Risk factors for chronic kidney disease progression over 20 years for primary prevention in Japanese individuals at a preventive medicine research center: Focus on the influence of plasma glucose levels.

AIMS/INTRODUCTION: Chronic kidney disease (CKD) is a very important issue globally because of the risk of its progressing to end-stage renal disease. We aimed to identify factors contributing to long-term estimated glomerular filtration rate (eGFR) decline to determine an early diagnosis and prevent CKD progression. MATERIALS AND METHODS: From January 2003 to December 2006, 5,507 individuals underwent health checkups at our hospital's Preventive Medicine Research Center. We ultimately enrolled 2,175 individuals. The eGFR was ≥60 mL/min/1.73 m2 at the start of observation period, which was 20 years. The event onset time was the day that the eGFR became <30 mL/min during the 20-year period. Baseline risk factors - in particular, the effect of plasma glucose levels on the eGFR - were extracted and evaluated by using Fine and Gray analysis. RESULTS: During the 20-year observation, the hazard ratio (HR) of CKD progression was examined. A fasting plasma glucose (FPG) level ≥105 mg/dL was significantly associated with the risk of CKD progressing to an eGFR <30 mL/min. This trend was similar in the slope of eGFR. An FPG ≥105 mg/dL or an glycated hemoglobin level ≥6.5% was useful for intervening in CKD progression. Multivariate analysis showed that independent risk factors were an FPG level ≥105 mg/dL (HR 1.9; P < 0.001), age ≥60 years (HR 3.86; P < 0.001), obesity (HR 1.61; P < 0.01) and urinary protein (HR 1.55; P < 0.01). CONCLUSIONS: For early intervention against a reduction in the eGFR, detecting mild increases in FPG ≥105 mg/dL in patients with CKD with or without diabetes is useful.

Machine Learning for Predicting Chronic Renal Disease Progression in COVID-19 Patients with Acute Renal Injury: A Feasibility Study.

This study aimed to determine the feasibility of applying machine-learning methods to assess the progression of chronic kidney disease (CKD) in patients with coronavirus disease (COVID-19) and acute renal injury (AKI). The study was conducted on patients aged 18 years or older who were diagnosed with COVID-19 and AKI between April 2020 and March 2021, and admitted to a second-level hospital in Mérida, Yucatán, México. Of the admitted patients, 47.92% died and 52.06% were discharged. Among the discharged patients, 176 developed AKI during hospitalization, and 131 agreed to participate in the study. The study's results indicated that the area under the receiver operating characteristic curve (AUC-ROC) for the four models was 0.826 for the support vector machine (SVM), 0.828 for the random forest, 0.840 for the logistic regression, and 0.841 for the boosting model. Variable selection methods were utilized to enhance the performance of the classifier, with the SVM model demonstrating the best overall performance, achieving a classification rate of 99.8% ± 0.1 in the training set and 98.43% ± 1.79 in the validation set in AUC-ROC values. These findings have the potential to aid in the early detection and management of CKD, a complication of AKI resulting from COVID-19. Further research is required to confirm these results.

Depressive Symptoms, Antidepressants, and Clinical Outcomes in Chronic Kidney Disease: Findings from the CRIC Study.

Rationale & Objective: The extent to which depression affects the progression of chronic kidney disease (CKD) and leads to adverse clinical outcomes remains inadequately understood. We examined the association of depressive symptoms (DS) and antidepressant medication use on clinical outcomes in 4,839 adults with nondialysis CKD. Study Design: Observational cohort study. Setting and Participants: Adults with mild to moderate CKD who participated in the multicenter Chronic Renal Insufficiency Cohort Study (CRIC). Exposure: The Beck Depression Inventory (BDI) was used to quantify DS. Antidepressant use was identified from medication bottles and prescription lists. Individual effects of DS and antidepressants were examined along with categorization as follows: (1) BDI <11 and no antidepressant use, (2) BDI <11 with antidepressant use, (3) BDI ≥11 and no antidepressant use, and (4) BDI ≥11 with antidepressant use. Outcomes: CKD progression, incident cardiovascular disease composite, all-cause hospitalizations, and mortality. Analytic Approach: Cox regression models were fitted for outcomes of CKD progression, incident cardiovascular disease, and all-cause mortality, whereas hospitalizations used Poisson regression. Results: At baseline, 27.3% of participants had elevated DS, and 19.7% used antidepressants. Elevated DS at baseline were associated with significantly greater risk for an incident cardiovascular disease event, hospitalization, and all-cause mortality, but not CKD progression, adjusted for antidepressants. Antidepressant use was associated with higher risk for all-cause mortality and hospitalizations, after adjusting for DS. Compared to participants without elevated DS and not using antidepressants, the remaining groups (BDI <11 with antidepressants; BDI ≥11 and no antidepressants; BDI ≥11 with antidepressants) showed higher risks of hospitalization and all-cause mortality. Limitations: Inability to infer causality among depressive symptoms, antidepressants, and outcomes. Additionally, the absence of nonpharmacological data, and required exploration of generalizability and alternative analytical approaches. Conclusions: Elevated DS increased adverse outcome risk in nondialysis CKD, unattenuated by antidepressants. Additionally, investigation into the utilization and counterproductivity of antidepressants in this population is warranted.

We analyzed data from 4,839 nondialysis chronic kidney disease (CKD) patients in the Chronic Renal Insufficiency Cohort Study to explore how depression and antidepressants affect CKD-related outcomes. Using the Beck Depression Inventory (BDI), we assessed depressive symptoms (DS) and identified antidepressant use through medication records. Outcomes included CKD progression, cardiovascular events, hospitalizations, and mortality. Elevated DS at baseline raised the risk of cardiovascular events, hospitalizations, and mortality, regardless of antidepressant use. Antidepressant use alone was associated with higher mortality and hospitalization risks. In comparison to those without elevated DS and no antidepressant use, all other groups faced increased hospitalization and mortality risks. Elevated DS posed a significant risk to nondialysis CKD patients, and antidepressants did not mitigate this risk.

Triglyceride-glucose index change and chronic kidney disease progression in a Chinese hypertensive population.

Background: The impact of triglyceride-glucose (TyG) index variations on chronic kidney disease (CKD) progression remains unexplored. To investigate the effects of the TyG index and its dynamic changes on CKD progression. Method: This prospective cohort study included data from 8,418 hypertensive participants. The exposure variable in this study was defined as the difference between the TyG index at the last visit from that at baseline. The study's outcome variable was the progression of CKD, defined as follows: for subjects with an estimated glomerular filtration rate (eGFR) ≥60 mL/min, a ≥30% decrease in eGFR with a final follow-up value <60 mL/min; for those with an eGFR <60 mL/min, a ≥50% decrease in eGFR; or terminal renal failure requiring dialysis. Results: During a median follow-up period of 48 months, 1077 patients were diagnosed with CKD progression. In the fully adjusted Model 3, patients with a change in the TyG index <0 exhibited a significantly decreased 13% risk of CKD progression (HR: 0.87, 95% CI: 0.76-0.98) compared to those with a change in the TyG index≥0 group. Subgroup analyses showed that changes in the TyG index significantly increased the risk of CKD progression only in patients with diastolic blood pressure (DBP) <90mmHg. In the path analysis, baseline TyG was associated with follow-up eGFR (the standard regression coefficient was 1.26 [95% CI, 0.45-2.06]). Conclusions: Our findings suggest that TyG variability may serve as a useful tool for identifying individuals at risk of CKD progression, particularly hypertensive patients with normal DBP levels.

Left Ventricular Mass Index Predicts Renal Function Decline in Patients with Chronic Kidney Disease.

Background and Objectives: Several studies revealed a relation between abnormal cardiac remodeling and glomerular filtration rate (GFR) decline, but there are limited data regarding echocardiographic changes in chronic kidney disease (CKD). This study evaluated the abnormal cardiac structures characterizing patients with CKD, assessing the independent association between echocardiographic parameters and the risk of decline in renal function. Materials and Methods: In total, 160 patients with CKD were studied. All patients underwent an echocardiographic exam and 99mTc-DTPA renal scintigraphy to measure the GFR. After the baseline assessments, patients were followed prospectively for 12 months, or until the endpoint achievement, defined as a worsening in renal function (doubling of baseline serum creatinine, GFR decline ≥25%, the start of dialysis). Results: Patients with GFR values of 34.8 ± 15 mL/min, identifying stages III-IV of CKD, were associated with high levels of left ventricular mass index (LVMi) (101.9 ± 12.2 g/m2), which was related to proteinuria, systolic blood pressure, and pulmonary artery systolic pressure in a multiple regression model. During the observational period, 26% of patients reached the endpoint. Regression analysis revealed LVMi as a predictor of change in renal function after adjusting for kidney and cardiac risk factors. Multiple Cox regression indicated that an increase in LVMi was associated with a 12% increased risk of kidney disease progression (HR: 1.12; 95% CI: 1.04-1.16; p = 0.001). Conclusions: In patients with CKD, high LVMi represents an independent predictor of the progressive decline of the renal function, until the start of renal replacement therapy. Echocardiography can help identify patients at high risk for renal disease worsening in patients with CKD independently of clinical cardiac involvement.

Combining robust urine biomarkers to assess chronic kidney disease progression.

BACKGROUND: Urinary biomarkers may improve the prediction of chronic kidney disease (CKD) progression. Yet, data reporting the applicability of most commercial biomarker assays to the detection of their target analyte in urine together with an evaluation of their predictive performance are scarce. METHODS: 30 commercial assays (ELISA) were tested for their ability to quantify the target analyte in urine using strict (FDA-approved) validation criteria. In an exploratory analysis, LASSO (Least Absolute Shrinkage and Selection Operator) logistic regression analysis was used to identify potentially complementary biomarkers predicting fast CKD progression, determined as the 51CrEDTA clearance-based measured glomerular filtration rate (mGFR) decline (>10% per year) in a subsample of 229 CKD patients (mean age, 61 years; 66% men; baseline mGFR, 38 mL/min) from the NephroTest prospective cohort. FINDINGS: Among the 30 assays, directed against 24 candidate biomarkers, encompassing different pathophysiological mechanisms of CKD progression, 16 assays fulfilled the FDA-approved criteria. LASSO logistic regressions identified a combination of five biomarkers including CCL2, EGF, KIM1, NGAL, and TGF-α that improved the prediction of fast mGFR decline compared to the kidney failure risk equation variables alone: age, gender, mGFR, and albuminuria. Mean area under the curves (AUC) estimated from 100 re-samples was higher in the model with than without these biomarkers, 0.722 (95% confidence interval 0.652-0.795) vs. 0.682 (0.614-0.748), respectively. Fully-adjusted odds-ratios (95% confidence interval) for fast progression were 1.87 (1.22, 2.98), 1.86 (1.23, 2.89), 0.43 (0.25, 0.70), 1.10 (0.71, 1.83), 0.55 (0.33, 0.89), and 2.99 (1.89, 5.01) for albumin, CCL2, EGF, KIM1, NGAL, and TGF-α, respectively. INTERPRETATION: This study provides a rigorous validation of multiple assays for relevant urinary biomarkers of CKD progression which combination may improve the prediction of CKD progression. FUNDING: This work was supported by Institut National de la Santé et de la Recherche Médicale, Université de Paris, Assistance Publique Hôpitaux de Paris, Agence Nationale de la Recherche, MSDAVENIR, Pharma Research and Early Development Roche Laboratories (Basel, Switzerland), and Institut Roche de Recherche et Médecine Translationnelle (Paris, France).

The Angiogenesis Inhibitor Isthmin-1 (ISM1) Is Overexpressed in Experimental Models of Glomerulopathy and Impairs the Viability of Podocytes.

Focal segmental glomerulosclerosis (FSGS) is a major cause of end-stage renal disease and remains without specific treatment. To identify new events during FSGS progression, we used an experimental model of FSGS associated with nephroangiosclerosis in rats injected with L-NAME (Nω-nitro-L-arginine methyl ester). After transcriptomic analysis we focused our study on the role of Isthmin-1 (ISM1, an anti-angiogenic protein involved in endothelial cell apoptosis. We studied the renal expression of ISM1 in L-NAME rats and other models of proteinuria, particularly at the glomerular level. In the L-NAME model, withdrawal of the stimulus partially restored basal ISM1 levels, along with an improvement in renal function. In other four animal models of proteinuria, ISM1 was overexpressed and localized in podocytes while the renal function was degraded. Together these facts suggest that the glomerular expression of ISM1 correlates directly with the progression-recovery of the disease. Further in vitro experiments demonstrated that ISM1 co-localized with its receptors GRP78 and integrin αvß5 on podocytes. Treatment of human podocytes with low doses of recombinant ISM1 decreased cell viability and induced caspase activation. Stronger ISM1 stimuli in podocytes dropped mitochondrial membrane potential and induced nuclear translocation of apoptosis-inducing factor (AIF). Our results suggest that ISM1 participates in the progression of glomerular diseases and promotes podocyte apoptosis in two different complementary ways: one caspase-dependent and one caspase-independent associated with mitochondrial destabilization.

[Blood pressure goals in chronic kidney disease : What is the optimal blood pressure for inhibition of progression and risk reduction?] / Blutdruckzielwerte bei eingeschränkter Nierenfunktion : Was ist der optimale Blutdruck zur Progressionshemmung und Risikoreduktion?

Well-controlled blood pressure is an essential factor in inhibiting the progression of renal failure and also in controlling cardiovascular mortality and morbidity. For decades there has been an intensive search for the optimal blood pressure target values in order to reduce the progression of renal insufficiency to a physiological level as far as possible. In the last few decades, very different target blood pressure values have been defined, which time and again contribute more to confusion than clarity in everyday clinical practice. The present work considers the relevant guidelines; it analyzes the basis on which the sometimes widely varying guidelines were created. All guidelines agree that blood pressure control with a target of less than 140 mm Hg systolic should be achieved in patients with impaired renal function. The European guidelines recommend aiming for a target of 130-140 mm Hg systolic. The American guidelines go one step further and specify a systolic blood pressure target of less than 130 mm Hg. The Kidney Disease: Improving Global Outcomes (KDIGO) organization is even more ambitious. It recommends a blood pressure target of less than 120 mm Hg, whereby in contrast to the European and American guidelines, the level of evidence required in the guidelines is considered to be very weak and the goals should also be achieved if automated, standardized blood pressure measurement is carried out, which is rarely available in everyday practice and may not be feasible. The present overview discusses the arguments for lowering blood pressure with different goals and presents the evidence. Of course, the blood pressure goals in the presence or absence of albuminuria should also be considered.

Risk of cardiovascular disease, death, and renal progression in diabetes according to albuminuria and estimated glomerular filtration rate.

AIM: We aimed to examine risks of major cardiovascular events (MACEs), renal outcomes, and all-cause mortality in type 2 diabetes mellitus (T2DM) patients with different diabetic kidney disease (DKD) subtypes. METHODS: A total of 36,509 participants with T2DM recruited from 20 community sites across mainland China were followed up during 2011-2016. DKD subtypes were categorized based on albuminuria (urinary albumin-to-creatinine ratio, UACR ≥ 30 mg/g) and reduced estimated glomerular filtration rate (eGFR < 60 ml/min/1.73 m2) as Alb-/eGFR-, Alb+/eGFR-, Alb-/eGFR+, and Alb+/eGFR+. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) of developing clinical outcomes in DKD subtypes. RESULTS: More than half (53.5%) of participants with diabetes and reduced eGFR had normal UACR levels (Alb-/eGFR+), termed as non-albuminuria DKD. These patients had a modest increase in the risks of MACEs (hazard ratio, HR 1.42 [95% CI 1.08;1.88]) and mortality (HR 1.42 [1.04;1.92]) compared with patients without DKD, whereas CKD progression was not significantly increased (HR 0.97 [0.60;1.57]). Participants with albuminuria (Alb+/eGFR- or Alb+/eGFR+) had higher risks of clinical outcomes. Subgroup analysis revealed that the associations between non-albuminuria DKD and risks of MACEs and mortality were more evident in those aged <65 years. CONCLUSION: Non-albuminuria DKD accounts for more than half of DKD cases with low eGFR in Chinese diabetes patients. Diabetes patients with albuminuria are at higher risks of developing clinical outcomes and warrant early intervention, as well as patients with non-albuminuria DKD with age < 65 years.

Nontraditional Risk Factors for Progression Through Chronic Kidney Disease Risk Categories: The Coronary Artery Risk Development in Young Adults Study.

BACKGROUND: There may be nontraditional pathways of chronic kidney disease (CKD) progression that are complementary to classical pathways. Therefore, we aimed to examine nontraditional risk factors for incident CKD and its progression. METHODS: We used the generally healthy population (n = 4382) starting at age 27-41 years in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort, which is an observational longitudinal study. Nontraditional risk factors included forced vital capacity, inflammation, serum urate, and serum carotenoids. CKD risk category was classified using the estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) measured in 1995-1996 and repeated every 5 years for 20 years: No CKD, low risk, moderate risk, high risk, and very high risk. RESULTS: At baseline, 84.8% had no CKD (eGFR ≥60 mL/min/1.73 m2 and UACR <10 mg/g), 10.3% were in the low risk (eGFR ≥60 and UACR 10-29), and 4.9% had CKD (eGFR <60 and/or UACR ≥ 30). Nontraditional risk factors were significantly associated with the progression of CKD to higher categories. Hazard ratios per standard deviation of the predictor for incident CKD and its progression from the No CKD and low and moderate risk into CKD were inverse for forced vital capacity and serum carotenoids and positive for serum urate, GlycA, and C-reactive protein, the first 3 even after adjustment for conventional risk factors. CONCLUSION: Several nontraditional markers were significantly associated with an increased risk of progression to higher CKD categories in generally healthy young to middle-aged adults.

Protocol and Methods: Role of Levothyroxine on the Progression of Chronic Kidney Disease in Subclinical Hypothyroid Populations (LP-CKD) - A Multicenter Randomized Controlled Trial.

Introduction: Subclinical hypothyroidism (SCH) is highly prevalent and associated with chronic kidney disease (CKD). However, it is still unanswered whether the restoration of euthyroid status in these patients will be beneficial in retarding a decline in glomerular filtration rate in early CKD patients. We aim to evaluate the efficacy of levothyroxine therapy versus placebo in slowing estimated glomerular filtration rate (eGFR) decline among CKD patients (stage 2-4) with SCH. Methods: This study will be a multicentric, double-blind, randomized, parallel-group, placebo-controlled study. A total of 500 CKD patients, 250 patients in the treatment group and 250 patients in the placebo group, will be randomized. The randomization between the treatment arm and placebo arm will be performed as per the computer-generated random number table in a 1:1 ratio. The sample size was calculated based on the assumed reduction in eGFR after 1-year follow-up in the treatment and placebo groups of 10% and 25%, respectively, at a minimum two-sided 99% confidence interval and 90% power of the study and considering 20% loss on follow-up. Each patient will be followed every 3 months for at least 1 year after randomization. Individuals completing 1-year follow-up visits will be considered for analysis. The baseline and follow-up data will be compared between the treatment and placebo groups. The study will evaluate the efficacy and safety of levothyroxine therapy versus placebo in slowing eGFR decline among CKD patients (stage 2-4) with SCH. The primary endpoint will be the end of follow-up of the patients, reduction of eGFR by ≥50% from a baseline of that patient, or development of ESKD or death of the patients. The secondary endpoint will be any cardiovascular event or arrhythmia after the institution of the drug.

Reduced Blood Pressure Dipping Is A Risk Factor for the Progression of Chronic Kidney Disease in Children.

Background: Elevated blood pressure and proteinuria are well-established risk factors for chronic kidney disease (CKD) progression in children. This study aimed to analyze risk factors for CKD progress, emphasizing detailed ambulatory blood pressure (ABPM) data. Methods: In 55 children with CKD II−V, observed for ≥1 year or until initiation of kidney replacement therapy, we analyzed ABPM, clinical, and biochemical parameters. Results: At the beginning, the glomerular filtration rate (eGFR) was 66 (interquartile range­IQR: 42.8−75.3) mL/min/1.73 m2, and the observation period was 27 (16−36) months. The mean eGFR decline was 2.9 ± 5.7 mL/min/1.73 m2/year. eGFR decline correlated (p < 0.05) with age (r = 0.30), initial proteinuria (r = 0.31), nighttime systolic and mean blood pressure (r = 0.27, r = 0.29), and systolic and diastolic blood pressure dipping (r = −0.37, r = −0.29). There was no relation between mean arterial pressure during 24 h (MAP 24 h Z-score) and eGFR decline and no difference in eGFR decline between those with MAP 24 h < and ≥50 th percentile. In multivariate analysis, systolic blood pressure dipping (beta = −0.43), presence of proteinuria (beta = −0.35), and age (beta = 0.25) were predictors of eGFR decline. Conclusions: Systolic blood pressure dipping may be a valuable indicator of CKD progression in children.

Association Between Urinary Protein-to-Creatinine Ratio and Chronic Kidney Disease Progression: A Secondary Analysis of a Prospective Cohort Study.

Objective: Studies on the association between urinary protein-to-creatinine ratio (UPCR) and chronic kidney disease (CKD) progression are limited. This study aimed to investigate the relationship between UPCR and CKD progression in a Japanese population. Methods: The present research was a secondary analysis of a prospective cohort study. Eight hundred and ninety-six subjects from the research of CKD-ROUTE in Japan were included. All the patients were new visitors or first referred to the participating centers of nephrology between October 2010 and December 2011. The target-independent variable was UPCR measured at baseline. The dependent variable was CKD progression and the estimated glomerular filtration rate (eGFR) changes during follow-up. We used Cox proportional hazards regression to investigate the association between UPCR and CKD progression risk. To address UPCR and CKD progression's non-linearity, a multivariate Cox proportional hazards regression analysis with cubic spline functions model and smooth curve fitting (penalized spline method) were conducted. We further used a generalized linear mixed model to explore the relationship between UPCR and the changes of eGFR. Result: The mean age of the included patients was 67.2 ± 13.4 years old. Two hundred and thirty-four people occurred CKD progression during follow-up. The present study showed that UPCR was independently associated with CKD progression in the multivariate analysis [HR = 1.164, 95% CI (1.116, 1.215)]. The non-linear relationship between UPCR and CKD progression was explored in a dose-dependent manner, with an obvious inflection point of 1.699. Furthermore, our findings indicated that the tendency of the effect sizes on both the left and right sides of the inflection point was not consistent [left HR: 4.377, 95% CI (2.956, 6.483); right HR: 1.100, 95% CI (1.049-1.153)]. Using the linear mixed-effects regression model, we found that UPCR was an independent predictor of the longitudinal changes in eGFR (p < 0.001 for the interaction term with time). Conclusion: This study demonstrates a nonlinear positive relationship between UPCR and CKD progression in the Japanese population. UPCR is also an independent predictor of the longitudinal changes in eGFR.

Potential Surrogate Outcomes for Kidney Failure in Advanced CKD: Evaluation of Power and Predictive Ability in CKDopps.

RATIONALE & OBJECTIVE: Potential surrogate end points for kidney failure have been proposed in chronic kidney disease (CKD); however, they must be evaluated to ensure accurate, powerful, and harmonized research, particularly among patients with advanced CKD. The aim of the current study was to investigate the power and predictive ability of surrogate kidney failure end points in a population with moderate-to-advanced CKD. STUDY DESIGN: Analysis of longitudinal data of a large multinational CKD observational study (Chronic Kidney Disease Outcomes and Practice Patterns Study). SETTING & PARTICIPANTS: CKD stage 3-5 patients from Brazil, France, Germany, and the United States. OUTCOMES: Reaching an estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73 m2 or eGFR decline of ≥40%, and composite end points of these individual end points. ANALYTICAL APPROACH: Each end point was used as a time-varying indicator in the Cox model to predict the time to kidney replacement therapy (KRT; dialysis or transplant) and was compared by the number of events and prediction accuracy. RESULTS: 8,211 patients had a median baseline eGFR of 27 mL/min/1.73 m2 (interquartile range, 21-36 mL/min/1.73 m2) and 1,448 KRT events over a median follow-up of 2.7 years (interquartile range, 1.2-3.0 years). Among CKD stage 4 patients, the eGFR < 15 mL/min/1.73 m2 end point had higher prognostic ability than 40% eGFR decline, but the end points were similar for CKD stage 3 patients. The combination of eGFR < 15 mL/min/1.73 m2 and 40% eGFR decline had the highest prognostic ability for predicting KRT, regardless of the CKD stage. Including KRT in the composite can increase the number of events and, therefore, the power. LIMITATIONS: Variable visit frequency resulted in variable eGFR measurement frequency. CONCLUSIONS: The composite end point can be useful for CKD progression studies among patients with advanced CKD. Harmonized use of this approach has the potential to accelerate the translation of new discoveries to clinical practice by identifying risk factors and treatments for kidney failure.

Rapidly Progressing to ESRD in an Individual with Coexisting ADPKD and Masked Klinefelter and Gitelman Syndromes.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenetic hereditary renal disease, promoting end-stage renal disease (ESRD). Klinefelter syndrome (KS) is a consequence of an extra copy of the X chromosome in males. Main symptoms in KS include hypogonadism, tall stature, azoospermia, and a risk of cardiovascular diseases, among others. Gitelman syndrome (GS) is an autosomal recessive disorder caused by SLC12A3 variants, and is associated with hypokalemia, hypomagnesemia, hypocalciuria, normal or low blood pressure, and salt loss. The three disorders have distinct and well-delineated clinical, biochemical, and genetic findings. We here report a male patient with ADPKD who developed early chronic renal failure leading to ESRD, presenting with an intracranial aneurysm and infertility. NGS identified two de novo PKD1 variants, one known (likely pathogenic), and a previously unreported variant of uncertain significance, together with two SLC12A3 pathogenic variants. In addition, cytogenetic analysis showed a 47, XXY karyotype. We investigated the putative impact of this rare association by analyzing possible clinical, biochemical, and/or genetic interactions and by comparing the evolution of renal size and function in the proband with three age-matched ADPKD (by variants in PKD1) cohorts. We hypothesize that the coexistence of these three genetic disorders may act as modifiers with possible synergistic actions that could lead, in our patient, to a rapid ADPKD progression.

Association of morning hypertension with chronic kidney disease progression and cardiovascular events in patients with chronic kidney disease and hypertension.

BACKGROUND AND AIM: Associations of morning hypertension with chronic kidney disease are rarely investigated in prospective studies. We aim to investigate the predictive value of uncontrolled morning hypertension (UMH) to chronic kidney disease (CKD) progression and cardiovascular (CV) events in patients with CKD and hypertension. METHODS AND RESULTS: In this prospective two-center observational study, 304 hypertensive patients with CKD were enrolled. Time to total mortality, CKD progression and CV events was recorded; Kaplan-Meier survival function estimates and Multivariable Cox proportional hazard model were used to investigate associations between UMH and outcomes. The study protocol was approved by the Institutional Review Board (http://www.thaiclinicaltrials.org; TCTR20180313004). After a follow-up for median 30 months, 23 (7.6%) patients died, 34 (11.2%) had CKD progression, and 95 (31.3%) occurred new-onset CV events, respectively. UMH was shown to be a strong predictor of CKD progression [hazard ratio (HR) 2.46, 95% confidence interval (CI) 1.22-4.94] and CV events (HR 1.69, 95% CI 1.12-2.53). When morning hypertension was analyzed as a continuous variable, morning systolic blood pressure (per 10 mmHg) was also shown to be predictive to CKD progression (HR 1.28, 95% CI 1.07-1.53, P < 0.01) and CV events (HR 1.15, 95% CI 1.03-1.28, P < 0.01). CONCLUSIONS: UMH is strongly associated with CKD progression and CV events in patients with CKD and hypertension. UMH in CKD patients deserves further attentions.

Inflammation-based modified Glasgow prognostic score and renal outcome in chronic kidney disease patients: is there a relationship?

BACKGROUND: Chronic kidney disease (CKD) progression is presumably related to inflammatory response. The modified Glasgow prognostic score (mGPS), based on a combination of albumin and C-reactive protein, has been derived from oncology and validated in multiple diseases. AIMS: To evaluate the relationship between the mGPS and CKD progression. METHODS: The present retrospective unicentric cohort study included 547 CKD patients (age 60.2 years; 53% male; estimated glomerular filtration (eGFR) 42.0 mL/min; mean change -2 mL/min/year) admitted between 1 January 2007 and 31 December 2012. Patients' records were reviewed from the CKD diagnosis to one of the four outcomes: end-stage kidney disease (ESKD), death, loss to follow up or until 31 July 2017. RESULTS: The mGPS score was 0 for 420 (78%), 1 for 110 (19%) and 2 for 17 (3%) patients. More patients with rapid CKD progression were found in the group with the highest mGPS (P = 0.05). mGPS was negatively correlated with baseline eGFR and positively with albuminuria. In the multivariate analysis, mGPS was associated with the eGFR slope. During the study period, 130 (24%) patients died and 109 (20%) reached ESKD. The mean kidney survival time was 8.1 (95% confidence interval 7.9-8.4) years. Patients with zero mGPS had better kidney survival than those with the score of 1 and 2 (Kaplan-Meier, P = 0.02). However, the kidney survival differences were not present after adjusting for CKD progression risk factors. CONCLUSION: The inflammation-based mGPS score was associated with eGFR decline in CKD patients. Therefore, could prove useful in improving risk stratification of CKD patients.

GLP-1 receptor agonist versus DPP-4 inhibitor and kidney and cardiovascular outcomes in clinical practice in type-2 diabetes.

Whether glucagon-like peptide-1 receptor agonists (GLP1-RA) reduce detrimental kidney outcomes is uncertain. In secondary analyses, trials have shown consistent reductions in macroalbuminuria, but inconclusive results about kidney function decline. To help clarify this, we conducted a cohort study to compare kidney and cardiovascular outcomes in individuals who started GLP1-RA or dipeptidyl peptidase-4 inhibitors (DPP4i) (reduces degradation of endogenous GLP1). The primary outcome was a composite of sustained doubling of creatinine, kidney failure or kidney death. The secondary outcomes were three-point major adverse cardiovascular events (MACE) and its individual components. Propensity score weighted Cox regression was used to balance 53 confounders. A total of 19,766 individuals were included, of whom 5,699 initiated GLP1-RA, and were followed for a median 2.9 years. Mean age was 63 years, 26.2% had atherosclerotic cardiovascular disease and 16.0% had an estimated glomerular filtration rate (eGFR) under 60 ml/min/1.73m2. The adjusted hazard ratio for GLP1-RA vs. DPP4i was 0.72 (95% confidence interval 0.53-0.98) for the composite kidney outcome and 0.85 (0.73-0.99) for MACE, with absolute five-year risk reductions of 0.8% (0.1%-1.5%) and 1.6% (0.2%-2.9%), respectively. Hazard ratios were 0.79 (0.60-1.05) for cardiovascular death, 0.86 (0.68-1.09) for myocardial infarction and 0.74 (0.59-0.93) for stroke. Results were consistent within subgroups, including age, sex, eGFR and baseline metformin use. Thus, in our analysis of patients from routine clinical practice, the use of GLP1-RA was associated with a lower risk of kidney outcomes compared with DPP4i. Reductions in both kidney outcomes and MACE were similar in magnitude to those reported in large cardiovascular outcome trials.