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Biomedical subjects

K A Nath

Publications and source records attributed to K A Nath.

At least 73 records · Page 4Linked to original sources
PubMed1991

Increased ammoniagenesis as a determinant of progressive renal injury.

Loss of renal mass evokes increased ammoniagenesis in surviving nephrons, which in turn enables net acid excretion by the kidney. However, this compensatory increase in ammonia production in surviving nephrons triggers the alternative complement pathway, thereby instigating progressive tubulointerstitial injury. Ammonia has recently been identified as a stimulus to renal growth. Enhanced renal growth may serve as a forerunner for renal injury. The growth-promoting properties of ammonia may provide another mechanism through which augmented ammoniagenesis may underlie the enhancement of renal growth and injury observed in such models as the remnant kidney, hypokalemic nephropathy, high protein feeding, experimental diabetes nephropathy, and dietary deficiency of antioxidants.

Ammonia↗
PubMed1991

Hydrogen peroxide-induced renal injury. A protective role for pyruvate in vitro and in vivo.

Hydrogen peroxide (H2O2) contributes to renal cellular injury. alpha-Keto acids nonenzymatically reduce H2O2 to water while undergoing decarboxylation at the 1-carbon (1-C) position. We examined, in vitro and in vivo, the protective role of sodium pyruvate in H2O2-induced renal injury. Pyruvate effectively scavenged H2O2 in vitro, and suppressed H2O2-induced renal lipid peroxidation. Injury to LLC-PK1 cells induced by hydrogen peroxide was attenuated by pyruvate to an extent comparable to that seen with catalase. Studies utilizing [1-14C]pyruvate further demonstrated 1-C decarboxylation concurrent with cytoprotection by pyruvate from H2O2-induced injury. Pyruvate was also protective in vivo. Infusion of pyruvate before and during the intrarenal infusion of H2O2 attenuated H2O2-induced proteinuria. Systemic administration of pyruvate was also protective in the glycerol model of acute renal failure, a model also characterized by increased generation of H2O2. These findings indicate that pyruvate, a ubiquitous alpha-keto acid, scavenges H2O2 and protects renal tissue in vitro and in vivo from H2O2-mediated injury. These data suggest a potential therapeutic role for pyruvate in diseases in which increased generation of H2O2 is incriminated in renal damage.

Animals↗
PubMed1990

Dietary deficiency of antioxidants exacerbates ischemic injury in the rat kidney.

We examined the effects of dietary deficiency of vitamin E and selenium on the ischemia-reperfusion model of renal injury in the rat. Deficient diets imposed for six weeks on three-week-old weanling rats led to no significant differences in body weights, serum creatinine, GFR, RBF, TmPAH or urinary total protein excretory rates prior to ischemia. Twenty-four hours after one hour of ischemia, animals on the deficient diet demonstrated more markedly impaired GFR, RBF, TmPAH and urine to plasma creatinine concentrations and an increased renal failure index. Tubular damage was more severe injury in the deficient animals. Lipid peroxidation, 15 minutes after the release of the ischemic clamp, was increased in the deficient animals. We confirmed the effects of our dietary manipulation in impairing the oxidant scavenging system in the deficient animals since glutathione peroxidase activity was reduced to less than 5% in the basal state, and this striking reduction persisted following ischemia. Plasma vitamin E concentrations were also markedly depressed in the deficient diets. This dietary deficiency also worsened the course of acute renal injury and was accompanied by 50% mortality compared to 0% mortality in the control animals. Thus, dietary deficiency of vitamin E and selenium led to greater structural and functional renal impairment and increased lipid peroxidation following ischemia. These data provide support for the role of reactive oxygen species in mediating ischemia-reperfusion injury.

Animals↗
PubMed1990

Oxygen consumption and oxidant stress in surviving nephrons.

We investigated the effects of reduction of renal mass on rates of oxygen consumption, sodium transport, and indexes of oxidant stress in surviving nephrons. Rates of oxygen consumption in surviving nephrons were elevated by more than twofold compared with nephrons in intact kidneys in rats on standard protein intakes. Absolute rates of sodium reabsorption (TNa) in the surviving nephrons were increased with a lower ratio of TNa to oxygen consumption. To determine oxidant stress, we measured malondialdehyde (MDA) in the kidney and urine and the glutathione redox ratio in kidney tissue. MDA per nephron was increased in the subtotally nephrectomized model and was accompanied by increased absolute and fractional urinary excretion of MDA but not by an increase in kidney MDA per milligram protein. The glutathione redox ratios were similar. Since increased dietary protein intake worsens renal injury, we studied the effects of dietary protein manipulation (30 vs. 6%) on oxygen consumption, MDA levels, and the glutathione redox ratio. The kidneys of subtotally nephrectomized animals maintained on 30% protein diets exhibited increased rates of oxygen consumption. Increased dietary protein intake led to increased MDA per nephron, increased urinary excretion of MDA, and increased MDA per milligram protein in subtotally nephrectomized animals, and markedly increased the glutathione redox ratio. We conclude that, despite increased oxygen consumption, surviving nephrons compared with intact nephrons in rats on standard protein intake demonstrate no evidence of oxidant stress. Increased urinary clearance of MDA may provide a mechanism that prevents the buildup of lipid peroxidation. Subjecting the remnant nephron to increased protein increases oxygen consumption and imposes oxidant stress.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Induction of renal growth and injury in the intact rat kidney by dietary deficiency of antioxidants.

We report induction of renal growth and injury in the intact rat kidney using a diet deficient in vitamin E and selenium. This diet was imposed in 3-wk-old male weanling rats, and after 9 wk, enhancement of growth, characterized by increased wet weight, dry weight, protein content, and DNA content appeared. Morphometric analyses revealed increased kidney volume, tubular epithelial volume, and mean glomerular volume. There were no differences in nephron number. The animals on the deficient diet displayed increased urinary protein excretion at 9 wk. Renal injury was also characterized by an interstitial cellular infiltrate and diminutions in glomerular filtration rate. Enhanced growth and injury were antedated by increased renal ammoniagenesis. The deficient diet did not induce metabolic acidosis, potassium depletion, glucose intolerance, or elevated plasma amino acid concentration. Enhancement of renal growth and ammoniagenesis by the deficient diet was not suppressible by chronic alkali therapy. Stimulation of renal growth could not be ascribed to increased intrarenal iron, induction of ornithine decarboxylase, or alterations in glomerular hemodynamics. Stimulation of renal ammoniagenesis by dietary deficiency of antioxidants is a novel finding, as is induction of growth and injury. We suggest that increased renal ammoniagenesis contributes to induction of renal growth and injury.

Ammonia↗
PubMed1990

Role of ammonia in tubulointerstitial injury.

Accelerated rates of ammonia production by the renal proximal tubule constitute an important adaptation to chronic renal injury. Although serving to maintain net acid excretion, this augmented production of ammonia per nephron results in increased renal cortical levels of ammonia and contributes to progressive renal injury. Ammonia fosters progressive injury via its ability to modify the third component of complement and initiate alternative complement pathway activity. This interaction of ammonia with complement incites inflammation in models of nonimmune chronic renal disease in the rat and may contribute to tissue injury in pyelonephritis involving urease-positive organisms. The long recognized in vivo association between increased renal ammoniagenesis, renal growth, and progressive injury in several models of renal disease has been advanced by the recent demonstration of ammonia as a direct stimulus to growth of renal tubular epithelium in culture. Additionally, evidence from studies of acute ischemic renal injury suggests a contributory role for ammonia in mediating tissue injury in this model. Elevated renal levels of ammonia, therefore, contribute to tubulointerstitial injury primarily through the proinflammatory and growth-promoting properties of ammonia.

Acute Disease↗
PubMed1988

De novo focal glomerulosclerosis after kidney transplantation.

A transplanted kidney in a patient developed focal and segmental glomerulosclerosis, associated with severe systemic hypertension, proteinuria, progressive azotemia, and allograft hypertrophy. A pediatric kidney with two main arteries was used, and occlusion of the artery supplying the upper pole resulted in infarction of this portion of the allograft. Because other known factors predisposing to focal sclerosis were absent, it is postulated that renal hemodynamic changes associated with reduction in functioning renal mass, attended by striking stimuli for renal hypertrophy, resulted in progressive damage. The implications of these concepts are discussed in relation to the progression of renal diseases.

Adult↗
PubMed1988

Infection-related chronic interstitial nephropathy.

Kidney infection, when uncomplicated by anatomic abnormalities such as reflux or obstructing lesions, does not appear to lead to renal damage or hypertension. In children in whom predisposing anatomic causes (reflux) are particularly prominent or in adults who have or develop these abnormalities, progressive renal injury with hypertension can occur with infection. Infection appears to enhance the damaging effects of the underlying anatomic abnormalities. The mechanisms of progressive damage include the inflammatory effects of the infection itself, potentially "autoimmune" effects, and the inflammatory and infection-promoting effects of bacterial products, especially ammonia. After initial renal damage, the hemodynamic effects of systemic hypertension and of intrarenal hyperperfusion of residual nephrons may further promote progressive injury.

Chronic Disease↗
PubMed1987

Regulatory role of prostanoids in glomerular microcirculation of remnant nephrons.

The glomerular microcirculation of the remnant nephron is characterized by reduced afferent (RA) and efferent (RE) arteriolar resistances and markedly increased single nephron glomerular plasma flow and filtration rates. We investigated the role of prostanoid production in mediating these adaptive alterations in glomerular hemodynamics after the reduction of renal mass. Acute administration of indomethacin, 5 mg/kg iv in anesthetized euvolemic, Sprague-Dawley rats with intact kidneys led to no significant alteration in renal hemodynamics, whereas in similarly prepared subtotally nephrectomized rats such inhibition significantly reduced remnant kidney glomerular filtration rate from 0.57 +/- 0.07 to 0.45 +/- 0.05 ml/min and single nephron glomerular filtration rate (SNGFR) from 93 +/- 4 to 72 +/- 5 nl/min. This reduction in SNGFR was due to diminutions in the glomerular ultrafiltration coefficient (Kf) from basal values of 0.061 +/- 0.004 to 0.050 +/- 0.004 nl X s-1 X mmHg-1 and in initial glomerular capillary plasma flow rate (QA) from 416 +/- 42 to 321 +/- 42 nl/min. The decrease in QA was a consequence of proportional increases in RA and RE. In other groups of animals we demonstrated that urinary excretions of both vasodilatory as well as vasoconstrictor prostanoids per surviving nephron increase several fold in subtotally nephrectomized rats compared with rats with intact kidneys and that administration of indomethacin, 5 mg/kg iv, reduced urinary excretions of both vasodilatory prostaglandins, prostaglandin E and 6-keto-prostaglandin F1 alpha, as well as vasoconstrictor prostanoid, thromboxane B2, to the same degrees in both subtotally nephrectomized rats and rats with intact kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Dietary protein restriction in established renal injury in the rat. Selective role of glomerular capillary pressure in progressive glomerular dysfunction.

Dietary protein restriction imposed before renal injury is established in the remnant kidney model in the rat reduces glomerular hypertension and hyperperfusion and renal injury. We demonstrate that dietary protein restriction (6% vs. 20%) imposed on a background of established renal injury in the remnant model leads to a greater preservation of renal function as measured by glomerular filtration rate and fractional clearances of albumin and IgG, despite the persistence of systemic hypertension. In similarly prepared rats, dietary protein restriction (6% vs. 20%) led to a lower glomerular capillary hydraulic pressure, a higher ultrafiltration coefficient, and similar single nephron filtration rates. In addition, less impairment of glomerular permselectivity was demonstrable after protein restriction. Our data demonstrate that the preservation of renal function with dietary protein restriction after established glomerular injury follows upon reduction of glomerular capillary hydraulic pressure, despite constancy of single nephron filtration rate and plasma flow and persistence of arterial hypertension.

Animals↗
PubMed1985

Pathophysiology of chronic tubulo-interstitial disease in rats. Interactions of dietary acid load, ammonia, and complement component C3.

The human end-stage kidney and its experimental analogue, the remnant kidney in the rat, exhibit widespread tubulo-interstitial disease. We investigated whether the pathogenesis of such tubulo-interstitial injury is dependent upon adaptive changes in tubular function and, in particular, in ammonia production when renal mass is reduced. Dietary acid load was reduced in 1 3/4-nephrectomized rats by dietary supplementation with sodium bicarbonate (NaHCO3), while control rats, paired for serum creatinine after 1 3/4 nephrectomy, were supplemented with equimolar sodium chloride. After 4-6 wk, NaHCO3-supplemented rats demonstrated less impairment of tubular function as measured by urinary excretory rates for total protein and low molecular weight protein and higher transport maximum for para-aminohippurate per unit glomerular filtration rate, less histologic evidence of tubulo-interstitial damage, less deposition of complement components C3 and C5b-9, and a lower renal vein total ammonia concentration. Such differences in tubular function could not be accounted for simply on the basis of systemic alkalinization, and differences in tubular injury could not be ascribed to differences in glomerular function. Because nitrogen nucleophiles such as ammonia react with C3 to form a convertase for the alternative complement pathway, and because increased tissue levels of ammonia are associated with increased tubulo-interstitial injury, we propose that augmented intrarenal levels of ammonia are injurious because of activation of the alternative complement pathway. Chemotactic and cytolytic complement components are thereby generated, leading to tubulo-interstitial inflammation. Thus, alkali supplementation reduces chronic tubulo-interstitial disease in the remnant kidney of the rat, and we propose that this results, at least in part, from reduction in cortical ammonia and its interaction with the alternative complement pathway.

Acid-Base Equilibrium↗