The reduced expression of proximal tubular transporters in acquired Fanconi syndrome with κ light chain deposition.

In a case of acquired Fanconi syndrome associated with smoldering myeloma, we confirmed the deposition of protease-resistant κ light chain proteins in a proximal tubular injury and found the decreased expression of apical tubular transporters including sodium glucose co-transporter, sodium phosphate co-transporter, uric acid transporter 1, and a decrease of Na(+)/K(+)-ATPase in the basolateral membrane. The protease-resistant kappa light chain has a pathological role in the expression of tubular transporters in the proximal tubule and causes Fanconi syndrome associated with smoldering myeloma.

Prioritization of nasal polyp-associated genes by integrating GWAS and eQTL summary data.

Background: Nasal polyps (NP) are benign inflammatory growths of nasal and paranasal sinus mucosa that can substantially impair patients' quality of life by various symptoms such as nasal obstruction, insomnia, and anosmia. NP often relapse even after surgical treatment, and the curative therapy would be challenging without understanding the underlying mechanisms. Genome wide association studies (GWASs) on NP have been conducted; however, few genes that are causally associated with NP have been identified. Methods: We aimed to prioritize NP associated genes for functional follow-up studies using the summary data-based Mendelian Randomization (SMR) and Bayesian colocalization (COLOC) methods to integrate the summary-level data of the GWAS on NP and the expression quantitative trait locus (eQTL) study in blood. We utilized the GWAS data including 5,554 NP cases and 258,553 controls with 34 genome-wide significant loci from the FinnGen consortium (data freeze 8) and the eQTL data from 31,684 participants of predominantly European ancestry from the eQTLGen consortium. Results: The SMR analysis identified several genes including TNFRSF18, CTSK, and IRF1 that were associated with NP due to not linkage but pleiotropy or causality. The COLOC analysis strongly suggested that these genes and the trait of NP were affected by shared causal variants, and thus were colocalized. An enrichment analysis by Metascape suggested that these genes might be involved in the biological process of cellular response to cytokine stimulus. Conclusion: We could prioritize several NP associated genes including TNFRSF18, CTSK, and IRF1 for follow-up functional studies in future to elucidate the underlying disease mechanisms.

Estimating causal effects of genetically predicted type 2 diabetes on COVID-19 in the East Asian population.

Background: Observational studies suggested that type 2 diabetes mellitus (T2DM) was associated with an increased risk of coronavirus disease 2019 (COVID-19). However, Mendelian randomization (MR) studies in the European population failed to find causal associations, partly because T2DM was pleiotropically associated with body mass index (BMI). We aimed to estimate the causal effects of T2DM on COVID-19 outcomes in the East Asian (EAS) population using a two-sample MR approach. Methods: We obtained summary statistics from a genome-wide association study (GWAS) that included 433,540 EAS participants as the exposure dataset for T2DM risk and from COVID-19 Host Genetics Initiative GWAS meta-analyses (round 7) of EAS ancestry as the outcome dataset for COVID-19 susceptibility (4,459 cases and 36,121 controls), hospitalization (2,882 cases and 31,200 controls), and severity (794 cases and 4,862 controls). As the main MR analysis, we performed the inverse variance weighted (IVW) method. Moreover, we conducted a series of sensitivity analyses, including IVW multivariable MR using summary statistics for BMI from a GWAS with 158,284 Japanese individuals as a covariate. Results: The IVW method showed that the risk of T2DM significantly increased the risk of COVID-19 susceptibility (odds ratio [OR] per log (OR) increase in T2DM, 1.11; 95% confidence interval [CI], 1.02-1.20; P = 0.014) and hospitalization (OR, 1.15; 95% CI, 1.04-1.26; P = 0.005), although the risk of severity was only suggestive. Moreover, IVW multivariable MR analysis indicated that the causal effects of T2DM on COVID-19 outcomes were independent of the effect of BMI. Conclusions: Our MR study indicated for the first time that genetically predicted T2DM is a risk factor for SARS-CoV-2 infection and hospitalized COVID-19 independent of obesity in the EAS population.

Educational Attainment Decreases the Risk of COVID-19 Severity in the European Population: A Two-Sample Mendelian Randomization Study.

Observational studies have reported that the severity of COVID-19 depends not only on physical conditions but also on socioeconomic status, including educational level. Because educational attainment (EA), which measures the number of years of schooling, is moderately heritable, we investigated the causal association of EA on the risk of COVID-19 severity using the Mendelian randomization (MR) approach. A two-sample MR analysis was performed using publicly available summary-level data sets of genome-wide association studies (GWASs). A total of 235 single-nucleotide polymorphisms (SNPs) were extracted as instrumental variables for the exposure of EA from the Social Science Genetic Association Consortium GWAS summary data of 766,345 participants of European ancestry. The effect of each SNP on the outcome of COVID-19 severity risk was obtained from the GWAS summary data of 1,059,456 participants of European ancestry gathered from the COVID-19 Host Genetics Initiative. Using inverse variance weighted method, our MR study shows that EA was significantly associated with a lower risk of COVID-19 severity (odds ratio per one standard deviation increase in years of schooling, 0.540; 95% confidence interval, 0.376-0.777, P = 0.0009). A series of sensitivity analyses showed little evidence of bias. In conclusion, we show for the first time using a two-sample MR approach the associations between higher EA and the lower risk of COVID-19 severity in the European population. However, the genetic or epidemiological mechanisms underlying the association between EA and the risk of COVID-19 severity remain unknown, and further studies are warranted to validate the MR findings and investigate underlying mechanisms.

Causal effect of atrial fibrillation/flutter on chronic kidney disease: A bidirectional two-sample Mendelian randomization study.

Chronic kidney disease (CKD) and atrial fibrillation are both major burdens on the health care system worldwide. Several observational studies have reported clinical associations between CKD and atrial fibrillation; however, causal relationships between these conditions remain to be elucidated due to possible bias by confounders and reverse causations. Here, we conducted bidirectional two-sample Mendelian randomization analyses using publicly available summary statistics of genome-wide association studies (the CKDGen consortium and the UK Biobank) to investigate causal associations between CKD and atrial fibrillation/flutter in the European population. Our study suggested a causal effect of the risk of atrial fibrillation/flutter on the decrease in serum creatinine-based estimated glomerular filtration rate (eGFR) and revealed a causal effect of the risk of atrial fibrillation/flutter on the risk of CKD (odds ratio, 9.39 per doubling odds ratio of atrial fibrillation/flutter; 95% coefficient interval, 2.39-37.0; P = 0.001), while the causal effect of the decrease in eGFR on the risk of atrial fibrillation/flutter was unlikely. However, careful interpretation and further studies are warranted, as the underlying mechanisms remain unknown. Further, our sample size was relatively small and selection bias was possible.

Estimating causal effects of atherogenic lipid-related traits on COVID-19 susceptibility and severity using a two-sample Mendelian randomization approach.

BACKGROUND: As the number of COVID-19 deaths continues to rise worldwide, the identification of risk factors for the disease is an urgent issue, and it remains controversial whether atherogenic lipid-related traits including serum apolipoprotein B, low-density lipoprotein (LDL)-cholesterol, and triglyceride levels, are risk factors. The aim of this study was to estimate causal effects of lipid-related traits on COVID-19 risk in the European population using a two-sample Mendelian randomization (MR) approach. METHODS: We used summary statistics from a genome-wide association study (GWAS) that included 441,016 participants from the UK Biobank as the exposure dataset of lipid-related traits and from COVID-19 Host Genetics Initiative GWAS meta-analyses of European ancestry as the outcome dataset for COVID-19 susceptibility (32,494 cases and 1,316,207 controls), hospitalization (8316 cases and 1,549,095 controls), and severity (4792 cases and 1,054,664 controls). We performed two-sample MR analyses using the inverse variance weighted (IVW) method. As sensitivity analyses, the MR-Egger regression, weighted median, and weighted mode methods were conducted as were leave-one-out sensitivity analysis, the MR-PRESSO global test, PhenoScanner searches, and IVW multivariable MR analyses. A P value below 0.0055 with Bonferroni correction was considered statistically significant. RESULTS: This MR study suggested that serum apolipoprotein B or LDL-cholesterol levels were not significantly associated with COVID-19 risk. On the other hand, we inferred that higher serum triglyceride levels were suggestively associated with higher risks of COVID-19 susceptibility (odds ratio [OR] per standard deviation increase in lifelong triglyceride levels, 1.065; 95% confidence interval [CI], 1.001-1.13; P = 0.045) and hospitalization (OR, 1.174; 95% CI, 1.04-1.33; P = 0.012), and were significantly associated with COVID-19 severity (OR, 1.274; 95% CI, 1.08-1.50; P = 0.004). Sensitivity and bidirectional MR analyses suggested that horizontal pleiotropy and reverse causation were unlikely. CONCLUSIONS: Our MR study indicates a causal effect of higher serum triglyceride levels on a greater risk of COVID-19 severity in the European population using the latest and largest GWAS datasets to date. However, as the underlying mechanisms remain unclear and our study might be still biased due to possible horizontal pleiotropy, further studies are warranted to validate our findings and investigate underlying mechanisms.

Single-nucleotide polymorphism rs4664308 in PLA2R1 gene is associated with the risk of idiopathic membranous nephropathy: a meta-analysis.

Although many studies investigated the associations between single-nucleotide polymorphisms (SNPs) in the M-type phospholipase A2 receptor-1 (PLA2R1) gene and susceptibility to idiopathic membranous nephropathy (IMN), some showed inconsistent results. Here, we conducted a meta-analysis examining the associations between PLA2R1 SNPs and IMN susceptibility after systematic searches in the PubMed and Web of Science databases. Our meta-analysis for rs4664308 A>G including 2,542 IMN patients and 4,396 controls in seven studies showed a significant association between the G allele and a lower risk of IMN, as determined using an allelic model (odds ratio, 0.45; 95% confidence interval [0.41-0.50]), an additive model (for GG vs. AA: 0.26; [0.21-0.33]; for AG vs. AA: 0.40; [0.36-0.45]), a dominant model (0.37; [0.34-0.42]) and a recessive model (0.38; [0.31-0.48]). Our meta-analysis also suggested associations between rs3828323, rs35771982, rs3749117 and rs3749119 and IMN susceptibility although high heterogeneities and/or publication biases were observed. We did not study in our meta-analysis, but other studies indicated that high-risk genotype combinations of rs2187668 in the human leucocyte antigen-DQ a-chain 1 gene and rs4664308 in the PLA2R1 gene had even stronger associations and could affect the formation of anti-PLA2R1 antibodies, suggesting these SNPs could be novel therapeutic targets.

The APLNR gene polymorphism rs7119375 is associated with an increased risk of development of essential hypertension in the Chinese population: A meta-analysis.

Hypertension (HT) has recently been defined as a systolic blood pressure (BP) of ≥130 mm Hg and/or a diastolic BP of ≥80 mm Hg. It is important to further understand the pathophysiology of essential HT as its proportion is larger among most of the diagnosed HT cases. The apelin and apelin receptor (APLNR) are known to play roles in regulating BP, but the putative associations of single nucleotide polymorphisms in the APLNR gene with the risk of development of essential HT have not yet been fully investigated. Herein, we conducted a meta-analysis to investigate the relationship between single nucleotide polymorphisms in the APLNR gene and the risk of essential HT.We conducted a search in the PubMed and Web of Science databases for eligible studies. The pooled odds ratios (ORs) with their 95% confidence intervals (CI) were calculated using random-effects models when heterogeneity was expected across the studies. Otherwise, fixed-effect models were used.Regarding the SNP rs7119375, 5 studies were analyzed, which included a total of 3567 essential HT patients and 3256 healthy controls. Four of the 5 studies were from China and 1 was from Mexico. The meta-analysis showed the existence of a significant association between the AA genotype of rs7119375 and the risk of developing essential HT in the Chinese population, as determined using additive and recessive models (OR, 2.11; 95% CI, 1.12-3.96; I = 86% for AA vs GG. OR, 1.53; 95% CI, 1.21-1.94; I = 28% for AA vs AG. OR, 1.88; 95% CI, 1.13-3.12; I = 79% for AA vs AG + GG).Our study showed, for the first time, the existence of an association between rs7119375 and the risk of development of essential HT in the Chinese population, although the sample size was small and there was considerable population heterogeneity. The apelin/APLNR system could be a novel therapeutic target for the treatment of essential HT, and more studies are warranted to further investigate the association.

The resistive index is a marker of renal function, pathology, prognosis, and responsiveness to steroid therapy in chronic kidney disease patients.

To evaluate the significance of the renal resistive index (RI) as a noninvasive marker of renal histological damage and a prognostic indicator, we examined RI by Doppler ultrasonography in 202 chronic kidney disease (CKD) patients who underwent renal biopsy. RI increased as the CKD stage progressed and correlated with age, systolic blood pressure, estimated glomerular filtration rate (eGFR), and renal histological changes, including glomerulosclerosis, arteriolosclerosis, and tubulointerstitial damage. Prognostic evaluation with a median follow-up period of 38.5 months revealed that patients with RI ≥ 0.7 (high RI group, n = 39) had significantly poorer renal survival than those with RI < 0.65 (normal RI group, n = 120) and 0.65 ≤ RI < 0.7 (high-normal RI group, n = 43). The patients in the high-normal RI group showed good response to steroids. However, in the high RI group, steroid therapy did not significantly improve renal survival. Of the clinical indices studied, RI ≥ 0.7, hypertension, proteinuria, and low eGFR at diagnosis were independent risk factors for worsening renal dysfunction. In conclusion, RI in CKD patients was considered as a marker of renal function, histological damage, and renal prognosis, and a possible determinant of indication for steroids.

Detection of myeloperoxidase in membranous nephropathy-like deposits in patients with anti-neutrophil cytoplasmic antibody-associated glomerulonephritis.

Anti-neutrophil cytoplasmic antibody-associated glomerulonephritis is usually classified as a pauci-immune type. However, it sometimes shows immune complex deposition of unknown origin. We examined the glomerular localization of myeloperoxidase by double immunofluorescence and immunoelectron microscopy in cases of anti-neutrophil cytoplasmic antibody-associated glomerulonephritis with membranous nephropathy-like immunoglobulin G deposition to investigate the immune complex antigens in these cases. Six (35%) of the biopsy samples from 17 cases with anti-neutrophil cytoplasmic antibody-associated glomerulonephritis showed granular deposition of immunoglobulin G along the glomerular capillary walls. Light microscopy revealed necrotizing crescentic glomerulonephritis with segmental thickening of the glomerular basement membrane. Electron microscopy showed electron-dense deposits in intramembranous and mesangial areas. However, the size and distribution of the deposits were irregular and segmental in the examined cases, unlike typical global and subepithelial lesions of membranous nephropathy. Double immunofluorescence using Alexa Fluor 594-labeled anti-myeloperoxidase antibody and fluorescein isothiocyanate-labeled anti-immunoglobulin G antibody, as well as immunoelectron microscopy using anti-myeloperoxidase antibody labeled with 25-nm gold particles revealed partial colocalization of myeloperoxidase and immunoglobulin G within the glomerular basement membrane and mesangium. In some cases of anti-neutrophil cytoplasmic antibody-associated glomerulonephritis, myeloperoxidase may form immune complexes and develop membranous nephropathy-like lesions.

Long-term renal prognosis of IgA nephropathy with therapeutic trend shifts.

OBJECTIVE: We compared the effect of treatments in the long-term renal survival of IgA nephropathy. METHODS: One hundred and fourteen patients with biopsy-proven IgA nephropathy were retrospectively divided into 4 groups, reflecting shifts in treatment trends from 1985 to 2005: patients without treatment (no treatment group; n=36), patients treated only with anti-platelet drugs (anti-platelet group; n=12), those treated mainly with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) (ACEI/ARB group; n =29), and prednisolone-treated patients (PSL group; n =37). RESULTS: Baseline blood pressure, serum creatinine and renal histological findings were similar among the 4 groups; however, the urinary protein level was significantly severer in the PSL group. After a mean follow-up of 7.0+/-0.5 years, end-stage renal disease occurred in 11 patients (31%) in the no treatment group, 5 patients (42%) in the anti-platelet group and 3 patients (8%) in the PSL group, but in only 1 patient (3%) in the ACEI/ARB group. Kaplan-Meier renal survival after 20 years was significantly better in the ACEI/ARB group than in the anti-platelet group or in the no treatment group (p<0.05). The patients that reached complete remission (CR) by steroid therapy showed less baseline urinary protein and milder histological lesions than those who did not reach CR. The non-CR group showed increases in serum creatinine and eGFR reduction rate. CONCLUSION: Treatment with renin-angiotensin system inhibitors showed the greatest improvement of 20-year renal survival in IgA nephropathy patients. Steroid therapy achieved complete remission in some early-stage cases.

Suppressing renal NADPH oxidase to treat diabetic nephropathy.

Renal nicotinamide adenine dinucleotide phosphate reduced form (NADPH) oxidase is an important source of oxidative stress and its expression is enhanced in the glomerulus and distal tubules of diabetic nephropathy. High glucose-induced protein kinase C signalling or renal angiotensin II signalling increases the membrane translocation of cytosolic component p47phox. NADPH oxidase-derived reactive oxygen species (ROS) in the podocytes damage the glomerular basement membrane and the slit diaphragm causing proteinuria, and mesangial and glomerular endothelial NADPH oxidase increase TGF-beta and cause collagen and fibronectin accumulation. Tubular NADPH oxidase stimulated by angiotensin II or aldosterone contributes to sodium retention and to tubulointerstitial damage. Thus, inhibition of the renal renin-angiotensin II-aldosterone system with angiotensin-converting enzyme inhibitor, angiotensin II type 1 receptor blocker or selective aldosterone inhibitor indirectly suppresses NADPH oxidase reducing renal ROS, proteinuria and glomerulosclerosis. Statins are also effective in blocking the membrane translocation of Rac, especially in diabetes with hypercholesterolemia where ROS is produced by the intrinsic NADPH oxidase and by the activated macrophages. A medical herb, picrorhiza, inhibits the membrane translocation of p47phox, is a specific inhibitor of NADPH oxidase and, more so than superoxide dismutase mimetics, may be a promising strategy for the treatment of diabetic nephropathy.

Double-edged action of SOD mimetic in diabetic nephropathy.

Oxidative stress plays an important role in the pathogenesis of diabetic complications, and we investigated the effect of superoxide dismutase (SOD) mimetic, tempol, in diabetic nephropathy. Streptozotocin-induced diabetic rats were treated with tempol from 2 weeks until 8 weeks. The expression of NADPH oxidase, catalase, and myeloperoxidase (MPO), superoxide dismutase activity, and production of peroxide and hypochlorite were evaluated. Tempol treatment prevented the increase in NADPH oxidase and peroxide production in the glomeruli of diabetic rat. Catalase was decreased without change in SOD activity, and MPO was enhanced in the kidney of diabetic rats. Tempol treatment stimulated SOD activity and increased the conversion of superoxide to hydrogen peroxide, and hydrogen peroxide on its hand was converted to hypochlorite by the increased MPO. The reduction of peroxide by tempol was followed by the decrease in TGF-beta and mesangial matrix expansion. However, tempol did not reduce hypochlorite or urinary protein excretion. In conclusion, tempol inhibited glomerular matrix expansion via suppression of peroxide production and TGF-beta, but it failed to reduce proteinuria, probably due to the increased hypochlorite production in diabetic nephropathy.

Spironolactone with ACE inhibitor is effective in gross hematuria caused by nephroptosis.

Gross hematuria caused by nephroptosis is difficult to treat and sometimes requires surgical treatment. We experienced a case of a 64-year-old woman with gross hematuria due to nephroptosis and glomerular thin basement membrane that showed remission of hematuria with the blockade of the renin-angiotensin-aldosterone system with an angiotensin-converting enzyme inhibitor and spironolactone.

Effects of NADPH oxidase inhibitor in diabetic nephropathy.

BACKGROUND: We used apocynin to test the hypothesis that superoxide anion (O(-) (2)) from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase underlies the development of diabetic nephropathy in the rat. METHODS: Rats received apocynin (16 mg/kg/day) from 2 to 8 weeks after inducing diabetes mellitus (DM) with streptozotocin. RESULTS: DM increased excretion of hydrogen peroxide (H(2)O(2)), lipid peroxidation products (LPO), nitric oxide products (NOx), and protein. The kidneys of rats with DM had increased expression of p47phox and gp91phox and endothelial nitric oxide synthase (eNOS), and increased mesangial matrix with expression of fibronectin and collagen I. Apocynin prevented the increase in excretion of H(2)O(2), LPO, and protein in diabetic rats, increased renal NOx generation, and prevented the increased renal expression of gp91phox and the membrane fraction of p47phox, and reverted the mesangial matrix expansion. CONCLUSION: Activation of NADPH oxidase with translocation of p47phox to the membrane underlies the oxidative stress and limited NO generation, despite enhanced eNOS expression in a model of diabetic nephropathy. Apocynin prevents these changes and the associated proteinuria.

Nitric oxide generated by nNOS in the macula densa regulates the afferent arteriolar diameter in rat kidney.

Nitric oxide (NO) derived from neuronal NO synthase (nNOS) in the macula densa is a modulator of tubuloglomerular feedback. However, little is known about the regulation of the afferent arteriolar diameter by NO from the macula densa in salt-sensitive hypertension. We investigated the relationship between nNOS in the macula densa and the afferent arteriolar diameter in deoxycorticosterone acetate (DOCA)-salt hypertensive rats treated with angiotensin converting enzyme (ACE) inhibitor or thiazide for 5 weeks. DOCA rats had reduced nNOS expression in the macula densa compared to controls and reduction of NO production evaluated with 4,5-diaminofluorescein diacetate in the juxtaglomerular apparatus (JGA). Treatment with ACE inhibitor and thiazide increased nNOS and NO production in the JGA. The diameter of the afferent arteriole observed by SEM using microvascular casts was smaller in DOCA rats compared to control rats, and ACE inhibitor or thiazide dilated the afferent arteriole with a positive correlation to nNOS immunoreactivity in the macula densa. In conclusion, the afferent arteriolar diameter might be regulated by NO derived from nNOS in the macula densa in DOCA-salt hypertensive rats.

Fibrillary glomerulonephritis associated with essential thrombocytosis.

A 68-year-old man with a 30-year history of essential thrombocytosis developed nephrotic syndrome. Renal biopsy showed massive deposits of Congo red-negative periodic acid Schiff (PAS)-positive substance in the mesangium and capillary wall that was positive for IgG. Electron microscopic examination revealed 10- to 20-nm fibrils in the deposits, and there was no other organ involvement; thus, we diagnosed fibrillary glomerulonephritis. This is the first report of a case of fibrillary glomerulonephritis associated with essential thrombocytosis.