Faculty Bibliography

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

The goal of this article is to propose a randomized controlled trial (RCT) that tests a hypothesis that dietary manipulation prevents recurrent kidney stones. Dietary interventions based on epidemiologic and pathophysiologic data are reviewed. The only diet trial successful in preventing stones showed that calcium intake of 1,200 mg/d, accompanied by restriction of animal protein, salt, and oxalate ingestion, was superior to 400 mg of calcium and restricted oxalate intake. This study may be worth repeating in women and in a society in which salt restriction might be less effective (eg, United States). The net result of diet trials establishes significant positive effects on urine chemistries, but these have not yet shown efficacy with regard to stone recurrence. Oxalate restriction alone could be effective, but many questions regarding which populations to study are not defined, and dietary oxalate's contribution to stone formation is disputed. Would such a study be limited to patients identified as having high dietary oxalate intake or high intestinal oxalate absorption? Would colonization with Oxalobacter formigenes influence the result? The increased prevalence of stones is linked to weight gain and obesity, making weight loss a possible therapy to prevent stones. Randomized trials show that diets consisting of low-fat content or low-caloric content cause modest weight loss and might be effective in reducing stone formation. Because the efficacy of thiazides in the prevention of stones in patients with hypercalciuria is clear, I propose dietary comparison of higher calcium intake to thiazides for the prevention of calcium-based kidney stones

A subgroup of hemodialysis patients experience high serum ferritin and low tansferrin saturation for reasons not clearly understood. Here we determined the economic impact of administering sodium ferric gluconate complex to patients with serum ferritin levels higher than 500 ng/ml and a transferrin saturation less than 25% based on the Dialysis Patients Response to IV Iron with Elevated Ferritin (DRIVE) study and its extension, DRIVE II. A cost effectiveness model was developed, consistent with the DRIVE studies, using decision analysis with a 12-week time horizon. The primary effectiveness measure was the mean hemoglobin increase in the intent to treat patient groups comparing epoetin with or without sodium ferric gluconate complex. Costs were computed using projected 2007 US Medicare reimbursements for the treatments and for serious adverse events, with the effectiveness factored by the increase in hemoglobin. The net savings for sodium ferric gluconate complex plus epoetin treatment was $1390 compared to epoetin alone for each g/dl hemoglobin increase over 12 weeks of study. Sensitivity analyses were performed to test the impact of change in the variables (using medians or means and actual 2005 or projected 2007 Medicare reimbursements) and these affirmed the robustness of the model. Our study shows that treatment of patients with high ferritin and low transferrin saturation levels, as defined in DRIVE, with sodium ferric gluconate complex and epoetin resulted in significant savings compared to epoetin alone

Extracorporeal removal techniques such as hemodialysis, charcoal hemoperfusion, and peritoneal dialysis have been used to remove toxins from the body. To define trends in the use of these techniques for toxin removal, we analyzed the 19,351 cases requiring extracorporeal removal reported to U.S. poison centers from 1985-2005. The number of such patients who received hemodialysis, excluding those with other medical indications, (normalized per million calls) increased from 231 to 707 whereas hemoperfusion decreased from 53 to 12 in the years 1985-2005. Peritoneal dialysis decreased from 2.2 in 1985 to 1.6 in 1991. The most common toxins removed by hemodialysis were lithium and ethylene glycol. There were more dialysis treatments for poisonings with valproate and acetaminophen in 2001-2005 than for methanol and theophylline, although hemodialysis for acetaminophen removal is generally not recommended. Theophylline was the most common toxin removed by hemoperfusion from 1985-2000, but carbamazepine became the most frequent toxin for removal during 2001-2005. Our study shows that the profile of toxins and the type of extracorporeal technique used to remove the toxins have changed over the years.Kidney International advance online publication, 17 September 2008; doi:10.1038/ki.2008.462

Cystinuria is an inherited disorder characterized by the impaired reabsorption of cystine in the proximal tubule of the nephron and the gastrointestinal epithelium. The only clinically significant manifestation is recurrent nephrolithiasis secondary to the poor solubility of cystine in urine. Although cystinuria is a relatively common disorder, it accounts for no more than 1% of all urinary tract stones. Thus far, mutations in 2 genes, SLC3A1 and SLC7A9, have been identified as being responsible for most cases of cystinuria by encoding defective subunits of the cystine transporter. With the discovery of mutated genes, the classification of patients with cystinuria has been changed from one based on phenotypes (I, II, III) to one based on the affected genes (I and non-type I; or A and B). Most often this classification can be used without gene sequencing by determining whether the affected individual's parents have abnormal urinary cystine excretion. Clinically, insoluble cystine precipitates into hexagonal crystals that can coalesce into larger, recurrent calculi. Prevention of stone formation is the primary goal of management and includes hydration, dietary restriction of salt and animal protein, urinary alkalinization, and cystine-binding thiol drugs