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Role of bariatric surgery in chronic kidney disease patients Bariatric surgery represents the elective treatment of severe obesity (BMI≥40Kg/m²) since it results in better control of cardiovascular risk factors and comorbidities typically associated with obesity, like diabetes, hypertension and dyslipidemia. Obesity is a recognized independent risk factor for chronic kidney disease and for progression of renal insufficiency. Pathomechanisms are still incompletely known. Obesity is associated with hyper-filtration, microalbuminuria and proteinuria all of which favor renal disease and its progression. This narrative review reports on the available evidence linking bariatric surgery and renal function since this surgery may affect proteinuria, hyper-filtration and glomerular filtration rate. Although available data are limited in particular in cases with more advanced stages of renal failure, bariatric surgery associates with improved filtration and lower proteinuria in patients with mild to moderate renal insufficiency. In patients with more advanced stages of renal failure, surgery should be considered if obesity represents a relative contraindication to transplantation. Surgery seems to improve graft survival. Further, nephrologists should be informed on the metabolic and nutritional changes associated with bariatric surgery, which could be responsible for untoward effects requiring early identification and treatment. Bariatric surgery could be a valid therapeutic option in renal patients to improve the negative clinical outcomes of obese subjects. [ABSTRACT FROM AUTHOR]

Background Mast cell activation can lead to nonclassical activation of the Renin-Angiotensin-Aldosterone System. However, the relevance of this to human chronic kidney disease is unknown. We assessed the association between serum tryptase, a product of mast cell activation, and progression to end-stage renal disease or mortality in patients with advanced chronic kidney disease. We stratified patients by use of angiotensin-converting enzyme inhibitors/angiotensin receptor II blockers ( ACEi/ ARB). Materials and methods This was a prospective cohort study of 446 participants recruited into the Renal Impairment in Secondary Care study. Serum tryptase was measured at recruitment by sandwich immunoassay. Cox regression analysis was undertaken to determine variables associated with progression to end-stage renal disease or death. Results Serum tryptase concentration was independently associated with progression to end-stage renal disease but not with death. In patients treated with ACEi or ARB, there was a strong independent association between higher tryptase concentrations and progression to end-stage renal disease; when compared to the lowest tertile, tryptase concentrations in the middle and highest tertiles had hazard ratios [ HR] of 5·78 (95% confidence interval [ CI] 1·19-28·03, P = 0·029) and 6·19 (95% CI 1·49-25·69, P = 0·012), respectively. The other independent risk factors for progression to end-stage renal disease were lower age, male gender, lower estimated glomerular filtration rate and higher urinary albumin creatinine ratio. Conclusion Elevated serum tryptase concentration is an independent prognostic factor for progression to end-stage renal disease in patients with chronic kidney disease who are receiving treatment with an ACEi or ARB. [ABSTRACT FROM AUTHOR]

Background The long-term prognosis of clinically early IgA nephropathy (IgAN) patients remains to be clarified. We investigated the long-term outcomes of IgAN patients with an apparently benign presentation and evaluated prognostic factors for renal survival. Methods We included patients with biopsy-proven IgAN who had estimated glomerular filtration rates (eGFR) ≥60 mL/min/1.73 m2, normal blood pressure, and proteinuria <0.5 g/day at the time of biopsy. The primary outcome was progression to end-stage renal disease (ESRD). The secondary outcome was a 50% increase in serum creatinine level or an increase in proteinuria to >1 g/day. Results The analysis included 153 patients who met the inclusion criteria. At diagnosis, their median systolic blood pressure was 120 (110-130) mmHg, eGFR was 85.9 (74.9-100.1) mL/min/1.73 m², and proteinuria was 0.25 (0.13-0.38) g/day. Of these, 4 patients died and 6 reached ESRD. The 30-year renal survival rate was 85.5%. Three patients had increased serum creatinine levels and 11 developed proteinuria. Remission was observed in 35 (22.9%) patients. A moderate or severe degree of interstitial fibrosis (adjusted odd ratio [OR] 5.93, 95% confidence interval [CI] 1.44-24.45, P = 0.014) and hypoalbuminemia (adjusted OR 6.18, 95% CI 1.20-31.79, P = 0.029) were independent predictors of the secondary outcome. Conclusions This study showed that the prognosis of early IgAN was not always favorable, even resulting in progression to ESRD in some cases. Hypoalbuminemia and interstitial fibrosis should also be considered important prognostic factors in clinically early IgAN patients. [ABSTRACT FROM AUTHOR]

Background. Although current guidelines recommend the evaluation of mineral and bone metabolism in patients with all stages of chronic kidney disease (CKD), the prevalence of altered mineral ion homeostasis in the pediatric posttransplant population is unknown. Moreover, the contribution of abnormal mineral ion metabolism to graft outcomes in this population has not been evaluated.Methods. Serum calcium, phosphorus, 25(OH)vitamin D, 1,25(OH)2vitamin D, parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23) levels were evaluated 4.9 ± 0.5 years after transplantation in 68 stable pediatric renal allograft recipients. Patients were subsequently followed for 2 years.Results. At baseline, mean estimated glomerular filtration rate (GFR) was 60 ± 2 mL/min/1.73m2. Serum calcium and phosphorus values were within the reference interval. PTH values were elevated but did not differ by CKD stage. 25(OH)vitamin D levels were low in nearly half of all subjects. Tubular reabsorption of phosphate and 1,25(OH)2vitamin D values were lower, while FGF-23 and PTH values were higher in more advanced stages of CKD. Thirty percent of patients with FGF-23 values >110 RU/mL had a decrease in GFR of >50% (P < 0.05) and FGF-23 values predicted future episodes of rejection.Conclusions. Despite normal serum calcium and phosphorus levels in the majority of prevalent pediatric renal transplant recipients, abnormalities in PTH, 25(OH)vitamin D and FGF-23 are common. FGF-23 levels may be associated with increased risk for deterioration of kidney function and episodes of rejection. [ABSTRACT FROM AUTHOR]

Polycystic kidney disease is characterized by the progressive enlargement of kidneys due to expanding fluid-filled cysts with the rate of renal volume increase held to be a marker of disease progression. Magnetic resonance imaging (MRI) is used to monitor changes in renal volume in patients with polycystic kidney disease; however, it has not been effectively used in mice to monitor changes in kidney volume during drug treatment studies. We used a powerful 9.4-T horizontal bore magnetic resonance scanner to track changes in kidney volume in pcy/pcy mice, an ortholog of nephronophthisis type 3. Mice were sequentially scanned from 4 to 30 weeks of age and kidney volumes determined from high-resolution images. Kidney volume and maximal cross-sectional surface area correlated positively with kidney weight and the histologic determination of surface area. The increase in kidney volume was exponential up to 20 weeks of age, after which there was a plateau consistent with the replacement of normal parenchyma by fibrotic tissue. Our study demonstrates that MRI accurately determines the rate of kidney volume increase in mice with polycystic kidney disease and hence may be useful in assessing the effectiveness of therapeutic agents to slow disease progression.Kidney International (2008) 73, 778–781; doi:10.1038/sj.ki.5002771; published online 9 January 2008 [ABSTRACT FROM AUTHOR]

Neutrophil gelatinase-associated lipocalin (Ngal, 24p3, SIP24, lipocalin 2, or siderocalin) was originally purified from neutrophils, but with unknown function. Recently, it was identified that Ngal activates nephron formation in the embryonic kidney, is rapidly and massively induced in renal failure and possesses kidney-protective activity. We would like to propose that blood, urine, and kidney Ngal levels are the real-time indicators of active kidney damage, rather than one of many markers of functional nephron number (as Forest Fire Theory). Ngal is a novel iron-carrier protein exerting pleiotropic actions including the upregulation of epithelial marker E-cadherin expression, opening an exciting field in cell biology.Kidney International (2007) 71, 967–970. doi:10.1038/sj.ki.5002165; published online 7 March 2007 [ABSTRACT FROM AUTHOR]

As long-term outcome studies of acute renal failure (ARF) are scarce and non-homogeneous, we studied 187 consecutive acute tubular necrosis (ATN) patients without previous nephropathies, discharged alive from our hospital between October 77 and December 92 and followed-up until December 99 (range 7–22 years; median 7.2). Variables were analyzed at the time of the acute episode and during follow-up. In 2000–2001 a clinical evaluation was made in 58 of the 82 patients still alive. Ten patients were lost to follow-up and 95 died. In 59% death was related with the disease present when the ATN developed. Kaplan–Meir survival curve showed 89, 67, 50, and 40% at 1, 5, 10, and 15 years, respectively, after discharge. Survival curves were significantly better (log-rank P<0.001) among the youngest, those surviving a polytrauma, those without comorbidity and surprisingly those treated in intensive care units. The proportional Cox model showed that age (hazard ratio (HR) 1.04 per year of age; P=0.000), presence of comorbid factors (HR 4.29; P=0.006), surgical admission (HR 0.45; P=0.000), and male sex (HR 1.72; P=0.020) were the variables associated with long-term follow-up. In the evaluated patients renal function was normal in 81%. Long-term outcome after ARF depends on absence of co-morbid factors, cause of initial admission and age. Although the late mortality rate is high and related with the original disease, renal function is adequate in most patients.Kidney International (2007) 71, 679–686. doi:10.1038/sj.ki.5002086; published online 31 January 2007 [ABSTRACT FROM AUTHOR]

Background. Autosomal dominant polycystic kidney disease (ADPKD) is a renal disease characterized by an important variability in clinical course, which cannot be fully explained by the genetic heterogeneity of the disease. Although the role for the angiotensin I-converting enzyme (ACE) insertion/deletion (I/D) polymorphism as a modifier factor in ADPKD renal deterioration has been suggested, direct evidence from genetic association studies remain inconclusive. To provide a more robust estimate of the putative effect of the ACE I/D polymorphism on the renal progression in ADPKD, we performed a meta-analysis pooling data from all relevant studies in which the role of the ACE I/D variant in ADPKD clinical features was evaluated. [ABSTRACT FROM PUBLISHER]

In recent years, it has become apparent that smoking has a negative impact on renal function, being one of the most important remediable renal risk factors. It has been clearly shown that the risk for high-normal urinary albumin excretion and microalbuminuria is increased in smoking compared to non-smoking subjects of the general population. Data from the Multiple Risk Factor Intervention Trial (MRFIT) indicate that at least in males, smoking increases the risk to reach end-stage renal failure. Smoking is particularly “nephrotoxic” in older subjects, subjects with essential hypertension and patients with preexisting renal disease. Of interest, the magnitude of the adverse renal effect of smoking seems to be independent of the underlying renal disease. Death-censored renal graft survival is decreased in smokers, indicating that smoking also damages the renal transplant. Cessation of smoking has been show to reduce the rate of progression of renal failure both in patients with renal disease or a renal transplant. The mechanisms of smoking-induced renal damage are only partly understood and comprise acute hemodynamic (e.g., increase in blood pressure and presumably intraglomerular pressure) and chronic effects (e.g., endothelial cell dysfunction). Renal failure per se leads to an increased cardiovascular risk. The latter is further aggravated by smoking. Particularly survival of smokers with diabetes mellitus on hemodialysis is abysmal. In the present review article the current state of knowledge about the renal risks of smoking is reviewed. It is the aim of the article to point out that smoking not only increases the risk of renal cell carcinoma or uroepithelial cell carcinoma, but also the risk of a faster decline of renal function. The latter is a relatively new negative aspect which has not been widely recognized.

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In a retrospective study of 33 patients the influence of different anamnestic, clinical and laboratory parameters on the progression of renal failure was investigated. The analysis of progression of renal failure was evaluated in terms of a reasonable criterium intuitively suggesting itself which is based on a non-linear fitting of the serum creatinine profile. Follow-up serum creatinine levels showed that renal function became worse in 28 cases, with terminal renal failure developing in 6 cases. In 5 patients significant improvement in kidney function was observed. The variables systolic and diastolic blood pressure, total amount of ingested analgesics, continued abuse and cessation of analgesics, frequency of urinary tract infections and amount of proteinuria had no significant influence on progression of renal failure. However, a strong relationship between the initial serum creatinine level and the progression of renal failure could be established. In conclusion our results indicate that long-term prognosis of analgesic nephropathy mainly depends on early diagnosis. [ABSTRACT FROM AUTHOR]

Background.Recently, intensified antihypertensive treatment has been recommended for patients with proteinuric renal disease, and a target blood pressure of 125/75 mmHg has been proposed. [ABSTRACT FROM PUBLISHER]

The Han: SPRD Pkd rat mutant is an autosomal dominant rat model with incomplete penetration of polycystic renal transformation. Progressive renal failure occurs in heterozygous male animals. The mechanisms of progression have not been elucidated. To identify some pathogenetic factors involved we subjected male SPRD Pkd rats (and their non-affected littermates as controls) to uninephrectomy (UNX), castration or enalapril treatment. To assess progression S-urea at age 150 days was chosen as endpoint. (i) In uninephrectomized male Han: SPRD Pkd (=12 animals per group) S-urea at age 150 days was consistently above 300 mg/dl, while it was 245 mg/dl (191–290) in control Han: SPRD Pkd. (ii) In castrated male Han: SPRD median S urea at 150 days was 100 mg/dl (69–211) compared to sham-operated male Han: SPRD controls (245; 191–290). Castration did not, however, prevent accelerated progression after uninephrectomy. (iii) Enalapril (50 mg/l) in the drinking fluid did not significantly lower median systolic blood pressure (by plethysmography) in animals on 0.2% sodium diet (at 185 days 160 mmHg; 140–170 versus 170; 140–195 in non-enalapril controls), although circulating ACE was significantly inhibited (17 U; 11–33 versus 89; 52–108 in controls). S-urea at age 185 days was not significantly different in the 2 groups. In conclusion, the Han: SPRD Pkd model differs from human ADPKD to some extent. Uninephrectomy accelerates renal failure in the rat, but not in humans. On the other hand, in contrast to human ADPKD the renin system is suppressed in the rat model and ACE inhibition does not affect the course of renal failure. [ABSTRACT FROM PUBLISHER]

The effects of a protein load on renal haemo-dynamics in patients with renal failure are controversial. We measured insulin clearance ( C and clearance (C) by constant infusion technique in six healthy subjects and 13 patients with biopsy-confirmed glomerulonephritis and chronic renal failure. The subjects were pre-equilibrated on their usual diet and studied before and 2 h after 1 g protein/kg as cooked red meat. In healthy subjects this caused a significant increase of C (from l36±7.2 (SD) to 148±7.9 ml/min/1.73 m) and of C (from 547±142 to 639±89). In contrast C decreased from 72.7±7.7 to 60.3±8.4 in patients with chronic renal failure, whereas C showed no significant change (from 275±67.8 to 278±72.7). A similar decrease of C was also seen with acute infusion of amino acids (AA). The change in C was not related to changes of PRA or concentrations of plasma amino acids. While absolute and fractional Na excretion increased in controls, they decreased in patients in parallel with the decrease of C. The decrease of C after infusion of AA was amplified by pre-equilibration on low-sodium diet (20 mmol Na/day). The effect of meat ingestion on C was not obliterated, however, by pretreatment with captopril (25 mg b.i.d. for 7 days). In conclusion, in patients with chronic renal failure, a paradoxical decrease in C is seen both after oral protein and after amino-acid infusion. [ABSTRACT FROM PUBLISHER]

Low-protein, low-phosphorus diets (LPD) are prescribed to patients with chronic renal failure (CRF) to slow down the rate of progression of CRF and to control uraemic symptoms. A satisfactory adherence of patients to the prescribed diet is needed to meet these two goals. We studied the compliance of CRF patients to a LPD providing daily (per kg body weight) 0.3 g protein, 3–5 mg phosphorus, 35 kcal, and supplemented with essential amino-acids and ketoanalogues. Forty CRF patients were studied for 23.3±10.8 months (range 12–45). Compliance to LPD was evaluated by dietary inquiry and protein intake estimated from urinary urea excretion. According to compliance to LPD, patients were retrospectively assigned to the compliant (=27) or the non-compliant (=13) group. GFR measured by the urinary clearance of [Cr]-EDTA was identical in the two groups at the start of the study: compliant patients 15.7±5.3 ml/mn, non-compliant patients 15.4±5.9 ml/mn. The decrease of GFR was − 0.08±0.22 ml/min per month in compliant patients versus −0.31±0.37 ml/min per month in non-compliant patients (<0.02). These results were not demonstrated if the progression of CRF was assessed by the linear regressions over time of creatinine clearance or the reciprocal of creatinine. Serum bicarbonate, serum phosphorus and PTH levels were corrected by LPD in compliant patients (< 0.005 for all parameters) but not in non-compliant patients. These results suggest that evaluation of compliance is necessary to assess the response of CRF patients to LPD, whether the aim is to slow the progression of CRF or to control its metabolic consequences. A beneficial effect of compliance to LPD was demonstrated upon these two goals. [ABSTRACT FROM PUBLISHER]

We compared the glomerular filtration rate (GFR) response to amino acids in patients with glomerular disease and polycystic kidney disease. The GFR response to infusion of amino acids (75 g/12 h), of dopamine (2 μg/kg per min), or their combination was evaluated in nine healthy probands and in patients with two types of renal diseases at various degrees of renal function: 15 patients with ADPKD and 11 patients with glomerular disease (IgA glomerulonephritis or diabetic nephropathy). Steady-state inulin infusion technique was used. In healthy subjects amino acids increased median C in response to amino acids was not found in glomerular disease. In contrast in most ADPKD patients median C increased after amino acids ( + 6.0 ml/min; range –4 to +68), (≪0.05). The response to amino acids was not modified by dopamine. The results demonstrate that amino acid-induced acute changes of glomerular filtration differ in polycystic kidney disease compared with glomerular disease. These observations may have implications with respect to mechanisms of progression. [ABSTRACT FROM PUBLISHER]

In recent years dietary protein restriction (DPR) to slow down the progression rate of chronic renal disease has been a major field in nephrological science. In this update a brief historical overview is given, as well as a critical review regarding the now available data from clinical trials. Furthermore, the theoretical backgrounds of DPR are discussed. It is concluded that DPR has profound effects on the kidney. In certain diseases, especially primary glomerular disease, the beneficial effect seems proven. However, many questions remain to be answered, e.g. how to apply reliable statistics in chronic renal failure, how to obtain and monitor patient compliance, and the definition of the exact target group since the diet has a selective effect. Most of these questions will be answered in the coming years when data becomes available from large scale multicenter trials. Awaiting these results, proposals for the treatment with diet are made, based on the facts that are now to our knowledge. [ABSTRACT FROM AUTHOR]

Low-protein diets have been used for roughly a century in order to alleviate uraemic symptoms and to delay progression of chronic renal failure (CRF). Currently a number of different low-protein diets are used, supplying either 0.6 g protein/kg body weight or 0.3-0.4 g supplemented with amino-acids or keto-acids. Single centre trials have attempted to demonstrate the efficacy of these diets in slowing down the progression of CRF. The results from these trials are, however, sometimes inconclusive, showing either a high efficiency of the low-protein diet or no efficiency at all. Conclusive data from multicentre trials, however, are not yet available. A crucial point in analysing the efficacy of low-protein diets is the degree of compliance with the protein restriction. Today, the data available indicate that somtimes only a poor degree of compliance is achieved both in single and in multicentre trials. [ABSTRACT FROM AUTHOR]

Background: Mechanisms underlying the pro gression of diabetic kidney disease to ESKD are not fully understood., Methods: We performed global microRNA (miRNA) analysis on plasma from two cohorts consisting of 375 individuals with type 1 and type 2 diabetes with late diabetic kidney disease, and targeted proteomics analysis on plasma from four cohorts consisting of 746 individuals with late and early diabetic kidney disease. We examined structural lesions in kidney biopsy specimens from the 105 individuals with early diabetic kidney disease. Human umbilical vein endothelial cells were used to assess the effects of miRNA mimics or inhibitors on regulation of candidate proteins., Results: In the late diabetic kidney disease cohorts, we identified 17 circulating miRNAs, represented by four exemplars (miR-1287-5p, miR-197-5p, miR-339-5p, and miR-328-3p), that were strongly associated with 10-year risk of ESKD. These miRNAs targeted proteins in the axon guidance pathway. Circulating levels of six of these proteins-most notably, EFNA4 and EPHA2-were strongly associated with 10-year risk of ESKD in all cohorts. Furthermore, circulating levels of these proteins correlated with severity of structural lesions in kidney biopsy specimens. In contrast, expression levels of genes encoding these proteins had no apparent effects on the lesions. In in vitro experiments, mimics of miR-1287-5p and miR-197-5p and inhibitors of miR-339-5p and miR-328-3p upregulated concentrations of EPHA2 in either cell lysate, supernatant, or both., Conclusions: This study reveals novel mechanisms involved in progression to ESKD and points to the importance of systemic factors in the development of diabetic kidney disease. Some circulating miRNAs and axon guidance pathway proteins represent potential targets for new therapies to prevent and treat this condition., (Copyright © 2021 by the American Society of Nephrology.)

The long-term sequelae of AKI have received increasing attention so that its associations with a number of adverse outcomes, including higher mortality and development of CKD, are now widely appreciated. These associations take on particular importance when considering the high incidence of AKI, with a lack of proven interventions and uncertainties around optimal care provision meaning that the long-term sequelae of AKI present a major unmet clinical need. In this review, we examine the published data that inform our current understanding of long-term outcomes following AKI and discuss potential knowledge gaps, covering long-term mortality, CKD, progression to ESKD, proteinuria, cardiovascular events, recurrent AKI, and hospital readmission., (Copyright © 2020 by the American Society of Nephrology.)

Background and Objectives: Protein carbamylation is a consequence of uremia and carbamylated lipoproteins contribute to atherogenesis in CKD. Proteins can also be carbamylated by a urea-independent mechanism, and whether carbamylated lipoproteins contribute to the progression of CKD has not been investigated., Design, Setting, Participants, & Measurements: A case-control study was performed to determine whether there were changes in plasma levels of carbamylated lipoproteins in individuals with type 2 diabetes with eGFR >60 ml/min per 1.73 m 2 compared with a group of age- and sex-matched healthy controls. A cohort of 1320 patients with type 2 diabetes with baseline eGFR ≥30 ml/min per 1.73 m 2 was longitudinally followed up to evaluate the association between carbamylated lipoproteins and progression of CKD. The primary kidney outcome was defined as doubling of serum creatinine and/or initiation of KRT during follow-up. Plasma carbamylated LDLs and HDLs was measured by ELISA., Results: In individuals with diabetes with eGFR >60 ml/min per 1.73 m 2 , both plasma carbamylated LDL and HDL levels were higher compared with healthy controls ( P <0.001). After a mean follow-up of 9 years of the diabetic cohort, individuals in the top quartile of carbamylated LDL (hazard ratio, 2.21; 95% confidence interval, 1.42 to 3.46; P <0.001) and carbamylated HDL (hazard ratio, 4.53; 95% confidence interval, 2.87 to 7.13; P <0.001) had higher risk of deterioration of kidney function compared with those in the lowest quartile. On multivariable Cox regression analysis, plasma carbamylated LDL was no longer associated with kidney outcome after adjusting for baseline eGFR and potential confounding factors. However, the association between plasma carbamylated HDL and kidney outcome remained significant and was independent of HDL cholesterol., Conclusions: Plasma carbamylated HDL but not carbamylated LDL was independently associated with progression of CKD in patients with type 2 diabetes., (Copyright © 2020 by the American Society of Nephrology.)

Background and Objectives: Low eGFR is known to be associated with frailty, but the association between the longitudinal decline of eGFR and incident frailty in older persons remains to be determined. The objective of this study was to investigate whether a fast decline on eGFR would be associated with incident frailty., Design, Setting, Participants, & Measurements: Community dwellers, aged ≥70, were included in this secondary analysis of the 5-year Multidomain Alzheimer Preventive Trial (MAPT). eGFR was calculated using CKD-Epidemiology Collaboration equation at baseline and at 6, 12, and 24 months. The lowest quartile of eGFR slope (-4.1 ml/min per 1.73 m 2 per yr) defined a fast decline. The frailty phenotype (unintentional weight loss, exhaustion, low physical activity, slow gait, low handgrip strength assessed with a 0-5 score, where higher is worse; a score ≥3 defines frailty) was assessed at baseline, 6, 12, 24, 36, 48, and 60 months. Cox models were used to test the association between fast eGFR decline and incident frailty., Results: A total of 833 participants were frail neither at baseline nor at 2 years and had appropriate follow-up data. Median (IQR) baseline eGFR was 73 (61-84) ml/min per 1.73 m 2 . Frailty occurred in 95 (11%) participants between 24 and 60 months. Among them, 31/207 (15%) had fast eGFR decline between baseline and 24 months, and 64/626 (10%) did not. In a Cox model adjusted for demographic variables, cardiovascular comorbidity, C-reactive protein, and baseline eGFR, a fast eGFR decline was associated with incident frailty (HR 1.67, 95% CI 1.03 to 2.71). Sensitivity analyses provided consistent findings., Conclusions: In community-dwelling older adults with relatively preserved baseline eGFR, a fast eGFR decline is associated with incident frailty., (Copyright © 2019 by the American Society of Nephrology.)

Background and Objectives: Posterior urethral valve is the most common cause of bladder outlet obstruction in infants. We aimed to describe the rate and timing of kidney-related and survival outcomes for children diagnosed with posterior urethral valves in United States children's hospitals using the Pediatric Health Information System database., Design, Setting, Participants, & Measurements: This retrospective cohort study included children hospitalized between January 1, 1992 and December 31, 2006, who were in their first year of life, had a diagnosis of congenital urethral stenosis, and underwent endoscopic valve ablation or urinary drainage intervention, or died. Records were searched up to December 31, 2018 for kidney-related mortality, placement of a dialysis catheter, and kidney transplantation. Cox regression analysis was used to identify risk factors, and Kaplan-Meier survival analysis used to determine time-to-event probability. Subgroup survival analysis was performed with outcomes stratified by the strongest identified risk factor., Results: Included were 685 children hospitalized at a median age of 7 (interquartile range, 1-37) days. Thirty four children (5%) died, over half during their initial hospitalization. Pulmonary hypoplasia was the strongest risk factor for death (hazard ratio, 7.5; 95% confidence interval [95% CI], 3.3 to 17.0). Ten-year survival probability was 94%. Fifty-nine children (9%) underwent one or more dialysis catheter placements. Children with kidney dysplasia had over four-fold risk of dialysis catheter placement (hazard ratio, 4.6; 95% CI, 2.6 to 8.1). Thirty-six (7%) children underwent kidney transplant at a median age of 3 (interquartile range, 2-8) years. Kidney dysplasia had a nine-fold higher risk of kidney transplant (hazard ratio, 9.5; 95% CI, 4.1 to 22.2)., Conclusions: Patients in this multicenter cohort with posterior urethral valves had a 5% risk of death, and were most likely to die during their initial hospitalization. Risk of death was higher with a diagnosis of pulmonary hypoplasia. Kidney dysplasia was associated with a higher risk of need for dialysis/transplant., Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019&#95;10&#95;03&#95;CJN04350419.mp3., (Copyright © 2019 by the American Society of Nephrology.)

Senescent cells have undergone permanent growth arrest, adopt an altered secretory phenotype, and accumulate in the kidney and other organs with ageing and injury. Senescence has diverse physiologic roles and experimental studies support its importance in nephrogenesis, successful tissue repair, and in opposing malignant transformation. However, recent murine studies have shown that depletion of chronically senescent cells extends healthy lifespan and delays age-associated disease-implicating senescence and the senescence-associated secretory phenotype as drivers of organ dysfunction. Great interest is therefore focused on the manipulation of senescence as a novel therapeutic target in kidney disease. In this review, we examine current knowledge and areas of ongoing uncertainty regarding senescence in the human kidney and experimental models. We summarize evidence supporting the role of senescence in normal kidney development and homeostasis but also senescence-induced maladaptive repair, renal fibrosis, and transplant failure. Recent studies using senescent cell manipulation and depletion as novel therapies to treat renal disease are discussed, and we explore unanswered questions for future research., (Copyright © 2019 by the American Society of Nephrology.)

Background As children progress to higher stages of AKI, the risk for adverse outcomes dramatically increases. No reliable methods exist to predict AKI progression in hospitalized children. To determine if biomarkers of inflammation and kidney injury can predict AKI progression, we conducted a three-center prospective cohort study of children undergoing cardiopulmonary bypass. Methods On the first day of serum creatinine-defined AKI, we measured urine biomarkers (neutrophil gelatinase-associated lipocalin [NGAL], IL-18, kidney injury molecule 1, liver fatty acid binding protein [L-FABP], albumin, and cystatin C) and plasma biomarkers (IFN, IL-1, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, TNF- α , NGAL, and cystatin C). We defined AKI progression as a worsening of AKI stage or persisting stage 3 AKI (≥2 consecutive days). Results In all, 176 of 408 (43%) children developed postoperative AKI. Among the children with AKI, we diagnosed stages 1, 2, and 3 AKI in 145 (82.5%), 25 (14%), and six (3.5%) children, respectively, on the first day of AKI; 28 (7%) children had AKI progression. On the first day of AKI, nine of 17 biomarkers were significantly higher in patients with than without AKI progression. Urine L-FABP (among injury biomarkers) and plasma IL-8 (among inflammatory biomarkers) had the highest discrimination for AKI progression: optimism-corrected area under the curve, 0.70; 95% confidence interval, 0.58 to 0.81 and optimism-corrected area under the curve, 0.80; 95% confidence interval, 0.69 to 0.91, respectively. Conclusions If validated in additional cohorts, plasma IL-8 could be used to improve clinical care and guide enrollment in therapeutic trials of AKI., (Copyright © 2018 by the American Society of Nephrology.)

Background and Objectives: Hepatitis C virus infection is common in patients with CKD and leads to accelerated progression to ESRD. Sofosbuvir is a potent direct-acting antiviral therapy against hepatitis C virus; however, there are concerns about its safety in patients with CKD. The objective of our study was to determine the safety and efficacy of sofosbuvir in patients with CKD., Design, Setting, Participants, & Measurements: We studied a retrospective observational cohort of patients with CKD defined by eGFR<60 ml/min per 1.73 m 2 , ≥30 mg albuminuria per 1 g creatinine, or ≥200 mg proteinuria per 1 g creatinine who received sofosbuvir-based therapy in a large health care system. Regression models were constructed to predict likelihood of sustained virologic response, detect adverse events, and examine changes in eGFR from baseline to follow-up., Results: Ninety-eight patients with CKD (42% stage 1 or 2 CKD and 58% stage 3 CKD) were included. Mean age was 62 years old, 78% were men, and 65% were white. Additionally, 49% of patients had diabetes, 38% of patients had cirrhosis, and 33% of patients had prior solid organ transplant. Overall sustained virologic response was 81% and varied by regimen used and viral genotype. Average baseline eGFR was equivalent to average on-treatment eGFR, but seven patients experienced a rise in creatinine ≥1.5 times baseline while taking sofosbuvir; all but one recovered. In patients with eGFR<60 ml/min per 1.73 m 2 at baseline (stage 3 CKD), regression models showed that hepatitis C cure was associated with a 9.3 (95% confidence interval, 0.44 to 18) ml/min per 1.73 m 2 improvement in eGFR during the 6-month post-treatment follow-up period. Adverse events were common (81%), but serious adverse events (17%) and treatment discontinuations (8%) were uncommon., Conclusions: Sofosbuvir-based direct-acting antiviral therapy is safe and effective in a cohort of patients with CKD infected with hepatitis C., (Copyright © 2017 by the American Society of Nephrology.)

Glomerular sclerotic lesions develop when the glomerular filtration surface area exceeds the availability of podocyte foot process coverage, but the mechanisms involved are incompletely characterized. We evaluated potential mechanisms using a transgenic (podocin promoter-AA-4E-BP1) rat in which podocyte capacity for hypertrophy in response to growth factor/nutrient signaling is impaired. FSGS lesions resembling human FSGS developed spontaneously by 7 months of age, and could be induced earlier by accelerating kidney hypertrophy by nephrectomy. Early segmental glomerular lesions occurred in the absence of a detectable reduction in average podocyte number per glomerulus and resulted from the loss of podocytes in individual glomerular capillary loops. Parietal epithelial cell division, accumulation on Bowman's capsule, and tuft invasion occurred at these sites. Three different interventions that prevented kidney growth and glomerular enlargement (calorie intake reduction, inhibition of mammalian target of rapamycin complex, and inhibition of angiotensin-converting enzyme) protected against FSGS lesion development, even when initiated late in the process. Ki67 nuclear staining and unbiased transcriptomic analysis identified increased glomerular (but not podocyte) cell cycling as necessary for FSGS lesion development. The rat FSGS-associated transcriptomic signature correlated with human glomerular transcriptomes associated with disease progression, compatible with similar processes occurring in man. We conclude that FSGS lesion development resulted from glomerular growth that exceeded the capacity of podocytes to adapt and adequately cover some parts of the filtration surface. Modest modulation of the growth side of this equation significantly ameliorated FSGS progression, suggesting that glomerular growth is an underappreciated therapeutic target for preservation of renal function., (Copyright © 2017 by the American Society of Nephrology.)

Hematuria is a cardinal symptom in IgA nephropathy, but its influence on the risk of disease progression has been scarcely investigated. We followed a cohort of 112 patients with IgA nephropathy for a mean±SEM period of 14±10.2 years, during which clinical and analytic risk factors (including urine sediment examination) were regularly recorded. According to the magnitude of time-averaged hematuria, we classified patients as those with persistent hematuria and those with negative or minimal hematuria. We also classified patients according to the magnitude of time-averaged proteinuria (>0.75 or ≤0.75 g/d). The proportion of patients reaching ESRD or a 50% reduction of renal function was significantly greater among patients with persistent hematuria than patients with minimal or negative hematuria (30.4% and 37.0% versus 10.6% and 15.2%, respectively; P =0.01). Multivariable analysis revealed time-averaged hematuria, time-averaged proteinuria, renal function at baseline, and the presence of tubulointerstitial fibrosis on renal biopsy as independent predictors of ESRD. After hematuria disappearance, which occurred in 46% of the patients, the rate of renal function decline changed from -6.45±14.66 to -0.18±2.56 ml/min per 1.73 m 2 per year ( P =0.001). Patients with time-averaged proteinuria >0.75 g/d had significantly poorer renal survival than those with time-averaged proteinuria ≤0.75 g/d. However, on further classification by time-averaged hematuria, only those patients with time-averaged proteinuria >0.75 g/d and persistent hematuria had significantly worse renal survival than those in the other three groups. In conclusion, remission of hematuria may have a significant favorable effect on IgA nephropathy outcomes., (Copyright © 2017 by the American Society of Nephrology.)

Individuals age >65 years old are the fastest expanding population demographic throughout the developed world. Consequently, more aged patients than before are receiving diagnoses of impaired renal function and nephrosclerosis-age-associated histologic changes in the kidneys. Recent studies have shown that the aged kidney undergoes a range of structural changes and has altered transcriptomic, hemodynamic, and physiologic behavior at rest and in response to renal insults. These changes impair the ability of the kidney to withstand and recover from injury, contributing to the high susceptibility of the aged population to AKI and their increased propensity to develop subsequent progressive CKD. In this review, we examine these features of the aged kidney and explore the various validated and putative pathways contributing to the changes observed with aging in both experimental animal models and humans. We also discuss the potential for additional study to increase understanding of the aged kidney and lead to novel therapeutic strategies., (Copyright © 2017 by the American Society of Nephrology.)

The cardiac natriuretic peptides (NPs), atrial NP and B-type NP, regulate fluid homeostasis and arterial BP through renal actions involving increased GFR and vascular and tubular effects. Guanylyl cyclase-A (GC-A), the transmembrane cGMP-producing receptor shared by these peptides, is expressed in different renal cell types, including podocytes, where its function is unclear. To study the effects of NPs on podocytes, we generated mice with a podocyte-specific knockout of GC-A (Podo-GC-A KO). Despite the marked reduction of GC-A mRNA in GC-A KO podocytes to 1% of the control level, Podo-GC-A KO mice and control littermates did not differ in BP, GFR, or natriuresis under baseline conditions. Moreover, infusion of synthetic NPs similarly increased the GFR and renal perfusion in both genotypes. Administration of the mineralocorticoid deoxycorticosterone-acetate (DOCA) in combination with high salt intake induced arterial hypertension of similar magnitude in Podo-GC-A KO mice and controls. However, only Podo-GC-A KO mice developed massive albuminuria (controls: 35-fold; KO: 5400-fold versus baseline), hypoalbuminemia, reduced GFR, and marked glomerular damage. Furthermore, DOCA treatment led to decreased expression of the slit diaphragm-associated proteins podocin, nephrin, and synaptopodin and to enhanced transient receptor potential canonical 6 (TRPC6) channel expression and ATP-induced calcium influx in podocytes of Podo-GC-A KO mice. Concomitant treatment of Podo-GC-A KO mice with the TRPC channel blocker SKF96365 markedly ameliorated albuminuria and glomerular damage in response to DOCA. In conclusion, the physiologic effects of NPs on GFR and natriuresis do not involve podocytes. However, NP/GC-A/cGMP signaling protects podocyte integrity under pathologic conditions, most likely by suppression of TRPC channels., (Copyright © 2016 by the American Society of Nephrology.)

Evidence suggests that autophagy promotes the development of cellular senescence. Because cellular senescence contributes to renal aging and promotes the progression from AKI to CKD, we investigated the potential effect of tubular autophagy on senescence induction. Compared with kidneys from control mice, kidneys from mice with conditional deletion of autophagy-related 5 (Atg5) for selective ablation of autophagy in proximal tubular S3 segments (Atg5(Δ) (flox/) (Δ) (flox)) presented with significantly less tubular senescence, reduced interstitial fibrosis, and superior renal function 30 days after ischemia/reperfusion injury. To correlate this long-term outcome with differences in the early injury process, kidneys were analyzed 2 hours and 3 days after reperfusion. Notably, compared with kidneys of control mice, Atg5(Δ) (flox/) (Δ) (flox) kidneys showed more cell death in outer medullary S3 segments at 2 hours but less tubular damage and inflammation at day 3. These data suggest that the lack of autophagy prevents early survival mechanisms in severely damaged tubular cells. However, if such compromised cells persist, then they may lead to maladaptive repair and proinflammatory changes, thereby facilitating the development of a senescent phenotype and CKD., (Copyright © 2016 by the American Society of Nephrology.)

Recent clinical studies indicate a strong link between AKI and progression of CKD. The increasing prevalence of AKI must compel the nephrology community to consider the long-term ramifications of this syndrome. Considerable gaps in knowledge exist regarding the connection between AKI and CKD. The 13th Acute Dialysis Quality Initiative meeting entitled "Therapeutic Targets of Human Acute Kidney Injury: Harmonizing Human and Experimental Animal Acute Kidney Injury" convened in April of 2014 and assigned a working group to focus on issues related to progression after AKI. This article provides a summary of the key conclusions and recommendations of the group, including an emphasis on terminology related to injury and repair processes for both clinical and preclinical studies, elucidation of pathophysiologic alterations of AKI, identification of potential treatment strategies, identification of patients predisposed to progression, and potential management strategies., (Copyright © 2016 by the American Society of Nephrology.)

AKI requiring RRT is associated with high mortality, morbidity, and long-term consequences, including CKD and ESRD. Many patients never recover kidney function; in others, kidney function improves over a period of many weeks or months. Methodologic constraints of the available literature limit our understanding of the recovery process and hamper adequate intervention. Current management strategies have focused on acute care and short-term mortality, but new data indicate that long-term consequences of AKI requiring RRT are substantial. Promotion of kidney function recovery is a neglected focus of research and intervention. This lack of emphasis on recovery is illustrated by the relative paucity of research in this area and by the lack of demonstrated effective management strategies. In this article the epidemiologic implications of kidney recovery after AKI requiring RRT are discussed, the available literature and its methodologic constraints are reviewed, and strategies to improve the understanding of factors that affect kidney function recovery are proposed. Measures to promote kidney function recovery are a serious unmet need, with a great potential to improve short- and long-term patient outcomes., (Copyright © 2015 by the American Society of Nephrology.)