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Background Febuxostat is recommended for patients with chronic kidney disease (CKD) associated with hyperuricemia to lower the serum uric acid (sUA) concentration. However, it remains uncertain how this drug affects correlations between several laboratory parameters regarding glomerular filtration and renal tubular reabsorption of uric acid. Methods We enrolled 148 patients with CKD with hyperuricemia. Of them, 122 were treated with febuxostat, and 26 were treated without it. Clinical and laboratory parameters were recorded to calculate the estimated glomerular filtration rate (eGFR), fractional excretion of uric acid (FEUA), and the estimated 24-h urinary excretion of uric acid (eEUA). We retrospectively examined the correlations between those parameters to compare the patients treated with febuxostat to those without it. Results A significant inverse correlation between eGFR and FEUA was demonstrated in both patients treated with febuxostat and those without it. In patients treated with febuxostat, a significant inverse correlation was demonstrated between eGFR and sUA, whereas no significant correlation was demonstrated in those without it. There was a significant positive correlation between FEUA and eEUA in patients treated with febuxostat, whereas no significant correlation was revealed in those without it. Conclusions FEUA increased as eGFR declined in our study population. Febuxostat changed the correlation patterns between the clinical laboratory parameters. An additional administration of uricosuric agents would be helpful for further sUA lowering by increasing both FEUA and eEUA in patients treated with febuxostat.

Background Verinurad is a human uric acid (UA) transporter (URAT1) inhibitor known to decrease serum UA (sUA) levels and that may reduce albuminuria. In a Phase 2a study (NCT03118739), treatment with verinurad + febuxostat lowered urine albumin-to-creatinine ratio (UACR) at 12 weeks by 39% (90% confidence interval 4–62%) among patients with Type 2 diabetes mellitus, hyperuricaemia and albuminuria. The Phase 2b, randomized, placebo-controlled Study of verinurAd and alloPurinol in Patients with cHronic kIdney disease and hyperuRicaEmia (SAPPHIRE; NCT03990363) will examine the effect of verinurad + allopurinol on albuminuria and estimated glomerular filtration rate (eGFR) slope among patients with chronic kidney disease (CKD) and hyperuricaemia. Methods Adults (≥18 years of age) with CKD, eGFR ≥25 mL/min/1.73 m2, UACR 30–5000 mg/g and sUA ≥6.0 mg/dL will be enrolled. Approximately 725 patients will be randomized 1:1:1:1:1 to 12, 7.5 or 3 mg verinurad + allopurinol, allopurinol or placebo. An 8-week dose-titration period will precede a 12-month treatment period; verinurad dose will be increased to 24 mg at Month 9 in a subset of patients in the 3 mg verinurad + allopurinol arm. The primary efficacy endpoint the is change from baseline in UACR at 6 months. Secondary efficacy endpoints include changes in UACR, eGFR and sUA from baseline at 6 and 12 months. Conclusions This study will assess the combined clinical effect of verinurad + allopurinol on kidney function in patients with CKD, hyperuricaemia and albuminuria, and whether this combination confers renoprotection beyond standard-of-care.

Background The transtheoretical model (TTM) is composed of the multiple stages according to patient's consciousness and is believed to lead people to realize the importance of healthier behaviors. We examined the association of TTM stages with the decline of estimated glomerular filtration rate (eGFR). Method We used the annual health checkup data and health insurance claims data of the Japan Health Insurance Association in Kyoto prefecture between April 2012 and March 2016. TTM stages of change obtained from questionnaires at the first health checkup and categorized into 6 groups. The primary outcome was defined as a more than 30% decline in eGFR from the first health checkup. We fitted multivariable Cox proportional-hazards model for time-to-event analyses adjusting for age, sex, eGFR, body mass index, blood pressure, blood sugar, dyslipidemia, uric acid, urinary protein, and existence of kidney diseases at first health checkup. Result We analyzed 239,755 employees and the mean follow-up was 2.9 years (standard deviation: 1.2 years). As compared with stage 1 group, the risk of eGFR decline was significantly low in the stage 3 group (hazard ratios (HRs), 0.77 (95% Confident Interval (CI), 0.65-0.91)); in stage 4 group (HRs, 0.80, 95%CI, 0.65-0.98); in stage 5 group (HRs, 0.79, 95%CI, 0.66-0.95)Conclusion: Compared with the precontemplation stage (stage 1), the preparation, action and maintenance stages (stage3, 4 and 5), were associated with a lower risk of eGFR decline.

Background Tolvaptan is the first effective drug treatment for autosomal dominant polycystic kidney disease (ADPKD) patients, but few long-term observations of the effects of tolvaptan have been reported. Methods In this single center, retrospective cohort study, we investigated nine patients who participated in a phase 3 trial of tolvaptan for ADPKD patients at our hospital between 2008 and 2014. Six of the patients discontinued tolvaptan at the end of the clinical trial and were defined as the discontinuation group, and three continued to take it; these were defined as the continuation group. The observation period was 3 years before and after the end of the tolvaptan trial, and we compared the following data in each group: serum creatinine, estimated glomerular filtration rate (eGFR), total kidney volume, serum sodium concentration, and urine specific gravity. Results eGFR was significantly improved after the end of the trial in the continuation group (P = 0.0446), but there was no significant change in the regression line before and after the end of the trial in the discontinuation group. The increases in mean total kidney volume rates over the 3 years before and after the trial were 0.01 %/year vs. 0.067 %/year in the discontinuation group (P = 0.0247). On the other hand, serum sodium concentration and urine specific gravity showed no change during the observation period. Conclusion This study suggested that long-term administration of tolvaptan may improve renal function and inhibit total kidney volume growth.

Background. The effect of pregnancy on the course of estimated glomerular filtration rate (eGFR) is unknown in kidney transplant recipients (KTRs). Methods. We conducted a nationwide multicenter cohort study in KTRs with pregnancy (>20 wk) after kidney transplantation (KT). Annual eGFRs after KT until death or graft loss and additional eGFRs before each pregnancy were collected according to protocol. Changes in eGFR slope before and after each pregnancy were analyzed by generalized estimating equations multilevel analysis adjusted for transplant vintage. Results. We included 3194 eGFR measurements before and after pregnancy in 109 (55%) KTRs with 1, 78 (40%) with 2, and 10 (5%) with 3 pregnancies after KT. Median follow-up after first delivery post-KT was 14 y (interquartile range, 18 y). Adjusted mean eGFR prepregnancy was 59 mL/min/1.73 m2(SEM [standard error of the mean] 1.72; 95% confidence interval [CI], 56-63), after the first pregnancy 56 mL/min/1.73 m2(SEM 1.70; 95% CI, 53-60), after the second pregnancy 56 mL/min/1.73 m2(SEM 2.19; 95% CI, 51-60), and after the third pregnancy 55 mL/min/1.73 m2(SEM 8.63; 95% CI, 38-72). Overall eGFR slope after the first, second, and third pregnancies was not significantly worse than prepregnancy (P = 0.28). However, adjusted mean eGFR after the first pregnancy was 2.8 mL/min/1.73 m2(P = 0.08) lower than prepregnancy. Conclusions. The first pregnancy has a small, but insignificant, effect on eGFR slope in KTRs. Midterm hyperfiltration, a marker for renal reserve capacity, was associated with better eGFR and death-censored graft survival. In this KTR cohort with long-term follow-up, no significant effect of pregnancy on kidney function was detected.

Background There is no a unified opinion in the treatment of IgA nephropathy. This prospective cohort study was to explore the effectiveness and safety of tacrolimus for treatment of IgA (Immunoglobulin A) nephropathy patients. Methods In this study, we assigned 50 patients with biopsy-proven IgA nephropathy in a 1:1.5 ratio to receive oral tacrolimus or full-dose glucocorticoid for 6 months. All the patients had 24-h urine protein excretion ≥ 2.0 g/24 h and estimated glomerular filtration rate ≥ 50 mL/min/1.73 m2. Primary endpoint was rate of complete remission. Results After 6 months of treatment, seven participants achieved complete remission in the tacrolimus group and twelve participants in the glucocorticoid group, the complete remission rate was 35% and 40%, respectively. There were not significantly differences between two groups (P = 0.7). However, the serum creatinine level from baseline was an increase of 13 ± 13.5 μmol/L in the tacrolimus group and a decrease of 8.2 ± 20 μmol/L in the glucocorticoid group. When patients stopped taking tacrolimus for 3 months, creatinine level can almost fall to normal level. Thus, patients with renal insufficiency have a high incidence in the tacrolimus group. Conclusions Tacrolimus was noninferior to full-dose glucocorticoid in inducing proteinuria remission at 6 months. This suggested that those IgA nephropathy patients who are unwilling to full-dose glucocorticoid could consider tacrolimus, but need to pay attention to the impact on renal function.

Increased pulse pressure (IPP) is associated with an estimated glomerular filtration ≤ 60/mL/min/1.73 mTo determine the usefulness of IPP as a diagnostic test for K/DOQI stage III-b CKD.Diagnostic test study that included adult patients without comorbidities, registered in the Health Workers Cohort. The CKD-EPI formula was used to calculate glomerular filtration. Pulse pressure was determined by subtracting diastolic from systolic blood pressure. Sensitivity, specificity, positive predictive value, negative predictive value and prevalence were calculated using standard formulas. A ROC curve was generated to determine the area under the curve.A total of 6,215 patients were included. An IPP ≥ 50 mmHg was observed to have a sensitivity of 74 %, specificity of 70 %, positive predictive value of 1 %, negative predictive value of 100 % and a prevalence of 1 %. The inflection point in the ROC curve to identify K/DOQI III-b CKD was 0.71.An IPP ≥ 50 mmHg is useful as a diagnostic test to identify people with K/DOQI stage III-b CKD.La presión de pulso ampliada (PPA) se asocia a un filtrado glomerular calculado ≤ 60/mL/minuto/1.73 mDeterminar la utilidad de la PPA como prueba diagnóstica de IRC estadio K/DOQI III-b.Estudio de prueba diagnóstica que incluyó a pacientes adultos sin comorbilidades, registrados en la Cohorte de Trabajadores de la Salud. Se utilizó la fórmula CKD-EPI para calcular la filtración glomerular. Se determinó la presión de pulso restando la presión arterial diastólica a la presión arterial sistólica. Se calculó sensibilidad, especificidad, valor predictivo positivo, valor predictivo negativo y prevalencia. Se elaboró una curva ROC para determinar el área bajo la curva.Se incluyeron 6215 pacientes. Se observó que una PPA ≥ 50 mm Hg tuvo sensibilidad de 74 %, especificidad de 70 %, valor predictivo positivo de 1 %, valor predictivo negativo de 100 % y prevalencia de 1 %. El punto de inflexión en la curva ROC para identificar IRC K/DOQI III-b fue de 0.71.La PPA ≥ 50 mm Hg es útil como prueba diagnóstica para identificar a personas con IRC estadio K/DOQI III-b.

Introduction Association between chronic kidney disease (CKD) and ischaemic heart disease (IHD) is well known. Clinically, because of the use of intra-arterial contrast, coronary angiograms are sometimes not performed to avoid further deterioration in kidney function amongst CKD patients. Therefore, our aim is to identify whether intervention for non-ST elevation myocardial infarction (NStemi) is associated with increased mortality or further renal deterioration. Method A retrospective observational cohort study was undertaken involving 144 patients with diagnosis of IHD in the CKD.QLD registry from May 2011 to August 2017, with minimum of 2 years follow-up. Patients were divided into two groups based on whether they obtained an interventional or medical management for NStemi. Results 59 patients had medical management and 85 patients had intervention for IHD. Patients in the medical management group were observed to be significantly older (median:78vs69years,p Conclusion In this observational study, intervention for IHD was associated with increased survival with no change in renal disease progression in comparison to medically managed patients. This article is protected by copyright. All rights reserved.

BACKGROUND Acute kidney injury (AKI) during hospitalization is frequent and associated with adverse outcomes. We have now evaluated the association between renal function recovery after AKI and short-term post-discharge mortality. METHODS This is a retrospective study of all AKI episodes codified in the electronic records of a single center in 2013 and 2014. Epidemiological data and comorbidities at baseline and laboratory values at admission and discharge were collected. Persistent kidney dysfunction after AKI was defined as a last serum creatinine equal or above 1.2-fold over baseline level. Patients were followed for 30 days after discharge. RESULTS Out of 1720 evaluated patients, 1541 (89%) were analyzed. Of them, 869 (56%) recovered renal function. Independent predictors of renal function recovery after AKI were lower baseline estimated glomerular filtration rate (eGFR) (p

Background The association between renal morphological findings and changes in renal function in patients undergoing transcatheter aortic valve implantation (TAVI) is unexplored. Aims We aimed to investigate the association between renal morphological findings and changes in renal function in patients undergoing TAVI. Methods Among 283 consecutive patients undergoing TAVI between 2018 and 2021, the study sample included 224 patients. Renal morphological measurements were performed by preoperative multi-detector computed tomography. Estimated glomerular filtration rate (eGFR) improvement and deterioration were defined as positive or negative changes in an eGFR of ≥10% one month after TAVI. The renal cortex thickness index was defined as the ratio of total renal cortex thickness to body surface area. Results The incidences of eGFR improvement and deterioration were 33.9% and 24.1%, respectively. The renal cortex thickness index had a significant correlation with changes in eGFR (r=0.34, pl0.01). The index of the area under the curve of renal cortex thickness for eGFR improvement and deterioration were 0.73 and 0.68, respectively. The cut-off values were 5.82 mm/m2 for eGFR improvement (odds ratio [OR]: 0.10; 95% confidence interval: 0.05-0.20; pl0.01) and 4.89 mm/m2 for eGFR deterioration (OR: 9.07; 95% confidence interval: 4.55-18.6; pl0.01). Conclusions The renal cortex thickness index was associated with changes in renal function in patients who underwent TAVI. Its measurements might be useful for predicting the renal function change in patients undergoing TAVI.

The association between the estimated glomerular filtration rate (eGFR) and atherosclerotic cardiovascular disease (ASCVD) risk is unknown. We aimed to evaluate whether eGFR can be used as a predictor in ASCVD risk assessment.Using baseline data from 28,187 participants from Shanghai Suburban Adult Cohort and Biobank study, we adopted Pooled Cohort Equations (PCEs) and Prediction for ASCVD Risk in China (China-PAR) to estimate 10-year ASCVD risk. Multivariate logistic regression was used to analyze the relationship between 10-year ASCVD risk and eGFR. The receiver operating characteristic (ROC) curve was used to evaluate predictive value of eGFR for 10-year high ASCVD risk. Compared with normal eGFR, both men and women with reduced eGFR had a higher prevalence of ASCVD risk factors. With the decrease of eGFR level, the median of 10-year ASCVD risk gradually increased. For men, the adjusted odds ratios (95% confidence interval (CI)) of 10-year high ASCVD risk by PCEs associated with eGFR (60-74 and60 mL/min/1.73 meGFR may be an important risk factor in predicting and stratifying ASCVD risk. Consideration should be given to integrating eGFR into existing risk assessment tools to improve predictive performance.

RATIONALE & OBJECTIVE: The utility of conventional upper reference limits (URL) for N-terminal pro brain natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hsTnT) in chronic kidney disease (CKD) remains debated. We analyzed the distribution of hsTnT and NT-proBNP in people with CKD in ambulatory settings to examine the diagnostic value of conventional URL in this population. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: We studied participants of the Chronic Renal Insufficiency Cohort with CKD and no self-reported history of cardiovascular disease (CVD). EXPOSURE: Estimated glomerular filtration rate (eGFR). OUTCOMES: NT-proBNP and hsTnT at baseline. ANALYTICAL APPROACH:. We described the proportion of participants above the conventional URL for NT-proBNP (125 pg/ml) and hsTnT (14 ng/L) overall, and by eGFR. We then estimated 99(th) percentile URL for NT-proBNP and hsTnT. Using quantile regression of the 99(th) percentile, we modeled the association of eGFR with NT-proBNP and hsTnT. RESULTS: Among 2,312 CKD participants, 40% and 43% had levels of NT-proBNP and hsTnT above conventional URL, respectively. In those with eGFR

An increase of glomerular filtration rate (GFR) is a common observation in early diabetes and is considered a key risk factor for subsequent kidney injury. However, the mechanisms underlying diabetic hyperfiltration have not been fully clarified. Here, we tested the hypothesis that macula densa neuronal nitric oxide synthase (NOS1) is upregulated via sodium glucose cotransporter type 1 (SGLT1) in diabetes, which then inhibits tubuloglomerular feedback (TGF) promoting glomerular hyperfiltration. Therefore, we examined changes in cortical NOS1 expression and phosphorylation, nitric oxide production in the macula densa, TGF response, and GFR during the early stage of insulin-deficient (Akita) diabetes in wild-type and macula densa-specific NOS1 knockout mice. A set of sophisticated techniques including microperfusion of juxtaglomerular apparatus in vitro, micropuncture of kidney tubules in vivo, and clearance kinetics of plasma fluorescent-sinistrin were employed. Complementary studies tested the role of SGLT1 in SGLT1 knockout mice and explored NOS1 expression and phosphorylation in kidney biopsies of cadaveric donors. Diabetic mice had upregulated macula densa NOS1, inhibited TGF and elevated GFR. Macula densa-selective NOS1 knockout attenuated the diabetes-induced TGF inhibition and GFR elevation. Additionally, deletion of SGLT1 prevented the upregulation of macula densa NOS1 and attenuated inhibition of TGF in diabetic mice. Furthermore, the expression and phosphorylation levels of NOS1 were increased in cadaveric kidneys of diabetics and positively correlated with blood glucose as well as estimated GFR in the donors. Thus, our findings demonstrate that the macula densa SGLT1-NOS1-TGF pathway plays a crucial role in the control of GFR in diabetes.

Some patients with diabetic kidney disease (DKD) show a fast progression of kidney dysfunction and are known as a "fast decliner" (FD). Therefore, it is critical to understand pathomechanisms specific for fast decline. Here, we performed a comprehensive metabolomic analysis of patients with stage G3 DKD and identified increased urinary lysophosphatidylcholine (LPC) in fast decline. This was confirmed by quantification of urinary LPC using mass spectrometry and identified urinary LPC containing saturated fatty acids palmitic (16:0) and stearic (18:0) acids was increased in FDs. The upsurge in urinary LPC levels was correlated with a decline in estimated glomerular filtration rate after 2.5 years. To clarify a pathogenic role of LPC in FD, we studied an accelerated rat model of DKD and observed an increase in LPC (16:0) and (18:0) levels in the urine and kidney tubulointerstitium as the disease progressed. These findings suggested that local dysregulation of lipid metabolism resulted in excessive accumulation of this LPC species in the kidney. Our in vitro studies also confirmed LPC-mediated lipotoxicity in cultured proximal tubular cells. LPC induced accumulation of lipid droplets via activation of peroxisome proliferator-activated receptor-δ followed by upregulation of the lipid droplet membrane protein perilipin 2 and decreased autophagic flux, thereby inducing organelle stress and subsequent apoptosis. Thus, LPC (16:0) and (18:0) may mediate a fast progression of DKD and may serve as a target for novel therapeutic approaches.

Introduction: Studies have shown that the renin angiotensin aldosterone system (RAAS) and inflammation are related to kidney injury progression. The aim of this study was to evaluate RAAS molecules and chemokine (C-C motif) ligand 2 (CCL2) in 82 patients with chronic kidney disease (CKD). Methods: Patients were divided into two groups: patients diagnosed with CKD and patients without a CKD diagnosis. Glomerular filtration rate (GFR) and albumin/creatinine ratio (ACR) were determined, as well as plasma levels of angiotensin-(1-7) [Ang-(1-7)], angiotensin-converting enzyme (ACE)1, ACE2, and plasma and urinary levels of CCL2. Results: CCL2 plasma levels were significantly higher in patients with CKD compared to the control group. Patients with lower GFR had higher plasma levels of ACE2 and CCL2 and lower ratio ACE1/ACE2. Patients with higher ACR values had higher ACE1 plasma levels. Conclusion: Patients with CKD showed greater activity of both RAAS axes, the classic and alternative, and higher plasma levels of CCL2. Therefore, plasma levels of RAAS molecules and CCL2 seem to be promising prognostic markers and even therapeutic targets for CKD. Resumo Introdução: Estudos têm mostrado que o sistema renina angiotensina aldosterona (SRAA) e a inflamação estão relacionados à progressão da lesão renal. O objetivo deste estudo foi avaliar moléculas do SRAA e o Ligante 2 de Quimiocina com Motivo C-C (CCL2) em 82 pacientes com doença renal crônica (DRC). Métodos: Os pacientes foram divididos em dois grupos: pacientes diagnosticados com DRC e pacientes sem diagnóstico de DRC. Foram determinadas a taxa de filtração glomerular (TFG) e a relação albumina/creatinina (RAC), assim como os níveis plasmáticos de angiotensina-(1-7) [Ang-(1-7)], enzima conversora de angiotensina (ECA)1, ECA2 e níveis plasmáticos e urinários de CCL2. Resultados: Os níveis plasmáticos de CCL2 foram significativamente mais altos em pacientes com DRC em comparação com o grupo controle. Pacientes com TFG mais baixa apresentaram níveis plasmáticos mais elevados de ECA2 e CCL2 e menor relação ECA1/ECA2. Pacientes com valores de RAC mais altos apresentaram níveis plasmáticos de ECA1 mais elevados. Conclusão: Pacientes com DRC mostraram maior atividade de ambos os eixos do SRAA, o clássico e o alternativo, e níveis plasmáticos mais altos de CCL2. Portanto, os níveis plasmáticos de moléculas do SRAA e CCL2 parecem ser marcadores prognósticos promissores e até mesmo alvos terapêuticos para a DRC.

Rationale & objective Current guidelines for nephrology referral are based on laboratory criteria. We sought to evaluate whether nephrology referral patterns reflect current clinical practice guidelines and to estimate the change in referral volume if they were based on the estimated risk of kidney failure. Study design Observational cohort. Setting & participants Retrospective study of 399,644 veterans with chronic kidney disease (October 1, 2015 through September 30, 2016). Exposure Laboratory referral criteria based on Veterans Affairs/Department of Defense guidelines, categories of predicted risk for kidney failure using the Kidney Failure Risk Equation, and the combination of laboratory referral criteria and predicted risk. Outcome Number of patients identified for referral. Analytical approach We evaluated the number of patients who were referred and their predicted 2-year risk for kidney failure. For each exposure, we estimated the number of patients who would be identified for referral. Results There were 66,276 patients who met laboratory indications for referral. Among these patients, 11,752 (17.7%) were referred to nephrology in the following year. The median 2-year predicted risk of kidney failure was 1.5% (interquartile range, 0.3%-4.7%) among all patients meeting the laboratory referral criteria. If referrals were restricted to patients with a predicted risk of ≥1% in addition to laboratory indications, the potential referral volume would be reduced from 66,276 to 38,229 patients. If referrals were based on predicted risk alone, a 2-year risk threshold of 1% or higher would identify a similar number of patients (72,948) as laboratory-based criteria with median predicted risk of 2.3% (interquartile range, 1.4%-4.6%). Limitations Missing proteinuria measurements. Conclusions The current laboratory-based guidelines for nephrology referral identify patients who are, on average, at low risk for progression, most of whom are not referred. As an alternative, referral based on a 2-year kidney failure risk exceeding 1% would identify a similar number of patients but with a higher median risk of kidney failure.

Rationale & objective High anion gap acidosis frequently develops in patients with advanced chronic kidney disease (CKD) and might be involved in kidney injury. Its impact on kidney outcomes, however, has not been well studied. We sought to examine the association between time-updated anion gap and the risk of kidney failure with replacement therapy (KFRT) among patients with advanced CKD. Study design Retrospective cohort study. Setting & participants 1,168 patients with CKD glomerular filtration rate categories 3b-5 (G3b-G5) who had available data on anion gap. Exposure High time-updated anion gap defined as values ≥ 9.2 (top 25th percentile). Outcome KFRT and death. Analytical approach Marginal structural models were fit to characterize the association between anion gap and study outcomes while accounting for potential time-dependent confounding. Results The mean baseline estimated glomerular filtration rate (eGFR) of the study participants was 28 mL/min/1.73 m2. Over a median follow-up period of 3.1 years, 317 patients progressed to KFRT (7.5 per 100 patient-years), and 146 died (3.5 per 100 patient-years). In the marginal structural models, a high anion gap was associated with a higher rate of KFRT (HR, 3.04 [95% CI, 1.94-4.75]; P Limitations Observational study design and selection bias due clinical indications for measuring anion gap. Conclusions Among patients with advanced CKD, high anion gap was associated with an increased risk of progression to KFRT and death.

Uremic symptoms are common in patients with advanced chronic kidney disease, but the toxins that cause these symptoms are unknown. To evaluate this, we performed a cross-sectional study of the 12 month post-randomization follow-up visit of Modification of Diet in Renal Disease (MDRD) participants reporting uremic symptoms who also had available stored serum. We quantified 1,163 metabolites by liquid chromatography-tandem mass spectrometry. For each uremic symptom, we calculated a score as the severity multiplied by the number of days the symptom was experienced. We analyzed the associations of the individual symptom scores with metabolites using linear models with empirical Bayesian inference, adjusted for multiple comparisons. Among 695 participants, the mean measured glomerular filtration rate (mGFR) was 28 mL/min/1.73 m(2). Uremic symptoms were more common in the subgroup of 214 patients with an mGFR under 20 mL/min/1.73 m(2) (mGFR under 20 subgroup) than in the full group. For all metabolites with significant associations, the direction of the association was concordant in the full group and the subgroup. For gastrointestinal symptoms (bad taste, loss of appetite, nausea, and vomiting), eleven metabolites were associated with symptoms. For neurologic symptoms (decreased alertness, falling asleep during the day, forgetfulness, lack of pep and energy, tiring easily/weakness), seven metabolites were associated with symptoms. Associations were consistent across sensitivity analyses. Thus, our proof of principle study demonstrates the potential for metabolomics to understand metabolic pathways associated with uremic symptoms. Larger, prospective studies with external validation are needed.

Background and aim Three vessels disease (3VD) has been associated with worse prognosis and higher mortality. Chronic kidney disease (CKD) is an independent risk factor for premature death, mostly due to coronary artery disease (CAD). We aim to examine the prognostic impact of 3VD on all-cause mortality in a cohort of high cardiovascular risk subjects undergoing coronary angiography (CA) and to explore whether low eGFR ( Methods and results One-thousand-seventeen subjects (759M, mean age 68.4 + 11 years) consecutive subjects undergoing CA from 2016 to 2018 were evaluated. Subjects were classified according to the severity of CAD as follows: group “three vessels disease” (3VD), and “no three vessels disease” (No 3VD). Serum creatinine was measured to estimate glomerular filtration rate (eGFR). The whole population was divided into 4 groups (A, B, C, D), according to the presence/absence of low eGFR and/or 3VD. One-hundred-fourteen deaths occurred (median follow-up:44 months). The risk of death in subjects with 3VD was almost 2-time higher than subject without 3VD (adjusted HR= 1.61; 95% CI 1.094-2.373, p= 0.0157). Among 4 subgroups, subjects with low eGFR and 3VD (Group D) had the highest risk of death (adjusted HR=3.881; 95% CI 2.256-6.676, p Conclusions Low eGFR significantly amplifies the risk of all-cause mortality associated to 3VD. Our results strengthen the role of kidney disease as a risk multiplier for cardiovascular and all-cause mortality and highlight the need to prevent its onset and progression.

Qualitative and quantitative measurement of urine protein excretion is one of the most common tests performed during pregnancy. For more than 100 years, proteinuria was necessary for the diagnosis of preeclampsia, but recent guidelines recommend that proteinuria is sufficient but not necessary for the diagnosis. Still, in clinical practice, most patients with gestational hypertension will be diagnosed as having preeclampsia based on the presence of proteinuria. Although the reference standard for measuring urinary protein excretion is a 24-hour urine collection, spot urine protein-to-creatinine ratio is a reasonable "rule-out" test for proteinuria. Urine dipstick screening for proteinuria does not provide any clinical benefit and should not be used to diagnose proteinuria. The classic cutoff cited to define proteinuria during pregnancy is a value of >300 mg/24 hours or a urine protein-to-creatinine ratio of at least 0.3. Using this cutoff, the rate of isolated proteinuria in pregnancy may reach 8%, whereas preeclampsia occurs among 3% to 8% of pregnancies. Although this threshold is widely accepted, its origin is not based on evidence on adverse pregnancy outcomes but rather on expert opinion and results of small studies. After reviewing the available data, the most important factor that influences maternal and neonatal outcome is the severity of blood pressures and presence of end organ damage, rather than the excess protein excretion. Because the management of gestational hypertension and preeclampsia without severe features is almost identical in frequency of surveillance and timing of delivery, the separation into 2 disorders is unnecessary. If the management of women with gestational hypertension with a positive assessment of proteinuria will not change, we believe that urine assessment for proteinuria is unnecessary in women who develop new-onset blood pressure at or after 20 weeks' gestation. Furthermore, we do not recommend repeated measurement of proteinuria for women with preeclampsia, the amount of proteinuria does not seem to be related to poor maternal and neonatal outcomes, and monitoring proteinuria may lead to unindicated preterm deliveries and related neonatal complications. Our current diagnosis of preeclampsia in women with chronic kidney disease may be based on a change in protein excretion, a baseline protein excretion evaluation is critical in certain conditions such as chronic hypertension, diabetes, and autoimmune or other renal disorders. The current definition of superimposed preeclampsia possesses a diagnostic dilemma, and it is unclear whether a change in the baseline proteinuria reflects another systemic disease such as preeclampsia or whether women with chronic disease such as chronic hypertension or diabetes will experience a different "normal" pattern of protein excretion during pregnancy. Finally, limited data are available regarding angiogenic and other biomarkers in women with chronic kidney disease as a potential aid in distinguishing the worsening of baseline chronic kidney disease and chronic hypertension from superimposed preeclampsia.

OBJECTIVE To evaluate the association between preoperative statin use with changes in estimated glomerular filtration rate (eGFR) following robotic-assisted partial nephrectomy (RAPN). METHODS 389 consecutive patients undergoing RAPN were evaluated. Associations of preoperative statin use with change in eGFR from pre-RAPN to POD1, 1 month, 6 months, and 12 months after RAPN were evaluated using longitudinal mixed-effects regression models with random patient-specific intercepts and slopes while accounting for imbalance of preoperative patient and tumor characteristics between groups with stabilized inverse propensity score weighting. Post-operative eGFR change from baseline was measured as total change, maintaining eGFR within 10% of baseline, and as going from eGFR > 60 ml/min/1.73m2 to < 60 ml/min/1.73m2. RESULTS 167 (43.0%) of 389 patients were on statin therapy preoperatively. Statin patients were older (66 vs. 58 years old) and had higher rates of comorbidities including diabetes mellitus (31.7% vs. 14.9%) and hypertension (82.6% vs. 45%). Statin patients tended to have lower preoperative eGFR (mean±SD, 71.1±17.6 vs. 77.4±19.4 ml/min/1.73m2). There was no evidence of an association of preoperative statin use with changes in eGFR at any time point following RAPN (P=0.66). CONCLUSION Patients on pre-operative statins undergoing RAPN had lower eGFR preoperatively compared to those not taking those medications. There was no evidence of an association between preoperative statin use and change in post-RAPN eGFR in the immediate post-operative period or at 1 year following surgery.

Background: Individuals with chronic kidney disease (CKD) have a high burden of cardiovascular disease (CVD). Abnormalities in cardiac structure and function represent subclinical CVD and can be assessed by cardiac magnetic resonance imaging (cMRI). Methods: We investigated differences in cMRI parameters in 140 individuals with CKD stages 3b-4 who participated in the CKD Optimal Management with BInders and NicotinamidE (COMBINE) trial and in 24 age-and sex matched healthy volunteers. Among COMBINE participants, we examined the associations of estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (UACR), phosphate, fibroblast growth factor 23 (FGF23), and parathyroid hormone (PTH) with baseline (N=140) and 12-month change (N=112) in cMRI parameters. Results: Mean (standard deviation [SD]) age of the COMBINE participants and healthy volunteers were 64.9 (11.9) and 60.4 (7.3) years. The mean (SD) baseline eGFR in COMBINE participants was 32.1 (8.0) and 85.9 (16.0) ml/ min/1.73m2 in healthy volunteers. The median (interquartile range [IQR]) UACR in COMBINE participants was 154 (20.3 - 540.0) mg/g. Individuals with CKD had lower mitral valve E/A ratio compared to healthy volunteers (β estimate -0.13 CKD vs. non-CKD, 95% confidence interval [CI] -0.24, -0.012). Among COMBINE participants, multivariable linear regression analyses showed that higher UACR was significantly associated with lower mitral valve E/A ratio (β-estimate per 1 unit increase in natural log UACR -0.06, 95% CI -0.09, -0.03). This finding was preserved among individuals without baseline CVD. UACR was not associated with 12-month change in any cMRI parameter. eGFR, phosphate, FGF23, and PTH were not associated with any cMRI parameter in cross-sectional or change analyses. Conclusions: Individuals with CKD stages 3b-4 have evidence of cMRI abnormalities. Albuminuria was independently associated with diastolic dysfunction assessed by mitral valve E/A ratio in individuals with CKD with and without clinical CVD, but was not associated with change in any cMRI parameter.

Acute kidney injury (AKI) is a common complication after cardiac surgery (CS). Because a therapeutic regimen remains scarce, the early implementation of preventive strategies is crucial. The authors investigated risk factors and the typical clinical course of CS-associated AKI (CS-AKI) to derive strategies for perioperative clinical routines.Retrospective data analysis.The data were collected from clinical routines in a maximum care university hospital.Patients.The authors retrospectively analyzed data from 538 patients who underwent CS.The median age of the 466 patients included was 66.6 years; 65.7% were men. AKI occurred in 131 (28.1%) patients, mainly (89.0%) starting postoperatively within 72 hours p. Thirty-one (6.7%) patients showed Kidney Disease Improving Global Outcome AKI stage 3. AKI was significantly more frequent in patients with chronic kidney disease (p0.001), emergency admission (p0.001), heart failure (p0.001), and postoperative complications (p0.001). In a multivariate analysis, postoperative CS-AKI risk significantly decreased with each 1 or 10 mL/min preoperative glomerular filtration rate (GFR) (odds ratio, 0.962 and 0.677; 95% confidence interval, 0.947-0.977 and 0.577-0.793; p0.001 and p0.0001). Only in patients who developed Kidney Disease Improving Global Outcome AKI stage 3, an early postoperative trend to decreased GFR and increased creatinine levels was observed.Especially in patients with preexisting CKD and signs of CS-AKI occurring on the day of surgery, close monitoring of renal function should be performed for at least 72 hours after CS to detect an onset of AKI early and initiate renal protective strategies. Optimal preoperative fluid management might prevent postoperative AKI.

Background: Acute changes in glomerular filtration rate (GFR) can occur following initiation of interventions for chronic kidney disease (CKD) progression. These complicate the interpretation of treatment effects on long term progression of (CKD). We sought to assess the magnitude and consistency of acute effects in randomized clinical trials (RCT) and explore factors that might impact them. Methods: We performed a meta-analysis of 53 RCTs for CKD progression enrolling 56,413 participants that had at least one estimated GFR measurement by six months following randomization. We defined acute treatment effects as the mean difference in GFR slope from baseline to 3 months between randomized groups. We performed univariable and multivariable meta-regression to assess the impact of intervention type, disease state, baseline GFR and albuminuria on the magnitude of acute effects. Results: The mean acute effect across all studies was -0.21 mL/min/1.73m2 (95% CI -0.63 to 0.22) over three months, with substantial heterogeneity across interventions (95% coverage interval across studies, -2.50 to +2.08 mL/min/1.73m2). Negative average acute effects were observed in renin angiotensin system blockade, blood pressure lowering and sodium-glucose cotransporter 2 inhibitor trials while positive acute effects were observed in trials of immunosuppressive agents. Larger negative acute effects were observed in trials with higher mean baseline GFR. Conclusion: The magnitude and consistency of acute GFR effects varies across different interventions, and is larger at higher baseline GFR. Understanding the nature and magnitude of the acute effects can help inform the optimal design of RCTs in CKD evaluating kidney disease progression.

High‐dose methotrexate (HDMTX) pharmacokinetics (PKs), including the best estimated glomerular filtration rate (eGFR) equation that reflects methotrexate (MTX) clearance, requires investigation. This prospective, observational, single‐center study evaluated adult patients with lymphoma treated with HDMTX. Samples were collected at predefined time points up to 96 h postinfusion. MTX and 7‐hydroxy‐MTX PKs were estimated by standard noncompartmental analysis. Linear regression determined which serum creatinine‐ or cystatin C‐based eGFR equation best predicted MTX clearance. The 80 included patients had a median (interquartile range [IQR]) age of 68.6 years (IQR 59.2–75.6), 54 (67.5%) were men, and 74 (92.5%) were White. The median (IQR) dose of MTX was 7.6 (IQR 4.8–11.3) grams. Median clearance was similar across three dosing levels at 4.5–5.6 L/h and was consistent with linear PKs. Liver function, weight, age, sex, concomitant chemotherapy, and number of previous MTX doses did not impact clearance. MTX area under the curve (AUC) values varied over a fourfold range and appeared to increase in proportion to the dose. The eGFRcys (ml/min) equation most closely correlated with MTX clearance in both the entire cohort and after excluding outlier MTX clearance values (r = 0.31 and 0.51, respectively). HDMTX as a 4‐h infusion displays high interpatient pharmacokinetic variability. Population PK modeling to optimize MTX AUC attainment requires further evaluation. The cystatin C‐based eGFR equation most closely estimated MTX clearance and should be investigated for dosing and monitoring in adults requiring MTX as part of lymphoma management.

Metformin treatment improved ADPKD disease severity in a relevant, slowly progressive ADPKD mouse model that recapitulates a PKD-associated PKD1 mutation. Relative to controls, metformin reduced kidney weight/body weight, cystic index and BUN levels, while improving GFR, blood pressure and anemia. Metformin also reduced key inflammatory and injury markers, along with cell proliferation markers. These findings suggest several beneficial effects of metformin in this ADPKD mouse model, which may help inform new ADPKD therapies in patients.

Galectin-3 (Gal-3) is a biomarker involved in fibrosis and vascular inflammation. Gal-3 has been linked to chronic kidney disease (CKD) and patients with peripheral artery disease (PAD). Conflicting reports exist about the relevance of Gal-3 in PAD. The study aims to elucidate a possible link between serum and urinary Gal-3 and long-term survival in PAD patients without critical limb ischemia and mild to moderate CKD.Galectin-3 (Gal-3) was measured in serum (n = 311) and urine (n = 266) of PAD patients (age 69 (62-77) years) by bead-based multiplex assay. Urinary Gal-3 concentration was normalized to urine creatinine (cr) levels. Mortality data were retrieved from the Austrian central death registry after a median observation period of 9.2 years. Survival analyses were performed by the Kaplan-Meier method and Cox-regression.Serum Gal-3 was higher in patients with claudication symptoms (p = 0.001) and correlated inversely with the patients' ankle-brachial index (R = -0.168, p = 0.009). Serum Gal-3 and urinary Gal-3 (uGal-3/cr) were associated with the estimated glomerular filtration rate (R = -0.359, p 0.001; R = -0.285, p 0.001). Serum Gal-3 was not linked to all-cause mortality [HR 1.17 (CI 0.96-1.42)] over 9.2 years. However, uGal-3/cr was associated with all-cause mortality [HR 1.60 (CI 1.31-1.95)]. This association sustained multivariable adjustment for cardiovascular risk factors and renal function [HR 1.71 (CI 1.35-2.17)].This study is the first to show an association of uGal-3/cr and long-term mortality in patients with PAD. Gal-3 was not predictive of long-term mortality but seems to be a marker of PAD severity in patients without critical limb ischemia.

The clinical research on BH4 is limited because of the difficulties on its measurement. In this study, we used our own established LC-MS/MS method to examine the plasma BH4 levels in diabetes to determine whether it could be used as a biomarker for the prediction of kidney injury in those patients.Hospitalized diabetes patients in Renmin Hospital of Wuhan University from Jan to Aug 2021 were recruited. To assess the association between plasma BH4 with ACR or eGFR in diabetes, a total of 142 patients with type 2 diabetes (T2DM) were enrolled. They were divided into three groups by albuminuria levels: normoalbuminuria (n = 68), microalbuminuria (n = 48), and macroalbuminuria (n = 26) according to ACR; or into two groups by eGFR: eGFR≥90 or eGFR90 ml/min for correlation and logistic regression analysis. Plasma BH4 level was measured by LC-MS/MS along with other biochemical indices.Plasma BH4 concentrations were decreased as ACR progressed. BH4 (r = -0.55, P 0.001) and 2h C-Peptide (CP-2h) (r = -0.248, P = 0.003) levels were negatively correlated with ACR. Moreover, multivariable logistic regression analysis showed BH4 concentrations (B = -0.468, P 0.001) and CP-2h (B = -0.257, P = 0.028) were independently associated with ACR progression. ROC curve showed that BH4 level has a predictive value on ACR (95%CI 0.686-0.841, sensitivity 69.1%, specificity 73%). Moreover, in diabetes patients with eGFR≥90 ml/min, plasma BH4 level (P = 0.008) is higher than those in diabetes with eGFR90 ml/min and BH4 was remained independently associated with eGFR after multivariable logistic regression analysis (B = -0.193, P = 0.048).Our established LC-MS/MS method could be used on human plasma BH4 measurements and our data suggested that BH4 level can be used as a biomarker for kidney injury in diabetes indicated by its association with ACR progression and early renal function decline.

Aims/Introduction The sodium–glucose cotransporter 2 inhibitor, canagliflozin, reduced kidney failure and cardiovascular events in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial. We carried out a post‐hoc analysis to evaluate the efficacy and safety of canagliflozin in a subgroup of participants in East and South‐East Asian (EA) countries who are at high risk of renal complications. Materials and Methods Participants with an estimated glomerular filtration rate of 30 to 300–5,000 mg/g were randomized to 100 mg of canagliflozin or a placebo. The effects of canagliflozin treatment on pre‐specified efficacy and safety outcomes were examined using Cox proportional hazards regression between participants from EA countries (China, Japan, Malaysia, the Philippines, South Korea and Taiwan) and the remaining participants. Results Of 4,401 participants, 604 (13.7%) were from EA countries; 301 and 303 were assigned to the canagliflozin and placebo groups, respectively. Canagliflozin lowered the risk of primary outcome (composite of end‐stage kidney disease, doubling of serum creatinine level, or renal or cardiovascular death) in EA participants (hazard ratio 0.54, 95% confidence interval 0.35–0.84). The effects of canagliflozin on renal and cardiovascular outcomes in EA participants were generally similar to those of the remaining participants. Safety outcomes were similar between the EA and non‐EA participants. Conclusions In the CREDENCE trial, the risk of renal and cardiovascular events was safely reduced in participants from EA countries at high risk of renal events., A post‐hoc analysis was carried out to evaluate the efficacy and safety of canagliflozin in a subgroup of participants in East and South‐East Asian countries in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial. Canagliflozin lowered the risk of primary composite outcome (composite of end‐stage kidney disease, doubling of serum creatinine level, or death from renal or cardiovascular causes) in East and South‐East Asian participants (hazard ratio 0.54, 95% confidence interval 0.35–0.84). Canagliflozin safely reduced the risk of renal and cardiovascular events in participants from East and South‐East Asian countries at high risk of renal events.

Kidney dysfunction can profoundly influence many organ systems, and recent evidence suggests a potential role for increased albuminuria in the development of mild cognitive impairment (MCI) or dementia. Epidemiological studies conducted in different populations have demonstrated that the presence of increased albuminuria is associated with a higher relative risk of MCI or dementia both in cross-sectional analyses and in studies with long-term follow-up. The underlying pathophysiological mechanisms of albuminuria’s effect are as yet insufficiently studied, with several important knowledge gaps still present in a complex relationship with other MCI and dementia risk factors. Both the kidney and the brain have microvascular similarities that make them sensitive to endothelial dysfunction involving different mechanisms, including oxidative stress and inflammation. The exact substrate of MCI and dementia is still under investigation, however available experimental data indicate that elevated albuminuria and low glomerular filtration rate are associated with significant neuroanatomical declines in hippocampal function and grey matter volume. Thus, albuminuria may be critical in the development of cognitive impairment and its progression to dementia. In this review, we summarize the available evidence on albuminuria’s link to MCI and dementia, point to existing gaps in our knowledge and suggest actions to overcome them. The major question of whether interventions that target increased albuminuria could prevent cognitive decline remains unanswered. Our recommendations for future research are aimed at helping to plan clinical trials and to solve the complex conundrum outlined in this review, with the ultimate goal of improving the lives of patients with chronic kidney disease., Graphical Abstract Graphical Abstract

Introduction Women with advanced kidney disease are advised to wait until after transplant to pursue pregnancy, but the impact of pregnancy on estimated glomerular filtration rate (eGFR) decline and kidney histology is unclear. Methods We identified a cohort of women aged 18 to 44 years at transplant from 1996 to 2014 at our 3-site program (N = 816) and determined whether they had a pregnancy >20 weeks gestation post-transplant by chart review. Outcomes included rate of change in eGFR after pregnancy, changes in kidney histology before and after pregnancy, graft failure, and 50% reduction in eGFR. Results There were 37 women with one or more pregnancies lasting longer than 20 weeks gestation post-transplant. Comparing women with and without pregnancy post-transplant, there was a significant increase in the rate of eGFR decline after pregnancy (−2.4 ml/min per 1.73 m2 per year vs. −1.9 ml/min per 1.73 m2 per year in women with no pregnancy, P < 0.001). Pregnancy did not affect the risk of graft failure, death-censored graft failure, or 50% reduction in eGFR. Conclusion Pregnancy affects the rate of eGFR decline in the allograft. Postpregnancy biopsy findings revealed an increase in vascular injury, which could be a potential mechanism. We did not find a significant increase in risk of graft failure or reduction in eGFR by 50% owing to pregnancy., Graphical abstract

Chronic kidney disease (CKD) is an important health issue that affects ~ 9.1% of the world adult population. Serum creatinine is the most commonly used biomarker for assessing kidney function and is utilized in different equations for estimating creatinine clearance or glomerular filtration rate (GFR). The Cockcroft-Gault formula for adults and "original" Schwartz formula for children have been the most commonly used equations for estimating kidney function during the last 3-4 decades. Introduction of standardized serum creatinine bioanalytical methodology has reduced interlaboratory variability but is not intended to be used with Cockcroft-Gault or original Schwartz equations. More accurate equations (for instance, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) for adults and bedside Schwartz or Chronic Kidney Disease in Children Schwartz equation for children) based on standardized serum creatinine values (and another biomarker-cystatin C) have been introduced and validated in recent years. Recently, the CKD-EPI equation refitted without a race variable was introduced. Clinical practice guidance in nephrology advocates a shift to these equations for managing health care of patients with CKD. The guidance also recommends use of albuminuria in addition to GFR for CKD diagnosis and management. Significant research with large data sets would be necessary to evaluate whether this paradigm would also be valuable in drug dose adjustments. This article attempts to highlight some important advancements in the field from a clinical pharmacology perspective and is a call to action to industry, regulators, and academia to rethink the current paradigm for assessing kidney function to enable dose recommendation in patients with CKD.

Many kidney donor candidates with impaired fasting glucose (IFG) and all candidates with diabetes are currently excluded from kidney donation, fearing the development of an accelerated course of diabetic kidney disease in the remaining kidney.We studied mortality, proteinuria, and end-stage kidney disease (ESKD) in 8280 donors who donated between 1963 and 2007 according to donation fasting plasma glucose (FPG):100 mg/dL (n = 6204), 100-125 mg/dL (n = 1826), and ≥126 mg/dL (n = 250).Donors with IFG and those with FPG ≥126 mg/dL were older, less likely to be non-Hispanic White, had a higher body mass index, and were more likely to be related to their recipient. After 15.7 ± 10.5 y from donation to study close, 4.4% died, 29.4% developed hypertension, 13.8% developed proteinuria, and 41 (0.5%) developed ESKD. In both the logistic and Cox models, IFG was associated with a higher diabetes risk (adjusted hazard ratio [aHR], 1.65; 95% confidence interval [CI], 1.18-2.30) and hypertension (aHR, 1.35; 95% CI, 1.10-1.65; P = 0.003 for both), but not higher risk of proteinuria or ESKD. The multivariable risk of mortality in donors with ≥126 mg/dL was higher than the 2 other groups, but risks of proteinuria, cardiovascular disease, and reduced estimated glomerular filtration rate were similar to those with FPG126 mg/dL. Three cases of ESKD developed in the 250 donors with FPG ≥126 mg/dL at 18.6 ± 10.3 y after donation (aHR, 5.36; 95% CI, 1.0-27.01; P = 0.04).Donors with IFG and the majority of donors with ≥126 mg/dL do well and perhaps should not be routinely excluded from donation.

Background Physiologically regulated insulin secretion and euglycemia are achievable in type 1 diabetes (T1D) by islet or pancreas transplantation. However, pancreas transplant alone (PTA) remains a debated approach, with uncertainties on its relative benefits and risks. We determined the actual long-term (10 years) efficacy and safety of PTA in carefully characterized T1D subjects. Methods This is a single-centre, cohort study in 66 consecutive T1D subjects who received a PTA between April 2001 and December 2007, and were then all followed until 10 years since transplant. Main features evaluated were patient survival, pancreas graft function, C-peptide levels, glycemic parameters, and the function of the native kidneys. Results Ten-year actual patient survival was 92.4%. Optimal (insulin-independence) or good (minimal insulin requirement) graft function was observed in 57.4 and 3.2% of patients, respectively. Six (9.0%) patients developed stage 5 or 4 chronic kidney disease. In the remaining individuals bearing a successful PTA, eGFR decline per year was -2.29±2.69 ml/min/1.73m. Reduction of eGFR at 1 year post-PTA was higher in those with pre-PTA hyperfiltration and higher HbA1c concentrations; eGFR changes afterwards significantly correlated with diabetes duration. In recipients with normoglycemia at 10 years, 74% of normo- or micro-albuminuric subjects pre-PTA remained stable, and 26% progressed towards a worse stage; conversely, in 62.5% of the macro-albuminuric individuals albuminuria severity regressed. Conclusions These long-term effects of PTA on patient survival, graft function and the native kidneys support PTA as a suitable approach to treat diabetes in selected T1D patients.

With the increased incidence and survival of lung transplant (LTx) recipients, the risk for chronic sequelae such as chronic kidney disease (CKD) is on the rise. Data on the long-term renal outcome are scarce. We performed a retrospective chart review of 171 adults with LTx from January 1, 2014, to January 1, 2019. Primary outcomes were prevalence of CKD/end-stage renal disease, acute kidney injury (AKI) as a risk factor for future CKD, and all-cause mortality in recipients with CKD compared with the non-CKD group. Secondary outcomes were frequency of utilization of modalities for CKD (urinalysis, imaging, biopsy, nephrology consultations). Baseline median creatinine and estimated glomerular filtration rate (eGFR) were 0.8 mg/dL and 90 mL/min/1.73 m2, respectively. Of the participants, 60% (96 of 161), 67% (102 of 153), 79% (37 of 47), 86% (10 of 12) had CKD at the end of 6, 12, 36, and 60 months, respectively, and 16% were on dialysis at the end of the study period; 3% received a subsequent renal transplant, and 27% mortality was noted over a 5-year follow-up period. The odds of CKD development in patients with an AKI during index hospitalization vs no AKI was 6.22 (2.87 to 13.06, P

Glutaric aciduria type I (GA-I, OMIM # 231670 ) is an autosomal recessive inborn error of metabolism caused by deficiency of the mitochondrial enzyme glutaryl-CoA dehydrogenase (GCDH). The principal clinical manifestation in GA-I patients is striatal injury most often triggered by catabolic stress. Early diagnosis by newborn screening programs improved survival and reduced striatal damage in GA-I patients. However, the clinical phenotype is still evolving in the aging patient population. Evaluation of long-term outcome in GA-I patients recently identified glomerular filtration rate (GFR) decline with increasing age. We recently created the first knock-in rat model for GA-I harboring the mutation p.R411W (c.1231 C>T), corresponding to the most frequent GCDH human mutation p.R402W. In this study, we evaluated the effect of an acute metabolic stress in form of high lysine diet (HLD) on young Gcdhki/ki rats. We further studied the chronic effect of GCDH deficiency on kidney function in a longitudinal study on a cohort of Gcdhki/ki rats by repetitive 68Ga-EDTA positron emission tomography (PET) renography, biochemical and histological analyses. In young Gcdhki/ki rats exposed to HLD, we observed a GFR decline and biochemical signs of a tubulopathy. Histological analyses revealed lipophilic vacuoles, thinning of apical brush border membranes and increased numbers of mitochondria in proximal tubular (PT) cells. HLD also altered OXPHOS activities and proteome in kidneys of Gcdhki/ki rats. In the longitudinal cohort, we showed a progressive GFR decline in Gcdhki/ki rats starting at young adult age and a decline of renal clearance. Histopathological analyses in aged Gcdhki/ki rats revealed tubular dilatation, protein accumulation in PT cells and mononuclear infiltrations. These observations confirm that GA-I leads to acute and chronic renal damage. This raises questions on indication for follow-up on kidney function in GA-I patients and possible therapeutic interventions to avoid renal damage.

Background: Epidemiological studies have suggested that elevated serum uric acid may contribute to the progression of chronic kidney disease. However, no large prospective study has examined whether hyperuricemia is an independent risk factor for the progression of autosomal dominant polycystic kidney disease (ADPKD). Methods: We measured uric acid in stored serum samples from the 2-year study visit of 671 participants from the HALT PKD multicenter trials. Participants were categorized according to uric acid tertiles. For Study A (participants aged 15-49 years with preserved kidney function, n=350), we used linear mixed effects models to examine the association between uric acid and repeated measures of height-adjusted total kidney volume (htTKV), the primary outcome for Study A. For Study B (participants aged 18-64 with decreased kidney function, n=321), we used Cox proportional hazards models to assess the hazard for the combined endpoint of 50% loss in estimated glomerular filtration rate (eGFR), end-stage kidney disease (ESKD), or death, the primary outcome for Study B. To assess the association of uric acid with the slope of eGFR decline (secondary outcome of HALT A and B), we used linear mixed effects models for the combined population of Study A and B. Results: In the unadjusted model, the annual change in htTKV was 2.7% higher in the highest uric acid tertile compared to the lowest (p Conclusion: Elevated serum uric acid is not an independent risk factor for disease progression in ADPKD.

Magnesium is involved in the regulation of blood pressure (BP). Abnormalities in serum magnesium are common in chronic kidney disease (CKD), yet its association with the development of hypertension and CKD progression in patients with CKD is unclear. We analyzed data from 3866 participants from the CRIC Study (Chronic Renal Insufficiency Cohort). Linear regression assessed the association of serum magnesium with baseline systolic BP (SBP) and diastolic BP (DBP). Logistic regression explored the association of serum magnesium with various definitions of hypertension. Cox proportional hazards models explored assessed the risk of incident hypertension and CKD progression. Mean serum magnesium was 2.0 mEq/L (±0.3 mEq/L). Higher magnesium was associated with lower SBP (−3.4 mm Hg [95% CI, −5.8 to −1.0 per 1 mEq/L]) and lower DBP (−2.9 mm Hg [95% CI, −4.3 to −1.5 per 1 mEq/L]). Higher magnesium was associated with a lower risk of American Heart Association–defined hypertension (SBP≥130 mm Hg or DBP≥80 mm Hg) at baseline (adjusted hazard ratio, 0.65 [95% CI, 0.49–0.86 per 1 mEq/L]), a lower risk of suboptimally controlled BP (SBP≥120 mm Hg or DBP≥80 mm Hg; adjusted odds ratio, 0.58 [95% CI, 0.43–0.78 per 1 mEq/L]). In time-to-event analyses, higher baseline serum magnesium was associated with a nominally lower risk of incident CRIC-defined hypertension (adjusted hazard ratio, 0.77 [95% CI, 0.46–1.31 per 1 mEq/L]). Higher magnesium was associated with a significantly lower risk of CKD progression (adjusted hazard ratio, 0.68 [95% CI, 0.54–0.86 per 1 mEq/L]). In patients with CKD, higher serum magnesium is associated with lower SBP and DBP, and with a lower risk of hypertension and CKD progression. In patients with CKD, whether magnesium supplementation could optimize BP control and prevent disease progression deserves further investigation.

UMOD variants associated with higher levels of urinary uromodulin (uUMOD) increase the risk of chronic kidney disease (CKD) and hypertension. However, uUMOD levels also reflect functional kidney tubular mass in observational studies, questioning the causal link between uromodulin production and kidney damage. We used Mendelian randomization to clarify causality between uUMOD levels, kidney function and blood pressure in individuals of European descent. The link between uUMOD and estimated glomerular filtration rate (eGFR) was first investigated in a population-based cohort of 3851 individuals. In observational data, higher uUMOD associated with higher eGFR. Conversely, when using rs12917707 (an UMOD polymorphism) as an instrumental variable in one-sample Mendelian randomization, higher uUMOD strongly associated with eGFR decline. We next applied two-sample Mendelian randomization on four genome wide association study consortia to explore causal links between uUMOD and eGFR, CKD risk (567,460 individuals) and blood pressure (757,461 individuals). Higher uUMOD levels significantly associated with lower eGFR, higher odds for eGFR decline or CKD, and higher systolic or diastolic blood pressure. Each one standard deviation (SD) increase of uUMOD decreased log-transformed eGFR by -0.15 SD (95% confidence interval -0.17 to -0.13) and increased log-odds CKD by 0.13 SD (0.12 to 0.15). One SD increase of uUMOD increased systolic blood pressure by 0.06 SD (0.03 to 0.09) and diastolic blood pressure by 0.08 SD (0.05 to 0.12). The effect of uUMOD on blood pressure was mediated by eGFR, whereas the effect on eGFR was not mediated by blood pressure. Thus, our data support that genetically driven levels of uromodulin have a direct, causal and adverse effect on kidney function outcome in the general population, not mediated by blood pressure.

Backgrounds: Metabolic syndrome is a subclinical status in promoting atherosclerotic cardiovascular disease and type 2 diabetes mellitus. The significance of metabolic syndrome and pathophysiology in chronic kidney disease is not investigated. Methods: We enrolled adult patients with CKD stages 3 to 5 from December 2006 to December 2007. Metabolic syndrome was defined by the US National Cholesterol Education Programme Adult Treatment Panel III guidelines. Plasma levels of angiogenic growth factors were measured. Univariate and multivariate logistic regression analyses were used. Results: Total 451 patients were analyzed with median estimated glomerular filtration rate of 27.0 ml/min per 1.73m2 (interquartile range 14.3–41.3). Patients with metabolic syndrome were older (P = 0.002), had higher percentage using diuretics (P = 0.002) but lower percentage using pentoxifylline (P = 0.017). Patients with metabolic syndrome had higher levels of high-sensitivity C-reactive protein (P < 0.0001), uric acid (P = 0.009) and angiopoietin-2 (P = 0.001). Multivariate logistic regression analyses revealed significant association between plasma levels of angiopoietin-2 and metabolic syndrome (P = 0.042). Conclusion: The prevalence of metabolic syndrome in advanced CKD was higher than general population. CKD patients with metabolic syndrome had higher levels of high-sensitivity C-reactive protein, uric acid and angiopoietin-2. Plasma levels of angiopoietin-2 were significantly associated with metabolic syndrome in patients with CKD. Metabolic syndrome in CKD may be not only a prognostic factor but also an interventional target, possibly through ameliorating inflammation. Prospective and interventional studies are necessary to establish the pathophysiology.

Aims Cardiac resynchronization therapy (CRT) in appropriately selected patients with heart failure improves symptoms and survival. It is necessary to correctly identify patients who will benefit most from this therapy. We aimed to assess the predictive power of the multidisciplinary team's clinical judgement in the short‐term death after CRT implantation. Methods and results Patients with heart failure and referred for the first CRT implant were prospectively included. Prior to implantation, all patients underwent a systematic assessment with a team composed of social work, nurse, psychologist, nutritionist, and clinical cardiologist. Based on this assessment, patients could be contraindicated to CRT or referred to the procedure as favourable or unfavourable. All patients should complete 12 months of follow‐up; 172 patients were referred for CRT, 21 (12.2%) were contraindicated after the multidisciplinary team evaluation, 71 (47%) referred to CRT as non‐favourable implants, and 80 (53%) as favourable implants. All‐cause mortality occurred in only 2 (2.5%) patients in the favourable group and in 30 (42.3%) in the non‐favourable group, P

Rationale & Objective: Although patients with chronic kidney disease (CKD) are at risk for work disability and loss of employment, not all experience work disruption. We aimed to describe the barriers to and facilitators of sustained employment experienced by Dutch patients with CKD.Study Design: Qualitative study using semi-structured interviews.Setting & Participants: 27 patients with CKD glomerular filtration rate categories 3b-5 (G3b-G5) from 4 nephrology outpatient clinics in The Netherlands.Analytical Approach: Content analyses with constant comparison of interview data based on the International Classification of Functioning, Disability and Health framework.Results: Participants were 6 patients with CKD G3b-G4, 8 patients receiving maintenance dialysis, and 13 patients with functioning kidney transplants. We identified health-related barriers (symptoms, physical toll of dialysis/transplantation, limited work capacity) and facilitators (few physical symptoms, successful posttransplantation recovery, absence of comorbidities, good physical condition), personal barriers (psychological impact, limited work experience) and facilitators (positive disposition, job satisfaction, work attitude, person-job fit), and environmental barriers and facilitators. Environmental barriers were related to nephrology care (waiting time, use of a hemodialysis catheter) and work context (reorganization, temporary contract, working hours, physical demands); environmental facilitators were related to nephrology care (personalized dialysis, preemptive transplant), work context (large employer, social climate, job requiring mental rather than physical labor, flexible working hours, adjustment of work tasks, reduced hours, remote working, support at work, peritoneal dialysis exchange facility), and support at home. Occupational health services and social security could be barriers or facilitators.Limitations: The study sample of Dutch patients may limit the transferability of these findings to other countries.Conclusions: The wide range of barriers and facilitators in all International Classification of Functioning, Disability and Health components suggests great diversity among patients and their circumstances. These findings underline the importance of personalized nephrology and occupational health care as well as the importance of individually tailored workplace accommodations to promote sustained employment for patients with CKD.

Background Historically, a glomerular filtration rate (GFR) of less than 50 mL/min per 1.73 m2 has been considered a contraindication to lung transplantation. Combined or sequential lung–kidney transplantation is an option for those with a GFR less than 30 mL/min per 1.73 m2. Patients with a GFR of 30 to 50 mL/min per 1.73 m2 are provided with no options for transplantation. This study explores factors associated with improved survival in patients who undergo isolated lung transplantation with a GFR of 30 to 50 mL/min per 1.73 m2. Methods The United Network for Organ Sharing database was queried for adult patients undergoing primary isolated lung transplantation between January 2007 and March 2018. Regression models were used to identify factors associated with improved survival in lung recipients with a preoperative GFR of 30 to 50 mL/min per 1.73 m2. The propensity score method was used to match highly performing patients (outpatient recipients aged less than 60 years) with a GFR of 30 to 50 mL/min per 1.73 m2 with patients who had a GFR greater than 50 mL/min per 1.73 m2. Kaplan-Meier, Cox, and logistic regression analyses compared outcomes in matched populations. Results A total of 21,282 lung transplantations were performed during the study period. Compared with patients with a GFR greater than 50 mL/min per 1.73 m2, survival was significantly worse for patients with a GFR of 30 to 50 mL/min per 1.73 m2. Multivariate analysis of patients with a GFR of 30 to 50 mL/min per 1.73 m2 demonstrated outpatient status and age less than 60 years to be predictive of superior survival. After propensity matching, survival of this highly performing subset with a GFR of 30 to 50 mL/min per 1.73 m2 was no different from that of patients with a normal GFR. Conclusions Outpatient recipients aged less than 60 years represent an optimal subset of patients with a GFR of 30 to 50 mL/min per 1.73 m2. Lung transplant listing should not be declined based only on a GFR less than 50 mL/min per 1.73 m2.

INTRODUCTION Patients receiving intravenous iodinated contrast media for computed tomography (CT) are predisposed to contrast-induced nephropathy. Chronic kidney disease is an important risk factor, and hydration is the mainstay of prevention. While inpatients can undergo intravenous hydration, limited knowledge exists regarding regimens for outpatients. We employed a rapid outpatient hydration protocol to reduce postponement of imaging appointments for patients with suboptimal estimated glomerular filtration rate (eGFR). METHODS From June 2015, we amended our CT preparation protocol to mandate rapid hydration (oral, intravenous or both) for patients with an eGFR of 30–60 mL/min/1.73 m2. Patients receiving this hydration protocol from June to November 2015 were followed up for one month to monitor any admissions for fluid overload, and up to one year to determine the long-term effect on eGFR. RESULTS 226 outpatients received the hydration protocol, which correlated with a 95% reduction in postponement of imaging appointments. No complications of fluid overload from hydration were encountered. A significant association was observed between age and decrease in eGFR, but this was not significant when stratified by drop in eGFR category. No statistical significance was found between decrease in eGFR and gender or race. Higher baseline eGFR was less likely to be associated with decrease in eGFR after imaging. Type of hydration was not related to a drop in eGFR category for patients with an eGFR of 45–59 mL/min/1.73 m2. CONCLUSION We defined a shorter hydration regimen that is safe to use in the outpatient setting.

Little is known as regards frailty in patients with functional tricuspid regurgitation (FTR). Thus, in this study, we aimed to investigate the prevalence, characteristics, and impact of frailty on patients with severe FTR.This prospective study included 110 consecutive patients with severe FTR who were assessed via transthoracic echocardiography at an outpatient clinic. Patients were dichotomized using short physical performance battery (SPPB). To better understand the whole picture of frailty in patients with FTR, other frailty scales were also assessed (frailty checklist, clinical frailty scale, gait speed, and Columbia frailty scale). The primary endpoint was the combination of all-cause mortality and heart failure hospitalization.According to each definition of frailty, 28%-46% were identified to be frail. Those with SPPB score of < 9 were older, had greater New York Heart Association (NYHA) functional classification, and had lower albumin level and estimated glomerular filtration rate compared with those with SPPB score of ≥ 9. They also have smaller tricuspid valve coaptation depth and worse right ventricular fractional area change (RV-FAC) than those with SPPB score of ≥ 9 despite having similar TR severity. The primary endpoint at 1 year was noted in 31% of patients. The SPPB score has excellent discriminatory performance for predicting the primary endpoint (area under the curve 0.82, 95% confidence interval [CI] 0.76-0.91) in receiver operating characteristic analysis and was independently associated with the primary endpoint after adjustment in multivariate analysis (adjusted hazard ratio 0.81, 95% CI, 0.73-0.90; P < 0.001).Frailty has been widely prevalent in the elderly patient population with FTR; in fact, it has been determined to be strong parameter for poor outcomes.

Background The assessment of phosphate homeostasis in clinical practice relies not only on circulating phosphate levels but also on phosphate tubular reabsorption, ideally assessed using the tubular maximum phosphate reabsorption per glomerular filtration rate (TmP/GFR). TmP/GFR reference values were established before the onset of isotope-dilution mass spectrometry-standardized (IDMS) creatinine assays and thus need to be updated. Our objective is to provide reference values for TmP/GFR from childhood to adulthood, using the gold-standard of GFR assessment and IDMS-standardized creatinine values. Methods We retrospectively analysed all the inulin and iohexol clearances [measured glomerular filtration rate (mGFR)] performed in children and in adults screened for a living-donation in our unit since the beginning of IDMS-creatinine assays. TmP/GFR was calculated on a fasting sample, using the conventional formula without correction for tubular reabsorption of phosphate (TRP) in subjects below 19 years of age. Results A total of 2051 subjects (1711 children, 340 adults), aged from 1.9 to 73.4 years with normal GFR, normal phosphate and normal calcium levels, were included for TmP/GFR analysis. As expected, there was a progressive decrease along puberty in both genders of plasma phosphate and TmP/GFR, the decrease occurring earlier in girls. After the age of 19 years, there was a stabilization of plasma phosphate and TmP/GFR levels until the age of 55 years, phosphate levels and TmP/GFR being slightly lower in men than in women. Conclusion We present the largest cohort describing TmP/GFR reference values in the era of IDMS-standardized creatinine assays. We believe that these data will help physicians to better diagnose and manage patients with abnormal phosphate metabolism in daily clinical routine.

Background Cognitive impairment is common among persons with chronic kidney disease (CKD), due in part to reduced kidney function. Given that physical activity (PA) is known to mitigate cognitive decline, we examined whether associations between CKD stage and global/domain-specific cognitive function differ by PA. Methods We leveraged 3223 participants (≥60 years of age) enrolled in National Health and Nutrition Examination Survey (NHANES, 2011–2014), with at least one measure of objective cognitive function [immediate recall (CERAD-WL), delayed recall (CERAD-DR), verbal fluency (AF), executive function/processing speed (DSST), global (average of four tests) or self-perceived memory decline (SCD)]. We quantified the association between CKD stage {no CKD: estimated glomerular filtration rate [eGFR] ≥60 mL/min/1.73 m2 and albuminuria [albumin:creatinine ratio (ACR)] Results Among NHANES participants, 34.9% had CKD stages G1–G3, 2.6% had stages G4 and G5 and 50.7% had low PA. CKD stages G4 and G5 were associated with lower global cognitive function {difference = −0.38 standard deviation [SD] [95% confidence interval (CI) −0.62 to −0.15]}. This association differed by PA (Pinteraction = 0.01). Specifically, among participants with low PA, those with CKD stages G4 and G5 had lower global cognitive function [difference = −0.57 SD (95% CI −0.82 to −0.31)] compared with those without CKD. Among those with high PA, no difference was found [difference = 0.10 SD (95% CI −0.29–0.49)]. Similarly, the CKD stage was only associated with immediate recall, verbal fluency, executive function and processing speed among those with low PA; no associations were observed for delayed recall or self-perceived memory decline. Conclusions CKD is associated with lower objective cognitive function among those with low but not high PA. Clinicians should consider screening older patients with CKD who have low PA for cognitive impairment and encourage them to meet PA guidelines.

Background Despite renin–angiotensin–aldosterone system blockade and immunosuppressive treatment, focal segmental glomerulosclerosis (FSGS) often progresses to kidney failure. The objective of this prespecified analysis of the dapagliflozin and prevention of adverse outcomes in chronic kidney disease trial (DAPA-CKD) was to assess efficacy and safety of dapagliflozin in a small subgroup of participants with FSGS confirmed by kidney biopsy. Methods In DAPA-CKD, patients with an estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73 m2 and urinary albumin:creatinine ratio (UACR) 200–5000 mg/g (22.6–565 mg/mol) were randomized to dapagliflozin 10 mg once daily or placebo as an adjunct to standard care and followed for median 2.4 years. The primary composite endpoint was sustained eGFR decline ≥50%, end-stage kidney disease, or kidney or cardiovascular death. The endpoint of interest for this analysis was eGFR slope (acute effects from baseline to Week 2 and chronic effects from Week 2 to end of treatment). Results Of 104 participants with biopsy-confirmed FSGS, 45 were randomized to dapagliflozin and 59 to placebo. Mean (standard deviation) age was 54.0 (14.3) years, mean eGFR 41.9 (11.5) mL/min/1.73 m2 and median (interquartile range) UACR 1248 (749–2211) mg/g. The primary outcome occurred in 4 (8.9%) and 7 (11.9%) participants randomized to dapagliflozin and placebo, respectively [hazard ratio 0.62, 95% confidence interval (95% CI) 0.17, 2.17]. Dapagliflozin led to a larger acute reduction (standard error) in eGFR compared with placebo (−4.5, 95% CI −5.9 to −3.1 versus −0.9, −2.1 to 0.4 mL/min/1.73 m2/2 weeks). Thereafter, mean rates of chronic eGFR decline with dapagliflozin and placebo were −1.9 (−3.0, −0.9) and −4.0 (−4.9, −3.0) mL/min/1.73 m2/year, respectively (difference 2.0, 95% CI 0.6 to 3.5, mL/min/1.73 m2/year). Adverse events leading to study drug discontinuation were similar in both groups; there were fewer serious adverse events with dapagliflozin. Conclusions Among DAPA-CKD participants with FSGS, dapagliflozin reduced the rate of chronic decline of eGFR compared with placebo, although this difference was not statistically significant.

Whether the definition of hypertension according to 2017 AHA/ACC guidelines and blood pressure (BP) changes was related to the increased risk of chronic kidney disease (CKD) remained debated. This prospective cohort study aimed to investigate the association of BP and long‐term BP change with CKD risk with different glucose metabolism according to the new hypertension guidelines. This study examined 12 951 participants and 11 183 participants derived from the older people cohort study, respectively. Participants were divided into three groups based on blood glucose and the risks were assessmented by the logistic regression model. During a 10 years of follow‐up period, 2727 individuals developed CKD (21.1%). Compared with those with BP