Glycolytic lactate in diabetic kidney disease.

Lactate elevation is a well-characterized biomarker of mitochondrial dysfunction, but its role in diabetic kidney disease (DKD) is not well defined. Urine lactate was measured in patients with type 2 diabetes (T2D) in 3 cohorts (HUNT3, SMART2D, CRIC). Urine and plasma lactate were measured during euglycemic and hyperglycemic clamps in participants with type 1 diabetes (T1D). Patients in the HUNT3 cohort with DKD had elevated urine lactate levels compared with age- and sex-matched controls. In patients in the SMART2D and CRIC cohorts, the third tertile of urine lactate/creatinine was associated with more rapid estimated glomerular filtration rate decline, relative to first tertile. Patients with T1D demonstrated a strong association between glucose and lactate in both plasma and urine. Glucose-stimulated lactate likely derives in part from proximal tubular cells, since lactate production was attenuated with sodium-glucose cotransporter-2 (SGLT2) inhibition in kidney sections and in SGLT2-deficient mice. Several glycolytic genes were elevated in human diabetic proximal tubules. Lactate levels above 2.5 mM potently inhibited mitochondrial oxidative phosphorylation in human proximal tubule (HK2) cells. We conclude that increased lactate production under diabetic conditions can contribute to mitochondrial dysfunction and become a feed-forward component to DKD pathogenesis.

Chronic kidney disease and risk of bloodstream infections and sepsis: a 17-year follow-up of the population-based Trøndelag Health Study in Norway.

PURPOSE: Bloodstream infections (BSI) and sepsis are important causes of hospitalization, loss of health, and death globally. Targetable risk factors need to be identified to improve prevention and treatment. In this study, we aimed to evaluate the association of chronic kidney disease (CKD) and risk of and mortality from BSI and sepsis in the general population during a 22-year period. METHODS: We conducted a prospective cohort study among participants in the population-based Norwegian HUNT Study, where 68,438 participated. The median follow-up time was 17.4 years. The exposures were estimated glomerular filtration rate (eGFR) and albumin-creatinine ratio (ACR) in urine. The outcomes were hazard ratios (HR) of hospital admission or death due to BSI or sepsis. The associations were adjusted for age, sex, diabetes, obesity, systolic blood pressure, smoking status, and cardiovascular disease. RESULTS: Participants with eGFR < 30 ml/min/1.732 had HR 3.35 for BSI (95% confidence intervals (CI) 2.12-5.3) and HR 2.94 for sepsis (95% CI 1.82-4.8) compared to normal eGFR (≥ 90 ml/min/1.732). HRs of death from BSI and sepsis were 4.2 (95% CI 1.71-10.4) and 4.1 (95% CI 1.88-8.9), respectively. Participants with severely increased albuminuria (ACR > 30 mg/mmol) had HR 3.60 for BSI (95% CI 2.30-5.6) and 3.14 for sepsis (95% CI 1.94-5.1) compared to normal albumin excretion (ACR < 3 mg/mmol). HRs of death were 2.67 (95% CI 0.82-8.7) and 2.16 (95% CI 0.78-6.0), respectively. CONCLUSION: In this large population-based cohort study, CKD was clearly associated with an increased risk of BSI and sepsis and related death.

X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements.

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

Structured Moderate Exercise and Biomarkers of Kidney Health in Sedentary Older Adults: The Lifestyle Interventions and Independence for Elders Randomized Clinical Trial.

Rationale & Objective: In the Lifestyle Interventions and Independence for Elders (LIFE) trial, a structured exercise intervention slowed kidney function decline in sedentary older adults. Biomarkers of kidney health could distinguish potential mechanisms for this beneficial effect. Study Design: Randomized controlled trial. Setting & Population: A total of 1,381 sedentary adults aged 70-89 years enrolled in the LIFE trial. Intervention: Structured, 2-year, moderate-intensity exercise intervention versus health education. Outcomes: Physical activity was measured by step count. Primary outcomes were changes in 14 serum and urine biomarkers of kidney health collected at baseline, year 1, and year 2. We determined the effect of randomization on changes in kidney measures and then evaluated observational associations of achieved activity on each measure. Results: Participants assigned to exercise walked on average 291 more steps per day than participants assigned to health education. The intervention was not significantly associated with changes in biomarkers of kidney health. In observational analyses, persons in the highest versus lowest quartile of activity (≥3,470 vs <1,568 steps/day) had significant improvement in urine albumin (mean, -0.22 mg albumin/g urine creatinine [interquartile range (IQR), -0.37 to -0.06]), alpha-1-microglobulin (-0.18 mg/L [-0.28 to -0.08]), trefoil factor-3 (-0.24 pg/mL [-0.35 to -0.13]), epidermal growth factor (0.19 pg/mL [0.06-0.32]), uromodulin (0.06 pg/mL [0.00-0.12]), interleukin 18 (-0.09 pg/mL [-0.15 to -0.03]), neutrophil gelatinase-associated lipocalin (-0.16 pg/mL [-0.24 to -0.07]), monocyte chemoattractant protein-1 (-0.25 pg/mL [-0.36 to -0.14]), clusterin (-0.16 pg/mL [-0.30 to -0.02]), serum tumor necrosis factor receptor-1 (-0.25 mg/dL [-0.39 to -0.11]) and tumor necrosis factor receptor-2 (-0.30 mg/dL [-0.44 to -0.16]). In sensitivity analyses, incremental changes in activity were most impactful on urine interleukin 18 and serum tumor necrosis factor-1. Limitations: The original study was not designed to assess the impact on kidney health. Non-white individuals and patients with advanced chronic kidney disease are underrepresented. Conclusions: Randomization to structured exercise did not improve kidney health at a group level. However, higher exercise was associated with concurrent improvements in biomarkers of glomerular injury, tubular function/repair, tubular injury, generalized inflammation, and tubulointerstitial repair/fibrosis. Plain-Language Summary: In the Lifestyle Interventions For Elders (LIFE) study, randomization to an exercise and physical activity intervention improved the slope of estimated glomerular filtration rate over 2 years compared with health education among older adults. In this study, we sought to determine whether there were specific biomarkers of kidney health that were affected by the exercise and physical activity intervention to investigate potential mechanisms for this positive impact on kidney decline. We found that randomization to the intervention did not improve any of the 14 measures of kidney tubule health. However, in observational analyses, higher activity was independently associated with improvements in several domains, especially tubular injury and generalized inflammation. These results help to clarify the impact of physical activity on kidney health.

Changes in Natriuretic Peptide Levels and Subsequent Kidney Function Decline in SPRINT.

RATIONALE & OBJECTIVE: Novel approaches to the assessment of kidney disease risk during hypertension treatment are needed because of the uncertainty of how intensive blood pressure (BP) lowering impacts kidney outcomes. We determined whether longitudinal N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurements during hypertension treatment are associated with kidney function decline. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: 8,005 SPRINT (Systolic Blood Pressure Intervention Trial) participants with NT-proBNP measurements at baseline and 1 year. EXPOSURE: 1-year change in NT-proBNP categorized as a ≥25% decrease, ≥25% increase, or <25% change (stable). OUTCOME: Annualized change in estimated glomerular filtration rate (eGFR) and ≥30% decrease in eGFR. ANALYTICAL APPROACH: Linear mixed-effect and logistic regression models were used to evaluate the association of changes in NT-proBNP with subsequent annualized change in eGFR and ≥30% decrease in eGFR, respectively. Analyses were stratified by baseline chronic kidney disease (CKD) status. RESULTS: Compared with stable 1-year NT-proBNP levels, a ≥25% decrease in NT-proBNP was associated with a slower decrease in eGFR in participants with CKD (adjusted difference, 1.09%/y; 95% CI, 0.35-1.83) and without CKD (adjusted difference, 0.51%/y; 95% CI, 0.21-0.81; P = 0.4 for interaction). Meanwhile, a ≥25% increase in NT-proBNP in participants with CKD was associated with a faster decrease in eGFR (adjusted difference, -1.04%/y; 95% CI, -1.72 to -0.36) and risk of a ≥30% decrease in eGFR (adjusted odds ratio, 1.44; 95% CI, 1.06-1.96); associations were stronger in participants with CKD than in participants without CKD (P = 0.01 and P < 0.001 for interaction, respectively). Relationships were similar irrespective of the randomized BP arm in SPRINT (P > 0.2 for interactions). LIMITATIONS: Persons with diabetes and proteinuria >1 g/d were excluded. CONCLUSIONS: Changes in NT-proBNP during BP treatment are independently associated with subsequent kidney function decline, particularly in people with CKD. Future studies should assess whether routine NT-proBNP measurements may be useful in monitoring kidney risk during hypertension treatment. PLAIN-LANGUAGE SUMMARY: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a biomarker in the blood that reflects mechanical stress on the heart. Measuring NT-proBNP may be helpful in assessing the risk of long-term losses of kidney function. In this study, we investigated the association of changes in NT-proBNP with subsequent kidney function among individuals with and without chronic kidney disease. We found that increases in NT-proBNP are associated with a faster rate of decline of kidney function, independent of baseline kidney measures. The associations were more pronounced in individuals with chronic kidney disease. Our results advance the notion of considering NT-proBNP as a dynamic tool for assessing kidney disease risk.

Estimated Kidney Tubular Secretion and Kidney, Cardiovascular, and Mortality Outcomes in CKD: The Systolic Blood Pressure Intervention Trial.

Rational & Objective: Many drugs, metabolites, and toxins are cleared by the kidneys via tubular secretion. Whether novel endogenous measures of tubular secretion provide information about kidney, cardiovascular, and mortality risk is uncertain. Study Design: Longitudinal subgroup analysis of clinical trial participants. Setting & Participants: 2,089 Systolic Blood Pressure Intervention Trial participants with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 at baseline. Exposure: Summary score incorporating urine-to-plasma ratios of 10 endogenous secretion markers measured in paired urine and plasma samples at baseline. Outcome: The primary outcome was longitudinal change in eGFR. Secondary outcomes included chronic kidney disease (CKD) progression (≥50% eGFR decline or incident kidney failure requiring dialysis or kidney transplantation), a cardiovascular disease (CVD) composite (myocardial infarction, acute coronary syndrome, stroke, acute decompensated heart failure, or death from cardiovascular causes), and mortality. Analytical Approach: Linear mixed-effect models were used to evaluate the association between the secretion score and change in eGFR, and Cox proportional hazards models were used to evaluate associations with CKD progression, CVD, and mortality. Results: At baseline, mean age was 73 ± 9 years and eGFR was 46 ± 11 mL/min/1.73 m2. During a median follow-up of 3.3 years, mean change in eGFR was -1.44% per year, and 72 CKD progression events, 272 CVD events, and 144 deaths occurred. In multivariable analyses, lower secretion score was associated with faster eGFR decline and greater risk of CKD progression, CVD, and mortality. After further adjustment for baseline eGFR and albuminuria, each 1-standard deviation lower secretion score was associated with faster eGFR decline (-0.65% per year; 95% CI, -0.84% to -0.46%), but not CKD progression (HR, 1.23; 95% CI, 0.96-1.58), CVD (HR, 1.02; 95% CI, 0.89-1.18), or mortality (HR, 0.90; 95% CI, 0.74-1.09). The secretion score association with eGFR decline appeared stronger in participants with baseline eGFR <45 mL/min/1.73 m2 (P for interaction < 0.001). Limitations: Persons with diabetes and proteinuria >1 g/d were excluded. Conclusions: Among SPRINT participants with CKD, lower estimated tubular secretion was associated with faster eGFR decline, independent of baseline eGFR and albuminuria, but not with CKD progression, CVD, or mortality.

Clinical Risk Factors For Kidney Tubule Biomarker Abnormalities Among Hypertensive Adults With Reduced eGFR in the SPRINT Trial.

BACKGROUND: Urine biomarkers of kidney tubule health may distinguish aspects of kidney damage that cannot be captured by current glomerular measures. Associations of clinical risk factors with specific kidney tubule biomarkers have not been evaluated in detail. METHODS: We performed a cross-sectional study in the Systolic Blood Pressure Intervention Trial among 2,436 participants with a baseline estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2. Associations between demographic and clinical characteristics with urine biomarkers of kidney tubule health were evaluated using simultaneous multivariable linear regression of selected variables. RESULTS: Each standard deviation higher age (9 years) was associated with 13% higher levels of chitinase-3-like protein-1 (YKL-40), indicating higher levels of tubulointerstitial inflammation and repair. Men had 31% higher levels of alpha-1 microglobulin and 16% higher levels of beta-2 microglobulin, reflecting worse tubule resorptive function. Black race was associated with significantly higher levels of neutrophil gelatinase-associated lipocalin (12%) and lower kidney injury molecule-1 (26%) and uromodulin (22%). Each standard deviation (SD) higher systolic blood pressure (SBP) (16 mmHg) was associated with 10% higher beta-2 microglobulin and 10% higher alpha-1 microglobulin, reflecting lower tubule resorptive function. CONCLUSIONS: Clinical and demographic characteristics, such as race, sex, and elevated SBP, are associated with unique profiles of tubular damage, which could reflect under-recognized patterns of kidney tubule disease among persons with decreased eGFR.

Markers of Kidney Tubular Secretion and Risk of Adverse Events in SPRINT Participants with CKD.

BACKGROUND: Kidney tubular secretion is an essential mechanism for clearing many common antihypertensive drugs and other metabolites and toxins. It is unknown whether novel measures of tubular secretion are associated with adverse events (AEs) during hypertension treatment. METHODS: Among 2089 SPRINT (Systolic Blood Pressure Intervention Trial) participants with baseline eGFR <60 ml/min per 1.73 m2, we created a summary secretion score by averaging across the standardized spot urine-to-plasma ratios of ten novel endogenous tubular secretion measures, with lower urine-to-plasma ratios reflecting worse tubular secretion. Multivariable Cox proportional hazards models were used to evaluate associations between the secretion score and risk of a composite of prespecified serious AEs (hypotension, syncope, bradycardia, AKI, electrolyte abnormalities, and injurious falls). The follow-up protocol for SPRINT routinely assessed two laboratory monitoring AEs (hyperkalemia and hypokalemia). RESULTS: Overall, 30% of participants experienced at least one AE during a median follow-up of 3.0 years. In multivariable models adjusted for eGFR and albuminuria, lower (worse) secretion scores at baseline were associated with greater risk of the composite AE outcome (hazard ratio per 1-SD lower secretion score, 1.16; 95% confidence interval, 1.04 to 1.27). In analyses of the individual AEs, lower secretion score was associated with significantly greater risk of AKI, serious electrolyte abnormalities, and ambulatory hyperkalemia. Associations were similar across randomized treatment assignment groups. CONCLUSION: Among SPRINT participants with CKD, worse tubular secretion was associated with greater risk of AEs, independent of eGFR and albuminuria.

Cardiorenal syndrome and the association with fitness: Data from a telerehabilitation randomized clinical trial.

AIMS: To investigate the associations of cardiorespiratory fitness with cardiac, vascular, renal and cardiorenal characteristics in chronic heart failure in a telerehabilitation randomized clinical trial. Secondly, to evaluate the associations of cardiorenal syndrome with the effects of exercise. METHODS AND RESULTS: Sixty-nine heart failure patients attended baseline examination, and 61 patients were randomly assigned 1:1 to 3-month telerehabilitation or control. Data were collected at baseline and 3-month post-intervention, including echocardiography and vascular ultrasound, laboratory tests, exercise test with peak oxygen consumption (VO2peak ) measurement and 6-min walk test (6MWT). Baseline VO2peak and 6MWT distance was 0.85 mL*min-1 *kg-1 lower and 20 m shorter per 10 mL/min/1.73m2 lower estimated glomerular filtration rate (both P < 0.001). Heart failure patients with cardiorenal syndrome had 3.5 (1.1) mL*min-1 *kg-1 lower VO2peak and diastolic dysfunction grade 2-3, and elevated filling pressure was >50% more common compared with those without (all P < 0.05). At the 3-month post-intervention follow-up, only the non-CRS patients in the intervention group increased VO2peak (0.73 (0.51) mL*min-1 *kg-1 ), whereas VO2peak in the CRS subpopulation of controls decreased (-1.34 (0.43) mL*min-1 *kg-1 ). Cardiorenal syndrome was associated with a decrease in VO2peak in CRS patients compared with non-CRS patients, -0.91 (0.31) vs. 0.39 (0.35) mL*min-1 *kg-1 respectively, P = 0.013. CONCLUSIONS: Cardiorenal syndrome was negatively associated with VO2peak and 6MWT distance in chronic HF, and the associations were stronger than for heart failure phenotypes and other characteristics. The effect of exercise was negatively associated with cardiorenal syndrome. Exercise seems to be as important in heart failure patients with cardiorenal syndrome, and future studies should include CRS patients to reveal the most beneficial type of exercise.

Direction- and Angle-Assisted Buttonhole Cannulation of Arteriovenous Fistula in Hemodialysis Patients: A Multicenter Randomized Controlled Trial.

RATIONALE & OBJECTIVE: Arteriovenous fistula cannulation with the buttonhole technique is often preferred by patients but has been associated with an increased infection risk. Guidelines disagree on whether it should be abandoned, thus we assessed a technologically simple method to facilitate gentler arteriovenous fistula cannulation with potentially less discomfort and damage to the epithelial lining of the buttonhole tract. STUDY DESIGN: 8-week, prospective, open-label, randomized controlled trial. SETTING & PARTICIPANTS: Patients with buttonhole tracts receiving hemodialysis at 7 dialysis centers in Norway were randomized to the intervention group (43 patients, 658 cannulations) or control group (40 patients, 611 cannulations). INTERVENTION: Direction and angle of the established buttonhole tract were marked on the forearm skin in the intervention group, whereas the control group had no structured cannulation information system. OUTCOMES: The primary outcome was successful cannulation, defined as correct placement of both blunt needles at the first attempt without needing to change needles, perform extra perforations, or reposition the needle. The secondary outcomes were patient-reported difficulty of cannulation (verbal rating scale: 1 = very easy, 6 = impossible) and intensity of pain (numeric rating scale: 0 = no pain, 10 = unbearable pain). RESULTS: After a 2-week run-in period, successful cannulation was achieved in 73.9% and 74.8% of the patients in the intervention and control groups, respectively (relative risk [RR], 0.99; 95% CI, 0.87-1.12; P = 0.85). However, the probability of a difficult arterial cannulation (verbal rating scale, 3-6) was significantly lower in the intervention group (RR, 0.69; 95% CI, 0.55-0.85; P = 0.001). There were no improvements for venous cannulations. Furthermore, the probability of a painful cannulation (numeric rating scale, 3-10) was lower in the intervention group (RR, 0.72; 95% CI, 0.51-1.02; P = 0.06). LIMITATIONS: Unable to evaluate hard end points such as infections and thrombosis owing to the small sample size. CONCLUSIONS: Marking direction and angle of cannulation did not improve cannulation success rates; however, patients more often reported an unproblematic procedure and less pain. FUNDING: None. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01536548).

Trans-ethnic Mendelian-randomization study reveals causal relationships between cardiometabolic factors and chronic kidney disease.

BACKGROUND: This study was to systematically test whether previously reported risk factors for chronic kidney disease (CKD) are causally related to CKD in European and East Asian ancestries using Mendelian randomization. METHODS: A total of 45 risk factors with genetic data in European ancestry and 17 risk factors in East Asian participants were identified as exposures from PubMed. We defined the CKD by clinical diagnosis or by estimated glomerular filtration rate of <60 ml/min/1.73 m2. Ultimately, 51 672 CKD cases and 958 102 controls of European ancestry from CKDGen, UK Biobank and HUNT, and 13 093 CKD cases and 238 118 controls of East Asian ancestry from Biobank Japan, China Kadoorie Biobank and Japan-Kidney-Biobank/ToMMo were included. RESULTS: Eight risk factors showed reliable evidence of causal effects on CKD in Europeans, including genetically predicted body mass index (BMI), hypertension, systolic blood pressure, high-density lipoprotein cholesterol, apolipoprotein A-I, lipoprotein(a), type 2 diabetes (T2D) and nephrolithiasis. In East Asians, BMI, T2D and nephrolithiasis showed evidence of causality on CKD. In two independent replication analyses, we observed that increased hypertension risk showed reliable evidence of a causal effect on increasing CKD risk in Europeans but in contrast showed a null effect in East Asians. Although liability to T2D showed consistent effects on CKD, the effects of glycaemic phenotypes on CKD were weak. Non-linear Mendelian randomization indicated a threshold relationship between genetically predicted BMI and CKD, with increased risk at BMI of >25 kg/m2. CONCLUSIONS: Eight cardiometabolic risk factors showed causal effects on CKD in Europeans and three of them showed causality in East Asians, providing insights into the design of future interventions to reduce the burden of CKD.

Increased risk of ischaemic heart disease after kidney donation.

BACKGROUND: Previous reports suggest increased risk of hypertension and cardiovascular mortality after kidney donation. In this study we investigate the occurrence of ischaemic heart disease and cerebrovascular disease, diabetes and cancer in live kidney donors compared with healthy controls eligible for donation. METHODS: Different diagnoses were assessed in 1029 kidney donors and 16 084 controls. The diagnoses at follow-up were self-reported for the controls and registered by a physician for the donors. Stratified logistic regression was used to estimate associations with various disease outcomes, adjusted for gender, age at follow-up, smoking at baseline, body mass index at baseline, systolic blood pressure at baseline and time since the donation. RESULTS: The mean observation time was 11.3 years [standard deviation (SD) 8.1] for donors versus 16.4 years (SD 5.7) for controls. The age at follow-up was 56.1 years (SD 12.4) in donors versus 53.5 years (SD 11.1) in controls and 44% of donors were males versus 39.3% in the controls. At follow-up, 35 (3.5%) of the donors had been diagnosed with ischaemic heart disease versus 267 (1.7%) of the controls. The adjusted odds ratio for ischaemic heart disease was 1.64 (confidence interval 1.10-2.43; P = 0.01) in donors compared with controls. There were no significant differences for the risks of cerebrovascular disease, diabetes or cancer. CONCLUSIONS: During long-term follow-up of kidney donors, we found an increased risk of ischaemic heart disease compared with healthy controls. This information may be important in the follow-up and selection process of living kidney donors.

Discovery and prioritization of variants and genes for kidney function in >1.2 million individuals.

Genes underneath signals from genome-wide association studies (GWAS) for kidney function are promising targets for functional studies, but prioritizing variants and genes is challenging. By GWAS meta-analysis for creatinine-based estimated glomerular filtration rate (eGFR) from the Chronic Kidney Disease Genetics Consortium and UK Biobank (n = 1,201,909), we expand the number of eGFRcrea loci (424 loci, 201 novel; 9.8% eGFRcrea variance explained by 634 independent signal variants). Our increased sample size in fine-mapping (n = 1,004,040, European) more than doubles the number of signals with resolved fine-mapping (99% credible sets down to 1 variant for 44 signals, ≤5 variants for 138 signals). Cystatin-based eGFR and/or blood urea nitrogen association support 348 loci (n = 460,826 and 852,678, respectively). Our customizable tool for Gene PrioritiSation reveals 23 compelling genes including mechanistic insights and enables navigation through genes and variants likely relevant for kidney function in human to help select targets for experimental follow-up.

The causal effects of serum lipids and apolipoproteins on kidney function: multivariable and bidirectional Mendelian-randomization analyses.

BACKGROUND: The causal nature of the observed associations between serum lipids and apolipoproteins and kidney function are unclear. METHODS: Using two-sample and multivariable Mendelian randomization (MR), we examined the causal effects of serum lipids and apolipoproteins on kidney function, indicated by the glomerular-filtration rate estimated using creatinine (eGFRcrea) or cystatin C (eGFRcys) and the urinary albumin-to-creatinine ratio (UACR). We obtained lipid- and apolipoprotein-associated genetic variants from the Global Lipids Genetics Consortium (n = 331 368) and UK Biobank (n = 441 016), respectively, and kidney-function markers from the Trøndelag Health Study (HUNT; n = 69 736) and UK Biobank (n = 464 207). The reverse causal direction was examined using variants associated with kidney-function markers selected from recent genome-wide association studies. RESULTS: There were no strong associations between genetically predicted lipid and apolipoprotein levels with kidney-function markers. Some, but inconsistent, evidence suggested a weak association of higher genetically predicted atherogenic lipid levels [indicated by low-density lipoprotein cholesterol (LDL-C), triglycerides and apolipoprotein B] with increased eGFR and UACR. For high-density lipoprotein cholesterol (HDL-C), results differed between eGFRcrea and eGFRcys, but neither analysis suggested substantial effects. We found no clear evidence of a reverse causal effect of eGFR on lipid or apolipoprotein traits, but higher UACR was associated with higher LDL-C, triglyceride and apolipoprotein B levels. CONCLUSION: Our MR estimates suggest that serum lipid and apolipoprotein levels do not cause substantial changes in kidney function. A possible weak effect of higher atherogenic lipids on increased eGFR and UACR warrants further investigation. Processes leading to higher UACR may lead to more atherogenic lipid levels.

Physicians' Recognition and Management of Kidney Disease: A Randomized Vignette Study Evaluating the Impact of the KDIGO 2012 CKD Classification System.

RATIONALE & OBJECTIVE: The Kidney Disease Outcome Quality Initiative (KDOQI) and Kidney Disease: Improving Global Outcomes (KDIGO) chronic kidney disease (CKD) classification systems published in 2002 and 2012, respectively, are recommended worldwide and based on strong epidemiologic data. However, their impact on CKD recognition and management is not well evaluated in clinical practice, and we therefore investigated whether they help physicians recognize and appropriately care for patients with CKD. STUDY DESIGN: Randomized vignette experiment with fractional factorial design based on 6 kidney-related scenarios and 3 laboratory presentation methods reflecting the CKD guidelines. Participants evaluated 1 of 3 subsets of the 18 vignettes (ie, 6 vignettes each with 4 answer alternatives). SETTING & PARTICIPANTS: 249 interns, general practitioners, and residents/fellows attending postgraduate meetings and courses in Norway and the United States. INTERVENTION: Kidney-related results (serum creatinine level and urinary albumin excretion) were presented as the "minimal data" (high/low levels), KDOQI-2002 (estimated glomerular filtration rate [eGFR] reported automatically), or KDIGO-2012 (eGFR + albuminuria categorization + risk for complications) laboratory report. OUTCOME: CKD management choice by physicians. RESULTS: When kidney laboratory data were presented as the KDOQI-2002 report (automatic eGFR calculation), there was a significantly higher odds for correct patient management decisions compared with the minimal data report (OR, 1.57; P < 0.001). Additional significant improvement was obtained with the KDIGO-2012 report (OR, 2.28 for correct answer vs minimal data report [P < 0.001]; OR, 1.45 compared to KDOQI-2002 report [P = 0.005]). The KDIGO classification system improved physician management in 4 of the 6 clinical scenarios covering a wide range of kidney-related topics. Interaction analysis showed that general practitioners and those with 1 to 3 years of internal medicine experience had the greatest improvements with the new presentation techniques. LIMITATIONS: Physicians' management was evaluated by theoretical scenarios rather than direct patient care. CONCLUSIONS: Automatic GFR estimation, albuminuria categorization, and notification of the associated risk for complications improve most physicians` recognition and management of a wide range of CKD clinical scenarios.

Clinical Phenotypes and Long-term Prognosis in White Patients With Biopsy-Verified Hypertensive Nephrosclerosis.

INTRODUCTION: Hypertensive nephrosclerosis is considered the second most common cause of end-stage renal disease (ESRD), but it is still an insufficiently studied and controversial disease entity. More information on the phenotype and prognosis is needed to improve clinical diagnostics and treatment. METHODS: We included all Norwegian patients with chronic kidney disease (CKD) referred for kidney biopsy between 1988 and 2012 whose clinical presentation was consistent with, but not primarily suspicious for, hypertensive nephrosclerosis (n = 4920); follow-up continued until 2013. RESULTS: A total of 918 patients (19%) had biopsy-verified hypertensive nephrosclerosis (i.e., arterionephrosclerosis). Their most common biopsy indications were proteinuria (57%), low estimated glomerular filtration rate (eGFR) (44%), hematuria (34%), or combinations of these indications. Multivariable logistic regression analysis revealed that arterionephrosclerosis was significantly associated with higher age, male sex, not having diabetes, higher blood pressure, lower proteinuria, and not having hematuria (P < 0.01 for all). Body mass index, cholesterol, high-density lipoprotein cholesterol, and eGFR were not significantly associated with arterionephrosclerosis (P > 0.05 for all). The most common biopsy-verified diagnoses in patients fulfilling the clinical criteria for hypertensive nephrosclerosis were arterionephrosclerosis (40%), glomerulonephritis (22%), and interstitial nephritis (14%), reflecting that the criteria had low sensitivity (0.17) and high specificity (0.94). ESRD and mortality risks did not differ in patients with arterionephrosclerosis compared to patients with glomerulonephritis, interstitial nephritis, or other relevant diagnoses (P > 0.1 for both), whereas patients with diabetic kidney disease had a 2-fold higher risk (P < 0.001 for both). CONCLUSION: Arterionephrosclerosis is a high-risk disease, often with an atypical phenotype with proteinuria and hematuria contributing to low accuracy for current clinical criteria for hypertensive nephrosclerosis.

Increased long-term risk for hypertension in kidney donors - a retrospective cohort study.

Kidney donors may be at increased risk of end-stage renal disease and premature mortality. Elevated blood pressure after donation may contribute to the increased risks. In this cohort study, we have assessed long-term risk for the development of hypertension in kidney donors compared to a control group potentially eligible as donors. Follow-up data were obtained from previous living kidney donors. A healthy control group with baseline assessment from similar time periods as the donor nephrectomies was selected. Hypertension was defined as blood pressure >140/90, use of blood pressure medication, or established diagnosis of hypertension. Stratified logistic regression was used to estimate risk of hypertension at follow-up, adjusted for systolic blood pressure at baseline, age at follow-up, time since donation/baseline, gender, smoking at baseline, and BMI at baseline. A total of 368 donors (36%) had hypertension at follow-up, and 241 of these (23%) were using blood pressure medication. In adjusted stratified logistic regression analyses, odds ratio for hypertension was significantly increased (1.25, 95% confidence interval 1.12-1.39, P < 0.001) in donors compared with controls. Kidney donors appear to be at increased long-term risk for hypertension compared with healthy controls. This finding supports regular follow-up of blood pressure in kidney donors.

Circulating microRNAs May Serve as Biomarkers for Hypertensive Emergency End-Organ Injuries and Address Underlying Pathways in an Animal Model.

There is an incomplete understanding of the underlying pathophysiology in hypertensive emergencies, where severely elevated blood pressure causes acute end-organ injuries, as opposed to the long-term manifestations of chronic hypertension. Furthermore, current biomarkers are unable to detect early end-organ injuries like hypertensive encephalopathy and renal thrombotic microangiopathy. We hypothesized that circulating microRNAs (c-miRs) could identify acute and chronic complications of severe hypertension, and that combinations of c-miRs could elucidate important pathways involved. We studied the diagnostic accuracy of 145 c-miRs in Dahl salt-sensitive rats fed either a low-salt (N = 20: 0.3% NaCl) or a high-salt (N = 60: 8% NaCl) diet. Subclinical hypertensive encephalopathy and thrombotic microangiopathy were diagnosed by histopathology. In addition, heart failure with preserved ejection fraction was evaluated with echocardiography and N-terminal pro-brain natriuretic peptide; and endothelial dysfunction was studied using acetylcholine-induced aorta ring relaxation. Systolic blood pressure increased severely in animals on a high-salt diet (high-salt 205 ± 20 mm Hg vs. low-salt 152 ± 18 mm Hg, p < 0.001). Partial least squares discriminant analysis revealed 68 c-miRs discriminating between animals with and without hypertensive emergency complications. Twenty-nine c-miRs were strongly associated with hypertensive encephalopathy, 24 c-miRs with thrombotic microangiopathy, 30 c-miRs with heart failure with preserved ejection fraction, and 28 c-miRs with endothelial dysfunction. Hypertensive encephalopathy, thrombotic microangiopathy and heart failure with preserved ejection fraction were associated with deviations in many of the same c-miRs, whereas endothelial dysfunction was associated with a different set of c-miRs. Several of these c-miRs demonstrated fair to good diagnostic accuracy for a composite outcome of hypertensive encephalopathy, thrombotic microangiopathy and heart failure with preserved ejection fraction in receiver-operating-curve analyses (area-under-curve 0.75-0.88). Target prediction revealed an enrichment of genes related to several pathways relevant for cardiovascular disease (e.g., mucin type O-glycan biosynthesis, MAPK, Wnt, Hippo, and TGF-beta signaling). C-miRs could potentially serve as biomarkers of severe hypertensive end-organ injuries and elucidate important pathways involved.