Abstract. It is unclear whether increased muscle mass or body fat confer the survival advantage in hemodialysis patients with high body-mass index (BMI). Twenty-four-hour urinary creatinine (UCr) excretion was used as a measure of muscle mass. The outcomes of hemodialysis patients with high BMI and normal or high muscle mass (inferred low body fat) and high BMI and low muscle mass (inferred high body fat) were studied to study the effects of body composition on outcomes. In 70,028 patients who initiated hemodialysis in the United States from January 1995 to December 1999 with measured creatinine clearances reported in the Medical Evidence form, all-cause and cardiovascular mortality were examined in Cox and parametric survival models. When compared with normal BMI (18.5 to 24.9 kg/m 2 ) group, patients with high BMI (Ն25 kg/m 2 ) had lower hazard of death (hazard ratio [HR], 0.85; P Ͻ 0.001). However, when compared with normal BMI patients with UCr Ͼ25th percentile (0.55 g/d), high BMI patients with UCr Ͼ0.55 g/d had lower hazard of all-cause (HR, 0.85; P Ͻ 0.001) and cardiovascular death (HR, 0.89; P Ͻ 0.001), and high BMI patients with UCr

Abstract. Previous studies showed that sicker patients were initiated on dialysis at higher GFR as estimated by the Modification of Diet in Renal Disease (MDRD) formula. It was previously shown that patients with low creatinine production were malnourished and had low serum creatinine levels and creatinine clearances (CrCl) but high MDRD GFR at initiation of dialysis. Therefore, a propensity score approach was used to examine the associations of MDRD GFR and measured CrCl at the initiation of dialysis with subsequent mortality. Baseline data and outcomes were obtained from the Dialysis Morbidity Mortality Study Wave II. Propensity scores for early initiation derived by logistic regression were used in Cox models to examine mortality. Each 5-ml/min increase in MDRD GFR at initiation of dialysis in the entire cohort was associated with increased hazard of death in multivariable Cox model (hazard ratio [HR] 1.14; P ϭ 0.002). In the subgroup of patients with reported CrCl, higher MDRD GFR was associated with increased risk of death (for each 5-ml/min increase, HR 1.27; P Ͻ 0.001) but not CrCl (for each 5-ml/min increase, HR 0.98; P ϭ 0.81). These divergent results might reflect erroneous GFR estimation by the MDRD formula. Furthermore, these data do not support earlier initiation of dialysis. Therefore, for patients without clinical indications for initiation of dialysis, the appropriate GFR level for initiation of dialysis is unknown.Early initiation of dialysis might improve nutrition with consequent decrease in hospitalization, mortality, and costs (1-8). However, early initiation of dialysis also exposes the patient to complications of dialysis, unnecessary lifestyle restriction, and potential increased costs. Thus, the optimal timing of initiation of dialysis is unclear.There are two methodologic issues that need to be considered in observational studies of optimal timing of dialysis. First, randomized controlled trials are considered the gold standard in comparison of different interventions, as effective randomization coupled with sufficient sample size would result in equal distribution of baseline factors across treatment groups. There may be significant imbalances in distribution of key parameters across treatment groups in observational studies because certain clinical conditions might be indications for therapy with one intervention (in this case, early initiation of dialysis) than the other. Indeed, previous studies of the United States Renal Data System (USRDS) data showed that sicker patients were initiated on dialysis at higher GFR as estimated by the Modification of Diet in Renal Disease (MDRD) formula (9). The use of propensity stratification based on propensity scores has been shown to reduce or eliminate the imbalances in distribution of baseline covariables across treatment groups in nonrandomized studies (10,11).Second, the MDRD formula has not been validated in patients with advanced renal failure. Our earlier study showed that patients with low creatinine production were malnourished and had ...

The prorenin receptor (PRR), a recently discovered component of the renin-angiotensin system, is expressed in the nephron in general and the collecting duct in particular. However, the physiological significance of nephron PRR remains unclear, partly due to developmental abnormalities associated with global or renal-specific PRR gene knockout (KO). Therefore, we developed mice with inducible nephron-wide PRR deletion using Pax8-reverse tetracycline transactivator and LC-1 transgenes and loxP flanked PRR alleles such that ablation of PRR occurs in adulthood, after induction with doxycycline. Nephron-specific PRR KO mice have normal survival to ∼1 yr of age and no renal histological defects. Compared with control mice, PRR KO mice had 65% lower medullary PRR mRNA and protein levels and markedly diminished renal PRR immunofluorescence. During both normal water intake and mild water restriction, PRR KO mice had significantly lower urine osmolality, higher water intake, and higher urine volume compared with control mice. No differences were seen in urine vasopressin excretion, urine Na(+) and K(+) excretion, plasma Na(+), or plasma osmolality between the two groups. However, PRR KO mice had reduced medullary aquaporin-2 levels and arginine vasopressin-stimulated cAMP accumulation in the isolated renal medulla compared with control mice. Taken together, these results suggest nephron PRR can potentially modulate renal water excretion.

The physiological and pathophysiological significance of collecting duct (CD)-derived renin, particularly as it relates to blood pressure (BP) regulation, is unknown. To address this question, we generated CD-specific renin knockout (KO) mice and examined BP and renal salt and water excretion. Mice containing loxP-flanked exon 1 of the renin gene were crossed with mice transgenic for aquaporin-2-Cre recombinase to achieve CD-specific renin KO. Compared with controls, CD renin KO mice had 70% lower medullary renin mRNA and 90% lower renin mRNA in microdissected cortical CD. Urinary renin levels were significantly lower in KO mice (45% of control levels) while plasma renin concentration was significantly higher in KO mice (63% higher than controls) during normal-Na intake. While no observable differences were noted in BP between the two groups with varying Na intake, infusion of angiotensin II at 400 ng·kg(-1)·min(-1) resulted in an attenuated hypertensive response in the KO mice (mean arterial pressure 111 ± 4 mmHg in KO vs. 128 ± 3 mmHg in controls). Urinary renin excretion and epithelial Na(+) channel (ENaC) remained significantly lower in the KO mice following ANG II infusion compared with controls. Furthermore, membrane-associated ENaC protein levels were significantly lower in KO mice following ANG II infusion. These findings suggest that CD renin modulates BP in ANG II-infused hypertension and these effects are associated with changes in ENaC expression.

There is a lack of data on patient preferences for intense hemodialysis (IHD). In this study, we conducted a cross-sectional survey to identify patient preferences and patient-centered barriers for IHD. A questionnaire on preferences and anticipated barriers, anticipated benefits, and quality of life for three in-center IHD schedules (daytime 2 hr six times/week [DHD], nocturnal 8 hr three times/week [ND3], and nocturnal 8 hr six times/week [ND6]) was administered to 100 chronic hemodialysis patients. A majority of patients (68%) were willing to undergo DHD for symptomatic benefits or increase in survival. An increase in energy level (94%) and improvement in sleep (57%) were the most common potential benefits that would justify DHD, but only 19% would undergo DHD for an increase in survival of < or =3 years. Only 20% and 7% would consider ND3 and ND6, respectively. The most common reported barriers were inadequate time for self (50%) and family (53%), followed by transportation difficulties (53%). Most patients would undergo DHD for symptomatic or survival benefits, but not ND3 or ND6. Disruption of personal time, however, is an important consideration. Success of DHD program would depend on arrangements for transportation to dialysis unit.

The physiological significance of the renal tubular prorenin receptor (PRR) has been difficult to elucidate due to developmental abnormalities associated with global or renal-specific PRR knockout (KO). We recently developed an inducible renal tubule-wide PRR KO using the Pax8/LC1 transgenes and demonstrated that disruption of renal tubular PRR at 1 mo of age caused no renal histological abnormalities. Here, we examined the role of renal tubular PRR in blood pressure (BP) regulation and Na(+) excretion and investigated the signaling mechanisms by which PRR regulates Na(+) balance. No detectable differences in BP were observed between control and PRR KO mice fed normal- or low-Na(+) diets. However, compared with controls, PRR KO mice had elevated plasma renin concentration and lower cumulative Na(+) balance with normal- and low-Na(+) intake. PRR KO mice had an attenuated hypertensive response and reduced Na(+) retention following angiotensin II (ANG II) infusion. Furthermore, PRR KO mice had significantly lower epithelial Na(+) channel (ENaC-α) expression. Treatment with mouse prorenin increased, while PRR antagonism decreased, ENaC activity in isolated split-open collecting ducts (CD). The prorenin effect was prevented by protein kinase A and Akt inhibition, but unaffected by blockade of AT1, ERK1/2, or p38 MAPK pathways. Taken together, these data indicate that renal tubular PRR, likely via direct prorenin/renin stimulation of PKA/Akt-dependent pathways, stimulates CD ENaC activity. Absence of renal tubular PRR promotes Na(+) wasting and reduces the hypertensive response to ANG II.

The need for accessible and inexpensive microfluidic devices requires new manufacturing methods and materials that can replace traditional soft lithography and polydimethylsiloxane (PDMS). Here, we use fused deposition modeling (FDM) 3D printing to create transparent, flexible, and biocompatible microfluidic devices with channel dimensions consistently under 100 µm and as small as 40 µm. Channels consistently printed about 100 µm smaller than designed, but were repeatable and predictable. We demonstrate that thermoplastic polyurethane (TPU) has properties that may be useful for microfluidic applications, while remaining cost-efficient (~$0.01 per device) and optimal for rapid prototyping (fabrication time < 25 min). FDM printing of TPU was shown to be able to produce high aspect ratio channels. Methods to compensate for sagging of bridging layers are provided. The 3D printed TPU was shown to be 85% transparent, durable, flexible, robust, and capable of withstanding high pressures when compared with PDMS. 3D printed TPU was also found to be compatible with cell culture, suggesting its usefulness in many biological applications.

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