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Saulo Klahr

Publications and source records attributed to Saulo Klahr.

At least 19 recordsLinked to original sources
PubMed2006

Cyst number but not the rate of cystic growth is associated with the mutated gene in autosomal dominant polycystic kidney disease.

Data from serial renal magnetic resonance imaging of the Consortium of Radiologic Imaging Study of PKD (CRISP) autosomal dominant polycystic kidney disease (PKD) population showed that cystic expansion occurs at a consistent rate per individual, although it is heterogeneous in the population, and that larger kidneys are associated with more rapid disease progression. The significance of gene type to disease progression is analyzed in this study of the CRISP cohort. Gene type was determined in 183 families (219 cases); 156 (85.2%) had PKD1, and 27 (14.8%) had PKD2. PKD1 kidneys were significantly larger, but the rate of cystic growth (PKD1 5.68%/yr; PKD2 4.82%/yr) was not different (P = 0.24). Cyst number increased with age, and more cysts were detected in PKD1 kidneys (P < 0.0001). PKD1 is more severe because more cysts develop earlier, not because they grow faster, implicating the disease gene in cyst initiation but not expansion. These insights will inform the development of targeted therapies in autosomal dominant PKD.

Adolescent↗
PubMed2006

Volume progression in polycystic kidney disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive enlargement of cyst-filled kidneys. METHODS: In a three-year study, we measured the rates of change in total kidney volume, total cyst volume, and iothalamate clearance in patients with ADPKD. Of a total of 241 patients, in 232 patients without azotemia who were 15 to 46 years old at baseline we used magnetic-resonance imaging to correlate the total kidney volume and total cyst volume with iothalamate clearance. Statistical methods included analysis of variance, Pearson correlation, and multivariate regression analysis. RESULTS: Total kidney volume and total cyst volume increased exponentially, a result consistent with an expansion process dependent on growth. The mean (+/-SD) total kidney volume was 1060+/-642 ml at baseline and increased by a mean of 204+/-246 ml (5.27+/-3.92 percent per year, P<0.001) over a three-year period among 214 patients. Total cyst volume increased by 218+/-263 ml (P<0.001) during the same period among 210 patients. The baseline total kidney volume predicted the subsequent rate of increase in volume, independently of age. A baseline total kidney volume above 1500 ml in 51 patients was associated with a declining glomerular filtration rate (by 4.33+/-8.07 ml per minute per year, P<0.001). Total kidney volume increased more in 135 patients with PKD1 mutations (by 245+/-268 ml) than in 28 patients with PKD2 mutations (by 136+/-100 ml, P=0.03). CONCLUSIONS: Kidney enlargement resulting from the expansion of cysts in patients with ADPKD is continuous and quantifiable and is associated with the decline of renal function. Higher rates of kidney enlargement are associated with a more rapid decrease in renal function.

Adult↗
PubMed2006

Comparison of methods for determining renal function decline in early autosomal dominant polycystic kidney disease: the consortium of radiologic imaging studies of polycystic kidney disease cohort.

A decline in renal function suggests progression of chronic kidney disease. This can be determined by measured GFR (e.g., iothalamate clearance), serum creatinine (SCr)-based GFR estimates, or creatinine clearance. A cohort of 234 patients with autosomal dominant polycystic kidney disease and baseline creatinine clearance>70 ml/min were followed annually for four visits. Iothalamate clearance, SCr, and creatinine clearance were obtained at each visit. Estimated GFR (eGFR) was determined with the Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault equations. Renal function slopes had a mean residual SD of 10.7% by iothalamate clearance, 8.2% by MDRD equation, 7.7% by Cockcroft-Gault equation, and 14.8% by creatinine clearance. By each method, a decline in renal function (lowest quintile slope) was compared among baseline predictors. Hypertension was associated with a decline in iothalamate clearance (odds ratio [OR] 5.8; 95% confidence interval [CI] 2.3 to 14), eGFR (OR [MDRD] 2.0 [95% CI 1.0 to 4.2] or OR [Cockcroft-Gault] 1.9 [95% CI 0.9 to 3.9]), and creatinine clearance (OR 2.0; 95% CI 1.0 to 4.2). Each doubling of kidney volume at baseline was associated with a decline in iothalamate clearance (OR 2.4; 95% CI 1.5 to 3.7), eGFR (OR 1.7 [95% CI 1.1 to 2.6] or 2.1 [95% CI 1.4 to 3.3]), and creatinine clearance (OR 1.7; 95% CI 1.1 to 2.5). Predictor associations were strongest with measured GFR. Misclassification from changes in non-GFR factors (e.g., creatinine production, tubular secretion) conservatively biased associations with eGFR. Misclassification from method imprecision attenuated associations with creatinine clearance.

Adolescent↗
PubMed2004

L-arginine as a therapeutic tool in kidney disease.

Infusion of L-arginine in experimental animals increases renal plasma flow (RPF) and glomerular filtration rate (GFR). It is likely that a component of these hemodynamic changes are mediated by nitric oxide (NO) as suggested by studies with specific antagonists of L-arginine metabolism. L-arginine administration ameliorates the infiltration of the renal parenchyma by macrophages in rats with obstructive nephropathy or rats with puromycin-induced nephrotic syndrome. L-arginine administration also blunts the increase in interstitial volume, collagen IV, and alpha-smooth muscle actin. Rats with a remnant kidney given 1% L-arginine in the drinking water had a greater GFR and RPF. L-arginine administration also decreased proteinuria. Diabetic rats given L-arginine had significantly lower excretion of protein and cyclic guanosine monophosphate than diabetic rats not receiving L-arginine. Despite persistent hyperglycemia, the administration of L-arginine prevented the development of hyperfiltration and ameliorated proteinuria in diabetic rats. In the setting of ischemic acute renal failure, the administration of L-arginine had a beneficial effect on GFR and RPF, decreased O2- production, diminished up-regulation of soluble guanylate cyclase, and prevented up-regulation of inducible NO synthase (iNOS). The pharmacokinetics of L-arginine indicate that side effects are rare and mostly mild and dose dependent.

Animals↗
PubMed2003

High urine volume and low urine osmolality are risk factors for faster progression of renal disease.

BACKGROUND: Increased fluid intake slows renal disease progression in animal models. The relevance of these findings to human renal disease is not clear, although increased fluid intake often is recommended to patients with chronic renal insufficiency. This study tested the hypothesis that urine volume, urine osmolality (Uosm), or both are significantly associated with glomerular filtration rate (GFR) decline in patients with chronic renal insufficiency. METHODS: This is a retrospective analysis of Modification of Diet in Renal Disease (MDRD) study A patients with (N = 139) and without polycystic kidney disease (PKD; N = 442). The key outcome measure was GFR slope in relation to mean 24-hour urine volume and Uosm during follow-up in study A (mean, 2.3 years). RESULTS: The regression of GFR slope on mean follow-up 24-hour urine volume (adjusted for body surface area and MDRD diet and blood pressure group) showed that the greater the urine volume, the faster the GFR decline in patients both with and without PKD. For example, the difference in GFR slope for those with a mean follow-up 24-hour urine volume of 2.4 versus 1.4 L was -1.01 mL/min/y (confidence interval, -0.27 to -1.75) for patients without PKD and -1.20 mL/min/y (confidence interval, -0.06 to -2.34) for those with PKD. A similar but inverse relationship was shown between GFR decline and mean 24-hour Uosm in patients with (P = 0.01) and without PKD (P = 0.001). These associations remained significant after adjustment for 13 relevant baseline and follow-up covariates. CONCLUSION: Sustained high urine volume and low Uosm are independent risk factors for faster GFR decline in patients with chronic renal insufficiency. Thus, high fluid intake does not appear to slow renal disease progression in humans. We suggest that until better evidence becomes available, patients with chronic renal insufficiency should generally let their thirst guide fluid intake. The advice to avoid "pushing fluids" might be particularly important for patients with PKD.

Disease Progression↗
PubMed2003

Bone morphogenic protein-7 (BMP-7), a novel therapy for diabetic nephropathy.

BACKGROUND: Bone morphogenic protein-7 (BMP-7), an essential developmental renal morphogen, is a secreted differentiation factor of the adult collecting duct. It activates receptors in the collecting duct, distal nephron, proximal tubule, and glomerulus. BMP-7 is therapeutic in tubulointerstitial nephritis raising the question of broader efficacy in chronic kidney disease (CKD). METHODS: Diabetes was induced in 200 g rats by a single dose of streptozotocin. After 16 weeks, glomerular hypertrophy and proteinuria were established, and therapy with BMP-7 (10, 30, or 100 microg/kg intravenously twice a week), enalapril (20 mg/kg), or vehicle was begun and continued until 32 weeks. Kidney weight, glomerular filtration rate (GFR), urine albumin excretion, blood pressure, pathology, and BMP-7 expression were measured. RESULTS: Diabetic vehicle-treated rats developed renal insufficiency by 32 weeks (GFR, 0.34 +/- 0.02 mL/min/100 g body weight vs. 0.55 +/- 0.02 in normal). In the diabetic BMP-7 high-dose-treated rats, GFR was preserved (0.70 +/- 0.08, P < 0.01 vs. vehicle), and higher than diabetic enalapril-treated rats (0.58 +/- 0.06). Kidney weights of vehicle-treated animals were not affected, but were reduced in all of the treatment groups (P < 0.001). Proteinuria was reversed to normal by BMP-7 in a dose-dependent manner. The reduction in proteinuria by the intermediate dose of BMP-7 was similar to the effect of enalapril therapy. Glomerular area and interstitial volume were significantly decreased in the BMP-7 and enalapril-treated animals. Glomerular sclerosis was prevented by BMP-7 therapy more effectively than by enalapril. Enalapril controlled hypertension throughout the course of therapy while BMP-7 did not affect blood pressure until the final 4 weeks of therapy. Diabetic vehicle-treated rats lost BMP-7 expression in the kidney. BMP-7 and enalapril therapy restored BMP-7 expression at high levels. CONCLUSION: BMP-7 partially reversed diabetic-induced kidney hypertrophy, restoring GFR, urine albumin excretion, and glomerular histology toward normal. Restoration of BMP-7 expression was associated with a successful repair reaction and a reversal of the ill-fated injury response.

Albuminuria↗
PubMed2003

Renal structure in early autosomal-dominant polycystic kidney disease (ADPKD): The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohort.

BACKGROUND: Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by gradual renal enlargement and cyst growth prior to loss of renal function. Standard radiographic imaging has not provided the resolution and accuracy necessary to detect small changes in renal volume or to reliably measure renal cyst volumes. The Consortium for Radiologic Imaging Studies in Polycystic Kidney Disease (CRISP) is longitudinally observing ADPKD individuals using high-resolution magnetic resonance (MR) imaging to determine if change in renal and cyst volumes can be detected over a short period of time, and if they correlate with decline in renal function early in disease. METHODS: Standardization studies were conducted in phantoms and four subjects at each participating clinical center. After, in the full-scale protocol, healthy ADPKD individuals 15 to 45 years old with creatinine clearance>70 mL/min underwent standardized MR renal imaging, renal iothalamate clearance, comprehensive clinical evaluation, and determination of 24-hour urinary albumin and electrolyte excretion. Stereology was used from T1-weighted images to quantify renal volume, and region-growing thresholding was used from T2-weighted images to determine cyst volume. Renal structures were evaluated in relation to demographic, clinical, and biochemical variables using means/medians, standard deviations, and Pearson correlations. RESULTS: Reliability coefficients for MR renal and cyst volume measurements in phantoms were 99.9% and 89.2%, respectively. In the full-scale protocol, 241 ADPKD individuals (145 women and 96 men) were enrolled. Total renal, cyst, and % cyst volume were significantly greater in each decade group. Hypertensive individuals demonstrated greater renal, cyst, and % cyst volume than normotensive subjects. Age-adjusted renal (r = -0.31, P < 0.0001), cyst (r = -0.36, P < 0.0001), and % cyst volume (r = -0.35, P < 0.0001) were inversely related to glomerular filtration rate (GFR). Age-adjusted renal volume (r = 0.42, P < 0.0001), cystic (r = 0.39, P < 0.0001, and % cyst volume (r = 0.41, P < 0.0001) were related with urinary albumin excretion. CONCLUSION: MR measures of renal and cyst volume are reliable and accurate in patients with ADPKD. ADPKD is characterized by significant cystic involvement that increases with age. Structure (renal and cyst volume) and function (GFR) are inversely related and directly related with the presence of hypertension and urinary albumin excretion in individuals with normal renal function.

Adolescent↗
PubMed2003

Magnetic resonance measurements of renal blood flow as a marker of disease severity in autosomal-dominant polycystic kidney disease.

BACKGROUND: Autosomal-dominant polycystic kidney disease (ADPKD) is an inherited disorder characterized by renal cyst growth, early development of hypertension, and late occurrence of renal insufficiency. Despite evidence for the importance of nephroangiosclerosis in the progression of renal insufficiency in ADPKD, evaluation of renal blood flow (RBF) as a surrogate marker of disease severity has received little attention. METHODS: Flow phantoms and repeat RBF measurements assessed accuracy and reproducibility. One hundred twenty-seven ADPKD subjects with creatinine clearances >70 mL/min underwent measurements of RBF, total, and cyst renal volumes, and % cyst volumes by magnetic resonance (MR) and of glomerular filtration rate (GFR). Renal vascular resistance (RVR) was calculated. MR blood flow sequences utilized a two-dimensional cine phase-contrast breath-hold pulse sequence perpendicular to the renal arteries. Flow rates were calculated utilizing FLOW software. Volumetric analysis was performed using stereology and region-based thresholding. RESULTS: Excellent accuracy and intraobserver and interobserver reproducibility were demonstrated. Anatomic (total kidney volume, total cyst volume, and % cyst volume), hemodynamic (RBF and RVR), and functional (GFR) parameters were strongly correlated. Left polycystic kidneys were larger and had more severe disease. Regression analysis showed that age, diagnosis of hypertension, anatomic parameters and hemodynamic parameters were significant predictors of GFR. Multiple linear regression analysis identified age and hemodynamic parameters only as separate predictors of GFR. Anatomic, hemodynamic, and functional parameters discriminated between normotensive and hypertensive subjects despite antihypertensive treatments. CONCLUSION: Renal hemodynamic parameters measured by MR correlate with anatomic and functional indices of disease severity, are the strongest predictors of renal function, and deserve further consideration as an outcome measure in clinical trials to guide therapy in ADPKD.

Adult↗
PubMed2003

Obstructive nephropathy and renal fibrosis: The role of bone morphogenic protein-7 and hepatocyte growth factor.

BACKGROUND: The nephropathy induced by ureteral obstruction is associated with increased interstitial volume due to matrix deposition, fibroblast differentiation/proliferation, and monocyte infiltration. Recent studies indicate that transforming growth factor-beta (TGF-beta) is linked to renal fibrosis. Tumor necrosis factor (TNF-alpha) has a role in the recruitment of inflammatory cells. We found that infiltration of macrophages of the interstitium in unilateral ureteral obstruction (UUO) occurred as early as four hours after the onset of UUO. METHODS: Recent studies indicate that a renal tubular development morphogen, bone morphogenetic protein-7 (BMP-7), is effective in preventing the tubulointerstitial nephritis in the setting of obstructive nephropathy. The mechanism of action appears to be preservation of epithelial cell phenotype, inhibition of epithelial-mesenchymal transdifferentiation, and inhibition of injury-induced epithelial cell apoptosis. Hepatocyte growth factor (HGF) also inhibited tubulointerstitial fibrosis. RESULTS: In a treatment protocol in rats with ureteral ligation, BMP-7 restored renal function. The preservation of glomerular filtration rate (GFR) was accompanied by a significant decrease in cortical interstitial volume. In diabetic rats given BMP-7 proteinuria was normalized. In mice with ureteral obstruction, HGF suppressed the expression of TGF-beta and of platelet-derived growth factor. The onset of tubulointerstitial fibrosis was almost completely inhibited by HGF. CONCLUSION: Both BMP-7 and HGF attenuate the tubulointerstitial fibrosis due to ureteral obstruction. They also increase GFR and renal plasma flow.

Animals↗
PubMed2003

Progression of chronic renal disease.

Risk factors for progression of kidney disease include hypertension, proteinuria, male sex, obesity, diabetes mellitus, hyperlipidemia, smoking, high-protein diets, phosphate retention, and metabolic acidosis. Angiotensin II production upregulates the expression of transforming growth factor-beta1, tumor necrosis factor-alpha, nuclear factor-kappaB, and several adhesion molecules and chemoattractants. In addition to angiotensin, other vasoactive compounds, such as thromboxane A(2), endothelin, and prostaglandins, are upregulated. Treatment with one of several growth factors may ameliorate the progression of kidney disease: insulin-like growth factor-1, hepatocyte growth factor, and bone morphogenetic protein-7.

Angiotensin II↗
PubMed2003

ACE inhibition increases expression of the ETB receptor in kidneys of mice with unilateral obstruction.

Unilateral ureteral obstruction (UUO) is a well-established model for the study of interstitial fibrosis in the kidney. It has been shown that the renin-angiotensin system plays a central role in the progression of interstitial fibrosis. Recent studies indicate that endothelin, a powerful vasoconstrictive peptide, may play an important role in some types of renal disease. To investigate the effects of angiotensin II on endothelin and its receptors in the kidney, mice were subjected to UUO and treated with or without enalapril, an orally active angiotensin-converting enzyme inhibitor, in their drinking water (100 mg/l). The animals were killed 5 days later. Using RT coupled with PCR, we measured the levels of endothelin-1, endothelin A, and endothelin B (ET(B)) along with transforming growth factor-beta, TNF-alpha, and collagen type IV mRNA expression in the kidney with UUO and the contralateral kidney along with interstitial expansion in the kidney cortex by a standard point counting method. We found that enalapril administration ameliorated the increased expression of ET-1 mRNA in the obstructed kidney by 44% (P < 0.02). Although the level of endothelin A mRNA expression was significantly increased in the obstructed kidney, it was not affected by enalapril. We found that enalapril treatment increased ET(B) mRNA expression by 115% (P < 0.05) and protein expression (measured by Western blot) in the kidney with an obstructed ureter. Enalapril treatment alone inhibited the expansion of interstitial volume due to UUO by 52%. Cotreatment with enalapril and the ET(B) receptor antagonist BQ-788 inhibited the expression of interstitial volume by only 19%. This study confirms that enalapril inhibits the interstitial fibrosis in UUO kidneys. It also suggests a beneficial and unforeseen effect of enalapril on the obstructed kidney by potentially stimulating the production of nitric oxide through an increased expression of the ET(B) receptor.

Angiotensin II↗