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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., Identifying causal variants and genes in genome-wide association studies remains a challenge, an issue that is ameliorated with larger sample sizes. Here the authors meta-analyze kidney function genome-wide association studies to identify new loci and fine-map loci to home in on variants and genes involved in kidney function.

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).

Potassium disorders are common in patients with kidney disease, particularly in patients with tubular disorders and low glomerular filtration rate. A multidisciplinary group of researchers and clinicians met in October 2018 to identify evidence and address controversies in potassium management. The issues discussed encompassed our latest understanding of the regulation of tubular potassium excretion in health and disease; the relationship of potassium intake to cardiovascular and kidney outcomes, with increasing evidence showing beneficial associations with plant-based diet and data to suggest a paradigm shift from the idea of dietary restriction toward fostering patterns of eating that are associated with better outcomes; the paucity of data on the effect of dietary modification in restoring abnormal serum potassium to the normal range; a novel diagnostic algorithm for hypokalemia that takes into account the ascendency of the clinical context in determining cause, aligning the educational strategy with a practical approach to diagnosis; and therapeutic approaches in managing hyperkalemia when chronic and in the emergency or hospital ward. In sum, we provide here our conference deliberations on potassium homeostasis in health and disease, guidance for evaluation and management of dyskalemias in the context of kidney diseases, and research priorities in each of the above areas.

Funder: Government Department of Business, Funder: Energy and Industrial Strategy (BEIS), Funder: Vice-Chancellor Fellowship from the University of Bristol, Funder: Shanghai Thousand Talents Program, Funder: Academy of Medical Sciences (AMS) Springboard Award, Funder: BBSRC Innovation fellowship, Funder: NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol, 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 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.

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.

Introduction Hypertensive nephrosclerosis is among the leading causes of end-stage renal disease, but its pathophysiology is poorly understood. We wanted to explore early metabolic changes using gene expression and targeted metabolomics analysis. Methods We analyzed gene expression in kidneys biopsied from 20 patients with nephrosclerosis and 31 healthy controls with an Affymetrix array. Thirty-one amino acids were measured by liquid chromatography coupled with mass spectrometry (LC-MS) in urine samples from 62 patients with clinical hypertensive nephrosclerosis and 33 age- and sex-matched healthy controls, and major findings were confirmed in an independent cohort of 45 cases and 15 controls. Results Amino acid catabolism and synthesis were strongly underexpressed in hypertensive nephrosclerosis (13- and 7-fold, respectively), and these patients also showed gene expression patterns indicating decreased fatty acid oxidation (12-fold) and increased interferon gamma (10-fold) and cellular defense response (8-fold). Metabolomics analysis revealed significant distribution differences in 11 amino acids in hypertensive nephrosclerosis, among them tyrosine, phenylalanine, dopamine, homocysteine, and serine, with 30% to 70% lower urine excretion. These findings were replicated in the independent cohort. Integrated gene-metabolite pathway analysis showed perturbations of renal dopamine biosynthesis. There were also significant differences in homocysteine/methionine homeostasis and the serine pathway, which have strong influence on 1-carbon metabolism. Several of these disturbances could be interconnected through reduced regeneration of tetrahydrofolate and tetrahydrobiopterin. Conclusion Early hypertensive nephrosclerosis showed perturbations of intrarenal biosynthesis of dopamine, which regulates natriuresis and blood pressure. There were also disturbances in serine/glycine and methionine/homocysteine metabolism, which may contribute to endothelial dysfunction, atherosclerosis, and renal fibrosis., Graphical abstract

IMPORTANCE Early identification of individuals at elevated risk of developing chronic kidney disease (CKD) could improve clinical care through enhanced surveillance and better management of underlying health conditions.OBJECTIVE To develop assessment tools to identify individuals at increased risk of CKD, defined by reduced estimated glomerular filtration rate (eGFR).DESIGN, SETTING, AND PARTICIPANTS Individual-level data analysis of 34 multinational cohorts from the CKD Prognosis Consortium including 5 222 711 individuals from 28 countries. Data were collected from April 1970 through January 2017. A 2-stage analysis was performed, with each study first analyzed individually and summarized overall using a weighted average. Because clinical variables were often differentially available by diabetes status, models were developed separately for participants with diabetes and without diabetes. Discrimination and calibration were also tested in 9 external cohorts (n = 2 253 540).EXPOSURES Demographic and clinical factors.MAIN OUTCOMES AND MEASURES Incident eGFR of less than 60 mL/min/1.73 m(2).RESULTS Among 4 441 084 participants without diabetes (mean age, 54 years, 38% women), 660 856 incident cases (14.9%) of reduced eGFR occurred during a mean follow-up of 4.2 years. Of 781 627 participants with diabetes (mean age, 62 years, 13% women), 313 646 incident cases (40%) occurred during a mean follow-up of 3.9 years. Equations for the 5-year risk of reduced eGFR included age, sex, race/ethnicity, eGFR, history of cardiovascular disease, ever smoker, hypertension, body mass index, and albuminuria concentration. For participants with diabetes, the models also included diabetes medications, hemoglobin A(1c), and the interaction between the 2. The risk equations had a median C statistic for the 5-year predicted probability of 0.845 (interquartile range [IQR], 0.789-0.890) in the cohorts without diabetes and 0.801 (IQR, 0.750-0.819) in the cohorts with diabetes. Calibration analysis showed that 9 of 13 study populations (69%) had a slope of observed to predicted risk between 0.80 and 1.25. Discrimination was similar in 18 study populations in 9 external validation cohorts; calibration showed that 16 of 18 (89%) had a slope of observed to predicted risk between 0.80 and 1.25.CONCLUSIONS AND RELEVANCE Equations for predicting risk of incident chronic kidney disease developed from more than 5 million individuals from 34 multinational cohorts demonstrated high discrimination and variable calibration in diverse populations. Further study is needed to determine whether use of these equations to identify individuals at risk of developing chronic kidney disease will improve clinical care and patient outcomes.

BACKGROUNDThe chronic kidney disease (CKD) public health burden is substantial and has not declined as expected with current interventions on disease treatments. A large number of clinical, biological, and behavioural risk factors have been associated with CKD. However, it is unclear which of them are causal.OBJECTIVETo systematically test whether previously reported risk factors for CKD are causally related to the disease in European and East Asian ancestries.DESIGNTwo-sample Mendelian randomization (MR) and non-linear MR analyses.PARTICIPANTS53,703 CKD cases and 960,624 controls of European ancestry from CKDGen, UK Biobank and HUNT, and 13,480 CKD cases and 238,118 controls of East Asian ancestry from Biobank Japan, China Kadoorie Biobank and Japan-Kidney-Biobank/ToMMo.MEASURESSystematic literature mining of PubMed studies identified 45 clinical risk factors and biomarkers with robustly associated genetic variants, including phenotypes related to blood pressure, diabetes, glucose, insulin, lipids, obesity, smoking, sleep disorders, nephrolithiasis, uric acid, coronary artery disease, bone mineral density, homocysteine, C-reactive protein, micro-nutrients and thyroid function, which were selected as exposures. The outcome was CKD (defined by clinical diagnosis or by estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73m2).RESULTSEight risk factors showed evidence of causal effects on CKD in European ancestry, including 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 Asian ancestry, BMI, T2D and nephrolithiasis showed evidence of causal effects on CKD. Hypertension showed reliable evidence of a strong causal effect on CKD in Europeans but in contrast appeared to show a null effect in East Asians, suggesting the possibility of different causal risk factors in Europeans and East Asians. Although liability to T2D showed consistent effects on CKD, the effect of glycemic traits on CKD was weak, suggesting T2D may have glucose-independent mechanisms to influence CKD. Nonlinear MR indicated a threshold relationship between genetically predicted BMI and CKD, with increased risk at BMI above 25 kg/m2.LIMITATIONDue to the unbalanced distribution of data between ancestries, we could only test 17 of the 45 risk factors in East Asian participants.CONCLUSIONSEight CKD-associated risk factors showed evidence of causal effects on the disease in over 1.2 million European and East Asian ancestries. These risk factors were predominantly related to cardio-metabolic health, which supports the shared causal link between cardio-metabolic health and kidney function. This study provides evidence of potential intervention targets for primary prevention of CKD, which could help reduce the global burden of CKD and its cardio-metabolic co-morbidities.Research in contextEvidence before this studyChronic kidney disease (CKD) has a major effect on global health, both as a direct cause of morbidity and mortality, and as an important complication for cardio-metabolic diseases. However, even with the existing interventions, the burden of CKD has not declined as expected over the last 30 years. Existing epidemiological studies of CKD have mainly focused on disease treatment in patients from specific populations and estimated association rather than causality. A systematic assessment of the causal determinants of CKD in different populations is urgently needed, to help promote a shift from treatment of CKD patients to prevention of the disease in high-risk groups. The use of genetic data and the latest Mendelian randomization (MR) methodologies offers a cost-effective way to evaluate the potential intervention targets for prevention of CKD in high-risk groups.Added value of this studyIn this study, we systematically constructed a causal atlas of 45 risk factors on CKD in European and East Asian ancestries using MR. To maximise power of these analyses and accuracy of the findings, we collected and harmonised CKD genetic association data from six large-scale biobanks (in over 1.1 million Europeans and 250,000 East Asians). By applying a comprehensive MR framework, including linear two-sample MR, bidirectional MR, multivariable MR and non-linear MR approaches, we identified eight risk factors with reliable evidence of causal effects on CKD in European ancestry studies, including 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 Asian studies, BMI, T2D and nephrolithiasis also showed causal effects on CKD. Among other factors, hypertension showed reliable evidence of a strong causal effect on CKD in Europeans but in contrast appeared to show a null effect in East Asians. This MR finding together with previous literature evidence opens up the possibility that hypertension could play different causal roles on CKD across ancestries. For diabetes and glycemic phenotypes, our MR and sensitivity analyses suggested the causal role of liability of T2D on CKD but suggested weak effects of glycemic phenotypes on CKD. This aligns with the recent trial of SGLT2 inhibitors on kidney disease, which implies T2D may have glucose-independent mechanisms to influence CKD. For lipids phenotypes, we found good evidence to support the role of high-density lipoprotein cholesterol on CKD and further suggested the effects of two lipids targets: circulating CETP level and lipoprotein A concentration. For body weight, our study quantified a threshold relationship between BMI and CKD, with increased risk at BMI above 25 kg/m2. The causal relationship between nephrolithiasis and CKD were reported in previous studies, but our study confirmed the causal links between the two for the first time.Implication of all the available evidenceThis study makes a significant advance in comprehensively prioritising intervention targets for CKD in over 1.2 million participants. Our study presents causal evidence from both European and East Asian population samples, widening the generalisability of the causal atlas. Importantly, the prioritised risk factors are predominantly related to cardio-metabolic health, which supports the shared causal link between cardio-metabolic health and kidney function. Clinically, the high-quality evidence from this study highlights the value of exploring these causal factors in the general population and prioritizes drug targets and life-style interventions for CKD primary prevention, which could help reduce the global burden of CKD and its cardio-metabolic co-morbidities.

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. This article is available under the Creative Commons CC-BY-NC-ND license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed.

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.

Background and Aims During long-term follow-up kidney donors are at increased risk of hypertension and end-stage renal disease after donation. Hypertension is a known risk factor for development of cardiovascular disease, but it is unknown whether kidney donors are at increased risk of cardiovascular disease. We evaluated a large Norwegian kidney donor cohort and assessed prevalence of ischemic heart disease after donation compared to healthy controls. Prevalence of cancer, diabetes and cerebrovascular disease was also calculated. Method Follow-up data were retrospectively retrieved from past kidney donors. Healthy non-donor controls from a general population screening study were selected. Controls were selected according to standard donation criteria, assessed in similar time periods as the living donors. Stratified logistic regression was used to estimate associations with various disease outcomes. The diagnoses at follow-up were self-reported for the controls and registered by a physician for the donors. A total of 1029 donors and 16084 controls were included. Results Mean observation time was eleven years after donation. Forty-four per cent of donors were male and mean age at follow-up was 56 years. Among the controls, 39 % were male and mean age at follow-up was 53 years. At the time of follow up, 3.5 % of donors vs 1.7 % of controls had been diagnosed with ischemic heart disease, 3.7 % vs 4.4 % cancer, 1.8 % vs 1.4 % cerebrovascular disease and 4.1 % vs 1.9 % diabetes. After adjusting for gender, age at follow up, smoking at baseline, BMI at baseline, systolic blood pressure at baseline and time since donation (time since participation in general population survey for controls), odds ratio for ischemic heart disease was 1.64 (CI 1.10-2.43; P=0.01) in previous kidney donors compared with healthy controls. Other outcomes did not differ significantly between donors and controls. Conclusion During long-term follow-up of kidney donors we find an increased risk of ischemic heart disease compared to healthy controls. This information may be important in the follow-up and selection process of living kidney donors.

Background. Hypertensive nephrosclerosis is the presumed underlying cause in many end-stage kidney disease (ESKD) patients, but the diagnosis is disputed and based on clinical criteria with low diagnostic accuracy. Objective. To evaluate and improve the diagnostic process for nephrosclerosis patients. Methods. We included adults from the populationbased HUNT study (n = 50 552), Norwegian CKD patients referred for kidney biopsy 1988–2012 (n = 7261), and unselected nephrology clinic patients (n = 193) used for matching. Decision tree analysis and ROC curve-based methods of optimal cut-offs were used to improve clinical nephrosclerosis criteria. Results. Nephrosclerosis prevalence was 2.7% in the general population, and eGFR decline and risk for kidney-related hospital admissions and ESKD were comparable to patients with diabetic kidney disease. In the biopsy cohort, current clinical criteria had very low sensitivity (0.13) but high specificity (0.94) for biopsy-verified arterionephrosclerosis. A new optimized diagnostic algorithm based on proteinuria (155 mm Hg) and age (>75 years) only marginally improved diagnostic accuracy (sensitivity 0.19, specificity 0.96). Likewise, there were still false-positive cases with treatable diagnoses like glomerulonephritis, interstitial nephritis and others (40% of all test positive). Decision curve analysis showed that the new criteria can lead to higher clinical utility, especially for patients considering the potential harms to be close to the potential benefits, while the more risk-tolerant ones (harm:benefit ratio < 1:4) should consider kidney biopsy. Conclusion. Further improvements of the current clinical criteria seem difficult, so risks and benefits of kidney biopsy could be more actively discussed with selected patients to reduce misclassification and direct treatment. © 2020 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine. This is an open access article under the terms of the Creative Commons Attribution-Non Commercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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., Graphical abstract

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.

Chronic kidney disease (CKD) is a growing health burden currently affecting 10–15% of adults worldwide. Estimated glomerular filtration rate (eGFR) as a marker of kidney function is commonly used to diagnose CKD. We analyze eGFR data from the Nord-Trøndelag Health Study and Michigan Genomics Initiative and perform a GWAS meta-analysis with public summary statistics, more than doubling the sample size of previous meta-analyses. We identify 147 loci (53 novel) associated with eGFR, including genes involved in transcriptional regulation, kidney development, cellular signaling, metabolism, and solute transport. Additionally, sex-stratified analysis identifies one locus with more significant effects in women than men. Using genetic risk scores constructed from these eGFR meta-analysis results, we show that associated variants are generally predictive of CKD with only modest improvements in detection compared with other known clinical risk factors. Collectively, these results yield additional insight into the genetic factors underlying kidney function and progression to CKD., Estimated glomerular filtration rate (eGFR) is a measure of kidney function and used to characterize chronic kidney disease. Here, Graham et al. identify 53 novel loci for eGFR in a GWAS meta-analysis, a subset of which are associated with other common diseases, such as diabetes and hypertension, based on PheWAS.

Item does not contain fulltext BACKGROUND: Change in albuminuria as a surrogate endpoint for progression of chronic kidney disease is strongly supported by biological plausibility, but empirical evidence to support its validity in epidemiological studies is lacking. We aimed to assess the consistency of the association between change in albuminuria and risk of end-stage kidney disease in a large individual participant-level meta-analysis of observational studies. METHODS: In this meta-analysis, we collected individual-level data from eligible cohorts in the Chronic Kidney Disease Prognosis Consortium (CKD-PC) with data on serum creatinine and change in albuminuria and more than 50 events on outcomes of interest. Cohort data were eligible if participants were aged 18 years or older, they had a repeated measure of albuminuria during an elapsed period of 8 months to 4 years, subsequent end-stage kidney disease or mortality follow-up data, and the cohort was active during this consortium phase. We extracted participant-level data and quantified percentage change in albuminuria, measured as change in urine albumin-to-creatinine ratio (ACR) or urine protein-to-creatinine ratio (PCR), during baseline periods of 1, 2, and 3 years. Our primary outcome of interest was development of end-stage kidney disease after a baseline period of 2 years. We defined an end-stage kidney disease event as initiation of kidney replacement therapy. We quantified associations of percentage change in albuminuria with subsequent end-stage kidney disease using Cox regression in each cohort, followed by random-effects meta-analysis. We further adjusted for regression dilution to account for imprecision in the estimation of albuminuria at the participant level. We did multiple subgroup analyses, and also repeated our analyses using participant-level data from 14 clinical trials, including nine clinical trials not in CKD-PC. FINDINGS: Between July, 2015, and June, 2018, we transferred and analysed data from 28 cohorts in the CKD-PC, which included 693 816 individuals (557 583 [80%] with diabetes). Data for 675 904 individuals and 7461 end-stage kidney disease events were available for our primary outcome analysis. Change in ACR was consistently associated with subsequent risk of end-stage kidney disease. The adjusted hazard ratio (HR) for end-stage kidney disease after a 30% decrease in ACR during a baseline period of 2 years was 0.83 (95% CI 0.74-0.94), decreasing to 0.78 (0.66-0.92) after further adjustment for regression dilution. Adjusted HRs were fairly consistent across cohorts and subgroups (ie, estimated glomerular filtration rate, diabetes, and sex), but the association was somewhat stronger among participants with higher baseline ACR than among those with lower baseline ACR (pinteraction

Knowledge on how changing risk factors influence the progression of albuminuria over time is still limited. Furthermore, large population-based cohorts are needed to study the association between albuminuria change and mortality risk in nondiabetic study participants.We evaluated changes of albuminuria in 6282 nondiabetic individuals from the Norwegian population-based Nord-Trøndelag Health study. Using three albumin/creatinine ratios (ACR), we studied the influence of cardiovascular risk factors on ACR change from baseline to follow-up 11 years later. We evaluated the next 8-year mortality risk by using flexible parametric methods to identify nonlinear main effects and their two-way interactions.Mean albuminuria increased significantly over 11 years (1.82-3.02 mg/mmol, P 0.0001), but two-thirds of individuals had stable levels (ΔACR -1.40 to 1.40 mg/mmol). Higher age, ACR, and SBP as well as smoking and lower glomerular filtration rate at baseline were associated with increasing albuminuria. Study participants in the upper quartile of the increasing group had mean adjusted hazard ratio 1.31 (P = 0.004) for all-cause mortality compared with those with stable ACR. Those with decreasing ACR also had increased mortality, but the risk was strongly attenuated when adjusting for comorbidity. It also decreased the first 3 years before increasing. There was a strong interaction between baseline ACR and ΔACR. Increasing albuminuria had strongest effect on mortality in study participants with moderately increased baseline values.Both increasing and decreasing albuminuria are significant independent predictors of mortality in nondiabetic individuals, but must be interpreted in light of baseline values. Cutoffs and clinical usefulness in nondiabetic study participants should be further investigated.

Surveillance of chronic kidney disease (CKD) prevalence over time and information on how changing risk factors influence this trend are needed to evaluate the effects of general practice and public health interventions. Because very few studies addressed this, we studied the total adult population of a demographically stable county representative of Norway using cross-sectional studies 10 years apart (Nord-Trøndelag Health Study (HUNT)2 and Nord-Trøndelag Health Study (HUNT)3, 65,237 and 50,586 participants, respectively). Thorough quality-control procedures and comparisons of methods over time excluded analytical drift, and multiple imputations of missing data combined with nonattendance weights contributed to unbiased estimates. CKD prevalence remained stable in Norway from 1995 through 1997 (11.3%) to 2006 through 2008 (11.1%). The association of survey period with CKD prevalence was modified by a strong decrease in blood pressure, more physical activity, and lower cholesterol levels. Without these improvements, a 2.8, 0.7, and 0.6 percentage points higher CKD prevalence could have been expected, respectively. In contrast, the prevalence of diabetes and obesity increased moderately, but the proportion of diabetic patients with CKD decreased significantly (from 33.4% to 28.6%). A CKD prevalence of 1 percentage point lower would have been expected without these changes. Thus, CKD prevalence remained stable in Norway for more than a decade in association with marked improvements in blood pressure, lipid levels, and physical activity and despite modest increases in diabetes and obesity.

Background: The association between albuminuria and coronary heart disease (CHD) is well-known, but uncertainties related to day-to-day variability and effect modification of gender complicate the risk assessment process. This study evaluates the associations of CHD with albuminuria level in men and women based on the number of urine samples. Methods: Nine thousand one hundred and fifty-eight adults provided 3 urine samples and were followed for 14 years in the population-based HUNT-2 cohort study. The association of myocardial infarction or coronary death with different albumin-creatinine ratio (ACR) cut-offs, based on gender and number of positive ACRs, were estimated by hazard ratios (HRs) and adjusted for by Framingham variables. Results: Associations between ACR and CHD were similar in men and women. For example, HRs for moderately increased (3.0≤ ACR ≤30.0 mg/mmol) vs. normal albuminuria (ACR sex-equality = 0.3). However, median intra-individual day-to-day ACR coefficient of variation was 22.4% in women vs. 17.5% in men (p < 0.001). Two or 3 positive ACRs were required to establish a significant association with CHD at levels below 4.0 mg/mmol in women, while one positive ACR implied a significant association at all levels in men. Based on receiver-operating-characteristics curves, the Youden index suggested possible equal cut-offs for women (1.12 mg/mmol) and men (0.88 mg/mmol), p = 0.06. Conclusions: There were no significant gender differences in the association between albuminuria and coronary events. However, women had increased intra-individual albuminuria variability compared to men, necessitating several positive urine samples if mildly increased albuminuria is used in coronary risk evaluation.

Proteins get the job done and make up our phenotype: they give organisms their structure, transport molecules, catalyze chemical reactions, take care of cell signaling, etc . Proteomics is the large-scale study of proteins, an analogy to genomics and metabolomics, with the “omics” term

Chronic Kidney Disease (CKD) is a growing health burden currently affecting 10-15% of adults worldwide. Estimated glomerular filtration rate (eGFR) as a marker of kidney function is commonly used to diagnose CKD. Previous genome-wide association study (GWAS) meta-analyses of CKD and eGFR or related phenotypes have identified a number of variants associated with kidney function, but these only explain a fraction of the variability in kidney phenotypes attributed to genetic components. To extend these studies, we analyzed data from the Nord-Trøndelag Health Study (HUNT), which is more densely imputed than previous studies, and performed a GWAS meta-analysis of eGFR with publicly available summary statistics, more than doubling the sample size of previous meta-analyses. We identified 147 loci (53 novel loci) associated with eGFR, including genes involved in transcriptional regulation, kidney development, cellular signaling, metabolism, and solute transport. Moreover, genes at these loci show enriched expression in urogenital tissues and highlight gene sets known to play a role in kidney function. In addition, sex-stratified analysis identified three regions (prioritized genes:PPM1J, MCL1, andSLC47A1) with more significant effects in women than men. Using genetic risk scores constructed from these eGFR meta-analysis results, we show that associated variants are generally predictive of CKD but improve detection only modestly compared with other known clinical risk factors. Collectively, these results yield additional insight into the genetic factors underlying kidney function and progression to CKD.

Rationale & Objective Chronic kidney disease (CKD) is complicated by abnormalities that reflect disruption in filtration, tubular, and endocrine functions of the kidney. Our aim was to explore the relationship of specific laboratory result abnormalities and hypertension with the estimated glomerular filtration rate (eGFR) and albuminuria CKD staging framework. Study Design Cross-sectional individual participant-level analyses in a global consortium. Setting & Study Populations 17 CKD and 38 general population and high-risk cohorts. Selection Criteria for Studies Cohorts in the CKD Prognosis Consortium with data for eGFR and albuminuria, as well as a measurement of hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, or calcium, or hypertension. Data Extraction Data were obtained and analyzed between July 2015 and January 2018. Analytical Approach We modeled the association of eGFR and albuminuria with hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, and calcium values using linear regression and with hypertension and categorical definitions of each abnormality using logistic regression. Results were pooled using random-effects meta-analyses. Results The CKD cohorts (n = 254,666 participants) were 27% women and 10% black, with a mean age of 69 (SD, 12) years. The general population/high-risk cohorts (n = 1,758,334) were 50% women and 2% black, with a mean age of 50 (16) years. There was a strong graded association between lower eGFR and all laboratory result abnormalities (ORs ranging from 3.27 [95% CI, 2.68-3.97] to 8.91 [95% CI, 7.22-10.99] comparing eGFRs of 15 to 29 with eGFRs of 45 to 59 mL/min/1.73 m 2), whereas albuminuria had equivocal or weak associations with abnormalities (ORs ranging from 0.77 [95% CI, 0.60-0.99] to 1.92 [95% CI, 1.65-2.24] comparing urinary albumin-creatinine ratio > 300 vs < 30 mg/g). Limitations Variations in study era, health care delivery system, typical diet, and laboratory assays. Conclusions Lower eGFR was strongly associated with higher odds of multiple laboratory result abnormalities. Knowledge of risk associations might help guide management in the heterogeneous group of patients with CKD. © 2018. This is the authors’ accepted and refereed manuscript to the article. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ "

The incidence of renal replacement therapy varies across countries. However, little is known about the epidemiology of chronic kidney disease (CKD) outcomes. Here we describe progression and mortality risk of patients with CKD but not on renal replacement therapy at outpatient nephrology clinics across Europe using individual data from nine CKD cohorts participating in the European CKD Burden Consortium. A joint model assessed the mean change in estimated glomerular filtration rate (eGFR) and mortality risk simultaneously, thereby accounting for mortality risk when estimating eGFR decline and vice versa, while also correcting for the measurement error in eGFR. Results were adjusted for important risk factors (baseline eGFR, age, sex, albuminuria, primary renal disease, diabetes, hypertension, obesity and smoking) in 27,771 patients from five countries. The adjusted mean annual eGFR decline varied from 0.77 (95% confidence interval 0.45, 1.08) ml/min/1.73m2 in the Belgium cohort to 2.43 (2.11, 2.75) ml/min/1.73m2 in the Spanish cohort. As compared to the Italian PIRP cohort, the adjusted mortality hazard ratio varied from 0.22 (0.11, 0.43) in the London LACKABO cohort to 1.30 (1.13, 1.49) in the English CRISIS cohort. These results suggest that the eGFR decline showed minor variation but mortality showed the most variation. Thus, different health care organization systems are potentially associated with differences in outcome of patients with CKD within Europe. These results can be used by policy makers to plan resources on a regional, national and European level.

Background: Acute kidney injury (AKI) is a serious global public health problem. We aimed to quantify the risk of AKI associated with estimated glomerular filtration rate (eGFR), albuminuria (albumin-creatinine ratio [ACR]), age, sex, and race (African American and white).Study Design: Collaborative meta-analysis.Setting & Population: 8 general-population cohorts (1,285,049 participants) and 5 chronic kidney disease (CKD) cohorts (79,519 participants). Selection Criteria for Studies: Available eGFR, ACR, and 50 or more AKI events.Predictors: Age, sex, race, eGFR, urine ACR, and interactions.Outcome: Hospitalized with or for AKI, using Cox proportional hazards models to estimate HRs of AKI and random-effects meta-analysis to pool results.Results: 16,480 (1.3%) general-population cohort participants had AKI over a mean follow-up of 4 years; 2,087 (2.6%) CKD participants had AKI over a mean follow-up of 1 year. Lower eGFR and higher ACR were strongly associated with AKI. Compared with eGFR of 80 mL/min/1.73 m(2), the adjusted HR of AKI at eGFR of 45 mL/min/1.73 m2 was 3.35 (95% CI, 2.75-4.07). Compared with ACR of 5 mg/g, the risk of AKI at ACR of 300 mg/g was 2.73 (95% CI, 2.18-3.43). Older age was associated with higher risk of AKI, but this effect was attenuated with lower eGFR or higher ACR. Male sex was associated with higher risk of AKI, with a slight attenuation in lower eGFR but not in higher ACR. African Americans had higher AKI risk at higher levels of eGFR and most levels of ACR.Limitations: Only 2 general-population cohorts could contribute to analyses by race; AKI identified by diagnostic code.Conclusions: Reduced eGFR and increased ACR are consistent strong risk factors for AKI, whereas associations of AKI with age, sex, and race may be weaker in more advanced stages of CKD. (C) 2015 by the National Kidney Foundation, Inc.

Chronic kidney disease (CKD) is a public health problem with very high prevalence and mortality. Yet, there is a paucity of effective treatment options, partly due to insufficient knowledge of underlying pathophysiology. We combined metabolomics (GCMS) with kidney gene expression studies to identify metabolic pathways that are altered in adults with non-diabetic stage 3–4 CKD versus healthy adults. Urinary excretion rate of 27 metabolites and plasma concentration of 33 metabolites differed significantly in CKD patients versus controls (estimate range − 68% to + 113%). Pathway analysis revealed that the citric acid cycle was the most significantly affected, with urinary excretion of citrate, cis-aconitate, isocitrate, 2-oxoglutarate and succinate reduced by 40–68%. Reduction of the citric acid cycle metabolites in urine was replicated in an independent cohort. Expression of genes regulating aconitate, isocitrate, 2-oxoglutarate and succinate were significantly reduced in kidney biopsies. We observed increased urine citrate excretion (+ 74%, p = 0.00009) and plasma 2-oxoglutarate concentrations (+ 12%, p = 0.002) in CKD patients during treatment with a vitamin-D receptor agonist in a randomized trial. In conclusion, urinary excretion of citric acid cycle metabolites and renal expression of genes regulating these metabolites were reduced in non-diabetic CKD. This supports the emerging view of CKD as a state of mitochondrial dysfunction., Highlights • Urinary excretion rate and plasma concentration of 60 metabolites differed significantly in CKD patients versus controls. • Pathway analysis revealed that the citric acid cycle was the most significantly affected. • Expression of genes regulating TCA cycle was significantly reduced in kidney biopsies. Chronic kidney disease (CKD) is very common and carries a high risk of complications and death. Patients with advanced disease have severe fatigue, organ dysfunction beyond the kidneys, and disturbances in sugar, protein and fat metabolism. We found many metabolites that differed significantly in kidney patients versus healthy controls. Analysis revealed that the citric acid cycle was the most significantly affected metabolic pathway. The citric acid cycle is performed in the cells` mitochondria and is the central metabolic hub where fuel molecules are converted into energy. This supports the view of CKD as a state of mitochondrial dysfunction.

Albuminuria is a well-documented predictor of cardiovascular (CV) mortality. However, day-to-day variability is substantial, and there is no consensus on the number of urine samples required for risk prediction. To resolve this we followed 9158 adults from the population-based Nord-Trøndelag Health Study for 13 years (Second HUNT Study). The predictive performance of models for CV death based on Framingham variables plus 1 versus 3 albumin-creatinine ratio (ACR) was assessed in participants who provided 3 urine samples. There was no improvement in discrimination, calibration, or reclassification when using ACR as a continuous variable. Difference in Akaike information criterion indicated an uncertain improvement in overall fit for the model with the mean of 3 urine samples. Criterion analyses on dichotomized albuminuria information sustained 1 sample as sufficient for ACR levels down to 1.7 mg/mmol. At lower levels, models with 3 samples had a better overall fit. Likewise, in survival analyses, 1 sample was enough to show a significant association to CV mortality for ACR levels above 1.7 mg/mmol (adjusted hazard ratio 1.37; 95% CI 1.15-1.63). For lower ACR levels, 2 or 3 positive urine samples were needed for significance. Thus, multiple urine sampling did not improve CV death prediction when using ACR as a continuous variable. For cutoff ACR levels of 1.0 mg/mmol or less, additional urine samples were required, and associations were stronger with increasing number of samples.

BACKGROUND Diuretics are an important part of the therapy for a number of medical conditions such as heart, liver and kidney failure and hypertension. This article presents updated knowledge on the use of diuretics in kidney disease. METHOD The article is based on a literature search in PubMed, information obtained from textbooks on neurophysiology and kidney disease and on the authors' clinical experience. RESULTS Kidney disease affects the pharmacokinetics and pharmacodynamics of diuretics, and this must be taken into account when selecting a drug and determining the dosage. This applies particularly to nephrotic syndrome and severe chronic renal disease (GFR < 30 ml/min/1.73 m²). INTERPRETATION Knowledge of the pharmacology of diuretics is crucial to the rational use of diuretics in renal disease. Dose titration under close clinical monitoring and an optimal dosage interval make it possible to find the lowest possible effective dose and reduce the occurrence of side effects.

Summary Background and objectives A recent meta-analysis found that about 30% of women with a previous preeclamptic pregnancy had persistent microalbuminuria at follow-up. The analysis was, however, based on small studies, and more data are needed. Design, setting, participants, & measurements Using data from the Medical Birth Registry in Norway, this study identified women with or without preeclampsia in their first pregnancy 9–11 years previously (1998–2000). Women with diabetes, rheumatic disease, essential hypertension, or renal disease before first pregnancy and/or preeclampsia in later pregnancies were excluded. Eighty-nine women with and 69 women without preeclampsia participated in the study. Urinary albumin-to-creatinine ratio (ACR) was measured in three morning urine samples. Estimated GFR (eGFR) was calculated using the CKD-Epidemiology Collaboration formula. Results Median urinary ACR in follow-up urine samples was 0.53 mg/mmol for women with and 0.50 mg/mmol for women without preeclampsia (P=0.54). Only one woman (1%) with previous preeclampsia had urinary ACR >2.5 mg/mmol in two of three urine samples. Preeclampsia was not associated with urinary ACR above the 75th percentile. Women with preeclampsia did not have significantly higher eGFR than women without preeclampsia (107.9 versus 104.9 ml/min per 1.73 m2; P=0.12), but preterm preeclampsia was significantly associated with eGFR above the 75th percentile (P=0.03). Conclusions In this population-based study of otherwise healthy women, preeclampsia 10 years earlier was not associated with increased risk of persisting microalbuminuria. Estimated GFR was not significantly different between women with and those without preeclampsia, but preterm preeclampsia was associated with high normal eGFR.

Despite major improvements in the treatment of patients with diabetes mellitus, many patients still suffer from progressive diabetic kidney disease. More research is needed to improve treatment and to understand why some patients develop complications while others do not. Mitochondrial dysfunction has turned out to be central to the pathogenesis of diabetes, and we will review some new aspects in this field and the potential for treatment. The conventional theory has been that the intracellular surplus of glucose leads to mitochondrial overproduction of superoxide that contributes to general cell damage and activation of deleterious pathways specific for diabetes complications. However, recent data suggests that reduced mitochondrial activity could be the basis for disease progression and complications through increased inflammation and pro-fibrotic factors. Physical exercise is a very strong stimulus to mitochondrial biogenesis, and we now understand many of the underlying signaling pathways. Clinical trials have also shown that training, especially high-intensity training, can delay the onset of diabetes and improve insulin resistance. Furthermore, intermittent fasting and various pharmacological agents are other potential options for stimulating mitochondrial function and reducing the risk of development and progression of diabetic kidney disease.

BACKGROUND There are concerns regarding potential long-term risks to the living kidney donor. Cardiovascular mortality has not been evaluated. The aim of this study was to assess overall and cardiovascular mortality in previous kidney donors compared with a general population sample. METHODS All live kidney donors in Norway in the period 1963-2007 were included. Controls matched 3:1 for age, gender and year of birth were provided by Statistics, Norway. Cause of death was retrieved from the death master file. Vital status as of 1 January 2010 was provided for all participants, and cause of death was available until 1 January 2008. Comparative survival analyses were performed by Kaplan-Meier curves and log-rank test. Age-stratified death rates were calculated and compared with a selected group with a health status hypothetically allowing donation. RESULTS There were 2269 living kidney donors in the study period. At donation, mean age was 47.6 + 12.6 years, 41.3% were male. Median observation time was 14.3 years. A total of 324 donors died during the study period. Causes of death were similar for donors and controls. By Kaplan-Meier analysis, overall and cardiovascular mortality was lower for previous kidney donors than for matched controls (P < 0.001 and P = 0.004, respectively). Age-stratified death rates were elevated for the oldest group of donors. CONCLUSIONS Overall and cardiovascular mortality results are partially reassuring. However, the seemingly elevated mortality rate among the oldest donors requires further study.

Background Chronic kidney disease (CKD) screening beyond patients with diabetes mellitus or hypertension increasingly is discussed. Some guidelines recommend kidney function testing of patients with benign prostatic hyperplasia; however, the significance of extending this to general population screening is unclear. Study Design Prospective cohort study. Setting & Participants 30,466 men from the HUNT II (Second Health Study in Nord-Trondelag; 1995-1997) representing 66.8% of the entire adult male population in Nord-Trondelag County, Norway. Predictor The International Prostate Symptom Score was used to detect the presence and severity of lower urinary tract symptoms (LUTS), a surrogate measure of benign prostate hyperplasia suitable for use in general practice. Outcomes Kidney failure was defined as starting renal replacement therapy or CKD death with a documented stable estimated glomerular filtration rate 2 . Results During 10.5 years of follow-up, 78 men developed kidney failure. Kidney failure risks were 2.60 (95% CI, 1.47-4.58) and 4.08 (95% CI, 1.74-9.53) times higher for men with moderate and severe LUTS compared with men with no/mild LUTS, respectively. However, age-stratified analysis showed that the incidence rate ratio for moderate/severe LUTS versus no/mild LUTS was 1.27 (95% CI, 0.76-2.13), and multivariable Cox analysis showed no significant association between LUTS and risk of kidney failure. Screening effectiveness was improved only slightly by including men with moderate/severe LUTS in addition to patients with diabetes, hypertension, or cardiovascular disease. Better effectiveness was achieved by simply including all men older than 60 years. Limitations The ability of the International Prostate Symptom Score to predict the presence and severity of obstruction is only moderate. Ascertainment of severe CKD (estimated glomerular filtration rate, 30-15 mL/min/1.73 m 2 ) was not possible. Conclusion LUTS were not significantly associated with future kidney failure after adjusting for age and therefore in isolation are not a basis for kidney failure screening.

The worldwide high prevalence of chronic kidney disease (CKD) and the increasing number of patients reaching end-stage renal disease (ESRD) are a matter of major concern. The most widely accepted classification system of CKD is that proposed by the Kidney Disease Outcomes Quality Initiative (KDOQI) in 2002. When applying this system, it has become apparent that the prevalence of CKD is particularly high in elderly subjects. The fact that this system is mainly based on estimated glomerular filtration rate (eGFR), subdividing the severity of CKD into five stages, is a matter of debate. A main issue is that although a reduced eGFR is often encountered in elderly subjects, most of these subjects do not have a renal disease leading to an increased risk of ESRD, i.e. the predictive power of ESRD is unsatisfactory. Recent advances have been put forward to improve (1) estimation of GFR and (2) prediction of ESRD. In this review, we discuss the currently available data with a focus on the elderly and propose an improved classification system of CKD which is characterized by a substantially better diagnostic accuracy for progression to ESRD. This is simply and cost-effectively accomplished by subdividing stage 3 CKD into two groups (eGFR 30–44 and 45–59 ml/min/1.73 m2) and by complementing all levels of eGFR with information about urinary albumin excretion, i.e. whether normoalbuminuria, microalbuminuria, or macroalbuminuria is present. The consequence should be a revision of the 2002 KDOQI CKD classification system according to these findings, which would be a significant step forward, particularly for elderly CKD patients.

Background. A recent study has shown that preeclampsia is an important risk marker for end-stage renal disease (ESRD), but the underlying mechanisms are unclear. The present study investigated whether previous preeclampsia was associated with progression of established kidney disease. Material and methods. Data from the Norwegian Kidney Biopsy Registry and the Medical Birth Registry of Norway were linked. We included women who, after their last pregnancy, had had a representative kidney biopsy in 1988-2005. Women were followed up for the development of ESRD using data from the Norwegian Renal Registry. Baseline was set at the time of biopsy and Cox regression statistics were performed. Results. Of the 582 included women, 76 developed ESRD 3.9 ± 3.4 years (range, 0.08-16 years) after diagnosis. Mean age at first birth was 24.0 ± 4.8 years and at the time of diagnosis 41.3 ± 9.7 years. Women with clinically diagnosed preeclampsia in their first pregnancy had a relative risk of ESRD of 1.2 (95% CI, 0.63―2.4) and women with preterm birth had a relative risk of 2.1 (95% CI, 1.2-3.9). After extensive adjustments for clinical and histopathological variables at the time of diagnosis, the relative risks were 1.1 (95% CI, 0.50―2.6) and 2.4 (95% CI, 1.2-4.6), respectively. Compared to women with a first term birth without preeclampsia, women with term preeclampsia were diagnosed at a younger age (36 vs 42 years) and women with preterm birth without preeclampsia had a lower estimated glomerular filtration rate at diagnosis (48 vs 64 mi/min/1.73 m 2 ). Conclusion. In women with kidney disease diagnosed at kidney biopsy, previous preeclampsia does not seem to be a risk marker for progression to ESRD.

Case-control studies have shown an association between low birth weight and risk for renal failure. The Medical Birth Registry of Norway, which comprises data on all births in Norway since 1967, and the Norwegian Renal Registry, which comprises data on all patients who have developed ESRD in Norway since 1980, were used to examine whether birth-related variables were associated with risk for ESRD. Of the 2,183,317 children born between 1967 and 2004, 526 were found in the ESRD registry. Compared with birth weight in the 10th to 90th percentiles, births

Although it is beyond any doubt that smoking is the number one preventable cause of death in most countries, smoking as an independent progression factor in renal disease has been questioned against the background of evidence-based criteria. This is because information from large, randomized, prospective studies that investigate the effects of smoking on renal function in healthy individuals as well as in patients with primary or secondary renal disease are lacking. Since 2003, a substantial number of clinical and experimental data concerning the adverse renal effects of smoking have been published, including large, prospective, population-based, observational studies. These more recent data together with evidence from experimental studies clearly indicate that smoking is a relevant risk factor, conferring a substantial increase in risk for renal function deterioration. This review summarizes the present knowledge about the renal risks of smoking as well as the increased cardiovascular risk caused by smoking in patients with chronic kidney disease. The conclusion is that smoking is an important renal risk factor, and nephrologists have to invest more efforts to motivate patients to stop smoking.

Background: Diabetes mellitus and hypertension are risk factors for acute kidney injury (AKI). Whether estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (ACR) remain risk factors for AKI in the presence and absence of these conditions is uncertain.Study Design: Meta-analysis of cohort studies.Setting & Population: 8 general-population (1,285,045 participants) and 5 chronic kidney disease (CKD; 79,519 participants) cohorts.Selection Criteria for Studies: Cohorts participating in the CKD Prognosis Consortium.Predictors: Diabetes and hypertension status, eGFR by the 2009 CKD Epidemiology Collaboration creatinine equation, urine ACR, and interactions.Outcome: Hospitalization with AKI, using Cox proportional hazards models to estimate HRs of AKI and random-effects meta-analysis to pool results.Results: During a mean follow-up of 4 years, there were 16,480 episodes of AKI in the general-population and 2,087 episodes in the CKD cohorts. Low eGFRs and high ACRs were associated with higher risks of AKI in individuals with or without diabetes and with or without hypertension. When compared to a common reference of eGFR of 80 mL/min/1.73 m(2) in nondiabetic patients, HRs for AKI were generally higher in diabetic patients at any level of eGFR. The same was true for diabetic patients at all levels of ACR compared with nondiabetic patients. The risk gradient for AKI with lower eGFRs was greater in those without diabetes than with diabetes, but similar with higher ACRs in those without versus with diabetes. Those with hypertension had a higher risk of AKI at eGFRs. 60 mL/min/1.73 m(2) than those without hypertension. However, risk gradients for AKI with both lower eGFRs and higher ACRs were greater for those without than with hypertension.Limitations: AKI identified by diagnostic code.Conclusions: Lower eGFRs and higher ACRs are associated with higher risks of AKI among individuals with or without either diabetes or hypertension. (C) 2015 by the National Kidney Foundation, Inc.

Background: The contrast between a high prevalence of chronic kidney disease (CKD) and the low incidence of end-stage renal disease highlights the need for new biomarkers of progression beyond albuminuria testing. Urinary proteomics is a promising method, but more studies focusing on progression rate and patients with hypertensive nephropathy are needed. Results: We analyzed urine samples with capillary electrophoresis coupled to a mass-spectrometer from 18 well characterized patients with CKD stage 4–5 (of whom six with hypertensive nephropathy) and 17 healthy controls. Classification scores based on a previously developed panel of 273 urinary peptides were calculated and compared to urine albumin dipstick results. Urinary proteomics classified CKD with a sensitivity of 0.95 and specificity of 1.00. Overall diagnostic accuracy (area under ROC curve) was 0.98, which was better than for albuminuria (0.85, p = 0.02). Results for hypertensive nephropathy were similar to other CKD diagnoses. Adding the proteomic score to an albuminuria model improved detection of rapid kidney function decline (>4 ml/min/1.73 m2 per year) substantially: area under ROC curve increased from 0.762 to 0.909 (p = 0.042), and 38% of rapid progressors were correctly reclassified to a higher risk and 55% of slow progressors were correctly reclassified to a lower risk category. Reduced excretion of collagen types I–III, uromodulin, and other indicators of interstitial inflammation, fibrosis and tubular dysfunction were associated with CKD diagnosis and rapid progression. Patients with hypertensive nephropathy displayed the same findings as other types of CKD. Conclusions: Urinary proteomic analyses had a high diagnostic accuracy for CKD, including hypertensive nephropathy, and strongly improved identification of patients with rapid kidney function decline beyond albuminuria testing. Keywords: Chronic kidney disease, Hypertensive nephropathy, Urine, Albuminuria, Proteomics, Disease progression © 2015 Øvrehus et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

ESRD incidence is much lower in Europe compared with the United States. This study investigated whether this reflects a difference in the prevalence of earlier stages of chronic kidney disease (CKD) or other mechanisms. CKD prevalence in Norway was estimated from the population-based Health Survey of Nord-Trondelag County (HUNT II), which included 65,181 adults in 1995 through 1997 (participation rate 70.4%). Data were analyzed using the same methods as two US National Health and Nutrition Examination Surveys in 1988 through 1994 (n = 15,488) and 1999 through 2000 (n = 4101). The primary analysis used gender-specific cutoffs in estimating persistent albuminuria for CKD stages 1 and 2. ESRD rates and other relevant data were extracted from national registries. Total CKD prevalence in Norway was 10.2% (SE 0.5): CKD stage 1 (GFR >90 ml/min per 1.73 m2 and albuminuria), 2.7% (SE 0.3); stage 2 (GFR 60 to 89 ml/min per 1.73 m2 and albuminuria), 3.2% (SE 0.4); stage 3 (GFR 30 to 59 ml/min per 1.73 m2), 4.2% (SE 0.1); and stage 4 (GFR 15 to 29 ml/min per 1.73 m2), 0.2% (SE 0.01). This closely approximates reported US CKD prevalence (11.0% in 1988 through 1994 and 11.7% in 1999 through 2000). The relative risk for progression from CKD stages 3 or 4 to ESRD in US white patients compared with Norwegian patients was 2.5. This was only modestly modified by adjustment for age, gender, and diabetes. Age and GFR at start of dialysis were similar, hypertension and cardiovascular mortality in the populations were comparable, but US white patients were referred later to a nephrologist and had higher prevalence of obesity and diabetes. In conclusion, CKD prevalence in Norway was similar to that in the United States, suggesting that lower progression to ESRD rather than a smaller pool of individuals at risk accounts for the lower incidence of ESRD in Norway.

The incidence of end-stage renal disease is especially high in men, and some studies indicated that smoking is a risk factor for men only. We investigated associations between obesity, smoking, and physical inactivity and chronic kidney disease (CKD) in the general population and whether risk for CKD was restricted to men.This was a cross-sectional health survey of the entire adult population of Nord-Trondelag County, Norway, 1995 to 1997, with a 70.6% participation rate. Glomerular filtration rate (GFR) was estimated in all subjects 20 years and older from calibrated serum creatinine levels by using the simplified Modification of Diet in Renal Disease Study formula, and CKD cases are defined as those with a GFR less than 45 mL/min/1.73 m2 (0.75 mL/s).A total of 30,485 men and 34,708 women were included, and prevalences of GFR less than 45 mL/min/1.73 m2 (0.75 mL/s) were 0.8% and 1.1%, respectively. Age- and sex-adjusted logistic regression analyses showed dose-response relations for body mass index, smoking history, and physical activity. Relative risks were 1.77 (95% confidence interval [CI], 1.47 to 2.14) for obesity (body mass indexor = 30 kg/m2), 1.52 (95% CI, 1.13 to 2.06) for smoking (25 pack-years), and 2.14 (95% CI, 1.39 to 3.30) for physical inactivity (no or some physical activity in leisure time). For subjects with all these risk factors, relative risk was 5.10 (95% CI, 2.36 to 11.01). These results remained significant after adjusting for other known risk factors. No biological interactions between sex and obesity, smoking, or physical activity were found.Obesity, smoking, and physical inactivity were associated significantly with CKD. Men were not more susceptible to these risk factors than women.

Background Guidelines recommend the modification of diet in the renal disease (MDRD) formula or the Cockcroft-Gault formula for estimating the glomerular filtration rate (GFR). However, there is an ongoing discussion whether the MDRD formula should be used in the general population as several studies have found a large underestimation of its GFR estimates. Methods In this study, 1,029 low-risk subjects, eligible for kidney donation according to internationally accepted criteria were selected from the population-based second Health Survey of Nord-Trondelag (HUNT II). Serum creatinine values traceable to isotope dilution mass spectrometry were used with the re-expressed MDRD formula recently published. The 2.5th, 50th and 97.5th percentiles of GFR by age were calculated and compared to reference values from the literature, which are based on GFR measured with gold standard methods in potential kidney donors. Results The difference between the 50th percentiles for MDRD estimates and measured GFR in the literature was small and constant over age: +0.5 ml/min/1.73 m(2) at age 20 and -2.0 ml/min/1.73 m(2) at age 80. Bias for Cockcroft-Gault estimates varied from 0.0 ml/min/1.73 m(2) to -21.4 ml/min/1.73 m(2). Other formulae also had a too steep age correction, and bias among the elderly varied from -10 to -30 ml/min/1.73 m(2). Hence, 30-80% of the general population above age 60 had GFR estimates below their age-specific 2.5th percentile of normal kidney function, while the MDRD formula was much more conservative (13.3%). Conclusion The MDRD formula gave nearly unbiased estimates for normal GFR. All other formulae tested had, especially in the elderly, a much larger negative bias and cannot be recommended for use in the general population.

Modern renal physiology arose during the scientific revolution of the 1840s in Europe with mechanistic experiments playing a central role. Carl Ludwig, a German physiologist, was the first to describe the principle of glomerular ultrafiltration driven by physical forces alone [1]. However, an understanding of the fundamental mechanisms of kidney function awaited the advent of micropuncture techniques by Wearn and Richards in 1924 [2]. Since then, numerous research groups have provided us with knowledge on glomerular haemodynamics, filtration barrier function and the processes of tubular reabsorption and secretion. We also know that tubular and interstitial pathological processes can affect glomerular function. Therefore, the glomerular filtration rate (GFR) is now regarded as the best overall measure of kidney function, reflecting reduced clearance of waste products and also to some extent disturbed regulation of electrolytes, water balance and hormone production. Inulin clearance was established early as the gold standard method for measuring the GFR. This substance completely fulfils the requirements of no extra-renal clearance, free filtration and no tubular reabsorption or secretion [3]. However, the method is complicated from both an analytical and a practical point of view with the need for continuous intravenous infusion. It has, therefore, seldom been used in clinical practice and nor is it widely used in research institutions today. Plasma clearance of exogenous markers like iothalamate, iohexol and EDTA is available instead for measuring the GFR in most hospitals and are considered equally accurate. Although considered as reference methods, their accuracy is not very high with coefficients of variation reported in the range of 5–20% [4]. Although less complicated than the classical inulin clearance technique, these methods are also very expensive and take hours per patient. Serum creatinine and various formulas based on this cheap, fast and universally available analyte, therefore, remains the cornerstone of kidney function assessment. The relationship between serum creatinine and GFR is non-linear and influenced by several non-kidney variables, and numerous formulas for estimating the GFR have been published over the past 40 years. The Cockcroft Gault formula gained worldwide popularity despite being based on only 249 hospitalized males with kidney function measured as 48-h urine creatinine clearance, which includes tubular creatinine secretion [5]. Later studies have shown that the formula gives a suboptimal performance as a proxy for true GFR in several settings including in the elderly and in advanced kidney disease, where tubular creatinine secretion can lead to 35% overestimation of GFR [6–8]. In 1999, Levey et al. [9] published a new formula based on 1628 chronic kidney disease (CKD) patients from the Modification of Diet in Renal Disease (MDRD) study with the GFR measured as urinary iothalamate. These patients all had a GFR of 60 mL/min/ 1.73 m. Ten years later, Levey et al., therefore, published a new serum creatinine-based formula [the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula] using the highest available standards: serum creatinine traceable to isotope-dilution mass spectrometry standards from an impressive 8254 subjects, iothalamate clearance for measuring true GFR, separate study groups for developing and validating the formula, a sufficiently high number of black participants and participants with a wide range of kidney functions [10]. P O L A R V IE W S IN N E P H R O L O G Y

Background The natural course of longitudinal changes in peritoneal permeability and membrane area has been studied mostly by performing single-dwell studies in selected patients during treatment with peritoneal dialysis. Purpose To evaluate the permeability characteristics of the peritoneal membrane by measuring drained ultrafiltration volume relative to initial glucose concentration in dialysis fluid from the start to the end of continuous ambulatory peritoneal dialysis (CAPD) treatment in a selected cohort of patients with and without peritonitis. Design A retrospective analysis of a group of patients whose peritoneal function was prospectively followed by recording drained ultrafiltration volume and glucose concentration in dialysis fluid for each dwell time, every day, during the time in CAPD treatment. Mean values from a 1-month period starting after the first 3 weeks of CAPD treatment were compared with the mean values from the last month of treatment. Approximately 11 500 exchanges were analyzed. Evaluations were done separately for short (day) and long (night) dwell times. Patients and Statistics Of 132 patients commencing CAPD treatment in the time period selected for inclusion, 51 had enough data to be included in this study. Of these, 29 patients experienced one or more episodes of successfully treated peritonitis. The selection of patients was not based upon patient characteristics, but upon criteria to satisfy predefined demands, such as number of measurements in each period, time since an episode of peritonitis, and time on CAPD treatment. Data were analyzed in three different groups: patients with episodes of peritonitis, patients without peritonitis, and both groups together. To assess changes between monthly mean at the start and at the end of CAPD, paired t-test was performed. Patients were also stratified into two groups according to low and high glucose in dialysis fluid at the start of CAPD (cutoff = 2 g/dL). Additionally, we used linear regression analyses to predict the level of drained ultrafiltration volume for a given level and change in glucose concentration. Mean treatment time for the entire group was 20 months (median 14.3 months), ranging from 6 to 69 months. Results No statistical differences in glucose concentrations were found between the periods compared. In the entire group there was an increase in ultrafiltration volume from the start to the end of CAPD treatment, for both day ( p = 0.009) and night ( p = 0.013) exchanges. Also, for patients without peritonitis, an increase appeared for day ( p = 0.046) and night exchanges ( p = 0.053). However, for the cohort with peritonitis, only an insignificant increase was indicated. Patient characteristics, diabetic patients, the need for glucose in dialysis fluid when commencing CAPD treatment, the number of episodes of peritonitis, and time on CAPD did not influence the change in ultrafiltration. Regression analyses showed higher ultrafiltration response to a given level and change in glucose concentration at the end of CAPD treatment compared to the start values, also for the cohort with peritonitis. The regression coefficient between these variables was also significantly changed for both day ( p < 0.0001) and night ( p = 0.027) exchanges. Conclusion A significant change in the regression coefficient between glucose in dialysis fluid and ultrafiltration volume reflects an increase in ultrafiltration response to a given level and change in glucose concentration during time on CAPD treatment. A parallel change after 5- and 9-hour dwells can be explained by a decrease in peritoneal surface area combined with a lesser decrease in peritoneal conductivity. However, changes in Starling forces across the peritoneal membrane are possible even in the absence of changes in peritoneal membrane characteristics.