Faculty Bibliography

BACKGROUND: Individuals with advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD) have high plasma total homocysteine (tHcy) levels, which may be a risk factor for cognitive impairment. Whether treatment with high-dose B vitamins to decrease high tHcy levels improves cognition in persons with kidney disease is unknown. STUDY DESIGN: Randomized controlled trial. SETTING & PARTICIPANTS: A substudy of 659 patients (mean age, 67.3 +/- 11.7 years) who participated in a randomized double-blind clinical trial 5 years in duration conducted in 36 US Department of Veterans Affairs medical centers of the effect on all-cause mortality of vitamin-induced lowering of plasma tHcy level. 236 (35.8%) were treated by using dialysis (ESRD) and 423 (64.2%) had a Cockcroft-Gault estimated creatinine clearance of 30 mL/min or less (advanced CKD). All had high tHcy levels (>/=15 mumol/L) at baseline. Cognitive assessments began during the follow-up period of the main trial 3 years after treatment began; participants subsequently were retested 1 year later to assess cognitive change. INTERVENTION: Daily high-dose B vitamin capsule (40 mg of folic acid, 100 mg of vitamin B(6), and 2 mg of vitamin B(12)) or placebo. OUTCOMES: Cognitive function at initial assessment and 1 year later. MEASUREMENTS: Telephone Interview of Cognitive Status-modified, supplemented with attention, working memory, and executive function tests. RESULTS: Initial cognitive function was impaired in approximately 19% of patients regardless of treatment assignment (vitamin or placebo) or kidney disease status (advanced CKD or ESRD). Treatment decreased tHcy levels by 26.7%. Unadjusted and adjusted analyses showed that treatment did not improve initial cognitive outcomes or affect subsequent cognitive status 1 year later. LIMITATIONS: Cognitive assessments began after treatment was initiated; cognitive assessment was limited. CONCLUSION: Treatment with high daily doses of B vitamins, which decreased tHcy levels, did not affect cognitive outcomes in patients with advanced CKD and ESRD

This issue provides a clinical overview of nephrolithiasis focusing on prevention, diagnosis, treatment, practice improvement, and patient information. Readers can complete the accompanying CME quiz for 1.5 credits. Only ACP members and individual subscribers can access the electronic features of In the Clinic. Non-subscribers who wish to access this issue of In the Clinic can elect 'Pay for View.' Subscribers can receive 1.5 category 1 CME credits by completing the CME quiz that accompanies this issue of In the Clinic. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including PIER (Physicians' Information and Education Resource) and MKSAP (Medical Knowledge and Self Assessment Program). Annals of Internal Medicine editors develop In the Clinic from these primary sources in collaboration with the ACP's Medical Education and Publishing division and with assistance of science writers and physician writers. Editorial consultants from PIER and MKSAP provide expert review of the content. Readers who are interested in these primary resources for more detail can consult www.acponline.org, http://pier.acponline.org, and other resources referenced within each issue of In the Clinic

BACKGROUND: Abnormalities in the gene regulating methylenetetrahydrofolate reductase (MTHFR) are associated with increased homocysteine levels and increased mortality in normal and chronic kidney disease (CKD) populations. STUDY DESIGN: Gene association study. SETTING & PARTICIPANTS: This was a substudy of 677 patients from 21 Veterans Affairs medical centers participating in a randomized clinical trial (Homocysteinemia in Kidney and End-Stage Renal Disease [HOST]) of the effect on all-cause mortality of vitamin-induced lowering of plasma homocysteine levels. Of 677 patients, 213 (31%) were treated by using dialysis (end-stage renal disease [ESRD]) and 464 (69%) had a Cockcroft-Gault estimated creatinine clearance less than 30 mL/min (advanced CKD). PREDICTOR: Polymorphisms C677T (rs1801133) and A1298C (rs1801131) of the MTHFR gene. OUTCOMES: Unadjusted and adjusted all-cause mortality. MEASUREMENTS: DNA was extracted from blood samples and amplified by means of polymerase chain reaction. RESULTS: The adjusted hazard ratio in a recessive model of the relationship between the C677T polymorphism and all-cause mortality in all patients was 1.47 (95% confidence interval, 1.00 to 2.16; P = 0.05). In patients with ESRD with the mutant TT genotype, the adjusted hazard ratio for mortality in all patients was 2.27 (95% confidence interval, 1.07 to 4.84; P = 0.03); patients with advanced CKD showed a similar, although not significant, trend. The risk of myocardial infarction (P = 0.05) and composite risk of myocardial infarction, stroke, lower-extremity amputation, and mortality (P = 0.02) were greater in patients with ESRD with the mutant T allele at nucleotide 677. The overall relationship between the A1298C polymorphism and mortality was not significant (P = 0.6). LIMITATIONS: Participants were 98% men; DNA samples were not obtained at enrollment in HOST; linkage disequilibrium with another causal polymorphism is a potential confounding factor; and power was reduced by the limited number of participants. CONCLUSIONS: These findings provide additional support for the hypothesis that the mutant TT genotype at nucleotide 677 of the gene regulating MTHFR activity may increase the mortality risk in patients with ESRD

BACKGROUND AND OBJECTIVES: Data from several countries suggest a recent world-wide increase in the prevalence of stone disease. However, these studies have not analyzed the effect that increases in utilization of imaging modalities have had on detection of asymptomatic stones. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A retrospective chart review of all patients who had an abdominal or retroperitoneal ultrasound in 2005 at a Department of Veterans' Affairs Medical Center was conducted. The charts of patients who had ultrasounds demonstrating kidney stones were further reviewed. Patients were classified into symptomatic and asymptomatic groups on the basis of their clinical history. Age and sex for all patients were recorded. For those patients with stones, additional data were recorded. Of all patients in the study, the percentage of those with asymptomatic stones was calculated. Taking into account uncertainty about symptomaticity in some patients, a sensitivity analysis for the presence or absence of gross and microhematuria was performed to determine a range for the percent of asymptomatic stones. Appropriate statistical tests were used to determine significance. RESULTS: The prevalence of all kidney stones in the study group was 8.6 %. Using the sensitivity analysis, 29.8 to 45.7% of all stones were asymptomatic. Of stones found on abdominal ultrasounds, 71.4% were asymptomatic, whereas 36.8% of stones found on retroperitoneal ultrasound were asymptomatic. CONCLUSIONS: Asymptomatic stones have a relatively high prevalence on ultrasound. Epidemiologic estimates of prevalence of nephrolithiasis need to account for increases in utilization of imaging modalities and the resulting detection bias

The effect of commercial oral rehydration solutions ('sports drinks') relative to water on risk of nephrolithiasis has not been studied previously. We studied the effect of two sports drinks, Performance (Shaklee Corp., Pleasanton, CA, USA) and Gatorade (Gatorade, Chicago, IL, USA) on urinary chemistry and measures of lithogenicity in non-stone formers. Performance has a pH of 4.3, and contains 21 mmol/L of sodium, 5.3 mmol/L of potassium, 0.8 mmol/L of calcium, and 19.5 mmol/L of citrate. Gatorade pH ranges from 2.9 to 3.2, and contains 20 mmol/L of sodium, 3.2 mmol/L of potassium, negligible calcium, and 13.9 mmol/L of citrate. Subjects drank 946 ml (32 oz) of tap water daily for 3 days, and recorded diet history. This was followed by a second 3-day experimental period during which subjects drank 946 ml (32 oz) of sports drink daily, duplicating diets from part 1. In each 3-day period, urine was collected for 24 h during days 2 and 3. Urine chemical analysis was performed, and supersaturations of calcium oxalate, calcium phosphate and uric acid were calculated. Nine subjects completed the study using Performance, ten used Gatorade. Urine volumes and creatinine excretions were not different during the control and experimental periods. Performance increased mean citrate excretion by 170 mg/day (95% CI 57-284 mg/day; P = 0.01) and increased urine pH by 0.31 (95% CI 0.03-0.59; P = 0.03). Gatorade did not significantly change urinary citrate excretion or pH. Neither drink caused significant differences in the excretion of sodium and calcium or any supersaturation value. Ingestion of Performance, but not Gatorade, led to an increase in mean urinary citrate excretion and pH as compared to water. The increase in citrate is likely to be a clinically significant effect. pH is an important determinant of alkali load in beverages containing organic anions. Performance, with more citrate and a higher pH than Gatorade, could represent a superior alternative to water for reducing urinary lithogenicity. Most sports drinks with significant carbohydrate content however may contain too many calories, and fructose, to be preferred beverages for stone prevention

Recent evidence suggests that targeting higher hemoglobin values with erythropoiesis stimulating agents (ESAs) may lack mortality benefits and may even result in adverse cardiovascular complications when used in chronic kidney disease patients. However, ESAs are frequently reported to result in improvements in health-related quality of life (HRQOL). The purpose of this review is to evaluate the magnitude and nature of ESA-associated improvements in HRQOL, as well as to understand how to interpret the clinical significance of HRQOL data. HRQOL findings should be analyzed not by statistical significance but rather by using a minimal clinically important difference approach, or, alternatively, a distribution-based approach (such as Cohen's effect size). HRQOL domains that are most improved with ESAs relate to physical symptoms, vitality, energy, and performance; domains of social functioning and mental health show modest improvement, whereas the domains of emotional functioning and pain show very little improvement. Additional domains not measured by commonly used instruments (such as the SF-36) that have been shown to improve with ESAs include sleep, cognitive functioning, and sexual functioning. The maximal increase in HRQOL per incremental increase in hemoglobin appears to occur in the range of 10-12 g/dl. Beyond this range, additional normalization of hemoglobin (to 12-14 g/dl) results in continued (albeit blunted) improvements in HRQOL.Kidney International advance online publication, 27 August 2008; doi:10.1038/ki.2008.414