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Rationale & Objective: The relation of vascular stiffness, endothelial function, and kidney function is incompletely elucidated in African Americans. Our hypothesis was that increased vascular stiffness and endothelial dysfunction are associated with low estimated glomerular filtration rate (eGFR) and albuminuria in African Americans., Study Design: Cross-sectional cohort analysis of data from the Jackson Heart Study., Settings & Patients: 2,244 Jackson Heart Study participants (2012-2017 after Exam 3) who had undergone noninvasive hemodynamic assessment using arterial tonometry., Predictors: Baseline carotid-femoral pulse wave velocity, pulsatile hemodynamics forward wave amplitude, and hyperemic brachial artery flow were measured. Reduced eGFR was defined as eGFR between 15 and 60 mL/min/1.73 m 2 ., Outcomes: Prevalent albuminuria, urinary albumin-creatinine ratio., Analytical Approach: 2-sample t test for continuous variables and χ 2 test for categorical variables in addition to logistic and linear regression models to assess the risk for chronic kidney disease with each proposed hemodynamic variable., Results: Among 2,244 participants, mean age was 66 ± 11 years and 64% were women. Reduced eGFR was present in 233 (10.4%), and elevated urinary albumin-creatinine ratio, in 232 (10.4%). In multivariable-adjusted analyses, higher carotid-femoral pulse wave velocity was associated with the presence of reduced eGFR (OR, 1.37 [95% CI, 1.08-1.75] per SD; P  = 0.01) and with prevalent albuminuria (OR, 1.66 [95% CI, 1.32-2.11]; P  < 0.001). Higher forward wave amplitude was significantly associated with prevalent albuminuria (OR, 1.37 [95% CI, 1.14-1.65]; P  = 0.001)., Limitations: Cross-sectional analyses cannot inform causality., Conclusions: Higher arterial stiffness and pulsatility are associated with higher odds of reduced eGFR in African Americans. Future studies should focus on whether improving arterial stiffness contributes to kidney protection in African Americans., (© 2021 The Authors.)

Baclofen is a centrally-acting γ-amino butyric acid agonist used mainly in the symptomatic management of spasticity originating from the spinal cord. It is absorbed completely from the gastrointestinal tract, metabolized by the liver to a minor degree, and excreted unchanged by the kidneys. Baclofen is moderately lipophilic and can cross the blood-brain barrier easily. At the usual dosage, it acts mainly at the spinal level without central nervous system (CNS) side effects. During renal failure, however, the elimination of the drug will decrease with a prolonged half-life, resulting in a larger area-under-the-curve exposure and disproportionate CNS toxicity. Clinically, these patients with renal failure may present with a variety of toxic symptoms manifesting at therapeutic/sub-therapeutic doses of baclofen. In cases of unexplained mental status changes in a patient receiving baclofen therapy, a careful assessment of renal function and a high suspicion of baclofen-induced encephalopathy will be key to the diagnosis.
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[This corrects the article DOI: 10.1371/journal.pgen.1006728.].

Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium ( n Stage1 : 111,666; n Stage2 : 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea ( PPM1J , EDEM3, ACP1, SPEG, EYA4, CYP1A1 , and ATXN2L ; P Stage1 <3.7×10 -7 ), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 ( P =5.4×10 -8 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2 -knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation., (Copyright © 2017 by the American Society of Nephrology.)

Background: Controversy exists regarding the association of cigarette smoking and renal dysfunction, particularly among African Americans, who are disproportionately affected by chronic kidney disease; therefore, we evaluated the relationship between cigarette smoking and rapid renal function (RRF) decline in the Jackson Heart Study., Methods and Results: Rates of RRF decline were determined among 3648 African American participants enrolled at baseline in the Jackson Heart Study. RRF decline was defined as an absolute decline of estimated glomerular filtration rate of 30% from visit 1 to visit 3. There were 422 current, 659 past, and 2567 never smokers identified at visit 1. After adjustment for age, sex, body mass index, diabetes, hypertension, cholesterol, physical activity, education, alcohol consumption, and prevalent cardiovascular disease, current smokers demonstrated a significantly higher incidence of RRF decline compared with never smokers (incidence rate ratio 1.83, 95% CI 1.31-2.56). Current smokers using 1 to 19 and ≥20 cigarettes daily had an increased incidence of RRF decline (incidence rate ratios of 1.75 [95% CI 1.18-2.59] and 1.97 [95% CI 1.17-3.31], respectively). There was a significant, progressive reduction in estimated glomerular filtration rate from visit 1 to visit 3 in current and past smokers compared with never smokers. Finally, current smokers had a 1.38-fold increase in C-reactive protein compared with never smokers, after controlling for covariates., Conclusions: In a large African American cohort, current cigarette smoking was independently associated with RRF decline in a dose-dependent manner. There was also evidence of increased inflammation (C-reactive protein) in current smokers, suggesting a potential mechanism for these relationships., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Rare genetic variants influence blood pressure (BP)., Methods and Results: Whole-exome sequencing was performed on DNA samples from 17 956 individuals of European ancestry and African ancestry (14 497, first-stage discovery and 3459, second-stage discovery) to examine the effect of rare variants on hypertension and 4 BP traits: systolic BP, diastolic BP, pulse pressure, and mean arterial pressure. Tests of ≈170 000 common variants (minor allele frequency, ≥1%; statistical significance, P≤2.9×10(-7)) and gene-based tests of rare variants (minor allele frequency, <1%; ≈17 000 genes; statistical significance, P≤1.5×10(-6)) were evaluated for each trait and ancestry, followed by multiethnic meta-analyses. In the first-stage discovery, rare coding variants (splicing, stop-gain, stop-loss, nonsynonymous variants, or indels) in CLCN6 were associated with lower diastolic BP (cumulative minor allele frequency, 1.3%; β=-3.20; P=4.1×10(-6)) and were independent of a nearby common variant (rs17367504) previously associated with BP. CLCN6 rare variants were also associated with lower systolic BP (β=-4.11; P=2.8×10(-4)), mean arterial pressure (β=-3.50; P=8.9×10(-6)), and reduced hypertension risk (odds ratio, 0.72; P=0.017). Meta-analysis of the 2-stage discovery samples showed that CLCN6 was associated with lower diastolic BP at exome-wide significance (cumulative minor allele frequency, 1.1%; β=-3.30; P=5.0×10(-7))., Conclusions: These findings implicate the effect of rare coding variants in CLCN6 in BP variation and offer new insights into BP regulation., (© 2015 American Heart Association, Inc.)

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.

Previously, genetic analyses identified that variants in Arhgef11 may influence kidney injury in the Dahl salt-sensitive (S) rat, a model of hypertensive chronic kidney disease. To understand the potential mechanism by which altered expression and/or protein differences in Arhgef11 could play a role in kidney injury, stably transduced Arhgef11 knockdown cell lines as well as primary cultures of proximal tubule cells were studied. Genetic knockdown of Arhgef11 in HEK293 and NRK resulted in reduced RhoA activity, decreased activation of Rho-ROCK pathway, and less stress fiber formation versus control, similar to what was observed by pharmacological inhibition (fasudil). Primary proximal tubule cells (PTC) cultured from the S exhibited increased expression of Arhgef11, increased RhoA activity, and up regulation of Rho-ROCK signaling compared to control (small congenic). The cells were also more prone (versus control) to TGFβ-1 induced epithelial-mesenchymal transition (EMT), a hallmark feature of the development of renal interstitial fibrosis, and characterized by development of spindle shape morphology, gene expression changes in EMT markers (Col1a3, Mmp9, Bmp7, and Ocln) and increased expression of N-Cadherin and Vimentin. S derived PTC demonstrated a decreased ability to uptake FITC-albumin compared to the small congenic in vitro, which was confirmed by assessment of albumin re-uptake in vivo by infusion of FITC-albumin and immunofluorescence imaging. In summary, these studies suggest that genetic variants in the S form of Arhgef11 via increased expression and/or protein activity play a role in promoting kidney injury in the S rat through changes in cell morphology (Rho-Rock and/or EMT) that impact the function of tubule cells.

Background: Studies suggest 24-h blood pressure (BP) variability has prognostic value for cardiovascular disease. Several factors associated with high 24-h BP variability are also common among individuals with chronic kidney disease (CKD). We hypothesized 24-h BP variability would be higher for individuals with versus without CKD., Methods: We analyzed 1,022 Jackson Heart Study participants who underwent ambulatory blood pressure monitoring (ABPM). Twenty-four hour BP variability was defined by two metrics: day-night standard deviation (SDdn) and average real variability (ARV). CKD was defined as ACR ≥ 30 mg/g or eGFR <60 mL/min/1.73 m(2)., Results: The mean SDdn of systolic BP (SBP) was 10.2 ± 0.2 and 9.1 ± 0.1 mmHg and the mean ARV of SBP was 9.2 ± 0.2 and 8.6 ± 0.1 mmHg for those with and without CKD, respectively (each p ≤ 0.001). After adjustment for age and sex, SDdn and ARV were 0.98 mmHg (95 % CI 0.59, 1.38) and 0.52 mmHg (95 % CI 0.18, 0.86), respectively, higher among participants with versus without CKD. These differences were not statistically significant after further multivariable adjustment including 24-h mean SBP. Older age, and higher total cholesterol and 24-h mean SBP were associated with higher SDdn and ARV of SBP among participants with CKD. Mean SDdn and ARV of diastolic BP (DBP) were higher for participants with versus without CKD but these associations were not present after multivariable adjustment., Conclusion: Data from the current study suggest that CKD is associated with higher 24-h BP variability, but the association is primarily explained by higher mean BP among those with CKD.

Previous studies have indicated that cytochrome P450 (CYP) metabolites of arachidonic acid (AA), i.e., 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs), play an important role in the regulation of renal tubular and vascular function. The present study for the first time profiled HETEs and epoxygenase derived dihydroxyeicosatetraenoic acid diHETEs levels in spot urines and plasma in 262 African American patients from the University of Mississippi Chronic Kidney Disease Clinic and 31 African American controls. Significant correlations in eGFR and urinary 20-HETE/creatinine and 19-HETE/creatinine levels were observed. The eGFR increased by 17.47 [p=0.001] and 60.68 [(p=0.005]ml/min/for each ng/mg increase in 20-HETE and 19-HETE levels, respectively. Similar significant positive associations were found between the other urinary eicosanoids and eGFR and also with 19-HETE/urine creatinine concentration and proteinuria. We found that approximately 80% of plasma HETEs and 30% diHETEs were glucuronidated and the fractional excretion of 20-HETE was less than 1%. These results suggest that there is a significant hepatic source of urinary 20-HETE glucuronide and EETs with extensive renal biotransformation to metabolites which may play a role in the pathogenesis of CKD., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: The safety and efficacy of percutaneous renal biopsy (PKB) are relatively little studied in a training setting. We sought to review our recent experience with bedside PKB in our training program., Methods: We performed a retrospective cohort review of our consecutive 2.5-year renal biopsy experience (May 2007-November 2009) at the University of Mississippi Nephrology Fellowship. All of the biopsies were performed exclusively by renal fellows using real-time ultrasound (US) visualization within the framework of a structured US-PKB training course., Results: A total of 64 patients underwent PKB during the index period; 50 (78.1%) of these procedures were performed on native kidneys. Participant age was 39.8 ± 13.7 years, blood pressures measured 140.1/85.3 ± 21.5/14.9 mm Hg, serum creatinine was 3.05 ± 3.15 mg/dL, and median random urine protein:creatinine ratio was 2.38 (25%-75% interquartile range 0.49-7.32). The biopsied kidneys measured 11.8 (±1.6) cm. We recovered 18.8 ± 11.5 glomeruli per procedure; two biopsies were unsuccessful. Focal glomerular sclerosis and lupus nephritis (22% and 25%, respectively) predominated among the specimens. Only three specimens returned with no diagnostic changes. There was a close correlation between preceding history and recovered diagnoses of diabetic changes and lupus nephritis (r 0.605 and 0.842; P < 0.0001 for both). Initial hemoglobin of 10.8 ± 1.8 g/dL dropped to 10.2 (1.9) g/dL after the procedure (P < 0.0001). Five (7.8%) patients needed transfusion; one patient experienced persistent urine leakage; however, none of the patients needed surgical or radiological intervention or died., Conclusions: In the setting of a well-structured training environment, US-guided PKB is a reasonably safe and valuable component of renal fellowship training.

High blood pressure (BP) is more prevalent and contributes to more severe manifestations of cardiovascular disease (CVD) in African Americans than in any other United States ethnic group. Several small African-ancestry (AA) BP genome-wide association studies (GWASs) have been published, but their findings have failed to replicate to date. We report on a large AA BP GWAS meta-analysis that includes 29,378 individuals from 19 discovery cohorts and subsequent replication in additional samples of AA (n = 10,386), European ancestry (EA) (n = 69,395), and East Asian ancestry (n = 19,601). Five loci (EVX1-HOXA, ULK4, RSPO3, PLEKHG1, and SOX6) reached genome-wide significance (p < 1.0 × 10(-8)) for either systolic or diastolic BP in a transethnic meta-analysis after correction for multiple testing. Three of these BP loci (EVX1-HOXA, RSPO3, and PLEKHG1) lack previous associations with BP. We also identified one independent signal in a known BP locus (SOX6) and provide evidence for fine mapping in four additional validated BP loci. We also demonstrate that validated EA BP GWAS loci, considered jointly, show significant effects in AA samples. Consequently, these findings suggest that BP loci might have universal effects across studied populations, demonstrating that multiethnic samples are an essential component in identifying, fine mapping, and understanding their trait variability., (Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

The relative effectiveness of anticoagulation strategies during continuous renal replacement therapy (CRRT) may vary according to the clinical circumstances. In this study, the case of a 46-year-old man who developed fungal mediastinitis with the pathogen Scedosporium prolificans after coronary bypass surgery is reported. Numerous debridements and multiple antifungal agents were not effective in this patient. Miltefosine, a non-Food and Drug Administration-approved agent, was started after institutional review board request and approval. CRRT was initiated with regional citrate anticoagulation (RCA) for clinical sepsis with acute kidney injury. Subsequently, crescendo clotting of the extracorporeal circuit (ECC) occurred. Multiple interventions, including escalating RCA, adding increasing heparin to RCA and exchanging the dialysis catheter, were not effective. Argatroban anticoagulation was started without further ECC clotting, and the patient recovered from both acute kidney injury and septic shock, despite continued miltefosine administration. Sepsis may contribute to recurrent ECC clotting. Argatroban, a direct thrombin inhibitor, had a disproportionate effectiveness to maintain ECC patency in this patient.

A previous genetic analysis comparing the Dahl salt-sensitive (S) rat with the spontaneously hypertensive rat identified a major locus on chromosome 2 that influences proteinuria in the S rat. In the present study, blood pressure, proteinuria, and renal hemodynamics were evaluated in congenic strains with small segments of the protective spontaneously hypertensive rat genome on the S background. Proteinuria and renal function were significantly improved in the congenic strains compared with the S. The causative locus interval was narrowed to <375 kb on the basis of congenic strains, haplotype data, comparative mapping, and concordance with human genetic studies. Sequencing of the coding region of genes in this region identified 36 single nucleotide polymorphisms (13 nonsynonymous and 23 synonymous). Gene expression profiling indicated that only a few genes exhibited differential expression. Arhgef11, Pear1, and Sh2d2 were identified as important candidate genes that may be linked to kidney injury in the S rat. In particular, Arhgef11 plays an important role in the activation of the Rho-ROCK signaling pathway. Inhibition of this pathway using fasudil resulted in a significant reduction of proteinuria in treated S rats (compared with untreated S). However, no difference was observed between treated or untreated spontaneously hypertensive rat or congenic strains. The homologous region in humans was found to be associated with estimated glomerular filtration rate in the Candidate Gene Association Resource population. In summary, these findings demonstrate that allelic variants in Arhgef11, acting through the Rho-ROCK pathway, could influence kidney injury in the S as well as provide insight into human kidney disease.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

Chronic kidney disease (CKD) is an increasing global public health concern, particularly among populations of African ancestry. We performed an interrogation of known renal loci, genome-wide association (GWA), and IBC candidate-gene SNP association analyses in African Americans from the CARe Renal Consortium. In up to 8,110 participants, we performed meta-analyses of GWA and IBC array data for estimated glomerular filtration rate (eGFR), CKD (eGFR <60 mL/min/1.73 m(2)), urinary albumin-to-creatinine ratio (UACR), and microalbuminuria (UACR >30 mg/g) and interrogated the 250 kb flanking region around 24 SNPs previously identified in European Ancestry renal GWAS analyses. Findings were replicated in up to 4,358 African Americans. To assess function, individually identified genes were knocked down in zebrafish embryos by morpholino antisense oligonucleotides. Expression of kidney-specific genes was assessed by in situ hybridization, and glomerular filtration was evaluated by dextran clearance. Overall, 23 of 24 previously identified SNPs had direction-consistent associations with eGFR in African Americans, 2 of which achieved nominal significance (UMOD, PIP5K1B). Interrogation of the flanking regions uncovered 24 new index SNPs in African Americans, 12 of which were replicated (UMOD, ANXA9, GCKR, TFDP2, DAB2, VEGFA, ATXN2, GATM, SLC22A2, TMEM60, SLC6A13, and BCAS3). In addition, we identified 3 suggestive loci at DOK6 (p-value = 5.3×10(-7)) and FNDC1 (p-value = 3.0×10(-7)) for UACR, and KCNQ1 with eGFR (p = 3.6×10(-6)). Morpholino knockdown of kcnq1 in the zebrafish resulted in abnormal kidney development and filtration capacity. We identified several SNPs in association with eGFR in African Ancestry individuals, as well as 3 suggestive loci for UACR and eGFR. Functional genetic studies support a role for kcnq1 in glomerular development in zebrafish., Competing Interests: The authors have declared that no competing interests exist.

The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10(-8)) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10(-8)). The top IBC association for SBP was rs2012318 (P= 6.4 × 10(-6)) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10(-6)) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.

Identification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 × 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.

Chronic renal failure (CRF) has been shown, in animal models and clinical studies, to significantly reduce nonrenal clearance and to alter the bioavailability of predominantly metabolized drugs. Phase II reactions and drug transporters such as P-glycoprotein (P-gp) and organic anion transporting polypeptide (OATP) are also affected. High levels of parathyroid hormone (PTH), cytokines, and uremic toxins are implicated in some of these effects, which have a clinically significant impact on drug disposition and increase the risk of adverse drug reaction.

Slow extended daily dialysis (SLEDD) is the newest form of dialysis that is being used increasingly to replace continuous venovenous hemodialysis (CVVHD) for critically ill patients; it is less expensive to administer and has similar safety for patients who are prone to hemodynamic instability. Unfortunately, there are limited data regarding the appropriate dosing of antimicrobial agents for patients undergoing SLEDD. Furthermore, many nonnephrologists are not familiar with the differences between SLEDD, other continuous renal replacement therapies--for example, CVVHD--and routine hemodialysis. Thus, there is potential for inaccurate and, at worst, inadequate dosing of critical antimicrobial agents for this patient population. We review the available pharmacokinetic data on SLEDD and give preliminary recommendations for how to approach dosing in this situation.

Background: Chronic renal failure (CRF) has been shown to significantly reduce the nonrenal clearance and alter bioavailability of drugs predominantly metabolized by the liver and intestine., Objectives: The purpose of this article is to review all significant animal and clinical studies dealing with the effect of CRF on drug metabolism and transport., Methods: A search of the National Library of Medicine PubMed was done with terms such as chronic renal failure, cytochrome P450 [CYP], liver metabolism, efflux drug transport and uptake transport, including relevant articles back to 1969., Results: Animal studies in CRF have shown a significant downregulation (40-85%) of hepatic and intestinal CYP metabolism. High levels of parathyroid hormone, cytokines and uremic toxins have been shown to reduce CYP activity. Phase II reactions and drug transporters such as P-glycoprotein and organic anion transporting polypeptide are also affected., Conclusion: CRF alters intestinal, renal and hepatic drug metabolism and transport producing a clinically significant impact on drug disposition and increasing the risk for adverse drug reactions.

Background: Hemodialysis patients experience a high degree of psychosocial impairment., Methods: The psychosocial status of hemodialysis patients after Hurricane Katrina was evaluated using the Hurricane Coping Self-Efficacy (HCSE) measure, the Short Form-12 Health Survey (physical component summary [PCS] and mental component summary [MCS]), and the Center for Epidemiologic Studies Short Depression Scale (CES-D). These scales were administered to 391 hemodialysis patients (86% participation rate), 7 to 14 months after Hurricane Katrina., Results: The mean score (standard deviation) was 36.2 (9.6) for the HCSE scale, 37.1 (10.9) and 46.7 (12.7) for the PCS and MCS, respectively, and 10.0 (6.5) on the CES-D. Symptoms of depression (CES-D scores > or =10) were present in 45.5% of patients. After age, race, and gender adjustment, evacuating less than 2 days before Hurricane Katrina making landfall and more fear of dying were associated with less favorable scores on the HCSE, MCS, and CES-D scales. Patients placed in a shelter and with a longer displacement had significantly lower MCS scores and more depressive symptoms. More depressive symptoms were observed among patients hospitalized in the month after the storm. Those who evacuated to a hotel, with more fear of dying and who were hospitalized in the month after Hurricane Katrina had lower scores on the PCS., Conclusions: Impaired psychosocial status was common among dialysis patients surviving Hurricane Katrina and associated with reduced coping. These data demonstrate the need for screening and management of psychosocial issues in hemodialysis patients after disasters.

Increased dietary linoleic acid has been associated with reduced blood pressure in clinical and animal studies possibly mediated by prostaglandins. Urinary linoleate and prostaglandin metabolite excretion were investigated in subjects exposed to a salt-loading/salt-depletion regimen. Twelve healthy subjects were recruited from the New Orleans population (before Hurricaine Katrina) and admitted to the Tulane-Louisiana State University-Charity Hospital General Clinical Research Center after a 5-day outpatient lead-in phase on a 160-mmol sodium diet. On inpatient day 1, the subjects were maintained on the 160-mmol sodium diet, and a 24-hour urine specimen was collected. On day 2, the subjects received 2 L of IV normal saline over 4 hours and continued on a 160-mmol Na(+) diet (total: 460 mmol of sodium). Two 12-hour urine collections were obtained. On day 3, the subjects received three 40-mg oral doses of furosemide, two 12-hour urine collections were obtained, and the subjects were given a 10-mmol sodium diet. Urinary oxidized lipids were measured by high-performance liquid chromatography-tandem quadrupole mass spectroscopy. The excretion of the urinary linoleate metabolites, dihydroxyoctadecamonoenoic acids, and trihydroxyoctadecamonoenoic acids increased significantly during intravenous salt loading as compared with day 1 and the salt-depleted periods. The urinary excretion of 6-keto- prostaglandin F1alpha was unaffected by salt loading but was dramatically increased 7- to 10-fold by salt depletion. Prostaglandin E2 excretion was positively correlated with sodium excretion. The salt-stimulated production of linoleic acid diols and triols may inhibit tubular sodium reabsorption, thereby assisting in the excretion of the sodium load.

Objectives: To determine: (1) the pharmacokinetics and safety of an investigational aminoquinoline active against multidrug-resistant malaria parasites (AQ-13), including its effects on the QT interval, and (2) whether it has pharmacokinetic and safety profiles similar to chloroquine (CQ) in humans., Design: Phase I double-blind, randomized controlled trials to compare AQ-13 and CQ in healthy volunteers. Randomizations were performed at each step after completion of the previous dose., Setting: Tulane-Louisiana State University-Charity Hospital General Clinical Research Center in New Orleans., Participants: 126 healthy adults 21-45 years of age., Interventions: 10, 100, 300, 600, and 1,500 mg oral doses of CQ base in comparison with equivalent doses of AQ-13., Outcome Measures: Clinical and laboratory adverse events (AEs), pharmacokinetic parameters, and QT prolongation., Results: No hematologic, hepatic, renal, or other organ toxicity was observed with AQ-13 or CQ at any dose tested. Headache, lightheadedness/dizziness, and gastrointestinal (GI) tract-related symptoms were the most common AEs. Although symptoms were more frequent with AQ-13, the numbers of volunteers who experienced symptoms with AQ-13 and CQ were similar (for AQ-13 and CQ, respectively: headache, 17/63 and 10/63, p = 0.2; lightheadedness/dizziness, 11/63 and 8/63, p = 0.6; GI symptoms, 14/63 and 13/63; p = 0.9). Both AQ-13 and CQ exhibited linear pharmacokinetics. However, AQ-13 was cleared more rapidly than CQ (respectively, median oral clearance 14.0-14.7 l/h versus 9.5-11.3 l/h; p < or = 0.03). QTc prolongation was greater with CQ than AQ-13 (CQ: mean increase of 28 ms; 95% confidence interval [CI], 18 to 38 ms, versus AQ-13: mean increase of 10 ms; 95% CI, 2 to 17 ms; p = 0.01). There were no arrhythmias or other cardiac AEs with either AQ-13 or CQ., Conclusions: These studies revealed minimal differences in toxicity between AQ-13 and CQ, and similar linear pharmacokinetics.

Peripheral arterial disease (PAD) is a well-established risk factor for clinical cardiovascular disease (CVD). The impact of a low ankle-brachial index (ABI), higher than the generally recognized 0.9 cutpoint for PAD, on CVD risk is not well characterized. We analyzed data from the 1999 to 2002 National Health and Nutrition Examination Survey (n = 4,895), a nationally representative sample of United States adults, to determine the prevalence of PAD (ABI <0.90), borderline PAD (ABI 0.90 to 0.99), a low-normal ABI (1.00 to 1.09), and a normal ABI (1.10 to 1.29), and the association of these ABI levels with CVD. The prevalence of PAD, borderline PAD, a low-normal ABI, and a normal ABI was 5.0%, 8.7%, 27.8%, and 54.8%, respectively. After age, race/ethnicity, and gender adjustment, the odds ratios of a 10-year coronary heart disease (CHD) risk of >or=20%, CHD, stroke, and CVD were higher at lower ABI levels (each p trend <0.01). After additional adjustment for potential confounders, the odds ratios associated with a low-normal ABI, borderline PAD, and PAD, compared with those with a normal ABI, were 1.24 (95% confidence interval [CI] 0.91 to 1.70), 1.34 (95% CI 0.99 to 1.83), and 1.87 (95% CI 1.29 to 2.73), respectively (p trend <0.001) for CVD and 1.20 (95% CI 0.82 to 1.77), 1.45 (95% CI 0.80 to 2.63), and 2.02 (95% CI 1.20 to 3.39), respectively (p trend = 0.015) for a 10-year risk of CHD of >or=20%. In contrast, a trend was not present for CHD and stroke after multivariate adjustment. In conclusion, subjects with a low-normal ABI or with borderline PAD need screening for CVD risk factors, and interventions may be appropriate to prevent cardiovascular events.

Background: The cytochrome P450 (CYP) epoxygenase pathway produces arachidonic acid metabolites that are vasoactive, that affect renal sodium handling, and that have been proposed to play a mechanistic role in hypertension. Multiple single nucleotide polymorphisms (SNP) in CYP2C8, 2C9, 2J2 and soluble epoxide hydrolase (sEH) have been identified, many of which have altered functional activity in vitro. We performed a case-control study to determine the prevalence of epoxygenase-related SNP in African American individuals and to evaluate whether these SNP are associated with increased risk of hypertension., Methods: Normotensive African American individuals (N = 107) and African American patients with hypertension (N = 108) were recruited. DNA was extracted from a venous blood sample and genotyped for CYP2C8*2,*3, CYP2C9*2-*5,*8,*11, CYP2J2 *2-*7, L50L, R49S, V113M, N124S, sEH R287Q, and sEH 403Rins variant alleles by allelic discrimination using real-time polymerase chain reaction. Genotype and allele frequencies were calculated and associations with hypertension were estimated using unconditional logistic regression, adjusting for age and sex., Results: No association was found between any of the variant alleles and hypertension. We did find that only the CYP2C8*3and CYP2C9*2 alleles were in strong linkage disequilibrium in both the hypertensive and healthy African American groups, a finding that was reported previously in healthy individuals of white ethnicity., Conclusions: These results suggest that these epoxygenase-related SNP are not associated with increased risk of hypertension in the African American population. There was significant linkage disequilibrium between CYP2C8*3 and CYP2C9*2 alleles that was not associated with hypertension.

Objective: To determine the in-vitro and in-vivo effects of the CYP2C9*11 polymorphism on (S)-warfarin metabolism., Methods and Results: The *11 allele that results in mutation of Arg335-->Trp occurred with a frequency of approximately 1% in Caucasian and African-American populations. Four subjects carrying the *1/*11 genotype were identified in a clinical cohort of 192 warfarin patients. Compared to control subjects with the *1/*11 genotype (n=127), the *1/*11 group exhibited a 33% reduction in warfarin maintenance dose, that was independent of study population age or INR. In-vitro studies directed towards understanding the mechanism of reduced in-vivo activity revealed very low levels of holo-CYP2C9.11 expression in insect cells and decreased solubility in the presence of detergent. Membrane preparations of CYP2C9.11 contained inactive P420 and exhibited a shorter half-life for thermally induced conversion of P450 to P420 than CYP2C9.1. Metabolic studies demonstrated that functional CYP2C9.11 possessed similar (S)-warfarin hydroxylation regioselectivity and modestly reduced catalytic efficiency relative to the wild-type enzyme., Conclusions: In-vivo reduction in CYP2C9 (S)-warfarin activity due to the CYP2C9*11 polymorphism may largely be a consequence of decreased enzyme stability resulting in compromised expression of holo-enzyme. Increased enzyme lability of CYP2C9.11 may be related to improper folding due to the disruption of conserved salt-bridge and hydrogen bonding contacts in the loop region between the J and J' helices of the protein.

There is abundant evidence that chronic renal failure (CRF) and end-stage renal disease (ESRD) alter drug disposition by affecting protein and tissue binding and reducing systemic clearance of renally cleared drugs. What is not fully appreciated is that CRF can significantly reduce nonrenal clearance and alter the bioavailability of drugs predominantly metabolized by the liver. Animal studies in CRF have shown a major down-regulation (40-85%) of hepatic cytochrome P-450 metabolism involving specific isozymes. Phase II reactions such as acetylation and glucuronidation are also involved, with some isozymes showing induction and others inhibition. Hepatic enzymes exhibiting genetic polymorphisms such as N-acetyl-transferase-2 (NAT-2), which is responsible for the rapid and slow acetylator phenotypes, have been shown to be inhibited by ESRD and reversed by transplantation. There is some evidence pointing to the possibility of inhibitory factors circulating in the serum in ESRD patients which may be dialyzable. This review includes all significant animal and clinical studies using the search terms "chronic renal failure,""cytochrome P-450," and "liver metabolism" over the past 10 years obtained from the National Library of Medicine MEDLINE database, including relevant articles back to 1969.

Background: We retrospectively compared the decline of cardiac troponin I after acute myocardial infarction (AMI) in patients with normal renal function and those with end-stage renal disease (ESRD) who were receiving hemodialysis., Methods: We reviewed 257 cases with a discharge diagnosis of AMI or AMI plus ESRD; 222 were excluded due to inadequate data or evidence of ongoing myocardial necrosis. Decline of cardiac troponin I values was followed over a mean (+/- SD) of 2.75 +/- 1.2 days in patients with normal renal function and 2.7 +/- 2.0 days in ESRD patients. Average apparent half-life and apparent elimination rate constant of troponin I were compared between groups., Results: Of 35 patients with AMI, 16 had ESRD and were receiving hemodialysis, and 19 had normal renal function. Mean (+/- SD) apparent half-lives of troponin I in the ESRD group and the group with normal renal function were 1.48 +/- 0.77 days and 1.08 +/- 0.63 days, respectively. The mean apparent elimination rate constants of cardiac troponin I were 0.64 +/- 0.33 days(-1) in the ESRD group and 0.91 +/- 0.55 days(-1) in the group with normal renal function., Conclusion: The difference in apparent half-life and apparent elimination rate constant of cardiac troponin I between patients with normal renal function and those with ESRD is not statistically significant.

Background: The 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors lovastatin and simvastatin have been associated with rhabdomyolysis in cardiac transplant recipients. Herein, we report a case of a 52-year-old male recipient of a cardiac transplant who developed rhabdomyolysis and acute renal failure caused by simvastatin precipitated by multiple drug interactions., Methods: The patient had a history of cardiac transplantation (5 years before) and presented with a 2-day history of dark urine preceded by 2 weeks of diffuse myalgias. He had been maintained on cyclosporine throughout the entire post-transplant period. Simvastatin was added and pravastatin was discontinued 2 months before admission. Two weeks before the onset of muscle symptoms, digoxin and verapamil were started for new-onset atrial fibrillation. Creatinine phosphokinase levels peaked at 950,000 IU with serum creatinine of 3.3 mg/dL (baseline, 1.8 mg/dL)., Results: Review of the medication history indicates a temporal association between the addition of 3 drugs (simvastatin, verapamil, and digoxin) to the medication regimen already containing cyclosporine and the episode of rhabdomyolysis. All of these drugs are cytochrome P450 3A4 and/or P-glycoprotein substrates that are known from previous pharmacokinetic studies to individually produce substantial increases in levels of simvastatin., Conclusion: We believe this case illustrates that avoiding the use of drugs that are cytochrome P450 3A4 and/or P-glycoprotein substrates reduces the risk of rhabdomyolysis caused by 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors.

Tumor necrosis factor-alpha (TNF-alpha) has been shown to have somnogenic properties. Plasma levels of this cytokine have been found to increase significantly during dialysis with a bioincompatible (cuprophane) membrane in patients with postdialysis fatigue (PDF). We conducted a crossover study with random assignment to ascertain whether a biocompatible membrane might attenuate the increase of TNF-alpha and severity of PDF. Sixteen patients on maintenance hemodialysis underwent dialysis with either cuprophane (n = 8) or polymethylmethacrylate (PMMA; n = 8) membranes for 1 week and then switched to the opposite membrane during the second week. Predialysis and postdialysis measurements of plasma TNF-alpha levels were performed during the first and last dialysis treatments of each week. A fatigue score was determined from the sum of duration of fatigue and sleep within 6 hours of the completion of dialysis. TNF-alpha levels increased by an average of 18.3% during dialysis with cuprophane membranes but only 2.4% with PMMA membranes (P = 0.04). Despite this, fatigue scores remained unaltered (approximately 4 of 6). Hence, the biocompatible membrane, PMMA, failed to alleviate PDF. This suggests that dialytic stimulation of TNF-alpha plays no substantial role in the pathogenesis of PDF.

Postdialysis fatigue (PDF) has been ascribed to excessive ultrafiltration and decline in osmolality during hemodialysis. We evaluated the potential role for the sommogenic cytokines, interleukin-1 beta (IL-1beta) and tumor necrosis factor alpha (TNFalpha), in the genesis of PDF Patients dialyzing with cuprophane membrane were assigned to PDF (N=25) and non-PDF (N=25) groups based on a fatigue index questionnaire. Pre- and postdialysis samples were obtained from 3 consecutive treatments and later assayed for serum levels of IL-1beta and TNFalpha by ELISA. Our results show significant intradialytic elevation of TNFalpha in both non-PDF groups (non-PDF: pre- 3.36+/-0.80 pg/ml to post 3.75+/-0.88 pg/ml, p<0.04; PDF: pre- 5.95+/-0.80 pg/ml to post- 8.66-/+1.35 pg/ml, p<0.02). The degree of intradialytic augmentation was significantly greater for TNFalpha in the PDF group (46+/-18% vs 11+/-5%; p<0.03). There were no significant intradialytic changes in serum levels of IL-1beta in either the PDF or non-PDF groups. There also were no significant differences in dialysis-related body weights, systolic blood pressures, or osmolalities. These findings suggest that TNFalpha may be involved in the pathogenesis of PDF.

Valproic acid is an anticonvulsant drug known to inhibit the glucuronidation of zidovudine (AZT) in human liver microsomes. Zidovudine is metabolized by glucuronidation to the inactive 5'-glucuronide with a short plasma half-life (1.0 +/- 0.2 hour). This case presentation confirms that valproic acid inhibits glucuronidation in vivo, and this is the first documented observation of increased cerebrospinal fluid levels of zidovudine because of an interaction with valproic acid in a patient with acquired immune deficiency syndrome (AIDS). The peak plasma AZT level for the control period was 119 ng/mL, which increased almost 3-fold to 344 ng/mL with valproic acid (1.5 g/day). The plasma AZT trough was 47 ng/mL, which also increased almost 3-fold to 124 ng/mL with valproic acid. The molar ratio of plasma 5'-glucuronide/AZT at the peak was reduced from 1.77 (control) to 1.07 with valproic acid. The 5'-glucuronide/AZT ratio at the trough was reduced markedly from 5.0 (control) to 0.93 with valproic acid, suggesting in vivo inhibition of glucuronidation. Cerebrospinal AZT levels, drawn 30 minutes after peak plasma levels, increased from 27 ng/mL for the control to 47 ng/mL with valproic acid, which paralleled the change in peak plasma concentrations. This interaction with valproic acid may contribute to higher AZT levels in the brains of patients with human immunodeficiency virus-related (HIV) encephalopathy.

Objective: To determine whether the urinary excretion of 6-hydroxychlorzoxazone is an index of CYP2E1 activity in vivo., Methods: Male volunteers (n = 27; age range, 17 to 36 years) who were abstinent from alcohol were studied. Chlorzoxazone, 500 mg, was given orally and plasma was collected at 31/2, 41/2, 51/2, and 61/2 hours after dosing. Urine was collected for 8 hours. Ten volunteers participated in full kinetic studies to define the absorption phase and plasma area under the concentration-time curve of chlorzoxazone and the urinary kinetics of the 6-hydroxy metabolite. Chlorzoxazone and the 6-hydroxy metabolite were measured by high-performance liquid chromatography. CYP2E1 activity was expressed as a hydroxylation index (HI = mmole oral chlorzoxazone dose/mmole 6-hydroxychlorzoxazone in 8-hour urine)., Results: There was a significant positive correlation between plasma elimination rate constant for chlorzoxazone (Ke) and urinary excretion of the metabolite (n = 27, r = 0.42, p < 0.03) and a significant negative correlation between plasma Ke and HI (n = 27, r = -0.41, p < 0.04). The mean absorption rate constant for chlorzoxazone of 3.11 +/- 4.67 hr-1 was fivefold greater than the plasma Ke of 0.57 +/- 0.17 hr-1 for the full kinetic studies. The formation clearance of the 6-hydroxy metabolite was negative between plasma Ke of the parent compound and disposition rate constant for urinary excretion of the 6-hydroxy metabolite (n = 15, r = 0.85, p < 0.0001)., Conclusions: The urinary excretion of 6-hydroxychlorzoxazone is limited by formation rate and may be useful as an in vivo probe of CYP2E1 activity.

Immunoglobulin light chains, beta 2-microglobulin, insulin, and lysozyme are low-molecular-weight proteins (LMWP) shown to bind to renal brush border membranes. Competition among these proteins and the role of electrical charge in binding to brush border membranes have not been resolved. To investigate these factors, we performed displacement experiments with [125I]-labeled beta 2-microglobulin (pI = 5.6) using six species of LMWP over a pI range of 4.4-11.0. The inhibition constants, Ki, of these six competing ligands, kappa- and lambda-light chains, lysozyme, insulin, cytochrome c, and myoglobin, determined from the log displacement curves, ranged from 4 x 10(-5) to 8 x 10(-4) M. These experiments show marked cross-competition among LMWP for binding to brush border membranes. There was no correlation between Ki and pI indicating that the molecular structure is a more important determinant of LMWP binding to brush border membranes than net electrical charge.

Propranolol, metoprolol, acebutolol, nadolol and atenolol were incubated with isolated rat skeletal muscle mitochondria at 30 degrees C, and the rate of oxygen consumption was measured with an oxygen microelectrode. The potency of these drugs to inhibit state III respiration was correlated with lipid solubility as measured by the octanol/water partition coefficient. The most lipid-soluble beta-blocker, propranolol, had an ED50 of 0.6 mmol/l. The most water-soluble one, atenolol, showed no inhibition at concentrations up to 16 mmol/l. Inhibition of respiratory control ratio, state IV respiration and ADP/O ratio occurred at 2 mmol/l for propranolol, 16 mmol/l for metoprolol and was not consistently observed for the other beta-blockers at the concentrations tested. The inhibition of state III respiration of skeletal muscle mitochondria by lipid-soluble beta-blockers may be one of the causes of the fatigue observed in some patients receiving these drugs.

To test our hypothesis that a circulating factor(s) may be causing the renal salt and urate wasting in patients (pts) with intracranial diseases, we exposed rats to the plasma of these patients and studied sodium and lithium transport. We selected 21 neurosurgical pts, 13 of whom had increased fractional excretion (FE) of urate, and 14 age and sex-matched controls. Plasma from pts and controls were injected IP (0.5 mL) and infused, 0.2 ml prime and 1.8 mL at 0.01 mL/min, to Sprague Dawley rats anesthetized with Inactin. Renal transport of sodium (Na), lithium (Li) and potassium (K) was determined. There were higher mean +/- SEM for FENa, 0.59 +/- 0.07% vs 0.29 +/- 0.05%, P < 0.01, FELi, 36.6 +/- 1.9% vs 24.0 +/- 1.6%, P < 0.001 and K excretion rates, 1.69 +/- 0.13 vs 1.31 +/- 0.09 mumol/min, p < 0.02, in rats infused with plasma of pts as compared to controls, respectively. FENa decreased with increasing dilution of plasma of 2 pts with ICD. There was no difference in mean weight of rats, blood pressure, urine flow rate or insulin clearance between pts and controls. These data suggest that pts with ICD have a plasma factor(s) which decreases net Na, Li and K reabsorption.

Based on our demonstration of a high incidence of hypouricemia, tubular urate transport abnormality, and cerebral atrophy in patients with acquired immunodeficiency syndrome (AIDS), we performed prospective renal clearance studies in 29 consecutive neurosurgical patients with intracranial diseases of multiple etiologies to test our hypothesis that patients with intracranial disorders had defective tubular urate transport. Similar studies were performed in 21 age-matched controls. None of the subjects had serum creatinine greater than 123.8 mumol/L (1.4 mg/dL), sickle cell or liver diseases, or received intravenous fluid or uricosuric drugs at the time of study. Seven patients had no surgical procedures, 12 were studied after a neurosurgical procedure, and 10 had preoperative and postoperative studies. Ten had more than one postoperative study. Twelve had 24-hour urine collections. We found that 18 of 29 patients had elevated fractional excretion (FE) of urate greater than 10%. There was no difference in preoperative and postoperative FE urate by nonpaired t test for all patients and by paired t test in the 10 patients who had preoperative and postoperative studies performed. Seven patients had hypouricemia, defined as serum urate less than or equal to 0.18 mmol/L (3 mg/dL). Only one had hyponatremia (serum sodium less than 130 mmol/L). Urate excretion averaged 3.6 +/- 0.32 mmol (603 +/- 52.7 mg)/24 h, suggesting that the hypouricemia was not due to decreased urate production. None of the medications or surgical procedures could be considered to have caused the urate transport abnormality, nor was it associated with any specific intracranial location or type of disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunoglobulin light chains are low-molecular-weight proteins filtered at the renal glomerulus and catabolized within the proximal tubular epithelium. Excessive production and urinary excretion of light chains are associated with renal dysfunction. They also interfere with proximal renal tubule epithelial functions in vitro. We studied the binding of 125I-labeled kappa- and lambda-light chains, obtained from the urine of multiple myeloma patients, to rat and human renal proximal tubular brush-border membranes. Light-chain binding to brush borders was also demonstrated immunologically by flow cytometry. Computer analysis of binding data was consistent with presence of a single class of low-affinity, high-capacity, non-cooperative binding sites with relative selectivity for light chains on both rat and human kidney brush-border membranes. The dissociation constants of light chains ranged from 1.6 X 10(-5) to 1.2 X 10(-4) M, and maximum binding capacity ranged from 4.7 +/- 1.3 X 10(-8) to 8.0 +/- 0.9 X 10(-8) (SD) mol/mg protein at 25 degrees C. Kappa- and lambda-light chains competed with each other for binding with comparable affinity constants. Competition by albumin and beta-lactoglobulin, however, was much weaker, suggesting relative site selectivity for light chains. These binding sites probably function as endocytotic receptors for light chains and possibly other low-molecular-weight proteins.

Clinical evaluations of hypouricemia in patients with the acquired immunodeficiency syndrome (AIDS) have shown that it is a common disorder resulting from defective renal handling of uric acid. We prospectively studied renal urate handling in 23 patients and reviewed the records of 73 consecutive patients with AIDS or AIDS-related complex (ARC), who were seen in our AIDS clinic between March 1985 and April 1988, to determine the incidence, significance, and, when possible, the cause of hypouricemia. Hypouricemia was defined as serum urate less than or equal to 0.18 mmol/L (3 mg/dL). Renal clearance studies were performed in 23 patients, 10 hypouricemic and 13 nonhypouricemic. Eight patients (six with hypouricemia) underwent central venous pressure (CVP) monitoring, which was performed for clinical signs and symptoms of extracellular volume depletion. Fourteen (eight with hypouricemia) had daily urine urate measured. Hypouricemia was found in 21 (21.9%) of 96 patients. It was more common in females and intravenous (IV) drug abusers, and was associated with more opportunistic illnesses, particularly mycobacterium avium intracellulare (MAI) and cytomegalovirus (CMV) infections. Hypouricemia occurred in three patients with ARC and 18 patients with AIDS and was associated with cerebral atrophy in all 12 hypouricemic and 14 of 28 nonhypouricemic patients who had cranial computed tomography (CT) scans. During a comparable follow-up period, 71.4% of the hypouricemic as compared with 38.7% of nonhypouricemic patients died. Eleven developed hypouricemia as outpatients. Fractional excretion of uric acid (FEua) was elevated in the eight patients with CVP less than 1 cm of water, and in 10 of 10 with and nine of 13 without hypouricemia, despite CVP less than 1 cm water in eight.(ABSTRACT TRUNCATED AT 250 WORDS)

We performed prospective and retrospective studies of 96 consecutive patients with acquired immune deficiency syndrome (AIDS) or AIDS-related complex (ARC) to determine the incidence, pathogenesis, and clinical significance of hyponatremia, defined as serum sodium levels less than or equal to 130 mmol/L on more than one occasion. Thirty (31.3%), six with ARC and 24 with AIDS, had hyponatremia, and it developed in 20 as outpatients. Age, gender, duration of illness, and weight loss did not differ between groups. The hyponatremic patient had more opportunistic illnesses, including Pneumocystis carinii pneumonia and cytomegalovirus infections, and had a mortality of 70% as compared to 36.4% of the patients without hyponatremia. The probability of 50% survival after diagnosis of human immunodeficiency virus (HIV) infection in the hyponatremic group was 11.5 months, as compared to 39 months for those without hyponatremia, p less than 0.001. The probability of 50% survival after development of hyponatremia was 4.5 months and the median length of time to development of hyponatremia was 12.5 months after diagnosis of HIV infection. Eighty-eight percent had hypovolemia and 12% normovolemia. Seventeen of 21 with hypovolemia had no evident source of fluid loss. Two had Addison's disease, and 15 had unexpectedly high urine sodium concentration without evidence of renal or adrenal insufficiency. Hyponatremia occurs commonly in ambulatory patients with ARC or AIDS, appears in patients with higher mortality and morbidity, and does not represent a terminal event. Most patients had hypovolemia and unexpectedly high urine sodium concentration, suggesting defective renal sodium conservation.