Onset Of End-stage Renal Disease Research Articles

Provision of transplant education for patients starting dialysis: Disparities persist

BackgroundAll patients starting dialysis should be informed of kidney transplant as a renal replacement therapy option. Prior research has shown disparities in provision of this information. In this study, we aimed to identify patient sociodemographic and dialysis facility characteristics associated with not receiving transplant information at the time of dialysis initiation. We additionally sought to determine the association of receiving transplant information with waitlist and transplant outcomes. MethodsWe retrospectively analyzed CMS-2728 forms filed from 2007 to 2019. The primary outcome was report of provision of information about transplant on the Centers for Medicare and Medicaid Services Form CMS-2728. For patients not informed at the time of dialysis, we collected the reported reason for not being informed (medically unfit, declined information, unsuitable due to age, psychologically unfit, not assessed, or other). Cox proportional-hazards model estimates were used to study determinants of addition to the waitlist and transplant (secondary outcomes). ResultsFifteen percent of patients did not receive information about transplant (N = 133,414). Non-informed patients were more likely to be older, female, white, and on Medicare. Patients informed about transplant had a shorter time between end-stage renal disease onset and addition to the waitlist; they also spent a shorter time on the waitlist before receiving a transplant. Patients at chain dialysis facilities were more likely to receive information, but this did not translate into higher waitlist or transplant rates. Patients at independent facilities acquired by chains were more likely to be informed but less likely to be added to the waitlist post acquisition. ConclusionsDisparities continue to persist in providing information about transplant at initiation of dialysis. Patients who are not informed have reduced access to the transplant waitlist and transplant. Maximizing the number of patients informed could increase the number of patients referred to transplant centers, and ultimately transplanted. However, policy actions should account for differences in protocols stemming from facility ownership.

Long-term comparison of renal and metabolic outcomes after sodium–glucose co-transporter 2 inhibitor or glucagon-like peptide-1 receptor agonist therapy in type 2 diabetes

BackgroundRenal outcomes in patients with type 2 diabetes following treatment with sodium–glucose co-transporter-2 inhibitors (SGLT2is) or glucagon-like peptide-1 receptor agonists (GLP1RAs) have not been directly compared. This study compared the impact of SGLT2i and GLP1RA therapy on renal function and metabolic parameters.MethodsPatients with type 2 diabetes who initiated SGLT2i or GLP1RA therapy in a tertiary hospital between January 2009 and August 2023 were included to assess composite renal outcomes, such as a 40% decline in estimated glomerular filtration rate (eGFR), onset of end-stage renal disease, renal death, or new-onset macroalbuminuria. Alterations in blood pressure, glucose regulation parameters, lipid profile, and anthropometric parameters, including body fat and muscle masses, were examined over 4-years.ResultsA total of 2,112 patients were enrolled using a one-to-three propensity-score matching approach (528 patients for GLP1RAs, 1,584 patients for SGLT2i). SGLT2i treatment was favoured over GLP1RA treatment, though not significantly, for composite renal outcomes (hazard ratio [HR], 0.63; p = 0.097). SGLT2i therapy preserved renal function effectively than GLP1RAs (decrease in eGFR, ≥ 40%; HR, 0.46; p = 0.023), with improving albuminuria regression (HR, 1.72; p = 0.036). SGLT2i therapy decreased blood pressure and body weight to a greater extent. However, more patients attained HbA1c levels < 7.0% with GLP1RAs than with SGLT2is (40.6% vs 31.4%; p < 0.001). GLP1RA therapy enhanced β-cell function and decreased LDL-cholesterol levels below baseline values.ConclusionsSGLT2is were superior for preserving renal function and reducing body weight, whereas GLP1RAs were better for managing glucose dysregulation and dyslipidaemia.

High remnant-cholesterol levels increase the risk for end-stage renal disease: a nationwide, population-based, cohort study

BackgroundThe effect of remnant-cholesterol (remnant-C) on incident end-stage renal disease (ESRD) has not been studied longitudinally. This retrospective cohort study evaluated the association between remnant-C and the development of ESRD in a nationwide Korean cohort.MethodsParticipants in a National Health Insurance Service health examination (n = 3,856,985) were followed up until the onset of ESRD. The median duration of follow-up was 10.3 years. The Martin-Hopkins equation was used to determine low-density lipoprotein cholesterol (LDL-C) levels from directly measured triglyceride, high-density lipoprotein cholesterol (HDL-C), and total cholesterol levels. Remnant-C levels were determined by subtracting HDL-C and LDL-C from total cholesterol. The risk for incident ESRD was calculated for each quartile of remnant-C, adjusting for conventional risk factors such as baseline renal function, comorbidities, and total cholesterol levels.ResultsESRD developed in 11,073 (0.29%) participants. The risk for ESRD exhibited a gradual increase according to higher levels of remnant-C, with a 61% increased risk in the highest quartile than in the lowest (hazard ratio [HR] 1.61 [95% confidence interval (CI) 1.50–1.72]). The elevated risk for ESRD in the highest quartile versus the lowest quartile was more prominent in younger than in older subjects (20–29 years, HR 4.07 [95% CI 2.85–5.83]; 30–39 years, HR 2.39 [95% CI 1.83–3.13]; ≥ 70 years, HR 1.32 [95% CI 1.16–1.51]). In addition, the increased risk for ESRD related to higher remnant-C levels was greater in females than in males.ConclusionsIndependent of conventional risk factors, remnant-C levels were positively associated with incident ESRD, particularly in younger populations and adult females. Reducing remnant-C levels may be a novel preventive strategy against ESRD.

#993 The molecular effects of SGLT2i (Empagliflozin) on α-Klotho and Nephrin/Podocin proteins in type II diabetic mice model

Abstract Background and Aims Type 2 diabetes mellitus (T2DM), especially hyperglycemia, is associated with increased glucose cell toxicity and oxidative stress that can lead to irreversible damage in the kidney such as diabetic nephropathy (DN). DN is one of the most common microvascular complications of diabetes and is the leading cause of end-stage renal disease (ESRD) and replacement therapy. Several works in the setting of early experimental diabetic nephropathy using the recent anti-diabetic drugs such as sodium-glucose transporter type 2 inhibitors in the prevention, development or amelioration of renal injury. The exact mechanisms, by which these drugs ameliorate glomerular injury from hyperglycemia, had not been clarified well. Klotho and Podocin-Nephrin proteins are an important proteins involved in the tubule-glomerular injury. The Klotho is a circulating anti-ageing hormone with anti-oxidative and anti-inflammatory properties with vascular protective effects in animal studies. Podocin &amp; Nephrin are important component of the glomerular foot-process membrane, the slit-diaphragm. Recently, several experimental reports showed decreased α-Klotho, Nephrin and Podocin expression in different models of diabetic nephropathy. Method We used BTBR mouse strain with the ob/ob leptin-deficiency mutation, which develops T2DM with hyperglycemia and DN; C57/BL mice were the control (CON). EMPA was administrated to T2DM mice (T2DM+EMPA) via drinking water for 12 weeks. Blood parameters were measured repeatedly, and at sacrifice, mice kidneys were harvested for histological and biochemical analyses. We evaluated renal glomerular structure of Nephrin, Podocin and α-Klotho proteins expression. Results EMPA treatment reduced T2DM blood glucose vs C57 group (P &amp;lt; 0:01), and increase urine glucose in EMPA+DM group (P &amp;lt; 0:001) EMPA vs. C57BL/6 and DM). Histological analyses in kidney sections, revealed decreased α-Klotho expression in glomeruli of DM mice vs Control mice (15.95 ± 0.64 vs 36 ± 2.42, (P &amp;lt; 0:01), and restored back in DM+ EMPA mice vs control mice (27.64 ± 0.94 vs 15.95 ± 0.64, P &amp;lt; 0:01). Podocin expression in glomeruli: control mice 31.3 ± 3.7 VS DM mice 21.26 ± 1.22 and DM + EMPA mice 28.22 ± 0.50 VS DM mice 21.26 ± 1.22 Conclusion Hyperglycemia (DM type II) reduces Podocin-Nephrin and α-Klotho proteins expression in the glomeruli kidney and upregulated by EMPA treatment. SGLT2i (EMPA) treatment in DM patients can significantly reduce progression of DN and onset of ESRD probably through its effect on α-Klotho/Podocin-Nephrin proteins.

Genotype-phenotype of autosomal dominant polycystic kidney disease in Malta

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is characterized by the development of multiple renal cysts causing kidney enlargement and end-stage renal disease (ESRD) in half the patients by 60 years of age. The aim of the study was to determine the genetic aetiology in Maltese patients clinically diagnosed with ADPKD and correlate the clinical features. MethodsA total of 60 patients over 18 years of age clinically diagnosed with ADPKD were studied using a customized panel of genes that had sufficient evidence of disease diagnosis using next generation sequencing (NGS). The genes studied were PKD1, PKD2, GANAB, DNAJB11, PKHD1 and DZIP1L. Selected variants were confirmed by bidirectional Sanger sequencing with specifically designed primers. Cases where no clinically significant variant was identified by the customized gene panel were then studied by Whole Exome Sequencing (WES). Microsatellite analysis was performed to determine the origin of an identified recurrent variant in the PKD2 gene. Clinical features were studied for statistical correlation with genetic results. ResultsGenetic diagnosis was reached in 49 (82%) of cases studied. Pathogenic/likely pathogenic variants PKD1 and PKD2 gene were found in 25 and in 23 cases respectively. The relative proportion of genetically diagnosed PKD1:PKD2 cases was 42:38. A pathogenic variant in the GANAB gene was identified in 1 (2%) case. A potentially significant heterozygous likely pathogenic variant was identified in PKHD1 in 1 (2%) case. Potentially significant variants of uncertain significance were seen in 4 (7%) cases of the study cohort. No variants in DNAJB11 and DZIP1L were observed. Whole exome sequencing (WES) added the diagnostic yield by 10% over the gene panel analysis. Overall no clinically significant variant was detected in 6 (10%) cases of the study population by a customized gene panel and WES. One recurrent variant the PKD2 c.709+1G > A was observed in 19 (32%) cases. Microsatellite analysis showed that all variant cases shared the same haplotype indicating that their families may have originated from a common ancestor and confirmed it to be a founder variant in the Maltese population.The rate of decline in eGFR was steeper and progression to ESRD was earlier in cases with PKD1 variants when compared to cases with PKD2 variants. Cases segregating truncating variants in PKD1 showed a significantly earlier onset of ESRD and this was significantly worse in cases with frameshift variants. Overall extrarenal manifestations were commoner in cases segregating truncating variants in PKD1. ConclusionsThis study helps to show that a customized gene panel is the first-line method of choice for studying patients with ADPKD followed by WES which increased the detection of variants present in the PKD1 pseudogene region. A founder variant in the PKD2 gene was identified in our Maltese cohort with ADPKD. Phenotype of patients with ADPKD is significantly related to the genotype confirming the important role of molecular investigations in the diagnosis and prognosis of polycystic kidney disease. Moreover, the findings also highlight the variability in the clinical phenotype and indicate that other factors including epigenetic and environmental maybe be important determinants in Autosomal Dominant Polycystic Kidney Disease.

Single-Center Experience of Pediatric Cystic Kidney Disease and Literature Review.

Pediatric cystic kidney disease (CyKD) includes conditions characterized by renal cysts. Despite extensive research in this field, there are no reliable genetics or other biomarkers to estimate the phenotypic consequences. Therefore, CyKD in children heavily relies on clinical and diagnostic testing to predict the long-term outcomes. A retrospective study aimed to provide a concise overview of this condition and analyze real-life data from a single-center pediatric CyKD cohort followed during a 12-year period. Medical records were reviewed for extensive clinical, laboratory, and radiological data, treatment approaches, and long-term outcomes. During the study period, 112 patients received a diagnosis of pediatric CyKD. Male patients were more involved than female (1:0.93). Fifty-six patients had a multicystic dysplastic kidney; twenty-one of them had an autosomal dominant disorder; fifteen had an isolated renal cyst; ten had been diagnosed with autosomal recessive polycystic kidney disease; three had the tuberous sclerosis complex; two patients each had Bardet-Biedl, Joubert syndrome, and nephronophthisis; and one had been diagnosed with the trisomy 13 condition. Genetic testing was performed in 17.9% of the patients, revealing disease-causing mutations in three-quarters (75.0%) of the tested patients. The most commonly presenting symptoms were abdominal distension (21.4%), abdominal pain (15.2%), and oligohydramnios (12.5%). Recurrent urinary tract infections (UTI) were documented in one-quarter of the patients, while 20.5% of them developed hypertension during the long-term follow-up. Antibiotic prophylaxis and antihypertensive treatment were the most employed therapeutic modalities. Seventeen patients progressed to chronic kidney disease (CKD), with thirteen of them eventually reaching end-stage renal disease (ESRD). The time from the initial detection of cysts on an ultrasound (US) to the onset of CKD across the entire cohort was 59.0 (7.0-31124.0) months, whereas the duration from the detection of cysts on an US to the onset of ESRD across the whole cohort was 127.0 (33.0-141.0) months. The median follow-up duration in the cohort was 3.0 (1.0-7.0) years. The patients who progressed to ESRD had clinical symptoms at the time of initial clinical presentation. This study is the first large cohort of patients reported from Croatia. The most common CyKD was the multicystic dysplastic kidney disease. The most common clinical presentation was abdominal distention, abdominal pain, and oliguria. The most common long-term complications were recurrent UTIs, hypertension, CKD, and ESRD.

A Dynamic Prediction Model for Renal Progression in Primary Membranous Nephropathy.

Objective: This study aimed to build and validate a practical web-based dynamic prediction model for predicting renal progression in patients with primary membranous nephropathy (PMN). Method: A total of 359 PMN patients from The First Affiliated Hospital of Fujian Medical University and 102 patients with PMN from The Second Hospital of Longyan between January 2018 to December 2023 were included in the derivation and validation cohorts, respectively. Renal progression was delineated as a decrease in eGFR of 30% or more from the baseline measurement at biopsy or the onset of End-Stage Renal Disease (ESRD). Multivariable Cox regression analysis was employed to identify independent prognostic factors. A web-based dynamic prediction model for renal progression was built and validated, and the performance was assessed using. An analysis of the receiver operating characteristic and the decision curve analysis. Results: In the derivation cohort, 66 (18.3%) patients experienced renal progression during the follow-up period (37.60 ± 7.95 months). The final prediction rule for renal progression included hyperuricemia (HR=2.20, 95%CI 1.26 to 3.86), proteinuria (HR=2.16, 95%CI 1.47 to 3.18), significantly lower serum albumin (HR=2.34, 95%CI 1.51 to 3.68) and eGFR (HR=1.96, 95%CI 1.47 to 2.61), older age (HR=1.85, 95%CI 1.28 to 2.61), and higher sPLA2R-ab levels (HR=2.08, 95%CI 1.43 to 3.18). Scores for each variable were calculated using the regression coefficients in the Cox model. The developed web-based dynamic prediction model, available online at http://imnpredictmodel1.shinyapps.io/dynnomapp, showed good discrimination (C-statistic = 0.72) and calibration (Brier score, P = 0.155) in the validation cohort. Conclusion: We developed a web-based dynamic prediction model that can predict renal progression in patients with PMN. It may serve as a helpful tool for clinicians to identify high-risk PMN patients and tailor appropriate treatment and surveillance strategies.

Clinical significance of IgM and C3 deposition in children with primary immunoglobulin A nephropathy.

Mesangial IgM and C3 deposition is commonly observed in patients with primary immunoglobulin A nephropathy (IgAN), but its characteristics and prognosis have rarely been reported. The aim of this study was to investigate the relationship between combined mesangial IgM and C3 deposition and disease progression in children with IgAN. One hundred sixteen children diagnosed with IgAN between 2016 and 2020 were selected. Renal biopsies were scored by Oxford classification including the presence of mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis and crescents.The primary renal outcome was an event of either ≥ 50% reduction of eGFR from the baseline value or the onset of end-stage renal disease within the follow-up period.Cox regression analysis was performed to examine the effect of the combined mesangial IgM and C3 deposition on renal outcomes. Forty-seven (40.52%) patients presented combined mesangial IgM and C3 deposition. Compared with children without combined IgM and C3 deposition, children with combined IgM and C3 deposition presented higher mesangial hypercellularity, endocapillary hypercellularity and cresentic lesions in kidney biopsies, and higher prevalence of renal dysfunction (19.15% versus 2.90%; P = 0.007). Renal outcome was alsosignificantly worse as revealed by Kaplan-Meier curves (P = 0.0034). Multivariable Cox analysis identified tubular atrophy/interstitial fibrosis lesions [hazard ratio (HR) 14.843, 95% CI, 3.497-62.997, P < 0.001] and intensity of IgM deposition (HR 2.838, 95% CI, 1.321-6.094, P = 0.007) as independent risk factors for poor renal function. Combined mesangial IgM and C3 deposition was associated with unfavorable histopathological features. Mesangial IgM deposition was an independent risk factor for poor renal outcomes in children with primary IgAN.

Prevalence of Microalbuminuria Among Diabetes Patients in Africa: A Systematic Review and Meta-Analysis.

Microalbuminuria (MAU) is considered the earliest sign of diabetic nephropathy among diabetes patients. In order to effectively manage diabetic nephropathy and its consequences early, detection of microalbuminuria as soon as possible, especially for diabetes patients, is critical. Therefore, the present study aimed to determine the pooled prevalence of microalbuminuria among diabetes patients in Africa. Electronic databases such as Google Scholar, PubMed, African Journals Online, Web of Science, Cochrane Library, EMBASE, and ResearchGate were searched for articles and grey literature. The STATA version 14 software was used to conduct the meta-analysis. I2 and Cochran's Q test were employed to assess the presence of heterogeneity between studies. Due to the presence of heterogeneity, a random effect model was used. The publication bias was assessed using the symmetry of the funnel plot and Egger's test statistics. Moreover, subgroup analysis, trim and fill analysis, and sensitivity analysis were also done. The overall pooled prevalence of microalbuminuria among diabetes patients in Africa was 37.11% (95% CI 31.27-42.95). Substantial heterogeneity was observed between studies, with I2 values of 94.7%. Moreover, this meta-analysis showed that the pooled estimate of microalbuminuria among type 1 and type 2 diabetes patients was 35.34% (95% CI: 23.89-46.80, I2=94.2), and 40.24% (95% CI: 32.0-48.47, I2=94.9) respectively. MAU, on the other hand, was more common in people with diabetes for more than 5 years 38.73% (95% CI: 29.34-48.13) than in people with diabetes for less than 5 years 31.48% (95% CI: 18.73-44.23). This systematic review and meta-analysis found a high prevalence of microalbuminuria among diabetes patients. As a result, early detection of microalbuminuria is critical for preventing and treating microvascular complications such as diabetic nephropathy and the onset of end-stage renal disease.

#3788 PROGNOSTIC ROLE OF THE NEUTROPHIL-TO-LYMPHOCYTE RATIO IN PATIENTS WITH CHRONIC KIDNEY DISEASE

Abstract Background and Aims The neutrophil-to-lymphocyte ratio (NLR) has been demonstrated to have prognostic value in cardiovascular disease, infection, inflammatory disease, and several types of cancer. Therefore, it is expected that NLR has predictive value in patients with chronic kidney disease (CKD) but it has not been validated. Here, I aimed to investigate the possibility of NLR as a predictor of progression of CKD. Method This retrospective observational study included 141 patients with non-dialysis CKD. Subjects were divided into terciles (T1, T2, and T3) according to NLR. The primary outcome of interest was defined as a composite renal event, which included a decline in the estimated glomerular filtration rate (eGFR) of at least 50% or onset of end-stage renal disease (ESRD) during the follow-up period. Results The median follow-up duration was 5.45 ± 2.11 years. The median NLR for each group was 1.35 ± 0.05 in T1 (n=47), 2.16 ± 0.04 in T2 (n=47) and 4.29 ± 0.73 in T3 (n=47). The group with the highest NLR (T3) had higher baseline CKD and serum creatinine and lower eGFR levels than the group with the lowest NLR (T1). The cumulative incidence of composite renal events was significantly increased in T3, compared to T1 (p &amp;lt; 0.001, log-rank test). Cox regression analysis revealed that high NLR was independently associated with the risk of composite renal events (adjusted hazard ratio 2.85, 95% confidence interval 1.18-6.93). Conclusion A higher NLR reflects the more advanced stage of CKD and suggests that a role for NLR as a biomarker for predicting CKD progression.

Нефропатический цистиноз: механизмы развития и методы лечения

Nephropathic cystinosis is a rare inherited disease characterized by cristallization of cystine in lyzosomes. Cystine accumulation is caused by the mutations in the CTNS gene encoding for cystinosine, a cystine transporter. Cystinosis commonly affects the kidneys leading to renal Fanconi sysnrome during the first year of life, followed by progressive kidney failure that necessitates initiation of renal replacement therapy in childhood or adolescence. In adulthood, patients also present with various systemic manifestations including photophobia, hypothyroidism, diabetes mellitus, hypogonadism (in males), myopathy, neurological disorders. Corneal crystal accumulation can be detected in all patients with cystinosis by slit-lamp examination. A diagnosis of cystinosis can be confirmed by measuring cystine levels in white blood cells and genetic testing. Early diagnosis is of vital importance given the availability of cysteamine, the specific cystinedepleting therapy, that delays the onset of end-stage renal disease and extrarenal manifestations.

Serum triglycerides level is independently associated with renal outcomes in patients with non-dialysis chronic kidney disease: Results from KNOW-CKD study.

To investigate whether high serum triglycerides (TG) level is associated with adverse renal outcomes in patients with non-dialysis chronic kidney disease (CKD), a total of 2,158 subjects from a prospective cohort study (Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease) were divided into the quartile by serum TG level. The primary outcomes were composite renal events, which is defined as a composite of decline of kidney function (the first occurrence of > 50% decline of estimated glomerular filtration rate or doubling of serum creatinine from the baseline) or onset of end-stage renal disease (initiation of dialysis or kidney transplantation). During the median follow-up of 6.940 years, the cumulative incidence of composite renal event was significantly differed by serum TG level in Kaplan-Meier curve analysis (P < 0.001, by Log-rank test). Cox regression analysis demonstrated that, compared to that of the 1st quartile, the risk of composite renal event was significantly higher in the 4th quartile (adjusted hazard ratio 1.433, 95% confidence interval 1.046 to 1.964). The association between high serum TG level and adverse renal outcome remained consistent in the cause-specific hazard model. Subgroup analyses revealed that the association is modified by age, estimated glomerular filtration rate, and spot urine albumin-to-creatinine ratio. In conclusion, high serum TG level is independently associated with adverse renal outcomes in patients with non-dialysis CKD. Interventional studies are warranted to determine whether lowering serum TG levels may alter the natural course of CKD.

Non-High-Density Lipoprotein Cholesterol and Progression of Chronic Kidney Disease: Results from the KNOW-CKD Study

As the relation between serum non-high-density lipoprotein cholesterol (nHDL) level and renal outcomes has never been investigated in patients with non-dialysis chronic kidney disease (CKD) yet, we here aimed to unveil the association of nHDL with CKD progression. A total of 2152 patients with non-dialysis CKD at stages 1 to 5 from the KNOW-CKD study were categorized into the tertile (i.e., 1st (T1), 2nd (T2), and 3rd (T3) tertiles) by nHDL, and were prospectively analyzed. The primary outcome was the composite renal event, defined as a composite of decline of kidney function or onset of end-stage renal disease. Kaplan-Meier survival curves analysis demonstrated that the cumulative incidence of the composite renal event was significantly increased in T1 and T3, compared to T2 (p = 0.028, by Log-rank test). Cox regression analysis revealed that both T1 (adjusted hazard ratio 1.309, 95% confidence interval 1.074-1.595) and T3 (adjusted hazard ratio 1.272, 95% confidence interval 1.040-1.556) are associated with significantly increased risk of a composite renal event, compared to T2. The restricted cubic spline plot demonstrated a non-linear, U-shaped association between nHDL and the risk of a composite renal event. In conclusion, both low and high serum nHDL levels are associated with increased risk of CKD progression.

The Molecular Effects of SGLT2i Empagliflozin on the Autophagy Pathway in Diabetes Mellitus Type 2 and Its Complications.

Background Type 2 diabetes mellitus (T2DM), especially hyperglycemia, is associated with increased glucose cell toxicity and oxidative stress that can lead to irreversible damage in the kidney such as diabetic nephropathy (DN). Autophagy plays a key role in the degradation of damaged intracellular proteins in order to maintain intracellular homeostasis and cell integrity. The disturbance of autophagy is involved in the pathogenesis of diabetic nephropathy. We aim to investigate the molecular effect of sodium-glucose transporter 2 inhibitor (SGLT2i) on the expression of ATG5 and its downstream collaborator LC3-II in diabetic nice model. Material and Methods. We used eight weeks old male mice: twenty C57BL/6 wild type (C57BL/6), twenty BTBR ob/ob (DM), and twenty BTBR ob/ob that were treated with empagliflozin (DM+EMPA), FDA approved SGLT2i. Lysate from murine renal cortex was analyzed by Western blot and immunohistochemistry. ATG5, LC3B, and fibronectin expression were analyzed in murine kidney tissues. All mice were sacrificed 13 weeks after the beginning of the experiment. Results Histological and Western blot analyses reveal decrease ATG5, LC3-II, and fibronectin levels at renal specimens taken from DM mice. EMPA treatment reduced T2DM mice body weight and blood glucose and increased urine glucose. Further, it upregulated all of the abovementioned proteins. Conclusions Hyperglycemia reduces LC3-II and ATG5 protein levels which contribute to deficiencies in the autophagy process, with development and progression of DN. SGLT2i significantly reduces progression of DN and onset of end-stage renal disease in T2DM patients, probably through its effect on autophagy.

A disease progression model estimating the benefit of tolvaptan on time to end-stage renal disease for patients with rapidly progressing autosomal dominant polycystic kidney disease

BackgroundTolvaptan was approved in the United States in 2018 for patients with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression as assessed in a 3-year phase 3 clinical trial (TEMPO 3:4). An extension study (TEMPO 4:4) showed continued delay in progression at 2 years, and a trial in patients with later-stage disease (REPRISE) provided confirmatory evidence of efficacy. Given the relatively shorter-term duration of the clinical trials, estimating the longer-term benefit associated with tolvaptan via extrapolation of the treatment effect is an important undertaking.MethodsA model was developed to simulate a cohort of patients with ADPKD at risk of rapid progression and predict their long-term outcomes using an algorithm organized around the Mayo Risk Classification system, which has five subclasses (1A through 1E) based on estimated kidney growth rates. The model base-case population represents 1280 patients enrolled in TEMPO 3:4 beginning in chronic kidney disease (CKD) stages G1, G2, and G3 across Mayo subclasses 1C, 1D, and 1E. The algorithm was used to predict longer-term natural history health outcomes. The estimated treatment effect of tolvaptan from TEMPO 3:4 was applied to the natural history to predict the longer-term treatment benefit of tolvaptan. For the cohort, analyzed once reflecting natural history and once assuming treatment with tolvaptan, the model estimated lifetime progression through CKD stages, end-stage renal disease (ESRD), and death.ResultsWhen treated with tolvaptan, the model cohort was predicted to experience a 3.1-year delay of ESRD (95% confidence interval: 1.8 to 4.4), approximately a 23% improvement over the estimated 13.7 years for patients not receiving tolvaptan. Patients beginning tolvaptan treatment in CKD stages G1, G2, and G3 were predicted to experience estimated delays of ESRD, compared with patients not receiving tolvaptan, of 3.8 years (21% improvement), 3.0 years (24% improvement), and 2.1 years (28% improvement), respectively.ConclusionsThe model estimated that patients treated with tolvaptan versus no treatment spent more time in earlier CKD stages and had later onset of ESRD. Findings highlight the potential long-term value of early intervention with tolvaptan in patients at risk of rapid ADPKD progression.

Tuberculosis treatment delay and nosocomial exposure remain important risks for patients undergoing regular hemodialysis.

Studies have reported an increased tuberculosis (TB) incidence among patients with end-stage renal disease (ESRD). This nationwide nested Case-control study investigated the risk of active TB due to nosocomial exposure and its correlation with the delay in TB treatment in hemodialysis patients. Adult (aged ≥20 years) patients with incident ESRD over 2000-2010 were identified from Taiwan National Health Insurance Research Database; 2331 patients with incident active TB (Case) were matched with 11,655 patients without TB (control) by age, sex, year of ESRD onset, Charlson comorbidity index, chronic obstructive pulmonary disease, and diabetes mellitus, at a 1:5 case-to-control ratio. Compared with the control group, the Case group had greater nosocomial exposure to index patients with pulmonary TB (2.36 vs. 0.11 month of exposure, p<0.001). Nosocomial exposure increased active TB risk (adjusted odds ratio [OR; 95% confidence interval, CI]: 1.60 [1.55-1.66] per month of exposure), particularly when the exposure time was either within 6 months before the index case was diagnosed or 6-15 months before the ESRD patient became an incident active TB case. For patients with active TB, cough-related medication prescriptions (proxy for cough symptoms) exponentially increased over 6 months before TB treatment. Nosocomial exposure attributed to delay in the diagnosis of index pulmonary TB is important in TB transmission among patients undergoing regular hemodialysis. Additional studies investigating how TB can be diagnosed and treated early are warranted. Our study revealed that nosocomial exposure, attributed to delay in pulmonary TB diagnosis, is important in TB transmission among patients undergoing regular hemodialysis. Strategies to diagnose and treat TB early are crucial to infection control, and they warrant further investigations.

A single-center analysis of genotype-phenotype characteristics of Chinese patients with autosomal dominant polycystic kidney disease by targeted exome sequencing.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is mainly caused by PKD1 and PKD2 mutations. However, only a few studies have investigated the genotype and phenotype characteristics of Asian patients with ADPKD. This study aimed to investigate the relationship between the natural course of ADPKD genotype and phenotype. Methods: Genetic studies of PKD1/2 genes of Chinese patients with ADPKD in a single center were performed using targeted exome sequencing and next-generation sequencing on peripheral blood DNA. Results: Among the 140 patients analyzed, 80.00% (n = 112) harbored PKD1 mutations, 11.43% (n = 16) harbored PKD2 mutations, and 8.57% (n = 12) harbored neither PKD1 nor PKD2 mutations. The average age at dialysis was 52.60 ± 11.36, 60.67 ± 5.64, and 52.11 ± 14.63 years, respectively. The renal survival rate of ADPKD patients with PKD1 mutations (77/112) was significantly lower than that of those with PKD2 mutations (9/16), leading to an earlier onset of end-stage renal disease (ESRD). Renal prognosis was poor for those with nonsense mutations, and they required earlier renal replacement therapy. Conclusions: The genotype and phenotype characteristics of ADPKD patients potentially vary across ethnic groups. Our findings supplement the genetic profiles of Chinese ADPKD patients, could serve as a guide for therapy monitoring and prognosis assessment of ADPKD, and may improve the clinical diagnosis.

Urinary Angiotensinogen and Progression of Chronic Kidney Disease: Results from KNOW-CKD Study

The prognostic value of urinary angiotensinogen (UAGT) in patients with chronic kidney disease (CKD) has not been completely evaluated, although the association of UAGT with renal outcomes has been suggested in specific subsets of CKD. In the present study, to investigate the association of UAGT with renal outcomes in patients with non-dialysis CKD irrespective of the primary cause, a total of 1688 subjects from the Korean Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD) were prospectively analyzed. The subjects were divided into the quintile by UAGT to urine creatinine ratio (UAGT/Cr) level. The primary outcomes of interest were composite renal event, which included decline in kidney function and onset of end-stage renal disease during follow-up periods. The median follow-up duration was 6.257 years. Cox regression model analysis unveiled that the risk of composite renal event was significantly higher in the fifth quintile (adjusted hazard ratio 1.528, 95% confidence interval 1.156 to 2.021) compared to that of the first quartile. The association between high UAGT/Cr level and adverse renal outcome remained consistent in sensitivity analyses, including the analysis of the cause-specific hazard model. Subgroup analyses revealed that the association of UAGT level with renal outcomes is modified by certain clinical contexts, such as BMI and albuminuria. In conclusion, high UAGT level is associated with adverse renal outcomes in patients with non-dialysis CKD. Further studies are warranted to elaborate and expand the predictive role of UAGT as a biomarker for renal outcomes in CKD.

Prescribing Patterns of Hydroxychloroquine and Glucocorticoids Among Lupus Patients After New-Onset End-Stage Renal Disease.

Optimal strategies for managing lupus medications after end-stage renal disease (ESRD) have not been addressed. The objective was to identify the current US-wide prescribing patterns of hydroxychloroquine (HCQ) and oral glucocorticoids (GS) among systemic lupus erythematosus (SLE) patients with incident ESRD enrolled in the US Renal Data System (USRDS) registry. We identified incident ESRD patients age ≥18 years with SLE as a primary cause of ESRD between January 2006 and June 2013. Patients who were started on dialysis at ESRD onset and enrolled in Medicare Part D within 93 days as required by Medicare were included. Among the 2,654 new-onset ESRD patients with Part D, the median duration of follow-up was 761 days (interquartile range [IQR] 374-1,375). At baseline, 1,076 patients (41%) were not receiving HCQ or GS, 220 (8%) were prescribed HCQ alone, 509 (19%) were prescribed both HCQ and GS, and 849 (32%) were prescribed GS alone. Of the 1,983 patients who either never received or discontinued HCQ after ESRD onset, 667 (34%) continued GS to the end of the follow-up period. The median GS dose was lower for patients taking HCQ (14 mg [IQR 9-21]) compared to patients who were never prescribed HCQ (15 mg [IQR 9-27]) or patients who discontinued HCQ after ESRD (17 mg [IQR 10-27]; P=0.001). Approximately one-third of patients with lupus nephritis and new-onset ESRD received GS monotherapy at high doses. As GS-related complications contribute to hospitalizations and deaths in SLE ESRD, changing these prescribing practices may improve morbidity and mortality outcomes.

NPHP3 splice acceptor site variant is associated with infantile nephronophthisis and asphyxiating thoracic dystrophy; A rare combination

Nephronophthisis (NPHP) is a group of rare inherited ciliopathy disorders characterized by the multicystic dysplastic kidney, oligohydramnios, and tubulointerstitial nephritis that progresses to end-stage renal disease (ESRD). NPHP is a clinically and genetically heterogeneous disorder with extrarenal symptoms including skeletal deformities, nervous system anomalies, and ophthalmologic features. Three clinical subtypes, infantile, juvenile, and adolescent, have been recognized based on age of onset of ESRD. Infantile nephronophthisis with asphyxiating thoracic dystrophy is a very rare association. Here, we investigated a consanguineous family having two neonates with a clinical phenotype of lethal infantile NPHP associated with asphyxiating thoracic dystrophy. Whole exome sequence data analysis identified a splice acceptor site variant (Chr3-132408107-CCT-C; NM_153240.4: c.2694-2_2694-1del) in the NPHP3 gene. The segregation of a variant in the family was confirmed by Sanger sequencing. The lethal phenotype in our case might be due to respiratory insufficiency secondary to a severely restricted thoracic cage. Present work is an exclusive depiction of lethal infantile NPHP phenotype in association with asphyxiating thoracic dystrophy that has not been reported before in families segregating NPHP3 mutations. Moreover, this work expands the phenotypic spectrum of NPHP3 variants. Overall, our findings add to the increasing body of evidence that mutations in ciliary genes/proteins show pleiotropic effects with phenotypic overlap between related disorders and apparently unrelated clinical entities.