Progressive CKD Research Articles

Stenosis of the Glomerulotubular Neck Is Associated with Progressive CKD

Stenosis of the Glomerulotubular Neck Is Associated with Progressive CKD

Impact of Fermentable and Viscous Dietary Fiber on Gut-Derived Uremic Toxins in Rats with Progressive CKD

Impact of Fermentable and Viscous Dietary Fiber on Gut-Derived Uremic Toxins in Rats with Progressive CKD

Progressive CKD Is Associated with Multiple Kidney Cyst Formation in Adult and Elderly Patients with Genetic Variations of Kidney Disease

Progressive CKD Is Associated with Multiple Kidney Cyst Formation in Adult and Elderly Patients with Genetic Variations of Kidney Disease

Fewer Podocytes Associate with Progressive CKD Independent of Glomerular Volume and Nephrosclerosis or Clinical Characteristics

Fewer Podocytes Associate with Progressive CKD Independent of Glomerular Volume and Nephrosclerosis or Clinical Characteristics

Effect of Lisinopril on Glomerular and Tubular Injury in a Surgical Rat Model of Progressive CKD and Kidney Failure

Effect of Lisinopril on Glomerular and Tubular Injury in a Surgical Rat Model of Progressive CKD and Kidney Failure

Improving the management of chronic kidney disease in primary care by enhancing laboratory reports with additional information and follow-up procedures

Identifying people at risk for progressive chronic kidney disease and connecting them with recommended care is crucial for providing timely and optimal treatment. The ASSIST-CKD (A programme to Spread eGFR [estimated glomerular filtration rate] graph Surveillance for the early identification, Support and Treatment of people with progressive CKD [chronic kidney disease]) trial evaluated the effect of graphical eGFR reporting to primary care physicians on late presentation to a nephrologist in the United Kingdom. Trial data were obtained from the UK Renal Registry. Although the results were neutral, the data generated from the ASSIST-CKD trial are informative and provide useful estimates of the intervention effect. The trial also provides valuable insights into the challenges of implementing complex interventions in busy health care environments, which can be used to guide the designs of future interventions.

Proteomics profiling and association with cardiorenal complications in type 2 diabetes subtypes in Asian population

AimAmong multi-ethnic Asians, type 2 diabetes (T2D) clustered in three subtypes; mild obesity-related diabetes (MOD), mild age-related diabetes with insulin insufficiency (MARD-II) and severe insulin-resistant diabetes with relative insulin insufficiency (SIRD-RII) had differential cardio-renal complication risk. We assessed the proteomic profiles to identify subtype specific biomarkers and its association with diabetes complications. Methods1448 plasma proteins at baseline were measured and compared across the T2D subtypes. Multivariable cox regression was used to assess associations between significant proteomics features and cardio-renal complications. ResultsAmong 645 T2D participants (SIRD-RII [19%], MOD [45%], MARD-II [36%]), 295 proteins expression differed significantly across the groups. These proteins were enriched in cell adhesion, neurogenesis and inflammatory response processes. In SIRD-RII group, ADH4, ACY1, THOP1, IGFBP2, NEFL, ENTPD2, CALB1, HAO1, CTSV, ITGAV, SCLY, EDA2R, ERBB2 proteins significantly associated with progressive CKD and LILRA5 protein with incident heart failure (HF). In MOD group, TAFA5, RSPO3, EDA2R proteins significantly associated with incident HF. In MARD-II group, FABP4 protein significantly associated with progressive CKD and PTPRN2 protein with major adverse cardiovascular events. Genetically determined NEFL and CALB1 were associated with kidney function decline. ConclusionsEach T2D subtype has unique proteomics signature and association with clinical outcomes and underlying mechanisms.

Machine learning progressive CKD risk prediction model is associated with CKD-mineral bone disorder

BackgroundRecently, we developed the machine learning (ML)-based Progressive CKD Risk Classifier (PCRC), which accurately predicts CKD progression within 5 years. While its performance is robust, it is unknown whether PCRC categorization is associated with CKD-mineral bone disorder (CKD-MBD), a critical, yet under-recognized, downstream consequence. Therefore, we aimed to 1) survey real-world testing utilization data for CKD-MBD and 2) evaluate ML-based PCRC categorization with CKD-MBD. MethodsThe cohort study utilized deidentified data from a US laboratory outpatient network, composed of 330,238 outpatients, over 5 years. The main outcomes were: 1) Laboratory testing utilization of eGFR, urine albumin creatinine ratio (UACR), parathyroid hormone (PTH), calcium, phosphate; and 2) PCRC categorization and biochemical abnormalities associated with CKD-MBD over 5 years. ResultsWe identified significant under-utilization of laboratory testing for UACR, phosphate and PTH, which ranged from −40 % to −100 % against the minimum standard-of-care. At five years, the CKD progression group, as predicted by the PCRC, was associated with 15.5 % increase in phosphate (P value <<0.01) and 94.9 % increase in PTH (P value <<0.01), consistent with CKD-MBD. ConclusionsWe identified significant under-utilization of laboratory testing for CKD-MBD. Moreover, we demonstrated that CKD progression, as predicted by the PCRC, is associated with CKD-MBD, several years in advance of disease. To our knowledge, this investigation is the first to examine the role of predictive analytics for CKD progression on mineral bone disorder. While further studies are required, these findings have the potential to advance AI/ML-based risk stratification and treatment of CKD and CKD-MBD.

#1760 Four cases of ADTKD: AFM analysis of urine sediment

Abstract Background and Aims Autosomal Dominant Tubulointerstitial kidney disease (ADTKD) is a rare disease (16 per million), associated with CV events, hypertension, and gout. ADTKD is characterized by interstitial fibrosis, tubular atrophy, microcysts, and progressive CKD. We describe a case of a family with clinical characteristics of ADTKD and provide for the first time a characterization of their urinary sediment. Given the tendency of a specific type of ADTKD caused by UMOD mutation to form tubular crystals, we have also tested the ability of the urine from ADTKD patients to precipitate and form crystals in vitro. Method We examined clinical features and urinary sediment of a family with ADTKD: a 51 years old woman with CKD (eGFR 30 mL/min/1.73 m2, CDK-EPI 2021) and her three sons, a 20 years old male, two daughters of 26 and 24 years old, all with hyperuricemia. Genetic analysis is not yet available. The test of urine precipitation consisted of the analysis of crystals after air-drying a thin layer of urine after enrichment of the organic quota by triple centrifugation for 10 minutes at 1000 rpm. Urinary sediments were also studied by Atomic Force Microscopy (ICSPI nGauge AFM) to achieve a resolution of 20 nm of crystals. Results Clinical data for the four patients are reported in the table. None of the patients showed proteinuria. The urine sediment of all patients showed rare WBC (in greater amounts only in patient 1), rare amorphous granular casts, and rare tubular cells. Three patients showed formations of variably sized crystals in vitro. The precipitation test did not show crystals in patient 1, whereas patients 2-3 showed several rosette-type crystals often with a wagon-wheel concentric contour which resembled leucine crystals or CaCO3. Adding formalin to the samples resulted in a more clear organization of crystals in wagon-wheel structures. AFM imaging of the crystals showed rod-like structures branching with an angle of 35°. Conclusion ADTKD remains a poorly understood genetic condition with no specific treatment options. Our data suggest that patients with this condition may have an enhanced tendency to form crystals in vitro. Speculatively, this might induce tubular injury in vivo. Data from UMOD-ko animal models showed intrarenal crystals (not better specified). Genetic alterations of branched aminoacids metabolism (such as leucine in Maple syrup disease) can also cause tubular diseases, although the systemic manifestations are very different from our patients. Genetic analysis of our family will give further information on the proteins involved in these crystal structures.

Nonsteroidal mineralocorticoid receptor blockers as a new tool for managing cardiorenal risks in type 2 diabetes mellitus

Today, the importance of targeted cardionephroprotection is increasingly increasing as one of the vectors of a multifactorial therapeutic strategy to reduce the risk of development and progression of complications of type 2 diabetes. Pathological hyperactivation of the renin-angiotensin-aldosterone system (RAAS) and mineralocorticoid receptors (MCRs) is considered as one of the mechanisms for the development of cadiorenal syndrome (RCS) in diabetes. Blocking this pathophysiological pathway in patients with CKD and type 2 diabetes can break the vicious circle of mutually aggravating damage to the kidneys and heart. ACE inhibitors and angiotensin receptor blockers (ARBs) are currently the standard of care in patients with CRS due to diabetes. But despite their effectiveness, the residual risk of CKD progression within 4–5 years remains high in almost half of patients with type 2 diabetes, mainly due to multicomponent processes of MCR hyperactivation. This causes a range of pathological reactions affecting the entire body and may contribute to kidney, heart and CD disease in patients with type 2 diabetes by promoting inflammation and fibrosis. Functional and structural changes in the kidneys and heart develop, which leads to the development of metabolic disorders, arterial hypertension, cardiovascular complications and progressive CKD. Pharmacological blockade of aldosterone binding to MCR appears to be an effective additional line for preventing the progression of the pathological cascade of KRS reactions in type 2 diabetes. The recently developed selective non-steroidal MCR antagonist (nsAMPR) finerenone has convincingly demonstrated improved renal and cardiovascular outcomes in patients with CKD and type 2 diabetes. This review covers in detail the role of MCRs in the development of cardiorenal syndrome in type 2 diabetes and CKD, describes the mechanisms of effectiveness of MCR blockade in preventing the progression of cardiorenal syndrome in type 2 diabetes and the difference between non-steroidal MCRs and steroids, and presents the results of RCTs confirming the cardionephroprotective potential of nsAMCRs in CKD and diabetes. type 2, and the place of finerenone as a multifactorial therapeutic strategy for type 2 diabetes in clinical practice.

Role of Cell-Extracellular Matrix (ECM) Interactions for Renal Tubular Epithelial Cell Phenotypes in the Context of Progressive CKD

Role of Cell-Extracellular Matrix (ECM) Interactions for Renal Tubular Epithelial Cell Phenotypes in the Context of Progressive CKD

Tubular and Glomerular Size by Cortex Depth as Predictor of Progressive CKD after Radical Nephrectomy for Tumor.

Glomerular size differs by cortex depth. Larger nephrons are prognostic of progressive kidney disease, but it is unknown whether this risk differs by cortex depth or by glomeruli versus proximal or distal tubule size. We studied the average minor axis diameter in oval proximal and distal tubules separately and by cortex depth in patients who had radical nephrectomy to remove a tumor from 2019 to 2020. In adjusted analyses, larger glomerular volume in the middle and deep cortex predicted progressive kidney disease. Wider proximal tubular diameter did not predict progressive kidney disease independent of glomerular volume. Wider distal tubular diameter showed a gradient of strength of prediction of progressive kidney disease in the more superficial cortex than in the deep cortex. Larger nephrons are prognostic of progressive kidney disease, but whether this risk differs by nephron segments or by depth in the cortex is unclear. We studied patients who underwent radical nephrectomy for a tumor between 2000 and 2019. Large wedge kidney sections were scanned into digital images. We estimated the diameters of proximal and distal tubules by the minor axis of oval tubular profiles and estimated glomerular volume with the Weibel-Gomez stereological model. Analyses were performed separately in the superficial, middle, and deep cortex. Cox proportional hazard models assessed the risk of progressive CKD (dialysis, kidney transplantation, sustained eGFR <10 ml/min per 1.73 m 2 , or a sustained 40% decline from the postnephrectomy baseline eGFR) with glomerular volume or tubule diameters. At each cortical depth, models were unadjusted, adjusted for glomerular volume or tubular diameter, and further adjusted for clinical characteristics (age, sex, body mass index, hypertension, diabetes, postnephrectomy baseline eGFR, and proteinuria). Among 1367 patients were 62 progressive CKD events during a median follow-up of 4.5 years. Glomerular volume predicted CKD outcomes at all depths, but only in the middle and deep cortex after adjusted analyses. Proximal tubular diameter also predicted progressive CKD at any depth but not after adjusted analyses. Distal tubular diameter showed a gradient of more strongly predicting progressive CKD in the superficial than deep cortex, even in adjusted analysis. Larger glomeruli are independent predictors of progressive CKD in the deeper cortex, whereas in the superficial cortex, wider distal tubular diameters are an independent predictor of progressive CKD.

Targeting RNA-binding protein HuR to inhibit the progression of renal tubular fibrosis

BackgroundUpregulation of an RNA-binding protein HuR has been implicated in glomerular diseases. Herein, we evaluated whether it is involved in renal tubular fibrosis.MethodsHuR was firstly examined in human kidney biopsy tissue with tubular disease. Second, its expression and the effect of HuR inhibition with KH3 on tubular injury were further assessed in a mouse model induced by a unilateral renal ischemia/reperfusion (IR). KH3 (50 mg kg−1) was given daily via intraperitoneal injection from day 3 to 14 after IR. Last, one of HuR-targeted pathways was examined in cultured proximal tubular cells.ResultsHuR significantly increases at the site of tubular injury both in progressive CKD in patients and in IR-injured kidneys in mice, accompanied by upregulation of HuR targets that are involved in inflammation, profibrotic cytokines, oxidative stress, proliferation, apoptosis, tubular EMT process, matrix remodeling and fibrosis in renal tubulointerstitial fibrosis. KH3 treatment reduces the IR-induced tubular injury and fibrosis, accompanied by the remarkable amelioration in those involved pathways. A panel of mRNA array further revealed that 519 molecules in mouse kidney following IR injury changed their expression and 71.3% of them that are involved in 50 profibrotic pathways, were ameliorated when treated with KH3. In vitro, TGFβ1 induced tubular HuR cytoplasmic translocation and subsequent tubular EMT, which were abrogated by KH3 administration in cultured HK-2 cells.ConclusionsThese results suggest that excessive upregulation of HuR contributes to renal tubulointerstitial fibrosis by dysregulating genes involved in multiple profibrotic pathways and activating the TGFß1/HuR feedback circuit in tubular cells. Inhibition of HuR may have therapeutic potential for renal tubular fibrosis.

422-P: GLP-1 RA Should Be Used with SGLT2 Inhibitor in People with Rapidly Progressive CKD

Objective: Either GLP-1RA or SGLT2i is recommended to use in people with type 2 diabetes (T2D) with CKD. Whether these drugs jointly work for reno-protection are not well known. We evaluated add-on effects of GLP-1RA (liraglutide 95%) in Japanese people with T2D treated by SGLT2i by assessing individual eGFR trajectory. Methods: A total of 75 persons with T2D (CKD stage 3-4), treated by SGLT2i (empagliflozin 65%) were analyzed. At the time of recruitment, average age was 70.3±12.2 yr-old, the duration of diabetes was 15.4±10.1 yrs, and macroalbuminuria (Macro-Alb) existed in 49% (37/75). To trace the eGFR trajectory in each person, most rapid eGFR slope was calculated individually from the data for 46±20 months before using SGLT2i and 46±16 months after adding it. GLP-1RA was initially or additionally used in 53%. Results: 1) Proportion of responders (defined as their ratios of slopes are reduced &amp;gt; 1.0 after addition of SGLT2i) in each stage were as follows: stage 3a; (21/29), stage 3b; (21/28), stage 4; (16/18). Slopes in responders (58/75) were improved as follows, -7.8±9.9 to -0.8±3.0ml/min/1.73m2/year (P&amp;lt;0.001) with GLP-1RA use in 52%. Slopes in non-responders (17/75) were worsened as follows, -1.8±1.9 to -3.6±3.1ml/min/1.73m2/year (P&amp;lt;0.001), despite GLP-1RA use in 59%. Macro-Alb was observed in 53% and 35%, respectively. 2) Slopes in rapid decliners (defined as most rapid individual eGFR slope greater than -10.0ml/min/1.73m2/y) (13/75) were improved from -18.9±16.4 to -1.3±3.3ml/min/1.73m2/year (P&amp;lt;0.01) by combined use of GLP-1RA in 85% (11/13). Macro-Alb existed in 69% (9/13) and nephrosis in 54% (7/13). 3) Sub-analysis (one of different GLP-1RA initiation regimes): Baseline slopes -16.7±19.8 were improved to -5.0±5.8 (P&amp;lt;0.05) by adding GLP-1RA, then to -2.7±3.8 ml/min/1.73m2/year (vs baseline: P&amp;lt;0.03) by adding SGLT2i. (n=11) Macro-Alb highly existed in 82% (9/11) and nephrosis in 46% (5/11). Conclusion: GLP-1RA should be used with SGLT2i in rapid eGFR decliners or persons with Macro-Alb. Disclosure K.Kashima: None. H.Shimizu: None. M.Yamada: None.

#4534 FINERENONE ADDED TO RAS/SGLT2 BLOCKADE FOR NON-DIABETIC CHRONIC KIDNEY DISEASE: RESULTS OF A PRECLINICAL DOUBLE-BLINDED RANDOMIZED CONTROLLED TRIAL

Abstract Background and Aims Inhibitors of the renin-angiotensin system (RAS), sodium-glucose transporter (SGLT)-2, and the mineralocorticoid receptor (MR) have all demonstrated renoprotective effects in large clinical trials of diabetes-related CKD. Furthermore, dual RAS/SGLT2 blockade showed additive renoprotective effects also in non-diabetic CKD. We hypothesized that triple RAS/SGLT2/MR blockade would be even superior to dual RAS/SGLT2 blockade in non-diabetic CKD. Method We performed a “no touch” preclinical randomized controlled trial in Col4a3-deficient mice with spontaneous and progressive CKD (registry ID: PCTE0000266). Treatments were administered as food admix from 6-14 weeks of age at the following estimated doses: 10 mg/kg ramipril, 30 mg/kg empagliflozin, 10 mg/kg finerenone. The prespecified primary endpoint was total lifespan up to uremic death. Ancillary studies addressed baseline histology, and mechanistic studies on a subset of mice after 2.5 weeks of treatment. Results At the time of randomization, Col4a3-/- mice had albuminuria, elevated serum creatinine, glomerulosclerosis, tubular atrophy, and interstitial fibrosis. Total lifespan was 63.7 ± 9.99 days (vehicle), 77.25 ± 5.34 days (ramipril), 80.3 ± 10.98 days (ramipril+empagliflozin), and 103.05 ± 20.28 days (triple therapy), respectively. Artificial intelligence-based histopathology and RNA sequencing analysis documented a potent anti-sclerotic, -inflammation and -fibrotic effect of the triple combination. Conclusion Adding finereone to dual RAS/SGLT2 blockade significantly prolongs uremia-free lifespan even when started at an advanced stage of Alport nephropathy. Triple RAS/SGLT2/MR blockade could be a potent treatment strategy to prolong uremia-free lifespan in patients with CKD related to Alport syndrome and possibly other progressive kidney disorders.

Genome-Wide Association Study of CKD Progression.

Rapid progression of CKD is associated with poor clinical outcomes. Most previous studies looking for genetic factors associated with low eGFR have used cross-sectional data. The authors conducted a meta-analysis of genome-wide association studies of eGFR decline among 116,870 participants with CKD, focusing on longitudinal data. They identified three loci (two of them novel) associated with longitudinal eGFR decline. In addition to the known UMOD/PDILT locus, variants within BICC1 were associated with significant differences in longitudinal eGFR slope. Variants within HEATR4 also were associated with differences in eGFR decline, but only among Black/African American individuals without diabetes. These findings help characterize molecular mechanisms of eGFR decline in CKD and may inform new therapeutic approaches for progressive kidney disease. Rapid progression of CKD is associated with poor clinical outcomes. Despite extensive study of the genetics of cross-sectional eGFR, only a few loci associated with eGFR decline over time have been identified. We performed a meta-analysis of genome-wide association studies of eGFR decline among 116,870 participants with CKD-defined by two outpatient eGFR measurements of <60 ml/min per 1.73 m 2 , obtained 90-365 days apart-from the Million Veteran Program and Vanderbilt University Medical Center's DNA biobank. The primary outcome was the annualized relative slope in outpatient eGFR. Analyses were stratified by ethnicity and diabetes status and meta-analyzed thereafter. In cross-ancestry meta-analysis, the strongest association was rs77924615, near UMOD / PDILT ; each copy of the G allele was associated with a 0.30%/yr faster eGFR decline ( P = 4.9×10 -27 ). We also observed an association within BICC1 (rs11592748), where every additional minor allele was associated with a 0.13%/yr slower eGFR decline ( P = 5.6×10 -9 ). Among participants without diabetes, the strongest association was the UMOD/PDILT variant rs36060036, associated with a 0.27%/yr faster eGFR decline per copy of the C allele ( P = 1.9×10 -17 ). Among Black participants, a significantly faster eGFR decline was associated with variant rs16996674 near APOL1 (R 2 =0.29 with the G1 high-risk genotype); among Black participants with diabetes, lead variant rs11624911 near HEATR4 also was associated with a significantly faster eGFR decline. We also nominally replicated loci with known associations with eGFR decline, near PRKAG2, FGF5, and C15ORF54. Three loci were significantly associated with longitudinal eGFR change at genome-wide significance. These findings help characterize molecular mechanisms of eGFR decline and may contribute to the development of new therapeutic approaches for progressive CKD.

Age-Based Versus Young-Adult Thresholds for Nephrosclerosis on Kidney Biopsy and Prognostic Implications for CKD.

Nephrosclerosis (glomerulosclerosis, interstitial fibrosis, and tubular atrophy) is the defining pathology of both kidney aging and CKD. Optimal thresholds for nephrosclerosis that identify persons with a progressive disease are unknown. This study determined a young-age threshold (18-29 years) and age-based 95th percentile thresholds for nephrosclerosis on the basis of morphometry of kidney biopsy sections from normotensive living kidney donors. These thresholds were 7.1-fold to 36-fold higher in older (70 years or older) versus younger (aged 18-29 years) normotensive donors. Age-based thresholds, but not young-age threshold, were prognostic for determining risk of progressive CKD among patients who underwent a radical nephrectomy or a for-cause native kidney biopsy, suggesting that age-based thresholds are more useful than a single young-age threshold for identifying CKD on biopsy. Nephrosclerosis, defined by globally sclerotic glomeruli (GSG) and interstitial fibrosis and tubular atrophy (IFTA), is a pathology of both kidney aging and CKD. A comparison of risk of progressive CKD using aged-based thresholds for nephrosclerosis versus a single young-adult threshold is needed. We conducted morphometric analyses of kidney biopsy images for %GSG, %IFTA, and IFTA foci density among 3020 living kidney donors, 1363 patients with kidney tumor, and 314 patients with native kidney disease. Using normotensive donors, we defined young-age thresholds (18-29 years) and age-based (roughly by decade) 95th percentile thresholds. We compared age-adjusted risk of progressive CKD (kidney failure or 40% decline in eGFR) between nephrosclerosis that was "normal compared with young," "normal for age but abnormal compared with young," and "abnormal for age" in patients with tumor and patients with kidney disease. The 95th percentiles in the youngest group (18-29 years) to the oldest group (70 years or older) ranged from 1.7% to 16% for %GSG, 0.18% to 6.5% for %IFTA, and 8.2 to 59.3 per cm 2 for IFTA foci density. Risk of progressive CKD did not differ between persons with nephrosclerosis "normal compared with young" versus "normal for age but abnormal compared with young." Risk of progressive CKD was significantly higher with %GSG, %IFTA, or IFTA foci density that was abnormal versus normal for age in both cohorts. Given that increased risk of progressive CKD occurs only when nephrosclerosis is abnormal for age, age-based thresholds for nephrosclerosis seem to be better than a single young-age threshold for identifying clinically relevant CKD.

Editing of APOL1 mRNA reduces APOL1 expression and activation of innate immunity

The APOL1 gene encodes Apoliprotein L1, an innate immune response protein that confers protection against Trypanosomal diseases and likely other infectious diseases. 1 Thomson R. Genovese G. Canon C. et al. Evolution of the primate trypanolytic factor APOL1. Proc Natl Acad Sci U S A. 2014; 111: E2130-2139 Crossref PubMed Scopus (160) Google Scholar ,2 Limou S. Dummer P.D. Nelson G.W. et al. APOL1 toxin, innate immunity, and kidney injury. Kidney Int. 2015; 88: 28-34 Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar The G1 and G2 variants of APOL1, which are enriched in persons of West African ancestry, provide enhanced protection against Trypanosome infection, but persons with APOL1 high risk (HR) genotypes (two risk alleles) have markedly increased risk of progressive CKD. 2 Limou S. Dummer P.D. Nelson G.W. et al. APOL1 toxin, innate immunity, and kidney injury. Kidney Int. 2015; 88: 28-34 Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Because most individuals with HR genotypes do not develop kidney disease, it is likely that a “second hit” may be necessary to unmask the HR genotype-associated risk. APOL1 HR genotype is most strongly associated with severe kidney disease occurring in the setting of high interferon levels due to infection (HIV or COVID-19), 3 Kopp J.B. Nelson G.W. Sampath K. et al. APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol. 2011; 22: 2129-2137 Crossref PubMed Scopus (602) Google Scholar ,4 Kudose S. Batal I. Santoriello D. et al. Kidney Biopsy Findings in Patients with COVID-19. J Am Soc Nephrol. 2020; 31: 1959-1968 Crossref PubMed Scopus (245) Google Scholar lupus nephritis, 5 Freedman B.I. Langefeld C.D. Andringa K.K. et al. End-stage renal disease in African Americans with lupus nephritis is associated with APOL1. Arthritis Rheumatol. 2014; 66: 390-396 Crossref PubMed Scopus (203) Google Scholar interferon treatment, 6 Nichols B. Jog P. Lee J.H. et al. Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1. Kidney Int. 2015; 87: 332-342 Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar and kidney transplantation. 7 Santoriello D. Husain S.A. De Serres S.A. et al. Donor APOL1 high-risk genotypes are associated with increased risk and inferior prognosis of de novo collapsing glomerulopathy in renal allografts. Kidney Int. 2018; 94: 1189-1198 Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar As APOL1 expression is strongly induced by interferons, 6 Nichols B. Jog P. Lee J.H. et al. Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1. Kidney Int. 2015; 87: 332-342 Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar upregulation of toxic G1 and G2 variants in the setting of high interferon is hypothesized to be an important contributor to kidney injury. Thus, improved understanding of the factors that regulate APOL1 expression may provide new strategies to prevent or treat kidney disease in individuals with HR genotypes.

A STUDY OF ELECTROCARDIOGRAPHIC AND ECHOCARDIOGRAPHIC CHANGES IN PATIENTS OF CHRONIC KIDNEY DISEASE

Introduction: Chronic kidney disease is dened as the presence of kidney damage or an estimated glomerular ltration rate less than 60 ml/min/1.73 mt2, persisting for 3 months or more, irrespective of the cause. It is a state of progressive loss of kidney function ultimately resulting in the need for renal replacement therapy . A cardiovascular mortality that is 15 to 30 times greater than the age-adjusted cardiovascular mortality in the general population affects roughly 50% of people with ESRD. Therefore this study was undertaken for assessing electrocardiographic and echocardiographic ndings in CKD patients. Method: In this study 50 pts of chronic kidney disease as per KDIGO criteria were enrolled over a period of six months (Jan-June 2022).All relevant data were recorded and analyzed. Results: Among 50 pts, 26 percent of the patients each belonged to the age group of 61 to 70 years. 62 percent of the CKD patients were males while the remaining were females. While assessing the ECGndings among CKD patients, LVH and arrythmias were seen in 52 percent and 44 percent of the patients. While assessing the correlation of ECGndings with CKD severity grading, it was seen that ECG variables were signicantly deteriorate with increasing severity of CKD grading. While analysing ECHO ndings among CKD patients, abnormal ndings were seen in 88 percent of the patients . While assessing the correlation of ECHO ndings with CKD severity grading, it was seen that ECHO variables were signicantly deteriorate with increasing severity of CKD grading. Conclusion : LVH, LAE were very common ECG and ECHO abnormalities in CKD patients. Cardiac disorders are highly prevalent in patients with progressive CKD. All CKD patients must be evaluated for cardiac co-morbidities, since it might help to establish adequate treatment that may potentially improve patient's prognosis.

HIF1α-BNIP3-mediated mitophagy protects against renal fibrosis by decreasing ROS and inhibiting activation of the NLRP3 inflammasome

Chronic kidney disease affects approximately 14.3% of people worldwide. Tubulointerstitial fibrosis is the final stage of almost all progressive CKD. To date, the pathogenesis of renal fibrosis remains unclear, and there is a lack of effective treatments, leading to renal replacement therapy. Mitophagy is a type of selective autophagy that has been recognized as an important way to remove dysfunctional mitochondria and abrogate the excessive accumulation of mitochondrial-derived reactive oxygen species (ROS) to balance the function of cells. However, the role of mitophagy and its regulation in renal fibrosis need further examination. In this study, we showed that mitophagy was induced in renal tubular epithelial cells in renal fibrosis. After silencing BNIP3, mitophagy was abolished in vivo and in vitro, indicating the important effect of the BNIP3-dependent pathway on mitophagy. Furthermore, in unilateral ureteral obstruction (UUO) models and hypoxic conditions, the production of mitochondrial ROS, mitochondrial damage, activation of the NLRP3 inflammasome, and the levels of αSMA and TGFβ1 increased significantly following BNIP3 gene deletion or silencing. Following silencing BNIP3 and pretreatment with mitoTEMPO or MCC950, the protein levels of αSMA and TGFβ1 decreased significantly in HK-2 cells under hypoxic conditions. These findings demonstrated that HIF1α-BNIP3-mediated mitophagy played a protective role against hypoxia-induced renal epithelial cell injury and renal fibrosis by reducing mitochondrial ROS and inhibiting activation of the NLRP3 inflammasome.