American Journal of Kidney Diseases

Potential Interaction Between Sevelamer and Fat-Soluble Vitamins: A Hypothesis

Paweena Susantitaphong, Bertrand L. Jaber — 2012-02-01

Hyponatremia and Mortality in Patients With Cancer: The Devil Is in the Details

Fadi Fakhouri, Frédéric Lavainne, Alexandre Karras — 2012-02-01

Lipid-Lowering Therapy in Individuals With CKD: Lessons Learned From SHARP

Ashish Upadhyay, Daniel E. Weiner — 2011-10-28

Commentary on Baigent C, Landray MJ, Reith C, et al; on behalf of the SHARP Investigators. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011;377(9784):2181-2192.

Childhood Membranous Nephropathy and Dietary Antigens

Laurence H. Beck — 2011-10-21

Commentary on Debiec H, Lefeu F, Kemper MJ, et al. Early-childhood membranous nephropathy due to cationic bovine serum albumin. N Engl J Med. 2011;364(22):2101-2110.

Comparison of Calcium Acetate and Sevelamer on Vascular Function and Fibroblast Growth Factor 23 in CKD Patients: A Randomized Clinical Trial

2011-12-05

Background: Fibroblast growth factor 23 (FGF-23) is a marker of endothelial dysfunction and atherosclerotic complications in patients with chronic kidney disease (CKD). Because previous studies suggested that sevelamer may exert effects on FGF-23 level and endothelial function independently of its phosphate-lowering action, we tested the effect of sevelamer versus calcium acetate on vascular function and FGF-23 levels. Study Design: Randomized prospective open-label trial. Setting & Participants: Patients with stage 4 CKD with hyperphosphatemia (n = 100). Intervention: An 8-week intervention with sevelamer (n = 47) and calcium acetate (n = 53). Outcomes: The primary study outcome was change in flow-mediated vasodilatation in the forearm. The secondary outcome was change in FGF-23 levels. Results: Serum phosphate levels decreased in both treatment arms (P < 0.001), but more markedly in the sevelamer group (P < 0.001). Flow-mediated vasodilatation increased from 6.1% to 7.1% (P < 0.001) in sevelamer-treated patients, whereas it was unchanged in the calcium-acetate group (6.0% vs 6.0%). In a combined analysis, treatment-induced changes in flow-mediated vasodilatation were (P < 0.001) associated with simultaneous changes in FGF-23 levels (−27.1% [−33.2% to −8.8%] for the sevelamer group; 3.5% [−8.4% to 12.1%] for the calcium acetate group), as well as with C-reactive protein and fetuin A levels. These relationships were confirmed in multiple regression analysis adjusting for changes in serum phosphate levels and other factors. Limitations: Unblinded randomized controlled study that cannot establish mechanisms of effect. Conclusions: In hyperphosphatemic patients with stage 4 CKD, treatment with phosphate lowering induces measurable improvements in flow-mediated vasodilatation. Furthermore, independently of serum phosphate level, FGF-23 level changes induced by phosphate binders are associated with simultaneous changes in flow-mediated vasodilatation. These observations are compatible with the hypothesis that FGF-23 may contribute to vascular dysfunction in this population.

Effect of Vitamin K2 Supplementation on Functional Vitamin K Deficiency in Hemodialysis Patients: A Randomized Trial

2011-12-12

Background: Vascular calcification is a predictor of cardiovascular morbidity and mortality. Hemodialysis patients experience severe vascular calcifications. Matrix Gla protein (MGP) is a central calcification inhibitor of the arterial wall; its activity depends on vitamin K–dependent γ-glutamate carboxylation. Uncarboxylated MGP, formed as a result of vitamin K deficiency, is associated with cardiovascular disease. Recent studies suggest poor vitamin K status in hemodialysis patients. We therefore aimed to investigate whether daily vitamin K supplementation improves the bioactivity of vitamin K–dependent proteins in hemodialysis patients, assessed by circulating dephosphorylated-uncarboxylated MGP, uncarboxylated osteocalcin, and uncarboxylated prothrombin (PIVKA-II [protein induced by vitamin K absence II]). Study Design: Interventional randomized non–placebo-controlled trial with 3 parallel groups. Setting & Participants: 53 long-term hemodialysis patients in stable conditions, 18 years or older. 50 healthy age-matched individuals served as controls. Interventions: Menaquinone-7 (vitamin K2) treatment at 45, 135, or 360 μg/d for 6 weeks. Outcomes: Plasma levels of dephosphorylated-uncarboxylated MGP, uncarboxylated osteocalcin, and PIVKA-II. Measurements: Plasma levels were assessed using enzyme-linked immunosorbent assays. Results: At baseline, hemodialysis patients had 4.5-fold higher dephosphorylated-uncarboxylated MGP and 8.4-fold higher uncarboxylated osteocalcin levels compared with controls. PIVKA-II levels were elevated in 49 hemodialysis patients. Vitamin K2 supplementation induced a dose- and time-dependent decrease in circulating dephosphorylated-uncarboxylated MGP, uncarboxylated osteocalcin, and PIVKA-II levels. Response rates in the reduction in dephosphorylated-uncarboxylated MGP levels were 77% and 93% in the groups receiving 135 μg and 360 μg of menaquinone-7, respectively. Limitations: Small sample size. Conclusions: This study confirms that most hemodialysis patients have a functional vitamin K deficiency. More importantly, it is the first study showing that inactive MGP levels can be decreased markedly by daily vitamin K2 supplementation. Our study provides the rationale for intervention trials aimed at decreasing vascular calcification in hemodialysis patients by vitamin K supplementation.

Serum Creatinine Measurement Immediately After Cardiac Surgery and Prediction of Acute Kidney Injury

2011-10-04

Background: After heart surgery, acute kidney injury (AKI) confers substantial long-term risk of death and chronic kidney disease. We hypothesized that small changes in serum creatinine (SCr) levels measured within a few hours of exit from the operating room could help discriminate those at low versus high risk of AKI. Study Design: Prospective cohort of 350 elective cardiac surgery patients (valve or coronary artery bypass grafting) recruited in Winnipeg, Canada. Baseline SCr level was obtained at the preoperative visit 2 weeks before surgery. The postoperative SCr level was drawn within 6 hours of completion of surgery and then daily while the patient was in the hospital. Predictor: Immediate (ie, <6 hours) postoperative SCr level change (ΔSCr), categorized as within 10% (reference), decrease >10%, or increase >10% relative to baseline. Outcome: AKI, defined according to the new KDIGO (Kidney Disease: Improving Global Outcomes) consensus definition as an increase in SCr level >0.3 mg/dL within 48 hours or >1.5 times baseline within 1 week. Measurements: We compared the C statistic of logistic models with and without inclusion of immediate postoperative ΔSCr. Results: After surgery, 176 patients (52%) experienced a decrease >10% in SCr level, 26 (7.4%) experienced an increase >10%, and 143 had ΔSCr within ±10% of baseline. During hospitalization, 53 (14%) developed AKI. Bypass pump time, baseline estimated glomerular filtration rate, and European System for Cardiac Operative Risk Evaluation (euroSCORE) were associated with AKI in a parsimonious base logistic model. Added to the base model, immediate postoperative ΔSCr was associated strongly with subsequent AKI and significantly improved model discrimination over the base model (C statistic, 0.78 [95% CI, 0.71-0.85] vs 0.69 [95% CI, 0.62-0.77]; P < 0.001). A ≥10% SCr level decrease predicted significantly lower AKI risk (OR, 0.37; 95% CI, 0.18-0.76), whereas a ≥10% SCr level increase predicted significantly higher (OR, 6.38; 95% CI, 2.37-17.2) AKI risk compared with the reference category. Limitations: We used a surrogate marker of AKI. External validation of our results is warranted. Conclusion: In elective cardiac surgery patients, measurement of immediate postoperative ΔSCr improves prediction of AKI.

Periodontal Disease and Decreased Kidney Function in Japanese Elderly

2011-10-17

Background: Early detection of decreased kidney function can help prevent the progression of kidney disease to kidney failure and cardiovascular events. Potentially significant associations between kidney function and periodontal disease have been reported in cross-sectional studies. However, no longitudinal study has been performed and no study has been performed in Japan. The aim of this longitudinal study was to investigate the effect of periodontal disease on kidney function in community-dwelling Japanese elderly. Study Design: Retrospective cohort. Setting & Participants: Members of this cohort were drawn from a longitudinal interdisciplinary study of aging. Included for this analysis were 317 participants (166 men, 151 women) aged 75 years in 2003. Predictor: The periodontal inflamed surface area (PISA), reflecting the amount of inflamed periodontal tissue, was calculated for each participant. Participants were classified in quartile groups according to PISA, then divided into 2 groups (highest quartile vs the other 3 groups combined). Outcomes: The primary outcome for the analysis was decreased kidney function, defined as a decrease in estimated glomerular filtration rate at follow-up. Measurements: Multivariable logistic regression analyses were performed to predict decreased kidney function on the basis of periodontal status, risk factors for kidney disease, and other potentially relevant covariates. Results: During the 2-year follow-up (2003-2005), 45 participants (14.2%) developed decreased kidney function. The highest PISA quartile was associated significantly with a greater cumulative incidence of decreased kidney function (OR, 2.24; 95% CI, 1.05-4.79) than the referent group (the other 3 quartiles) after adjusting for covariates. Limitations: Extension of interpreting the findings to other age groups is limited. Conclusion: These results suggest that periodontal disease may be a risk factor for decreased kidney function in Japanese elderly.

Genetic Association and Gene-Gene Interaction Analyses in African American Dialysis Patients With Nondiabetic Nephropathy

2011-11-28

Background: African Americans have increased susceptibility to nondiabetic nephropathy relative to European Americans. Study Design: Follow-up of a pooled genome-wide association study (GWAS) in African American dialysis patients with nondiabetic nephropathy; novel gene-gene interaction analyses. Setting & Participants: Wake Forest sample: 962 African American nondiabetic nephropathy cases, 931 non-nephropathy controls. Replication sample: 668 Family Investigation of Nephropathy and Diabetes (FIND) African American nondiabetic nephropathy cases, 804 non-nephropathy controls. Predictors: Individual genotyping of top 1,420 pooled GWAS-associated single-nucleotide polymorphisms (SNPs) and 54 SNPs in 6 nephropathy susceptibility genes. Outcomes: APOL1 genetic association and additional candidate susceptibility loci interacting with or independently from APOL1. Results: The strongest GWAS associations included 2 noncoding APOL1 SNPs, rs2239785 (OR, 0.33; dominant; P = 5.9 × 10−24) and rs136148 (OR, 0.54; additive; P = 1.1 × 10−7) with replication in FIND (P = 5.0 × 10−21 and 1.9 × 10−05, respectively). rs2239785 remained associated significantly after controlling for the APOL1 G1 and G2 coding variants. Additional top hits included a CFH SNP (OR from meta-analysis in the 3,367 African American cases and controls, 0.81; additive; P = 6.8 × 10−4). The 1,420 SNPs were tested for interaction with APOL1 G1 and G2 variants. Several interactive SNPs were detected; the most significant was rs16854341 in the podocin gene (NPHS2; P = 0.0001). Limitations: Nonpooled GWASs have not been performed in African American patients with nondiabetic nephropathy. Conclusions: This follow-up of a pooled GWAS provides additional and independent evidence that APOL1 variants contribute to nondiabetic nephropathy in African Americans and identified additional associated and interactive nondiabetic nephropathy susceptibility genes.

Hyponatremia in Hospitalized Cancer Patients and Its Impact on Clinical Outcomes

Simit M. Doshi, Pankaj Shah, Xiudong Lei, Amit Lahoti, Abdulla K. Salahudeen — 2011-10-17

Background: Hyponatremia is the most common electrolyte abnormality in clinical practice, yet little is known about its frequency in patients with cancer or its impact on their clinical outcomes. Study Design: Retrospective analysis of prospectively collected data. Setting & Participants: Patients with cancer admitted to the University of Texas M.D. Anderson Cancer Center in 2006 for 3 months. Predictor: Serum sodium levels categorized as eunatremia (serum sodium, 135-147 mEq/L) and mild (134-130 mEq/L), moderate (129-120 mEq/L), and severe (<120 mEq/L) hyponatremia. Outcomes: (1) Length of hospital stay and (2) 90-day mortality. Results: In 4,702 admissions in 3,357 patients with cancer, hyponatremia (serum sodium <135 mEq/L) was noted in 47% of admissions. It was mild in 36%, moderate in 10%, and severe in 1%. Hyponatremia was acquired during the hospital stay in 24%. Using the first admission data, mean length of stay was 5.6 ± 5.0 days for patients with eunatremia and 9.9 ± 9.2, 13.0 ± 14.1, and 11.5 ± 12.6 days for those with mild, moderate, and severe hyponatremia, respectively. The respective HRs in the multivariate Cox model for longer hospital stay, using patients with eunatremia as reference, were 1.92 (95% CI, 1.75-2.13; P < 0.01), 2.94 (95% CI, 2.56-3.45; P < 0.01), and 2.32 (95% CI, 1.32-4.00; P = 0.01). 283 (8.4%) deaths occurred during 90 days, and in the multivariate model, the respective HRs for 90-day mortality for mild, moderate, and severe hyponatremia were 2.04 (95% CI, 1.42-2.91; P < 0.01); 4.74 (95% CI, 3.21-7.01; P < 0.01), and 3.46 (95% CI, 1.05-11.44; P = 0.04). These findings were consistent when analyses were repeated with sodium levels in tertiles. Limitations: Observational study, retrospective, inability to adjust for all comorbid conditions. Conclusion: Hyponatremia in patients with cancer is associated with longer hospital stay and higher mortality. Whether long-term correction of hyponatremia would improve these outcomes remains to be determined.

Association of Filtered Sodium Load With Medullary Volumes and Medullary Hypoxia in Hypertensive African Americans as Compared With Whites

2011-11-30

Background: African Americans develop hypertension earlier with more target manifestations than whites despite having a higher glomerular filtration rate (GFR) for any level of serum creatinine. Study Design & Participants: This study tested the hypothesis that increased GFR and sodium reabsorption in African Americans is associated with increased metabolic work and medullary hypoxia in 49 nondiabetic patients with essential hypertension (29 whites and 20 African Americans) following a constant-sodium diet (150 mEq/d) and renin-angiotensin system blockade. Predictors: Ethnicity, age, measured GFR, sodium excretion, and body mass index. Outcomes: We examined cortical and medullary volumes and blood flows using multidetector computed tomography and intrarenal deoxyhemoglobin (R2*) using blood oxygen level–dependent magnetic resonance. Results: Blood pressure and sodium excretion were similar, whereas African Americans were more obese and had higher iothalamate GFRs. Renal cortical volumes did not differ, but medullary volumes adjusted for body size and age were higher in African Americans (32.3 ± 11.2 vs 25.1 ± 7.4 cm3/m2 body surface area; P < 0.001). Sodium reabsorption and blood flows were higher in African Americans. Basal cortical deoxyhemoglobin values were similar between ethnic groups, whereas medullary R2* was higher in African Americans (39.7 ± 5.1 vs 36.3 ± 6.5/s; P = 0.02), but decreased to levels similar to whites after furosemide treatment. Levels of the circulating isoprostane prostaglandin F2α were higher in African Americans and daily urinary prostaglandin F2α excretion in African Americans correlated directly with renal blood flow (R = 0.71; P < 0.01). Limitations: Studies were limited to treated volunteers with normal kidney function without knowledge of prior nutrient intake. Conclusions: These data show for the first time that increased sodium reabsorption in obese African American patients with hypertension was associated with enlarged medullary volumes, functional hypoxia related to solute reabsorption, and a direct relationship between blood flows and urinary isoprostane levels. Our results support a model of increased oxygen consumption and oxidative stress in African Americans that may accelerate hypertension and target-organ injury compared with white patients with essential hypertension.

Predialysis Serum Sodium Level, Dialysate Sodium, and Mortality in Maintenance Hemodialysis Patients: The Dialysis Outcomes and Practice Patterns Study (DOPPS)

2011-09-26

Background: Predialysis serum sodium concentrations recently have been linked to patient characteristics and outcomes in hemodialysis patients and may have implications for the dialysate sodium prescription. Study Design: Prospective cohort study. Participants: 11,555 patients from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS), phases I (1996-2001) and III (2005-2008). Predictors: Demographics, comorbid conditions, laboratory measurements (model 1); mean serum sodium level, dialysate sodium concentration (model 2). Outcomes: Serum sodium level, using adjusted linear mixed models (model 1); all-cause mortality, using Cox proportional hazards models (model 2). Results: Median follow-up was 12 months, with 1,727 deaths (15%) occurring during the study period (12,274 patient-years). Mean serum sodium level in the DOPPS countries was 138.5 ± 2.8 mEq/L. Japan had the highest (139.1 ± 2.6 mEq/L) and Australia/New Zealand had the lowest mean serum sodium level (137.4 ± 2.8 mEq/L). Serum sodium level was associated positively with male sex, black race, body mass index, serum albumin level, and creatinine level and negatively with neurologic and psychiatric disease, white blood cell count, and intradialytic weight loss (0.16 mEq/L lower per 1% loss). Higher serum sodium level was associated with lower adjusted all-cause mortality in a continuous model (HR, 0.95 per 1 mEq/L higher; 95% CI, 0.93-0.97). Dialysate sodium prescription was not associated with serum sodium level. Mortality analyses restricted to the serum sodium tertile with the highest mortality (serum sodium <137 mEq/L) showed lower mortality risk in patients with dialysate sodium prescriptions >140 mEq/L. Limitations: Causality cannot be established in this observational study, which does not consider potential effects of dialysate sodium level on postdialysis thirst, dietary salt and water intake, interdialytic weight gain, and cardiovascular stability. Conclusions: Lower serum sodium levels are associated with certain hemodialysis patient characteristics and higher adjusted risk of death. The lower mortality observed in our adjusted analyses in patients with serum sodium levels <137 mEq/L dialyzed against dialysate sodium prescriptions >140 mEq/L is intriguing, may be related to intradialytic cardiovascular stability, and deserves further study.

Appraising Stroke Risk in Maintenance Hemodialysis Patients: A Large Single-Center Cohort Study

Albert Power, Kakit Chan, Seema K. Singh, David Taube, Neill Duncan — 2011-09-26

Background: Stroke incidence in hemodialysis patients is up to 10 times greater than in the general population and is associated with a worse prognosis. Factors influencing stroke risk by subtype and subsequent prognosis are poorly described in the literature. Study Design: Retrospective single-center cohort study. Setting & Participants: 2,384 established maintenance hemodialysis patients at a single center from January 1, 2002, to June 1, 2009. Predictor: Patient demographics, comorbid conditions. Outcomes: Incidence of acute stroke (International Classification of Diseases, 9th Revision codes 430, 431, 432.9, 433.1, and 434.1 with evidence of compatible neuroimaging), patient survival. Measurements: Cumulative patient survival, incidence of acute fatal and nonfatal stroke. Results: 127 strokes occurred during 9,541 total patient-years of follow-up. First (incident) stroke occurred at a rate of 14.9/1,000 patient years (95% CI, 12.2-17.9) with a predominance of ischemic compared with hemorrhagic subtypes (11.2 vs 3.7/1,000 patient-years). 54% of hemorrhagic strokes occurred in patients of South Asian ethnicity compared with ischemic strokes, which occurred predominantly in white patients (45% of events). Diabetes mellitus (HR, 1.92; 95% CI, 1.29-2.85; P = 0.001) and prior cerebrovascular disease (HR, 4.54; 95% CI, 3.07-6.72; P < 0.001) were independently associated with incident cerebrovascular accident on multivariate analysis. Acute stroke was associated with worse patient survival (HR, 3.26; 95% CI, 2.47-4.30; P < 0.001) and overall 1-year mortality of 24%, which was significantly worse in patients with hemorrhagic events (39% vs 19% mortality for ischemic subtypes). Serum albumin level >3.5 g/L (HR, 0.38; 95% CI, 0.19-0.76; P = 0.007) and C-reactive protein level >3.0 mg/l (HR, 1.36; 95% CI, 1.12-1.64; P = 0.002) influenced survival after stroke on multivariate analysis. Limitations: Retrospective analysis of data cannot prove causality. Conclusions: The high incidence of stroke in hemodialysis patients is associated with high mortality, especially hemorrhagic subtypes. Strict management of hypertension, better appreciation of hemodialysis anticoagulation, and large-scale interventional studies are urgently required to direct prevention and treatment of this significant disease.

Progression of Coronary Artery Calcification and Thoracic Aorta Calcification in Kidney Transplant Recipients

2011-09-26

Background: Vascular calcification independently predicts cardiovascular disease, the major cause of death in kidney transplant recipients (KTRs). Longitudinal studies of vascular calcification in KTRs are few and small and have short follow-up. We assessed the evolution of coronary artery (CAC) and thoracic aorta calcification and their determinants in a cohort of prevalent KTRs. Study Design: Longitudinal. Setting & Participants: The Agatston score of coronary arteries and thoracic aorta was measured by 16-slice spiral computed tomography in 281 KTRs. Predictors: Demographic, clinical, and biochemical parameters were recorded simultaneously. Outcomes & Measurements: The Agatston score was measured again 3.5 or more years later. Results: Repeated analyzable computed tomographic scans were available for 197 (70%) KTRs after 4.40 ± 0.28 years; they were not available for the rest of patients because of death (n = 40), atrial fibrillation (n = 1), other arrhythmias (n = 4), refusal (n = 35), or technical problems precluding confident calcium scoring (n = 4). CAC and aorta calcification scores increased significantly (by a median of 11% and 4% per year, respectively) during follow-up. By multivariable linear regression, higher baseline CAC score, history of cardiovascular event, use of a statin, and lower 25-hydroxyvitamin D3 level were independent determinants of CAC progression. Independent determinants of aorta calcification progression were higher baseline aorta calcification score, higher pulse pressure, use of a statin, older age, higher serum phosphate level, use of aspirin, and male sex. Significant regression of CAC or aorta calcification was not observed in this cohort. Limitations: Cohort of prevalent KTRs with potential survival bias; few patients with diabetes and nonwhites, limiting the generalizability of results. Conclusion: In contrast to previous small short-term studies, we show that vascular calcification progression is substantial within 4 years in prevalent KTRs and is associated with several traditional and nontraditional cardiovascular risk factors, some of which are modifiable.

Polycystic Kidney Disease Presenting With Hypertension and Hypokalemia

Kai Ming Chow, Ronald Ching-Wan Ma, Cheuk Chun Szeto, Philip Kam-Tao Li — 2011-10-03

Hypokalemic hypertension is a common condition leading to the diagnosis of secondary hypertension. We report the case of a 60-year-old woman for whom the diagnosis of autosomal dominant polycystic kidney disease arose during the investigation of possible hyperaldosteronism. Activation of the renin system, as supported by recent studies, can explain the mechanism of hypokalemia and hypertension in this inherited cystic kidney disorder. Clinicians should be aware of this relatively uncommon clinical phenomenon of secondary hypertension in polycystic kidney disease. Increased understanding of the disorder's underlying mechanism should lay the foundation for better appreciation of potentially effective blood pressure treatments. The availability of a direct renin inhibitor may redirect research toward finding a remedy for this troublesome disease.

Recurrent Acute Kidney Injury Following Bath Salts Intoxication

Adedotun Adebamiro, Mark A. Perazella — 2011-11-28

“Bath salts” are becoming recognized as a frequently abused and highly addictive substance that can be obtained legally in some areas. These agents contain stimulant compounds, such as methylenedioxopyrrovalerone and mephedrone, that have been associated with sympathomimetic effects and psychotic features, such as paranoia, delusions, agitation, and confusion. They may have a benign course; however, intoxication with these agents may lead to severe cardiovascular and neurologic complications and death. We report a case of recurrent acute kidney injury associated with repeated bath salts intoxication. The patient, who presented with neurologic and cardiovascular symptoms and signs, also developed rhabdomyolysis, hyperuricemia, and metabolic acidosis as part of the clinical presentation. Bath salts intoxication should be included on the list of substances that can cause acute kidney injury and other metabolic abnormalities.

Tuberous Sclerosis Complex–Associated Angiomyolipomas: Focus on mTOR Inhibition

Klemens Budde, Jens Gaedeke — 2011-11-30

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder promoting the development of benign tumors in multiple organ systems, including the skin, brain, and kidneys. In contrast to asymptomatic spontaneous angiomyolipomas, angiomyolipomas in patients with TSC are mostly bilateral and are accompanied by other typical clinical features of TSC. Kidney angiomyolipomas are benign tumors composed of blood vessels, adipose tissue, and smooth muscle and are associated with spontaneous bleeding and potential life-threatening hemorrhage if >4 cm. Current treatment options for angiomyolipoma are focused on conserving kidney function and limiting potentially fatal hemorrhage. TSC is caused by mutations in either TSC1 or TSC2 suppressor genes, resulting in increased mammalian target of rapamycin (mTOR) activity. Preclinical studies have shown the efficacy of mTOR inhibitors in inhibiting the growth of patient-derived cell lines and suppressing tumors in animal models of TSC. In the clinical setting, mTOR inhibitors have shown promising efficacy in patients with TSC-associated angiomyolipomas and subependymal giant cell astrocytomas. This review explores the diagnosis and current management of TSC-associated angiomyolipomas, the relevance of the mTOR pathway in the pathogenesis of TSC, and the potential promise of mTOR-inhibitor therapy as a systemic therapeutic approach to treat the underlying cause of TSC.

New Insights Into Human Minimal Change Disease: Lessons From Animal Models

Sumant S. Chugh, Lionel C. Clement, Camille Macé — 2011-10-05

The pathogenesis of minimal change disease (MCD), considered to be the simplest form of nephrotic syndrome, has been one of the major unsolved mysteries in kidney disease. In this review, recent landmark studies that have led to the unraveling of MCD are discussed. A recent study now explains the molecular basis of major clinical and morphologic changes in MCD. Overproduction of angiopoietin-like 4 (ANGPTL4) in podocytes in MCD causes binding of ANGPTL4 to the glomerular basement membrane, development of nephrotic-range selective proteinuria, diffuse effacement of foot processes, and loss of glomerular basement membrane charge, but is not associated with changes shown by light microscopy in the glomerular and tubulointerstitial compartments. At least some of this ability of ANGPTL4 to induce proteinuria is linked to a deficiency of sialic acid residues because oral supplementation with sialic acid precursor N-acetyl-d-mannosamine improves sialylation of podocyte-secreted ANGPTL4 and significantly decreases proteinuria. Animal models of MCD, recent advances in potential biomarkers, and studies of upstream factors that may initiate glomerular changes also are discussed. In summary, recent progress in understanding MCD is likely to influence the diagnosis and treatment of MCD in the near future.

Managing Older Adults With CKD: Individualized Versus Disease-Based Approaches

C. Barrett Bowling, Ann M. O'Hare — 2011-12-22

The last decade has seen the evolution and ongoing refinement of a disease-oriented approach to chronic kidney disease (CKD). Disease-oriented models of care assume a direct causal association between observed signs and symptoms and underlying disease pathophysiologic processes. Treatment plans target underlying disease mechanisms with the goal of improving disease-related outcomes. Because average glomerular filtrate rates tend to decrease with age, CKD becomes increasingly prevalent with advancing age and those who meet criteria for CKD are disproportionately elderly. However, several features of geriatric populations may limit the utility of disease-oriented models of care. In older adults, complex comorbid conditions and geriatric syndromes are common; signs and symptoms often do not reflect a single underlying pathophysiologic process; there can be substantial heterogeneity in life expectancy, functional status, and health priorities; and information about the safety and efficacy of recommended interventions often is lacking. For all these reasons, geriatricians have tended to favor an individualized patient-centered model of care over more traditional disease-based approaches. An individualized approach prioritizes patient preferences and embraces the notion that observed signs and symptoms often do not reflect a single unifying disease process and instead reflect the complex interplay between many different factors. This approach emphasizes modifiable outcomes that matter to the patient. Prognostic information related to these and other outcomes generally is used to shape rather than dictate treatment decisions. We argue that an individualized patient-centered approach to care may have more to offer than a traditional disease-based approach to CKD in many older adults.

Renal Sarcoidosis Presenting as Acute Kidney Injury With Granulomatous Interstitial Nephritis and Vasculitis

Varun Agrawal, Giovanna M. Crisi, Vivette D. D'Agati, Benjamin J. Freda — 2011-12-16

Among the various renal manifestations of sarcoidosis, granulomatous inflammation confined to the tubulointerstitial compartment is the most commonly reported finding. We present the case of a 66-year-old man with acute kidney injury, hypercalcemia, mild restrictive pulmonary disease, and neurologic signs of parietal lobe dysfunction. Kidney biopsy showed diffuse interstitial inflammation with noncaseating granulomas that exhibited the unusual feature of infiltrating the walls of small arteries with destruction of the elastic lamina, consistent with granulomatous vasculitis. The findings of granulomatous interstitial nephritis on kidney biopsy, hypercalcemia, and possible cerebral and pulmonary involvement in the absence of other infectious, drug-induced, or autoimmune causes of granulomatous disease established the diagnosis of sarcoidosis. Pulse methylprednisolone followed by maintenance prednisone therapy led to improvement in kidney function, hypercalcemia, and neurologic symptoms. Vasculocentric granulomatous interstitial nephritis with granulomatous vasculitis is a rare and under-recognized manifestation of renal sarcoidosis.

The DOPPS Practice Monitor for US Dialysis Care: Trends Through April 2011

2011-12-12

More than 380,000 people receive maintenance dialysis for the treatment of end-stage kidney failure in the United States. In 2008, Medicare expenditures for dialysis patients totaled $22 billion, or 4.8% of the total Medicare budget. The new end-stage renal disease prospective payment system (PPS), a program begun by the US Centers for Medicare & Medicaid Services in January 2011, is intended to control dialysis costs through bundled payments (that is, fewer dialysis-related medications and services are now separately billable). The Quality Incentive Program, beginning in 2012 with the evaluation of dialysis unit clinical data collected in 2010, is the first Medicare program that ties provider or facility payments to performance, as defined by meeting particular quality measures.

Commentary on ‘The DOPPS Practice Monitor for US Dialysis Care: Trends Through April 2011’: No Surprises Yet

Wolfgang C. Winkelmayer, Daniel E. Weiner — 2012-02-01

The initial announcement, finalization, and ultimate implementation of the end-stage renal disease prospective payment system (PPS), also called the expanded bundle, were accompanied by much angst in the nephrology community and agitation among high-profile stakeholders. Overnight, fee-for-service reimbursement by the US Centers for Medicare & Medicaid Services (CMS) to dialysis providers for many dialysis-related services, including most medications administered in the dialysis unit, was replaced by adjusted lump-sum payments for each hemodialysis treatment provided. Included in these new per-session payments were many of the most costly elements of dialysis care, including erythropoiesis-stimulating agents (ESAs), intravenous iron supplements, and intravenous vitamin D analogues, along with their oral equivalents. Other items also were newly included in the “bundled” payment, such as laboratory tests routinely used for the monitoring of patients receiving maintenance dialysis and elements of care associated with vascular access–related infections.

Potassium and Metabolic Alkalosis

Troels Ring — 2012-02-01

In the review on metabolic alkalosis by Gennari, the section on potassium depletion discusses the 2 studies in humans by Jones et al and Hernandez et al. In these studies, persons with normal intake of sodium chloride developed metabolic alkalosis during potassium depletion. In both studies, net acid excretion decreased both during development and maintenance of alkalosis in persons on normal sodium chloride intake. In persons on a very low intake (2-7 mmol/d) of sodium chloride, net acid excretion increased during generation of alkalosis, but again decreased (129.0 ± 3.0 vs 139.0 ± 4.0, P = 0.069) during maintenance. It appears questionable to infer, based on the animal studies cited in the review, that alkalosis during potassium depletion is necessarily due to increased renal net acid excretion when the cited human studies tell another story. The effect of dietary intake of sodium chloride on acid-base equilibrium was recently discussed by Frassetto et al, who found an acidifying effect of increased intake that specifically was not explained by elements in the acid-base balance as conventionally presented. Mechanistically it is perhaps no great wonder that bicarbonate and chloride will behave in an opposite fashion, because Pitts and Lotspeich found them to be transported in competition in the nephron, so chloride loading results in bicarbonate excretion and vice versa. The role of the kidney in acid-base equilibrium is still to be fully understood.

Metabolic Alkalosis Due to Hypercalcemia

Dinette E. Agterhuis, Kenrick Berend — 2012-02-01

Gennari presented an interesting classification on the causes of metabolic alkalosis. One remark, however, may be justified. Hypercalcemia should be included in the differential diagnosis of metabolic alkalosis. Hypercalcemia activates the calcium-sensing receptor, which enhances calcium excretion by its action in the thick ascending limb of the loop of Henle. This results in diuresis, volume depletion, metabolic alkalosis, and a decrease in glomerular filtration rate. Also, an increase in renal reabsorption of calcium occurs as a result of metabolic alkalosis and volume depletion, contributing to the maintenance of hypercalcemia.

In Reply to ‘Potassium and Metabolic Alkalosis’ and ‘Metabolic Alkalosis due to Hypercalcemia’

F. John Gennari — 2012-02-01

I certainly agree with Dr Ring that the role of the kidney in acid-base disorders is not fully understood. I hope my review emphasized that point. Dr Ring, however, has misread what I wrote. I made no comment on the mechanism by which potassium depletion induces metabolic alkalosis, only the factors that sustain it. Induction of metabolic alkalosis by potassium depletion in the experiments he cited was almost certainly due to transcellular ionic shifts because renal net acid excretion decreased. The increase in serum bicarbonate concentration, however, was sustained by enhanced renal hydrogen ion secretion. The authors discuss these issues in the cited papers and I agree with their analysis. Potassium depletion increases ammonium production and excretion, an effect that serves to facilitate acid excretion, but it has no specific effects on total net acid excretion. The main point of my review is that all forms of metabolic alkalosis in individuals with functioning kidneys are sustained by an increase in hydrogen ion secretion along the nephron, and I proposed that a key site where hydrogen ion secretion is stimulated is in the intercalated cells of the collecting duct. Potassium depletion has many effects that all serve to stimulate renal hydrogen ion secretion and these are elucidated in my review. To say that bicarbonate and chloride have opposite effects on renal acid-base balance provides no insight into mechanisms. I hope that my review provides potential mechanisms for the changes in renal bicarbonate reabsorption observed in metabolic alkalosis, and that it will provoke an ongoing dialogue and stimulate new experiments designed to answer the questions raised.

Predialysis Care: Intertwined Roles of Nephrologists and Dietitians

Chia-Ter Chao — 2012-02-01

Slinin et al provide an important analysis about the impact of dietitian care on mortality of incident hemodialysis patients. As the third table in their supplementary online material shows, the benefit of dietitian care for more than 12 months is offset when the analysis is adjusted for the variable of care by a nephrologist. With this in mind, I would like to offer several other explanations for the mortality differences observed by Slinin et al.

In Reply to 'Predialysis Care: Intertwined Roles of Nephrologists and Dietitians'

Yelena Slinin, Areef Ishani — 2012-02-01

We thank Dr Chao for commenting on our article dealing with prehemodialysis care by dietitians, in which we reported an independent association between predialysis dietitian care for longer than 12 months and decreased mortality during the first year on dialysis. Dr Chao suggests that more patients without dietitian care start dialysis with a catheter, and this difference likely contributes to the difference in mortality. We adjusted the analyses for hemodialysis access at initiation, so the difference in vascular access at initiation is not the likely explanation for the difference in patient outcomes. Nevertheless, we agree that the observed difference in survival could have resulted from unequal distribution of unobserved confounders between patients with and without dietitian care. We did not look at specific causes of death because of poor agreement between causes of death reported to the US Renal Data System by providers and those from the death certificate ascertained through the National Death registry.

What Dominates Living Donor Kidney Transplantation: Altruism or Loss of Dignity?

Kamyar Ghabili, Mohammadali M. Shoja — 2012-02-01

We were deeply moved by the altruistic kidney donations of Dr Levey and his colleague, as described in the recent perspective by Levey et al. The authors encourage transplant professionals and agencies to increase access to the living kidney donation system, with particular emphasis on donor autonomy, medical care, and long-term surveillance after transplant. However, we suggest that prior to taking practical measures to expand this system in the United States, transplant professionals and agencies consider and plan for the ethical issues that may accompany kidney donation by unrelated individuals.

In Reply to ‘What Dominates Living Donor Kidney Transplantation: Altruism or Loss of Dignity?’

Gabriel Danovitch, Susan Hou, Andrew S. Levey — 2012-02-01

In our recent perspective, as in our article 25 years ago, we focused on voluntary kidney donation from living kidney donors. Voluntarism is a core principle of the Declaration of Istanbul on Organ Trafficking and Transplant Tourism, as is donor protection and advocacy, promotion of deceased donation, and professional and governmental transparency of practice. As noted by Drs Shoja and Ghabili in their letter, the experience in Iran demonstrates the consequences for the living donor when this approach is ignored. We appreciate the concern voiced by our colleagues and recognize that even in a system based on voluntary kidney donation, the need to safeguard the dignity and health of the living donor requires constant vigilance. The US Department of Health and Human Services–mandated donor follow-up that we envisioned in our article would address both the physical and emotional health of donors.

Erratum regarding “Sulodexide for Kidney Protection in Type 2 Diabetes Patients With Microalbuminuria: A Randomized Controlled Trial” (Am J Kidney Dis 2011; 58:729-736)

2011-11-24

In the article entitled “Sulodexide for Kidney Protection in Type 2 Diabetes Patients With Microalbuminuria: A Randomized Controlled Trial” (Lewis et al, American Journal of Kidney Diseases 58(5):729-736, 2011), there was an omission in the Acknowledgements section. The listing of Investigators of the Collaborative Study Group should have included Study Investigator Jose L. Cangiano (San Juan, Puerto Rico).

Masthead

2012-02-01

The American Journal of Kidney Diseases (ISSN 0272-6386) is published monthly by Elsevier Inc., 360 Park Avenue South, New York, NY 10010-1710. Periodicals postage paid at New York, NY and additional mailing offices.

Editorial Board

2012-02-01

March Highlights

2012-02-01

Postpartum Hypertension Mira Rho

Abbreviated Information for Authors

2012-02-01

The American Journal of Kidney Diseases (AJKD) serves clinicians and scientists who treat and investigate kidney disease and associated conditions. AJKD is dedicated to providing high-quality, clinically relevant information in the form of original research articles, case reports, narrative reviews, editorials, and features.

Announcements

2012-02-01

The Department of Nephrology, Dialysis and Transplantation of the San Bortolo Hospital in Vicenza, and the International Renal Research Institute of Vicenza will be holding the 30th International Vicenza Course on Peritoneal Dialysis from June 12 to June 15, 2012 in Vicenza, Italy. The first course was held in 1982 and began a long-lasting tradition of science and education. The 2012 course will feature lectures on anatomy and physiology of the peritoneal membrane, recent developments in peritoneal transport, present and future techniques, new devices and dialysis solutions, and recently published and ongoing clinical trials. The deadline for registration is April 30, 2012. For more information visit www.vicenzanephrocourses.com/conferences/30.

This Month in AJKD

2012-02-01

See Doshi et al, pages 222-228; and Fakhouri et al, pages 168-169. Hyponatremia is the most frequently observed electrolyte abnormality in hospitalized patients. Doshi et al studied the frequency and severity of hyponatremia in hospitalized patients with cancer, examining the association of hyponatremia with length of stay and mortality, noting that those patients with cancer whose hyponatremia corrected had a lower risk of morality. In the accompanying editorial, Fakhouri et al note that Doshi and colleagues demonstrate a strong association between hyponatremia and mortality, but are lacking hard evidence of a causal link between the two. The editorialists agree with the authors that additional studies are needed to determine whether correction of hyponatremia itself or the ability to correct hyponatremia is the driver of improved outcomes.

Bound by a Promise: Advance Directives and “Uninformed Consent”

Joseph A. Abdelmalek, Dena E. Rifkin — 2012-02-01

“But it is too solemn—I think it is not right—to make a promise when I am ignorant what it will bind me to.” Dorothea Casaubon, from George Eliot's Middlemarch Up to the day of surgery, Mr Miller's chart read like most medical charts. Preoperative cardiac evaluation by primary care: check. Anesthesia preoperative note: check. Consent for surgery: check. Consent for transfusion: check. Inventory of belongings: check. Advance directive on file: check.

Quiz Page February 2012: Acute Kidney Injury in an Adolescent With a Family History of Autoimmune Disorders

Emma Allain-Launay, Nicolas Blin, Anne Moreau, Gwenaëlle Roussey-Kesler — 2012-02-01

A 15-year-old girl was admitted to the hospital with weakness, vomiting, abdominal pain, and darkening of the urine for several days. Type 1 diabetes mellitus was diagnosed 2 years previously, with positive titers of antibodies against glutamic acid decarboxylase and islet cell autoantigen 512. Her medications included glargine and fast insulin. Her family history was associated strongly with autoimmunity: her mother had Hashimoto thyroiditis and 2 sisters also had anti–glutamic acid decarboxylase and anti–islet cell autoantigen 512 antibodies, the youngest being diabetic.

American Journal of Kidney Diseases

Potential Interaction Between Sevelamer and Fat-Soluble Vitamins: A Hypothesis

Hyponatremia and Mortality in Patients With Cancer: The Devil Is in the Details

Lipid-Lowering Therapy in Individuals With CKD: Lessons Learned From SHARP

Childhood Membranous Nephropathy and Dietary Antigens

Comparison of Calcium Acetate and Sevelamer on Vascular Function and Fibroblast Growth Factor 23 in CKD Patients: A Randomized Clinical Trial

Effect of Vitamin K2 Supplementation on Functional Vitamin K Deficiency in Hemodialysis Patients: A Randomized Trial

Serum Creatinine Measurement Immediately After Cardiac Surgery and Prediction of Acute Kidney Injury

Periodontal Disease and Decreased Kidney Function in Japanese Elderly

Genetic Association and Gene-Gene Interaction Analyses in African American Dialysis Patients With Nondiabetic Nephropathy

Hyponatremia in Hospitalized Cancer Patients and Its Impact on Clinical Outcomes

Association of Filtered Sodium Load With Medullary Volumes and Medullary Hypoxia in Hypertensive African Americans as Compared With Whites

Predialysis Serum Sodium Level, Dialysate Sodium, and Mortality in Maintenance Hemodialysis Patients: The Dialysis Outcomes and Practice Patterns Study (DOPPS)

Appraising Stroke Risk in Maintenance Hemodialysis Patients: A Large Single-Center Cohort Study

Progression of Coronary Artery Calcification and Thoracic Aorta Calcification in Kidney Transplant Recipients

Polycystic Kidney Disease Presenting With Hypertension and Hypokalemia

Recurrent Acute Kidney Injury Following Bath Salts Intoxication

Tuberous Sclerosis Complex–Associated Angiomyolipomas: Focus on mTOR Inhibition

New Insights Into Human Minimal Change Disease: Lessons From Animal Models

Managing Older Adults With CKD: Individualized Versus Disease-Based Approaches

Renal Sarcoidosis Presenting as Acute Kidney Injury With Granulomatous Interstitial Nephritis and Vasculitis

The DOPPS Practice Monitor for US Dialysis Care: Trends Through April 2011

Commentary on ‘The DOPPS Practice Monitor for US Dialysis Care: Trends Through April 2011’: No Surprises Yet

Potassium and Metabolic Alkalosis

Metabolic Alkalosis Due to Hypercalcemia

In Reply to ‘Potassium and Metabolic Alkalosis’ and ‘Metabolic Alkalosis due to Hypercalcemia’

Predialysis Care: Intertwined Roles of Nephrologists and Dietitians

In Reply to 'Predialysis Care: Intertwined Roles of Nephrologists and Dietitians'

What Dominates Living Donor Kidney Transplantation: Altruism or Loss of Dignity?

In Reply to ‘What Dominates Living Donor Kidney Transplantation: Altruism or Loss of Dignity?’

Erratum regarding “Sulodexide for Kidney Protection in Type 2 Diabetes Patients With Microalbuminuria: A Randomized Controlled Trial” (Am J Kidney Dis 2011; 58:729-736)

Masthead

Editorial Board

Contents

March Highlights

Abbreviated Information for Authors

Announcements

This Month in AJKD

Bound by a Promise: Advance Directives and “Uninformed Consent”

Quiz Page February 2012: Acute Kidney Injury in an Adolescent With a Family History of Autoimmune Disorders