High-Density Lipoprotein Lipidomics in Chronic Kidney Disease.

BACKGROUND: Patients with chronic kidney disease (CKD) have dysfunctional high-density lipoprotein (HDL) particles as compared with the general population. Understanding the lipid composition of HDL may provide mechanistic insight. We tested associations of estimated glomerular filtration rate (eGFR) and albuminuria with relative HDL abundance of ceramides, sphingomyelins, and phosphatidylcholines in participants with CKD. METHODS: We studied 490 participants with CKD from the Seattle Kidney Study. HDL was isolated from plasma; targeted lipidomics was used to quantify the relative abundance of ceramides, sphingomyelins, and phosphatidylcholines per 10 µg of total HDL protein. We evaluated the associations of eGFR and albuminuria with levels of individual lipids and lipid classes (including 7 ceramides, 6 sphingomyelins, and 24 phosphatidylcholines) using multivariable linear regression, controlling for multiple comparisons via the false discovery rate. RESULTS: The mean (SD) eGFR was 45 (24) mL/min/1.73 m2; the median (IQR[interquartile range]) albuminuria was 108 (16, 686) mg/g (12.2 [1.8, 77.6] mg/mmol) urine creatinine. After adjusting for demographics, past medical history, laboratory values, and medication use, eGFR was not associated with higher relative abundance of any class of lipids or individual lipids. Greater albuminuria was significantly associated with a higher relative abundance of total ceramides and moderate-long R-chain sphingomyelins, ceramides 22:0 and 24:1, hexosylceramide 16:0, sphingomyelin 16:0, and phosphatidylcholines 29:0, 30:1, and 38:2; the strongest association was for hexosylceramide 16:0 (increase per doubling of urine albumin to creatinine ratio 0.022 (95% CI, 0.012-0.032). CONCLUSIONS: Greater albuminuria was significantly associated with specific alterations in the lipid composition of HDL in participants with CKD.

Kidney Tubulointerstitial Fibrosis and Tubular Secretion.

RATIONALE & OBJECTIVE: Tubular secretion plays an important role in the efficient elimination of endogenous solutes and medications, and lower secretory clearance is associated with risk of kidney function decline. We evaluated whether histopathologic quantification of interstitial fibrosis and tubular atrophy (IFTA) is associated with lower tubular secretory clearance in persons undergoing kidney biopsy. STUDY DESIGN: Cross-sectional. SETTINGS & PARTICIPANTS: The Boston Kidney Biopsy Cohort is a study of persons undergoing native kidney biopsies for clinical indications. EXPOSURES: Semiquantitative score of IFTA reported by 2 trained pathologists. OUTCOMES: We measured plasma and urine concentrations of 9 endogenous secretory solutes using a targeted liquid chromatography/mass spectrometry assay. We used linear regression to test associations of urine-to-plasma ratios (UPRs) of these solutes with IFTA score after controlling for estimated glomerular filtration rate (eGFR) and albuminuria. RESULTS: Among 418 participants, mean age was 53 years, 51% were women, 64% were White, and 18% were Black. Mean eGFR was 50mL/min/1.73m2, and median urinary albumin-creatinine ratio was 819mg/g. Compared with individuals with≤25% IFTA, those with>50% IFTA had 12%-37% lower UPRs for all 9 secretory solutes. Adjusting for age, sex, race, eGFR, and urine albumin and creatinine levels attenuated the associations, yet a trend of lower secretion across groups remained statistically significant (P<0.05 for trend) for 7 of 9 solutes. A standardized composite secretory score incorporating UPR for all 9 secretory solutes using the min-max method showed similar results (P<0.05 for trend). LIMITATIONS: Single time point and spot measures of secretory solutes. CONCLUSIONS: Greater IFTA severity is associated with lower clearance of endogenous secretory solutes even after adjusting for eGFR and albuminuria.

Prediction of Kidney Drug Clearance: A Comparison of Tubular Secretory Clearance and Glomerular Filtration Rate.

BACKGROUND: Although proximal tubular secretion is the primary mechanism of kidney drug elimination, current kidney drug dosing strategies are on the basis of eGFR. METHODS: In a dedicated pharmacokinetic study to compare GFR with tubular secretory clearance for predicting kidney drug elimination, we evaluated stable outpatients with eGFRs ranging from 21 to 140 ml/min per 1.73 m2. After administering single doses of furosemide and famciclovir (metabolized to penciclovir), we calculated their kidney clearances on the basis of sequential plasma and timed urine measurements. Concomitantly, we quantified eight endogenous secretory solutes in plasma and urine using liquid chromatography-tandem mass spectrometry and measured GFR by iohexol clearance (iGFR). We computed a summary secretion score as the scaled average of the secretory solute clearances. RESULTS: Median iGFR of the 54 participants was 73 ml/min per 1.73 m2. The kidney furosemide clearance correlated with iGFR (r=0.84) and the summary secretion score (r=0.86). The mean proportionate error (MPE) between iGFR-predicted and measured furosemide clearance was 30.0%. The lowest MPE was observed for the summary secretion score (24.1%); MPEs for individual secretory solutes ranged from 27.3% to 48.0%. These predictive errors were statistically indistinguishable. Penciclovir kidney clearance was correlated with iGFR (r=0.83) and with the summary secretion score (r=0.91), with similar predictive accuracy of iGFR and secretory clearances. Combining iGFR with the summary secretion score yielded only modest improvements in the prediction of the kidney clearance of furosemide and penciclovir. CONCLUSIONS: Secretory solute clearance measurements can predict kidney drug clearances. However, tight linkage between GFR and proximal tubular secretory clearance in stable outpatients provides some reassurance that GFR, even when estimated, is a useful surrogate for predicting secretory drug clearances in such patients.

Cadherin-11, Sparc-related modular calcium binding protein-2, and Pigment epithelium-derived factor are promising non-invasive biomarkers of kidney fibrosis.

Kidney fibrosis constitutes the shared final pathway of nearly all chronic nephropathies, but biomarkers for the non-invasive assessment of kidney fibrosis are currently not available. To address this, we characterize five candidate biomarkers of kidney fibrosis: Cadherin-11 (CDH11), Sparc-related modular calcium binding protein-2 (SMOC2), Pigment epithelium-derived factor (PEDF), Matrix-Gla protein, and Thrombospondin-2. Gene expression profiles in single-cell and single-nucleus RNA-sequencing (sc/snRNA-seq) datasets from rodent models of fibrosis and human chronic kidney disease (CKD) were explored, and Luminex-based assays for each biomarker were developed. Plasma and urine biomarker levels were measured using independent prospective cohorts of CKD: the Boston Kidney Biopsy Cohort, a cohort of individuals with biopsy-confirmed semiquantitative assessment of kidney fibrosis, and the Seattle Kidney Study, a cohort of patients with common forms of CKD. Ordinal logistic regression and Cox proportional hazards regression models were used to test associations of biomarkers with interstitial fibrosis and tubular atrophy and progression to end-stage kidney disease and death, respectively. Sc/snRNA-seq data confirmed cell-specific expression of biomarker genes in fibroblasts. After multivariable adjustment, higher levels of plasma CDH11, SMOC2, and PEDF and urinary CDH11 and PEDF were significantly associated with increasing severity of interstitial fibrosis and tubular atrophy in the Boston Kidney Biopsy Cohort. In both cohorts, higher levels of plasma and urinary SMOC2 and urinary CDH11 were independently associated with progression to end-stage kidney disease. Higher levels of urinary PEDF associated with end-stage kidney disease in the Seattle Kidney Study, with a similar signal in the Boston Kidney Biopsy Cohort, although the latter narrowly missed statistical significance. Thus, we identified CDH11, SMOC2, and PEDF as promising non-invasive biomarkers of kidney fibrosis.

Association Between Kidney Clearance of Secretory Solutes and Cardiovascular Events: The Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: The clearance of protein-bound solutes by the proximal tubules is an innate kidney mechanism for removing putative uremic toxins that could exert cardiovascular toxicity in humans. However, potential associations between impaired kidney clearances of secretory solutes and cardiovascular events among patients with chronic kidney disease (CKD) remains uncertain. STUDY DESIGN: A multicenter, prospective, cohort study. SETTING & PARTICIPANTS: We evaluated 3,407 participants from the Chronic Renal Insufficiency Cohort (CRIC) study. EXPOSURES: Baseline kidney clearances of 8 secretory solutes. We measured concentrations of secretory solutes in plasma and paired 24-hour urine specimens using liquid chromatography-tandem mass spectrometry (LC-MS/MS). OUTCOMES: Incident heart failure, myocardial infarction, and stroke events. ANALYTICAL APPROACH: We used Cox regression to evaluate associations of baseline secretory solute clearances with incident study outcomes adjusting for estimated GFR (eGFR) and other confounders. RESULTS: Participants had a mean age of 56 years; 45% were women; 41% were Black; and the median estimated glomerular filtration rate (eGFR) was 43 mL/min/1.73 m2. Lower 24-hour kidney clearance of secretory solutes were associated with incident heart failure and myocardial infarction but not incident stroke over long-term follow-up after controlling for demographics and traditional risk factors. However, these associations were attenuated and not statistically significant after adjustment for eGFR. LIMITATIONS: Exclusion of patients with severely reduced eGFR at baseline; measurement variability in secretory solutes clearances. CONCLUSIONS: In a national cohort study of CKD, no clinically or statistically relevant associations were observed between the kidney clearances of endogenous secretory solutes and incident heart failure, myocardial infarction, or stroke after adjustment for eGFR. These findings suggest that tubular secretory clearance provides little additional information about the development of cardiovascular disease events beyond glomerular measures of GFR and albuminuria among patients with mild-to-moderate CKD.

Comparison of host endothelial, epithelial and inflammatory response in ICU patients with and without COVID-19: a prospective observational cohort study.

BACKGROUND: Analyses of blood biomarkers involved in the host response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection can reveal distinct biological pathways and inform development and testing of therapeutics for COVID-19. Our objective was to evaluate host endothelial, epithelial and inflammatory biomarkers in COVID-19. METHODS: We prospectively enrolled 171 ICU patients, including 78 (46%) patients positive and 93 (54%) negative for SARS-CoV-2 infection from April to September, 2020. We compared 22 plasma biomarkers in blood collected within 24 h and 3 days after ICU admission. RESULTS: In critically ill COVID-19 and non-COVID-19 patients, the most common ICU admission diagnoses were respiratory failure or pneumonia, followed by sepsis and other diagnoses. Similar proportions of patients in both groups received invasive mechanical ventilation at the time of study enrollment. COVID-19 and non-COVID-19 patients had similar rates of acute respiratory distress syndrome, severe acute kidney injury, and in-hospital mortality. While concentrations of interleukin 6 and 8 were not different between groups, markers of epithelial cell injury (soluble receptor for advanced glycation end products, sRAGE) and acute phase proteins (serum amyloid A, SAA) were significantly higher in COVID-19 compared to non-COVID-19, adjusting for demographics and APACHE III scores. In contrast, angiopoietin 2:1 (Ang-2:1 ratio) and soluble tumor necrosis factor receptor 1 (sTNFR-1), markers of endothelial dysfunction and inflammation, were significantly lower in COVID-19 (p < 0.002). Ang-2:1 ratio and SAA were associated with mortality only in non-COVID-19 patients. CONCLUSIONS: These studies demonstrate that, unlike other well-studied causes of critical illness, endothelial dysfunction may not be characteristic of severe COVID-19 early after ICU admission. Pathways resulting in elaboration of acute phase proteins and inducing epithelial cell injury may be promising targets for therapeutics in COVID-19.

Relationship Between Chronic Kidney Disease, Glucose Homeostasis, and Plasma Osteocalcin Carboxylation and Fragmentation.

OBJECTIVE: Chronic kidney disease (CKD) is associated with reduced insulin sensitivity, through mechanisms that are not well understood. Low vitamin K intake and incomplete carboxylation of the vitamin K-dependent protein osteocalcin may promote insulin resistance. We assessed relationships of osteocalcin concentration, carboxylation, and fragmentation with CKD and glucose homeostasis in a cross-sectional study. METHODS: We included 87 participants without diabetes: 50 (27 female) with moderate to severe CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2 not treated with dialysis) and 37 (17 female) healthy controls. Total osteocalcin was measured by immunoassay, and osteocalcin carboxylation and fragmentation status by liquid chromatography-electrospray ionization-based mass spectrometric immunoassay. Endpoints included glucose tolerance (based on 2-hour oral glucose tolerance test), insulin sensitivity (hyperinsulinemic-euglycemic clamp), and pancreatic beta-cell function (intravenous glucose tolerance test). RESULTS: The total plasma osteocalcin concentration was higher in the CKD group (mean [standard deviation] 102.9 [147.5]) than that in the control group (53.6 [51.1] ng/mL, P = .03), and more osteocalcin was circulating as fragments. The extent of osteocalcin carbocylation did not differ between individuals with and without CKD. Osteocalcin concentration, carboxylation, and fragmentation were not associated with any measure of glucose homeostasis in multivariable-adjusted analyses. CONCLUSIONS: In CKD, circulating osteocalcin concentrations are elevated, in part due to larger proportions of fragmented forms. However, osteocalcin carboxylation status is not significantly different between individuals with and without CKD. Our data also do not provide support for the hypothesis that differences in osteocalcin carboxylation may explain reduced insulin sensitivity in individuals with CKD.

Kidney Clearance of Secretory Solutes Is Associated with Progression of CKD: The CRIC Study.

BACKGROUND: The secretion of organic solutes by the proximal tubules is an essential intrinsic kidney function. However, the clinical significance of the kidney's clearance of tubular secretory solutes is uncertain. METHODS: In this prospective cohort study, we evaluated 3416 participants with CKD from the Chronic Renal Insufficiency Cohort (CRIC) study. We measured plasma and 24-hour urine concentrations of endogenous candidate secretory solutes at baseline, using targeted liquid chromatography-tandem mass spectrometry. The study defined CKD progression by a ≥50% decline in the eGFR, initiation of maintenance dialysis, or kidney transplantation. We used Cox proportional hazards regression to test associations of secretory-solute clearances with CKD progression and mortality, adjusting for eGFR, albuminuria, and other confounding characteristics. RESULTS: Participants in this ancillary study had a mean age of 58 years and 41% were black; the median eGFR was 43 ml/min per 1.73 m2. After adjustment, lower kidney clearances of six solutes-kynurenic acid, pyridoxic acid, indoxyl sulfate, xanthosine, isovalerylglycine, and cinnamoylglycine-were associated with significantly greater risks of CKD progression, with clearance of kynurenic acid, a highly protein-bound solute, having the strongest association. Lower clearances of isovalerylglycine, tiglylglycine, hippurate, and trimethyluric acid were significantly associated with all-cause mortality after adjustment. CONCLUSIONS: We found lower kidney clearances of endogenous secretory solutes to be associated with CKD progression and all-cause mortality, independent of eGFR and albuminuria. This suggests that tubular clearance of secretory solutes provides additional information about kidney health beyond measurements of glomerular function alone.

Association of tubular solute clearances with the glomerular filtration rate and complications of chronic kidney disease: the Chronic Renal Insufficiency Cohort study.

BACKGROUND: The secretion of organic solutes by the proximal tubules is an essential intrinsic kidney function. The degree to which secretory solute clearance corresponds with the glomerular filtration rate (GFR) and potential metabolic implications of net secretory clearance are largely unknown. METHODS: We evaluated 1240 participants with chronic kidney disease (CKD) from the multicenter Chronic Renal Insufficiency Cohort (CRIC) Study. We used targeted mass-spectrometry to quantify candidate secretory solutes in paired 24-h urine and plasma samples. CRIC study personnel measured GFR using 125I-iothalamate clearance (iGFR). We used correlation and linear regression to determine cross-sectional associations of secretory clearances with iGFR and common metabolic complications of CKD. RESULTS: Correlations between iGFR and secretory solute clearances ranged from ρ = +0.30 for hippurate to ρ = +0.58 for kynurenic acid. Lower net clearances of most secretory solutes were associated with higher serum concentrations of parathyroid hormone (PTH), triglycerides and uric acid. Each 50% lower kynurenic acid clearance was associated with a 21% higher serum PTH concentration [95% confidence interval (CI) 15-26%] and a 10% higher serum triglyceride concentration (95% CI 5-16%) after adjustment for iGFR, albuminuria and other potential confounders. Secretory solute clearances were not associated with statistically or clinically meaningful differences in serum calcium, phosphate, hemoglobin or bicarbonate concentrations. CONCLUSIONS: Tubular secretory clearances are modestly correlated with measured GFR among adult patients with CKD. Lower net secretory clearances are associated with selected metabolic complications independent of GFR and albuminuria, suggesting potential clinical and biological relevance.

Genetic Variants Associated with Circulating Fibroblast Growth Factor 23.

BACKGROUND: Fibroblast growth factor 23 (FGF23), a bone-derived hormone that regulates phosphorus and vitamin D metabolism, contributes to the pathogenesis of mineral and bone disorders in CKD and is an emerging cardiovascular risk factor. Central elements of FGF23 regulation remain incompletely understood; genetic variation may help explain interindividual differences. METHODS: We performed a meta-analysis of genome-wide association studies of circulating FGF23 concentrations among 16,624 participants of European ancestry from seven cohort studies, excluding participants with eGFR<30 ml/min per 1.73 m2 to focus on FGF23 under normal conditions. We evaluated the association of single-nucleotide polymorphisms (SNPs) with natural log-transformed FGF23 concentration, adjusted for age, sex, study site, and principal components of ancestry. A second model additionally adjusted for BMI and eGFR. RESULTS: We discovered 154 SNPs from five independent regions associated with FGF23 concentration. The SNP with the strongest association, rs17216707 (P=3.0×10-24), lies upstream of CYP24A1, which encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D. Each additional copy of the T allele at this locus is associated with 5% higher FGF23 concentration. Another locus strongly associated with variations in FGF23 concentration is rs11741640, within RGS14 and upstream of SLC34A1 (a gene involved in renal phosphate transport). Additional adjustment for BMI and eGFR did not materially alter the magnitude of these associations. Another top locus (within ABO, the ABO blood group transferase gene) was no longer statistically significant at the genome-wide level. CONCLUSIONS: Common genetic variants located near genes involved in vitamin D metabolism and renal phosphate transport are associated with differences in circulating FGF23 concentrations.

Serum 25-Hydroxyvitamin D Concentrations Are Associated with Computed Tomography Markers of Subclinical Interstitial Lung Disease among Community-Dwelling Adults in the Multi-Ethnic Study of Atherosclerosis (MESA).

Background: Activated vitamin D has anti-inflammatory properties. 25-Hydroxyvitamin D [25(OH)D] deficiency might contribute to subclinical interstitial lung disease (ILD). Objective: We examined associations between serum 25(OH)D concentrations and subclinical ILD among middle-aged to older adults who were free of cardiovascular disease at baseline. Methods: We studied 6302 Multi-Ethnic Study of Atherosclerosis (MESA) participants who had baseline serum 25(OH)D concentrations and computed tomography (CT) imaging spanning ≤ 10 y. Baseline cardiac CT scans (2000-2002) included partial lung fields. Some participants had follow-up cardiac CT scans at exams 2-5 and a full-lung CT scan at exam 5 (2010-2012), with a mean ± SD of 2.1 ± 1.0 scans. Subclinical ILD was defined quantitatively as high-attenuation areas (HAAs) between -600 and -250 Hounsfield units. We assessed associations of 25(OH)D with adjusted HAA volumes and HAA progression. We also examined associations between baseline 25(OH)D and the presence of interstitial lung abnormalities (ILAs) assessed qualitatively (yes or no) from full-lung CT scans at exam 5. Models were adjusted for sociodemographic characteristics, lifestyle factors (including smoking), and lung volumes. Results: The cohort's mean ± SD characteristics were 62.2 ± 10 y for age, 25.8 ± 10.9 ng/mL for 25(OH)D concentrations, and 28.3 ± 5.4 for body mass index (kg/m2); 53% were women, with 39% white, 27% black, 22% Hispanic, and 12% Chinese race/ethnicities. Thirty-three percent had replete (≥30 ng/mL), 35% intermediate (20 to <30 ng/mL), and 32% deficient (<20 ng/mL) 25(OH)D concentrations. Compared with those with replete concentrations, participants with 25(OH)D deficiency had greater adjusted HAA volume at baseline (2.7 cm3; 95% CI: 0.9, 4.5 cm3) and increased progression over a median of 4.3 y of follow-up (2.7 cm3; 95% CI: 0.9, 4.4 cm3) (P < 0.05). 25(OH)D deficiency was also associated with increased prevalence of ILAs 10 y later (OR: 1.5; 95% CI: 1.1, 2.2). Conclusions: Vitamin D deficiency is independently associated with subclinical ILD and its progression, based on both increased HAAs and ILAs, in a community-based population. Further studies are needed to examine whether vitamin D repletion can prevent ILD or slow its progression. The MESA cohort design is registered at www.clinicaltrials.gov as NCT00005487.

Diurnal and Long-term Variation in Plasma Concentrations and Renal Clearances of Circulating Markers of Kidney Proximal Tubular Secretion.

BACKGROUND: The renal proximal tubule is essential for removing organic solutes and exogenous medications from the circulation. We evaluated diurnal, prandial, and long-term biological variation of 4 candidate endogenous markers of proximal tubular secretion. METHODS: We used LC-MS to measure plasma and urine concentrations of hippurate (HA), cinnamoylglycine (CMG), indoxyl sulfate (IS), and p-cresol sulfate (PCS) in 25 healthy adults. We measured plasma concentrations of secreted solutes at 13 time points over a 24-h period, and again after 2 weeks and 14 weeks of follow-up. We further measured 24-h renal clearances of secreted solutes at baseline, 2 weeks, and 14 weeks. RESULTS: Plasma concentrations of secreted solutes varied over the 24-h baseline period. Diurnal variation was greatest for HA, followed by CMG, IS, and PCS. Plasma concentrations of HA (P = 0.002) and IS (P = 0.02), but not CMG and PCS, increased significantly following meals. Long-term intraindividual biological variation (CVI) in plasma concentrations of secreted solutes over 14 weeks varied from 21.8% for IS to 67.3% for PCS, and exceeded that for plasma creatinine (CVI, 7.1%). Variation in 24-h renal clearances was similar among the secreted solutes [intraindividual variation (CVA+I), 33.6%-47.3%] and was lower using pooled plasma samples from each study visit. CONCLUSIONS: Plasma concentrations of HA, CMG, IS, and PCS fluctuate within individuals throughout the day and over weeks. Renal clearances of these secreted solutes, which serve as estimates of renal proximal tubule secretion, are also subject to intraindividual biological variation that can be improved by additional plasma measurements.

Echocardiographic Measures and Estimated GFR Decline Among African Americans: The Jackson Heart Study.

BACKGROUND: Cardiac structural abnormalities, common in African Americans, are associated with adverse clinical outcomes. Associations between echocardiography-measured subclinical heart failure and kidney function decline are unknown and may identify novel risk factors for kidney disease in this population. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 2,418 Jackson Heart Study participants with baseline echocardiograms and longitudinal measures of estimated glomerular filtration rate (eGFR) calculated from the CKD-EPI creatinine equation. 2,219 participants had baseline eGFRs≥60mL/min/1.73m2. PREDICTORS: Left ventricular mass (LVM) and ejection fraction (LVEF) and pulmonary artery systolic pressure (PASP) quantified from baseline echocardiograms. OUTCOMES: Primary outcome was >30% eGFR decline or progression to end-stage renal disease (ESRD; need for dialysis therapy) over a mean of 8 years. Secondary outcome, eGFR<60mL/min/1.73m2 or progression to ESRD and eGFR decline >1mL/min/1.73m2 per year among those with baseline eGFRs≥60mL/min/1.73m2. MEASUREMENTS: Logistic regression models, adjusted for demographics, physical characteristics, comorbid conditions, and medication use. RESULTS: Mean age was 52.2±11.9 (SD) years, 37% of participants were men; mean baseline eGFR was 87.3±17.3mL/min/1.73m2. The primary and secondary outcomes occurred in 148 (6.1%) and 162 (7.1%) participants, respectively. In unadjusted models, every 25-g greater LVM was significantly associated with greater odds of eGFR decline > 30% or ESRD (OR, 1.38; 95% CI, 1.26-1.51) and incident eGFR<60mL/min/1.73m2 or ESRD (OR, 1.30; 95% CI, 1.20-1.42); only the former remained statistically significant after adjustment. There was no association of LVEF or PASP with either eGFR decline > 30% or ESRD (LVEF: adjusted OR, 0.95 [95% CI, 0.84-1.07]; PASP: adjusted OR, 0.98 [95% CI, 0.87-1.11]) or incident eGFR<60mL/min/1.73m2 or ESRD (LVEF: adjusted OR, 0.98 [95% CI, 0.86-1.11]; PASP: adjusted OR, 1.05 [95% CI, 0.94-1.18]) in multivariable models. LIMITATIONS: No midstudy creatinine measurement at examination 2. CONCLUSIONS: Greater LVM was significantly associated with eGFR decline > 30% or ESRD among African Americans in a community-based cohort. Treating and reversing elevated LVM may reduce the burden and progression of kidney disease in this high-risk population.

Acute kidney injury in allopurinol-induced DRESS syndrome: a case report of concurrent tubulointerstitial nephritis and kidney-limited necrotizing vasculitis
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Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare but potentially fatal adverse drug reaction with variable renal involvement. We report the case of a man who presented with allopurinol-induced DRESS and acute kidney injury (AKI) requiring hemodialysis. Kidney biopsy revealed eosinophilic tubulointerstitial nephritis and necrotizing vasculitis of the intralobular arteries without systemic markers of vasculitis. After cyclophosphamide and glucocorticoids, his symptoms and AKI resolved. To our knowledge, this is the first case of kidney-limited necrotizing vasculitis, questioning whether a biopsy should be routinely performed in patients with DRESS accompanied by severe AKI. It is possible that kidney-limited necrotizing vasculitis is an under-diagnosed manifestation of DRESS syndrome, and in such a setting, early recognition, stopping the offending agent, and use of aggressive immunosuppressive therapy, including cyclophosphamide, may lead to a favorable outcome.
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Tubular Secretion in CKD.

Renal function generally is assessed by measurement of GFR and urinary albumin excretion. Other intrinsic kidney functions, such as proximal tubular secretion, typically are not quantified. Tubular secretion of solutes is more efficient than glomerular filtration and a major mechanism for renal drug elimination, suggesting important clinical consequences of secretion dysfunction. Measuring tubular secretion as an independent marker of kidney function may provide insight into kidney disease etiology and improve prediction of adverse outcomes. We estimated secretion function by measuring secreted solute (hippurate, cinnamoylglycine, p-cresol sulfate, and indoxyl sulfate) clearance using liquid chromatography-tandem mass spectrometric assays of serum and timed urine samples in a prospective cohort study of 298 patients with kidney disease. We estimated GFR by mean clearance of creatinine and urea from the same samples and evaluated associations of renal secretion with participant characteristics, mortality, and CKD progression to dialysis. Tubular secretion rate modestly correlated with eGFR and associated with some participant characteristics, notably fractional excretion of electrolytes. Low clearance of hippurate or p-cresol sulfate associated with greater risk of death independent of eGFR (hazard ratio, 2.3; 95% confidence interval, 1.1 to 4.7; hazard ratio, 2.5; 95% confidence interval, 1.0 to 6.1, respectively). Hazards models also suggested an association between low cinnamoylglycine clearance and risk of dialysis, but statistical analyses did not exclude the null hypothesis. Therefore, estimates of proximal tubular secretion function correlate with glomerular filtration, but substantial variability in net secretion remains. The observed associations of net secretion with mortality and progression of CKD require confirmation.

Urinary uromodulin, kidney function, and cardiovascular disease in elderly adults.

Urinary uromodulin (uUMOD) is the most common secreted tubular protein in healthy adults. However, the relationship between uUMOD and clinical outcomes is still unclear. Here we measured uUMOD in 192 participants of the Cardiovascular Health Study with over a 30% decline in estimated glomerular filtration rate (eGFR) over 9 years, 54 with incident end-stage renal disease (ESRD), and in a random subcohort of 958 participants. The association of uUMOD with eGFR decline was evaluated using logistic regression and with incident ESRD, cardiovascular disease, heart failure, and mortality using Cox proportional regression. Mean age was 78 years and median uUMOD was 25.8 µg/ml. In a case-control study evaluating eGFR decline (192 cases and 231 controls), each 1-s.d. higher uUMOD was associated with a 23% lower odds of eGFR decline (odds ratio 0.77 (95% CI 0.62-0.96)) and a 10% lower risk of mortality (hazard ratio 0.90 (95% CI 0.83-0.98)) after adjusting for demographics, eGFR, albumin/creatinine ratio, and other risk factors. There was no risk association of uUMOD with ESRD, cardiovascular disease, or heart failure after multivariable adjustment. Thus, low uUMOD levels may identify persons at risk of progressive kidney disease and mortality above and beyond established markers of kidney disease, namely eGFR and the albumin/creatinine ratio. Future studies need to confirm these results and evaluate whether uUMOD is a marker of tubular health and/or whether it plays a causal role in preserving kidney function.

Genetic and environmental factors are associated with serum 25-hydroxyvitamin D concentrations in older African Americans.

BACKGROUND: Low circulating 25-hydroxyvitamin D [25(OH)D] is prevalent in African Americans, but predictors of vitamin D status are understudied compared to Caucasian populations. OBJECTIVE: We investigated whether certain environmental and genetic factors are predictors of circulating 25(OH)D in 989 elderly African Americans participating in the Health, Aging, and Body Composition (Health ABC) Study. METHODS: Regression analysis estimated the cross-sectional association of nongenetic (environmental) factors with 25(OH)D. Single nucleotide polymorphisms (SNPs) associated with 25(OH)D in Caucasian genome-wide association studies (GWASs) were analyzed for association with serum 25(OH)D, including analyses of all imputed SNPs in identified genomic regions. Genome-wide complex trait analysis (GCTA) evaluated the association of all (genome-wide) genotyped SNPs with serum 25(OH)D in the Health ABC Study with replication in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. RESULTS: Gender, study site, season of blood draw, body mass index, dietary supplement use, dairy and cereal consumption, Healthy Eating Index score, and walking >180 min/wk were associated with 25(OH)D (P < 0.05), jointly explaining 25% of the variation in circulating 25(OH)D. Multivitamin supplement use was the strongest predictor of circulating 25(OH)D, and supplement users had a 6.3-µg/L higher serum 25(OH)D concentration compared with nonusers. Previous GWAS-identified gene regions were not replicated in African Americans, but the nonsynonymous rs7041 SNP in group-specific component (vitamin D binding protein) was close to significance thresholds (P = 0.08), and there was evidence for an interaction between this SNP and use of multivitamin supplements in relation to serum 25(OH)D concentration (P = 0.04). Twenty-three percent (95% CI: 0%, 52%) of the variation in serum 25(OH)D was explained by total genetic variation in a pooled GCTA of 2087 Health ABC Study and MESA African-American participants, but population substructure effects could not be separated from other genetic influences. CONCLUSIONS: Modifiable dietary and lifestyle predictors of serum 25(OH)D were identified in African Americans. GCTA confirms that a proportion of 25(OH)D variability is attributable to genetic variation, but genomic regions associated with the 25(OH)D phenotype identified in prior GWASs of European Americans were not replicated in the Health ABC Study in African Americans.