Glomerular expression and urinary excretion of fatty acid-binding protein 4 in IgA nephropathy.

BACKGROUND: Fatty acid-binding protein 4 (FABP4) is secreted from adipocytes and macrophages in adipose tissue and acts as an adipokine. It has recently been reported that FABP4, but not liver-type FABP (L-FABP/FABP1), is also expressed in injured glomerular endothelial cells and infiltrating macrophages in the glomerulus and that urinary FABP4 (U-FABP4) is associated with proteinuria and kidney function impairment in nephrotic patients. However, the link between glomerular FABP4 and U-FABP4 has not been fully addressed in IgA nephropathy (IgAN). METHODS: We investigated the involvement of FABP4 in human and mouse IgAN. RESULTS: In patients with IgAN (n = 23), the ratio of FABP4-positive area to total area within glomeruli (G-FABP4-Area) and U-FABP4 were positively correlated with proteinuria and were negatively correlated with eGFR. In 4-28-week-old male grouped ddY mice, a spontaneous IgAN-prone mouse model, FABP4 was detected in glomerular endothelial cells and macrophages, and G-FABP4-Area was positively correlated with urinary albumin-to-creatinine ratio (r = 0.957, P < 0.001). Endoplasmic reticulum stress markers were detected in glomeruli of human and mouse IgAN. In human renal glomerular endothelial cells, FABP4 was induced by treatment with vascular endothelial growth factor and was secreted from the cells. Treatment of human renal glomerular endothelial cells or mouse podocytes with palmitate-bound recombinant FABP4 significantly increased gene expression of inflammatory cytokines and endoplasmic reticulum stress markers, and the effects of FABP4 in podocytes were attenuated in the presence of an anti-FABP4 antibody. CONCLUSION: FABP4 in the glomerulus contributes to proteinuria in IgAN, and U-FABP4 level is a useful surrogate biomarker for glomerular damage in IgAN.

Successful renal recovery from multiple myeloma-associated crystalline light chain cast nephropathy and accompanying acute kidney injury with early use of bortezomib-based therapy: a case report and literature review.

Crystalline light chain cast nephropathy is a rare distinct morphologic variant of light chain cast nephropathy which is the most common renal lesion associated with multiple myeloma. It is often related to high myeloma tumor burden, severe acute kidney injury, and an unfavorable prognosis. A 79-year-old Japanese man was referred to our medical center with anemia, proteinuria, and acute exacerbation of the serum creatinine accompanying anuria. A renal biopsy showed crystalline cast filling the tubular lumens, injured tubular cells, and inflammatory cells infiltration of interstitium. Serum and urine immunofixation detected a monoclonal protein (IgA-λ and Bence-Jones Protein-λ, respectively), and bone marrow examination observed 64% of plasma cells. IgA-λ type multiple myeloma-associated crystalline light chain cast nephropathy and accompanying acute kidney injury were confirmed. Hydration and emergency hemodialysis were immediately introduced, and the treatment with bortezomib and dexamethasone was initiated. The patient showed successful recovery in renal manifestations. We suggest that early use with bortezomib-based therapy should be considered for patients with acute kidney injury caused by multiple myeloma-associated crystalline light chain cast nephropathy.

Seasonal variation of serum 25-hydroxyvitamin D level in hemodialysis patients in the northernmost island of Japan.

BACKGROUND: Serum vitamin D level shows a seasonal variation, being lower in winter than in summer in healthy subjects. The aim of this study was to determine whether there is presence of such a seasonal variation in hemodialysis patients. METHODS: A total of 102 patients on hemodialysis were enrolled in February 2017 (winter) for analyses of serum levels of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] and treatments for chronic kidney disease-mineral and bone disorder (CKD-MBD). The examinations were repeated in August 2017 (summer). After exclusion of patients with malignancy, loss of follow-up and missing data, 78 patients contributed to the analyses. RESULTS: Serum level of 25(OH)D, but not that of 1,25(OH)2D, was significantly lower in winter (14.0 ng/mL) than in summer (15.5 ng/mL), though there was no significant difference in regimen for CKD-MBD treatment including vitamin D receptor activators (VDRAs) between the two seasons. Serum intact parathyroid hormone level tended to be higher and alkaline phosphatase was significantly higher in winter than in summer. Linear mixed-effects model analysis showed that level of 25(OH)D, but not that of 1,25(OH)2D, was significantly associated with season (winter and summer) after adjustment of age, sex, dialysis vintage, albumin level and use of drugs for CKD-MBD. CONCLUSION: Serum 25(OH)D has a seasonal variation, being lower in winter than in summer, independent of CKD-MBD treatment including treatment with VDRAs in Japanese hemodialysis patients. The impact of the seasonal variation on risk of vitamin D deficiency and its effect on prognosis remain to be investigated.

Association between diuretic administration before diagnosis and incidence of acute kidney injury in patients with minimal change disease: A single-center observational study.

ABSTRACT: We examined the association between diuretic administration before the diagnosis of minimal change disease and the incidence of acute kidney injury. Moreover, we examined whether the use of diuretics affected the time to complete remission in adults with such disease.The present study was a single-center, retrospective, observational cohort study. We included 107 patients with biopsy-proven minimal change disease who were treated at a tertiary referral center in Japan between January 1, 2000 and March 31, 2019. All biopsy specimens were examined by a board-certified renal pathologist. The patients were considered to have minimal change disease when the kidney biopsy specimen had no glomerular lesions or only mild focal mesangial prominence (not exceeding 3 or 4 cells per segment) by light microscopy and/or foot process effacement by electron microscopy. Logistic regression and Kaplan-Meier curve analyses were performed, comparing the data of patients who received diuretics or not.The median age was 47 (28-66) years, 52% of patients were women, and the median proteinuria dosage was 8.3 (5.3-11.2) g/d. When minimal change disease was diagnosed, 27% of patients were taking diuretics. Within 30 days after the diagnosis, acute kidney injury occurred in 27% of patients. On multivariable logistic regression analysis, the use of diuretics was significantly associated with a higher risk of acute kidney injury. The use of diuretics was also associated with a longer time to complete remission.Diuretic administration can be associated with an elevated acute kidney injury risk and longer remission time in adult patients with newly diagnosed minimal change disease.

Association Between Renal Adverse Effects and Mortality in Patients With Hepatocellular Carcinoma Treated With Lenvatinib.

BACKGROUND/AIM: Lenvatinib, a multitargeted tyrosine kinase inhibitor, was recently approved for hepatocellular carcinoma (HCC) treatment in Japan; however, the association between proteinuria following lenvatinib administration in HCC patients and early mortality is unknown. This study aimed to examine the association between nephrotic-range proteinuria (NRP) and mortality and evaluated the risk factors for NRP among Japanese HCC patients treated with lenvatinib. PATIENTS AND METHODS: We retrospectively analyzed 45 consecutive patients receiving lenvatinib from 2018-2019. Primary outcome was overall survival. Cox proportional hazards regression was used to evaluate the association between NRP and overall survival. Logistic regression analyses were used to identify NRP risk factors after lenvatinib initiation. RESULTS: The median age was 66 years, 56% were women, and 20% had pre-existing proteinuria. During a 1-year median follow-up, 24 died, and 5 developed NRP. Univariable logistic regression showed that pre-existing proteinuria was associated with higher NRP risk; however, the association was not significant after covariate adjustment. Following multivariable Cox analysis, NRP did not affect overall survival in advanced HCC patients receiving lenvatinib. CONCLUSION: Urinalysis findings should be monitored regularly in patients receiving lenvatinib because NRP incidence was comparable to that of prior studies. Identifying the predictors of NRP after lenvatinib initiation warrants further investigation.

Selective immunoglobulin M deficiency complicated by systemic lupus erythematosus and antiphospholipid syndrome: a case report and review of literature.

Selective immunoglobulin M deficiency (SIgMD) is the isolated absence of serum immunoglobulin M (IgM) with normal levels of other serum immunoglobulins. SIgMD is associated with infections and autoimmune diseases. While there are few reports on SIgMD complicated by systemic lupus erythematosus (SLE), there are no reports on SIgMD complicated by SLE and antiphospholipid syndrome (APS); we present the first report of this kind. A 61-year-old Japanese woman presented with microscopic hematuria and proteinuria. Clinical investigations revealed an elevated serum creatinine level, an undetectable serum IgM level, and seropositivity of antinuclear antibody, anti-Smith antibody, and double-stranded DNA antibody. Radiological investigations were unremarkable. Renal biopsy revealed focal and segmental mesangial cell proliferation; thickened glomerular capillary walls; and IgG, IgA, C3, and C1q deposition, which indicated class III (A/C) lupus nephritis (Renal Pathology Society/International Society of Nephrology classification). Furthermore, anti-CLß2GP1 antibody positivity and deep vein thrombosis were noted, which fulfilled the revised Sapporo classification criteria for the diagnosis of APS. Thus, she was diagnosed with SIgMD complicated by SLE and APS. The patient was treated with prednisolone, mycophenolate mofetil, and warfarin. After a 1-year follow-up, she achieved clinical remission of SLE and APS without infectious complications; however, the serum IgM level remained undetectable. In conclusion, SIgMD can be complicated by autoimmune disorders. Although rare, we recommend that SLE and APS be considered in patients with SIgMD who present with hematuria, proteinuria, and deep vein thrombosis. We also recommend measuring the titers of antinuclear antibodies, double-stranded DNA antibodies, and anti-CLß2GP1 antibodies.

Incidence and risk factors of acute kidney injury, and its effect on mortality among Japanese patients receiving immune check point inhibitors: a single-center observational study.

BACKGROUND: Immune checkpoint inhibitors (ICPis) are associated with multi-organ immune-related adverse effects. Here, we examined the incidence rate, recovery rate, and risk factors of acute kidney injury complicated with ICPis (ICPi-AKI) and evaluted the association between ICPi-AKI and mortality in Japanese patients. METHODS: We analyzed 152 consecutive patients receiving ICPis between 2015 and 2019. A logistic regression analysis was performed to identify risk factors for ICPi-AKI incidence and Cox regression analysis was performed to evaluate the association between ICPi-AKI and mortality. RESULTS: The mean patient age was 67 ± 10 years, with the median baseline serum creatinine level of 0.78 mg/dL. Twenty-seven patients (18%) developed ICPi-AKI, and 19 (73%) of them recovered. Pembrolizumab use and liver diseases were significant risk factors for the ICPi-AKI incidence. During the follow-up, 85 patients (59%) died, 17 patients (63%) with ICPi-AKI and 68 (54%) patients without ICPi-AKI, respectively. The ICPi-AKI incidence was not independently associated with mortality (adjusted hazard ratio, 0.85; 95% confidence intervals, 0.46-1.61). CONCLUSIONS: Our finding suggest that pembrolizumab use and liver diseases are associated with a higher risk of ICPi-AKI development, but ICPi-AKI did not affect mortality. Future multi-center studies are needed to develop optimal management and prevention strategies for this complication in patients receiving ICPis.

Association between Functional Independence Measure and mortality in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis: A single-center observational study.

OBJECTIVES: Previous studies have identified several predictors of mortality in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). However, functional dependence as a predictor of mortality has never been reported. In this study, we investigated whether Functional Independence Measure (FIM) was associated with mortality in AAV patients. METHODS: We analyzed 52 adults with biopsy-proven AAV in Teine Keijinkai Medical Center between January 2000 and March 2019. Adjusted Cox regression analyses were conducted to evaluate the association between three FIM-based groups and all-cause mortality. Estimates were calculated as hazard ratios with 95% confidence intervals (95% CIs). RESULTS: During a median follow-up of 2.3 years (interquartile range, 0.7-4.6 years), death occurred in 15 patients (29%). Compared to the highest-FIM group (91-126 points), the adjusted hazard ratios for the intermediate- (55-90 points) and lowest-FIM (18-54 points) groups were 3.59 (95% CIs, 0.40-32.0) and 15.7 (95% CIs, 2.07-119) for all-cause mortality, respectively. In addition, the lower-FIM groups were associated with higher mortality (p=.0179). CONCLUSION: This study suggested that the FIM score is a predictor of all-cause mortality in AAV patients. Future studies will have to investigate whether FIM assessment leads to better outcomes.

Significance of urinary fatty acid-binding protein 4 level as a possible biomarker for the identification of minimal change disease in patents with nephrotic-range proteinuria.

BACKGROUND: Fatty acid-binding protein 4 (FABP4), but not FABP1 (liver-type FABP), is ectopically induced in injured glomerular endothelial cells, and urinary FABP4 (U-FABP4) level is associated with proteinuria and renal dysfunction in a general population. METHODS: The clinical significance of U-FABP4 was investigated in 81 patients (male/female: 43/38, age: 57 ± 17 years) who underwent kidney biopsy. RESULTS: U-FABP4 was negatively correlated with estimated glomerular filtration rate (eGFR) (r = - 0.56, P < 0.01) and was positively correlated with age, blood pressure, triglycerides, proteinuria (r = 0.58, P < 0.01), plasma FABP4 and urinary FABP1 (U-FABP1) (r = 0.52, P < 0.01). Multivariable regression analysis showed that eGFR, proteinuria and U-FABP1 were independent predictors of U-FABP4. The level of U-FABP4, but not that of proteinuria, eGFR or U-FABP1, in minimal change nephrotic syndrome (MCNS) was significantly lower than the level in membranous nephropathy (MN) and that in diabetic nephropathy. Receiver operating characteristic curve analysis indicated that U-FABP4 level ≤ 0.78 µg/gCr predicted MCNS in patients who had nephrotic-range proteinuria with a high level of accuracy. When divided by the median value of U-FABP4 at baseline in 33 of the 81 patients who could be followed up, the yearly change (post-pre) in eGFR in the low U-FABP4 group was significantly greater than that in the high U-FABP4 group (median: 11.0 vs. -5.0 mL/min/1.73m2/year). CONCLUSIONS: U-FABP4 level is independently associated with proteinuria and renal dysfunction in patients with glomerular kidney disease. A low U-FABP4 level may predict MCNS in patients with nephrotic syndrome and would be a useful biomarker for differential diagnosis of MCNS and MN, which are common causes of nephrotic syndrome.

Association of blood pressure with mortality in hemodialysis patients with a tunneled cuffed catheter: A single-center observational study.

The use of tunneled cuffed catheters (TCCs) for permanent blood access is increasing as the hemodialysis population ages. However, the higher mortality and complication rates associated with their use have been significant concerns. This single-center observational cohort study aimed to investigate clinical factors affecting mortality and complications in Japanese hemodialysis patients with a TCC.We enrolled 64 consecutive patients receiving hemodialysis through a TCC between 2012 and 2019. The primary outcome was all-cause mortality and the secondary outcome was the incidence of catheter-related complications at 2 years. Cox proportional hazards models were used to examine variables associated with these outcomes.At 2 years, death from any cause and catheter-related complications occurred in 27/64 (42%) and 23/64 (36%) patients, respectively. There were 14 bacteremia events, 7 catheter obstructions, and 8 instances of restricted blood flow. Multivariate analysis showed that systolic blood pressure (SBP) < 100 mm Hg at the time of catheter insertion was associated with higher all-cause mortality (hazard ratio, 2.59; 95% confidence interval, 1.05-6.41) and catheter-related complications (hazard ratio, 2.57; 95% confidence interval, 1.52-22.2). The Kaplan-Meier analyses also showed that patients with SBP <100 mm Hg had higher mortality (P = .001) and a higher incidence of catheter-related complications (P = .0068).SBP <100 mm Hg at the time of catheter insertion is associated with mortality and catheter-related complications in hemodialysis patients using a TCC. Further multi-center studies are required to validate our results.

Gastrointestinal bleeding is associated with renal prognosis in adult patients with IgA vasculitis with nephritis.

BACKGROUND: Although the prediction of renal prognosis in patients with IgA vasculitis with nephritis (IgAVN) is important, the association between gastrointestinal bleeding (GIB) and its renal prognosis is unknown. This study investigated the effect of GIB on the progression to end-stage kidney disease (ESKD) in patients with IgAVN. METHODS: We compared the clinicopathological findings at diagnosis, therapy, and clinical outcomes between 10 patients with GIB and 20 patients without GIB in 30 patients with IgAVN aged ≥18 years at the renal biopsy. The primary outcome was the incidence of ESKD. Secondary outcomes included clinical remission and all-cause mortality. The outcomes and factors affecting the progression to ESKD were evaluated using the Kaplan-Meier method with log-rank test and Cox proportional hazards models. RESULTS: End-stage kidney disease, clinical remission, and deaths from any related cause occurred in 6, 17, and 2 patients, respectively. In Kaplan-Meier analyses, the GIB group showed a higher incidence of ESKD (50% vs 5%, P = .003) and a lower incidence of clinical remission (20% vs 75%, P = .003). Although the numbers were not statistically significant, this group tended to have a greater number of deaths than the non-GIB group (7% vs 0%, P = .07). In a multivariable Cox model adjusted for hypertension and urinary proteinuria, GIB could not demonstrate a significant association with ESKD (hazard ratio, 4.51; 95% confidence interval, 0.39-52.7; P = .23). CONCLUSION: IgAVN with GIB has worse renal outcome, but GIB does not have a statistically significant association with progression to ESKD.

Intradialytic exercise in the treatment of social frailty: a single-center prospective study-preliminary results during the unexpected COVID-19 pandemic.

BACKGROUND: Social frailty-the lack of a connection to society and infrequent social activities-has been reported to be associated with future declines in physical function in elderly individuals. This study aimed to evaluate both the association of social frailty with the physical function and the efficacy of intradialytic exercise as a therapy for social frailty among hemodialysis patients. METHODS: All 16 outpatient hemodialysis patients in the hemodialysis department of a single medical center were enrolled in this single-center prospective single-arm interventional study. Patients received five questions which asked about going out infrequently, lack of visiting friends, feeling unhelpful to friends or family, living alone, and lack of talking with someone. Those to whom two or more of the above were applicable were categorized as socially frail. All patients were placed into exercise therapy to be performed during their thrice-weekly hemodialysis visits. Participants' physical function (walking speed), muscle strength (grip strength), muscle mass (appendicular skeletal muscle mass index), and social frailty were evaluated at baseline and after 3 months of therapy. RESULTS: Four (25%) of the 16 participants (median age 71.5 years, 8 women) were categorized as being socially frail. In comparison to the non-socially frail group (non-SF), the socially frail group (SF) had a significantly lower walking speed (0.70 ± 0.12 m/s vs 1.15 ± 0.26 m/s, p = 0.005) and significantly worse performance on the Short Physical Performance Battery. Three months of intradialytic exercise therapy significantly improved their walking speed, from 1.04 ± 0.30 m/s to 1.16 ± 0.29 m/s (p = 0.003). intradialytic exercise therapy significantly improved walking speed in both the SF group and the non-SF group. The 2019 coronavirus disease pandemic unexpectedly occurred in the middle of the intervention period of this study, and although it was not statistically significant, the number of socially frail individuals among our participants increased to seven (43.8%, p = 0.248). CONCLUSIONS: Social frailty was associated with reduced physical function among hemodialysis patients. Intradialytic exercise therapy improved physical function regardless of the presence of social frailty. TRIAL REGISTRATION: UMIN-CTR, UMIN-CTR000038313. Registered November 1, 2019, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000043639.

Unusual manifestation of monoclonal gammopathy of undetermined significance: a false serum creatinine elevation.

A 72-year-old Japanese man with diabetes mellitus and hypertension presented with an acutely elevated serum creatinine level, from 1.02 to 4.13 mg/dL over 2 months as measured by the enzymatic method by pure-auto S CRE-N®. Renal biopsy could not identify the etiology of the elevating sCr. However, an elevated total protein level (8.2 g/dL) and lowering of the BUN and sCr ratio from 14.5 to 2.7 were found, and bone marrow biopsy showed less than 10% lymphoplasmacytic infiltration, compatible with monoclonal gammopathy of undetermined significance. The diagnosis of a false serum creatinine elevation due to monoclonal gammopathy of undetermined significance was confirmed with the serum cystatin C level at 1.05 mg/dL and the creatinine level of 0.97 mg/dL using Shikarikid-S CRE® method. Although cases of monoclonal gammopathy of undetermined significance with a false serum creatinine elevation as an initial presentation are rare, this condition should be considered in patients with paraproteinemia; measuring the renal function using cystatin C is important in such patients.

Palmoplantar pustulosis and IgA nephropathy.

We present a case of IgA nephropathy complicated with palmoplantar pustulosis. The skin lesion improved with tonsillectomy. The purposes of this article were to aid physicians in understanding that (a) IgA nephropathy should be considered in patients with palmoplantar pustulosis and (b) patients with these diseases should be referred to otolaryngology specialists for tonsillectomy.

Immunoglobulin A nephropathy secondary to Wilson's disease: a case report and literature review.

Immunoglobulin A nephropathy is the most common primary glomerulonephritis worldwide, and it can be associated with liver disease. However, cases of Immunoglobulin A nephropathy secondary to Wilson's disease are very rare. A 20-year-old Japanese man presented with microscopic hematuria, proteinuria, and renal dysfunction. A renal biopsy showed mesangial cell proliferation, immunoglobulin A deposition, and electron-dense deposit in the mesangial areas, all of which are consistent with Immunoglobulin A nephropathy. Computed tomography of the abdomen showed liver atrophy and splenomegaly, and the diagnosis of Wilson's disease was confirmed with decreased serum ceruloplasmin levels, increased urinary copper excretion, Kayser-Fleischer rings and copper deposition in the liver biopsy. The patient was treated successfully with trientine hydrochloride and zinc acetate and showed improvement in renal manifestations. Wilson's disease is a rare cause of secondary Immunoglobulin A nephropathy. We recommend that Wilson's disease should be considered the cause of secondary Immunoglobulin A nephropathy in juvenile patients with hematuria, proteinuria, and splenomegaly and suggest measuring the serum ceruloplasmin concentrations, urinary copper excretion, and evaluating Kayser-Fleischer rings in these patients.

Unexpected high plasma xanthine oxidoreductase activity in female subjects with low levels of uric acid.

Hypouricemia is a high-risk factor of exercise-induced acute kidney injury (EIAKI) probably through a lack of an antioxidant effect of uric acid. Xanthine oxidoreductase (XOR) is an enzyme that catalyzes the formation of uric acid from hypoxanthine and xanthine, leading to an increase in superoxide and reactive oxygen species. Activation of XOR has been proposed to promote oxidative stress-related tissue injury. We measured plasma XOR activity by a sensitive and accurate assay using a combination of liquid chromatography and triple quadrupole mass spectrometry in subjects with relatively low levels of uric acid (≤4.0 mg/dL) who were recruited from 627 subjects (male/female: 292/335) in the Tanno-Sobetsu Study, a population-based cohort. The numbers of subjects with uric acid ≤4.0 mg/dL, ≤3.0 mg/dL and ≤2.0 mg/dL were 72 (11.5%, male/female: 5/67), 13 (2.1%, all females) and 2 (0.3%, both females), respectively. Plasma XOR activities in 5 male subjects were below the median value of the 292 male subjects. In 12 (17.9%) of the 67 female subjects with uric acid ≤4.0 mg/dL, plasma XOR activities were above the upper quartile value of the 335 female subjects. Eleven of the 12 female subjects with high plasma XOR activity and a low uric acid level had liver dysfunction and/or insulin resistance. In conclusion, unexpected high plasma XOR activities were found in some female subjects with relatively low levels of uric acid. Measurement of plasma XOR activity may help to identify hypouricemic patients with a high risk for EIAKI.