Francis B. Gabbai

Intensive blood-pressure control in hypertensive chronic kidney disease.

BACKGROUND In observational studies, the relationship between blood pressure and end-stage renal disease (ESRD) is direct and progressive. The burden of hypertension-related chronic kidney disease and ESRD is especially high among black patients. Yet few trials have tested whether intensive blood-pressure control retards the progression of chronic kidney disease among black patients. METHODS We randomly assigned 1094 black patients with hypertensive chronic kidney disease to receive either intensive or standard blood-pressure control. After completing the trial phase, patients were invited to enroll in a cohort phase in which the blood-pressure target was less than 130/80 mm Hg. The primary clinical outcome in the cohort phase was the progression of chronic kidney disease, which was defined as a doubling of the serum creatinine level, a diagnosis of ESRD, or death. Follow-up ranged from 8.8 to 12.2 years. RESULTS During the trial phase, the mean blood pressure was 130/78 mm Hg in the intensive-control group and 141/86 mm Hg in the standard-control group. During the cohort phase, corresponding mean blood pressures were 131/78 mm Hg and 134/78 mm Hg. In both phases, there was no significant between-group difference in the risk of the primary outcome (hazard ratio in the intensive-control group, 0.91; P=0.27). However, the effects differed according to the baseline level of proteinuria (P=0.02 for interaction), with a potential benefit in patients with a protein-to-creatinine ratio of more than 0.22 (hazard ratio, 0.73; P=0.01). CONCLUSIONS In overall analyses, intensive blood-pressure control had no effect on kidney disease progression. However, there may be differential effects of intensive blood-pressure control in patients with and those without baseline proteinuria. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Center on Minority Health and Health Disparities, and others.)

Nitric oxide and angiotensin II. Glomerular and tubular interaction in the rat.

Nitric oxide (NO) has been proposed to modulate the renal response to protein as well as basal renal hemodynamics. We investigated whether NO and angiotensin II (AII) interact to control glomerular hemodynamics and absolute proximal tubular reabsorption (APR) during glycine infusion and in unstimulated conditions. In control rats, glycine increased single nephron GFR and plasma flow with no change in APR. The NO synthase blocker, NG-monomethyl L-arginine (LNMMA), abolished the vasodilatory response to glycine, possibly through activation of tubuloglomerular feedback due to a decrease in APR produced by LNMMA + glycine. Pretreatment with an AII receptor antagonist, DuP 753, normalized the response to glycine at both glomerular and tubular levels. In unstimulated conditions, LNMMA produced glomerular arteriolar vasoconstriction, decreased the glomerular ultrafiltration coefficient, and reduced single nephron GFR. These changes were associated with a striking decrease in APR. DuP 753 prevented both glomerular and tubular changes induced by LNMMA. In conclusion, NO represents a physiological antagonist of AII at both the glomerulus and tubule in both the basal state and during glycine infusion; and inhibition of NO apparently enhances or uncovers the inhibitory effect of AII on proximal reabsorption.

Nephrology consultation in acute renal failure ☆: Does timing matter?

PURPOSE Patients who develop acute renal failure in the intensive care unit (ICU) have extremely high rates of mortality and morbidity. The goals of this study were to identify correlates of the timing of nephrology consultation in acute renal failure, and to explore the relation between timing of consultation and outcomes. METHODS We explored associations among timing of nephrology consultation and in-hospital mortality, lengths of hospital and ICU stay, and recovery of renal function in 215 ICU patients with acute renal failure at four U.S. teaching hospitals. We used multivariable logistic regression and propensity scores to adjust for confounding and selection effects. RESULTS Nephrology consultation was delayed (>or=48 hours) in 61 patients (28%) (median time to consultation, 4 days). Lower serum creatinine levels (P <0.0001) and higher urine output (P = 0.002) were associated with delayed consultation. Delayed consultation was associated with increased mortality among dialyzed (31/42 [74%] vs. 50/103 [49%], P = 0.006) and nondialyzed patients (10/19 [53%] vs. 11/51 [22%], P = 0.01), and increases in lengths of hospital (median, 19 days vs. 16 days, P = 0.01) and ICU stay (17 days vs. 6 days, P <0.0001). The association between delayed consultation and mortality was attenuated by covariate adjustment, and was no longer statistically significant after adjustment for propensity score (odds ratio = 2.0; 95% confidence interval: 0.8 to 5.1). CONCLUSION In acute renal failure, delayed nephrology consultation was associated with increased mortality and morbidity, whether or not dialysis was ultimately required. Using observational data, we cannot determine whether these findings reflect residual confounding, selection bias, adverse effects of delayed recognition of acute renal failure, or the benefits of nephrology consultation.

Long-term Effects of Renin-Angiotensin System–Blocking Therapy and a Low Blood Pressure Goal on Progression of Hypertensive Chronic Kidney Disease in African Americans

BACKGROUND Antihypertensive drugs that block the renin-angiotensin system (angiotensin-converting enzyme inhibitors [ACEIs] or angiotensin receptor blockers) are recommended for patients with chronic kidney disease (CKD). A low blood pressure (BP) goal (BP, <130/80 mm Hg) is also recommended. The objective of this study was to determine the long-term effects of currently recommended BP therapy in 1094 African Americans with hypertensive CKD. METHODS Multicenter cohort study following a randomized trial. Participants were 1094 African Americans with hypertensive renal disease (glomerular filtration rate, 20-65 mL/min/1.73 m2). Following a 3x2-factorial trial (1995-2001) that tested 3 drugs used as initial antihypertensive therapy (ACEIs, calcium channel blockers, and beta-blockers) and 2 levels of BP control (usual and low), we conducted a cohort study (2002-2007) in which participants were treated with ACEIs to a BP lower than 130/80 mm Hg. The outcome measures were a composite of doubling of the serum creatinine level, end-stage renal disease, or death. RESULTS During each year of the cohort study, the annual use of an ACEI or an angiotensin receptor blocker ranged from 83.7% to 89.0% (vs 38.5% to 49.8% during the trial). The mean BP in the cohort study was 133/78 mm Hg (vs 136/82 mm Hg in the trial). Overall, 567 participants experienced the primary outcome; the 10-year cumulative incidence rate was 53.9%. Of 576 participants with at least 7 years of follow-up, 33.5% experienced a slow decline in kidney function (mean annual decline in the estimated glomerular filtration rate, <1 mL/min/1.73 m2). CONCLUSION Despite the benefits of renin-angiotensin system-blocking therapy on CKD progression, most African Americans with hypertensive CKD who are treated with currently recommended BP therapy continue to progress during the long term.

Arginine Feeding Modifies Cyclosporine Nephrotoxicity in Rats

Glycine (G) infusion causes renal vasodilation mediated by nitric oxide (NO). Cyclosporine A (CsA) nephrotoxicity is characterized by preglomerular vasoconstriction and decreased efferent arteriolar tone probably related to reduced NO and angiotensin II, respectively. L-Arginine (ARG) is a precursor to NO. To test the hypothesis that chronic CsA decreases renal NO activity, we compared the glomerular hemodynamic response to glycine infusion in rats after 8 d of CsA (30 mg/kg per d s.c.), CsA and ARG (1.6 g/kg per d p.o.) (A/CsA), and in two groups of pair-fed controls (CON, A/CON). Single nephron GFR (SNGFR), single nephron plasma flow (SNPF), glomerular capillary hydrostatic pressure gradient (delta P), proximal tubular reabsorption (APR), and kidney tissue angiotensin II (AIIk) were measured before and during G. CsA was associated with baseline decrements in SNGFR, SNPF, delta P, and AIIk, and with a blunted hemodynamic response to G. In CON, ARG did not affect baseline hemodynamics or modify the response to G. In CsA, ARG decreased baseline preglomerular resistance and restored the glomerular hemodynamic response to G. G was associated with a significant increase in AIIk in both CON and CsA. These findings suggest that (a) CsA is associated with decreased AIIk, and (b) CsA may diminish NO activity within the kidney, and that this capacity may be partially restored by arginine feeding.

Functional effects on glomerular hemodynamics of short-term chronic cyclosporine in male rats.

We evaluated the effects of chronic cyclosporine (CsA) administration on the determinants of nephron filtration rate (SNGFR) using micropuncture techniques (mp) in male Munich-Wistar rats. Animals received CsA (30 mg/kg SQ) in olive oil daily for 8 d before mp. Controls (PFC) were pair fed. SNGFR, glomerular capillary hydrostatic pressure gradient (delta P), nephron plasma flow (SNPF), plasma protein oncotic pressure (pi A), and glomerular ultrafiltration coefficient (LpA) were quantitated in each experiment. CsA was associated with a lower SNGFR due to decreases in SNPF and a major reduction in delta P but no decrease in LpA. Plasma volume expansion (PVE) caused SNGFR, delta P, and SNPF to increase in both CsA and PFC without eliminating the differences between CsA and PFC. CsA/PVE rats responded normally to angiotensin II (AII) infusion indicating that the low delta P associated with CsA is not due to unresponsiveness to AII. Prior renal denervation caused SNGFR and SNPF to increase in CsA-treated animals but failed to alter the reduction in glomerular capillary pressure after CsA or to eliminate the glomerular hemodynamic differences between treated animals and pair-fed controls. This constellation of glomerular hemodynamic abnormalities suggests that the renal effect of short-term chronic CsA administration is mediated primarily by a reduction in the afferent effective filtration pressure resulting from an imbalance between pre- and postglomerular vascular resistances.

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.

Sodium/Glucose Cotransporter 2 Inhibitors and Prevention of Diabetic Nephropathy: Targeting the Renal Tubule in Diabetes

Optimal prevention and treatment of chronic kidney disease in diabetes requires implementing therapies that specifically interfere with the pathogenesis of diabetic nephropathy. In this regard, significant attention has been given to alterations of the proximal tubule and resulting changes in glomerular filtration rate. At the onset of diabetes mellitus, hyperglycemia causes increases in proximal tubular reabsorption secondary to induction of tubular growth with associated increases in sodium/glucose cotransport. The increase in proximal reabsorption leads to a decrease in solute load to the macula densa, deactivation of the tubuloglomerular feedback, and increases in glomerular filtration rate. Because glomerular hyperfiltration currently is recognized as a risk factor for progression of kidney disease in diabetic patients, limiting proximal tubular reabsorption constitutes a potential target to reduce hyperfiltration. The recent introduction of sodium/glucose cotransporter 2 (SGLT2) inhibitors opens new therapeutic perspectives for this high-risk patient population. Experimental studies have shown that these new agents attenuate the progressive nature of diabetic nephropathy by blood glucose-dependent and -independent mechanisms. SGLT2 inhibition may prevent glomerular hyperfiltration independent of the effect of lowering blood glucose levels while limiting kidney growth, inflammation, and albuminuria through reductions in blood glucose levels. Clinical data for the potential role of the proximal tubule in the pathophysiology of diabetic nephropathy and the nephroprotective effects of SGLT2 inhibitors currently are limited compared to the more extensive experimental literature. We review the evidence supporting this working hypothesis by integrating the experimental findings with the available clinical data.

Relationship between Ambulatory BP and Clinical Outcomes in Patients with Hypertensive CKD

BACKGROUND AND OBJECTIVES Abnormal ambulatory BP (ABP) profiles are commonplace in CKD, yet the prognostic value of ABP for renal and cardiovascular outcomes is uncertain. This study assessed the relationship of baseline ABP profiles with CKD progression and subsequent cardiovascular outcomes to determine the prognostic value of ABP beyond that of clinic BP measurements. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Between 2002 and 2003, 617 African Americans with hypertensive CKD treated to a clinic BP goal of <130/80 mmHg were enrolled in this prospective, observational study. Participants were followed for a median of 5 years. Primary renal outcome was a composite of doubling of serum creatinine, ESRD, or death. The primary cardiovascular outcome was a composite of myocardial infarction, hospitalized congestive heart failure, stroke, revascularization procedures, cardiovascular death, and ESRD. RESULTS Multivariable Cox proportional hazard analysis showed that higher 24-hour systolic BP (SBP), daytime, night-time, and clinic SBP were each associated with subsequent renal (hazard ratio, 1.17-1.28; P<0.001) and cardiovascular outcomes (hazard ratio, 1.22-1.32; P<0.001). After controlling for clinic SBP, ABP measures were predictive of renal outcomes in participants with clinic SBP <130 mmHg (P<0.05 for interaction). ABP predicted cardiovascular outcomes with no interaction based on clinic BP control. CONCLUSIONS ABP provides additional information beyond that of multiple clinic BP measures in predicting renal and cardiovascular outcomes in African Americans with hypertensive CKD. The primary utility of ABP in these CKD patients was to identify high-risk individuals among those patients with controlled clinic BP.

Renal Functional Reserve in the Early Stage of Experimental Diabetes

The role of renal functional reserve (RFR; increase in plasma flow and glomerular filtration rate in response to protein loading) as an indicator of increased glomerular hydrostatic pressure and flow was evaluated in recent-onset poorly controlled diabetic rats. Streptozocin-induced diabetic (STZ-D) rats were studied with micropuncture (MP) technique after 10–15 days of diabetes (daily blood glucose level 15.3–18 mmol). We also studied STZ-D rats treated with the converting-enzyme inhibitor (CEI) enalapril or the angiotensin II (ANG II) receptor antagonist DuP 753 (DuP) for 3 days before MP. Nondiabetic rats (NOR) served as controls. Glomerular hemodynamics and proximal tubular reabsorption were measured in the control period and during intravenous glycine infusion. In NOR rats, glycine increased single-nephron plasma flow (SNPF) and single-nephron glomerular filtration rate (SNGFR). Although STZ-D rats did not exhibit hyperfiltration, SNGFR and SNPF were not modified by glycine, defining loss of RFR. CEI rats responded to glycine with an increase in SNGFR due to a rise in SNPF and a rise in the ultrafiltration coefficient. Interestingly, loss of RFR in STZ-D rats was associated with a decrease in absolute proximal reabsorption. The decrease in absolute proximal reabsorption was corrected by both CEI and DuP, although glomerular vasodilation was restored only in the CEI group. In conclusion, at the early stage of diabetes mellitus, loss of RFR does not detect hyperfiltration, but rather the presence of a tubular alteration probably dependent on ANG II. The CEI enalapril but not DuP restored RFR in diabetic rats, suggesting that other ANG II-independent effects of CEI are important in restoring a normal response to glycine.