rAAV6-mediated miR-29b delivery suppresses renal fibrosis Abstract Background Previous studies showed that microRNA-29b (miR-29b) inhibits renal fibrosis. Therefore, miR-29b replacement therapy represents a promising approach for treating renal fibrosis. However, an efficient method of kidney-targeted miRNA delivery has yet to be established. Recombinant adeno-associated virus (rAAV) vectors have great potential for clinical application. For kidney-targeted gene delivery, the most suitable AAV serotype has yet to be established. Here, we identified the most suitable AAV serotype for kidney-targeted gene delivery and determined that AAV-mediated miR-29b delivery can suppress renal fibrosis in vivo. Method To determine which AAV serotype is suitable for kidney cells, GFP-positive cells were identified by flow cytometry after the infection of rAAV serotype 1–9 vectors containing the EGFP gene. Next, we injected rAAV vectors into the renal pelvis to determine transduction efficiency in vivo. GFP expression was measured seven days after injecting rAAV serotype 1–9 vectors carrying the EGFP gene. Finally, we investigated whether rAAV6-mediated miR-29b delivery can suppress renal fibrosis in UUO mouse model. Results We found that rAAV6 vector is the most suitable for targeting kidney cells regardless of animal species in vitro and rAAV6 is the most suitable vector for kidney-targeted in vivo gene delivery in mice. Intra-renal pelvic injection of rAAV vectors can transduce genes into kidney TECs. Furthermore, rAAV6-mediated miR-29b delivery attenuated renal fibrosis in UUO model by suppressing Snail1 expression. Conclusion Our study has revealed that rAAV6 is the most suitable serotype for kidney-targeted gene delivery and rAAV6-mediated miR-29b delivery into kidney TECs can suppress established renal fibrosis.

Ratio of triglyceride to high-density lipoprotein cholesterol and risk of major cardiovascular events in kidney transplant recipients Abstract Background Dyslipidemia is common in kidney transplant (KT) recipients. We analyzed the ratio of triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) in KT recipients to identify risk factors for major cardiovascular events (MACE). Methods We retrospectively included KT recipients with a lipid profile performed 1 year after transplantation. We classified patients according to the TG/HDL-C divided into quintiles. Subsequently, we analyzed the association between TG/HDL-C and MACE, defined as heart failure, coronary artery disease, and cerebrovascular disease confirmed by imaging studies. Results A total of 1301 KT recipients were enrolled. The median follow-up duration was 7.4 years (interquartile range 4.4–11.1 years). During the follow-up period, 80 (6.2%) patients developed MACE, which included 38 of unstable anginas, 9 of MIs, 19 of heart failures, 18 of cerebral infarcts, and 4 of cerebral hemorrhages. The fourth and fifth quintiles of TG/HDL-C showed a significantly increased risk of MACE [fourth quintile: adjusted hazard ratio (aHR), 3.38; 95% confidence interval (CI) 1.44–7.95; p = 0.005, fifth quintile: aHR, 2.67; 95% CI 1.13–6.30; p = 0.02]) compared to the second quintile of TG/HDL-C. This association is particularly evident in subgroups of non-DM, HTN, no history of CVD, and statin users. Conclusions Higher TG/HDL-C levels may be associated with MACE risk in KT recipients.

Obstructive sleep apnea as a risk factor for incident end stage renal disease: a nationwide population-based cohort study from Korea Abstract Background Obstructive sleep apnea (OSA) is known to be associated with metabolic dysregulation and incident cardiovascular diseases. However, its association with end-stage renal disease (ESRD) has not been clarified. This study aimed to evaluate longitudinally whether OSA is an independent risk factor for ESRD. Methods This retrospective nationwide population-based cohort study included data on 67,359 patients with OSA and 336,795 age-, sex- and years of the enrollment-matched controls without OSA obtained from the Korean National Health Insurance Service database from 2009 to 2014. The study population was followed up from baseline to the date of ESRD diagnosis or until 2016. A Cox proportional-hazards model with multivariable adjustment was used to evaluate the association between OSA and incident ESRD. Results A significantly higher incident ESRD risk (adjusted hazard ratio: 1.29, 95% confidence interval 1.02–1.62) was observed for patients older than 40 years with OSA than for matched controls, when adjusted for age, sex, income status, smoking, alcohol consumption, body mass index, diabetes, hypertension, dyslipidemia, estimated glomerular filtration rate, and proteinuria. The OSA group remained predictive of higher risk of ESRD incidence in subgroups of age ≥ 65 years, female sex, hypertension, dyslipidemia, proteinuria, and chronic kidney disease. Conclusion OSA was associated with a higher risk of incident ESRD. Understanding the association between OSA and ESRD might provide further insights to establish national health care policy.

The association between genotypes of urate transporter-1, Serum uric acid, and mortality in the community-based population: the Yamagata (Takahata) Study Abstract Background The urate transporter-1 (URAT1) is crucial in developing hyperuricemia via reabsorption of uric acid in renal tubules, and its function is regulated by several single nucleotide polymorphisms (SNPs) within SLC22A12 gene encoding URAT1. This study investigated whether the genetic predisposition of URAT1 is associated with the mortality in general population. Methods This study enrolled 1596 participants (male 45%, mean age 61 years) who registered at local health checkup in Takahata, Japan, and the association between the rs505802 genotypes in SLC22A12 gene and the 7-year mortality, was examined. Results The serum uric acid levels (mean ± SD) at baseline in the subjects with GG and AG + AA genotypes of rs505802 were 5.1 ± 1.3 mg/dL and 5.0 ± 1.5 mg/dL, respectively. Kaplan–Meier analysis revealed that the mortality was nonsignificantly higher in the subjects with GG genotype than in those with AG + AA genotype (P = 0.09). Cox proportional hazard model adjusted with age, gender, renal function, comorbidities, and other possible confounders, demonstrated that the GG genotype was significantly associated with the mortality [hazard ratio (HR) 2.23, 95% confidence interval (CI) 1.05–4.85, (vs. AG + AA genotype)]. Furthermore, adjustment with serum uric acid levels, along with aforementioned confounders retained the significant association (HR 2.26, 95% CI 1.05–4.85). Conclusions This study revealed that the genetic predisposition of URAT1 was independently associated with mortality in the Japanese community-based population. This association might be due to the mechanism independent of serum uric acid levels.

A clinicopathological comparison between IgA nephropathy and Henoch–Schönlein purpura nephritis in children: use of the Oxford classification Abstract Background There is controversy over whether IgA nephropathy (IgAN) and Henoch–Schönlein purpura nephritis (HSPN) are the same diseases. This study focuses on the clinicopathological comparison between HSPN and IgAN in children. Methods Children with IgAN and HSPN who had a diagnostic renal biopsy were enrolled. This study collected the clinical data of patients at biopsy, re-evaluated the pathological lesions of patients according to the Oxford Classification (MEST-C), and made a retrospective comparison between IgAN and HSPN on different stratifications of the course (Tc) and proteinuria. Results A total of 142 children with IgAN and 57 children with HSPN were enrolled. Various stratification showed the same result, which suggested that IgAN showed more mesangial proliferation (M). HSPN showed more segmental glomerulosclerosis in the Tc > 12 m group than IgAN (S 60.0% vs. 9.10%, P = 0.008). In the non-nephrotic-range and nephrotic-range proteinuria group, there were no significant differences in MEST-C scores between IgAN and HSPN. Conclusion M is more common in IgAN. HSPN had more S than IgAN over the course of more than 12 months. These results indicate the differences in the pathogenesis in IgAN and HSPN. We propose early biopsy and active treatment of HSPN within 12 months to delay the development of chronic lesions.

Low birth weight is associated with decline in renal function in Japanese male and female adolescents Abstract Background Low birth weight (LBW) is a risk factor for chronic kidney disease (CKD) in later life and is becoming increasingly common in developed countries, including Japan. Furthermore, a serial decrease in birth weight has been associated with an increasing prevalence of CKD stage 2 in male Japanese adolescents. Sex-specific differences affect CKD susceptibility, and the association between birth weight and CKD in women, has not been elucidated. In this study, we investigated the sex-specific effect of LBW on renal function. Methods Annual cross-sectional data of 2417 Japanese adolescents (males 1736; females 681), aged 15–16 years, were evaluated over 8 years (2007–2014). Results Over the study period, mean birth weights decreased significantly in males (p < 0.01) and females (p < 0.05). Furthermore, both sexes showed significant decrease in estimated glomerular filtration rates corresponding to the birth weight reduction. The prevalence of CKD stage 2 also increased in males (from 26.0 to 32.4%, p < 0.01) and females (from 6.3 to 18.5%, p < 0.05). The incidence of CKD stage 2 was significantly related to history of LBW (males: odds ratio 1.73; 95% confidence interval 1.06–2.80; p < 0.05; females: odds ratio 3.29; 95% confidence interval 1.25–8.02; p < 0.05). Conclusions Our data revealed that renal function and birth weight have decreased over time, in healthy Japanese adolescents. In view of the recent declining trend demonstrated by birth weight in Japan, we speculate that the prevalence of CKD might increase in the future.

Impact of persistent preformed and de novo donor-specific antibodies detected at 1 year after kidney transplantation on long-term graft survival in Japan: a retrospective study Abstract Background We evaluated the impact of persistent preformed donor-specific antibody (DSA) and de novo DSA (dnDSA) detected at 1 year posttransplantation on long-term death-censored graft survival. Methods One hundred and sixty adult patients who received living kidney allograft with pretransplant-negative T-cell complement-dependent cytotoxicity crossmatch (CDCXM), and without periodic screening for DSA, were eligible for this study. All enrolled patients were retrospectively tested for DSA using the Luminex assay. The presence of DSA was analyzed in stored serum samples collected at 1 year posttransplantation. If the recipients had DSA, it was analyzed in the pretransplant serum sample. The detection of DSA solely in the 1 year posttransplant sample was defined as dnDSA, and DSA detection in both pretransplant and 1 year posttransplant samples was defined as persistent preformed DSA. Results DSAs were identified in 14 (8.8%) of the 160 patients. Seven patients had persistent preformed DSA, 6 had dnDSA, and 1 had both persistent preformed and dnDSA at 1 year posttransplantation. Death-censored allograft survival rates of patients with DSA versus those without DSA at 7 and 11 years were 77.9 vs. 97.8% and 60.6 vs. 89.2%, respectively. The graft survival rate was lower in patients with persistent preformed DSA and/or dnDSA. Each case of preformed DSA and dnDSA was associated with long-term graft survival. Conclusion The presence of persistent preformed DSA or dnDSA at 1 year posttransplantation may be a predictor of long-term graft survival. Further study is needed to evaluate whether periodic screening for DSA improves long-term graft survival.

Clinicopathological analysis of ANCA-associated glomerulonephritis focusing on plasma cell infiltrate Abstract Background When we encounter glomerulonephritis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides demonstrating many plasma cell infiltrations, histological overlapping of immunoglobulin G4-related disease (IgG4-RD) often comes into the differential diagnosis. No previous study has focused on the degree of plasma cells in the kidney infiltrate in ANCA-associated glomerulonephritis (ANCA-GN), and the significance of massive plasma cell infiltrate has not been investigated. Methods To clarify the plasma cell ratio in renal biopsy specimens of ANCA-GN and the histological characteristic of “plasma cell-rich” ANCA-GN, 20 cases of ANCA-GN were reviewed and clinicopathologically analyzed. Results Plasma cell ratio was widely distributed between 1.4 and 81%, and the median ratio was 10%. Three patients were categorized in “plasma cell-rich” ANCA-GN, defined as over 45% plasma cell ratio. They tended to include many active glomerular lesions compared to chronic lesions and to display severe tubulointerstitial inflammation. It is suggested that plasma cell-rich ANCA-GN may be acute onset of the disease, and the target of early inflammation may also be in the tubulointerstitial region. Two of the three plasma cell-rich ANCA-GN cases demonstrated numerous IgG4+ cells, but no bird’s-eye pattern fibrosis or obliterative phlebitis. Conclusions Plasma cell-rich ANCA-GN is not rare and demonstrates distinct clinicopathological characteristics. This study also reminds us that the presence of the significant number of plasma cells in ANCA-GN, as such, is not a histological diagnostic basis for overlap ANCA-GN and IgG4-related disease.

Predictive performance of lipid accumulation product and visceral adiposity index for renal function decline in non-diabetic adults, an 8.6-year follow-up Abstract Background Lipid accumulation product (LAP) and visceral adiposity index (VAI) are surrogates for visceral adiposity dysfunction. Our aim was to evaluate potential association of these two indices with the incidence of renal function decline. Methods We included 6693 non-diabetic adults age ≥ 18 years, with estimated glomerular filtration rate (eGFR) ≥ 60 ml/min/1.73 m2, from the Tehran Lipid and Glucose Study 2002–2005 survey. Natural logarithmic transformation (Ln) was applied for LAP and VAI measures. The incidence of renal function decline, defined as eGFR < 60 ml/min/1.73 m2, was evaluated for each gender, across tertiles of Ln LAP, Ln VAI, body mass index (BMI), waist circumference (WC), waist to height ratio (WHtR) and waist to hip ratio (WHR), using Cox-proportional hazard models. Results Over a median 8.6 years of follow-up, 1670 new cases of renal function decline were identified (incidence rate 3.2%). After multivariable adjustment, the hazard ratios (HRs) with 95% CI across second and third tertiles of Ln LAP were 1.14 (0.86–1.50) and 1.33 (1.00–1.78) in men (P trend = 0.132); and 1.16 (0.90–1.50) and 1.24 (0.96–1.61) in women (P trend = 0.263), respectively. Multivariable adjusted HRs across second and third tertiles of Ln VAI were 1.40 (1.08–1.83) and 1.35 (1.02–1.78) in men (P trend = 0.031); and 0.93 (0.75–1.15) and 1.15 (0.93–1.41) in women (P trend = 0.072), respectively. HRs across tertiles of BMI, WC, WHtR and WHR were not significant for renal function decline among both genders in any adjustment models. Conclusion Among the adiposity indices assessed in this study, VAI seems to be an independent predictor of renal function decline only in males.