Effects of obstruction on renal functions

Following ureteral obstruction there is a progressive fall in glomerular filtration rate (GFR) due to a reduction in single nephron glomerular filtration rate (SNGFR) and a reduced number of filtering nephrons. Renal plasma flow also declines after a transient, prostaglandin-dependent increase, due to afferent and efferent arteriolar vasoconstriction. The vasoactive hormones thromboxane A₂ and angiotensin II are implicated in the pathogenesis of the vasoconstriction following ureteral obstruction and they also reduce the glomerular ultrafiltration coefficient by causing mesangial contraction. Ureteral obstruction also leads to profound changes in renal tubular cell function. These include altered sodium and water handling resulting in a post-obstructive diuresis and natriuresis and a failure to dilute or concentrate the urine. Potassium and divalent cation exchange is also affected, as is urinary acidification. Furthermore, the response of the tubule to hormones such as antidiuretic hormone and parathyroid hormone is impaired. The pathophysiology of these alterations in renal function is discussed.     

Effect of Intact Parathyroid Hormone on Hepatic Glucose Release in the Dog

The liver has been shown to remove parathyroid hormone (PTH) from its arterial circulation by a mechanism that is selective for the intact form of the peptide (PTH 1-84). The present studies demonstrate that PTH has biologic effects on the liver in vivo. Bovine PTH 1-84 stimulated hepatic glucose release in dogs with indwelling hepatic vein catheters from basal values of 31+/-8 to 68+/-9 mg/min per kg after bolus injections of PTH. The effect on hepatic glucose release was apparent by 5 min and persisted for the 80 min of observation. The NH(2)-terminal PTH fragment (syn b-PTH 1-34) had no effect. Bovine PTH 1-84 administered in doses designed to produce circulating levels of immunoreactive PTH similar to the endogenous levels observed in uremic dogs also increased the incorporation of (14)C from infused [(14)C]alanine into glucose, and increased estimated hepatic uptake of both chemical and [(14)C]alanine, while increasing hepatic glucose release. Thus, administration of "physiologic levels" of b-PTH 1-84 stimulated hepatic glucose release in part through increased gluconeogenesis in vivo, whereas syn b-PTH 1-34 had no demonstrable effect. Circulating levels of insulin rose after PTH administration, an increase which presumably represents a secondary response to the rise in glucose release.These results suggest that the liver is a target organ of PTH, and that PTH might potentially alter carbohydrate metabolism during hypersecretion. They also suggest that hepatic uptake of PTH may be related in part to production of a specific biologic effect rather than just simple peptide degradation.     

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.     

Inhibition by anticoagulant drugs of the progressive hypertension and uremia associated with renal infarction in rats

We confirmed our previously reported findings that subcutaneous administration of heparin (200 U q 12 hr) in rats with experimental partial renal infarction prevents the development of progressive renal failure and hypertension, as well as the glomerular abnormalities which occur in the remaining viable renal tissue. In the present study, heparin, in the dosage used to prevent progressive renal failure, caused a marked and sustained prolongation of the activated partial thromboplastin time and prothrombin time, as well as a transient prolongation of the bleeding time. Administration of coumadin at doses which caused a significant prolongation of the prothrombin time and bleeding time also inhibited the development of progressive hypertension and uremia in rats with experimental partial renal infarction. These findings indicate that inhibition of blood coagulation effectively protects rats with experimentally decreased renal mass from the development of progressive renal failure and hypertension and support the concept that the glomerular thrombosis plays an important role in the pathogenesis of these complications.     

Inhibition of transepithelial sodium transport in the frog skin by a low molecular weight fraction of uremic serum

An inhibitor of transepithelial sodium transport was found in a low molecular weight fraction obtained from serum of patients with far advanced chronic renal disease. In 18 nondialyzed patients, the mean inhibition of short circuit current (SCC) was 24.9 +/-2.2% (SE). With a comparable fraction from 11 normal subjects. SCC decreased by only 5.3 +/-1.5%. There was significantly greater inhibition with the serum fractions of patients with end stage renal disease being maintained on chronic hemodialysis than in the normal control group; but the degree of inhibition in the dialyzed population was significantly less than that observed in the nondialyzed chronically uremic patients. The inhibition of SCC produced by the serum fractions of a group of seven patients with acute renal failure was not significantly different from the control group despite the presence of high grade uremia in the former. The inhibitory fraction has characteristics identical with the uremic serum fraction which previously has been shown to inhibit p-aminohippurate (PAH) uptake by rabbit kidney cortical slices. With gel filtration through Sephadex G-25, the active fraction appears after the major peaks of substances as small as urea and sodium; hence it may have been retarded on the column. But its ultrafiltration characteristics suggest that its molecular weight may be less than 1000. The inhibitory capability was not destroyed by boiling, freezing, or digestion with chymotrypsin or pronase. Neither methylguanidine nor guanidinosuccinic acid in concentrations well above those present in the serum of uremic patients inhibited sodium transport in the frog skin. The data suggest that there is an inhibitor of sodium transport in the serum of patients with chronic uremia. The role of this material in the regulation of sodium excretion in uremia as well as its possible role as a uremic toxin are subjects of both theoretical and practical interest.