Development Of Kidney Failure Research Articles

Proteomics and Incident Kidney Failure in Individuals With CKD: The African American Study of Kidney Disease and Hypertension and the Boston Kidney Biopsy Cohort

Individuals with chronic kidney disease (CKD) are at increased risk of morbidity and mortality, particularly as they progress to kidney failure. Identifying circulating proteins that underlie kidney failure development may guide the discovery of new targets for intervention. Prospective cohort. 703 African American Study of Kidney Disease and Hypertension (AASK) and 434 Boston Kidney Biopsy Cohort (BKBC) participants with baseline proteomics data. Circulating proteins measured using SomaScan. Kidney failure, defined as dialysis initiation or kidney transplantation. Using adjusted Cox models, we studied associations of 6,284 circulating proteins with kidney failure risk separately in AASK and BKBC and meta-analyzed results. We then performed gene set enrichment analyses to identify underlying perturbations in biological pathways. In separate data sets with kidney-tissue level gene expression, we ascertained dominant regions of expression and correlated kidney tubular gene expression with fibrosis and estimated glomerular filtration rate (eGFR). Over median follow-up periods of 8.8 and 3.1 years, 210 AASK (mean age: 55 years, 39% female, mean GFR: 46mL/min/1.73m2) and 115 BKBC (mean age: 54 years, 47% female, mean eGFR: 51mL/min/1.73m2) participants developed kidney failure, respectively. We identified 143 proteins that were associated with incident kidney failure, of which only 1 (Testican-2) had a lower risk. Notable proteins included those related to vascular permeability (endothelial cell-selective adhesion molecule), glomerulosclerosis (ephrin-A1), glomerular development (ephrin-B2), intracellular sorting/transport (vesicular integral-membrane protein VIP36), podocyte effacement (pigment epithelium-derived factor), complement activation (complement decay-accelerating factor), and fibrosis (ephrin-A1, ephrin-B2, and pigment epithelium-derived factor). Gene set enrichment analyses detected overrepresented pathways that could be related to CKD progression, such as ephrin signaling, cell-cell junctions, intracellular transport, immune response, cell proliferation, and apoptosis. At the kidney level, glomerular expression predominated for genes corresponding to circulating proteins of interest, and several gene expression levels were correlated with eGFR and/or fibrosis. Possible residual confounding. Multimodal data identified proteins and pathways associated with the development of kidney failure.

Urinary Sodium Excretion and Kidney Disease Progression in IgA Nephropathy: A Cohort Study

Introduction: The role of dietary sodium intake in the risk of chronic kidney disease progression remains controversial. This study aimed to evaluate the association of urinary sodium excretion and progression of IgA nephropathy. Methods: We assessed 596 patients with IgA nephropathy, and urinary sodium excretion was measured at the time of kidney biopsy. Cox proportional hazards models and restricted cubic splines were used to assess the association between urinary sodium excretion and kidney disease progression events, defined as 50% eGFR decline or development of kidney failure. Results: After a mean follow-up of 58.9 months, a total of 75 (12.6%) participants of IgA nephropathy reached composite kidney disease progression events. The risk of kidney disease progression events was higher in patients with higher urinary sodium excretion. After adjustment for traditional risk factors, higher levels of ln-transformed urinary sodium excretion was associated with the kidney disease progression events in patients with IgA nephropathy (HR: 2.1; 95% CI: 1.4–3.2). In reference to the first tertile of urinary sodium excretion, hazard ratios were 1.9 (95% CI: 1.0–3.4) for the second tertile and 2.1 (95% CI: 1.1–3.9) for the third tertile. Conclusion: Higher levels of urinary sodium excretion were associated with kidney disease progression events in IgA nephropathy independent of clinical and biopsy characteristics.

Association between progression of coronary artery calcification and development of kidney failure with replacement therapy: Findings from KNOW-CKD study

Background and aimsHigh coronary artery calcification (CAC) burden is a significant risk factor for adverse cardiovascular and kidney outcomes. However, it is unknown whether changes in the coronary atherosclerotic burden can accompany changes in kidney disease progression. Here, we evaluated the relationship between CAC progression and the risk of kidney failure with replacement therapy (KFRT). MethodsWe analyzed 1173 participants with chronic kidney disease (CKD) G1 to G5 without kidney replacement therapy from the KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD). Participants were categorized into three groups according to the change in the CAC score between enrollment and year 4 (non-progressors, ≤0 AU; moderate progressors, 1–199 AU; and severe progressors, ≥200 AU). The primary outcome was the development of KFRT. ResultsDuring a follow-up period of 4690 person-years (median, 4.2 years), the primary outcome occurred in 230 (19.6 %) participants. The incidence of KFRT was 37.6, 54.3, and 80.9 per 1000 person-years in the non-, moderate, and severe progressors, respectively. In the multivariable cause-specific hazard model, the hazard ratios (HRs) for the moderate and severe progressors were 1.71 (95 % confidence interval [CI], 1.02–2.87) and 2.55 (95 % CI, 1.07–6.06), respectively, compared with non-progressors. A different definition of CAC progression with a threshold of 100 AU yielded similar results in a sensitivity analysis. ConclusionsCAC progression is associated with an increased risk of KFRT in patients with CKD. Our findings suggest that coronary atherosclerosis changes increase the risk of CKD progression.

Clinicopathologic Characteristics, Etiologies, and Outcome of Secondary Oxalate Nephropathy

ObjectiveTo report the clinicopathologic characteristics, prognostic indicators, prognosis, and transplant outcome of secondary oxalate nephropathy (ON). Patients and MethodsWe performed a retrospective analysis of 113 consecutive patients with secondary ON diagnosed at Mayo Clinic in Rochester, Minnesota, between January 1, 2001, and March 1, 2023. ResultsThe incidence of secondary ON among all native biopsies from Mayo Clinic patients over the study period (n=11,617) was 0.97%. ON was attributed to enteric hyperoxaluria in 60% of the 113 patients (68; most commonly Roux-en-Y gastric bypass), excessive ingestion of foods high in oxalate or oxalate precursors in 23% (26) (most commonly vitamin C), and idiopathic in 17% (19). Most patients presented with acute kidney injury (AKI) (particularly in the ingestion group) or AKI on chronic kidney disease, and 53% (60 of 113) were diabetic. Calcium oxalate crystals were accompanied by acute tubular injury, inflammation, and interstitial fibrosis and tubular atrophy. Concurrent pathologic conditions were present in 53% of the patients (60 of 113), most commonly diabetic nephropathy. After a median follow-up of 36 months, 27% of the patients (30 of 112) had kidney recovery, 19% (21 of 112) had persistent kidney dysfunction, 54% (61 of 112) had development of kidney failure, and 29% (32 of 112) died. The mean kidney survival was worse for patients with a concurrent pathologic lesion (30 months vs 96 months for those without a concurrent pathologic lesion; P<.001). Independent predictors of kidney failure were the degree of interstitial fibrosis and tubular atrophy and nadir estimated glomerular filtration rate but not the degree of crystal deposition. After a median follow-up of 58 months in 23 patients who received kidney transplant, 4 had graft loss (due to ON in 3). The 2-, 5-, and 10-year graft survivals were 90% (18 of 20), 79% (11 of 14), and 50% (6 of 12). ConclusionON is a rare cause of AKI or AKI on chronic kidney disease. Most patients have comorbid pathologic conditions, particularly diabetic nephropathy, which worsen the prognosis. Recurrence in the renal allograft and graft loss may occur if hyperoxaluria is not controlled.

Evaluación de los niveles de adropina en el tejido renal después del tratamiento con Metotrexato en ratas: un estudio experimental prospectivo

In this study, it was aimed to investigate Adropin levels in kidney tissues after Methotrexate (MTX) administration to identify potential changes following administration of agents with antioxidant/anti–inflammatory potential. Twenty four adult rats male albino Wistar rats were used in this study, and randomly divided into four groups. Control: These rats did not receive any treatment during the 14–day (d) experiment. N–acetylcysteine (NAC): These rats were administered 100 mg·kg-1·day-1 NAC intraperitoneally (i.p.) for 14 d. MTX: A single dose of 20 mg·kg-1 MTX was administered i.p. at the beginning of the study. MTX+ NAC: A single dose of 20 mg·kg-1 MTX was administered i.p. at the beginning of the study, and the rats were given 100 mg·kg-1·day-1 NAC i.p. for 14 d. Total antioxidant, and serum Adropin levels were found to be the lowest in the MTX group while the oxidant levels were significantly lower in the MTX group than in the MTX+NAC group (P&lt;0.001). TUNEL positivity was similar among the groups, and no significant differences were observed. It was considered that these findings have shed light on the role of Adropin in the development of kidney failure following MTX administration.

Association Between Progression of Coronary Artery Calcification and Development of Kidney Failure with Replacement Therapy: Findings from KNOW-CKD Study

Association Between Progression of Coronary Artery Calcification and Development of Kidney Failure with Replacement Therapy: Findings from KNOW-CKD Study

Abnormal lactate metabolism is linked to albuminuria and kidney injury in diabetic nephropathy

Diabetic nephropathy (DN) is characterized by abnormal kidney energy metabolism, but its causes and contributions to DN pathogenesis are not clear. To examine this issue, we carried out targeted metabolomics profiling in a mouse model of DN that develops kidney disease resembling the human disorder. We found a distinct profile of increased lactate levels and impaired energy metabolism in kidneys of mice with DN, and treatment with an angiotensin-receptor blocker (ARB) reduced albuminuria, attenuated kidney pathology and corrected many metabolic abnormalities, restoring levels of lactate toward normal while increasing kidney ATP content. We also found enhanced expression of lactate dehydrogenase isoforms in DN. Expression of both the LdhA and LdhB isoforms were significantly increased in kidneys of mice, and treatment with ARB significantly reduced their expression. Single-cell sequencing studies showed specific up-regulation of LdhA in the proximal tubule, along with enhanced expression of oxidative stress pathways. There was a significant correlation between albuminuria and lactate in mice, and also in a Southeast Asian patient cohort consisting of individuals with type 2 diabetes and impaired kidney function. In the individuals with diabetes, this association was independent of ARB and angiotensin-converting enzyme inhibitor use. Furthermore, urinary lactate levels predicted the clinical outcomes of doubling of serum creatinine or development of kidney failure, and there was a significant correlation between urinary lactate levels and biomarkers of tubular injury and epithelial stress. Thus, we suggest that kidney metabolic disruptions leading to enhanced generation of lactate contribute to the pathogenesis of DN and increased urinary lactate levels may be a potential biomarker for risk of kidney disease progression.

The ASSESS-AKI Study found urinary epidermal growth factor is associated with reduced risk of major adverse kidney events

Biomarkers of tubular function such as epidermal growth factor (EGF) may improve prognostication of participants at highest risk for chronic kidney disease (CKD) after hospitalization. To examine this, we measured urinary EGF (uEGF) from samples collected in the Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) Study, a multi-center, prospective, observational cohort of hospitalized participants with and without AKI. Cox proportional hazards regression was used to investigate the association of uEGF/Cr at hospitalization, three months post-discharge, and the change between these time points with major adverse kidney events (MAKE): CKD incidence, progression, or development of kidney failure. Clinical findings were paired with mechanistic studies comparing relative Egf expression in mouse models of kidney atrophy or repair after ischemia-reperfusion injury. MAKE was observed in 20% of 1,509 participants over 4.3 years of follow-up. Each 2-fold higher level of uEGF/Cr at three months was associated with decreased risk of MAKE (adjusted hazards ratio 0.46, 95% confidence interval: 0.39-0.55). Participants with the highest increase in uEGF/Cr from hospitalization to three-month follow-up had a lower risk of MAKE (adjusted hazards ratio 0.52; 95% confidence interval: 0.36-0.74) compared to those with the least change in uEGF/Cr. A model using uEGF/Cr at three months combined with clinical variables yielded moderate discrimination for MAKE (area under the curve 0.73; 95% confidence interval: 0.69-0.77) and strong discrimination for kidney failure at four years (area under the curve 0.96; 95% confidence interval: 0.92-1.00). Accelerated restoration of Egf expression in mice was seen in the model of adaptive repair after injury, compared to a model of progressive atrophy. Thus, urinary EGF/Cr may be a biomarker of distal tubular health, with higher concentrations and increased uEGF/Cr post-discharge independently associated with reduced risk of MAKE in hospitalized patients.

Determinants of Kidney Failure in Primary Hyperoxaluria Type 1: Findings of the European Hyperoxaluria Consortium

Primary hyperoxaluria type 1 (PH1) has a highly heterogeneous disease course. Apart from the c.508G>A (p.Gly170Arg) AGXT variant, which imparts a relatively favorable outcome, little is known about determinants of kidney failure. Identifying these is crucial for disease management, especially in this era of new therapies. In this retrospective study of 932 patients with PH1 included in the OxalEurope registry, we analyzed genotype-phenotype correlations as well as the impact of nephrocalcinosis, urolithiasis, and urinary oxalate and glycolate excretion on the development of kidney failure, using survival and mixed model analyses. The risk of developing kidney failure was the highest for 175 vitamin-B6 unresponsive ("null") homozygotes and lowest for 155 patients with c.508G>A and c.454T>A (p.Phe152Ile) variants, with a median age of onset of kidney failure of 7.8 and 31.8 years, respectively. Fifty patients with c.731T>C (p.Ile244Thr) homozygote variants had better kidney survival than null homozygotes (P= 0.003). Poor outcomes were found in patients with other potentially vitamin B6-responsive variants. Nephrocalcinosis increased the risk of kidney failure significantly (hazard ratio [HR] 3.17 [2.03-4.94], P< 0.001). Urinary oxalate and glycolate measurements were available in 620 and 579 twenty-four-hour urine collections from 117 and 87 patients, respectively. Urinary oxalate excretion, unlike glycolate, was higher in patients who subsequently developed kidney failure (P= 0.034). However, the 41% intraindividual variation of urinary oxalate resulted in wide confidence intervals. In conclusion, homozygosity for AGXT null variants and nephrocalcinosis were the strongest determinants for kidney failure in PH1.

#5476 SEX DIFFERENCES IN INCIDENT KIDNEY FAILURE AND THE IMPACT OF RISK FACTORS IN A POPULATION STUDY

Abstract Background and Aims Chronic kidney disease (CKD) has different effects on women and men. Women are more likely to have CKD, but men are more likely to develop kidney failure requiring treatment (KFRT: dialysis or transplantation). Recent studies have highlighted sex differences in CKD progression and there is a need to determine if this relates to differential effects of risk factors. Method We used primary care data stored within the electronic health records repository Secure Anonymised Information Linkage Databank (SAIL) for adults with CKD stages G3/4 (estimated glomerular filtration rate (eGFR) 15-59 mL/min/1.73 m2) living in Wales, UK. We studied the relationship between sex and the development of kidney failure (KFRT or incident eGFR&amp;lt;15 mL/min/1.73 m2 for ≥3 months). Sex-specific rates of kidney failure were compared using an event plot with patients censored on the date of death. Cox proportional hazards models tested associations between sex and kidney failure, before and after adjustment for other known risk factors (age, baseline eGFR, smoking, social deprivation, diabetes mellitus and hypertension). Interactions between sex and risk factors were sought and interaction terms were retained if these were statistically significant (p-value&amp;lt;0.05). Models were then stratified by sex to compare the impact of risk factors in men and women. Results 135,635 patients (median age 78 years, 57% female, median baseline eGFR 50 mL/min/1.73 m2) were followed up for a median of 6.8 years, representing a total of 782,237 patient years. 1.1% of women and 2.3% of men developed kidney failure. An unadjusted Cox model including both sexes showed a hazard ratio of 2.06 (95% confidence interval 1.89-2.24) for men. After adjustment for all risk factors and inclusion of interaction terms (between sex and baseline eGFR and sex and age), men were not more likely to develop kidney failure (aHR 0.91, 0.60-1.38) (Figure 1A). In sex-stratified models, kidney failure was most likely to develop in those with low baseline eGFR, younger age, current and ex-smokers, patients with diabetes mellitus and patients with hypertension (Figure 1B). Diabetes was a more important risk factor for kidney failure in women (aHR in women 1.73 (1.51-1.98) compared with men (aHR 1.56, 1.39-1.74). Hazard ratios for other risk factors were similar in men and women. Conclusion We found that sex differences in rates of kidney failure are related to a differential impact of risk factors – in particular diabetes – on CKD progression. These results warrant further investigation with a need to determine whether risk reduction strategies should be different in men and women with CKD, or whether current diagnosis, monitoring and treatment strategies are either applied differentially or have different benefit and harms by sex.

#4204 MULTIPARAMETRIC MAGNETIC RESONANCE IMAGING BIOMARKERS OUTPERFORM LAB BIOMARKERS FOR PREDICTING PROGRESSION OF DIABETIC KIDNEY DISEASE

Abstract Background and Aims We recently showed that comprehensive non-contrast multiparametric Magnetic Resonance Imaging (mpMRI) allowed functional and structural assessment of diabetic kidney disease (DKD) and that an imaging endpoint, R1 cortex, showed significant predictive property for progression of DKD. We further investigated the performance of other MRI and lab biomarkers for predicting disease progression. Method In this prospective study, 38 DKD subjects aged 18–79 years and 20 age- and gender-matched healthy volunteers (HV) were included at baseline. 31 DKD subjects (2 stage 2, 13 stage 3, 14 stage 4, and 2 stage 5) and 17 HV were re-examined at 2 years ± 6 months. Clinical and lab examination, iohexol clearance for measured glomerular filtration rate (mGFR), urine albumin:creatinine ratio (UACR) and mpMRI were performed at both visits. A wide range of MRI biomarkers associated with kidney hemodynamics, oxygenation and macro/microstructure were included for evaluation. Disease progression was defined by at least one of the following at 2 years: decrease in mGFR slope of &amp;gt;5 mL/year/1.73 m2; worsening UACR category; or any major adverse kidney event defined as sustained decrease in eGFR of &amp;gt;40%; doubling of serum creatinine from baseline; development of kidney failure with mGFR &amp;lt;15 ml/min/1.73 m2; or death from renal cause. Univariable logistic regression analyses were performed to discriminate between progressors and non-progressors using each relevant lab and imaging endpoint as a predictor variable. Results Mean 2-year mGFR decline (ml/min/1.73 m2) in DKD patients was -2.7± 5.4 and in HV -1.9 ± 10.7. 13/31 (42%) DKD subjects and 4/17 (24%) HV progressed. Key lab biomarkers are shown in Table 1 and MRI biomarkers in Table 2. Conclusion Of all analyzed biomarkers, only the imaging biomarker R1 cortex, which reflects molecular environment viscosity, fibrosis, and inflammation (interstitial oedema, cellular swelling) showed significant predictive property for progression of DKD. UACR trended towards significance but was not statistically significant. R1 cortex outperformed all other imaging and lab biomarkers, but further studies with R1 cortex as a pre-specified endpoint are required to confirm these results.

Dietary Patterns, Apolipoprotein L1 Risk Genotypes, and CKD Outcomes Among Black Adults in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Cohort Study

Dietary factors may impact inflammation and interferon production, which could influence phenotypic expression of Apolipoprotein1 (APOL1) genotypes. We investigated whether associations of dietary patterns with kidney outcomes differed by APOL1 genotypes. Prospective cohort. 5,640 Black participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS). Five dietary patterns derived from food frequency questionnaires: Convenience foods, Southern, Sweets and Fats, Plant-based, and Alcohol/Salads. Incident chronic kidney disease (CKD), CKD progression, and kidney failure. Incident CKD was defined as a change in estimated glomerular filtration rate (eGFR) to<60mL/min/1.73m2 accompanied by a≥25% decline from baseline eGFR or development of kidney failure among those with baseline eGFR≥60mL/1.73m2 body surface area. CKD progression was defined as a composite of 40% reduction in eGFR from baseline or development of kidney failure in the subset of participants who had serum creatinine levels at baseline and completed a second in-home visit/follow-up visit. We examined associations of dietary pattern quartiles with incident CKD (n=4,188), CKD progression (n=5,640), and kidney failure (n=5,640). We tested for statistical interaction between dietary patterns and APOL1 genotypes for CKD outcomes and explored stratified analyses by APOL1 genotypes. Among 5,640 Black REGARDS participants, mean age was 64 years (standard deviation=9), 35% were male, and 682 (12.1%) had high-risk APOL1 genotypes. Highest versus lowest quartiles (Q4 vs Q1) of Southern dietary pattern were associated with higher adjusted odds of CKD progression (OR, 1.28; 95% CI, 1.01-1.63) but not incident CKD (OR, 0.92; 95% CI, 0.74-1.14) or kidney failure (HR, 1.48; 95% CI, 0.90-2.44). No other dietary patterns showed significant associations with CKD. There were no statistically significant interactions between APOL1 genotypes and dietary patterns. Stratified analysis showed no consistent associations across genotypes, although Q3 and Q4 versus Q1 of Plant-based and Southern patterns were associated with lower odds of CKD progression among APOL1 high- but not low-risk genotypes. Included overlapping dietary patterns based on a single time point and multiple testing. In Black REGARDS participants, Southern dietary pattern was associated with increased risk of CKD progression. Analyses stratified by APOL1 genotypes suggest associations may differ by genetic background, but these findings require confirmation in other cohorts.

Pathogenetic relationship between kidney pathologies and the microcirculatory capillary layer in dogs under the influence of Babesia canis

With babesiosis in dogs, the capillary network is especially strongly affected due to the stimulation of the hemostasis system and the development of thrombus formation in the microvasculature. Acute renal failure and even death of animals are caused by shock phenomena and the syndrome of disseminated intravascular coagulation. Clinical, laboratory (hematological, biochemical, coagulometric, hemodynamic, enzyme immunoassay) methods of research were conducted. Dogs with babesiosis have fever, anemia, and hemoglobinuria, hematologically established anemia, systemic inflammation, thrombotic condition. Hemodynamic parameters determine the state of shock, which in dynamics becomes decompensated and irreversible. The appearance of poikilocytes in the blood of sick dogs indicates significant metabolic disorders in their body. The coagulogram reveals the syndrome of disseminated intravascular coagulation. Syndrome markers significantly changed with a trend to increase during nephropathy. In addition, uremia, hyperuricemia, hyperkalemia, hyponatremia, hyperphosphatemia, creatininemia were found in the sick dogs, which are reliable indicators and determine the development of an acute form of glomerulonephritis and progressive acute renal failure. According to the study of the general biochemical status in animals, hepatopathy in the form of acute hepatitis and pancreatitis, and general intoxication syndrome were established. In our findings: during acute spontaneous babesiosis, dogs developed nephropathy, which has two clinical stages: hemoglobinuria and oliguria/anuria. The pathogenetic basis for the development of glomerulonephritis and acute renal failure is the syndrome of disseminated intravascular coagulation in response to the influence of a pathogen, which causes shock, forming a vicious circle of shock. Under such conditions, renal failure increases and eventually leads to the death of the animal. The studied data will contribute to the expansion of the conceptual understanding of the pathogenesis of canine babesiosis and determine the leading role of complications in the development of kidney failure.

Baseline anxiety disorders are associated with progression of diabetic kidney disease in type 2 diabetes

Background Diabetic kidney disease (DKD) is a leading cause of kidney failure worldwide. Anxiety has been associated with disease progression in non-diabetes patients. We aimed to examine the prospective association between anxiety and progression of DKD in type 2 diabetes. Methods We conducted a prospective cohort study of 2040 participants with type 2 diabetes at the Diabetes Center of Shanghai General Hospital between May 2017 and June 2020. Anxiety disorders at baseline were diagnosed by a structured clinical interview based on the 10th Revision of International Classification of Disease (ICD). Progression of DKD was identified as the transition from one urinary albumin excretion rate (AER) stage to the next or the development of kidney failure during the follow-up period. Results At baseline, 403 (19.8%) had a diagnosis of anxiety disorders, of whom 107 (26.6%) also received a depression diagnosis. During a median follow-up time of 3.2 years, deterioration of the kidney status occurred in 340 (16.7%) individuals. After adjustment for potential confounders including depression or an anxiety × depression interaction term, anxiety disorders were independently related to an increased risk of progression of DKD (HR 1.539, 95% CI 1.130–2.095, p = 0.006; HR 1.536, 95% CI 1.111–2.122, p = 0.009, respectively). Conclusions Anxiety disorders at baseline, independent of possible confounders, were associated with the progression of DKD in type 2 diabetes. Whether therapeutic interventions for anxiety reduce the risk needs to be investigated.

Genotype and phenotype analysis and transplantation strategy in children with kidney failure caused by NPHP

BackgroundNephronophthisis-related ciliopathies (NPHP-RC) have strong genotype and phenotype heterogeneity, and the transplantation strategy of Boichis syndrome is still controversial. Our purpose was to examine associations of genotype and phenotype in children with NPHP-RC and analyze the transplantation strategies of different phenotypes.MethodsThe records of children with NPHP treated at our center from 01/2018 to 03/2021 were retrospectively reviewed. Inclusion criteria were a diagnosis of NPHP, received kidney transplantation, and received whole exome sequencing (WES) or nephropathy gene panel testing.ResultsTwenty-nine children with NPHP were included. Nine children (31%) had NPHP1 mutations, and all presented with isolated nephropathy. Eighteen of 20 patients with non-NPHP1 mutations had compound heterozygous mutations, and 70% had extrarenal phenotype. Age at disease presentation (11.2 ± 1.94 years) and the development of kidney failure (12.4 ± 2.70 years) were later in children with NPHP1 mutations than those with non-NPHP1 mutations (5.2 ± 2.83 years and 5.7 ± 2.92 years, respectively). Four of six children with NPHP3 mutations were diagnosed with Boichis syndrome due to liver fibrosis. Isolated kidney transplantation resulted in good outcomes for patients with mild or moderate liver fibrosis without portal hypertension, while cholestasis was common postoperatively and could be resolved with ursodeoxycholic acid.ConclusionsNPHP1 mutations are the most common in children with NPHP, and the phenotype of NPHP1 mutation is significantly different from that of non-NPHP1 mutation. For NPHP patients with mild to moderate liver fibrosis without portal hypertension, timely treatment of cholestasis could prevent the rapid progression of liver function damage after isolated kidney transplantation.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information

Angiopoietin-2 inhibition attenuates kidney fibrosis by hindering chemokine C-C motif ligand 2 expression and apoptosis of endothelial cells

Plasma levels of angiopoietin-2 are increased in patients with chronic kidney disease (CKD). Moreover, mouse models of progressive kidney disease also demonstrate increased angiopoietin-2 in both plasmas and kidneys. The role of dysregulated angiopoietins in the progression of kidney disease has not been thoroughly investigated. Here, we found in a cohort of 319 patients with CKD that plasma angiopoietin-2 and angiopoietin-2/angiopoietin-1 ratios were positively associated with the development of kidney failure. In mice with progressive kidney disease induced by either ureteral obstruction or ischemia-reperfusion injury, overexpression of human angiopoietin-1 in the kidney tubules not only reduced macrophage infiltration in the initial stage post-injury but also attenuated endothelial cell apoptosis, microvascular rarefaction, and fibrosis in the advanced disease stage. Notably, angiopoietin-1 attenuated chemokine C-C motif ligand 2 (CCL2) expression in the endothelial cells of the fibrosing kidneys, and these protective effects led to attenuation of functional impairment. Mechanistically, angiopoietin-1 reduced CCL2-activated macrophage migration and protected endothelial cells against cell apoptosis induced by angiopoietin-2 and Wnt ligands. Based on this, we applied L1-10, an angiopoietin-2 inhibitor, to the mouse models of progressive kidney disease and found inhibitory effects on macrophage infiltration, microvascular rarefaction, and fibrosis. Thus, we defined the detrimental impact of increased angiopoietin-2 on kidney survival of patients with CKD which appears highlighted by angiopoietin-2 induced endothelial CCL2-activated macrophage infiltration and endothelial cell apoptosis in their kidneys undergoing fibrosis.

Complement Factor I deficiency: A novel homozygous CFI gene mutation

Complement Factor I deficiency is a very rare autosomal recessive disease, with only 38 cases reported in the literature. It is caused by a homozygous mutation in the CFI gene (complement Factor I), which encodes for the Factor I protein, an important regulator of the complement system. Clinically, complement Factor I deficiency presents various symptoms in several organs. We report the case of a child with a history of seizures and unexplained recurrent fever. Whole exome sequencing revealed a novel homozygous missense CFI gene mutation (V270F) of unknown significance. Using multiple bioinformatics tools, we suggest the probable pathogenicity of this mutation. This analysis will help us manage precisely his case, preventing infections and the development of kidney failure, a possible and fatal consequence of complement Factor I deficiency. This study emphasizes the importance of molecular analysis in the diagnosis of rare and atypical diseases and in the establishment of appropriate and effective care.

Intermediate Renal Outcomes, Kidney Failure, and Mortality in Obese Kidney Donors.

Obesity is associated with the two archetypal kidney disease risk factors: hypertension and diabetes. Concerns that the effects of diabetes and hypertension in obese kidney donors might be magnified in their remaining kidney have led to the exclusion of many obese candidates from kidney donation. We compared mortality, diabetes, hypertension, proteinuria, reduced eGFR and its trajectory, and the development of kidney failure in 8583 kidney donors, according to body mass index (BMI). The study included 6822 individuals with a BMI of <30 kg/m2, 1338 with a BMI of 30-34.9 kg/m2, and 423 with a BMI of ≥35 kg/m2. We used Cox regression models, adjusting for baseline covariates only, and models adjusting for postdonation diabetes, hypertension, and kidney failure as time-varying covariates. Obese donors were more likely than nonobese donors to develop diabetes, hypertension, and proteinuria. The increase in eGFR in obese versus nonobese donors was significantly higher in the first 10 years (3.5 ml/min per 1.73m2 per year versus 2.4 ml/min per 1.73m2 per year; P<0.001), but comparable thereafter. At a mean±SD follow-up of 19.3±10.3 years after donation, 31 (0.5%) nonobese and 12 (0.7%) obese donors developed ESKD. Of the 12 patients with ESKD in obese donors, 10 occurred in 1445 White donors who were related to the recipient (0.9%). Risk of death in obese donors was not significantly increased compared with nonobese donors. Obesity in kidney donors, as in nondonors, is associated with increased risk of developing diabetes and hypertension. The absolute risk of ESKD is small and the risk of death is comparable to that of nonobese donors.

The Indian Chronic Kidney Disease (ICKD) study: baseline characteristics.

ABSTRACTBackgroundChronic kidney disease (CKD) is an important cause of morbidity and mortality worldwide. There is a lack of information on epidemiology and progression of CKD in low–middle income countries. The Indian Chronic Kidney Disease (ICKD) study aims to identify factors that associate with CKD progression, and development of kidney failure and cardiovascular disease (CVD) in Indian patients with CKD.MethodsICKD study is prospective, multicentric cohort study enrolling patients with estimated glomerular filtration rate (eGFR) 15–60 mL/min/1.73 m2, or >60 mL/min/1.73 m2 with proteinuria. Clinical details and biological samples are collected at annual visits. We analysed the baseline characteristics including socio-demographic details, risk factors, disease characteristics and laboratory measurements. In addition, we compared characteristics between urban and rural participants.ResultsA total of 4056 patients have been enrolled up to 31 March 2020. The mean ± SD age was 50.3 ± 11.8 years, 67.2% were males, two-thirds of patients lived in rural areas and the median eGFR was 40 mL/min/1.73 m2. About 87% were hypertensive, 37% had diabetes, 22% had CVD, 6.7% had past history of acute kidney injury and 23% reported prior use of alternative drugs. Diabetic kidney disease, chronic interstitial nephritis (CIN) and CKD-cause unknown (CKDu) were the leading causes. Rural participants had more occupational exposure and tobacco use but lower educational status and income. CIN and unknown categories were leading causes in rural participants.ConclusionsThe ICKD study is the only large cohort study of patients with mild-to-moderate CKD in a lower middle income country. Baseline characteristics of study population reveal differences as compared with other cohorts from high-income countries.

The extent of tubulointerstitial inflammation is an independent predictor of renal survival in lupus nephritis.

Lupus nephritis (LN) is a major complicationin patients with systemic lupus erythematosus (SLE). Tubulointerstitial injury is an inflammatory process that, if not attenuated, can promote renal damage. Despite this, the current 2003 ISN/RPS "glomerulocentric" classification does not include a score for tubulointerstitialinjury. We sought to establish predictors for tubulointerstitial injury and to determine their influence on renal outcomes. This is a retrospective study of a cohort of 166 patients with biopsy-proven LN diagnosed in a Spanish referral center, with a median follow-up of 86months. Chronic tubulointerstitiallesions were defined as interstitial fibrosis and tubular atrophy (IF/TA), whereas tubulointerstitialinflammation (TII) was defined as an acute interstitiallesion. Activity (0-24) and chronicity (0-12) indices were assigned. Composite outcome, definedas advanced CKD or development of kidney failure. The prevalenceof tubulointerstitiallesions was 69.3%. Eighty-one of the biopsies had features of tubulointerstitial inflammationand only 6 of these81 (7%) patients had moderate/severe tubulointerstitial inflammation. The incidence ofinterstitial fibrosis and tubular atrophywas 56.6%. Renal survival was shorter in patients with moderate/severe as compared with absent/mild interstitial fibrosis and tubular atrophy(median: 15-19years, p = 0.009). In the Cox regression model, the grade ofinterstitial fibrosis and tubular atrophy was independently associated with shorter renal survival (hazard ratio: 3.9, 95% CI 1.4-10.5; p = 0.008) after adjusting for degree of IF/TA and hypertension or diabetes. The extent of tubulointerstitial inflammation emerged as an independent predictor of renal survival after adjusting for the grade ofinterstitial fibrosis and tubular atrophy and co-morbid conditions includinghypertension or diabetes. Regarding disease duration at the time of renal biopsy, no significant association was found between the interstitial fibrosis and tubular atrophygroups. The results reported herein need to be validated in future studies to include also groups of patients who usually have a worse prognosis. Consensus on histological classification is needed to aid in definingprognosis.