The Role of Alterations in Alpha-Klotho and FGF-23 in Kidney Transplantation and Kidney Donation.

Cardiovascular disease and mineral bone disorders are major contributors to morbidity and mortality among patients with chronic kidney disease and often persist after renal transplantation. Ongoing hormonal imbalances after kidney transplant (KT) are associated with loss of graft function and poor outcomes. Fibroblast growth factor 23 (FGF-23) and its co-receptor, α-Klotho, are key factors in the underlying mechanisms that integrate accelerated atherosclerosis, vascular calcification, mineral disorders, and osteodystrophy. On the other hand, kidney donation is also associated with endocrine and metabolic adaptations that include transient increases in circulating FGF-23 and decreases in α-Klotho levels. However, the long-term impact of these alterations and their clinical relevance have not yet been determined. This manuscript aims to review and summarize current data on the role of FGF-23 and α-Klotho in the endocrine response to KT and living kidney donation, and importantly, underscore specific areas of research that may enhance diagnostics and therapeutics in the growing population of KT recipients and kidney donors.

Genetics and reverse epidemiology among patients on chronic hemodialysis.

A reversal in the association between traditional and nontraditional risk factors and clinical outcomes is often encountered in patients with chronic illness, including among those with advanced chronic kidney disease (CKD) on maintenance hemodialysis (MHD). The effects of the malnutrition-inflammation complex syndrome (MICS) may play a significant role in the reversal of this risk factor-outcomes association. the MICS, this syndrome complex is not universal in its prevalence among MHD patients. The significant inter- and intra-individual differences in the prevalence of inflammation, oxidative stress, and malnutrition, indicates the influence of genetic factors in this variability. In recent years, enormous advancement in the field of molecular genetics, genomics and bioinformatics, have revolutionized studies of the genetic epidemiology of several diseases. However, genetic association studies are at a preliminary stage in the population with advanced CKD (Table 1). Preliminary studies of the impact of polyphisms in inflammation and oxidative stress-related genes and genes affecting body composition and metabolism suggest that genetic variation may indeed affect the phenotype of the MHD population. Further, some of these gene polymorphisms may also contribute to a reversal of the association between traditional risk factors, such as BMI, blood pressure, and cholesterol and clinical outcomes in this vulnerable patient population. Genetic studies in patients with advanced CKD pose enormous challenges, including recruitment of sufficient numbers of patients to achieve adequate statistical power, resolution of immense genotypic and phenotypic heterogeneity, and gene-environment and gene-gene interactions. However, well-designed adequately powered studies with carefully defined phenotypes may potentially allow definition of risk profiles characterized by combinations of relevant Single nucleotide polymorphisms in the setting of given environmental factors. Accurate risk stratification that takes into account genetic information would allow more informed targeting of pharmacologic intervention and better refined clinical trial methodologies.

Protective effect of intravenous levocarnitine on subsequent-month hospitalization among prevalent hemodialysis patients, 1998 to 2003.

BACKGROUND: Levocarnitine deficiency in hemodialysis patients is common. Although the effect of intravenous levocarnitine therapy was studied in small trials, the effect on global outcomes in larger populations is unclear. STUDY DESIGN: Retrospective observational study. SETTING & PARTICIPANTS: Centers for Medicare & Medicaid Services data; prevalent hemodialysis patients, 1998 to 2003. PREDICTOR: Intravenous levocarnitine use, clinical characteristics, comorbid conditions. OUTCOMES & MEASUREMENTS: Effect of 1 g or greater per dialysis session of levocarnitine for 10 or more sessions during a month on subsequent hospitalization days. Repeated-measures and marginal structural models were fit, the latter to account for time-dependent confounding. RESULTS: Of the study population, 3% to 7% received levocarnitine for 1 month per year or more. Treated patients were older with more severe comorbidity and larger erythropoietin doses than untreated patients. In repeated-measures model analysis adjusted for demographic characteristics and disease severity, 1 g or greater per dialysis session of levocarnitine for 10 or more sessions during a month was associated with a 10.8% (95% confidence interval, 9.7 to 11.9; P < 0.01) subsequent-month decrease in hospitalization days. In marginal structural model analysis, levocarnitine therapy was associated with a 21.7% (95% confidence interval, 18.4 to 24.9; P < 0.01) decrease in hospitalization days. LIMITATIONS: Algorithm for identifying comorbid conditions from claims validated only for diabetes; biochemical marker levels unavailable in Medicare claims; levocarnitine therapy quantified only while patients were not hospitalized. CONCLUSION: Because hemodialysis patients are hospitalized about 15 days yearly, the association of monthly levocarnitine regimen with lower hospitalization rate is clinically significant. The causality of this association must be confirmed by randomized clinical trials.

NADPH oxidase p22phox and catalase gene variants are associated with biomarkers of oxidative stress and adverse outcomes in acute renal failure.

Reactive oxygen species are important mediators of injury in acute renal failure (ARF). Although polymorphisms that affect key pro- and antioxidant enzymes might alter the susceptibility to oxidative stress-mediated injury, the use of genetic epidemiology for the study of oxidative stress-related genes has received little attention in ARF. The relationship of single-nucleotide polymorphisms in the coding region (C to T substitution at position +242) of the pro-oxidant enzyme NADPH oxidase p22phox subunit gene and in the promoter region (C to T substitution at position -262) of the antioxidant enzyme catalase gene to adverse clinical outcomes was evaluated prospectively in a cohort of 200 hospitalized patients with established ARF of mixed cause and severity. Genomic DNA was extracted from peripheral blood leukocytes and analyzed with a restriction fragment length polymorphism PCR method. Genotype-phenotype associations were characterized by measuring circulating nitrotyrosine and catalase activity. Observed and expected genotype frequencies were not significantly different, and overall baseline characteristics were not significantly different according to the various genotype groups. A genotype-phenotype association was demonstrable between the NADPH oxidase p22phox genotypes and plasma nitrotyrosine level (P = 0.06), as well as between the catalase genotypes and whole-blood catalase activity (P < 0.001). Compared with the NADPH oxidase p22phox CC genotype group, the T-allele group had a higher cumulative probability of remaining hospitalized (P = 0.03). Compared with the NADPH oxidase p22phox CC genotype, the T-allele carrier state was associated with 2.1-fold higher odds for dialysis requirement or hospital death (P = 0.01). This association persisted with 2.0- to 2.2-fold higher odds for this composite outcome after adjustment for race; gender; age; and the Acute Physiology and Chronic Health Evaluation II score (P = 0.03), the Multiple Organ Failure score (P = 0.01), or presence of sepsis (P = 0.02). The polymorphism in the gene that encodes the NADPH oxidase p22phox subunit at position +242 is associated with dialysis requirement or hospital death among patients with ARF. Larger studies are needed to confirm these relationships.

Relationship of urine output to dialysis initiation and mortality in acute renal failure.

BACKGROUND: A non-oliguric state is considered a good prognostic indicator in acute renal failure (ARF), and may lead to withholding renal replacement therapy in anticipation of recovery. The present study explores the relationship between urine volume and the start of dialysis and hospital mortality in patients with ARF. METHODS: In a non-concurrent cohort of patients with ARF treated exclusively with intermittent hemodialysis (IHD), demographic, clinical and laboratory characteristics were collected at the time of the first nephrology consultation and at the start of dialysis. Multiple linear and logistic regression analyses were used to identify factors associated with the time to initiation of dialysis and hospital mortality, respectively. RESULTS: Urine volume correlated with the time from admission to start of dialysis (r = 0.60; p < 0.001). Higher urine volume, lower serum creatinine and lower APACHE II score were independently associated with increased time from admission to start of dialysis. Hospital mortality was independently associated with a higher urine volume (odds ratio, OR 3.8, 95% confidence interval, CI, 1.1-12.8, p = 0.03), a higher MOF score (OR 4.9, 95% CI 1.1-21.6, p = 0.03) and a higher number of dialysis treatments performed in the 1st week (OR 3.7, 95% CI 1.2-11.3, p = 0.03). CONCLUSIONS: Among patients with ARF requiring IHD, increased urine output is associated with higher mortality. This observation may reflect physician bias toward later initiation of dialysis in non-oliguric ARF. Further research is needed to help identify patients with non-oliguric ARF who require early dialytic support.

Factors associated with urea reduction ratio in acute renal failure.

Prescription and delivery of hemodialysis (HD) in acute renal failure (ARF) may be affected by patient-related factors such as hemodynamic instability, catabolism, variable extracellular fluid volume, and coagulation disturbances. This study was undertaken in a cohort of patients with ARF requiring HD, to quantify patient- and dialysis-related variables that influence dialysis delivery. The urea reduction ratio (URR) was calculated for each HD session. Patient-related variables included age, gender, weight, mean arterial pressure, and Acute Physiological and Chronic Health Evaluation (APACHE) II and Multiple Organ Failure (MOF) scores. Dialysis-related variables were dialyzer characteristics (membrane type, surface area, KoA, and K(UF)), blood flow rate (Qb), session length, anticoagulant use, vascular access, and ultrafiltration volume. The analysis of factors associated with URR was performed using mixed linear statistical models. The cohort consisted of 81 adult patients with ARF who underwent 419 consecutive dialysis sessions. Mean (+/- SD) age was 60 +/- 18 years; 57% were male. At dialysis initiation, APACHE II score was 23 +/- 8 and MOF score 2 +/- 1. The number of HD treatments averaged 5.5 +/- 6.1/patient and 0.8 +/- 0.2/patient/day, mean URR was 54 +/- 15%, and session length 3.2 +/- 1.1 h; 58% used a femoral venous catheter, and 92% polysulfone dialyzers. Among patient-related variables, the only independent predictor of delivered dose of dialysis, as measured by URR was the predialysis weight (P < 0.01). Among the dialysis-related variables, treatment time (P < 0.01), dialyzer surface area (P < 0.01), dialyzer K(UF) (P = 0.04), blood flow rate (P < 0.01), and the use of a femoral venous catheter (P < 0.01) were also independently associated with URR. An interaction between vascular access site and blood flow rate was also found to be significant (P < 0.01). This study underscores the importance of the dialysis prescription parameters and vascular access site in influencing the dialysis dose in critically ill patients, and argues against the importance of patient-related characteristics such as disease severity.