Remnant Nephrons Research Articles

Diuretic strategies in patients with renal failure.

A thorough understanding of the clinical pharmacology of diuretic agents, particularly loop diuretics, is crucial in patients with abnormal (and those with normal) renal function. Renal insufficiency represents a pathophysiological state characterised by diuretic resistance. Diuretic resistance is defined as a diminished pharmacological response, or diminished natriuresis, to a given dose of a diuretic. The phenomenon of diuretic resistance is demonstrated by a shift in the dose-response curve relating urinary diuretic excretion rates (dose) with sodium excretion (response). Pharmacokinetic factors underlie the diuretic resistance observed in patients with renal failure. Diminished renal blood flow and sodium filtration, accumulation of organic acids that inhibit tubular secretion of the diuretic, and inadequate cumulative sodium excretion to meet patients' needs contribute to the diuretic-resistant state. In contrast, the pharmacological response of remnant (i.e. remaining) nephrons to diuretic agents remains intact. The time course of delivery of diuretics to their intraluminal site of action is an independent determinant of natriuretic response. An administration regimen that continuously maintains effective rates of excretion of diuretics into the urine would be expected to cause a greater overall natriuretic effect than the same amount of diuretic administered in intermittent doses. Thus, diuretic administration strategies that take account of the altered pharmacological responses in patients with renal failure are necessary to provide effective and safe treatment. Additionally, such strategies warrant revision by the prescribing physician as renal function changes over time.

Glomerular permeselectivity to macromolecules in reflux nephropathy: microalbuminuria during acute hyperfiltration due to aminoacid infusion

Reflux nephropathy is an important cause of chronic renal failure in children. After the parenchymal scar, the progression is thought to be mediated by glomerular hypertension in remnant nephrons resulting in modifications in permselectivity to macromolecules. Proteinuria correlates with a progressive course. The glomerular permselectivity to macromolecules in basal conditions and after acute hemodynamic stress was investigated in 28 children whose bilateral vesico-ureteric reflux (VUR) had been previously surgically corrected (meanly 5.6 years before) and with normal creatinine clearance (CrCl). Bilateral renal scarring (0 to 8 scale for both kidneys) was 4.3 +/- 1.6. Albuminuria (UAE) was evaluated in basal conditions and under acute hyperfiltration induced by amino acid (Aa) infusion. After isotonic saline at 310 ml/hour/1.73 m2, 6 mg/kg/min of Aa were infused for 2 hrs. UAE was significantly higher than controls in basal conditions (p < 0.01), and further increased after Aa infusion (p < 0.02). Microalbuminuria was detectable in 53.5% of the children in basal conditions and in 64.3% after Aa. Also urinary beta 2 microglobulin significantly increased at the end of the test (p < 0.001). CrCl significantly increased at the first hour (p < 0.05). Children with severe renal parenchymal scarring had greater UAE (p < 0.01) and beta 2M (p < 0.02) values after provocative test than those with mild renal damage. In 8 children GFR and ERPF were measured by means of inulin and p-hippurate clearance respectively. The variations in UAE during Aa infusion were significantly correlated with GFR dynamics (p < 0.05) while they were not influenced by ERPF modifications.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal pathology in patients with reflux nephropathy. The turning point in irreversible renal disease.

In reflux nephropathy both interstitial and glomerular damage advances with an increase in the scarring grade even in macroscopically normal regions. Based on various histologic findings, sclerosis and the enlargement of glomeruli rapidly accelerate between stages c-a and c-b, as shown by the combined Smellie's scarring grade of the bilateral kidneys. These two steep histologic changes in stage c-b are followed by a remarkable reduction in renal function (DTPA-GFR) and an increase in the amount of urinary protein. These clinicopathological changes thus suggest that hemodynamic changes or overloading in the functional remnant nephrons possibly start in stage c-a. It is also suggested that glomerular enlargement is an index of progressive disease in reflux nephropathy. Among our specimens, most cases of glomerular sclerosis were global while focal segmental glomerulosclerosis was very rare. These findings thus suggest that the global sclerosis observed in our specimens is clearly different from focal segmental glomerulosclerosis.

The Antiproteinuric Effect of Antihypertensive Agents in Diabetic Nephropathy-Reply

In Reply.— It is clear that converting enzyme inhibitors reduce urinary albumin excretion through alterations in both renal hemodynamics and glomerular permselectivity. 1-3 The mechanism, however, by which calcium antagonists reduce urinary albumin excretion is unclear. Gansevoort et al make a persuasive argument that the antiproteinuric effects of calcium antagonists are related to their antihypertensive rather than their renal effects. However, recent studies clearly document that certain classes of calcium antagonists have renal effects that help explain their antiproteinuric effects. At least three major changes occur in the kidney following a prolonged history of diabetes. First, there is expansion of the mesangial matrix. Second, there is altered glomerular permeability to albumin and other molecules secondary to alterations in charge and size selectivity of the glomerular capillary membrane. Last, there is a persistent elevation in intraglomerular capillary pressure that is sustained in the intact remnant nephrons as renal disease progresses. Clearly,

The progression of renal damage in reflux nephropathy--clinical analysis of proteinuria in children with vesicoureteral reflux

To clarify the mechanism for reflux nephropathy to progress to irreversible or marginal renal damages, this study was conducted. We studied 57 cases of VUR in children followed-up more than 3 years after anti-reflux operation and investigated the correlation between changes of urinary protein excretion and clinical data. In general, proteinuria is the most important feature heralding a poor outcome in patients with reflux nephropathy. 9 cases (15.8%) in our series were positive of proteinuria postoperatively. In this positive group, scarring grade had been higher and renal size had been smaller significantly before operation than in other group. From these facts, it would appear that prognosis of refluxing kidney was determined by volume of remnant kidney, and glomerular hyperfiltration of remnant nephron would affect the progression of reflux nephropathy. According to the relationship between changes of urinary protein excretion and scarring grade or renal size, poor prognosis (proteinuria will worsen) would be more than 5 of scarring grade score (cumulation of bilateral scarring grades, Smellie's a = 1, b = 2, c = 3, d = 4) and less than -4S.D. in cumulative renal ratio preoperatively. Then border to progression in reflux nephropathy was between 2 and 4 of scarring grade score, and between -2S.D, and -4S.D. in cumulative renal ratio. In this marginal progression urinary protein excretion and GFR were found to be 100-300 mg/day and 60-75 ml/min, respectively.

Dietary Protein Intake and the Glomerular Adaptations to Partial Nephrectomy in Dogs

After partial nephrectomy (Nx) in rats, a temporal pattern of progressively declining renal function often develops. This pattern has been attributed to the development of glomerular hyperfiltration, hypertension and hypertrophy in remnant nephrons. In rats, dietary protein restriction prevents these adaptive changes in remnant nephrons, thereby preserving renal structure and function. However, long-term studies of the temporal pattern of renal function have failed to identify a consistently progressive deterioration of renal function in partially Nx dogs, and a protective effect of protein restriction has not been apparent in this species. To address these issues in dogs, we evaluated the single nephron adaptations to partial Nx in dogs and the effect of dietary protein restriction on these adaptations. Results of our micropuncture studies in partially Nx dogs indicate that remnant nephrons of dogs exhibit glomerular hyperfiltration (single nephron glomerular filtration rate of 144 +/- 8 vs. 71 +/- 4 nL/min in controls, P less than 0.05), hypertension (glomerular capillary pressure of 75.1 +/- 1.6 vs. 63.2 +/- 1.9 mmHg in controls) and hypertrophy (glomerular volume of 3.54 +/- 0.24 x 10(6) vs. 2.04 +/- 0.05 x 10(6) microns3 in controls, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Glomerular renin synthesis and storage in the remnant kidney in the rat

The intrarenal renin-angiotensin system can exert local control of the nephron and its circulation. In the subtotally nephrectomized model of chronic renal disease in the rat, angiotensin appears to play a prominent role in glomerular function. Glomeruli in this model demonstrate greater staining for intraglomerular renin by immunofluorescence microscopy than do those in control rats. Glomeruli from remnant nephrons contain increased renin content. Also, glomeruli from remnant nephrons contain an increased proportion of the mRNA for renin. Adriamycin-induced nephrosis did not evoke the same degree of renin staining and did not lead to increased glomerular expression of the renin gene, findings that argue against permselective defects and glomerular trapping as the sole cause of the glomerular renin in the remnant kidney model. Thus, renin synthesis and accumulation occur in the remnant glomerulus and this migration may underlie in part the dependence of glomerular function on the renin-angiotensin system in this model.

Reduction of Remnant Nephron Hypermetabolism by Protein Restriction

To study the metabolic mechanisms involved in the protective effect of dietary protein restriction on the progression of chronic renal failure, experiments were performed in Sprague-Dawley rats subjected to five-sixths nephrectomy and pair-fed on isocaloric low (4%) protein (LP) or high (50%) protein (HP) diets. Protein restriction reduced the severity of uremia, with lower blood urea nitrogen (BUN) concentrations (8.9 +/- 1.1 v 30.0 +/- 2.9 mmol/L [25 +/- 3 v 84 +/- 8 mg/dL] both n = 12, P less than 0.01), and resulted in lower mortality at 2 weeks (0% v 33%, P less than 0.05), 4 weeks (16% v 58%, P less than 0.05), and 10 weeks (16 v 83%, P less than 0.01). Isolated perfusion of the remnant kidney at 3 weeks demonstrated reduced O2 consumption (QO2) (0.77 +/- 0.2 v 2.56 +/- 0.5 mumol/min/g, both n = 7, P less than 0.05) in the absence of significant differences in inulin clearance (239 +/- 53 v 341 +/- 39 microL/min/g, NS) and net sodium reabsorption (34 +/- 8 v 49 +/- 6 mumol/min/g, NS) in rats fed the LP diet. A lower renal QO2 in protein-restricted animals was also demonstrated in vivo (4.1 +/- 0.9 v 13.8 +/- 2.7 mumol/min/g, P less than 0.01). In vivo P-31 nuclear magnetic resonance (NMR) studies of remnant kidneys did not demonstrate any difference in the steady-state tissue concentrations of adenosine triphosphate (ATP) or inorganic phosphate between rats fed LP and HP diets. Dietary protein restriction decreases the severity of uremia and diminishes renal QO2 in the remnant kidney model.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for a Pathogenic Linkage Between Glomerular Hypertrophy and Sclerosis

Primary renal disease of immunologic or nonimmunologic mechanisms induces loss of substantial nephron population. It is presumed that the initial loss of functioning nephrons causes alterations of function and metabolism in remnant nephrons, which per se are self-inflictive, leading to further loss of nephrons. The ultimate outcome of this vicious cycle is the end-stage kidney. The potential role of various pathophysiologic mechanisms has been explored. These studies have shown a tight link between glomerular hypertrophy and sclerosis. Analysis of individual glomeruli show a biphasic pattern of these two parameters. Early development of glomerular sclerosis takes place along with the hypertrophy of the glomerulus, and further advancement of sclerosis occurs with shrinkage in glomerular size. Thus, we propose that, after initial nephron loss, the remnant glomeruli are exposed to increased growth-promoting factors, which are self-inflictive in nature due to their capacity to produce excessive amounts of extracellular matrix in the mesangial area. When the excessive matrix obliterates the glomerular capillary lumen, a typical sclerotic lesion appears. This is a vicious and accelerating process, since sclerosis induces further reduction in the nephron population, thereby imposing greater influence of growth-promoting factors even on glomeruli that are initially resistant.

Chronic effects of omega-3 fatty acids (fish oil) in a rat 5/6 renal ablation model.

It has been proposed that fish oil dietary supplementation in the chronic rat 5/6 renal ablation model may be either protective or toxic. These conflicting hypotheses were tested in rats who underwent renal ablation or sham surgery. Twenty rats received sham surgery, and 40 received 5/6 renal ablation. All rats were fed a regular laboratory diet up to 1 week postsurgery. At that time, one half of the renal ablation group was provided with an isocaloric diet supplemented with 24% MaxEPA (fish oil), 1% safflower oil, and antioxidants. The renal ablation rats developed hypertension, albuminuria, gammaglobulinuria, and a decline in glomerular filtration rate, which was less in the fish oil group compared with that in the regular laboratory diet group at 10 and 20 wk postsurgery. The fish oil renal ablation rats had significantly less glomerulosclerosis than did the regular laboratory diet renal ablation animals, and no more glomerular fibrin deposition than did the sham controls. The renal ablation regular laboratory diet rats had a significant dyslipidemia at 20 wk which was prevented in the fish oil renal ablation cohort. The fish oil renal ablation rats also demonstrated a significant decline in renal tissue arachidonic acid incorporation and a concomitant increase in eicosapentaenoic acid and docosahexaenoic acid incorporation. The mortality of the renal ablation group was greater than that of the sham controls but not significantly different for the fish oil or the regular laboratory diet groups. These results support the hypothesis that the fish oil diet containing specific antioxidant, vitamin E, and essential fatty acid supplementation is protective in the rat remnant nephron model and prevents the evolution of glomerulosclerosis with associated renal functional impairment, while preserving glomerular filtration.

Mechanism of the Unique Susceptibility of Deep Cortical Glomeruli of Maturing Kidneys to Severe Focal Glomerular Sclerosis

The alterations in single glomerular hemodynamics, glomerular size, and development of glomerular sclerosis after subtotal nephrectomy were assessed in approximately 32-d-old young and greater than 3-mo-old adult Munich-Wistar rats. In 6 wk, young rats developed more pronounced glomerular sclerosis and more marked elevation in blood urea nitrogen. The deep (versus superficial) cortical region of young rats was characterized by having a greater number of glomeruli with advanced sclerosis. Single nephron glomerular filtration rate of superficial glomeruli of the young increased to a much greater extent than whole kidney glomerular filtration rate, whereas there were comparable post-subtotal nephrectomy increases in whole kidney glomerular filtration rate in these two age groups, indicating that the deep glomeruli were exposed to a lesser hemodynamic load than were the superficial. Since the remnant nephrons of young and adult rats achieved equally high glomerular pressures and comparably large glomerular size shortly after subtotal nephrectomy, the unique susceptibility of young glomeruli to sclerosis is attributed to the intrinsic property of these glomeruli, rather than the abnormal hemodynamics or stimuli promoting hypertrophy and mesangial matrix accumulation imposed upon the glomeruli.

Absence of glomerular injury or nephron loss in a normotensive rat remnant kidney model

Severe reduction in renal mass (greater than 50%) in the rat uniformly results in progressive glomerular injury and loss of remnant nephrons postulated to be due to increases in glomerular function (hyperfiltration) and/or size (hypertrophy). Reduction in renal mass in the rat also leads to the development of systemic and/or glomerular hypertension. To examine the independent contributions of systemic hypertension and glomerular hyperfiltration and/or hypertrophy to progressive glomerular injury, a normotensive rat remnant kidney model was developed in the Wistar-Kyoto (WKY) strain. Of the 34 WKY rats that underwent 5/6 nephrectomy, 25 remained normotensive and without evidence of morphologic glomerular injury and/or nephron loss for up to 14 to 16 weeks, despite glomerular hyperfiltration and hypertrophy comparable to that previously observed in other rat strains. Micropuncture studies at approximately six weeks after reduction in renal mass demonstrated markedly increased SNGFR in remnant nephrons of normotensive rats as compared to controls (66 +/- 7 vs. 25 +/- 4 nl/min, P less than 0.01), but glomerular capillary pressures (PGC) estimated from stop flow pressures were only slightly increased (52.7 +/- 1 vs. 47.3 +/- 1 mm Hg, P less than 0.01). These data indicate that compensatory glomerular hyperfiltration and hypertrophy after 5/6 nephrectomy may not lead to progressive glomerular injury provided hypertension does not develop. These data further suggest that in the absence of systemic hypertension, increases in PGC required for adaptive hyperfiltration, may not be sufficient to initiate progressive glomerular injury and nephron loss.

Glomerular and tubular adaptive responses to acute nephron loss in the rat. Effect of prostaglandin synthesis inhibition.

These studies, using in vivo micropuncture techniques in the Munich-Wistar rat, document the magnitude of changes in glomerular and tubular function and structure 24 h after approximately 75% nephron loss (Nx) and compared these results with those obtained in sham-operated rats. The contribution of either nephron hypertrophy or renal prostaglandin to these adjustments in nephron function was also explored. After acute Nx, single nephron GFR (SNGFR) was increased, on average by approximately 30%, due primarily to glomerular hyperperfusion and hypertension. The approximately 45% reduction in preglomerular and the constancy in postglomerular vascular resistances was entirely responsible for these adaptations. Although increases in fluid reabsorption in proximal convoluted tubules correlated closely with increase in SNGFR, the fractional fluid reabsorption between late proximal and early distal tubular segments was depressed. Nephron hypertrophy could not be substantiated based on either measurements of protein content in renal tissue homogenates or morphometric analysis of proximal convoluted tubules. However, acute Nx was associated with increased urinary excretory rates per functional nephron for 6-keto-PGF1 alpha and TXB2. Prostaglandin synthesis inhibition did not affect function in control nephrons, but this maneuver was associated with normalization of glomerular and tubular function in remnant nephrons. The results suggest that enhanced synthesis of cyclooxygenase-dependent products is one of the earliest responses to Nx, and even before hypertrophy the pathophysiologic effects of prostaglandin may be important contributors to the adaptations in remnant nephron function.

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)

Perinatal Radiation-Induced Renal Damage in the Beagle

The developing perinatal kidney is particularly sensitive to radiation. The pathogenesis of the radiation-induced lesion is related to the destruction of outer cortical developing nephrons and direct radiation injury with secondary hemodynamic alterations in remnant nephrons. In this study, which is part of a life span investigation of the effects of whole-body gamma radiation during prenatal and early postnatal life, dogs were given 0, 0.16, 0.83, or 1.25 Gy irradiation at either 55 days postcoitus or 2 days postpartum and were examined morphometrically and histopathologically at 70 days of age. Although irradiated dogs showed no reduction in the total number of nephrons per kidney, there was a significant increase in the total number and relative percentage of immature, dysplastic glomeruli. In addition, deeper cortical glomeruli of irradiated kidneys exhibited mesangial sclerosis similar to that associated with progressive renal failure in our previous studies. These findings are in accord with those reported at doses of 2.24 to 3.57 Gy and demonstrate that the perinatal kidney is affected by radiation doses much lower than previously demonstrated.

Glomerular hypertrophy aggravates epithelial cell injury in nephrotic rats.

Glomerular function and structure were assessed after reduction of nephron number and restriction of protein intake in rats with adriamycin nephrosis. Rats received an injection of adriamycin and were divided into three groups with similar values for albuminuria after 4 wk. Group 1 rats then served as controls, group 2 rats were subjected to four-fifths renal ablation, and group 3 rats were placed on a low protein diet (8% protein) while group 1 and group 2 rats remained on a standard diet (24% protein). Micropuncture and morphometric studies were performed 10 d later. Estimated single-nephron albuminuria (SNalb) was increased by renal ablation in group 2 and decreased by protein restriction in group 3 (group 1, 20 +/- 2 micrograms/d; group 2, 68 +/- 7 micrograms/d; group 3, 12 +/- 1 microgram/d, P less than 0.05 groups 2 and 3 vs. 1). Increased SNalb was associated with increased glomerular volume in group 2 and reduced SNalb was associated with reduced glomerular volume in group 3. (group 1, 1.44 +/- 0.04 x 10(6) microns 3; group 2, 1.66 +/- 0.08 x 10(6) microns 3; group 3, 1.26 +/- 0.03 x 10(6) microns 3, P less than 0.05 groups 2 and 3 vs. 1). Increased SNalb in group 2 was not associated with an increase in glomerular transcapillary hydraulic pressure. The area of epithelial cell detachment from the peripheral capillary wall was markedly increased in group 2 but not perceptibly altered in group 3 (group 1, 16 +/- 5 x 10(2) microns 2; group 2, 65 +/- 17 x 10(2) microns 2; group 3, 18 +/- 5 x 10(2) microns 2; P less than 0.05 group 2 vs. 1). These studies show that glomerular hypertrophy is associated with increased epithelial cell detachment from the peripheral capillary wall and with increased remnant nephron albuminuria after reduction of nephron number in rats with established nephrosis.

Renal Vasodilatory Response to Intravenous Glycine in the Aging Rat Kidney

Studies were performed in the awake, chronically catheterized male Sprague-Dawley rat to investigate renal hemodynamics in the baseline state and also in response to a large intravenous (IV) amino acid (glycine) load. Studies were performed in young adult rats (age 3 to 4 months), old rats (age 18 months), and senescent rats (age 22 to 24 months). Histologic evaluation of the kidney permitted a correlation between structural and functional changes with aging. Histology showed progressive glomerular damage (sclerosis) with aging. In 18-month-old rats, the glomerular filtration rate (GFR) was normal, which, considering the level of glomerular injury (only 64% normal glomeruli), must indicate heterogeneity of glomerular function, with some hyperfunctioning glomeruli. By 22 to 24 months of age (at which time approximately 50% mortality has occurred in males of this strain), GFR is substantially reduced, as is renal plasma flow rate (RPF). Severe glomerular damage was observed histologically (only 34% normal glomeruli), indicating widespread heterogeneity of glomerular function. Young adult rats displayed a substantial renal vasodilation in response to acute IV glycine infusion, which resulted in approximately 25% increases in GFR and RPF. The renal vascular responsivity to glycine was diminished at 18 months and was completely absent in 22- to 24-month-old rats. This altered renal vasodilatory response to glycine probably reflects both structural changes associated with aging and also the compensatory vasodilation of intact hyperfunctioning remnant nephrons as other nephrons are lost due to aging.

Effects of systemic hypertension, antidiuretic hormone, and prostaglandins on remnant nephrons.

Renal function was evaluated in normal and after 30 days of 5/6 renal mass reduction (CRF) in Munich-Wistar (MW) rats, spontaneously hypertensive rats with superficial glomeruli (EPM), and in Brattleboro rats with congenital diabetes insipidus (DI). Mean arterial pressure was higher in EPM-Control and EPM-CRF rats as compared with MW and DI rats. MW and EPM rats with CRF showed increases of 120% and 196%, respectively, in single nephron glomerular filtration rate as compared with their controls. However, DI rats with CRF did not show any increase in single nephron glomerular filtration rate as compared with the control group. Therefore, the data suggest that the presence of hypertension enhances the adaptive mechanisms on remnant kidney's function. Conversely, in the absence of antidiuretic hormone, adaptive mechanisms of remnant nephrons did not occur. In addition, it was observed that rats with CRF submitted to prostaglandin blockade with indomethacin showed for MW rats a 55% and 20% reduction in ultrafiltration coefficient and in single nephron glomerular filtration rate, respectively. Decreases of 60% and 30% in ultrafiltration coefficient and single nephron glomerular filtration rate, respectively, were observed for EPM rats. In contrast, DI rats did not show any alteration on renal function after indomethacin. It seems, therefore, that prostaglandins play a role in remnant nephron function of MW and EPM rats, but in the absence of antidiuretic hormone, prostaglandins do not affect remnant glomerular hemodynamics.

Attenuation of hypermetabolism in the remnant kidney by dietary phosphate restriction in the rat

In vivo energy metabolism in remnant and normal kidney nephrons and the effect of dietary phosphate restriction on energy metabolism were studied. Tissue concentrations of ATP did not differ between remnant and normal kidneys; however, the tissue concentration of inorganic phosphate (Pi) was higher in remnant kidneys (1.17 +/- 0.10 vs. 0.82 +/- 0.09 mumol/g, P less than 0.05) as assessed by 31P-nuclear magnetic resonance (NMR). Intracellular pH was also higher in remnant kidneys (7.48 +/- 0.04 vs. 7.20 +/- 0.05, P less than 0.01), as was oxygen consumption (QO2) when normalized for rate of net tubular sodium reabsorption (Tna; 0.032 +/- 0.005 vs. 0.018 +/- 0.002 mumol.min-1.g-1, P less than 0.01). Compared with glycine supplemented controls, dietary phosphate restriction induced by the phosphate binder diaminodihydroacetoacetate, a maneuver which independently of protein restriction has been shown to ameliorate the progression of chronic renal failure, resulted in no major change in tissue levels of ATP, intracellular pH, or TNa+ but decreased Pi (0.62 +/- 0.07 vs. 1.40 +/- 0.11 mumol/g, P less than 0.01) and QO2 (4.0 +/- 0.4 vs. 7.7 +/- 1.0 mumol.min-1.g-1, P less than 0.01) in remnant kidneys. For the amount of sodium reabsorption performed, remnant kidneys are hypermetabolic, and this hypermetabolism is attenuated by dietary phosphate restriction. These data suggest that hypermetabolism may be involved in the tubulointerstitial mechanisms operant in the progression of chronic renal failure that occurs in the rat remnant kidney, and that attenuation of this abnormality may be the mechanism by which dietary phosphate restriction ameliorates this process.

Urinary plasminogen activator activity in progressive renal failure.

The purpose of this study was to discover how functional nephrons produce the plasminogen activator as renal function progresses to renal failure. Urine Plasminogen activator (U-PA) activity was measured by the fibrin plate method in 73 patients with various degrees of renal function deterioration from various underlying diseases and in one healthy individual in order to evaluate the plasminogen activator activity of remanant nephrons. The plasminogen activator activity of the 12 consecutive urine samples from the healthy individual showed that is varied according to the time of day, but there was no circadian rhythm. The urine plasminogen activator activity correlated with the osmolality (r = 0.51, P<0.001) and creatinine (r = 0.56, P<0.001) of the urine, suggesting that it is concentrated at distal nephrons. The fractional sodium excretion rate (FeNa) increased abruptly when GFR decreased below 25 L/day. This pattern was very similar with the relation between total U-PA activity/GFR and GFR. The correlation between total U-PA activity and FeNa was not significant, but there was a significant direct correlation between total U-PA activity/GFR and FeNa (r = 0.775, P<0.0001). There was no relationship between the 24-hour urine protein and total U-PA activity or total U-PA activity/GFR. The total urine plaminogen activator activity correlated with the 24-hour urine Na (r = 0.3, P<0.0001) and volume (r = 0.434, P<0.0001) but not with total U-PA activity/GFR. The total U-PA activity correlated with GFR (r = 0.41, P<0.0001) but the total U-PA activity/GFR correlated inversely with the GFR (r = 0.552, P<0.0001). Our result suggests that as the renal mass decreases, the total urine plasminogen activator activity decline, but remnant nephrons produce larger amounts of plasminogen activator activity than do normal nephrons.