The impact of malnutrition on kidney function.

Malnutrition is the most common cause of mortality in the world. It affects underdeveloped as well as industrialized societies, in the latter demonstrating a prevalence in hospitalized patients of between 30 and 50%. Although the prevalence has decreased in recent studies, the problem is still significant among a selected group of patients. The clinical manifestations of malnutrition may be evident on physical examination but alterations in renal function may not show up at the initial exam. Clinical and experimental models of protein-calorie malnutrition have confirmed significant alterations in renal hemodynamics, renal concentration capacity, and renal acid excretion. Children and adults with malnutrition have been shown to have a decreased glomerular filtration rate and renal plasma flow (RPF), as well as a lowered capacity to concentrate the urine and excrete an acid load. Moreover, clinical and experimental models of protein-calorie malnutrition have unravelled the roles of the renin-angiotensin system, renal prostaglandins, and urea production in the renal function changes associated with malnutrition. We have reviewed the most pertinent and recent studies from our and other laboratories which have improved our understanding of renal functional alterations in malnutrition.

Modulation of ANG II receptor and its mRNA in normal rat by low-protein feeding.

Low-protein feeding results in reduced plasma renin activity (PRA), low prostaglandin production, high intrarenal vascular resistance, and reduced renal plasma flow (RPF) and glomerular filtration rate (GFR) in normal, intact rats. The hemodynamic changes are reversed by converting enzyme inhibitors. In this study, normal rats were fed normal protein (NP) or low protein (LP). PRA was 10.1 +/- 1.3 for NP vs. 5.1 +/- 1.7 ng.ml-1 x h-1 for LP (P < 0.001). Mean arterial pressure fell in both LP and NP during treatment with losartan (DuP-753, a specific angiotensin AT1-receptor inhibitor), but GFR and RPF in LP + losartan became indistinguishable from values obtained in NP and NP + losartan rats. Plasma Na and K and urine excretions of these two electrolytes were unchanged. Angiotensin II (ANG II) binding to isolated glomeruli (n = 19) revealed a dissociation constant of 1.11 +/- 0.22 vs. 1.22 +/- 0.20 nM (not significant) and maximal binding of 763 +/- 89 vs. 432 +/- 75 fmol/mg protein (P < 0.001), indicating an increased number of receptors without changes in affinity in LP. An increased number of receptors in LP compared with NP was also observed by quantitative autoradiography. These results reflect a predominant intrarenal alteration in the response to ANG II in LP. Northern blot and in situ hybridization analysis of the AT1 receptor mRNA showed enhanced gene expression in cortex (glomeruli) and medulla in LP. Dietary protein is an important modulator of the intrarenal actions of ANG II. We show for the first time that protein in the diet modulates the expression of the AT1 receptor gene and that ANG II mediates the hemodynamic changes of LP feeding through the AT1 receptor.

Angiotensin II and catecholamines interaction in short-term low protein feeding.

Renal and systemic hemodynamic responses to an alpha-adrenergic agonist (norepinephrine, NE) and an alpha-adrenergic antagonist (phentolamine, PHEN) were studied in weanling rats pair-fed isocaloric diets containing either normal (NP, 23%) or low (LP, 6%) protein. Mean arterial pressure (MAP) rose less with NE and fell more with PHEN in LP than in NP. Plasma NE and epinephrine (E; 46 +/- 5 and 51 +/- 4 ng/ml) were higher in LP than in NP (26 +/- 3 and 39 +/- 3 ng/ml). These could not be attributed to changes in red cell mass nor the volumes of plasma, extracellular, or interstitial fluid in LP versus NP. Plasma angiotensin II (Ang II), renin (PRA), and aldosterone (PA) were lower in LP than in NP. An increased number without changes in affinity of glomerular Ang II receptors was found in LP compared to NP, while alpha 1- and alpha 2-adrenergic receptors were down-regulated in LP as compared to NP without changes in affinity for the alpha 1 receptor but with an increase in renal alpha 2 receptor affinity. LP (vs. NP) decreased GFR and RPF, and increased renal vascular resistance (RVR). NE decreased RPF equally in NP versus LP but raised RVR approximately twofold in NP versus LP. PHEN decreased RPF and increased RVR less in LP than in NP. Moreover, PHEN increased renal renin content approximately seven-fold over the basal NP values. Exogenous Ang II increased RVR and lowered RPF more in LP than in NP. Enalapril abolished all the hemodynamic changes of LP and restored the systemic response to NE.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms of ozolinone-induced renin release and diuresis.

Dextrorotatory (+) and levorotatory (-) ozolinone (ozo) were injected directly into the left renal artery of volume-expanded anesthetized dogs. (+)Ozo (40 micrograms/kg/min) had no effect on urine flow and fractional excretion of Na+, Cl-, or K+ when compared with the basal period. Comparison of (-)ozo to (+)ozo revealed the following: urine flow 4.0 +/- 0.3 v 0.9 +/- 0.1 mL/min (P < .001); FENa+ 29.8 +/- 3.0 v 5.6 +/- 0.3% (P < .001); FECl- 35.7 +/- 4.1 v 5.8 +/- 0.4% (P < .001); FEK+ 87 +/- 4 v 49 +/- 5% (P < .001). Glomerular filtration rate (GFR) and renal plasma flow (RPF) did not change. The renin secretory rate (RSR) was significantly higher with (-)ozo than with (+)ozo (498 +/- 113 v 210 +/- 53 ng A I/mL/hr.mL/min). Moreover, (-)ozo significantly increased urine PG excretion compared to basal values: 466 +/- 63 v 263 +/- 30 pg/min (P < .05). Indomethacin (2 mg/kg) markedly blunted the effects of (-)ozo on PG and RSR, and completely abolished the rise in PRA. (+)Ozo had no significant effect on urine PG excretion. Neither (-)ozo nor (+)ozo had an effect on renin production in isolated glomeruli. By contrast, (-)ozo but not (+)ozo increased PGE2 synthesis in papillary and medullary slices. The data are consistent with the proposal that the effect of (-)ozo on renin secretion and PRA is through a PG-dependent mechanism, and that it requires an intact macula densa mechanism.

Renal renin, angiotensinogen, and ANG I-converting-enzyme gene expression: influence of dietary protein.

Low-protein (LP) feeding (6%) of rats results in renal hemodynamic changes that are abolished by converting enzyme and nonpeptide AT1 inhibitors, suggesting a role for intrarenal angiotensin II (ANG II). Dietary protein is a stimulus for the expression of renal renin mRNA in intact and partially nephrectomized rats. In the present study, LP increased renal renin immunoreactivity and renin mRNA as assessed by in situ hybridization and Northern blot analysis; whole kidney expression of angiotensinogen mRNA was unaltered. Whole kidney, cortical, and medullary ANG I-converting-enzyme (ACE) mRNA was also increased in LP vs. normal protein. The changes occurred despite a reduced protein synthetic rate (RNA-to-DNA ratio) in the kidney of LP, which did not change expression of renal glyceraldehyde-3-phosphate dehydrogenase mRNA. These studies show for the first time that LP diet increases the expression of renal renin and ACE mRNA in intact rats; these may be responsible for the renal hemodynamic changes of LP.

Effect of high-protein diet on renal concentration capacity in rabbits.

In the present studies, we have found that New Zealand White rabbits kept on normal rabbit chow (16% protein, LP) are unable to raise fractional free water reabsorption [TCH2O divided by glomerular filtration rate (GFR)] as the fractional osmotic load (Cosm/GFR) is increased. Acute administration of urea (400 mosmol/l) or indomethacin (10 mg/kg iv bolus, followed by 0.25 mg/min infusion) corrects the defect. Moreover, rabbits kept for 2 wk on a 40% protein diet (HP) showed marked improvement in their renal concentration capacity. Balance studies showed that, in rabbits on HP, urine prostaglandin E2 (PGE2) excretion was lower while GFR, urine urea, and osmolar excretion were significantly higher than in rabbits in the LP group. Medullary tissue electrolytes in the HP vs. LP group were as follows: urea, 1,035 +/- 90 vs. 790 +/- 60 mmol.l-1 x g wet tissue wt-1; tissue Na+, 548 +/- 96 vs. 298 +/- 37 meq.l-1 x g wet wt-1; and K+, 201 +/- 43 vs. 99 +/- 16 meq.l-1 x g wet wt-1. Also, medullary slices from animals on HP had a lower PGE2 synthesis than those on LP when stimulated with angiotensin II (ANG II). Papillary plasma flow (PPF) measured by the accumulation of 125I-labeled albumin, after infusion of vasopressin, was 13.7 +/- 2.0 in the HP group and 22.7 +/- 3.4 ml.min-1 x 100 g-1 in the LP group. These findings suggest that lower PPF and higher urea and electrolyte content in the medullary interstitium of HP intake results from inability to produce medullary PGE2 even during ANG II or antidiuretic hormone (ADH) stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of macula densa in diuretics-induced renin release.

Diuretic therapy may enhance renin release by various mechanisms, principally contraction of extracellular fluid volume and its effects, including a fall in arterial pressure. Awake hydropenic or volume-expanded rats received diuretics (amiloride and hydrochlorothiazide) that are known inhibitors of NaCl transport beyond the macula densa; also the well-known Na(+)-K(+)-2 Cl- transport system inhibitor furosemide was administered. We also evaluated the effect of a dose of ethacrynic acid (a drug that shares the same mechanism of action as furosemide but is not diuretic in the rat). The direct action of the diuretics on renin-producing cells was examined in isolated glomeruli; a rise in renin release was observed with the calmodulin inhibitor trifluoperazine (10(-5) M). Renin release in intact hydropenic rats was not altered by diuretic therapy, but furosemide increased plasma renin activity in hydropenic as well as in volume-expanded rats. This demonstrates the importance of furosemide inhibition of transport in the macula densa for its renin secretory action. None of the diuretics (amiloride, hydrochlorothiazide, ethacrynic acid, or furosemide) elicited changes in renin release from glomeruli (10(-6) to 10(-3) M); amiloride and hydrochlorothiazide (10(-4) to 10(-3) M) did not change renin release from slices, but 10(-3) M ethacrynic acid and furosemide increased renin secretion in this preparation. This suggests that an effect on the macula densa is essential in loop diuretic-mediated renin release.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal and hemodynamic effects of atrial natriuretic peptide in patients with cirrhosis.

The effects of anaritide, a 25-amino-acid synthetic analogue of ANP, were evaluated in 28 patients with cirrhosis complicated by ascites and/or edema. Each patient received two doses of the agent, as well as an infusion of placebo. Six different doses were tested ranging from 0.015-0.300 microgram/kg/min. The infusions lasted for 2 hours and were flanked by both baseline and recovery periods. There was a significant effect of placebo on urinary sodium and chloride excretion rates but no effect on urine flow rate. In response to anaritide, the urine flow rate increased at 0.03, 0.06, 0.075, and 0.100 microgram/kg/min. The sodium and chloride excretion rates increased at all doses except the highest dose. There was no definite effect of anaritide on urinary potassium, calcium, and phosphate excretion rates. There was also no significant effect on creatinine clearance. The mean arterial pressure decreased in response to the 0.060, 0.075, and 0.100 microgram/kg/min doses. In addition, five of the patients receiving the highest dose (0.300 microgram/kg/min) had decreases in their systolic pressures to 90 mm Hg or less. In conclusion, anaritide is natriuretic and diuretic in patients with cirrhosis complicated by ascites and/or edema. Its effect, however, on arterial pressure may limit its therapeutic potential in this patient population.

Functional studies in experimental renal cortical necrosis in the rat.

Necrosis of the outer two-thirds of the cortex (CN) was induced with boiling water in the left kidney of rats. Two days afterward, morphological damage was shown to be limited to the superficial cortex; deep nephron population was well-preserved. Glucose reabsorption under basal and glucose loading conditions, and extraction of p-aminohippurate, used as indices of proximal tubule integrity, were normal in control and experimental kidneys 48 h after cortical necrosis. Basal fractional water and electrolyte excretion did not differ between control and experimental kidneys. Calculated mean single-nephron glomerular filtration rate (GFR) and plasma flow for superficial (SupGFR and SupNPF) and juxtamedullary nephrons (JMGFR and JMPF) were similar to those obtained by micropuncture and Hanssen's technique for SupGFR, and for JMGFR by Hanssen's. Volume expansion led to a 27% increase in calculated SupGFR, but no change in JMGFR. The JMPF increased by 81%, whereas SupNPF increased by only 23%, suggesting that, in this model, GFR of deep nephrons may be independent of plasma flow. The results indicate that deep nephrons retain their functional integrity 48 h after cortical necrosis. After volume expansion fractional excretion of sodium was greater, and fractional water reabsorption less, in CN than in control kidneys. Thus handling of sodium and water by superficial and deep nephrons under basal conditions was similar, but reabsorptive capacity for deep nephrons of CN was lower during volume expansion. The present studies suggest that deep nephrons can maintain relatively normal function in cortical necrosis.

Mechanism of inhibition of glycolysis by vanadate.

Vanadate is known to inhibit several phosphatases including Na+, K+-ATPase, alkaline phosphatase, and glyceraldehyde-3-P dehydrogenase. Inhibition presumably results because vanadium adopts a stable structure which resembles the transition state of phosphate during the reactions involving these enzymes. We performed experiments to further examine the effects of vanadate (VO3-4) on erythrocyte (red blood cells (RBC] glycolytic intermediates. RBC obtained from human subjects were centrifuged and washed with lactated Ringer's 5% dextrose. 31P nuclear magnetic resonance analysis of the RBC revealed the characteristic peaks for the 3-phosphate and 2-phosphate of 2,3-diphosphoglycerate (DPG), inorganic phosphate (Pi), and ATP. Incubation of RBC with 10(-6) M VO3-4 led to a disappearance of ATP and 2,3-DPG while the peak for Pi increased. By the end of 4 h over 90% of the VO3-4 had been reduced to VO2+ (vanadyl) in the RBC. The effects of 10(-4) M iodoacetamide and 10(-5) M ethacrynic acid, known inhibitors of glyceraldehyde-3-P dehydrogenase that act by interactions with sulfhydryl groups (-SH) of the enzyme, were similar to those of VO3-4. Incubation with vanadyl did not affect the peaks for Pi, 2-DPG, or 3-DPG. Furthermore, using electron spin resonance we demonstrated that in the presence of glyceraldehyde-3-P dehydrogenase, VO3-4 is reduced to VO2+. The findings demonstrate that VO3-4 inhibits glycolysis at micromolar concentrations and that the ion is reduced to VO2+ in the cell. The similarity of the effect of VO3-4 to those of iodoacetamide and ethacrynic acid suggests that interactions with -SH groups is its mechanism of inhibition. Since under physiological conditions intracellular VO3-4 concentrations are in the micromolar range and may exist in oxidized and/or reduced forms, VO3-4 could regulate the activity of glyceraldehyde-3-P dehydrogenase through changes in the redox state of the enzyme rather than by substituting for the PO3-4 ion.

Na+-K+-ATPase inhibitors and renin release: relationship to calcium.

The inhibition of renin secretion and the vasoconstrictive action of cardiac glycosides may be attributed to increases in cytosolic calcium as a result of inhibition of Na+-K+-ATPase. These studies examined in the dog in vivo the role of calcium on the renal actions of ouabain as assessed from the modifying effects of calcium channel blockers. Since vanadate, another Na+-K+-ATPase, inhibitor, enhances in vitro the binding of ouabain to Na+-K+-ATPase, we examined the capacity of vanadate to modify the renal effects of ouabain in vivo. Infusion of ouabain (1 microgram X kg-1 X min-1) into the renal artery decreased RBF, GFR, and renin secretion, and produced diuresis and natriuresis. When ouabain was infused in dogs receiving the calcium channel blocker verapamil (100 microgram/min), it failed to suppress renin secretion or cause renal vasoconstriction. In addition, verapamil produced diuresis and natriuresis, which were greatly enhanced by ouabain (e.g., verapamil FENa 12.0 +/- 1.1----34.2 +/- 5.1%). The data strongly suggest that calcium entry into cells is a major mediator of the renin inhibitory effect and of the renal vasoconstriction induced by cardiac glycosides. The natriuresis observed during the calcium channel blocker infusion suggests that this drug may have a direct tubular effect on sodium reabsorption. Superimposition of vanadate (0.5 mumol/min) on ouabain infusion led to massive natriuresis (FENa, 5 +/- 1----35 +/- 4%), renal vasodilation (RBF 90 +/- 12----170 +/- 15 ml/min), and an increase in renin secretion (delta, 100%).(ABSTRACT TRUNCATED AT 250 WORDS)

Critical role of extracellular calcium in vanadate-induced renal vasoconstriction.

Intra-arterial infusion of vanadate (VO4) in dogs produces a reduction in renal blood flow (RBF), glomerular filtration rate (GFR), urine flow (V), and the fractional excretion of sodium (FENa+). To evaluate the role of Ca2+ in these changes VO4 was infused into the renal artery in the presence of the calcium antagonists trifluoperazine (TFP), verapamil, or EGTA. TFP inhibited the effect of VO4 on RBF (TFP + VO4:64.1, VO4:38.5 ml/min; P less than 0.05), GFR (TFP + VO4:22.9, VO4:9.3, ml/min; P less than 0.05) and V (TFP + VO4: 0.80, VO4: 0.38 ml/min; P less than 0.05) without changing FENa+ (TFP + VO4: 3.8, VO4: 3.2%). Similar changes were obtained with verapamil as well as with EGTA. Furthermore thyroparathyroidectomy (TPTX) decreased serum calcium (control: 8.78, TPTX: 4.98 mg/100 ml; P less than 0.05) and blunted the effects of VO4 on renal hemodynamics. Reestablishing normal serum Ca2+ by an intra-arterial infusion of CaCl2 elicited the VO4 effects of vasoconstriction and decreased GFR; V was not affected and FENa+ rose. The data support the idea that influx of extracellular calcium into smooth muscle cells mediates the hemodynamic effects of VO4 in the dog.