Todd W.B. Gehr

Effect of increased renal venous pressure on renal function.

OBJECTIVEnAcute renal failure is seen with the acute abdominal compartment syndrome (AACS). Although the cause of acute renal failure in AACS may be multifactorial, renal vein compression alone has not been investigated. This study evaluated the effects of elevated renal vein pressure (RVP) on renal function.nnnMETHODSnTwo groups of swine (18-22 kg) were studied after left nephrectomy and placement of a renal artery flow probe to measure renal artery blood flow, renal vein catheter, and ureteral cannula. Two hours were allowed for equilibration and an inulin infusion was begun to calculate inulin clearance for measurement of glomerular filtration rate. Group 1 animals (n = 4) had RVP elevated by 30 mm Hg for 2 hours with renal vein constriction. RVP was then returned to baseline for 1 hour. In group 2 (n = 4), the RVP was not elevated. The cardiac index (2.9 +/- 0.5 L/min/m2) and mean arterial pressure (101 +/- 9 mm Hg) remained stable. Plasma renin activity and serum aldosterone were measured every 60 minutes.nnnRESULTSnElevation of RVP (0-30 mm Hg above baseline) in the experimental group showed a significant decrease in renal artery blood flow index (2.7 to 1.5 mL/min per g) and glomerular filtration rate (26 to 8 mL/min) compared with control. In addition, there was significant elevation of plasma serum aldosterone (14 to 25 microng/dL) and plasma renin activity (2.6 to 9.5 microng/mL per h) as well as urinary protein leak in the experimental animals compared with control. These changes were partially or completely reversible as RVP returned toward baseline.nnnCONCLUSIONnElevated RVP alone leads to decreased renal artery blood flow and glomerular filtration rate and increased plasma renin activity, serum aldosterone, and urinary protein leak. These changes are consistent with the renal pathophysiology seen in AACS, morbid obesity, and preeclampsia. The changes are partially or completely reversed by decreasing renal venous pressure as occurs with abdominal decompression for AACS.

MicroRNA profiles in allograft tissues and paired urines associate with chronic allograft dysfunction with IF/TA

Despite the advances in immunosuppression, renal allograft attrition over time remains unabated due to chronic allograft dysfunction (CAD) with interstitial fibrosis (IF) and tubular atrophy (TA). We aimed to evaluate microRNA (miRNA) signatures in CAD with IF/TA and appraise correlation with paired urine samples and potential utility in prospective evaluation of graft function. MiRNA signatures were established between CAD with IF/TA versus normal allografts by microarray. Validation of the microarray results and prospective evaluation of urine samples was performed using real‐time quantitative‐PCR (RT‐qPCR). Fifty‐six miRNAs were identified in samples with CAD‐IF/TA. Five miRNAs were selected for further validation based on array fold change, p‐value and in silico predicted mRNA targets. We confirmed the differential expression of these five miRNAs by RT‐qPCR using an independent set of samples. Differential expression was detected for miR‐142‐3p, miR‐204, miR‐107 and miR‐211 (p < 0.001) and miR‐32 (p < 0.05). Furthermore, differential expression of miR‐142‐3p (p < 0.01), miR‐204 (p < 0.01) and miR‐211 (p < 0.05) was also observed between patient groups in urine samples. A characteristic miRNA signature for IF/TA that correlates with paired urine samples was identified. These results support the potential use of miRNAs as noninvasive markers of IF/TA and for monitoring graft function.

Effects of Increased Renal Parenchymal Pressure on Renal Function

OBJECTIVEnAcute renal failure is seen with the acute abdominal compartment syndrome (AACS). The cause of acute renal failure in AACS is thought to be multifactorial, including increased renal venous pressure, renal parenchymal pressure (RPP), and decreased cardiac output. Previous studies have established the role of renal venous pressure as an important mediator of this renal derangement. In this study, we evaluate the role of renal parenchymal compression on renal function.nnnMETHODSnTwo groups of swine (20-26 kg) were studied after left nephrectomy and placement of a renal artery flow probe and ureteral cannula. Two hours were allowed for equilibration, and an inulin infusion was begun to calculate inulin clearance as a measurement of glomerular filtration. In group 1 animals (n = 6), RPP was elevated by 30 mm Hg for 2 hours with renal parenchymal compression. RPP then returned to baseline for 1 hour. In group 2 (n = 6), the RPP was not elevated. The cardiac index, preload, and mean arterial pressure remained stable. Blood samples for plasma renin activity and plasma aldosterone were taken at baseline and at hourly intervals.nnnRESULTSnElevation of RPP in the experimental group showed no significant decrease in renal blood flow index or glomerular filtration when compared with control animals. There were no significant elevations of plasma aldosterone or plasma renin activity in the experimental animals when compared with control.nnnCONCLUSIONnElevated renal compression alone did not create the pathophysiologic derangements seen in AACS. However, prior data from this laboratory found that renal vein compression alone caused a decreased renal blood flow and glomerular filtration and an increased plasma renin activity, plasma aldosterone, and urinary protein leak. These changes are partially or completely reversed by decreasing renal venous pressure as occurs with abdominal decompression for AACS. These data strengthen the proposal that renal vein compression, and not renal parenchymal compression, is the primary mediator of the renal derangements seen in AACS.

Superiority of Icodextrin Compared with 4.25% Dextrose for Peritoneal Ultrafiltration

Several clinical observations suggest the superiority of icodextrin compared with 4.25% dextrose in optimizing peritoneal ultrafiltration (UF), but no rigorous controlled evaluation has hitherto been performed. For comparing icodextrin and 4.25% dextrose during the long dwell of automated peritoneal dialysis, a multicenter, randomized, double-blind trial was conducted in 92 patients (control, 45; icodextrin, 47) with 4-h dialysate to plasma ratio creatinine >0.70 and D/D(0) glucose <0.34. Long-dwell net UF and the UF efficiency ratio (net UF volume per gram of dialysate carbohydrate absorbed) were determined at baseline, week 1, and week 2. The control and treatment groups were comparable at baseline (all patients using 4.25% dextrose for the long dwell) with regard to mean (+/-SEM) net UF (201.7 +/- 103.1 versus 141.6 +/- 75.4 ml, respectively; P = 0.637) and the percentage of patients with negative net UF (control, 37.8%; treatment, 42.6%; P = 0.641). During the study period, net UF was unchanged from baseline in the control group but increased significantly (P < 0.001) in the icodextrin group from 141.6 +/- 75.4 to 505.8 +/- 46.8 ml at week 1 and 540.2 +/- 46.8 ml at week 2. In the icodextrin group, the incidence of negative net UF was significantly lower (P < 0.0001) than in the control group. Findings were similar for UF efficiency ratio. Rash was reported significantly more often in the icodextrin group. This study showed that in high-average and high transporters, icodextrin is superior to 4.25% dextrose for long-dwell fluid and solute removal.

Clinical Pharmacokinetics of Losartan

Losartan is the first orally available angiotensin-receptor antagonist without agonist properties. Following oral administration, losartan is rapidly absorbed, reaching maximum concentrations 1–2 hours post-administration. After oral administration approximately 14% of a losartan dose is converted to the pharmacologically active E 3174 metabolite. E 3174 is 10- to 40-fold more potent than its parent compound and its estimated terminal half-life ranges from 6 to 9 hours. The pharmacokinetics of losartan and E 3174 are linear, dose-proportional and do not substantially change with repetitive administration. The recommended dosage of losartan 50 mg/day can be administered without regard to food. There are no clinically significant effects of age, sex or race on the pharmacokinetics of losartan, and no dosage adjustment is necessary in patients with mild hepatic impairment or various degrees of renal insufficiency. Losartan, or its E 3174 metabolite, is not removed during haemodialysis.The major metabolic pathway for losartan is by the cytochrome P450 (CYP) 3A4, 2C9 and 2C10 isoenzymes. Overall, losartan has a favorable drug-drug interaction profile, as evidenced by the lack of clinically relevant interactions between this drug and a range of inhibitors and stimulators of the CYP450 system. Losartan does not have a drug-drug interaction with hydrochlorothiazide, warfarin or digoxin. Losartan should be avoided in pregnancy, as is the case with all other angiotensin-receptor antagonists. When given in the second and third trimester of pregnancy, losartan is often associated with serious fetal toxicity. Losartan is a competitive antagonist that causes a parallel rightward shift of the concentration-contractile response curve to angiotensin-II, while E 3174 is a noncompetitive ‘insurmountable’ antagonist of angiotensin-II.The maximum recommended daily dose of losartan is 100mg, which can be given as a once-daily dose or by splitting the same total daily dose into two doses. Losartan reduces blood pressure comparably to other angiotensin-receptor antagonists. Losartan has been extensively studied relative to end-organ protection, with studies having been conducted in diabetic nephropathy, heart failure, post-myocardial infarction and hypertensive patients with left ventricular hypertrophy. The results of these studies have been sufficiently positive to support a more widespread use of angiotensin-receptor antagonists in the setting of various end-organ diseases. Losartan, like other angiotensin-receptor antagonists, is devoid of significant adverse effects.

Diuretic Combinations in Refractory Oedema States

SummaryDiuretic resistance is encountered in a number of disease states, such as chronic renal failure, nephrotic syndrome, congestive heart failure (CHF) and cirrhosis. Diuretic stratagems which produce sequential nephron segment blockade, and thus a synergistic diuretic response, are frequently necessary and are regularly employed in these conditions. Pharmacokinetic determinants of diuretic response, including dose administered, absolute bioavailability, and tubular transport capacity and transport rate, are reviewed here. Pharmacodynamic factors are perhaps more important to overall response, and often result in modification of the dose-response relationship; these are also reviewed here.Stratagems used to maximise the diuretic response to loop diuretics include correcting abnormal haemodynamic parameters, utilising larger doses or constant intravenous infusions, and using albumin as a vehicle to deliver the loop diuretic to the site of tubular secretion. If these measures fail, then diuretic combinations are useful. Perhaps the most effective is the combination of metolazone (a thiazidetype diuretic) and a loop diuretic. The rationale for and use of various diuretic combinations, with particular emphasis on the metolazone-loop diuretic combination, is reviewed here and applied to the major disease states associated with diuretic resistance.

Curcumin ameliorates renal failure in 5/6 nephrectomized rats: role of inflammation

TNF-alpha and NF-kappaB play important roles in the development of inflammation in chronic renal failure (CRF). In hepatic cells, curcumin is shown to antagonize TNF-alpha-elicited NF-kappaB activation. In this study, we hypothesized that if inflammation plays a key role in renal failure then curcumin should be effective in improving CRF. The effectiveness of curcumin was compared with enalapril, a compound known to ameliorate human and experimental CRF. Investigation was conducted in Sprague-Dawley rats where CRF was induced by 5/6 nephrectomy (Nx). The Nx animals were divided into untreated (Nx), curcumin-treated (curcumin), and enalapril-treated (enalapril) groups. Sham-operated animals served as a control. Renal dysfunction in the Nx group, as evidenced by elevated blood urea nitrogen, plasma creatinine, proteinuria, segmental sclerosis, and tubular dilatation, was significantly reduced by curcumin and enalapril treatment. However, only enalapril significantly improved blood pressure. Compared with the control, the Nx animals had significantly higher plasma and kidney TNF-alpha, which was associated with NF-kappaB activation and macrophage infiltration in the kidney. These changes were effectively antagonized by curcumin and enalapril treatment. The decline in the anti-inflammatory peroxisome proliferator-activated receptor gamma (PPARgamma) seen in Nx animals was also counteracted by curcumin and enalapril. Studies in mesangial cells were carried out to further establish that the anti-inflammatory effect of curcumin in vivo was mediated essentially by antagonizing TNF-alpha. Curcumin dose dependently antagonized the TNF-alpha-mediated decrease in PPARgamma and blocked transactivation of NF-kappaB and repression of PPARgamma, indicating that the anti-inflamatory property of curcumin may be responsible for alleviating CRF in Nx animals.

NADPH Oxidase-Mediated Triggering of Inflammasome Activation in Mouse Podocytes and Glomeruli During Hyperhomocysteinemia

AIMnOur previous studies have shown that NOD-like receptor protein (NALP3) inflammasome activation is importantly involved in podocyte dysfunction and glomerular sclerosis induced by hyperhomocysteinemia (hHcys). The present study was designed to test whether nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-mediated redox signaling contributes to homocysteine (Hcys)-induced activation of NALP3 inflammasomes, an intracellular inflammatory machinery in podocytes in vitro and in vivo.nnnRESULTSnIn vitro confocal microscopy and size-exclusion chromatography revealed that upon NADPH oxidase inhibition by gp91(phox) siRNA, gp91ds-tat peptide, diphenyleneiodonium, or apocynin, aggregation of inflammasome proteins NALP3, apoptosis-associated speck-like protein (ASC), and caspase-1 was significantly attenuated in mouse podocytes. This NADPH oxidase inhibition also resulted in diminished Hcys-induced inflammasome activation, evidenced by reduced caspase-1 activity and interleukin-1β production. Similar findings were observed in vivo where gp91(phox-/-) mice and mice receiving a gp91ds-tat treatment exhibited markedly reduced inflammasome formation and activation. Further, in vivo NADPH oxidase inhibition protected the glomeruli and podocytes from hHcys-induced injury as shown by attenuated proteinuria, albuminuria, and glomerular sclerotic changes. This might be attributed to the fact that gp91(phox-/-) and gp91ds-tat-treated mice had abolished infiltration of macrophages and T-cells into the glomeruli during hHcys.nnnINNOVATIONnOur study for the first time links NADPH oxidase to the formation and activation of NALP3 inflammasomes in podocytes.nnnCONCLUSIONnHcys-induced NADPH oxidase activation is importantly involved in the switching on of NALP3 inflammasomes within podocytes, which leads to the downstream recruitment of immune cells, ultimately resulting in glomerular injury and sclerosis.

At-home short daily hemodialysis improves the long-term health-related quality of life

Patients with chronic kidney disease treated by in-center conventional hemodialysis (3 times per week) have significant impairments in health-related quality of life measures, which have been associated with increased morbidity and mortality. FREEDOM is an ongoing prospective cohort study measuring the potential benefits of at-home short daily (6 times per week) hemodialysis. In this interim report we examine the long-term effect of short daily hemodialysis on health-related quality of life, as measured by the SF-36 health survey. This was administered at baseline, 4 and 12 months after initiation of short daily hemodialysis to 291 participants (total cohort), of which 154 completed the 12-month follow-up (as-treated cohort). At the time of analysis, the mean age was 53 years, 66% were men, 58% had an AV fistula, 90% transitioned from in-center hemodialysis, and 45% had diabetes mellitus. In the total cohort analysis, both the physical- and mental-component summary scores improved over the 12-month period, as did all 8 individual domains of the SF-36. The as-treated cohort analysis showed similar improvements with the exception of the role-emotional domain. Significantly, in the as-treated cohort, the percentage of patients achieving a physical-component summary score at least equivalent to the general population more than doubled. Hence, at-home short daily hemodialysis is associated with long-term improvements in various physical and mental health-related quality of life measures.

Effect of timing of dialysis on mortality in critically ill, septic patients with acute renal failure

Acute renal failure with concomitant sepsis in the intensive care unit is associated with significant mortality. The purpose of this study was to determine if the timing of initiation of renal replacement therapy (RRT) in septic patients had an effect on the 28‐day mortality. Retrospective data on medical intensive care unit patients with sepsis and acute renal failure requiring RRT were included. Renal replacement therapy started with a blood urea nitrogen (BUN) of <100u2003mg/dL was defined as “early” initiation, and initiation with a BUN ≥100u2003mg/dL was defined as “late.” Multivariate logistic regression analysis with the primary outcome of death at 14, 28, and 365 days following the initiation of RRT was performed. One hundred thirty patients were studied. The early dialysis (mean BUN 66u2003mg/dL) group had 85 patients; the late group (mean BUN 137u2003mg/dL) had 62 patients. The mean acute physiology and chronic health evaluation II score was 24.5 in both groups. The overall 14, 28, and 365‐day survival rates were 58.1%, 41.9%, and 23.6%. Survival rates for the early group were 67%, 47.7%, and 30.7% at 14, 28, and 365 days. Survival rates for the late group were 46.7%, 31.7%, and 13.3% at 14, 28, and 365 days. Upon logistic regression analysis, initiating dialysis with a BUN >100u2003mg/dL predicted death at 14 days (odds ratio [OR] 3.6, 95% confidence interval [CI] 1.7–7.6, P=0.001), 28 days (OR 2.6, 95% CI 1.2–5.7, P=0.01), and 365 days (OR 3.5, 95% CI 1.2–10, P=0.02). Septic patients who started dialysis with a BUN <100u2003mg/dL had improved mortality rates up to 1 year after initiation of dialysis in this single‐center, retrospective analysis.