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Background and Aims Hyperuricemia is associated with rapid deterioration of renal function in patients with chronic kidney disease (CKD). The two most common urate-lowering drugs available in the market are allopurinol and febuxostat. Randomized controlled trials (RTCs) have shown that the individual drugs have potential to slow down progression of renal function in patients with chronic kidney disease (CKD) and hyperuricemia. However, it is unclear which drug is more effective because of insufficient direct comparison between the two. Hence our study aims to perform a meta-analysis of RCTs to assess the renoprotective and urate-lowering effects between the two drugs in patients with CKD and hyperuricemia. Method A comprehensive literature search of randomized controlled trials using PubMed was performed with the following search terms: febuxostat, allopurinol, chronic kidney disease, renoprotection. Four prospective RCTs were selected and analyzed using Cochrane Revman v5.3. Outcomes assessed were change in serum creatinine, estimated glomerular filtration rate (eGFR), proteinuria and serum uric acid levels from baseline to 3 months post-initiation of therapy. Results Four relevant trials comprising of 486 patients were selected - 247 patients treated with febuxostat and 239 patients with allopurinol. No significant differences were found in the changes in serum creatinine (mean difference -0.04; CI -0.15, 0.07; P = 0.51) and eGFR (mean difference 1.57; CI -0.83, 3.97; P = 0.20) from baseline to 3 months between the febuxostat and allopurinol group. Decrease in proteinuria was significantly observed more in the febuxostat group (mean difference -50.13; CI -90.54; -9.71, P = 0.02). Similarly, serum uric acid levels were significantly more reduced in the febuxostat group (mean difference -1.11; CI -1.53, -0.68, P < 0.00001). Conclusion Our study showed that febuxostat is non-inferior in terms of delaying renal function decline (as measured by eGFR) but it offers a better anti-proteinuric as well as a urate-lowering effect. However, more studies are needed to assess the efficacy of febuxostat across the spectrum of chronic kidney disease, including those requiring hemodialysis.

Background and Aims We have recently demonstrated that small molecule inhibitors of CCR2 rapidly reduced proteinuria and preserved renal structure in animal models of diabetic nephropathy (DN) and focal segmental glomerular sclerosis (FSGS). Similar beneficial effects of CCR2 inhibition were also observed in DN patients in a large diabetic nephropathy Phase 2 clinical trial. Despite its rapid and robust effects in these kidney diseases, the mechanism by which CCR2 inhibition affords such renal protection remains unclear. CCR2 is well-known to be expressed on cells of the immune system, where it mediates inflammation and immunological functions by controlling the trafficking of monocytes and T cells. However, immune cell expression of CCR2 may not adequately explain the rapid pharmacologic benefits of CCR2 inhibitors in DN and FSGS because these diseases do not exhibit appreciable kidney inflammation. To better understand the protective mechanism(s) of CCR2 inhibition in renal diseases, we have used a variety of in vivo nephropathy models to determine if CCR2 is expressed on kidney parenchymal cells. Our results suggest that a subset of CD45 negative, renal parietal epithelial cells express CCR2. Method To characterize CCR2 expression in the kidney we used CCR2 RFP heterozygous mice (CCR2RFP/+) in which one copy of CCR2 was replaced by red fluorescent protein (RFP), whose expression is under the control of the endogenous CCR2 promoter. This approach provided a highly sensitive method for CCR2 detection by both flow cytometry and immunofluorescence, and compensated for the lack of validated, commercially available anti-CCR2 antibodies. Enriched glomerular cells were obtained by a non-enzymatic disruption of kidneys, followed by centrifugation at low speed (80gs), and sieving through 300µm and 150µm meshes. The Adriamycin (ADR)-nephropathy model with CCR2 RFP heterozygous mice was used to determine CCR2 expression on renal cells. 5/6 nephrectomy models of FSGS, as well as the db/db diabetic nephropathy model were used to access the change of activated parietal epithelial cells and proteinuria, both in the presence and absence of a CCR2 inhibitor in the setting of kidney injury. Results We observed dramatic increases in the number of activated parietal epithelial cells (PECs, identified as CD133+CD24+CD44hi cells by flow cytometry) in all three renal disease models. In the ADR nephropathy model, we found that in 30-40% of activated PEC cells within an enriched population of glomerular cells expressed CCR2/RFP. CD44hi RFP+ increased much more dramatically than CD44hi RFP- cells in response to ADR, and this was highly correlated with proteinuria, suggesting that CCR2 plays an important role in PEC cell activation and kidney pathology in ADR induced kidney injury. Furthermore, we found that blocking CCR2 with the CCR2-specific antagonist CCX872 significantly reduced both proteinuria and the number of activated PECs in the 5/6 nephropathy and db/db diabetic nephropathy models. Conclusion This is the first report that CCR2 is present on a subset of activated renal PECs. This population is markedly upregulated during kidney injury in a variety of murine models of nephropathy. Changes in the abundance CCR2+ activated PECs in the glomerular enriched preparations in response to CCR2 inhibition suggests that CCR2 antagonism may represent a novel approach for the treatment of chronic kidney disease.

Introduction: Regardless of the etiology, kidney fibrosis is the final outcome of progressive kidney diseases. Our recent study showed that levels of interleukin (IL)-20 subfamily members, including IL-19 and IL-24 significantly increased in newborn rat kidneys underwent unilateral ureteral obstruction (UUO). However, their precise role in the pathomechanism of renal fibrosis has not been investigated. Method: To study the role of IL-20 cytokine subfamily we applied a mouse model of UUO induced kidney fibrosis on wild type and IL-20 receptor beta gene knockout (IL-20Rβ KO) mice. Masson’s trichrome and Picro-Sirius Red staining were used to investigate the renal accumulation of extracellular matrix proteins. Real-time RT-PCR and western blot method were performed to measure the renal expression of fibrosis associated molecules. We also investigated the in vitro effect of IL-24 treatment on transforming growth factor beta (TGF-β) and platelet derived growth factor B (PDGF-B) expression of human proximal tubular epithelial (HK-2) cells by real-time RT-PCR and flow cytometry. Results: We found elevated level of IL-19, IL-24 and IL-20Rβ in the fibrotic kidneys. IL-20Rβ KO mice showed reduced extracellular matrix deposition and decreased α-smooth muscle actin expression compared to wild-type mice following UUO. Treatment of renal epithelial cells with IL-24 increased their TGF-β and PDGF-B production. Conclusion: Our study provides direct evidence of the pathogenic role of IL-20 cytokine subfamily in the development of renal fibrosis, possibly through the IL-24 mediated production of pro-fibrotic factors. Therefore, inhibition of IL-24 may have therapeutic effect in treatment of chronic kidney diseases.

Background. In dialysis patients, protein-energy wasting (PEW) is associated with high mortality, and some indicators of PEW, such as serum albumin value, subjective global assessment (SGA) score and handgrip strength (HGS), may predict mortality. However, whether PEW is associated with poor renal outcomes and whether the indicators of PEW can predict renal outcomes in patients with non-dialysis-dependent chronic kidney disease (CKD-ND) is still unclear.Methods. We enrolled 128 clinically stable patients with CKD-ND and followed up for 33.8 +/- 9.2 months. Baseline characteristics, echocardiographic information, laboratory data, HGS, SGA scores, anthropometric parameters, bio-impedance analyses and other indicators of PEW were examined in relation to the risk of reaching renal composite end points of pre-dialysis mortality or dialysis-dependent end-stage renal disease.Results. Twenty-six patients reached composite renal end points. Multivariate Cox regression analyses showed that HGS was an independent predictor of renal outcome in patients with CKD-ND of Stages 1-5 [CKD(1-5), hazard ratio (HR) = 0.90, P = 0.004] or advanced CKD-ND of Stages 3b [defined as estimated glomerular filtration rate (eGFR) of 30-44 mL/min/1.73m(2)] to 5 (CKD(3b-5), HR 0.91, P = 0.031), but not serum albumin, SGA score or other indicators of PEW. When the cutoffs were set at 24.65 kg in men with CKD(1-5), 20.15 kg in men with CKD(3b-5) and 10.15 kg in women with CKD(1-5) or CKD(3b-5), which were deduced from receiver-operating characteristics analyses, patients with lower HGS had significantly poor renal outcomes in Kaplan-Meier survival analyses in all subgroups and higher HR for reaching renal end points in multivariate Cox regression analyses in all subgroups except for women with CKD(3b-5), whose HR had marginal significance (HR = 3.78, P = 0.068) after adjusting for age and eGFR.Conclusions. This is the first study demonstrating that HGS is an independent predictor of composite renal outcomes in CKD-ND patients. HGS can be incorporated to clinical practice for assessing nutrition status and renal prognosis in patients with CKD-ND.

Background. The degree of renal scarring in kidney biopsy is an important prognostic factor in patients with chronic kidney diseases. We hypothesize that gene expression in the urinary sediment reflects the degree of renal damage. Methods. We studied 29 patients with chronic kidney disease who underwent kidney biopsy (12 immunoglobulin-A nephropathy and 17 glomerulosclerosis) and 10 healthy controls. The mRNA expressions of a panel of target genes in urinary sediment were measured by real-time quantitative polymerase chain reaction. The results were compared with the degree of histological damage and renal function decline. Results. There were significant differences in the urinary expression of transforming growth factor-b (TGF-b), monocyte chemotactic protein-1 (MCP-1) and collagen IV between disease groups and controls. Urinary TGF-b mRNA expression correlated significantly with estimated glomerular filtration rate (r ¼ � 0.412, P ¼ 0.029) and the degree of tubulointerstitial scarring (r ¼ 0.418, P ¼ 0.024). Urinary MCP-1 expression correlated with the degree of glomerulosclerosis (r ¼ 0.450, P ¼ 0.014), but not tubulointerstitial scarring. Urinary MCP-1 expression correlated with its corresponding level by enzyme-linked immunosorbent assay (ELISA) (r ¼ 0.650, P

Angiotensin-converting enzyme inhibitors are the drugs of choice in renal hypertension. The efficacy and safety of ramipril in adults has been proved; however, data on effectiveness of ramipril in children are few. The aim of the present study was to investigate the effect of ramipril on blood pressure (BP) and proteinuria in children with chronic kidney diseases.A total of 31 children (median age 11.3 years, range 1.9-19.8 years) with various chronic nephropathies and hypertension or proteinuria were prospectively treated with ramipril for 6 months. Blood pressure was evaluated using ambulatory BP monitoring and hypertension was defined as mean BP equal to or greater than the 95th percentile for healthy children. Proteinuria was defined as protein excretionor =100 mg/m(2)/24 h. The starting dose of ramipril was 1.5 mg/m(2)/24 h once daily. In 27 children it was given as monotherapy.The median decrease in ambulatory BP was 11 mm Hg for daytime systolic, 10 mm Hg for daytime and nighttime diastolic, and 8 mm Hg for nighttime systolic BP. Hypertension normalized in 55% of the children. Proteinuria decreased in 84% of the children with pathologic proteinuria; the median decrease was 51%. A positive correlation was found between initial proteinuria and change of proteinuria (r = 0.95, P.001). Glomerular filtration rate and serum potassium level did not change significantly. One child developed a cough that was believed to be related to ramipril.Ramipril is an effective and safe drug in children with chronic kidney diseases associated with hypertension, proteinuria, or both.

Chronic metabolic acidosis (CMA) is a common complication of the more advanced stages of chronic kidney diseases (CKD), and is associated with morbidity and mortality of CKD patients and possibly with the progression of renal disease. Nevertheless, there is limited evidence or information on the prevalence, the potential causal factors, the clinical impact and the effects of correction of CMA in kidney transplant recipients. In this review, we briefly look at the more relevant, though scanty, studies which have, over time, addressed the above-mentioned points, with the hope that in the future the interest of transplant nephrologists and surgeons will grow towards this unreasonably neglected issue.

Tertiary lymphoid tissues (TLTs) are inducible ectopic lymphoid tissues that develop at sites of chronic inflammation in nonlymphoid organs. As with lymph nodes, TLTs initiate adaptive immune responses and coordinate local tissue immunity. Although virtually ignored for decades, TLTs have recently received a great deal of attention for their ability to influence disease severity, prognosis and response to therapy in various diseases, including cancer, autoimmune disorders and infections. TLTs are also induced in kidneys of patients with chronic kidney diseases such as immunoglobulin A nephropathy and lupus nephritis. Nevertheless, TLTs in the kidney have not been extensively investigated and their mechanism of development, functions and clinical relevance remain unknown, mainly because of the absence of adequate murine kidney TLT models and limited availability of human kidney samples containing TLTs. We recently found that aged kidneys, but not young kidneys, exhibit multiple TLTs after injury. Interestingly, although they are a minor component of TLTs, resident fibroblasts in the kidneys diversify into several distinct phenotypes that play crucial roles in TLT formation. Furthermore, the potential of TLTs as a novel kidney injury/inflammation marker as well as a novel therapeutic target for kidney diseases is also suggested. In this review article we describe the current understanding of TLTs with a focus on age-dependent TLTs in the kidney and discuss their potential as a novel therapeutic target and kidney inflammation marker.

This year the medical community was pleasantly surprised by the results of the first large outcome trial that primarily examined the renal effects of the sodium-glucose cotransporter 2 (SGLT2) inhibitor canagliflozin (CANA) in subjects with diabetes and impaired kidney function. The Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE) trial showed that CANA, relative to placebo, reduces the risk for end-stage renal disease, doubling of creatinine or renal death by 34% [hazard ratio 0.66 (95% confidence interval 0.53–0.81]. These effects were consistent across baseline estimated glomerular filtration rate (eGFR) and haemoglobin A1c subgroups. In this review we combine the results of the CREDENCE trial with those of several cardiovascular outcome trials with SGLT2 inhibitors and show that, unexpectedly, patients with lower eGFR levels may have greater benefit with respect to cardiovascular outcome than patients with normal kidney function. The cardio- and renoprotective effects of SGLT2 inhibitors seem to be independent of their glucose-lowering effects, as shown in several post hoc analyses. In this review we discuss the alleged mechanisms of action that explain the beneficial effects of this novel class of drugs. Moreover, we discuss whether these findings indicate that this class of drugs may also be beneficial in non-diabetic chronic kidney diseases.

BackgroundRenal fibrosis is a key pathological feature and final common pathway leading to end-stage kidney failure in many chronic kidney diseases. Myofibroblast is the master player in renal fibrosis. However, myofibroblasts are heterogeneous. Recent studies show that bone marrow-derived macrophages transform into myofibroblasts by transforming growth factor (TGF)-β-induced macrophage–myofibroblast transition (MMT) in renal fibrosis.MethodsTGF-β signaling was redirected by inhibition of β-catenin/T-cell factor (TCF) to increase β-catenin/Foxo in bone marrow-derived macrophages. A kidney fibrosis model of unilateral ureteral obstruction was performed in EGFP bone marrow chimera mouse. MMT was examined by flow cytometry analysis of GFP+F4/80+α-SMA+ cells from unilateral ureteral obstruction (UUO) kidney, and by immunofluorescent staining of bone marrow-derived macrophages in vitro. Inflammatory and anti-inflammatory cytokines were analysis by enzyme-linked immunosorbent assay.ResultsInhibition of β-catenin/TCF by ICG-001 combined with TGF-β1 treatment increased β-catenin/Foxo1, reduced the MMT and inflammatory cytokine production by bone marrow-derived macrophages, and thereby, reduced kidney fibrosis in the UUO model.ConclusionsOur results demonstrate that diversion of β-catenin from TCF to Foxo1-mediated transcription not only inhibits the β-catenin/TCF-mediated fibrotic effect of TGF-β, but also enhances its anti-inflammatory action, allowing therapeutic use of TGF-β to reduce both inflammation and fibrosis at least partially by changing the fate of bone marrow-derived macrophages.

Background and Aims Around worldwide population, 10% are affected by chronic kidney diseases (CKD); hemodialysis is the common choice of renal replacement therapy. Cigarette smokers have higher Lead level than non-smoker population. As Tobacco leaves are grown on polluted soil, it is proven that Mercury poisoning depends on dose and duration of exposure. Aim of the study was to determine two important toxic heavy metals elements Lead and Mercury concentrations in regular hemodialysis patients smoker and non-smoker by comparison with normal subjects and its correlation to anemia. Method Blood samples were collected from CKD patients on maintenance hemodialysis for more than 6 months divided into non-smoker and smoker to be compared with samples from a control group of non-CKD, non-smoker persons. This study was conducted in September 2019 in Al Mokattam Insurance Hospital – Cairo and involved 60 persons of both sex. They were divided into 3 groups: CKD stage 5 patients on hemodialysis 40 patients and sub-divided into 2 groups; (smoker) 20 patients and (non-smoker) 20 patients and the history of eating fish and seafood was taken. The third group was a control group included 20 healthy non-smoker participants. Lead and Mercury were analyzed by electro thermal atomic absorption spectrophotometer in Al Borg central Laboratory. The complete blood count (CBC), kidney function tests and Iron parameters were also detected. Results duration on hemodialysis did not raise Lead or Mercury level in blood, while smoking raises Lead level in blood, and eating fish and sea food more than once per week increased Mercury level in blood. There was a relation between raised Lead level and anaemia in hemodialysis patients. Conclusion Lead Prolonged and Mercury measurement is important in hemodialysis patients with possible symptoms of heavy metal toxicity. Lead level monitoring is recommended in resistant anemia in hemodialysis patients.

Background and Aims Chronic kidney diseases (CKD) in children are a group of diseases that not only affects the kidneys but also all systems of the body particularly causing anemia, bone diseases and failure to thrive in that age group. Gastrointestinal tract (GIT) manifestations are not thoroughly highlighted in those patients although they definitely have repercussions on their growth and development. GIT diseases such as celiac disease (CD) has been long linked to renal manifestations either through increasing risk of kidney diseases or as a proved association. The aim of this study was screening for celiac disease and GIT symptoms among pediatric patients with chronic kidney disease. Method A case-control study included 90 CKD patients from Nephrology unit, Children’s Hospital, Ain Shams University, who has been diagnosed for at least 3 months and not receiving steroids or immunosuppressive therapy: 60 patients with end stage renal disease (ESRD) on regular hemodialysis (HD) & 30 with CKD on conservative treatment. Their ages ranged between 2-13 years old, 47 males, 43 females. 200 controls were also enrolled in the study (for GIT manifestations): healthy children with ages ranging from 2-13 years old, 77 males, 123 females within a period of 12 months. All patients & controls were interviewed about GIT manifestations they regularly experience and any GIT troubles they have. All CKD patients were screened for CD by Anti Tissue transglutaminase IgG and IgA blood testing. Results Reviewing the most significant GIT symptoms among patients, we found that 86.7% had mucoid diarrhea, 77.8% had abdominal distension, 75.6% had anorexia, 64.4% had epigastric pain, 51.1% had watery diarrhea, 30% had nausea, 30% had vomiting, and 25.6% had constipation. None suffered from hematemesis, melena or bloody diarrhea. GIT symptoms were significantly more pronounced in CKD patients compared to controls and even more in ESRD patients than CKD patients. All patients were negative for CD screening by Anti Tissue transglutaminase IgG and IgA. No significant correlations were seen between Anti Tissue transglutaminase IgG and IgA and age, sex, anthropometric measures (except for BMI), biochemical results (except for s. ferritin) or eitiology of renal disease were observed. Conclusion GIT troubles are more pronounced in children with CKD compared to age and sex matched healthy controls. CD is not particularly prevalent among CKD pediatric patients compared to the known percentage among this age population.

Background Heart failure with preserved ejection fraction (HFpEF) is an important comorbidity of atrial fibrillation (AF). However, it is sometimes difficult to detect HFpEF among AF patients with preserved EF, since AF and HF share similar symptoms. Purpose The aim of this study was to identify factors associated with having HFpEF in AF patients with preserved EF, and derive a new score for HFpEF in AF patients. Methods The Fushimi AF Registry is a community-based prospective survey of the AF patients in Fushimi-ku, Kyoto, Japan. Follow-up data were available for 4,466 patients, and 3,083 patients had preserved EF (≥50%). Of the 3,083 patients, 444 had prior HF hospitalization at baseline and we defined these patients as HFpEF. We examined the factors associated with having HFpEF, and derived a new score for detecting HFpEF in AF patients. Thereafter, we validated this score in patients without prior HF hospitalization. Result The mean age of the patients with EF ≥50% was 73.6 years, and 41.3% were female. Compared with the patients without prior HF hospitalization, HFpEF patients were older, more often female, less in body weight, had more heart disease (valvular heart disease, cardiomyopathy, old myocardial infarction, and coronary artery disease), chronic kidney diseases (CKD), anemia (Hb 45 mm), and dilation of cardio-thoracic ratio (CTR) (>54%) at baseline. In multivariate analysis, heart diseases, CKD, sustained AF, dilatation of CTR, left atrial enlargement, and anemia were significantly associated with HFpEF (Table 1). We derived a new score to diagnose HFpEF in AF patients (2 points for heart diseases, 1 point for CKD, sustained AF, dilatation of CTR, left atrial enlargement, and anemia; range 0 to 7 points). In a receiver-operating characteristic curve, optimal cut-off point for detecting HFpEF was 3 (Figure 1). We validated this score in patients without prior hospitalization for HF (n=2,639). Of these, 298 patients had HF symptoms of NYHA 2–4 (Symptomatic-HF), and 2,341 patients had neither prior HF hospitalization nor HF symptoms (No-HF). Notably, 207 patients (69.5%) in symptomatic-HF group and 748 patients (32.0%) in No-HF group were classified into HFpEF based on this new score. Furthermore, patients diagnosed as HFpEF by this score had higher incidence of new hospitalization for HF during the follow-up in both symptomatic-HF group and No-HF group. (Figure 2). Conclusion We derived a new score to diagnose HFpEF in AF patients based on the presence of prior HF hospitalization (2 points for heart diseases, 1 point for CKD, sustained AF, dilatation of CTR, left atrial enlargement, and anemia). In patients without prior HF hospitalization, sizable number of patients had high HFpEF score (≥3), and those patients showed higher incidence of new HF hospitalization. Funding Acknowledgement Type of funding source: None

Background and Aims Omaveloxolone, an Nrf2 activator, is an investigational drug that targets targets inflammation and mitochondrial dysfunction, metabolic, and bioenergetic pathways. Omaveloxolone is an analog of bardoxolone, methyl which has been shown to improve kidney function in multiple studies of chronic kidney diseases. The MOXIe Part 2 trial investigated omaveloxolone in patients with Friedreich’s ataxia (FA), a rare and serious hereditary disease caused by mitochondrial dysfunction that affects multiple organ systems resulting in ataxia, cardiomyopathy, and reduced lifespan. The study met its primary efficacy endpoint, and omaveloxolone improved neurological function, as assessed by the modified Friedreich’s ataxia rating scale (mFARS). We report the effect of omaveloxolone on kidney function in this patient population. Method The MOXIe trial (NCT02255435) was an international, multi-center, double-blind, placebo-controlled, randomized trial that enrolled 103 patients between 16 and 40 years of age with genetically confirmed FA. Patients were randomized 1:1 to receive either omaveloxolone 150 mg or placebo administered once daily for 48 weeks. The trial included 24 patients that were younger than 18 years of age. Baseline eGFR for the overall patient population receiving placebo or omaveloxolone was 109.2 ± 21.7 and 113.4 ± 14.7 mL/min/1.73 m2, respectively. Baseline eGFR for the pediatric population receiving placebo or omaveloxolone was 99.1 ± 33.7 and 106.3 ± 15.6 mL/min/1.73 m2, respectively. Serum creatinine was collected at baseline, Weeks 4, 12, 18, 24, 36 and 48 on-treatment and 4-weeks off-treatment at Week 52. Glomerular filtration rate was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for patients ≥ 18 years of age. For patients Results In placebo patients, mean (SD) eGFR decreased by 4.4 ± 11.0 mL/min/1.73 m2 from baseline whereas patients receiving omaveloxolone had an average increase of +7.0 ± 10.7 mL/min/1.73 m2 from baseline after 48 weeks, resulting in a difference of 11.4 mL/min/1.73 m2 between treatment groups. At Week 52, mean eGFR was -4.2 ± 10.9 mL/min/1.73 m2 relative to baseline in placebo patients and remained +0.9 ± 10.8 mL/min/1.73 m2 above baseline in omaveloxolone patients after 4-weeks off-treatment. In pediatric patients randomized to placebo, at week 48 eGFR decreased by -11.3 ± 14.3 mL/min/1.73 m2 whereas patients receiving omaveloxolone had an average increase of +5.5 ± 14.5 mL/min/1.73 m2 from baseline, resulting in a difference of 16.8 mL/min/1.73 m2 between treatment groups. Conclusion Patients with FA randomized to placebo in the MOXIe trial had eGFR declines over 48 weeks that were similar to rates of decline observed in the most rapidly progressing forms of chronic kidney disease. The rapid kidney function decline in FA reflects the multi-system nature of the disease whereby mitochondrial dysfunction, and associated chronic inflammation, affects not only the central nervous system but also the heart and possibly the kidney. In contrast to placebo, treatment with omaveloxolone improved eGFR in patients with FA and the effects were sustained through one year of treatment. The durability of eGFR improvements are consistent with those observed with its analog, bardoxolone methyl, in clinical trials for various forms of CKD.

Background and Aims Diabetic nephropathy (DN) and its most severe manifestation, end-stage renal disease (ESRD), remains one of the leading causes of reduced lifespan in people with diabetes. Identifying novel molecules that are involved in the pathogenesis of DN has both diagnostic and therapeutic implications. The gene co-expression network analysis (WGCNA) algorithm represents a novel systems biology approach that provide the approach of association between gene modules and clinical traits to find the module involvement into the certain phenotypic trait. The goal of this study was to identify hub genes and their roles in DN from the aspect of whole gene transcripts analysis. Method Various types of chronic kidney diseases (CKD), including DN, microarray-based mRNA gene expression data, listed in the Gene Expression Omnibus (GEO) database, were analyzed. Next, we constructed a weighted gene co-expression network and identified modules distinguishing DN from normal or other types of CKD by WGCNA. Functional annotations of the genes in modules specialized for DN were analyzed by Gene Ontology (GO) enrichment analysis. Through protein-protein interaction (PPI) analysis and hub gene screening, the hub genes specific for DN were obtained. Furthermore, we drew ROC curves to determine the diagnosis and differential diagnosis value to DN of hub genes. Finally, another study of microarray in the GEO database was selected to verify the expression level of hub genes and in the “Nephroseq” database, the correlation between the gene expression level and eGFR was analyzed. Results “GSE99339”, glomerular tissue microarray in 187 patients with a total of 10947 genes, was selected for analysis. After excluding the inappropriate cases, a total of 179 specimens were analyzed, including 14 cases of DN, 22 cases of focal segmental glomerulosclerosis (FSGS), 15 cases of hypertensive nephropathy (HT), 26 cases of IgA nephropathy (IgAN), 13 cases of minimal change disease (MCD), 21 cases of membranous nephropathy (MGN), 23 cases of rapidly progressive glomerulonephritis (RPGN), 30 cases of lupus nephritis (LN) and 14 cases of kidney tissue adjacent to tumor. Co-expression network analysis by WGCNA identified 23 distinct gene modules of the total 10947 genes and revealed “MEsaddlegreen” module was strongly correlated with DN (r=0,54), but not with other groups. GO functional annotation showed that these 64 genes in the “MEsaddlegreen” module mainly enriched in the deposition of extracellular matrix, which represents the specific and diagnostic pathophysiological process of DN. Further PPI and hub gene screening analysis revealed that LUM, ELN, FBLN1, MMP2, FBLN5 and FMOD can be served as hub genes, which had been proved to play an important role in the deposition of extracellular matrix. Furthermore, we found that the expression of hub genes was the highest in DN group and for the diagnosis value of DN by each gene, the area under the ROC curve is about 0.75∼0.95. The external verification of another study showed that compared with the normal control group, the expression of these hub genes was the highest in the DN group, and their expression level was negatively correlated with eGFR. Conclusion Using WGCNA and further bioinformatics approach, we identified six hub genes that appear to be identical to DN development. As such, they may represent potential diagnostic biomarkers as well as therapeutic targets with clinical utility.

Background and Aims Chronic kidney diseases disrupt normal bone-mineral axis endocrine functions causing the onset of mineral bone disorders (MBDs). The general and hemodialysis (HD) populations have been found to exhibit diurnal rhythms in phosphate (PO4), calcium (Ca), and parathyroid hormone (PTH) regulation (Trivedi et al. J Nephrol. 2015), but reference values for fluctuations have not been established in HD patients and do not consider PO4 binder use. We profiled the diurnal rhythms of MBD labs overall and stratified by PO4 binder use in a large nationally representative HD population in the United States. Method We used prevalent in-center HD patient (vintage >90 days) data on adults (age ≥18 years) treated at a dialysis organization in 2018. Mean annual pre-HD blood PO4, corrected Ca, and intact PTH levels were computed in 2-hour periods through 24 hours for the population and stratified by binder use. HD initiation time was a varying exposure, allowing patients to switch time groups if blood draws occurred in multiple time periods. Mean MBD lab levels with 95% confidence limits were plotted using nonparametric smoothing spline models to fit data and calculate trajectories throughout the day. Results The population of adult HD patients (n=156,873) was: mean age 62.8±14.3 years, 57.1% male, 58.2% white race, 41.9% with diabetes, 19.6% with congestive heart failure, and HD vintage 1510±1289 days. Mean pre-dialysis albumin=3.8±0.4 g/dL, PO4=5.4±1.5 mg/dL, corrected Ca=9.1±0.6 mg/dL, PTH=468±333 pg/dL for the population. Mean PO4, corrected Ca and PTH levels varied remarkably by 0.9 mg/dL, 0.2 mg/dL, and 186 pg/dL throughout the day. For PO4 and PTH, nadir levels occurred from 0900 to 1100 hours (5.3±1.6 mg/dL and 473±340 pg/dL), followed by a rise to a mid-day peak from 1700 to 1900 hours (5.8±1.8 mg/dL and 562±401 pg/dL), and the highest levels had a peak time from 2300 to 0100 hours (6.2±2.1 mg/dL and 659±389 pg/dL) (Figure 1A & C). Corrected Ca showed relatively inverse fluctuations to PO4 and PTH, with peak levels from 1100 to 1300 hours (9.2±0.7 mg/dL) and nadir levels from 1900 to 2100 hours (9.0±0.7 mg/dL) (Figure 1B). Similar fluctuations and levels were observed for PO4 and PTH among patients using any phosphate binder type (90.7%), however, patients not using a phosphate binder exhibited absolute values that were persistently lower at every timepoint (Figure 1D & F). Corrected Ca levels were similar by any binder use (Figure 1E). Conclusion Our results suggest PO4, Ca, and PTH levels have a diurnal variation of 0.9 mg/dL, 0.2 mg/dL, and 186 pg/dL in hemodialysis patients. PO4 and PTH exhibit a nadir in the morning, a mid-day peak and a larger nocturnal peak. Ca exhibits relatively inverse diurnal fluctuations with PO4 and PTH. Patients using any binder exhibit similar fluctuations and levels of PO4 and PTH; while patients not requiring a binder have similar fluctuations, yet persistently lower levels of PO4 and PTH. Given PO4 binder and calcimimetic therapies are commonly used for treatment of MBDs based on pre-dialysis blood levels, these findings provide insights for further research and pose the question if algorithms are warranted to compute daily time-adjusted levels for MBD laboratories.

Background and Aims The aging of the population and the increase in life expectancy have led to increasing numbers of elderly patients so greater numbers of elderly patients with chronic kidney diseases are surviving longer. Membranous nephropathy (MN) is the most important cause of glomerular disease in older patients (≥65 years). The aim of this study is to describe the epidemiological and clinical profile of elderly patients with MN and to analyze the diagnostic and management approach. Method We conducted a retrospective descriptive study in the nephrology department at Charles Nicolle hospital over a period of 44 years. All older patients (≥65 years) with histologically proven MN were included in this study. Results Thirty patients were collected. The mean age was 69.43 years (65-78 years) with a male predominance (sex ratio: 2.3) and low socio-economic level in 83.3% of cases. Sixteen patients were smokers (55.3%), 5 ethyl patients (16.7%), diabetes was present in 3 patients (10%) and hypertension in 11 patients (36.7%). Two cases of neoplasm were present, namely one case of prostatic adenocarcinoma and one case of gallbladder adenocarcinoma, all were diagnosed and treated along one year and ten years respectively, before the diagnosis of MN. The circumstances of discovery was dominated by oedema in 27 cases (86.27%), hypertension in 11 cases (36.7%) and elevated creatinine level in 9 cases (30%). Deep venous thrombosis was the circumstance of discovery in one case. At the time of diagnosis, the clinico-biological picture was dominated by high systolic blood pressure in 21 cases (67.6%), anasarca in 7 cases (23.3%), proteinuria in all cases and hematuria in 20 cases (66.6%). Biology revealed nephrotic syndrome (NS) in 28 cases (87.11%), hypercholesterolemia in 23 cases (76.6%), high serum creatinine in 14 cases (46.6%) with an average creatinine level of 123,85 µmol/l, anemia in 17 cases (56.6%) and anti-neutrophil cytoplasmic antibodies were positive in one case. MN was confirmed by a kidney biopsy in all cases. Twenty-two patients had idiopathic MN (IMN) and 2 patients had secondary MN. In fact, MN was associated with multiple myeloma in one case and secondary to hepatitis B in other case. Symptomatic treatment was indicated in all patients. Patients with secondary MN received etiopathogenic treatment. For the IMN, immunosuppressive therapy started early for 12 patients (40%) because of the severe NS and the deterioration of renal function. Eight patients (26.6%) received corticosteroids alone, three patients received corticosteroid with mycofenolate mofetil and one patient received corticosteroid with ciclosporin. We noted complete remission in 6 patients and end renal stage disease in 5 patients. Conclusion In studies of glomerular disease in the elderly, MN was the most common cause of NS. The clinical presentation is similar in older and younger patients, but older patients more often present with kidney failure and severe NS.

Background and Aims Chronic kidney disease is a common disease. Most chronic kidney diseases evolve from primary glomerulonephritis. Proteinuria is an independent risk factor for the progression of chronic kidney disease. The general consensus is that therapy administered to decrease proteinuria should include steroids and/or immunosuppressants, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers. However, the side effects of, and adverse reactions to, these agents reduce the benefits to patients. Therefore, additional effective drugs to decrease proteinuria are urgently needed. Shenyankangfu tablets (SYKFT) have been a widely applied Chinese patent medicine for many years to decrease proteinuria. However, there is a lack of research-derived data regarding the clinical use. Therefore, we designed the present trial to compare the efficacy and safety of SYKFT versus losartan potassium for control of proteinuria in patients with primary glomerulonephritis. Method This was a multicenter, prospective, double-blind, double-dummy, randomized controlled clinical trial. Primary glomerulonephritis patients aged 18 to 70 years, blood pressure ≤140/90 mmHg, estimated glomerular filtration rate ≥45 mL/min/1.73 m2, 24-hour proteinuria level of 0.5 to 3.0 g, were recruited in 41 hospitals across 19 provinces in China and were randomly divided into the following groups at a 1:1:1:1:1 ratio: SYKFT group, losartan potassium 50 mg group, losartan potassium 100 mg group, SYKFT plus losartan potassium 50 mg group, and SYKFT plus losartan potassium 100 mg group. All groups were followed up for 48 weeks; follow-up visits were performed, at weeks 0, 4, 8, 12, 24, 36, and 48. The primary efficacy outcome was the post-treatment change in the 24-hour proteinuria level, and the secondary efficacy outcomes was the post-treatment changes in the serum creatinine level, estimated glomerular filtration rate (eGFR), traditional Chinese medicine (TCM) syndrome score, and serum albumin level. The protocol was approved by the Ethics Committee of each participating center. This trial was registered at the clinicaltrials.gov (NCT02063100). Results A total of 720 participants were enrolled and 673 patients were included in the analysis. The difference in the urine protein reduction among different groups was statistically significant (Z=20.084, P=0.001). The urine protein reduction in the SYKFT group [-150.000 (-692.500, 153.000) mg/d], more than that in the losartan potassium 50mg alone group [-80.000 (-420.000, 295.250) mg/d, Z=-2.015, P=0.044], was not less than that in the losartan potassium 100mg group [-260.000 (-623.900, 84.000) mg/d, Z=-0.339, P=0.734]. The urine protein reduction in the SYKFT plus losartan potassium 50mg group [-269.150 (-755.000, 159.085) mg/d] was more than that in the losartan potassium 50mg alone group [Z=-2.582, P=0.010]. The urine protein reduction in the SYKFT plus losartan potassium 100mg group [-388.000 (-743.500, -10.000) mg/d] was more than that in the losartan potassium 100mg alone group [Z=-1.999, P=0.046]. The changes in serum creatinine, eGFR, and serum albumin from the baseline were not statistically significant among different groups (P all >0.05). The change in TCM syndrome scores between the patients who took SYKFT and who did not take SYKFT was statistically significant (P=0.003). Conclusion SYKFT can decrease the proteinuria of primary glomerulonephritis patients with minor- to moderate-range proteinuria. SYKFT plus losartan potassium therapy can decrease proteinuria to a relatively large extent compared with losartan potassium therapy alone. And SYKFT can also improve the TCM syndrome scores of the patients.

Background The occurrence of reno-cardiac syndrome is associated with poor clinical outcome. Uremic toxins in chronic kidney diseases disrupt intestinal equilibrium and increase aerobic bacteria/anerobic bacteria ratio. As a result indoxyl sulphate level in blood increases and contributes to pathogenesis of reno-cardiac syndrome. Probiotic and symbiotic are anerobic bacteria that correct the intestinal equilibrium. Aim of work We aimed to study the pathogenesis of reno-cardiac syndrome and compare the possible protective effects of probiotics and symbiotic. Design 48 white albino rats were assigned into 6 groups: Sham group, 5/6 nephrectomy, early and late probiotic treated nephrectomy rats, early and late symbiotic treated nephrectomy rats. Methods Heart was exposed to 30 min ischemia followed by 30 min reperfusion. PT, TPT, HRT, HR and CBF were measured at 5, 15 and 30 min of reperfusion. We measured serum levels of creatinine, urea, indoxyl sulphate, and heart tissue level of TGF-β and NADPH. Results uremic toxins, TGF-β and NADPH levels were significantly increased in all groups compared to sham group. In treated groups, uremic toxins significantly decreased while TGF-β and NADPH levels increased compared to nephrectomy group. PT, TPT, HRT, HR and CBF of the heart at 30 min reperfusion were decreased in nephrectomy group compared to sham one, while these functions were improved in treated groups compared to nephrectomy one. Conclusion Use of probiotic and symbiotic in reno-cardiac syndrome can protect the heart by improving the intestinal barrier, antioxidant effects and decreasing indoxyl sulphate level. Symbiotic had better outcomes than probiotic.

Plasticizer di-(2-ethylhexyl)phthalate (DEHP) is known as an endocrine disruptor and a peroxisome proliferator. A currently epidemiological study has suggested that daily high DEHP intake from phthalate-tainted foods in children may be a risk factor for renal dysfunction. DEHP can leach from medical devices such as blood storage bags and the tubing. Long-term exposure to DEHP is associated with nephropathy and exacerbates chronic kidney diseases (CKDs) progression. However, the detailed effects and molecular mechanisms remain unclear. Here, we hypothesized that DEHP and its major metabolite mono-(2-ethylhexyl)phthalate (MEHP) incited epithelial-to-mesenchymal transition (EMT) and lead to aggravate renal fibrosis progression. Treatment with low-cytotoxic concentration DEHP, but not MEHP, for 72 h obviously induced the morphological and phenotypic changes and EMT markers induction in normal rat renal tubular epithelial cells (NRK-52E). AKT inhibitor MK-2206 inhibited DEHP-induced EMT features and signals of AKT phosphorylation and downstream NF-κB and GSK3β. DEHP did not affect the expression of transforming growth factor-β1 mRNA. DEHP down-regulated the peroxisome proliferator-activated receptor (PPAR)α and PPARγ protein expressions. PPARγ agonist pioglitazone partially and significantly inhibited DEHP-induced EMT induction. In vivo DEHP exposure for 6 weeks enhanced the renal dysfunction and renal fibrosis and mortality rate, but decreased the PPARα and PPARγ protein expressions, in a folic acid-induced kidney fibrosis mouse model. Taken together, these results demonstrate for the first time that DEHP arouses EMT induction and renal fibrosis progression in renal tubular cells and is associated with PPARs downregulation. DEHP exposure potentially exacerbated renal fibrosis/nephropathy in a kidney disease condition.

Fibrosis, a characteristic of all chronic kidney diseases, is now recognized to be an independent predictor of disease progression. Deposition of pathological matrix in the walls of glomerular capillaries, the interstitial space and around arterioles both predicts and contributes to functional demise of the nephron and its surrounding vasculature. Recent identification of the major cell populations of fibroblast precursors in the kidney interstitium as pericytes and tissue-resident mesenchymal stem cells, and in the glomerulus as podocytes, parietal epithelial and mesangial cells, has enabled the study of the fibrogenic process in much greater depth directly in the fibroblast precursors. These cells are not only matrix-producing cells, but are also important innate immune surveillance cells that regulate the inflammatory process, exacerbate tissue damage by release of radicals and cytokines, and contribute to parenchymal and microvascular dysfunction by aberrant wound-healing responses. Innate immune signaling in fibroblasts and their precursors is intimately intertwined with the process of fibrogenesis. In addition, genomic and genetic studies also point to defective responses in loci close to genes involved in solute transport, metabolism, autophagy, protein handling and vascular homeostasis, principally in the epithelium and endothelium, as upstream drivers of the fibrotic process, indicating that cellular crosstalk is vital for development of fibrosis. As we move beyond TGFβ inhibition as a central target for fibrosis, targeting innate immune signaling and metabolic dysfunction appear increasingly tenable alternative targets for novel therapies.

BackgroundAlthough greater impairments in nerve functions parameters are most likely to occur with a lower kidney function, there is a paucity of information on the relationship between the kidney and peripheral nerve functions parameters in Type 2 diabetes.AimTo address the impact of peripheral nerve functions in Type 2 diabetes patients in different stages of chronic kidney diseases (CKD).DesignThis prospective study enrolled 238 patients with Type 2 diabetes at a tertiary medical center.MethodWe designed composite amplitude scores of nerve conductions (CAS) as a measure of severity of peripheral neuropathy (PN), and used estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR) parameters to stage CKD in Type 2 diabetes patients. The intrapersonal mean, standard deviation and coefficient of variation of eGFR for 238 patients were obtained in the 3 years prior to the study.ResultsThe patients who had lower eGFR and higher UACR were older, with longer diabetes duration, a greater percentage of retinopathy and PN and higher CAS. Multiple linear regression analysis revealed that diabetes duration and eGFR were independently associated with CAS, and a cut-off value of eGFR in the presence of PN was 65.3 ml/min/1.73 m2.ConclusionWe observed a close relationship between the severity of kidney and peripheral nerve function in patients with diabetes. If a patient’s eGFR value is below 65.3 ml/min/1.73 m2 or the UACR value is above 98.6 mg/dl, caution is needed with the presence of PN even in diabetic patients who are asymptomatic.

Kidney diseases in human immunodeficiency virus (HIV)-infected patients are often misdiagnosed. Despite reductions in morbidity and mortality owing to widespread use of highly effective combination antiretroviral therapy (cART), acute kidney injury (AKI) and chronic kidney disease (CKD) are still more common in these patients than in the general population, and are associated with poor health outcomes. HIV-associated nephropathy and HIV immune complex kidney diseases are the more recognizable HIV-related kidney diseases. However, a broad spectrum of kidney disorders related or not directly related with HIV infection can be observed, including cART-induced AKI, CKD, proximal tubular dysfunction, crystalluria and urolithiasis, among others. This review summarizes the major epidemiologic studies of kidney diseases in HIV-infected patients, discusses novel approaches that may potentially limit nephrotoxicity such as the use of tenofovir alafenamide, and outlines current screening measures for early diagnosis of kidney dysfunction or tubular damage, and for accurate detection of increased risk for acute or chronic kidney diseases. info:eu-repo/semantics/publishedVersion

BACKGROUND Despite overall improvement in prognosis, 10-30% of patients with lupus nephritis (LN) will develop end-stage renal disease. To date, renal biopsy is still the 'gold standard' test used to predict renal outcome. However, due to its invasive nature, new non-invasive biomarkers are required. Urinary exosomes, microvesicles released by every epithelial cell facing the urinary space, represent an ideal source of markers for renal dysfunction and injury. Here, we sought to evaluate miR-29c expression levels in urinary exosomes as a novel biomarker of renal fibrosis in LN. METHODS Urinary exosomes were isolated from 32 samples of patients with biopsy-proven LN, 15 non-lupus chronic kidney diseases and 20 healthy controls. Electronic microscopy and western blot were used to characterize the exosomes. Expression levels of miR-29c were detected by RT-PCR quantitative and correlated with clinical and histological parameters along with the expression levels of Smad2/3, TGF-β and MMP2/9. For comparison, miRNA expression was also evaluated in the urinary pellet. RESULTS MiR-29c levels in urinary exosomes showed a negatively strong correlation with the histological chronicity index (r = -0.898, P = 0.001) and glomerular sclerosis (r = -0.555, P = 0.007). No correlation with eGFR and creatinine levels was found. MiR-29c expression levels could predict the degree of chronicity in patients with LN with an area under the curve (AUC) of 0.946 (P < 0.001) and with high sensitivity and specificity (94% and 82%). Smad3 and MMP2 expression in urinary exosomes correlated negatively with miR-29c expression (r = -0.737 and -0.856, respectively). In the urinary pellet, no miR-29c expression was detected; however, upregulation of Smad3 and MMP2 was observed (3.54- and 5.85-fold increase). CONCLUSIONS Overall, miR-29c correlated with the degree of renal chronicity but not with renal function, suggesting it could be used as a novel non-invasive marker of early progression to fibrosis in patients with LN.

Natural and man-made mass disasters directly or indirectly affect huge populations, who need basic infrastructural help and support to survive. However, despite the potentially negative impact on survival chances, these health care issues are often neglected by the authorities. Treatment of both acute and chronic kidney diseases (CKDs) is especially problematic after disasters, because they almost always require complex technology and equipment, whereas specific drugs may be difficult to acquire for the treatment of the chronic kidney patients. Since many crush victims in spite of being rescued alive from under the rubble die afterward due to lack of dialysis possibilities, the terminology of ‘renal disaster’ was introduced after the Armenian earthquake. It should be remembered that apart from crush syndrome, multiple aetiologies of acute kidney injury (AKI) may be at play in disaster circumstances. The term ‘seismonephrology’ (or earthquake nephrology) was introduced to describe the need to treat not only a large number of AKI cases, but the management of patients with CKD not yet on renal replacement, as well as of patients on haemodialysis or peritoneal dialysis and transplanted patients. This wording was later replaced by ‘disaster nephrology’, because besides earthquakes, many other disasters such as hurricanes, tsunamis or wars may have a negative impact on the ultimate outcome of kidney patients. Disaster nephrology describes the handling of the many medical and logistic problems in treating kidney patients in difficult circumstances and also to avoid post-disaster chaos, which can be made possible by preparing medical and logistic scenarios. Learning and applying the basic principles of disaster nephrology is vital to minimize the risk of death both in AKI and CKD patients.

Onco-nephrology is a new and evolving subspecialized area in nephrology that deals with kidney diseases in cancer patients. As many newer cancer therapies emerge in the field of oncology, cancer patients are surviving longer than ever before. However, the benefits of the remarkable advances in cancer management have not been fully appreciated. Not only is cancer often associated with abnormalities that affect the kidney, but cancer therapy often leads to both acute and chronic kidney diseases. The development of cancer-associated kidney complications is associated with poor prognosis, whereas prompt recognition and treatment initiation are associated with improved outcomes in this population. Therefore, both nephrologists and oncologists should be familiar with the diagnosis and management of cancer-associated kidney complications. Another unique aspect of onco-nephrology is that significant improvements in predialysis and dialysis care in recent years have led to prolonged survival and a higher incidence of patients with chronic kidney disease suffering from cancer. Therefore, research is urgently needed to establish treatment for patients with chronic kidney disease. This update addresses the pathophysiology and treatment of various cancer-associated kidney complications, and highlights cancer treatment for patients with chronic kidney disease.

Renal fibrosis, particularly tubulointerstitial fibrosis, is the common final outcome of almost all chronic kidney diseases. However, the mechanisms involved in the development of renal fibrosis are poorly understood. The Akt (also known as protein kinase B, PKB) family is serine/threonine protein kinases that play critical roles in regulating growth, proliferation, survival, metabolism and other cellular activities. Cytokines, high-glucose medium, transforming growth factor-β1 or advanced glycation end-products activate Akt in different renal cells. Increased Akt activation has been found in experimental tubulointerstitial fibrosis. In addition, Akt activation is also an important node in diverse signaling cascades involved in kidney damage. These data give evidence for a role for Akt in renal fibrosis, but no reviews are available on the role of Akt in the process. Thus, our aim is to review the role of Akt activation and signaling in renal fibrosis.

Background Demographic and epidemiologic characteristics of Hepatitis E virus (HEV) infected patients in the United States are not well-described. HEV infection may result in severe complications and lead to chronic infection and cirrhosis, especially in immunocompromised patients. There are no widely accepted guidelines for HEV screening and testing in the United States. Identifying traits of known seropositive patients and comorbidities may inform better screening and prevention strategies. In this study, we describe rates of liver disease, transplant status, chronic kidney diseases, and diabetes mellitus among patients serologically tested for HEV at our institution. Methods We retrospectively reviewed all patients for whom HEV IgM or IgG serologic testing was performed across the Mayo Clinic enterprise using the Advanced Cohort Explorer tool. For patients with any documented HEV serologic test, we abstracted baseline patient characteristics and underlying comorbidities at the time of testing. We then grouped subjects according to serologic testing results by antibody type. Survival at one year from date of testing was also assessed. Results A total of 979 unique subjects were identified. The preponderance of subjects was Caucasian (781, 79.8%). Of subjects tested for HEV with serology, 123 (12.6%) had any positive serology. Breakdown of baseline characteristics and selected comorbidities are summarized in Table 1. The largest proportion of subjects, 458 (46.8%), were both IgG and IgM negative and 432 subjects received only IgM or IgG testing. Liver disease was more prevalent in patients with positive vs. negative testing (5.8% vs. 2.1%) as was higher age (average 55.1 years vs. 52.2). One-year survival was similar in all groups. Conclusion HEV serology is not commonly tested. Among those tested, seropositivity is uncommon. Our data show higher HEV seropositivity in older adults, which may represent increase risk of exposure over time. Higher percentage of positive testing was also observed in subjects with liver disease, which may indicate a possible etiologic association. Further population-based studies are needed to estimate prevalence of HEV infection and associated liver disease, outcomes in infected patients, and indications for testing in at-risk populations. Disclosures All authors: No reported disclosures.

BACKGROUND Loss-of-function mutations of vitamin D-24 hydroxylase have recently been recognized as a cause of hypercalcaemia and nephrocalcinosis/nephrolithiasis in infants and adults. True prevalence and natural history of this condition are still to be defined. METHODS We describe two adult patients with homozygous mutations and six related heterozygous carriers. Mineral and hormonal data in these patients were compared with that in 27 patients with stage 2-3 chronic kidney disease and 39 healthy adult kidney donors. RESULTS Probands had recurrent nephrolithiasis, chronic hypercalcaemia with depressed parathyroid hormone (PTH) and increased 1,25(OH)(2)D levels; carriers had nephrolithiasis (two of six), hypercalciuria (two of six) and high or normal-high 1,25(OH)(2)D (four of four). Corticosteroids did not reduce plasma and urine calcium levels, but ketoconazole did, indicating that 1,25(OH)(2)D production is not maximally depressed despite coexisting hypercalcaemia, high 1,25(OH)(2)D and depressed PTH, and that 1,25(OH)(2)D degradation through vitamin D-24 hydroxylase is a regulator of plasma 1,25(OH)(2)D levels. Both probands had vascular calcifications and high bone mineral content. One developed stage 3b renal failure: in this patient 1,25(OH)(2)D decreased within normal limits as glomerular filtration rate (GFR) fell and PTH rose to high-normal values, yet hypercalcaemia persisted and the ratio of 1,25(OH)(2)D to GFR remained higher than normal for any degree of GFR. CONCLUSIONS This natural model indicates that vitamin D-24 hydroxylase is a key physiologic regulator of calcitriol and plasma calcium levels, and that balanced reduction of 1,25(OH)(2)D and GFR is instrumental for the maintenance of physiologic calcium levels and balance in chronic kidney diseases.

Activated fibroblasts, denoted as myofibroblasts, express smooth muscle actin (SMA) and are considered key mediators of renal fibrosis. To identify and isolate these elusive cells, LeBleu et al. generated a new transgenic mouse model expressing a red fluorescent protein under the control of the alpha SMA promoter. Gene expression profiling from cultured myofibroblasts identified human epididymis protein 4 [HE4, also denoted whey acidic protein (WAP) four-disulphide core domain 2] as the most upregulated gene. Since the WAP domains are implicated in protease inhibition, the authors demonstrate the ability of recombinant HE4 to bind and inhibit a number of known proteases. To demonstrate an involvement of HE4 in disease pathology, the authors next showed that the neutralization of HE4 alleviates kidney fibrosis in murine disease models, i.e. 5/6 nephrectomy, unilateral ureteral obstruction and nephrotoxic serum-induced nephritis. Finally, they went on to verify the enhanced expression of HE4 in human fibrosis-associated fibroblasts in comparison to normal fibroblasts as well as in serum samples of patients with chronic kidney diseases. Thus, they conclude that HE4 can serve as a biomarker as well as a therapeutic target for the treatment of renal fibrosis.

The Nrf2/Keap1 system regulates the transcription of antioxidant and cytoprotective genes through direct Nrf2 binding to responsive elements in the promoter region of target genes or via Keap1-induced NF-kB inhibition. The association between oxidative stress and inflammation with progression of chronic kidney diseases (CKDs) directed attention towards bardoxolone methyl and its analogues, potent Nrf2/Keap1 inducers, as a potential modality of renoprotective intervention. In a phase II clinical trial (BEAM), bardoxolone methyl was shown to increase the estimated glomerular filtration rate (eGFR) in patients with CKD associated with type 2 diabetes. The study generated great interest but raised concerns as well, on the adverse event profile of the drug. Experiments in rats with type 2 diabetic nephropathy treated with bardoxolone methyl analogues reproduced some drawbacks of bardoxolone methyl therapy in humans. Despite these warnings, a long-term phase III trial (BEACON) was started that was prematurely terminated because of an excess serious adverse events and mortality. Lessons from the above studies suggest that before jumping into use in clinical practice, adequately designed experiments in animal models are needed to provide insights into pathogenetic mechanisms as well as unexpected side effects.

BACKGROUND It is highly likely that the rise in plasma prorenin and plasma renin during renin inhibitor treatment is induced at least as much by the fall in blood pressure (BP) as it is by the negative feedback of angiotensin II. This could potentially be harmful because high levels of renin and prorenin may stimulate the (pro)renin receptor, thus inducing profibrotic effects. To further understand this relationship, the influence of aliskiren on the urinary excretion of transforming growth factor-β1 (TGF-β1) and procollagen III N-terminal propeptide (PIIINP) was evaluated in patients with nondiabetic kidney diseases. METHODS Aliskiren 300 mg and perindopril 10 mg, were each individually administered for 12 weeks separated by a placebo period in a cross-over, randomized, double-blinded pilot study. RESULTS A 1,131% (P < 0.001) and 628% (P < 0.001) increase in plasma renin concentration was observed after the aliskiren and perindopril therapies, respectively, as compared to the placebo. Aliskiren and perindopril increased prorenin concentrations as compared to the placebo by 100% (P < 0.01) and 52.4% (P = 0.53), respectively. The TGF-β1 excretion was lower after tested therapies compared to the placebo (55.0 ± 7.56 vs. 56.21 ± 8.56 vs. 85.79 ± 14.11 pg/mg creatinine; P = 0.016); without differences between aliskiren and perindopril. PIIINP excretion did not differ between treatments. CONCLUSIONS The study shows that both aliskiren and perindopril suppress TGF-β1 in patients with chronic kidney diseases. This effect was observed despite significant increases in the renin and prorenin concentrations. Further studies involving histological assessments are required to elucidate the exact impact of these agents on renal fibrosis.

ObjectiveThe intrarenal renin–angiotensin system (RAS) activation plays a pivotal role in immunoglobulin A nephropathy (IgAN) pathogenesis, which is still largely undefined. Recently, vasopressin (AVP) has been advocated to contribute to the genesis and progression of chronic kidney diseases (CKD) directly, and indirectly, via RAS activation. Our aim is to explore the intrarenal activity of AVP, its relationship with RAS activity, as well as its modulation by therapies in IgAN.DesignIn this observational study, we measured plasma copeptin, a surrogate marker of AVP, the urine excretion of aquaporin 2 (AQP2), a protein reflecting renal AVP action, and angiotensinogen (AGT), a parameter of renal RAS activation, and their relationship with renal function in 44 IgAN patients at the time of renal biopsy, without any drug therapy, and after 6-month treatment with ACEi or steroid+ACEi. Twenty-one patients with other CKD and 40 healthy subjects were recruited as controls.MethodsELISAs were used to measure all variables of interest.ResultsAt baseline, IgAN patients showed higher urinary levels of AQP2, compared with controls and patients with other CKD. Urinary AQP2 and AGT levels strongly correlated with the presence of arterial hypertension. Steroids+ACEi caused the decrease of all the variables examined. The fall of urinary AQP2 and AGT following drug treatments was associated with the decrease of daily proteinuria.ConclusionOur findings would support the involvement of AVP–AQP2 axis, interacting with the RAS, in the progression of IgAN and candidate AQP2 as a possible novel marker of the disease.

Mesenchymal stem cells (MSCs) have regenerative properties in acute kidney injury, but their role in chronic kidney diseases is still unknown. More specifically, it is not known whether MSCs halt fibrosis. The purpose of this work was to investigate the role of MSCs in fibrogenesis using a model of chronic renal failure. MSCs were obtained from the tibias and femurs of male Wistar-EPM rats. Female Wistar rats were subjected to the remnant model, and 2|×|105 MSCs were intravenously administrated to each rat every other week for 8 weeks or only once and followed for 12 weeks. SRY gene expression was observed in female rats treated with male MSCs, and immune localization of CD73+CD90+ cells at 8 weeks was also assessed. Serum and urine analyses showed an amelioration of functional parameters in MSC-treated animals at 8 weeks, but not at 12 weeks. Masson's trichrome and Sirius red staining demonstrated reduced levels of fibrosis in MSC-treated animals. These results were corroborated by reduced vimentin, type I collagen, transforming growth factor β, fibroblast specific protein 1 (FSP-1), monocyte chemoattractant protein 1, and Smad3 mRNA expression and α smooth muscle actin and FSP-1 protein expression. Renal interleukin (IL)-6 and tumor necrosis factor α mRNA expression levels were significantly decreased after MSC treatment, whereas IL-4 and IL-10 expression levels were increased. All serum cytokine expression levels were decreased in MSC-treated animals. Taken together, these results suggested that MSC therapy can indeed modulate the inflammatory response that follows the initial phase of a chronic renal injury. The immunosuppressive and remodeling properties of MSCs may be involved in the decreased fibrosis in the kidney. Disclosure of potential conflicts of interest is found at the end of this article.

Background Incident and prevalent (I&P) rates in dialysis end-stage renal disease (ESRD) patients in Taiwan increased rapidly following the launch of National Health Insurance (NHI) in 1995. Our aim was to explore the impact of NHI on the status and trends of ESRD epidemiology in Taiwan. Methods This study was conducted using retrospective cohort analysis of data collected from the Taiwan national dialysis registry. Results From 1990 to 2001, I&P rates of ESRD patients increased 2.6 times from 126 to 331 per million populations (pmp) and 3.46 times from 382 to 1322 pmp, respectively. Increasing ESRD was seen in patients who were middle-aged, elderly and who had diabetic nephropathy as their primary renal disease. The mean age of I&P patients increased by 7.2 years and 7.1 years, respectively. All of these parameters increased markedly in 1995, the year of NHI implementation. First-year mortality decreased to 7.8 per 1000 patient-months in 1994, and then increased to 18.0 in 2001. The cumulative survival rate of the elderly subgroup (age >65) in the incident 1990-1994 cohort was greater than in the 1995-1999 cohort. These data indicated that NHI implementation significantly influenced the inflow and the mortality of ESRD patients. Conclusion In addition to presenting ESRD epidemiology in Taiwan, this study demonstrated that NHI implementation stimulated the growth of treated ESRD populations. Preventive plans mounted against chronic kidney diseases will be essential to reduce the growth of ESRD patient numbers and consequent economic burdens.

There are two areas of concern regarding the nephrotoxic potential of fluoride. A small and inclusive amount of research suggests that fluoridation of community water actually causes kidney disease. Kidney damage to tubular function and structure, and reduction in glomerular filtration rate occurred in residents of endemic fluoride areas [2] and anecdotal cases of fluoride intoxication [3] suggested a causal relationship between fluoride intake and renal failure. Ludlow et al. are correct that no evidence of an increased frequency of kidney disease or tubular dysfunction has been observed in early US epidemiological studies, comparing non-fluoridated areas (0.3mg/dl)toupto8mg/l fluoride in drinking water. None of these studies described renalfunctionoftheparticipantsorserialchangesinsimple urinalysis.Ofinterest,thedataofarecentlypublishedstudy suggested that drinking water contains fluoride levels over 2.0 mg/l—half of the fluoride concentration deemed safe by the US Environmental Protection Agency (EPA)—could cause damage to renal tubular structures in children. This conclusion is based on an investigation of 210 children living in areas of China with varying levels of fluoride in the community water (0.6–5.7 ppm). Children drinking water withmorethan2ppmfluoridewerefoundtohaveincreased levels of NAG and yGT in their urine—both markers of renal tubular damage [4]. It may be stated that there are no known adverse effects associated with the ingestion of relatively low levels of fluoride (1–2 ppm in drinking water) on a chronic basis. However, the actual levels of intake have to include fluoride not only in water, but also in the diet and in other fluoride containing products. Moreover, a fairly substantial body of research indicates that patients with chronic renal insufficiency are at an increased risk of chronic fluoride toxicity. Patients with reduced glomerular filtration rates have a decreased ability to excrete fluoride in the urine. These patients may develop skeletal fluorosis even at 1 ppm fluoride in the drinking water [5]. Whether or not the body burden of fluoride may further damage the diseased kidneys is unknown. The National Kidney Foundation in its ‘Position Paper on Fluoride—1980’ as well as the Kidney Health Australia express concern about fluoride retention in kidney patients. They caution physicians to monitor the fluoride intake of patients with advanced stages of kidney diseases. However, a number of reasons will account for the failure to monitor fluoride intake in patients with stages 4 and 5 of chronic kidney diseases and to detect early effects of fluoride retention on kidneys and bone. The safety margin for exposure to fluoride by renal patients is unknown, measurements of fluoride levels are not routine, the onset of skeletal fluorosis is slow and insidious, clinical symptoms of this skeletal disorder are vague, progression of renal functional decline is multifactorial and physicians are unaware of side effects of fluoride on kidneys or bone.