Urinary Markers of Fibrosis and Risk of Cardiovascular Events and Death in Kidney Transplant Recipients: The FAVORIT Trial.

Cardiovascular risk remains high in kidney transplant recipients (KTRs) despite improved kidney function after transplant. Urinary markers of kidney fibrosis and injury may help to reveal mechanisms of this risk. In a case-cohort study among stable KTRs who participated in the FAVORIT trial, we measured four urinary proteins known to correlate with kidney tubulointerstitial fibrosis on biopsy (urine alpha 1 microglobulin [α1m], monocyte chemoattractant protein-1 [MCP-1], procollagen type I [PINP] and type III [PIIINP] N-terminal amino peptide) and evaluated associations with cardiovascular disease (CVD) events (n = 300) and death (n = 371). In adjusted models, higher urine α1m (hazard ratio [HR] per doubling of biomarker 1.40 [95% confidence interval [CI] 1.21, 1.62]), MCP-1 (HR 1.18 [1.03, 1.36]), and PINP (HR 1.13 [95% CI 1.03, 1.23]) were associated with CVD events. These three markers were also associated with death (HR per doubling α1m 1.51 [95% CI 1.32, 1.72]; MCP-1 1.31 [95% CI 1.13, 1.51]; PINP 1.11 [95% CI 1.03, 1.20]). Higher concentrations of urine α1m, MCP-1, and PINP may identify KTRs at higher risk for CVD events and death. These markers may identify a systemic process of fibrosis involving both the kidney and cardiovascular system, and give new insights into mechanisms linking the kidney with CVD.

A randomized clinical trial of continuous versus intermittent dialysis for acute renal failure.

BACKGROUND: Acute renal failure (ARF) requiring dialysis in critically ill patients is associated with an in-hospital mortality rate of 50 to 80%. The worldwide standard for renal replacement therapy is intermittent hemodialysis (IHD). Continuous hemodialysis and hemofiltration techniques have recently emerged as alternative modalities. These two therapies have not been directly compared. METHODS: A multicenter, randomized, controlled trial was conducted comparing two dialysis modalities (IHD vs. continuous hemodiafiltration) for the treatment of ARF in the intensive care unit (ICU). One hundred sixty-six patients were randomized. Principal outcome measures were ICU and hospital mortality, length of stay, and recovery of renal function. RESULTS: Using intention-to-treat analysis, the overall ICU and in-hospital mortalities were 50.6 and 56.6%, respectively. Continuous therapy was associated with an increase in ICU (59.5 vs. 41.5%, P < 0.02) and in-hospital (65.5 vs. 47.6%, P < 0.02) mortality relative to intermittent dialysis. Median ICU length of stay from the time of nephrology consultation was 16.5 days, and complete recovery of renal function was observed in 34.9% of patients, with no significant group differences. Despite randomization, there were significant differences between the groups in several covariates independently associated with mortality, including gender, hepatic failure, APACHE II and III scores, and the number of failed organ systems, in each instance biased in favor of the intermittent dialysis group. Using logistic regression to adjust for the imbalances in group assignment, the odds of death associated with continuous therapy was 1.3 (95% CI, 0.6 to 2.7, P = NS). A detailed investigation of the randomization process failed to explain the marked differences in patient assignment. CONCLUSIONS: A randomized controlled trial of alternative dialysis modalities in ARF is feasible. Despite the potential advantages of continuous techniques, this study provides no evidence of a survival benefit of continuous hemodiafiltration compared with IHD. This study did not control for other major clinical decisions or other supportive management strategies that are widely variable (for example, nutrition support, hemodynamic support, timing of initiation, and dose of dialysis) and might materially influence outcomes in ARF. Standardization of several aspects of care or extremely large sample sizes will be required to answer optimally the questions originally posed by this investigation.

Suppression of inducible nitric oxide generation by agmatine aldehyde: beneficial effects in sepsis.

The induction of inducible nitric oxide synthase (iNOS) serves an important immuno-protective function in inflammatory states, but ungoverned nitric oxide (NO) generation can contribute to a number of pathologic consequences. Delineation of the mechanisms that can downregulate iNOS-generated NO in inflammation could have therapeutic relevance. Here we show that agmatine, a metabolite of arginine, inhibits iNOS mediated nitric oxide generation in cytokine stimulated cell culture preparations. This effect was not cell type specific. Increased diamine oxidase (DAO) and decreased aldehyde dehydrogenase (AldDH) activities are also representative of inflammatory settings. Increasing the conversion of agmatine to an aldehyde form by addition of purified DAO or suppression of aldehyde breakdown by inhibition of AldDH activity increases the inhibitory effects of agmatine in an additive fashion. Inhibitors of DAO, but not monoamine oxidase (MAO), decreased the inhibitory effects of agmatine, as did the addition of AldDH or reacting aldehydes with phenylhydrazine. We examined rats given lipopolysaccharide (LPS) to evaluate the potential effects of agmatine in vivo. Endotoxic rats administered agmatine prevented the decreases in blood pressure and renal function normally associated with sepsis. Agmatine treatment also increased the survival of LPS treated mice. Our data demonstrate the capacity of agmatine aldehyde to suppress iNOS mediated NO generation, and indicate a protective function of agmatine in a model of endotoxic shock. How agmatine may aid in coordinating the early NO phase and the later repair phase responses in models of inflammation is discussed.

Effects of nitric oxide synthase blockers on renal function.

Three isoforms of nitric oxide synthase (NOS) [neuronal NOS (bNOS), inducible NOS (iNOS) and endothelial NOS (eNOS)] are expressed in the kidney. The use of pharmacological inhibitors of these enzymes has been a major experimental tool to determine the role of nitric oxide (NO) in renal physiology and pathophysiology. Studies performed in both human and experimental animals demonstrate that NOS blockade increases renal vascular resistances and decreases the glomerular ultrafiltration coefficient. These studies also support the presence of an important interaction between NO, angiotensin and renal nerves in the control of renal function. Renal iNOS activity is significantly increased in various pathophysiological conditions including autoimmune tubulointerstitial nephritis and sepsis. Interestingly, recent evidence suggests that high NO levels secondary to increased iNOS activity may inhibit eNOS activity and through this mechanism lead to renal vasoconstriction and reductions in glomerular filtration rate. The use of NOS blockers has generated a great deal of information on the role of NO in the control of renal function and has also allowed us to begin to understand the high level of complexity of this system.

Early alteration in glomerular reserve in humans at genetic risk of essential hypertension: mechanisms and consequences.

Essential hypertension has a familial predisposition, but the phenotype of elevated blood pressure has delayed penetrance. Because the kidney is a crucial determinant of blood pressure homeostasis, we studied early glomerular alterations in still-normotensive young subjects at genetic risk of hypertension. Thirty-nine normotensive adults (mean age 29 to 31 years), stratified by genetic risk (parental family history [FH]) of hypertension (26 with positive FH [FH+], 13 with negative FH [FH-]), underwent intravenous infusion of mixed amino acids. Before and during amino acid administration, we measured glomerular filtration rate (GFR), putative second messengers of amino acids (nitric oxide [NO.] metabolites and cGMP), serum insulin and amino acid concentrations, and the FE(Li)+ as an index of renal proximal tubular reabsorption. The FH+ group had a blunted GFR rise in response to amino acids (2.43+/-8.16% versus 31.0+/-13.4% rise, P:=0.0126). The amino acid-induced change in GFR correlated (r=0.786, P:<0.01) with the change in urinary NO. metabolite excretion; a diminished rise in urinary NO. metabolite excretion in the FH+ group (P:=0.0105) suggested a biochemical mechanism for the different GFR responses between FH groups: a relative inability to convert arginine to NO. The FH+ group had a far lower initial cGMP excretion at baseline (261+/-21.1 versus 579+/-84.9 nmol. h(-1)/1.73 m(2), P:=0.001), although cGMP did not change during the amino acid infusion (P:=0.703). FH status, baseline GFR, and baseline serum insulin jointly predicted GFR response to amino acids (P:=0.0013), accounting for approximately 45% of the variance in GFR response. Decline in FE(Li)+, an inverse index of proximal tubular reabsorption, paralleled increase in GFR (r=-0.506, P:=0.01), suggesting differences in proximal tubular reabsorption during amino acids between the FH groups. GFR response to amino acid infusion was blunted in the FH+ group despite significantly higher serum concentrations of 6 amino acids (arginine, isoleucine, leucine, methionine, phenylalanine, and valine) in the FH+ group, suggesting a novel form of insulin resistance (to the amino acid-translocating action of insulin) in FH+ subjects. We conclude that blunted glomerular filtration reserve in response to amino acids is an early-penetrance phenotype seen even in still-normotensive subjects at genetic risk of hypertension and is linked to impaired formation of NO. in the kidney. Corresponding changes in GFR and fractional excretion of Li(+) suggest that altered proximal tubular reabsorption after amino acids is an early pathophysiologic mechanism. Resistance to the amino acid-translocating actions of insulin may play a role in the biological response to amino acids in this setting. This glomerular reserve phenotype may be useful in genetic studies of renal traits preceding or predisposing to hypertension.

Heparin-binding EGF-like growth factor contributes to reduced glomerular filtration rate during glomerulonephritis in rats.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF), a member of the epidermal growth factor (EGF) family, is expressed during inflammatory and pathological conditions. We have cloned the rat HB-EGF and followed the expression of HB-EGF in rat kidneys treated with anti- glomerular basement membrane (anti-GBM) antibody (Ab) to induce glomerulonephritis (GN). We observed glomerular HB-EGF mRNA and protein within 30 minutes of Ab administration and showed by in situ hybridization that glomerular HB-EGF mRNA expression was predominantly in mesangial and epithelial cells. Expression of HB-EGF correlated with the onset of decreased renal function in this model. To test the direct effect of HB-EGF on renal function, we infused the renal cortex with active rHB-EGF, prepared from transfected Drosophila melanogaster cells. This treatment induced a significant decrease in single nephron GFR (SNGFR), single nephron plasma flow, and glomerular ultrafiltration coefficient and an increase in the glomerular capillary hydrostatic pressure gradient. In addition, anti-HB-EGF Ab administered just before anti-GBM Ab blocked the fall in SNGFR and GFR at 90 minutes without any change in the glomerular histologic response. These studies suggest that HB-EGF expressed early in the anti-GBM Ab GN model contributes to the observed acute glomerular hemodynamic alterations.

Biological effects of arginine metabolites.

Arginine and its metabolites exert physiological effects on the vasculature and on the kidney and also provide important influences on the regulation of cell proliferation. We summarize the known information regarding two major metabolites of arginine: (a) nitric oxide (NO) and (b) agmatine, decarboxylated arginine. Both agents appear to interact in producing vasodilation and increases in glomerular filtration rate (GFR) in the kidney. There is evidence for inter-regulation of arginine pathways in the sense that agmatine is capable of inhibiting inducible nitric oxide synthase (iNOS), the inflammatory NOS isoform. Both NO and agmatine influence cell proliferation via effects on polyamine synthesis. In addition, both NO and agmatine exert inhibitory effects on ornithine decarboxylase (ODC) and the putrescine transporter by significantly different mechanisms. Therefore, arginine and arginine metabolites exert both vascular regulatory functions and impact on the regulation of cell proliferation. Significant inter-regulation among arginine pathways occurs within the three metabolic major pathways within the cell: (1) nitric oxide synthase (2) arginase and ornithine decarboxylase, and (3) arginine decarboxylase.

Role of nitric oxide in renal hemodynamics.

Studies performed over the last 10 years have evaluated the role of nitric oxide (NO) in the control of renal hemodynamics. This article reviews the effects of administration of nitric oxide synthase (NOS) blockers on renal function in experimental animals and human volunteers. These studies show that NOS blockade increases renal vascular resistances and decreases the glomerular ultrafiltration coefficient. These experimental studies also support the presence of an important interaction between NO, angiotensin II, and renal nerves in the control of renal function. The use of acute and chronic administration of NOS blockers has generated a great deal of new and exciting information regarding the role of NO in the regulation of normal renal function.

Effect of reduction of nitric oxide on plasma and kidney tissue angiotensin II levels.

Nitric oxide synthase (NOS) blockade increases blood pressure (BP) and modifies glomerular and tubular function. Angiotensin II (AII) blockade restores glomerular and tubular function but does not lower BP. We measured plasma renin activity (PRA), plasma (AIIp), and kidney tissue (AIIk) AII with radioimmunoassay to investigate the dissociation between renal and systemic effects of NOS blockade. Two period clearance studies followed by plasma and renal tissue harvesting were performed in seven groups of rats. Groups 1 and 1A served as controls. Groups 2 and 2A received NaCl-NaHCO3 during the first period and N(G)-monomethyl-L-arginine (L-NMMA, 0.5 mg/kg/min) during the second period. Group 3 was similar to group 2 but renal perfusion pressure (RPP) was maintained constant by using an aortic snare. Groups 4 and 4A received N(G)-nitro-L-arginine-methyl ester (L-NAME, 5 mg/100 mL of drinking water) for 2 weeks. NOS blockers decreased AIIp (group 1, 74 +/- 7 pg/mL; group 2, 22 +/- 1 pg/mL; group 3, 26 +/- 1 pg/mL; group 4, 19 +/- 3 pg/mL). The decrease in AIIp was a direct effect of L-NMMA independent of changes in perfusion pressure, as AIIp was similar in group 3 (normal RPP) and groups 2 and 4 (increased RPP). Measurements of PRA and AIIp demonstrated a similar reduction in PRA and AIIp in rats treated with NOS blocker. Although NOS blockers decreased AIIp, acute or chronic administration of NOS blockers did not modify AIIk (group 1, 1,192 +/- 51; group 2, 1,354 +/- 85; group 3, 1,348 +/- 180; group 4, 1,276 +/- 172 pg/kidney). Our findings demonstrate that NO blockers produce a dissociation between plasma and kidney AII levels. This dissociation can explain the beneficial effects of AII blockers on renal function and their lack of antihypertensive effects in anesthetized rats treated with NOS blockers.

Oral feeding of renal tubular antigen abrogates interstitial nephritis and renal failure in Brown Norway rats.

We have examined whether oral feeding of antigen can regulate the expression of autoimmune interstitial nephritis induced by antigen-in-adjuvant (RTA/CFA) immunization of Brown Norway rats. Male rats were divided into six experimental groups: Group I, RTA/CFA immunization alone; Groups II, III, and IV were pretreated with 1 mg (Group II), 5 mg (Group III), and 25 mg (Group IV) of oral tubular antigen every other day for ten days, followed by RTA/CFA immunization; Group V was pretreated with a control antigen, followed by RTA/CFA immunization; and Group VI was immunized with CFA alone. Renal histology, inulin clearance, DTH responses to RTA, and IgG antibody responses to RTA were monitored as endpoints of the study. Our results demonstrated that Group III and IV animals had significantly less severe renal injury, as assessed by inulin clearance and extent of renal cortical involvement by mononuclear cells. Group II and IV animals had suppressed DTH responses, and only Group IV animals had significantly depressed antigen-specific IgG serum titers. Group III animals had neither suppressed DTH responses or IgG titers. We conclude that oral administration of tubular antigen can modulate the intensity of interstitial nephritis produced by immunization, but that the regulatory mechanism is not dependent (at all doses of fed antigen) on suppressed DTH reactivity to RTA or suppressed antigen-specific IgG.

[Glomerular hemodynamics in the isolated and perfused kidney. Effect of the inhibition of nitric oxide synthase]. / La hemodinámica glomerular en el riñón aislado y perfundido. Efecto de la inhibición de la sintetasa del óxido nítrico.

The isolated perfused kidney (IPK) is characterized by a normal glomerular filtration rate associated with a very low filtration fraction (FF). This study utilized micropuncture studies in the IPK to investigate: 1) the determinants of the ultrafiltration process responsible for the decrease in FF, and 2) the effect of nitric oxide synthase (NOS) blocker (L-NMMA) on glomerular hemodynamics. Two groups of kidneys were studied, a control group (CTL, n = 6) and an experimental group (EXP, n = 6) in which L-NMMA (0.56mM) was added to the perfusate. Significant differences in perfusate flow rate were required to maintain a constant perfusion pressure in both groups of kidneys. Nephron filtration rate, glomerular capillary hydrostatic pressure gradient and the ultrafiltration coefficient were similar between groups and identical to the ones obtained with in vivo micropuncture studies. Both afferent and efferent glomerular resistances were significantly reduced, although L-NMMA administration increased significantly both resistances. Altogether, these data demonstrate that 1) the IPK is an excellent preparation to evaluate the effect of different agents on glomerular pressure and/or membrane permeability in the absence of systemic effects; 2) the decrease in glomerular resistances leads to a significant increase in perfusate flow required to maintain glomerular pressure within normal range, and 3) in the absence of any systemic effect, NOS blocker increases both afferent and efferent arteriolar resistances.

Inhibition of inducible nitric oxide synthase intensifies injury and functional deterioration in autoimmune interstitial nephritis.

T lymphocytes are exquisitely sensitive to the antiproliferative effects of nitric oxide. We examined the effects of oral administration of two nitric oxide synthase inhibitors, Nw-nitro-L-arginine methyl ester (L-NAME) and L-N6-(1-iminoethyl)lysine (L-NIL), on the course of T cell-dependent autoimmune interstitial nephritis in Brown Norway rats. Kidneys from rats immunized to produce interstitial nephritis display a net generation of nitric oxide end products. By immunohistochemical staining, the cytokine-inducible nitric oxide synthase (iNOS) is expressed in cortical tubular epithelial cells. Treatment with either inhibitor results in markedly more severe disease following immunization. Animals receiving L-NAME were hypertensive, while those treated with L-NIL, a highly selective inhibitor of iNOS, were not. Evaluation of the expression of IFN-gamma, IL-2, and IL-4 in diseased kidneys by quantitative reverse transcriptase-PCR demonstrated that L-NAME-treated animals displayed significantly augmented levels of IFN-gamma and IL-2 with preserved ratios of IFN-gamma/IL-4 and IL-2/IL-4, while L-NIL-treated animals had augmented levels of IL-2 and IFN-gamma with augmented IFN-gamma/IL-4 and IL-2/IL-4 ratios. Animals treated with L-NAME or L-NIL both had augmented Ag-specific IgG responses. The L-NAME group demonstrated increases in both the IgG2a and IgG1 subtypes, with a constant IgG2a/IgG1 ratio, while the L-NIL group demonstrated an increase in the ratio of the IgG2a/IgG1 response. These Ab and cytokine data suggest that the L-NIL-treated animals had a skewing of their immune response toward a Th1-like response. We conclude that in autoimmune interstitial nephritis, generation of nitric oxide through the iNOS pathway has host-protective effects, and suggest that this may be broadly applicable to T cell-mediated pathologies.

Renal response to blood pressure elevation in normal and glomerulonephritic rats.

Concurrent renal disease appears to augment greatly the adverse effects of systemic hypertension on renal function and the development of glomerulosclerosis. This study examined the effects of systemic hypertension and treatment of hypertension in groups of normal non-nephritic rats and rats submitted to 16 wk of glomerulonephritis induced by the administration of anti-glomerular basement membrane antibody. Hypertension was produced by application of a clip to the right renal artery and blood pressure was treated with an angiotensin-converting enzyme (ACE) inhibitor, quinapril. Glomerulosclerosis of two types developed: a diffuse type that is characteristic of anti-glomerular basement membrane glomerulonephritis, and a focal segmental glomerulosclerosis that is characteristic of systemic hypertension. Glomerulonephritis significantly reduced the capacity of ACE inhibitors to decrease systolic blood pressure in awake animals. In addition, glomerulonephritis produced significant effects on plasma angiotensin II concentrations, whereby ACE inhibition no longer lowered plasma angiotensin II levels and in fact produced an increase. Glomerular capillary hydrostatic pressure and hydrostatic pressure gradient correlated with systolic blood pressure and with the incidence of focal glomerulosclerosis in non-nephritic rats. However, in glomerulonephritis, systolic blood pressure no longer correlated with glomerular capillary pressure, and glomerular capillary pressure no longer correlated with the development of glomerulosclerosis, although systolic blood pressure did correlate with the degree of focal segmental glomerulosclerosis. Concurrent glomerulonephritis strongly conditions the effects of superimposed hypertension by altering the relationship between systemic blood pressure and glomerular capillary hydrostatic pressure and by decreasing the response of hypertension to therapy.

Effect of angiotensin II on the renal response to amino acid in rats.

Administration of the nitric oxide (NO) synthase blocker, N(G)-monomethyl L-arginine prevents the increase in glomerular filtration rate (GFR) normally observed with glycine, an effect that is restored by angiotensin II (AII) blockers. These findings suggest that changes in NO and AII dictate the presence or absence of renal vasodilation during amino acid (AA) infusion. We examined the effect of branched-chain (BCAA) and non-branched-chain (NBCAA) AA on GFR, NO, and AII to determine if abnormal NO or AII responses could explain the absence of vasodilation with BCAA. Our findings demonstrated that NBCAA increased GFR and NO and did not modify AII, either plasma (AIIp) or kidney (AIIk) AII. The response with BCAA was strikingly different. L-Valine increased GFR without modifying NO or AII. L-Leucine increased AIIk and NO but did not increase GFR. Administration of AII blockers (captopril or losartan) was associated with an increase in GFR during infusion of leucine. Single nephron studies demonstrated that increased AIIk with L-leucine was associated with decreased absolute proximal reabsorption and probably activation of the tubuloglomerular feedback. An AA-specific increase in AIIk is critical to inhibition of the normal renal response to AA infusion. NO generation is an important mediator but not the sole mechanism that determines the increase in GFR during amino acid infusion.

Activities of nitric oxide in normal physiology and uremia.

Nitric oxide (NO) generated from arginine exerts a variety of renal and extrarenal physiological and pathophysiological effects. NO is generated by two types of nitric oxide synthases: acutely responsive, constitutive NOS and slower, more persistent inducible NOS (iNOS). The latter is transcriptionally dependent, often stimulated by cytokines. NO regulates glomerular ultrafiltration, tubular reabsorption, and intrarenal renin secretion; many of these renal effects are mediated by interactions with angiotensin II and adrenergic (alpha 2) activity. Decreased NO activity also enhances tubuloglomerular feedback activity, which could contribute to renal vasoconstriction, NaCl retention, and elevated blood pressure. Loss of renal function could influence NO activity via: (1) endothelial dysfunction; (2) decreased arginine synthesis by kidney; (3) responses to arginine analogs that act as NOS inhibitors; (4) increased cytokine activity; and (5) altered oxidation:reduction status of cells, etc. For example, platelet dysfunction in uremia may be caused by cytokine-induced iNOS activation. Moreover, acutely responsive, constitutive NOS activity may be depressed in progressive loss of renal function. Decreased NO activity might contribute to baroreceptor dysfunction observed in hypertension and progressive renal disease. Studies of the impact of uremia suggest that iNOS may be chronically stimulated by cytokines, whereas acutely responsive, constitutive NOS activity may be concurrently depressed.

Interactive control of renal function by alpha 2-adrenergic system and nitric oxide: role of angiotensin II.

We studied the role of angiotensin II (AII) in the interactive control of renal function by the alpha 2-adrenergic system and nitric oxide (NO) in adult male Munich Wistar rats 5-7 days after ipsilateral renal denervation (DNX). Renal micropuncture was used under euvolemic conditions before (period 1) and during (period 2) systemic inhibition of NO synthase (NOS) with NG-monomethyl-L-arginine (L-NMMA) in three groups. Group 1 served as a DNX control. In group 2, the alpha 2-adrenergic agonist B-HT 933 (BHT) was infused systemically throughout the experiment. In group 3, the AII-receptor blocker, Iosartan (LOS), was infused before period 2 as well as throughout infusion of BHT. L-NMMA increased blood pressure (BP) to a similar degree in all three groups. In group 1, infusion of L-NMMA did not affect glomerular hemodynamics or tubular function. With BHT in group 2, L-NMMA reduced absolute proximal tubular reabsorption (APR) and by reducing nephron plasma flow (SNPF) and glomerular ultrafiltration coefficient (LpA) caused nephron filtration rate (SNGFR) to decrease, a response described in innervated kidneys. LOS in group 3 abrogated the BHT-facilitated reduction of LpA and SNGFR but not of SNPF and APR in response to L-NMMA. In group 1, urinary sodium excretion (UNaV) did not change and urinary flow rate (UV) increased slightly in period 2. L-NMMA combined with BHT, however, exerted a profound diuresis and natriuresis in group 2. These effects were further exaggerated with LOS. In a fourth group of DNX rats. LOS given alone before period 2 did not affect SNGFR, SNPF, LpA, APR, UV, or UNaV. We conclude that after subacute renal denervation alpha 2-adrenergic activation sensitizes (a) LpA to reduction by NOS inhibition through an AII-dependent mechanism, and (b) SNPF and proximal tubular reabsorption to reduction by L-NMMA regardless of the AII activity. Furthermore, our results suggest a potential role for the alpha 2-adrenergic system and AII in the diuretic and natriuretic effect of systemic NOS inhibition.

Role of angiotensin in the regulation of renal response to proteins.

Intrarenal and extrarenal humoral factors have been proposed as mediators and modulators of the renal hyperemic response to amino acid infusion. Among the potential modulators, angiotensin II (AII) constitutes the most important candidate due to its critical role in the control of glomerular and tubular function. The modulatory effect of AII has been assessed by (1) measuring the changes in plasma renin activity (PRA)/AII during the normal hyperemic response, and (2) by assessing the levels of PRA/AII and the response to AII-suppressing agents in conditions with no vasodilatory response during amino acid infusion. Administration of a protein load in normal animals or humans does not modify PRA/AII. Absence of a vasodilatory response in various experimental conditions (nitric oxide blockade in normal rats, experimental models of hypertension, diabetes mellitus, chronic glomerulonephritis, cyclosporine administration) is characterized by a significant decrease in proximal tubular reabsorption during amino acid infusion. Converting enzyme inhibitors or AII receptor antagonist restore normal tubular function and the increase in glomerular filtration rate during amino acid infusion. Absence of a vasodilatory response is also associated with increases in kidney AII levels in some of these conditions. These results suggest that (1) AII modulates the amino acid-induced hyperemia through its inhibitory effect on proximal tubular reabsorption and activation of the tubuloglomerular feedback system, and (2) that the expression of the modulatory effect of AII may depend on the interaction between AII and other intrarenal systems like nitric oxide.

Renal reserve in patients with high blood pressure.

The mechanism by which hypertension produces renal damage remains poorly defined. Experimental evidence suggests that glomerular hypertension/hyperfiltration constitutes a potential mechanism by which hypertension leads to chronic renal failure. Renal functional reserve has been used to investigate the presence or absence of hyperfiltration, both in experimental animals and humans. Micropuncture studies using the two-kidney, one-clip hypertension model have shown that glomerular hypertension/hyperfiltration is associated with loss of renal functional reserve. However, loss of renal functional reserve in this experimental model is not always indicative of hyperfiltration because some antihypertensive agents (Verapamil, Losartan) correct glomerular hypertension/hyperfiltration, but do not restore renal reserve. Renal reserve has also been evaluated in patients with essential hypertension. Some investigators have shown that hypertension is associated with loss of renal functional reserve which can be restored in some studies with antihypertensive therapy. However, normal renal reserve has also been shown in hypertensive patients. Altogether, these data suggest that renal functional reserve cannot be used to assess the role of hemodynamic mechanisms in hypertension-induced renal injury. Long-term follow-up studies are required to establish if loss of renal reserve is indicative of risk factors leading to renal failure in patients with systemic hypertension.

Glomerular and tubular interactions between renal adrenergic activity and nitric oxide.

Endothelium-dependent nitric oxide (EDNO) exerts control over the processes of glomerular filtration and tubular reabsorption. The importance of the renal nerves to the tonic influence of EDNO in the glomerular microcirculation and proximal tubule was tested by renal micropuncture in euvolemic adult male Munich-Wistar rats. The physical determinants of glomerular filtration and proximal reabsorption were assessed before and during administration of the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA), in control animals and in animals 5-9 days after either ipsilateral surgical renal denervation (DNX) or after either sham surgery (SHX). L-NMMA caused single-nephron glomerular filtration rate to decline in control and SHX animals but not in DNX rats. L-NMMA caused a reduction in proximal reabsorption in control and SHX rats, which was prevented by prior DNX. DNX did not alter urinary guanosine 3',5'-cyclic monophosphate excretion, and, although DNX upregulates glomerular angiotensin II (ANG II) receptors, prior DNX did not alter intrarenal ANG II content as evaluated by radioimmunoassay. Some component of renal adrenergic activity is required for the full expression of the glomerular and tubular effects of blockade of nitric oxide synthase.