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Mesangial expansion as a central mechanism for loss of kidney function in diabetic patients.

Diabetic nephropathy leading to kidney failure is a major complication of both type I (insulin-dependent) and type II (non-insulin-dependent) diabetes mellitus, and glomerular structural lesions (especially expansion of the mesangium) may constitute the principal cause of decline in kidney function experienced by a significant fraction of diabetic patients. Although the biochemical bases of these mesangial abnormalities remain unknown, an understanding of the natural history of diabetic nephropathy from a combined structural and functional approach can lead to greater pathophysiological insight. Work in animals has supported the concept that the metabolic disturbances of diabetes mellitus cause diabetic nephropathy, with structural and functional lesions prevented or reversed with improved or normalized glycemic control. Additional research must address this fundamental issue in humans, especially the response of advancing mesangial lesions to improved glycemic control. Factors not directly related to the metabolic perturbations of diabetes may serve to accelerate or diminish the pathophysiological processes of diabetic nephropathy. The elucidation and management of these factors, when coupled with improved glycemic control, may moderate the development or progression of diabetic kidney lesions in humans.

Albuminuria↗

Electric modification of kidney function. The excretion of radiographic contrast media and adriamycin.

The body consists of systems of conductive pathways for ionic flow of current induced by metabolic or injury potentials among tissues and cells. In vivo electrophoresis in biologically closed electric circuits (BCEC) are coupled to the mechanical transports of blood and lymph. Connections also exist with conductive media such as cerebrospinal fluid, bile, and urine. Artificial induction of current was applied over the kidneys in order to study modification of kidney function. It is thought that studies of this kind will increase our understanding of kidney function from a new angle of view and possibly add new therapeutic possibilities. In anesthetized pigs, one kidney was made anodic (electropositive) and the other cathodic (electronegative). Current was applied between electrodes in each ureter. Intravascularly injected, electronegatively charged aminotrizoate and ioxaglate were excreted mainly by the anodic kidney. Nonionic iohexol was urographically excreted by both kidneys. Excretion of electropositively charged Adriamycin by the cathodic kidney was identified macroscopically and by chemical analysis. Functional effects on the kidneys can be induced electrophoretically without causing injury.

Animals↗

Effect of the novel T-selective calcium channel antagonist mibefradil on kidney function in comparison with amlodipine.

In the present study, the renal effects of mibefradil (CAS 116666-63-8), a novel calcium channel antagonist which more selectively blocks T-type than L-type calcium channels, was tested by applying clearance techniques to anaesthetized rats. The effects of mibefradil on kidney function and on arterial blood pressure were compared with those of the long acting dihydropyridine-type calcium antagonist amlodipine (CAS 88150-42-9). The results show that, within a dosage range of 0.1 to 1.0 mg/kg i.v., mibefradil induced a dose-dependent decrease of arterial blood pressure. Kidney function was not significantly affected at a dose of 0.1 mg/kg. By increasing the dose to 0.3 mg/kg, mibefradil induced a significant increase in urine flow, renal sodium, chloride and potassium excretion. Also fractional sodium and chloride excretions were significantly enhanced at this dose. The diuretic and saluretic effects of mibefradil were accompanied by a significant increase in the glomerular filtration rate. At the highest dose of 1 mg/kg used, the blood pressure lowering effect of mibefradil was most pronounced and glomerular filtration rate rose only slightly and not significantly. At this dose, the enhancement of urine flow and urinary electrolyte excretion was smaller than at the dose of 0.3 mg/kg. The actions of mibefradil were qualitatively similar to those of the dihydropyridine derivate amlodipine which at a dose of 0.3 mg/kg produced nearly identical renal effects to mibefradil, but exerted stronger antihypertensive effects. This study demonstrates that mibefradil shares with amlidopine the property to induce, at appropriate doses, diuretic and saluretic effects with a concomitant increase in glomerular filtration rate.

Amlodipine↗

Embolization of non-tolerated non-functioning kidney graft: alternative to surgical removal.

The results of treatment by percutaneous transcatheter embolization in eight cases of non-tolerated non-functioning kidney graft are presented. The symptoms resulting from non-tolerance of the renal graft were fever, pain and haematuria. Embolization was well tolerated in all eight cases and the only adverse effect was post-embolization self-limited fever in five cases. The symptoms of non-tolerance of the graft disappeared immediately in all cases, with minimal morbidity and no mortality. In only one patient was it necessary to perform second embolization procedure to achieve permanent control of symptoms. We conclude that percutaneous embolization of non-tolerated non-functioning kidney graft is an effective procedure with significantly less morbidity than with surgical graft nephrectomy.

Adult↗

Kidney function after renal arterial embolism.

Seven patients with atrial fibrillation had acute unilateral renal pain associated with suppression of function in the affected kidney. This was ascribed to renal embolism. Arteriography performed in four patients showed abnormalities in the renal arterial tree in three, though thrombus in a main artery was present in only one.Considerable function returned spontaneously to the affected kidney in six patients as judged by intravenous pyelography or renography. In two patients the sole functioning kidney was affected, leading to acute oliguric renal failure, but renal function recovered in each case. The routine use of anticoagulants in persistent atrial fibrillation is justified by such cases.

Acute Kidney Injury↗

[Influence of agents of infusion-transfusion therapy on the status of kidney function in hemorrhagic shock].

The influence of autologous blood, rheopolyglucinum with mannitol and of two combined blood corrigents on tubular secretion (with respect to 131I-hippuran excretion) and glomerular filtration (with the use of 169Yb-DTPA) was studied in experiments on white mice with "irreversible" hemorrhagic shock. It was established that autoblood transfusion led to an insignificant recovery of tubular secretion and glomerular filtration in shock. Rheopolyglucinum with mannitol improved, to some extent, the kidney function, while the combined blood corrigents including rheopolyglucinum, mannitol, crystalloids and sodium succinate contributed to more complete recovery of the kidney function. The highest effect was recorded when the blood corrigent was supplemented by a compound resuming the electron transport along the mitochondrial respiratory chain. The use of the autoblood with combined blood corrigents (1:4) in severe hemorrhagic shock led to the same degree of recovery of tubular secretion and glomerular filtration as combined blood corrigents alone.

Animals↗

[Effect of gentamycin on the kidney functional state in experimental pyelonephritis].

The experiments with rats treated with gentamicin showed that nitrogen excretion function of the kidneys did not significantly change in the animals 3 months after induction of pyelonephritis, while in the animals not treated with the antibiotic there was a significant increase in excretion of alkaline phosphatase with urine. The nitrogen excretion function of the kidneys was not affected by gentamicin, except an increase in the urea blood level. Gentamicin promoted a significant rise in excretion of enzymes with urine, especially that of alkaline phosphatase. Treatment of healthy animals with gentamicin resulted in the increased excretion of alkaline phosphatase with urine and increased urea blood levels which was evident of the nephrotoxic effect of the aminoglycoside antibiotic. When such animals were treated with furosemide, the renal excretion of the enzyme and the blood creatinine urea levels decreased. Therefore, furosemide lowered nephropathy induced by gentamicin. The increase in the activity of the urine enzymes may be due to inflammatory changes in the kidney parenchymal on the one hand and the pephrotoxic effect of the drugs on the other hand. The urine enzymes may be used as important diagnostic tests in cases with kidney affections and indicators of safe treatment with nephrotoxic antibiotics.

Animals↗

[Information content of endogenous creatinine parameters for kidney function diagnosis in glomerulonephropathies].

The functional-diagnostic findings, namely serum creatinine level, 24-h creatinine clearance, 1-h (morning) creatinine clearance and inulin clearance, of 58 glomerulo-nephropathy patients were evaluated using regression and correlation analysis. For clinical nephrology it is recommended not to measure 24-h creatinine clearance. For the purpose of diagnosing kidney function the information content of the serum creatinine level is sufficient if the hyperbolic relation to the GFR is taken into account. For clinical-scientific nephrology standardized short-term creatinine estimation in combination with direct or indirect GFR measurement (and other parameters of kidney function) is advisable.

Creatinine↗

[Kidney functional dynamics in eliminating vasorenal hypertension by a kidney autograft].

In acute and chronic experiments on 45 dogs the authors obtained vasorenal hypertension, the elimination of which was fulfilled by means of autotransplantation of the kidney without transection of the ureter. The dynamical study of renal function was carried out through an analysis of arterial blood pressure, erythropoietic activity, blood serum, reticulocytic count, creatinine, residual nitrogen, diuresis, radioisotopic investigation, chromocystoscopy at open bladder, excretory urography, aortograhy, phlebography and morphometric studies of the renal glomeruli.

Animals↗

Co-administration of furosemide augments tacrolimus-induced impairment in kidney function in rats.

Sodium-depletion in rats reproduces functional and morphological tacrolimus nephrotoxicity observed in man. Potent diuretics induce sodium-depletion. Our objective was to determine the effect of a loop diuretic furosemide on tacrolimus-mediated functional and pathological impairment of the kidney in rats. Sprague-Dawley rats were divided into four groups; group 1, rats received vehicle (saline) only; group 2, rats were treated with tacrolimus (1 mg/kg body weight) and furosemide (5 mg/kg body weight); group 3, rats were treated with tacrolimus alone; and group 4, rats were treated with furosemide (5 mg/kg body weight) alone. On day 28, tail blood pressure was measured and the rats were placed in metabolic cages for urine collection. After 24 hr the rats were sacrificed. Tacrolimus alone tended to cause growth retardation, hypotension, hypomagnesemia and a rise in blood urea nitrogen. Furosemide co-administration enhanced the effects of tacrolimus on hypotension, hypomagnesemia and a rise in blood urea nitrogen. The renal histology characterized by cytoplasmic vacuolization of the proximal tubules was not different between the rats treated with both tacrolimus and furosemide and the rats treated with tacrolimus alone. A strong immunostaining for FKBP-12, a tacrolimus-binding protein, was observed in the medulla of the kidneys of rats treated with tacrolimus either with or without furosemide. These results indicate that furosemide further augments tacrolimus induced impairment in kidney function, and that furosemide should be used with discretion in patients on tacrolimus therapy.

Animals↗

[Parametric representation of kidney function using 99mTc-mercaptoacetyltriglycine (MAG3)].

99mTc-mercaptoacetyltriglycine (MAG3) has recently been introduced for imaging kidney function. Due to the much lower radiation dose per MBq, the total administered activity can be much higher than in the case of 131I-ortho-iodo-hippurate (OIH). The improved counting statistics make this tracer useful for parametric imaging of the kidneys. To investigate this potential of MAG3, its kinetics was compared with that of the reference tracer OIH in 38 patients. Parameters of extrarenal tracer kinetics such as the distribution volumes, the whole-body elimination times and the clearance rates showed a good correlation; however, the clearance rate of MAG3 was always lower than that of OIH. The intrarenal kinetics was investigated using the transfer function which was calculated by deconvolution analysis of the renographic curves. Parameters of the transfer function such as the amplitude, extraction fraction and mean transport time demonstrated a high correlation between the two tracers. Since MAG3 seems to be suitable for parametric imaging of kidney function, parametric images of perfusion, uptake, extraction and transport times were calculated by deconvolution analysis of the MAG3 pixel-renograms in various renal disorders. The parameters were distributed homogeneously throughout the parenchyma of normal kidneys. In a kidney with a hemodynamically significant renal artery stenosis the perfusion parameter was decreased and the time parameter was prolonged. Further examples of a renal graft acute tubular necrosis, an obstructive uropathy, an obstructive nephropathy and of a horse-shoe kidney demonstrate that the parametric images are useful for quantitative investigation of regional renal function.

Humans↗

Noninvasive estimation of kidney function by x-ray fluorescence analysis. Elimination rate and clearance of contrast media injected for urography in man.

A noninvasive method for the estimation of kidney function is described. The use of radioactive tracers and the sampling of plasma and urine are omitted. The method has been used in patients referred for urography and who had therefore been injected with routine amounts of iodine-containing urographic contrast medium. After urography, the elimination rates of urographic contrast medium from both serum and finger tissue were determined and compared during a 2-hour period that began two hours after injection of contrast medium. The elimination of iodine in finger tissue was measured noninvasively using x-ray fluorescence analysis. A strong degree of correlation was found between the elimination rates from serum and finger tissue and between the total clearances calculated from the serum and finger measurements. Thus, after urography estimation of kidney function may be obtained as a fringe benefit by x-ray fluorescence measurements of the elimination rate of an iodine-containing contrast medium from tissue or from serum.

Adolescent↗

The determination of relative kidney function in obstructive uropathy with 99Tcm-DMSA.

In this investigation differential kidney function studies were carried out for eight patients with obstructive uropathy and seven patients who did not suffer from obstruction. The aim of this investigation was to determine whether possible retention of 99Tcm-DMSA in the dilated system would lead to overestimation of the functional mass of an obstructed kidney. The clinical examination took place 4 and 24 h after i.v. injection of the 99Tcm-DMSA. From our results we conclude that this is not a major problem. It appeared that the 4 h values are as reliable as the 24 h values in the clinical situation.

Humans↗

[Concentration of C-peptide in correlation to kidney function (author's transl)].

Recently, the radioimmunological determination of C-peptide came into interest because of the jugdement of the remaining function of the islet apparatus in insulin-dependent diabetics. As the degradation of C-peptide preferably takes place in the kidney we performed an intravenous glucose load in 32 patients with kidney diseases. The following results were obtained: 1. In patients with a healthy carbohydrate metabolism a clear correlation exists between the concentration of creatinine on the one hand, the creatinine-clearance and the fasting C-peptide concentration respectively the measured amount of C-peptide on the other hand. 2. The more advanced the renal insufficiency the better is the correlation between the parameter of the kidney function and the C-peptide concentration. 3. In diabetic patients there shows to be no clear correlation between the C-peptide levels and the kidney function. --In insulin-dependent diabetics the amount of C-peptide is only of diagnostic use if the renal function is well known.

Adult↗

Selective reduction of donor-specific cytotoxic T lymphocyte precursors in patients with a well-functioning kidney allograft.

We have recently developed a sensitive limiting dilution (LD) culture system to measure human alloreactive cytotoxic T lymphocyte precursors (CTL-p) in a given lymphoid cell population. We have now used this system to determine frequencies of donor HLA antigen-inducible CTL-p in the peripheral blood of human allograft recipients at various stages after transplantation. All patients (1 pancreas recipient and 9 kidney recipients) were on continuous cyclosporine treatment throughout the study. We report that, in patients with a well-functioning kidney graft (6/9), the number of donor-reactive CTL-p among peripheral blood lymphocytes decreased within 3-8 months after transplantation--in some cases (2/6) more than 10-fold. In contrast, frequencies of CTL-p with specificity for third-part HLA antigens remained largely unaltered in these patients. Furthermore, no decrease of donor-reactive CTL-p frequencies was seen in 3 of 4 patients showing clinical symptoms of graft rejection. These results indicate that functional clonal deletion of antigraft-reactive CTL-p may contribute to the state of graft tolerance in certain patients with a well-functioning kidney allograft.

Cells, Cultured↗

Finerenone and Cardiovascular Outcomes According to Baseline Kidney Function in Patients With Heart Failure: The FINEARTS-HF Trial.

BACKGROUND: Finerenone is known to reduce the risk of worsening heart failure (HF) events and cardiovascular (CV) death in patients with HF with mildly reduced or preserved ejection fraction. OBJECTIVES: The authors explored whether the benefit of finerenone among patients with HF with mildly reduced or preserved ejection fraction differs according to baseline measures of kidney function. METHODS: FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure) was a global, randomized clinical trial of finerenone vs placebo among patients with HF with mildly reduced or preserved ejection fraction. Finerenone was titrated to 20 mg/d if the estimated glomerular filtration rate (eGFR) was &#x2264;60 mL/min/1.73 m2 or 40 mg/d if eGFR was >60 mL/min/1.73 m2. The authors used a semiparametric proportional rates method, stratified by left ventricular ejection fraction (<60%; &#x2265;60%) and region, to assess for differential treatment effects on the composite of total HF events and CV death according to the baseline eGFR (continuous and categories [&#x2265;60 mL/min/1.73 m2, 45 to <60 mL/min/1.73 m2, <45 mL/min/1.73 m2] and urine albumin-creatinine ratio (UACR) (<30 mg/g, 30 to <300 mg/g, &#x2265;300 mg/g). RESULTS: The effect of finerenone to reduce the primary endpoint of total HF events and CV death did not significantly differ according to baseline eGFR (Pinteraction = 0.14 and 0.07 for continuous and categorical eGFR, respectively) with rate ratio 0.72 (95% CI: 0.59-0.88) for eGFR &#x2265;60 mL/min/1.73 m2, 0.83 (95% CI: 0.65-1.06) for eGFR 45 to <60 mL/min/1.73 m2, and 1.02 (95% CI: 0.83-1.26) for eGFR <45 mL/min/1.73 m2. The corresponding absolute event rates were 9.2 vs 12.5, 16.5 vs 19.9, and 28.0 vs 28.0 per 100 patient-years for finerenone vs placebo, respectively. Similar results were noted for total worsening HF events. Finerenone lowered the risk of the composite CV outcome similarly across baseline categories of UACR (Pinteraction = 0.48). CONCLUSIONS: In the FINEARTS-HF trial (where the target dose of finerenone was determined by baseline kidney function), the effect of finerenone to reduce the composite of cardiovascular death and total HF events did not significantly differ across a range of baseline eGFR and UACR.

Humans↗