Progressive CKD Research Articles

In advanced progressive CKD, discontinuing RAS inhibitors did not improve eGFR at 3 y.

Bhandari S, Mehta S, Khwaja A, et al. Renin-angiotensin system inhibition in advanced chronic kidney disease. N Engl J Med. 2022;387:2021-32. 36326117.

Outcomes associated with acute kidney disease: A systematic review and meta-analysis.

Acute kidney disease (AKD) defines the period after kidney damage and it is a critical period of both repair and fibrotic pathways. However, the outcomes of patients with AKD have not been well-defined. In this meta-analysis, PubMed, Embase, Cochrane and China National Knowledge Infrastructure were searched on July 31,2022. We excluded studies including patients undergoing kidney replacement therapy at enrollment. The data was used to conduct a random-effects model for pool outcomes between patients with AKD and non-AKD (NKD). This study is registered with PROSPERO, CRD42021271773. The search generated 739 studies of which 21 studies were included involving 1,114,012 patients. The incidence rate of community-acquired AKD was 4.60%, 2.11% in hospital-acquired AKD without a prior AKI episode, and 26.11% in hospital-acquired AKD with a prior AKI episode. The all-cause mortality rate was higher in the AKD group (26.54%) than in the NKD group (7.78%) (odds ratio [OR]: 3.62, 95% confidence interval [CI]: 2.64 to 4.95, p<0.001, I2=99.11%). The rate of progression to end-stage kidney disease (ESKD) was higher in the AKD group (1.3%) than in the NKD group (0.14%) (OR: 6.58, p<0.001, I2=94.95%). The incident rate of CKD and progressive CKD was higher in the AKD group (37.2%) than in the NKD group (7.45%) (OR:4.22, p<0.001, I2=96.67%). Compared to the NKD group, patients with AKD without prior AKI had a higher mortality rate (OR: 3.00, p<0.001, I2=99.31%) and new-onset ESKD (OR:4.96, 95% CI, p=0.002, I2=97.37%). AKD is common in community and hospitalized patients who suffer from AKI and also occurs in patients without prior AKI. The patients with AKD, also in those without prior AKI had a higher risk of mortality, and new-onset ESKD than the NKD group. This study was supported by Ministry of Science and Technology (MOST) of the Republic of China (Taiwan) [grant number, MOST 107-2314-B-002-026-MY3, 108-2314-B-002-058, 110-2314-B-002-241, 110-2314-B-002-239], National Science and Technology Council (NSTC) [grant number, NSTC 109-2314-B-002-174-MY3, 110-2314-B-002-124-MY3, 111-2314-B-002-046, 111-2314-B-002-058], National Health Research Institutes [PH-102-SP-09], National Taiwan University Hospital [109-S4634, PC-1246, PC-1309, VN109-09, UN109-041, UN110-030, 111-FTN0011] Grant MOHW110-TDU-B-212-124005, Mrs. Hsiu-Chin Lee Kidney Research Fund and Chi-mei medical center CMFHR11136. JAN is supported, in part, by grants from the National Institute of Health, NIDDK (R01 DK128208 and P30 DK079337) and NHLBI (R01 HL148448-01).

Radiomic Features of Kidney Magnetic Resonance Imaging (MRI) to Characterize CKD and Progressive CKD

Radiomic Features of Kidney Magnetic Resonance Imaging (MRI) to Characterize CKD and Progressive CKD

Role of Apoptotic Cells in Mediating Progressive CKD

Role of Apoptotic Cells in Mediating Progressive CKD

The Dietary Fiber Inulin Beneficially Alters the Gut Microbiota and Microbially-Derived Metabolites in a Rat Model of Progressive CKD

The Dietary Fiber Inulin Beneficially Alters the Gut Microbiota and Microbially-Derived Metabolites in a Rat Model of Progressive CKD

Prognostic Implications of a Morphometric Evaluation for Chronic Changes on All Diagnostic Native Kidney Biopsies.

Semiquantitative visual inspection for glomerulosclerosis, interstitial fibrosis, and arteriosclerosis is often used to assess chronic changes in native kidney biopsies. Morphometric evaluation of these and other chronic changes may improve the prognostic assessment. We studied a historical cohort of patients who underwent a native kidney biopsy between 1993 and 2015 and were followed through 2021 for ESKD and for progressive CKD (defined as experiencing 50% eGFR decline, temporary dialysis, or ESKD). Pathologist scores for the percentages of globally sclerosed glomeruli (GSG), interstitial fibrosis and tubular atrophy (IFTA), and arteriosclerosis (luminal stenosis) were available. We scanned biopsy sections into high-resolution images to trace microstructures. Morphometry measures were percentage of GSG; percentage of glomerulosclerosis (percentage of GSG, ischemic-appearing glomeruli, or segmentally sclerosed glomeruli); percentage of IFTA; IFTA foci density; percentage of artery luminal stenosis; arteriolar hyalinosis counts; and measures of nephron size. Models assessed risk of ESKD or progressive CKD with biopsy measures adjusted for age, hypertension, diabetes, body mass index, eGFR, and proteinuria. Of 353 patients (followed for a median 7.5 years), 75 developed ESKD and 139 experienced progressive CKD events. Visually estimated scores by pathologists versus morphometry measures for percentages of GSG, IFTA, and luminal stenosis did not substantively differ in predicting outcomes. However, adding percentage of glomerulosclerosis, IFTA foci density, and arteriolar hyalinosis improved outcome prediction. A 10-point score using percentage of glomerulosclerosis, percentage of IFTA, IFTA foci density, and any arteriolar hyalinosis outperformed a 10-point score based on percentages of GSG, IFTA, and luminal stenosis >50% in discriminating risk of ESKD or progressive CKD. Morphometric characterization of glomerulosclerosis, IFTA, and arteriolar hyalinosis on kidney biopsy improves prediction of long-term kidney outcomes.

Apolipoprotein L1 Genotypes and the Association of Urinary Potassium Excretion with CKD Progression.

Progressive CKD in Black individuals is strongly associated with polymorphisms in the APOL1 gene, but it is unknown whether dietary risk factors for CKD progression vary in high- versus low-risk APOL1 genotypes. We investigated if APOL1 genotypes modify associations of dietary potassium and sodium with CKD progression and death. We analyzed 1399 self-identified Black participants enrolled in the Chronic Renal Insufficiency Cohort from April 2003 to September 2008. Exposures were calibrated 24-hour urine potassium and sodium excretion. The primary outcome was CKD progression defined as the time to 50% decline in eGFR or kidney failure. The secondary outcome was CKD progression or death. We tested for an interaction between urinary potassium and sodium excretion and APOL1 genotypes. Median 24-hour urinary sodium and potassium excretions in Black participants were 150 mmol (interquartile range, 118-188) and 43 mmol (interquartile range, 35-54), respectively. Individuals with high- and low-risk APOL1 genotypes numbered 276 (20%) and 1104 (79%), respectively. After a median follow-up of 5.23 years, CKD progression events equaled 605, and after 7.29 years, CKD progression and death events equaled 868. There was significant interaction between APOL1 genotypes and urinary potassium excretion with CKD progression and CKD progression or death (P=0.003 and P=0.03, respectively). In those with high-risk APOL1 genotypes, higher urinary potassium excretion was associated with a lower risk of CKD progression (quartiles 2-4 versus 1: hazard ratio, 0.83; 95% confidence interval, 0.50 to 1.39; hazard ratio, 0.54; 95% confidence interval, 0.31 to 0.93; and hazard ratio, 0.50; 95% confidence interval, 0.27 to 0.93, respectively). In the low-risk APOL1 genotypes, higher urinary potassium excretion was associated with a higher risk of CKD progression (quartiles 2-4 versus 1: hazard ratio, 1.01; 95% confidence interval, 0.75 to 1.36; hazard ratio, 1.23; 95% confidence interval, 0.91 to 1.66; and hazard ratio, 1.53; 95% confidence interval, 1.12 to 2.09, respectively). We found no interaction between APOL1 genotypes and urinary sodium excretion with CKD outcomes. Higher urinary potassium excretion was associated with lower versus higher risk of CKD progression in APOL1 high-risk and low-risk genotypes, respectively.

Suppression of NRF2 Activity by HIF-1α Promotes Fibrosis after Ischemic Acute Kidney Injury.

Acute kidney injury (AKI) is a rapid decline in renal function and can occur after ischemia/reperfusion injury (IRI) to the tubular epithelia. The nuclear factor erythroid-2-related factor 2 (NRF2) pathway protects against AKI and AKI-to-chronic kidney disease (CKD) progression, but we previously demonstrated that severe IRI maladaptively reduced NRF2 activity in mice. To understand the mechanism of this response, we subjected C57BL/6J mice to unilateral kidney IRI with ischemia times that were titrated to induce mild to severe injury. Mild IRI increased NRF2 activity and was associated with renal recovery, whereas severe IRI decreased NRF2 activity and led to progressive CKD. Due to these effects of ischemia, we tested the hypothesis that hypoxia-inducible factor-1α (HIF-1α) mediates NRF2 activity. To mimic mild and severe ischemia, we activated HIF-1α in HK-2 cells in nutrient-replete or nutrient-deficient conditions. HIF-1α activation in nutrient-replete conditions enhanced NRF2 nuclear localization and activity. However, in nutrient-deficient conditions, HIF-1α activation suppressed NRF2 nuclear localization and activity. Nuclear localization was rescued with HIF-1α siRNA knockdown. Our results suggest that severe ischemic AKI leads to HIF-1α-mediated suppression of NRF2, leading to AKI-to-CKD progression.

Absence of long-term changes in urine biomarkers after AKI: findings from the CRIC study

BackgroundMechanisms by which AKI leads to CKD progression remain unclear. Several urine biomarkers have been identified as independent predictors of progressive CKD. It is unknown whether AKI may result in long-term changes in these urine biomarkers, which may mediate the effect of AKI on CKD progression.MethodsWe selected 198 episodes of hospitalized AKI (defined as peak/nadir inpatient serum creatinine values ≥ 1.5) among adult participants in the Chronic Renal Insufficiency Cohort (CRIC) Study. We matched the best non-AKI hospitalization (unique patients) for each AKI hospitalization using pre-hospitalization characteristics including eGFR and urine protein/creatinine ratio. Biomarkers were measured in banked urine samples collected at annual CRIC study visits.ResultsUrine biomarker measurements occurred a median of 7 months before and 5 months after hospitalization. There were no significant differences in the change in urine biomarker-to-creatinine ratio between the AKI and non-AKI groups: KIM-1/Cr + 9% vs + 7%, MCP-1/Cr + 4% vs + 1%, YKL-40/Cr + 7% vs -20%, EGF/Cr -11% vs -8%, UMOD/Cr -2% vs -7% and albumin/Cr + 17% vs + 13% (all p > 0.05).ConclusionIn this cohort of adults with CKD, AKI did not associate with long-term changes in urine biomarkers.

Systematic Review and Meta-Analysis of Plasma and Urine Biomarkers for CKD Outcomes.

Sensitive and specific biomarkers are needed to provide better biologic insight into the risk of incident and progressive CKD. However, studies have been limited by sample size and design heterogeneity. In this assessment of the prognostic value of preclinical plasma and urine biomarkers for CKD outcomes, we searched Embase (Ovid), MEDLINE ALL (Ovid), and Scopus up to November 30, 2020, for studies exploring the association between baseline kidney biomarkers and CKD outcomes (incident CKD, CKD progression, or incident ESKD). We used random-effects meta-analysis. After screening 26,456 abstracts and 352 full-text articles, we included 129 studies in the meta-analysis for the most frequently studied plasma biomarkers (TNFR1, FGF23, TNFR2, KIM-1, suPAR, and others) and urine biomarkers (KIM-1, NGAL, and others). For the most frequently studied plasma biomarkers, pooled RRs for CKD outcomes were 2.17 (95% confidence interval [95% CI], 1.91 to 2.47) for TNFR1 (31 studies); 1.21 (95% CI, 1.15 to 1.28) for FGF-23 (30 studies); 2.07 (95% CI, 1.82 to 2.34) for TNFR2 (23 studies); 1.51 (95% CI, 1.38 to 1.66) for KIM-1 (18 studies); and 1.42 (95% CI, 1.30 to 1.55) for suPAR (12 studies). For the most frequently studied urine biomarkers, pooled RRs were 1.10 (95% CI, 1.05 to 1.16) for KIM-1 (19 studies) and 1.12 (95% CI, 1.06 to 1.19) for NGAL (19 studies). Studies of preclinical biomarkers for CKD outcomes have considerable heterogeneity across study cohorts and designs, limiting comparisons of prognostic performance across studies. Plasma TNFR1, FGF23, TNFR2, KIM-1, and suPAR were among the most frequently investigated in the setting of CKD outcomes.

Acute Kidney Injury Associates with Long-Term Increases in Plasma TNFR1, TNFR2, and KIM-1: Findings from the CRIC Study.

Some markers of inflammation-TNF receptors 1 and 2 (TNFR1 and TNFR2)-are independently associated with progressive CKD, as is a marker of proximal tubule injury, kidney injury molecule 1 (KIM-1). However, whether an episode of hospitalized AKI may cause long-term changes in these biomarkers is unknown. Among adult participants in the Chronic Renal Insufficiency Cohort (CRIC) study, we identified 198 episodes of hospitalized AKI (defined as peak/nadir inpatient serum creatinine values ≥1.5). For each AKI hospitalization, we found the best matched non-AKI hospitalization (unique patients), using prehospitalization characteristics, including eGFR and urine protein/creatinine ratio. We measured TNFR1, TNFR2, and KIM-1 in banked plasma samples collected at annual CRIC study visits before and after the hospitalization (a median of 7 months before and 5 months after hospitalization). In the AKI and non-AKI groups, we found similar prehospitalization median levels of TNFR1 (1373 pg/ml versus 1371 pg/ml, for AKI and non-AKI, respectively), TNFR2 (47,141 pg/ml versus 46,135 pg/ml, respectively), and KIM-1 (857 pg/ml versus 719 pg/ml, respectively). Compared with matched study participants who did not experience AKI, study participants who did experience AKI had greater increases in TNFR1 (23% versus 10%, P<0.01), TNFR2 (10% versus 3%, P<0.01), and KIM-1 (13% versus -2%, P<0.01). Among patients with CKD, AKI during hospitalization was associated with increases in plasma TNFR1, TNFR2, and KIM-1 several months after their hospitalization. These results highlight a potential mechanism by which AKI may contribute to more rapid loss of kidney function months to years after the acute insult.

MO030: Familial clustering of a rare UMOD variant in undiagnosed hereditary nephropathy suggests the presence of a common ancestral founder mutation

Abstract BACKGROUND AND AIMS ADTKD–UMOD (Autosomal dominant tubulointerstitial kidney disease–UMOD) is a rare genetic disease due to a heterozygous mutation in the UMOD gene encoding uromodulin. It is classically characterized by minimal proteinuria, slowly progressive CKD, hyperuricemia and early-onset gout. With increasing awareness and testing, pathogenic variants in UMOD are being identified more frequently although the nonspecific nature of most symptoms makes clinical diagnosis difficult. We report the surprising finding of a rare UMOD variant in 11 seemingly unrelated families referred to Sheffield or Nottingham renal genetics services over a 15-year period with undiagnosed hereditary kidney disease. METHOD The probands identified were initially referred to renal genetics services based in Sheffield and Nottingham between 2006 and 2021, where they underwent genetic testing and a comprehensive renal workup. All had a family history of ESRD. A pathogenic variant of UMOD, c.278_289delinsCCGCCTCCT was identified in 11 probands by gene or panel-based sequencing. Family members of the affected probands were invited for genetic testing and clinical follow-up. A retrospective review of all patients screened or with ESRD at both renal genetic clinics was conducted. Molecular modeling of the variant was performed using in-silico tools. RESULTS Clinical data from 60 members (11 pedigrees) was obtained. All individuals were born in the United Kingdom and of White British ethnicity. A total of 37 tested positive for the variant, 3 were negative and 19 were not tested due to being deceased (n = 13) and for unknown reasons (n = 6). The median age of ESRD was 52 (range 32, 76) years. More females had ESRD comprising 67% (20/30). Of patients with available data, 68% (30/44) had hypertension, 7.3% (3/41) had proteinuria &amp;gt;30 mg/g and 18% (7/40) had mild hematuria. A total of 11% (6/57) had experienced ≥1 episode of gout with a median onset of 42.5 (range 29–61) years. Only one patient had asymptomatic renal calculi. All patients with CKD who carried the UMOD mutation (n = 22) had hypertension, apart from two who had unknown hypertensive status (n = 1) or reflux nephropathy causing kidney scarring (n = 1). Renal histology where available (8) showed glomerulosclerosis and tubulointerstitial fibrosis. Ultrasound kidney lengths were normal or reduced and renal cysts were only occasionally detected. Molecular modeling of the variant showed structural changes in the cysteine-rich (C6) with EGFII-like Ca2+ binding domain of UMOD, predicted to disrupt disulfide-bond formation (fifth cysteine C94–sixth cysteine C106) as well as by altering the loop (93–97) between two β-sheets of EGFII domain (AlphaFold), possibly altering calcium ion binding (DeepFRI). This variant was initially reported as a recurrent mutation in four apparently unrelated families [1] and has since been noted in a further 11 families [2], all of White British ethnicity. CONCLUSION We have identified a rare pathogenic UMOD variant shared by 11 apparently unrelated families with familial ESRD within a contiguous geographical region of England. The nonspecific symptoms associated with this variant (especially the rarity of gout) were atypical from those with more classical UMOD variants leading to a delay in diagnosis. Our findings and those of others suggest that this is likely to represent a common ancestral variant rather than a recurrent variant within the UK population. 1. Smith GD, Robinson C, Stewart AP et al. Characterization of a recurrent in-frame UMOD indel mutation causing late-onset autosomal dominant end-stage renal failure. Clin J Am Soc Nephrol 2011; 6: 2766–2774. 2. Kidd K, Vylet'al P, Schaeffer C et al. Genetic and clinical predictors of age of ESKD in individuals with autosomal dominant tubulointerstitial kidney disease due to UMOD mutations. Kidney Int Rep 2020; 5:1472–1485.

MO240: The Evolution and Epidemiology of Membranous Nephropathy at a Single Centre Over Two Decades

Abstract BACKGROUND AND AIMS Membranous nephropathy (MN) commonly presents with nephrotic syndrome and carries significant risk of progression to end-stage kidney disease (ESKD) (33% without treatment, 10%–20% with). Patients may spontaneously remit (up to 40%), but are also at risk of relapse. A total of 80% of cases are primary (kidney-specific) and the majority of these are associated with antibodies to the M-type phospholipase A2 receptor (anti-PLA2R) or thrombospondin type 1 domain containing 7A antibodies (THS7DA). Treatment ranges from supportive care with renin–angiotensin system (RAS) blockade through to immunosuppression. Here we assessed the epidemiology of MN over 20 years at our centre (Salford Royal Hospital, UK) with particular reference to treatment administered and key clinical outcomes. METHOD A total of 238 patients with kidney biopsy-proven MN were identified from the local database between January 2000 and December 2020. Twenty-one were excluded (see Fig. 1) resulting in a total of 217 patients in whom demographic data, co-morbidities, remission and relapse rates, baseline laboratory values, treatment given, and outcomes were collected. Analyses compared effects of (i) immunosuppressed versus non-immunosuppressed, (ii) effect of modified Ponticelli versus other forms of immunosuppression and (iii) rates of remission. Univariate and multivariate cox regression determined factors that were associated with increased risk of renal replacement therapy (RRT) or death. RESULTS A total of 63.6% of the cohort were male, 88% Caucasian, 10.1% diabetic, 50.2% hypertensive and 15.2% had coexisting cardiovascular disease (Table 1). A total of 82.0% had primary MN. Median baseline eGFR was 72.7 mL/min/1.73 m2 and median baseline uPCR was 664 g/mol. A total of 157 patients (72.4%) went into remission (either spontaneous—75 (47.8%) or with treatment—85 (52.2%)), and of these 41.4% subsequently relapsed. A total of 89.4% received RAS blockade and 48.8% received immunosuppression. The median follow-up period was 56 months; 9.7% progressed to ESKD and 32.3% died. Patients who received immunosuppression had significantly more proteinuria than those who did not (765 g/mol versus 514 g/mol, P ≤ 0.001), were more likely to relapse (53.7% versus 28.0%, p ≤0.001) and were more likely to require RRT (15.1% versus 4.9%, P = .028). Those who received modified Ponticelli were less likely to relapse than those who received other forms of immunosuppression (34% versus 46%, P = .019), less likely to require RRT (3% versus 22%, P = .018) and less likely to die (11% versus 38%). Multivariate cox regression showed that pre-existing cardiovascular disease was a risk factor for death (HR 2.47, P &amp;lt; .001) and higher baseline eGFR and use of RAS blockade was associated with reduced risk of death (HR 0.98, P &amp;lt; .001 and HR 0.34, P = .012, respectively). CONCLUSION Despite advances in knowledge of underlying pathogenesis and increased treatment options, MN continues to pose a significant risk of progression to ESKD and death. This real-world study suggests that immunosuppression with modified Ponticelli is associated with lower rates of progressive CKD compared with MMF and calcineurin-inhibitor based therapy. Whilst many patients respond to treatment and can achieve remission, a significant proportion of these subsequently relapse. Identifying these patients early with judicial use of appropriate immunosuppression is key.

Longitudinal TNFR1 and TNFR2 and Kidney Outcomes: Results from AASK and VA NEPHRON-D.

Higher baseline levels of soluble TNF receptors (TNFR1 and TNFR2) have been associated with progressive CKD. Whether longitudinal changes in these biomarkers of inflammation are also associated with worse kidney outcomes has been less studied. We evaluated associations of longitudinal changes in TNFR1 and TNFR2 with ESKD in the African American Study of Kidney Disease and Hypertension (AASK; 38% female; 0% diabetes) and kidney function decline (first occurrence of ≥30 ml/min per 1.73 m2 or ≥50% eGFR decline if randomization eGFR ≥60 or <60 ml/min per 1.73 m2, respectively; ESKD) in the Veterans Affairs Nephropathy in Diabetes trial (VA NEPHRON-D; 99% male; 100% diabetes) using Cox models. Biomarkers were measured from samples collected at 0-, 12-, and 24-month visits for AASK (serum) and 0- and 12-month visits for VA NEPHRON-D (plasma). Biomarker slopes (AASK) were estimated using linear mixed-effects models. Covariates included sociodemographic/clinical factors, baseline biomarker level, and kidney function. There were 129 ESKD events over a median of 7.0 years in AASK (n=418) and 118 kidney function decline events over a median of 1.5 years in VA NEPHRON-D (n=754). In AASK, each 1 SD increase in TNFR1 and TNFR2 slope was associated with 2.98- and 1.87-fold higher risks of ESKD, respectively. In VA NEPHRON-D, each 1 SD increase in TNFR1 and TNFR2 was associated with 3.20- and 1.43-fold higher risks of kidney function decline, respectively. Among individuals with and without diabetes, longitudinal increases in TNFR1 and TNFR2 were each associated with progressive CKD, independent of initial biomarker level and kidney function.

POS-116 OUTCOMES OF ANTI PLA2R POSITIVE MEMBRANOUS NEPHROPATHY TREATED WITH MODIFIED PONTICELLI REGIMEN-A SINGLE CENTRE EXPERIENCE

Membranous nephropathy (MN) has various renal outcomes ranging from spontaneous remission to progressive CKD. The present study was done to determine outcome of anti PLA2R positive membranous nephropathy treated with modified Ponticelli regimen.

Roles of SIRT6 in kidney disease: a novel therapeutic target.

SIRT6 is an NAD+ dependent deacetylase that belongs to the mammalian sirtuin family. SIRT6 is mainly located in the nucleus and regulates chromatin remodeling, genome stability, and gene transcription. SIRT6 extensively participates in various physiological activities such as DNA repair, energy metabolism, oxidative stress, inflammation, and fibrosis. In recent years, the role of epigenetics such as acetylation modification in renal disease has gradually received widespread attention. SIRT6 reduces oxidative stress, inflammation, and renal fibrosis, which is of great importance in maintaining cellular homeostasis and delaying the chronic progression of kidney disease. Here, we review the structure and biological function of SIRT6 and summarize the regulatory mechanisms of SIRT6 in kidney disease. Moreover, the role of SIRT6 as a potential therapeutic target for the progression of kidney disease will be discussed. SIRT6 plays an important role in kidney disease. SIRT6 regulates mitochondrial dynamics and mitochondrial biogenesis, induces G2/M cycle arrest, and plays an antioxidant role in nephrotoxicity, IR, obstructive nephropathy, and sepsis-induced AKI. SIRT6 prevents and delays progressive CKD induced by hyperglycemia, kidney senescence, hypertension, and lipid accumulation by regulating mitochondrial biogenesis, and has antioxidant, anti-inflammatory, and antifibrosis effects. Additionally, hypoxia, inflammation, and fibrosis are the main mechanisms of the AKI-to-CKD transition. SIRT6 plays a critical role in the AKI-to-CKD transition and kidney repair through anti-inflammatory, antifibrotic, and mitochondrial quality control mechanisms. AKI Acute kidney injury, CKD Chronic kidney disease.

Discovery of Novel Proteomic Biomarkers for the Prediction of Kidney Recovery from Dialysis-Dependent AKI Patients.

AKI requiring dialysis (AKI-D) is associated with prolonged hospitalization, mortality, and progressive CKD among survivors. Previous studies have examined only select urine or serum biomarkers for predicting kidney recovery from AKI. Serum samples collected on day 8 of randomized RRT from 72 patients enrolled in the Veteran's Affairs/National Institutes of Health Acute Renal Failure Trial Network study were analyzed by the SOMAscan proteomic platform to profile 1305 proteins in each sample. Of these patients, 38 recovered kidney function and dialysis was discontinued, whereas another 34 patients remained on dialysis by day 28. Differential serum levels of 119 proteins, with 53 higher and 66 lower, were detected in samples from patients who discontinued dialysis, compared with patients who remained on dialysis by day 28. Patients were classified into tertiles on the basis of SOMAscan protein measurements for the 25 proteins most differentially expressed. The association of serum levels of each protein with kidney recovery was further evaluated using logistic regression analysis. Higher serum levels of CXCL11, CXCL2/CXCL3, CD86, Wnt-7a, BTK, c-Myc, TIMP-3, CCL5, ghrelin, PDGF-C, survivin, CA2, IL-9, EGF, and neuregulin-1, and lower levels of soluble CXCL16, IL1RL1, stanniocalcin-1, IL-6, and FGF23 when classified in tertiles were significantly associated with better kidney recovery. This significant association persisted for each of these proteins after adjusting for potential confounding risk factors including age, sex, cardiovascular SOFA score, congestive heart failure, diabetes, modality of intensive dialysis treatment, cause of AKI, baseline serum creatinine, day 8 urine volume, and estimated 60-day mortality risk. These results suggest concerted changes between survival-related proteins and immune-regulatory chemokines in regulating angiogenesis, endothelial and epithelial remodeling, and kidney cell regeneration, illustrating potential mechanisms of kidney recovery. Thus, this study identifies potential novel predictive biomarkers of kidney recovery in patients with AKI-D.

A Higher Foci Density of Interstitial Fibrosis and Tubular Atrophy Predicts Progressive CKD after a Radical Nephrectomy for Tumor.

Chronic tubulointerstitial injury on kidney biopsy is usually quantified by the percentage of cortex with interstitial fibrosis/tubular atrophy (IF/TA). Whether other patterns of IF/TA or inflammation in the tubulointerstitium have prognostic importance beyond percentage IF/TA is unclear. We obtained, stained, and digitally scanned full cortical thickness wedge sections of renal parenchyma from patients who underwent a radical nephrectomy for a tumor over 2000-2015, and morphometrically analyzed the tubulointerstitium of the cortex for percentage IF/TA, IF/TA density (foci per mm2 cortex), percentage subcapsular IF/TA, striped IF/TA, percentage inflammation (both within and outside IF/TA regions), and percentage subcapsular inflammation. Patients were followed with visits every 6-12 months. Progressive CKD was defined as dialysis, kidney transplantation, or 40% decline from the postnephrectomy eGFR. Cox models assessed the risk of CKD or noncancer mortality with morphometric measures of tubulointerstitial injury after adjustment for the percentage IF/TA and clinical characteristics. Among 936 patients (mean age, 64 years; postnephrectomy baseline eGFR, 48 ml/min per 1.73m2), 117 progressive CKD events and 183 noncancer deaths occurred over a median 6.4 years. Higher IF/TA density predicted both progressive CKD and noncancer mortality after adjustment for percentage IF/TA and predicted progressive CKD after further adjustment for clinical characteristics. Independent of percentage IF/TA, age, and sex, higher IF/TA density correlated with lower eGFR, smaller nonsclerosed glomeruli, more global glomerulosclerosis, and smaller total cortical volume. Higher density of IF/TA foci (a more scattered pattern with more and smaller foci) predicts higher risk of progressive CKD after radical nephrectomy compared with the same percentage of IF/TA but with fewer and larger foci.

IRF-4 deficiency reduces inflammation and kidney fibrosis after folic acid-induced acute kidney injury

The chronic phase following toxin-induced acute kidney injury (AKI) is characterized by robust inflammation and progressive kidney fibrosis. Interferon regulatory factor 4 (IRF-4) is a type of multifunctional transcription factor that has been deeply linked to inflammation and fibrotic diseases. However, the role of IRF-4 in kidney damage and renal fibrosis after toxin-induced AKI remain to be explored. In this work, we examined the effect of IRF-4 deficiency on inflammation and kidney fibrosis in an AKI-chronic kidney disease (CKD) transition model induced by folic acid (FA) injury. We showed that FA treatment resulted in severe acute tubular injury followed by inflammatory reaction and interstitial fibrosis in wild-type mice. A sharp elevation of IRF-4 levels was observed in FA-injured kidneys. IRF-4 knockout led to a substantial reduction of extracellular matrix (ECM) proteins deposition and inhibited myofibroblasts transformation in the kidneys of mice subjected to FA treatment. In addition, IRF-4 ablation impaired F4/80+ macrophages and CD3+ T lymphocytes infiltration into the FA-injured kidneys. Loss of IRF-4 reduced the production of inflammatory molecules such as CXCL16, IL-18, IL-6, and TGF-β1 in the kidneys in response to FA stress. Following FA injury, the kidneys of IRF-4 knockout mice had fewer bone marrow-derived myofibroblasts than wild-type controls. Moreover, IRF-4 disruption inhibited macrophages to myofibroblasts differentiation in the kidneys in response to FA stimuli. In vitro, IL-4 stimulated expression of α-smooth muscle actin and ECM proteins and promoted M2 macrophages to myofibroblasts transition in mouse bone marrow-derived monocytes, which was abolished in the absence of IRF-4. Thus, we identified an important role of IRF-4 in the pathogenesis of progressive CKD following FA-induced AKI.

Genetic Basis of Type IV Collagen Disorders of the Kidney.

The glomerular basement membrane is a vital component of the filtration barrier of the kidney and is primarily composed of a highly structured matrix of type IV collagen. Specific isoforms of type IV collagen, the α3(IV), α4(IV), and α5(IV) isoforms, assemble into trimers that are required for normal glomerular basement membrane function. Disruption or alteration in these isoforms leads to breakdown of the glomerular basement membrane structure and function and can lead to progressive CKD known as Alport syndrome. However, there is wide variability in phenotype among patients with mutations affecting type IV collagen that depends on a complex interplay of sex, genotype, and X-chromosome inactivation. This article reviews the genetic basis of collagen disorders of the kidney as well as potential treatments for these conditions, including direct alteration of the DNA, RNA therapies, and manipulation of collagen proteins.