 ml/min, were randomized to a group following a low protein diet or a very low protein diet (0.28 g/kg body wt/day supplemented with a mixture of keto acids and amino acids), and maintained at a usual or low blood pressure level. During the first four months of follow-up in Study A, GFR declined at a faster rate in patients assigned a low protein diet or low blood pressure goal. The "terminal" GFR slope (measured from the fourth month of follow-up and projected to 3 years of follow-up) was 28% less, as a mean, in patients in the low protein group versus those on the usual protein diet (P = 0.009). Also, the low blood pressure group showed a significantly (P = 0.006) slower progression of renal disease (29%) than the usual blood pressure group. The effects of low blood pressure on the GFR decline were significantly related to the level of proteinuria during the baseline period. The results of Study B strongly suggest beneficial effects of the very low protein diet on renal function in patients with a GFR less than 25 ml/min.

Blood Pressure↗
PubMed1996

Is there still a role for a diet very low in protein, with or without supplements, in the management of patients with end-stage renal failure?

Historically, studies in humans have not shown conclusively that low-protein diets ameloriate the progression of renal disease. However, recent trials have demonstrated that, in patients with advanced renal insufficiency, low-protein diets may slow the loss of renal function and defer the onset of end-stage renal disease.

Diet, Protein-Restricted↗
PubMed1996

Nitric oxide generation ameliorates the tubulointerstitial fibrosis of obstructive nephropathy.

Angiotensin-converting enzyme (ACE) inhibitors have been shown to minimize fibrosis of the kidney tubulointerstitium in several diseases. In addition to lowering angiotensin II levels, ACE inhibitors can increase kinin levels and subsequently increase nitric oxide formation. To determine whether nitric oxide generation is a component of the beneficial effect of ACE inhibitors on renal fibrosis, enalapril, enalapril plus NG-nitro-L-arginine methyl ester (L-NAME) or L-arginine was administered to rats that had undergone unilateral ureteral obstruction (UUO). Ureteral obstruction caused significant increases in interstitial volume, monocyte macrophage infiltration, interstitial collagen IV and alpha-smooth muscle actin expression, transforming growth factor-beta 1 mRNA, collagen IV mRNA, and tissue inhibitor of metalloproteinase-1 mRNA. Enalapril treatment significantly blunted the increase in all parameters during UUO. Cotreatment of the animals with enalapril and L-NAME reversed the beneficial effect of enalapril in the obstructed kidney for all parameters. Treatment of animals with UUO with L-arginine significantly blunted the increase in all parameters except for transforming growth factor-beta 1 mRNA expression. In the enalapril- plus-L-NAME-treated animals, there were modest but significant increases in monocyte/macrophage infiltration of the interstitium and glomerulus, and collagen IV and alpha-smooth muscle actin expression in the interstitium of the contralateral unobstructed kidney. The urine nitrite concentration was significantly increased by either enalapril or L-arginine treatment, whereas L-NAME significantly reduced urine nitrite concentration. These results suggest that treatment modalities that increase nitric oxide formation have a beneficial effect on the progression of cellular and molecular parameters of tubulointerstitial fibrosis caused by obstruction of the ureter.

Actins↗
PubMed1996

Polyunsaturated fatty acids and renal disease.

An upregulation of arachidonate metabolism often accompanies renal pathophysiologic states. The resulting eicosanoids contribute to, or modify, the underlying process. Recent investigations suggest that platelet-neutrophil interactions, as well as alterations in the expression of the inducible isoform of cyclooxygenase, play a critical role in mediating changes in arachidonate metabolism in renal inflammation. The importance of arachidonate to renal pathophysiology has been highlighted by prior investigations which have demonstrated a beneficial effect of dietary polyunsaturated fatty acid (PUFA) modulation in a variety of models of experimental renal disease. More recent work has established that this beneficial effect may depend upon alterations in both lipid mediator generation as well as changes in cell function. In light of the benefits of dietary PUFA modulation in models of experimental renal disease, there have been numerous recent clinical trials of dietary (n-3) PUFA supplementation in patients with a variety of renal disorders. These clinical trials suggest that such therapy may be an important addition to the clinical armamentarium, especially in the treatment of IgA nephropathy.

Animals↗
PubMed1996

Primary and secondary results of the modification of diet in renal disease study.

The modification of diet in renal disease (MDRD) study was a prospective, randomized, multicenter trial in 840 patients with chronic renal disease of diverse etiology. Patients in study A (585) had a GFR of 25-55 ml/min at baseline and patients in study B (255) had a GFR of 13-24 ml/min. After randomization to different diet and blood pressure groups the mean follow-up was 2.2 years. The results of the blood pressure and dietary interventions on GFR decline with time are summarized.

Adolescent↗
PubMed1996

The effect of ACE inhibitors on the expression of matrix genes and the role of p53 and p21 (WAF1) in experimental renal fibrosis.

Tubulointerstitial fibrosis in unilateral ureteral obstruction (UUO) is driven by increased levels of angiotensin II (AII). In this study we administered the angiotensin converting enzyme (ACE) inhibitor enalapril to rats with UUO after tubulointerstitial fibrosis was established. Treatment with the ACE inhibitor halted the progression of fibrosis and to a significant extent reversed some aspects of tubulointerstitial fibrosis. It is suggested that enalapril administration may be an effective means of preventing the progression of tubulointerstitial fibrosis.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Control of p53 and p21 (WAF1) expression during unilateral ureteral obstruction.

Long-term unilateral ureteral obstruction (UUO) initiates a series of renal events leading to proliferation of interstitial fibroblasts and proliferation/repair of tubular cells. This is evidenced by significant increases in proliferating cell nuclear antigen (PCNA) positive nuclei during UUO. Several pathologic settings requiring DNA replication and/or DNA repair are dependent upon the expression of p53 and at least one of two p53-dependent proteins, termed p21 (also called WAF1) and GADD45. We therefore sought to determine if p53, p21 (WAF1) or GADD45 mRNA levels were changed in obstruction. There was a progressive increase in the amount of p53 mRNA and p21 (WAF1) mRNA at 1, 3, 5 and 8 days of continuous UUO. The amount of GADD45 mRNA was found not to change. Treatment of the experimental animals with an ACE inhibitor on day 4 through day 8 of UUO significantly blunted the increase in p53 and p21 (WAF1) expression. ACE inhibitor treatment also significantly decreased the number of PCNA-positive renal cell nuclei during UUO. These results suggest that during ureteral obstruction the p53 and p21 (WAF1) genes are activated. ACE inhibitor treatment reduces p53 and p21 (WAF1) expression. This reduction is at least in part due to an inhibition of interstitial cell proliferation.

Animals↗
PubMed1995

Blood pressure control, proteinuria, and the progression of renal disease. The Modification of Diet in Renal Disease Study.

OBJECTIVE: To examine the relations among proteinuria, prescribed and achieved blood pressure, and decline in glomerular filtration rate in the Modification of Diet in Renal Disease Study. DESIGN: 2 randomized trials in patients with chronic renal diseases of diverse cause. SETTING: 15 outpatient nephrology practices at university hospitals. PATIENTS: 840 patients, of whom 585 were in study A (glomerular filtration rate, 25 to 55 mliters/min.1.73 m2) and 255 were in study B (glomerular filtration rate, 13 to 24 mliters/min.1.73 m2). Diabetic patients who required insulin were excluded. INTERVENTIONS: Patients were randomly assigned to a usual blood pressure goal (target mean arterial pressure, < or = 107 mm Hg for patients < or = 60 years of age and < or = 113 mm Hg for patients > or = 61 years of age) or a low blood pressure goal (target mean arterial pressure, < or = 92 mm Hg for patients < or = 60 years of age and < or = 98 mm Hg for patients > or = 61 years of age). MAIN OUTCOME MEASURES: Rate of decline in glomerular filtration rate and change in proteinuria during follow-up. RESULTS: The low blood pressure goal had a greater beneficial effect in persons with higher baseline proteinuria in both study A (P = 0.02) and study B (P = 0.01). Glomerular filtration rate declined faster in patients with higher achieved blood pressure during follow-up in both study A (r = -0.20; P < 0.001) and study B (r = -0.34; P < 0.001), and these correlations were stronger in persons with higher baseline proteinuria (P < 0.001 in study A; P < 0.01 in study B). In study A, the association between decline in glomerular filtration rate and achieved follow-up blood pressure was nonlinear (P = 0.011) and was stronger at higher mean arterial pressure. In both studies, the low blood pressure goal significantly reduced proteinuria during the first 4 months after randomization. This, in turn, correlated with a slower subsequent decline in glomerular filtration rate. CONCLUSIONS: Our study supports the concept that proteinuria is an independent risk factor for the progression of renal disease. For patients with proteinuria of more than 1 g/d, we suggest a target blood pressure of less than 92 mm Hg (125/75 mm Hg). For patients with proteinuria of 0.25 to 1.0 g/d, a target mean arterial pressure of less than 98 mm Hg (about 130/80 mm Hg) may be advisable. The extent to which lowering blood pressure reduces proteinuria may be a measure of the effectiveness of this therapy in slowing the progression of renal disease.

Adolescent↗
PubMed1995

Enhanced glomerular phospholipase activity in the obstructed kidney.

Previous study demonstrated that an increment of glomerular eicosanoid production may contribute to the haemodynamic changes in the obstructed kidney. To elucidate the mechanisms responsible for enhanced glomerular eicosanoid production, the present study was designed to investigate activities of related enzymes by isolated glomeruli from rat kidney with unilateral ureteral obstruction (UUO) or bilateral ureteral obstruction (BUO) for 24 hours. The activity of phospholipase A2 (PLA2) was determined by monitoring 14C] arachidonate release using 14C] phosphatidylcholine (PC) or 14C] phosphatidylethanolamine (PE) as a substrate. Phospholipase C (PLC) activity was assayed by measuring the release of [3H] inositol triphosphate [3H] IP3 from [3H] phosphatidylinositol 4,5 biphosphate ([3H] IP2). The activity of PE-specific PLA2 was increased in glomeruli from the kidney with BUO and the contralateral kidney of unilateral ureteral obstruction (CLK). PLC activity was significantly greater in the cytosolic fraction of glomeruli from kidneys with UUO, BUO and CLK compared to sham-operated control. The activity of PC-specific PLA2 was not significantly increased in any group. These results indicate that the increased synthesis of eicosanoids by glomeruli from obstructed kidney may be mediated by enhanced activities of PE-specific PLA2 and PLC. The increased activities of these phospholipases by glomeruli from CLK may contribute to a compensatory response.

Animals↗
PubMed1995

Role of angiotensin II in the tubulointerstitial fibrosis of obstructive nephropathy.

Chronic unilateral ureteral obstruction results in interstitial fibrosis of the affected kidney. Both an angiotensin-converting enzyme inhibitor, enalapril, and an angiotensin II receptor antagonist, SC-51316, ameliorate the increased production of extracellular matrix protein in the tubulointerstitium of the obstructed kidney. Blockade of angiotensin II synthesis or inability of angiotensin II to bind to its receptor lessened the increased levels of mRNA for transforming growth factor-beta and collagen IV found in the obstructed kidney of untreated rats. A monocyte/macrophage infiltration was present in the obstructed kidney of untreated rats or rats treated with the angiotensin II receptor antagonists. In contrast, this infiltrate was almost completely absent in the obstructed kidney of rats treated with enalapril. The reason for this different effect of enalapril compared with the angiotensin II receptor antagonist on the macrophage infiltrate seen in obstructive nephropathy has not been elucidated. We conclude that both an angiotensin-converting enzyme inhibitor (enalapril) and a receptor antagonist of angiotensin II ameliorate the tubulointerstitial fibrosis that follows complete unilateral ureteral obstruction in the rat. We suggest that an increased level of angiotensin II has a major role in the development of tubulointerstitial fibrosis following ureteral obstruction.

Angiotensin II↗
PubMed1995

Angiotensin II receptor antagonist ameliorates renal tubulointerstitial fibrosis caused by unilateral ureteral obstruction.

Unilateral ureteral obstruction (UUO) results in tubulointerstitial fibrosis of the obstructed kidney (OBK). In this study we report that a specific angiotensin II (Ang II) receptor antagonists, SC-51316, ameliorates the expansion of the renal cortical interstitium in the OBK of the rat at five days of UUO. This is similar to the effect of an angiotensin converting enzyme (ACE) inhibitor, enalapril. SC-51316 (20 mg/liter in the drinking water) or enalapril (200 mg/liter in the drinking water) was administered beginning 24 hours before UUO and continued through five days after UUO. The relative volume of the tubulointerstitium (Vv) was measured by a point-counting method, and monocyte/macrophage infiltration, alpha smooth muscle actin (alpha SMA), proliferating cell nuclear antigen (PCNA), and collagen type IV (collagen IV) protein deposition were examined histologically using specific antibodies. We also examined the mRNA levels of transforming growth factor beta 1 (TGF-beta 1) and collagen IV by reverse transcription polymerase chain reaction. In untreated rats with UUO, Vv was remarkably expanded; collagen IV and alpha SMA protein deposition in the interstitium and PCNA labeling of nuclei were increased. These changes were significantly ameliorated by administration of an ACE inhibitor or an Ang II receptor antagonist. A monocyte/macrophage infiltration was evident in the OBK of untreated or Ang II receptor antagonist treated rats but was greatly reduced in the OBK of rats given enalapril. Increased expression of TGF-beta 1 mRNA and collagen IV mRNA was blunted (40 to 75%) by the administration of Ang II receptor antagonist or enalapril. The Ang II receptor antagonist or the ACE inhibitor did not affect the contralateral kidney of rats with UUO or the control kidney of normal rats. This study indicates that the renin-angiotensin system has a major role in the pathogenesis of the tubulointerstitial fibrosis of obstructive nephropathy. The tubulointerstitial fibrosis of obstructive nephropathy is most likely mediated by an increased level of Ang II in renal tissue.

Actins↗
PubMed1995

Partial cloning and characterization of an arginine decarboxylase in the kidney.

Using homology-based polymerase chain reaction (PCR) amplification, we demonstrate the presence of arginine decarboxylase mRNA in tissues involved in arginine metabolism (brain, kidney, gut, adrenal gland, and liver of the rat) but not in organs (lung, heart, and spleen) in which arginine metabolism is low or absent. The polymerase chain reaction product from the kidney had a nucleotide sequence 61% identical to that of the E. coli biosynthetic arginine decarboxylase. On a whole tissue basis, kidney homogenates were three times more active than brain homogenates at decarboxylating [1-14C]arginine. Subcellular fractionation localized the arginine decarboxylase activity of the kidney to the mitochondria fraction. Agmatine, one of the products of arginine decarboxylation, was found to inhibit nitric oxide formation by post-mitochondrial supernatants of the brain or kidney. We propose that arginine is metabolized to two structurally different signaling molecules, nitric oxide and agmatine. Furthermore, agmatine can influence the nitric oxide synthase pathway.

Agmatine↗
PubMed1995

Dietary protein restriction, blood pressure control, and the progression of polycystic kidney disease. Modification of Diet in Renal Disease Study Group.

In the Modification of Diet in Renal Disease Study, a follow-up (mean, 2.2 yr) of 200 study participants with autosomal dominant polycystic kidney disease (ADPKD) was conducted to determine the effect of lowering protein intake and blood pressure on the rate of decline in GFR. The rate of decline was faster in participants with ADPKD than in persons with other diagnoses, reflecting, in part, faster disease progression in the ADPKD group. Baseline characteristics that predicted a faster rate of decline in GFR in persons with ADPKD were greater serum creatinine (independent of GFR), greater urinary protein excretion, higher mean arterial pressure (MAP), and younger age. In patients with initial GFR values between 25 and 55 mL/min per 1.73 m2, neither assignment to a low-protein diet group nor assignment to a low blood pressure group significantly reduced the rate of decline of GFR in ADPKD participants. Similarly, the decline in GFR was not related to achieved protein intake or MAP. In participants with GFR values between 13 and 24 mL/min per 1.73 m2, assignment to the low MAP group led to a somewhat more rapid decline in GFR. However, the more rapid decline in GFR did not appear to be due to a detrimental effect of low blood pressure or the antihypertensive agents used to reach the low blood pressure goal. Lower protein intake, but not prescription of the keto acid-amino acid supplement, was marginally associated with a slower progression of renal disease.

Adult↗