Faculty Bibliography

BACKGROUND:There is growing evidence that the accumulation of protein- bound uremic retention solutes, such as indoxyl sulfate, p-cresyl sulfate and kynurenic acid, play a role in the accelerated cardiovascular disease seen in patients undergoing chronic hemodialysis. Protein-binding, presumably to albumin, renders these solutes poor-dialyzable. We previously observed that the free fraction of indoxyl sulfate was markedly reduced at the end of hemodialysis. We hypothesized that solute binding might be pH-dependent and attributed the changes in free solute concentration to the higher serum pH observed at the end of standard hemodialysis with dialysis buffer bicarbonate concentration greater than 35 mmol/L. We observed that acidification of uremic plasma to pH 6 in vitro greatly increased the proportion of freeIS. METHODS:We tested our hypothesis by reducing the dialysate bicarbonate buffer concentration to 25 mmol/L for the initial half of the hemodialysis treatment ("isohydric dialysis"). Eight stable hemodialysis patients underwent "isohydric dialysis" for 90 minutes and then were switched to standard buffer (bicarbonate = 37mmol/L). A second dialysis, 2 days later, employed standard buffer throughout. RESULTS:We found a clearcut separation of blood pH and bicarbonate concentrations after 90 minutes of "isohydric dialysis" (pH = 7.37, bicarbonate = 22.4 mmol/L) and standard dialysis (pH = 7.49, bicarbonate = 29.0 mmol/L). Binding affinity varied widely among the 10 uremic retention solutes analyzed. Kynurenic acid (0.05 free), p-cresyl sulfate (0.12 free) and indoxyl sulfate (0.13 free) demonstrated the greatest degree of binding. Three solutes (indoxyl glucuronide, p-cresyl glucuronide, and phenyl glucuronide) were virtually unbound. Analysis of free and bound concentrations of uremic retention solutes confirmed our prediction that binding of solute is affected by pH. However, in a mixed models analysis, we found that the reduction in total uremic solute concentration during dialysis accounted for a greater proportion of the variation in free concentration, presumably an effect of saturation binding to albumin, than did the relatively small change in pH produced by isohydric dialysis. The effect of pH on binding appeared to be restricted to those solutes most highly protein-bound. The solutes most tightly bound exhibited the lowest dialyzer clearances. An increase in dialyzer clearance during isohydric and standard dialyses was statistically significant only for kynurenic acid. CONCLUSION/CONCLUSIONS:These findings provide evidence that the binding of uremic retention solutes is influenced by pH. The effect of reducing buffer bicarbonate concentration ("isohydric dialysis:"), though significant, was small but may be taken to suggest that further modification of dialysis technique that would expose blood to a greater decrease in pH would lead to a greater increase the free fraction of solute and enhance the efficacy of hemodialysis in the removal of highly protein-bound uremic retention solutes.

[This corrects the article DOI: 10.1371/journal.pone.0192770.].

Background: There is growing evidence that the accumulation of protein-bound uremic retention solutes, such as indoxyl sulfate (IS), p-cresyl sulfate (PCS) and kynurenic acid (KA), play a role in the accelerated cardiovascular disease seen in patients undergoing chronic hemodialysis. Protein-binding, presumably to albumin, renders these solutes poor-dialyzable. We had previously observed that the concentration of free solute and its unbound fraction were markedly reduced at the end of hemodialysis. We hypothesized that solute binding might be pH-dependent and the changes attributable to the higher serum pH at the end of hemodialysis. In vitro, acidification of uremic plasma to pH 6 greatly increased the proportion of unbound indoxyl sulfate.
Method(s): We tested our hypothesis by reducing the dialysate bicarbonate buffer concentration to 25 mEq/L for the initial half of hemodialysis ('isohydric dialysis'). Eight stable hemodialysis patients underwent 'isohydric dialysis' and, midway, were switched to standard buffer (37 mEq/L). A second dialysis, 2 days later, employed standard buffer throughout.
Result(s): We found a clearcut separation of blood pH and bicarbonate concentrations 90 minutes following 'isohydric dialysis' (pH = 7.37, HCO3 =22.4 mEq/l) and standard dialysis (pH= 7.49, HCO3 = 29.5). Analysis of free and bound concentrations of uremic retention solutes confirmed our prediction that binding of solute is affected by pH. However, in mixed models analysis, we found that the reduction in total uremic solute concentration during dialysis accounted for a greater proportion of the variation in free concentration, presumably an effect of saturation binding to albumin, than did the relatively small change in pH produced by isohydric dialysis.
Conclusion(s): These findings suggest that modification of dialysis technique that would expose blood to a transient decrease in pH might increase the free fraction of solute and enhance the efficacy of hemodialysis in the removal of protein-bound uremic retention solutes

BACKGROUND: Chronic kidney disease (CKD) associated with type 2 diabetes is the leading cause of kidney failure, with both inflammation and oxidative stress contributing to disease progression. Bardoxolone methyl, an oral antioxidant inflammation modulator, has shown efficacy in patients with CKD and type 2 diabetes in short-term studies, but longer-term effects and dose response have not been determined. METHODS: In this phase 2, double-blind, randomized, placebo-controlled trial, we assigned 227 adults with CKD (defined as an estimated glomerular filtration rate [GFR] of 20 to 45 ml per minute per 1.73 m(2) of body-surface area) in a 1:1:1:1 ratio to receive placebo or bardoxolone methyl at a target dose of 25, 75, or 150 mg once daily. The primary outcome was the change from baseline in the estimated GFR with bardoxolone methyl, as compared with placebo, at 24 weeks; a secondary outcome was the change at 52 weeks. RESULTS: Patients receiving bardoxolone methyl had significant increases in the mean (+/-SD) estimated GFR, as compared with placebo, at 24 weeks (with between-group differences per minute per 1.73 m(2) of 8.2+/-1.5 ml in the 25-mg group, 11.4+/-1.5 ml in the 75-mg group, and 10.4+/-1.5 ml in the 150-mg group; P<0.001). The increases were maintained through week 52, with significant differences per minute per 1.73 m(2) of 5.8+/-1.8 ml, 10.5+/-1.8 ml, and 9.3+/-1.9 ml, respectively. Muscle spasms, the most frequent adverse event in the bardoxolone methyl groups, were generally mild and dose-related. Hypomagnesemia, mild increases in alanine aminotransferase levels, and gastrointestinal effects were more common among patients receiving bardoxolone methyl. CONCLUSIONS: Bardoxolone methyl was associated with improvement in the estimated GFR in patients with advanced CKD and type 2 diabetes at 24 weeks. The improvement persisted at 52 weeks, suggesting that bardoxolone methyl may have promise for the treatment of CKD. (Funded by Reata Pharmaceuticals; BEAM ClinicalTrials.gov number, NCT00811889.)

OBJECTIVE: Utilization, outcomes, and retransplantation (ReTx) of liver allografts obtained by donation after cardiac death (DCD) are examined to identify mechanisms to optimize donation. SUMMARY AND BACKGROUND DATA: DCD for liver transplantation (LTX) has immediate potential to expand the donor pool but application is limited. METHODS: Retrospective analysis of the Scientific Registry of Transplant Recipients (SRTR) from January 2002 to April 2007 identified 855 DCD and 21,089 donation after brain death (DBD) adult, initial, whole-organ, liver-only LTX. Donor, recipient, and transplant characteristics were compared. Outcome measures were listing for ReTx within 1 year and graft survival determined as death or ReTx. RESULTS: DCD donors were younger (P < 0.001), with fewer African American and non-white race (P < 0.001), and fewer deaths secondary to stroke (P < 0.001). DCD recipients were older (P < 0.001), with lower Model for End-Stage Liver Disease (MELD) scores (P < 0.001), and less likely in intensive care (P = 0.02) or high-urgency status (P < 0.001). DCD allografts were more frequently imported from another allocation region (12% vs. 7%; P < 0.001). Cox regression analysis of time to DCD graft failure demonstrates higher DCD graft failure within the first 180 days (20.5% DCD vs. 11.5% DBD; P < 0.001) with convergence thereafter. DCD listing for ReTx and graft failure progressed continuously over 180 days versus 20 days in DBD. At ReTx, DCD recipients waited longer and received higher risk allografts (P = 0.039) more often from another region. More DCD recipients remain waiting for ReTx with fewer removed for death, clinical deterioration, or improvement. CONCLUSIONS: DCD utilization is impeded by early outcomes and a temporally different failure pattern that limits access to ReTx. Allocation policy that recognizes these limitations and increases access to ReTx is necessary for expansion of this donor population

BACKGROUND: Erectile dysfunction (ED) is highly prevalent in men with renal disease. The clearance of sildenafil citrate, a highly effective oral treatment for ED, is decreased in men with severe renal insufficiency, but the pharmacokinetic and hemodynamic profiles during maintenance hemodialysis in men with end-stage renal disease have not been studied. METHODS: Fifteen men undergoing chronic outpatient maintenance hemodialysis received a single 50-mg oral dose of sildenafil on 2 occasions, once 2 hours before, and once 2 hours after hemodialysis, with randomized assignment to sequence. Blood and dialysate samples were collected, and hemodynamic measurements were made. RESULTS: Hemodialysis did not significantly clear either sildenafil or its primary metabolite, UK-103,320. Administration after hemodialysis was associated with a 17% higher peak plasma concentration and earlier time to peak, which were not clinically meaningful, whereas the overall extent of absorption and the elimination half-life were not affected. The average extent of drug bound to plasma protein was approximately 96% in hemodialysis patients. Intradialytic hypotension was not observed more frequently when sildenafil was administered before hemodialysis. Systolic blood pressure tended to decrease less during hemodialysis when subjects were treated with sildenafil before dialysis. CONCLUSION: The present study demonstrates that sildenafil is not cleared by hemodialysis, and the pharmacokinetic profile resembles more closely that observed in normal volunteers than that observed in patients with severe renal insufficiency. In addition, we found that sildenafil does not promote intradialytic hypotension

OBJECTIVES: To evaluate the efficacy and tolerability of the selective alpha(1)-adrenergic antagonist doxazosin and the 5-alpha-reductase inhibitor finasteride, alone and in combination, for the symptomatic treatment of benign prostatic hyperplasia. METHODS: In a prospective, double-blind, placebo-controlled trial, 1095 men aged 50 to 80 years were randomized to treatment for 52 weeks with doxazosin, finasteride, the combination of doxazosin and finasteride, or placebo. The dose of finasteride (or its matched placebo) was 5 mg/day. Doxazosin (or its matched placebo) was initiated at 1 mg/day, and titrated up to a maximum of 8 mg/day over approximately 10 weeks according to the response of the maximal urinary flow rate (Qmax) and International Prostate Symptom Score (IPSS). The IPSS and Qmax were assessed at baseline and at weeks 10, 14, 26, 39, and 52 or at the endpoint. RESULTS: An intent-to-treat analysis of 1007 men showed doxazosin and doxazosin plus finasteride combination therapy produced statistically significant improvements in total IPSS and Qmax compared with placebo and finasteride alone (P <0.05). Finasteride alone was not significantly different statistically from placebo with respect to total IPSS and Qmax. All treatments were generally well tolerated. CONCLUSIONS: Doxazosin was effective in improving urinary symptoms and urinary flow rate in men with benign prostatic hyperplasia, and was more effective than finasteride alone or placebo. The addition of finasteride did not provide further benefit to that achieved with doxazosin alone