Cholesterol Crystal Embolism: Autopsy-proven Gastrointestinal Lesions, Pancreatitis, and End-stage Kidney Disease Which Developed after Undergoing Selective Abdominal Angiography.

A 78-year-old man with atherosclerosis was diagnosed with hepatocellular carcinoma by transfemoral angiography of the celiac and superior mesenteric arteries (SMA). After surgery, a serum examination revealed progressive renal failure with eosinophilia, leading to end-stage kidney disease, in addition to active gastric ulcers and pancreatitis. Cyanosis in the bilateral toes showed a cholesterol crystal embolism (CCE) in a skin biopsy. Autopsy revealed that CCE involved the arterioles of multiple organs, and its distribution was anatomically consistent with the vascular territories of the celiac artery and SMA. CCE should therefore be considered in patients presenting with multiple types of tissue damage in the vascular territories after angiography.

Polar vasculosis is associated with better kidney outcome in type 2 diabetes with biopsy-proven diabetic kidney disease: A multicenter cohort study.

AIMS/INTRODUCTION: This multicenter cohort study retrospectively assessed the association between polar vasculosis and the progression of diabetic kidney disease (DKD) in type 2 diabetes. MATERIALS AND METHODS: We enrolled 811 patients with type 2 diabetes, biopsy-proven DKD, and proteinuria (≥0.15 g/g creatinine [g/day]). The association between polar vasculosis and other kidney lesions was explored. The outcome was DKD progression defined as a composite of renal replacement therapy initiation or 50% decline in estimated glomerular filtration rate (eGFR) from baseline. RESULTS: Of the 811 cases, 677 (83.5%) had polar vasculosis. In multivariate logistic regression analysis, subendothelial widening of the glomerular basement membrane, glomerulomegaly, glomerular class in the Renal Pathology Society classification ≥IIb, vascular lesions, age, eGFR, and hemoglobin A1c were positively associated with polar vasculosis, whereas interstitial fibrosis and tubular atrophy (IFTA) was negatively associated with polar vasculosis. During a median follow-up of 5.2 years, progression of DKD occurred in 322 of 677 (7.4 events/100 person-years) and 79 of 134 (11.4 events/100 person-years) cases with and without polar vasculosis, respectively. Kaplan-Meier analysis showed that polar vasculosis was associated with lower cumulative incidences of DKD progression. Multivariate Cox regression analyses showed that polar vasculosis was associated with a lower risk of DKD progression, regardless of eGFR or proteinuria subgroups. These associations between polar vasculosis and better kidney outcome were unchanged considering all-cause mortality before DKD progression as a competing event. CONCLUSIONS: This study showed that polar vasculosis of DKD was associated with less advanced IFTA and a better kidney outcome in type 2 diabetes with proteinuria.

Intra-Brain and Plasma Levels of L-Serine Are Associated with Cognitive Status in Patients with Chronic Kidney Disease.

Introduction: The number of patients with chronic kidney disease (CKD) is increasing worldwide. Cognitive impairment is one of the comorbidities of CKD. With the increased number of aged population, novel biomarkers of impaired cognitive function are required. Intra-body profile of amino acid (AA) is reportedly altered in patients with CKD. Although some AAs act as neurotransmitters in the brain, it is not clear whether altered AA profile are associated with cognitive function in patients with CKD. Therefore, intra-brain and plasma levels of AAs are evaluated with respect to cognitive function in patients with CKD. Methods: Plasma levels of AAs were compared between 14 patients with CKD, including 8 patients with diabetic kidney disease, and 12 healthy controls to identify the alteration of specific AAs in CKD. Then, these AAs were evaluated in the brains of 42 patients with brain tumor using non-tumor lesion of the resected brain. Cognitive function is analyzed with respect to intra-brain levels of AAs and kidney function. Moreover, plasma AAs were analyzed in 32 hemodialyzed patients with/without dementia. Results: In patients with CKD, plasma levels of asparagine (Asn), serine (Ser), alanine (Ala), and proline (Pro) were increased as compared to patients without CKD. Among these AAs, L-Ser, L-Ala, and D-Ser show higher levels than the other AAs in the brain. Intra-brain levels of L-Ser was correlated with cognitive function and kidney function. The number of D-amino acid oxidase or serine racemase-positive cells was not correlated with kidney function. Moreover, the plasma levels of L-Ser are also decreased in patients with declined cognitive function who are treated with chronic hemodialysis. Conclusion: The decreased levels of L-Ser are associated with impaired cognitive function in CKD patients. Especially, plasma L-Ser levels may have a potential for novel biomarker of impaired cognitive function in patients with hemodialysis.

Membranous Nephropathy-Like Apolipoprotein E Deposition Disease with Apolipoprotein E Toyonaka and Homozygous Apolipoprotein E2/2 without Dyslipidemia, with Characteristic Electron-Dense Deposits.

Recently, several cases of novel apolipoprotein E (apoE)-related glomerular disease known as membranous nephropathy (MN)-like apoE deposition disease with apoE Toyonaka (Ser197Cys) and homozygous apoE2/2 have been reported. However, the clinical and pathological characteristics are uncertain due to the small number of reports. Here, we report an additional case with various clinical and pathological characteristics. A 28-year-old Japanese man with mild proteinuria and hematuria underwent a kidney biopsy. Examination under a light microscope revealed mesangial proliferation, mesangial matrix expansion, and segmental spike lesion. An immunofluorescence study showed no immunoglobulin or complement depositions. In the electron microscopic (EM) examination, massive deposits with various electron densities in the subepithelial, subendothelial, and paramesangial areas were more prominent than those reported in previous cases, which resembled microbubbles or microcysts on higher magnification. The glomerular basement membrane (GBM) structure was partly degenerated by these deposits. Serum triglyceride and cholesterol levels were within the normal range. However, the serum apoE concentration was significantly high, and glomerular apoE accumulation was detected in immunohistochemistry. The DNA sequence revealed apoE Toyonaka and homozygous apoE2/2 similar to that of the previous cases with MN-like apoE deposition disease. MN-like apoE deposition disease can manifest as only mild hematuria and proteinuria without dyslipidemia. Various characteristic deposits associated with GBM degeneration can be observed in the EM study.

Cyclin-dependent kinase 4-related tubular epithelial cell proliferation is regulated by Paired box gene 2 in kidney ischemia-reperfusion injury.

Paired box 2 (Pax2) is a transcription factor essential for kidney development and is reactivated in proximal tubular epithelial cells (PTECs) during recovery from kidney injury. However, the role of Pax2 in this process is still unknown. Here the role of Pax2 reactivation during injury was examined in the proliferation of PTECs using an ischemia-reperfusion injury (IRI) mouse model. Kidney proximal tubule-specific Pax2 conditional knockout mice were generated by mating kidney androgen-regulated protein-Cre and Pax2 flox mice. The degree of cell proliferation and fibrosis was assessed and a Pax2 inhibitor (EG1) was used to evaluate the role of Pax2 in the hypoxic condition of cultured PTECs (O2 5%, 24 hours). The number of Pax2-positive cells and Pax2 mRNA increased after IRI. Sirius red staining indicated that the area of interstitial fibrosis was significantly larger in knockout mice 14 days after IRI. The number of Ki-67-positive cells (an index of proliferation) was significantly lower in knockout than in wild-type mice after IRI, whereas the number of TUNEL-positive cells (an index of apoptotic cells) was significantly higher in knockout mice four days after IRI. Expression analyses of cell cycle-related genes showed that cyclin-dependent kinase 4 (CDK4) was significantly less expressed in the Pax2 knockout mice. In vitro data showed that the increase in CDK4 mRNA and protein expression induced by hypoxia was attenuated by EG1. Thus, Pax2 reactivation may be involved in PTEC proliferation by activating CDK4, thereby limiting kidney fibrosis.

Serum hemoglobin concentration and risk of renal function decline in early stages of diabetic kidney disease: a nationwide, biopsy-based cohort study.

BACKGROUND: Prognosticating disease progression in patients with diabetic kidney disease (DKD) is challenging, especially in the early stages of kidney disease. Anemia can occur in the early stages of kidney disease in diabetes. We therefore postulated that serum hemoglobin (Hb) concentration, as a reflection of incipient renal tubulointerstitial impairment, can be used as a marker to predict DKD progression. METHODS: Drawing on nationally representative data of patients with biopsy-proven DKD, 246 patients who had an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 at renal biopsy were identified: age 56 (45-63) years; 62.6% men; Hb 13.3 (12.0-14.5) g/dL; eGFR 76.2 (66.6-88.6) mL/min/1.73 m2; urine albumin-to-creatinine ratio 534 (100-1480) mg/g Crea. Serum Hb concentration was divided into quartiles: ≤12, 12.1-13.3, 13.4-14.5 and ≥14.6 g/dL. The association between serum Hb concentration and the severity of renal pathological lesions was explored. A multivariable Cox regression model was used to estimate the risk of DKD progression (new onset of end-stage kidney disease, 50% reduction of eGFR or doubling of serum creatinine). The incremental prognostic value of DKD progression by adding serum Hb concentration to the known risk factors of DKD was assessed. RESULTS: Serum Hb levels negatively correlated with all renal pathological features, especially with the severity of interstitial fibrosis (ρ = -0.52; P < 0.001). During a median follow-up of 4.1 years, 95 developed DKD progression. Adjusting for known risk factors of DKD progression, the hazard ratio in the first, second and third quartile (the fourth quartile was reference) were 2.74 [95% confidence interval (CI) 1.26-5.97], 2.33 (95% CI 1.07-5.75) and 1.46 (95% CI 0.71-3.64), respectively. Addition of the serum Hb concentration to the known risk factors of DKD progression improved the prognostic value of DKD progression (the global Chi-statistics increased from 55.1 to 60.8; P < 0.001). CONCLUSIONS: Serum Hb concentration, which reflects incipient renal fibrosis, can be useful for predicting DKD progression in the early stages of kidney disease.

Soluble receptor for advanced glycation end products protects from ischemia- and reperfusion-induced acute kidney injury.

The full-length receptor for advanced glycation end products (RAGE) is a multiligand pattern recognition receptor. High-mobility group box 1 (HMGB1) is a RAGE ligand of damage-associated molecular patterns that elicits inflammatory reactions. The shedded isoform of RAGE and endogenous secretory RAGE (esRAGE), a splice variant, are soluble isoforms (sRAGE) that act as organ-protective decoys. However, the pathophysiologic roles of RAGE/sRAGE in acute kidney injury (AKI) remain unclear. We found that AKI was more severe, with enhanced renal tubular damage, macrophage infiltration, and fibrosis, in mice lacking both RAGE and sRAGE than in wild-type (WT) control mice. Using murine tubular epithelial cells (TECs), we demonstrated that hypoxia upregulated messenger RNA (mRNA) expression of HMGB1 and tumor necrosis factor α (TNF-α), whereas RAGE and esRAGE expressions were paradoxically decreased. Moreover, the addition of recombinant sRAGE canceled hypoxia-induced inflammation and promoted cell viability in cultured TECs. sRAGE administration prevented renal tubular damage in models of ischemia/reperfusion-induced AKI and of anti-glomerular basement membrane (anti-GBM) glomerulonephritis. These results suggest that sRAGE is a novel therapeutic option for AKI.

Impact of the relationship between hemoglobin levels and renal interstitial fibrosis on long-term outcomes in type 2 diabetes with biopsy-proven diabetic nephropathy.

BACKGROUND: Progression of renal anemia has been shown to be associated with advanced renal tubulointerstitial lesions. This retrospective study investigated the impact of lower hemoglobin (Hb) levels and renal interstitial fibrosis and tubular atrophy (IFTA) on long-term outcomes in type 2 diabetes with biopsy-proven diabetic nephropathy. METHODS: A total of 233 patients were enrolled. The severity of IFTA was scored according to the classification by the Renal Pathology Society. Patients were stratified according to baseline Hb tertiles by IFTA status. The outcomes were the first occurrence of renal events (requirement for dialysis or 50 % decline in estimated glomerular filtration rate from baseline) and all-cause mortality. RESULTS: At baseline, 151 patients had severe IFTA. There were no patients who have been received erythropoiesis-stimulating agents at the time of renal biopsy. The severity of IFTA was the independent pathological factor of lower Hb levels. During the mean follow-up period of 8.6 years (maximum, 32.4 years), 119 renal events and 42 deaths were observed. Compared with the combined influence of the highest tertile of Hb and mild IFTA, the risks of renal events were higher for the middle tertile and for the lowest tertile of Hb in severe IFTA, whereas the risk of renal events was higher for the lowest tertile of Hb in mild IFTA. The risk of mortality was higher for the lowest tertile of Hb only in severe IFTA. There were significant interactions of tertile of Hb and IFTA in renal events and mortality. CONCLUSIONS: Impacts of lower Hb levels on long-term outcomes of diabetic nephropathy were greater in severe IFTA than in mild IFTA.

Two-year longitudinal trajectory patterns of albuminuria and subsequent rates of end-stage kidney disease and all-cause death: a nationwide cohort study of biopsy-proven diabetic kidney disease.

INTRODUCTION: Data on the association between longitudinal trajectory patterns of albuminuria and subsequent end-stage kidney disease (ESKD) and all-cause mortality in diabetic kidney disease (DKD) are sparse. RESEARCH DESIGN AND METHODS: Drawing on nationally representative data of 329 patients with biopsy-proven DKD and an estimated glomerular filtration rate above 30 mL/min/1.73 m2 at the time of biopsy, we used joint latent class mixed models to identify different 2-year trajectory patterns of urine albumin to creatinine ratio (UACR) and assessed subsequent rates of competing events: ESKD and all-cause death. RESULTS: A total of three trajectory groups of UACR were identified: 'high-increasing' group (n=254; 77.2%), 'high-decreasing' group (n=24; 7.3%), and 'low-stable' group (n=51; 15.5%). The 'low-stable' group had the most favorable risk profile, including the baseline UACR (median (IQR) UACR (mg/g creatinine): 'low-stable', 109 (50-138); 'high-decreasing', 906 (468-1740); 'high-increasing', 1380 (654-2502)), and had the least subsequent risk of ESKD and all-cause death among the groups. Although there were no differences in baseline characteristics between the 'high-decreasing' group and the 'high-increasing' group, the 'high-decreasing' group had better control over blood pressure, blood glucose, and total cholesterol levels during the first 2 years of follow-up, and the incidence rates of subsequent ESKD and all-cause death were lower in the 'high-decreasing' group compared with the 'high-increasing' group (incidence rate of ESKD (per 1000 person-years): 32.7 vs 77.4, p=0.014; incidence rate of all-cause death (per 1000 person-years): 0.0 vs 25.4, p=0.007). CONCLUSIONS: Dynamic changes in albuminuria are associated with subsequent ESKD and all-cause mortality in DKD. Reduction in albuminuria by improving risk profile may decrease the risk of ESKD and all-cause death.

Eight-year longitudinal study of whole blood gene expression profiles in individuals undergoing long-term medical follow-up.

Blood circulates throughout the body via the peripheral tissues, contributes to host homeostasis and maintains normal physiological functions, in addition to responding to lesions. Previously, we revealed that gene expression analysis of peripheral blood cells is a useful approach for assessing diseases such as diabetes mellitus and cancer because the altered gene expression profiles of peripheral blood cells can reflect the presence and state of diseases. However, no chronological assessment of whole gene expression profiles has been conducted. In the present study, we collected whole blood RNA from 61 individuals (average age at registration, 50 years) every 4 years for 8 years and analyzed gene expression profiles using a complementary DNA microarray to examine whether these profiles were stable or changed over time. We found that the genes with very stable expression were related mostly to immune system pathways, including antigen cell presentation and interferon-related signaling. Genes whose expression was altered over the 8-year study period were principally involved in cellular machinery pathways, including development, signal transduction, cell cycle, apoptosis, and survival. Thus, this chronological examination study showed that the gene expression profiles of whole blood can reveal unmanifested physiological changes.

The relationship between the modified National Institute of Health activity and chronicity scoring system, and the long-term prognosis for lupus nephritis: A retrospective single-center study.

BACKGROUND: The revision of International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification guidelines for lupus nephritis (LN) was suggested by a working group, who recommended a modified National Institute of Health (NIH) activity and chronicity scoring system to evaluate active and chronic LN lesions. However, whether this approach was useful for estimating long-term prognosis for LN patients is unclear. METHODS: We conducted a retrospective cohort study in Japanese subjects with biopsy-proven LN, between 1977 and 2018. Pathologic lesions were evaluated based on ISN/RPS 2003 classifications and the modified NIH scoring system. Patients were grouped by activity index (low, 0-5; moderate, 6-11; high, 12-24), and chronicity index (low, 0-2; moderate, 3-5; high, 6-12). The primary outcome was a composite of end-stage kidney disease (ESKD) or all-cause death, and the secondary outcome was ESKD alone. RESULTS: Sixty-six subjects with a median age of 31 years were included. During median follow-up (11.5 years), 15 patients reached the primary outcome: 10 had ESKD, four had died, and one had ESKD and died. Kaplan-Meier analysis showed that the cumulative primary outcome incidence increased with a higher chronicity index (log-rank trend p < 0.001). From multivariable survival analysis, moderate (hazard ratio [HR] 6.17, 95% confidence interval [CI] 1.14 to 33.20; p = 0.034) and high chronicity indices (HR 20.20, 95% CI 1.13 to 359.82; p = 0.041) were risk factors for the primary outcome. CONCLUSION: Moderate and high chronicity indices were associated with an increased ESKD risk for LN.

Anti-fibrotic potential of erythropoietin signaling on bone marrow derived fibrotic cell.

INTRODUCTION: The number of patients with end stage kidney disease (ESKD) are increasing world-side. While interstitial fibrosis (IF) is a common step for the progression to ESKD, therapeutic options for IF is still limited in clinical settings. We have reported that bone marrow-derived fibrotic cell, fibrocyte, is involved in the pathogenesis of kidney fibrosis. Also recent studies revealed that erythropoietin has protective effect on kidney diseases. However, it is unknown whether erythropoietin (EPO) inhibits fibrosis in progressive kidney injury. Therefore, we explored the impacts of EPO on kidney fibrosis with focusing on fibrocyte. METHOD: Fibrocyte was differentiated from peripheral mononuclear cells of healthy donor. Fibrocyte was stimulated with transforming growth factor beta (TGF)-ß with/without EPO treatment. Moreover, the therapeutic effect of EPO was evaluated in murine unilateral ureteral obstruction (UUO) model. RESULT: TGF-ß stimulation increased the expression of COL1 mRNA in fibrocyte. EPO signal reduced the expression of COL1 mRNA in dose dependent manner. EPO reduced mitochondrial oxidative stress and ameliorated mitochondrial membrane depolarization induced by TGF-ß stimulation. Moreover, EPO reduced the mRNA expression of mitochondria related molecules, TRAF6, in fibrocyte. In addition, the count of CD45+/αSMA + double-positive fibrocyte was decreased in the EPO-administered UUO kidneys. CONCLUSION: EPO signals function to prevent kidney fibrosis, particularly in fibrocyte. Regulating the renal accumulation of fibrocyte is a part of the anti-fibrotic functions of EPO.

Identification of candidate PAX2-regulated genes implicated in human kidney development.

PAX2 is a transcription factor essential for kidney development and the main causative gene for renal coloboma syndrome (RCS). The mechanisms of PAX2 action during kidney development have been evaluated in mice but not in humans. This is a critical gap in knowledge since important differences have been reported in kidney development in the two species. In the present study, we hypothesized that key human PAX2-dependent kidney development genes are differentially expressed in nephron progenitor cells from induced pluripotent stem cells (iPSCs) in patients with RCS relative to healthy individuals. Cap analysis of gene expression revealed 189 candidate promoters and 71 candidate enhancers that were differentially activated by PAX2 in this system in three patients with RCS with PAX2 mutations. By comparing this list with the list of candidate Pax2-regulated mouse kidney development genes obtained from the Functional Annotation of the Mouse/Mammalian (FANTOM) database, we prioritized 17 genes. Furthermore, we ranked three genes-PBX1, POSTN, and ITGA9-as the top candidates based on closely aligned expression kinetics with PAX2 in the iPSC culture system and susceptibility to suppression by a Pax2 inhibitor in cultured mouse embryonic kidney explants. Identification of these genes may provide important information to clarify the pathogenesis of RCS, human kidney development, and kidney regeneration.

Higher serum levels of autotaxin and phosphatidylserine-specific phospholipase A1 in patients with lupus nephritis.

BACKGROUND: Recent studies revealed that lysophospholipids (LPLs) and related molecules, such as autotaxin (ATX) and phosphatidylserine-specific phospholipase A1 (PS-PLA1 ), are candidates for novel biomarkers in melanoma, glaucoma and diabetic nephropathy. However, it is not clear whether serum levels of ATX/ PS-PLA1 would be associated with pathological and clinical findings of lupus nephritis (LN). METHODS: In this retrospective cohort study, serum samples were collected from 39 patients with LN and 37 patients with other glomerular diseases. The serum levels of ATX and PS-PLA1 were evaluated for an association with renal pathology and clinical phenotypes of LN. RESULTS: The serum levels of ATX and PS-PLA1 were higher in the patients with LN as compared to those with other glomerular diseases. Among the classes of LN, the patients with class IV showed the trend of lower serum levels of ATX. Moreover, the patients with lower levels of ATX exhibited higher scores of activity index (AI) and chronicity index (CI). The level of ATX tended to be negatively correlated with AI and CI. These results might be explained by the effect of treatment, because the serum levels of ATX and PS-PLA1 were inversely correlated with the daily amount of oral prednisolone. Moreover, they did not reflect the level of proteinuria or kidney survival in LN patients. CONCLUSION: Although the serum levels of ATX and PS-PLA1 were affected by the treatment, these levels were higher in the patients with LN. The potential clinical benefits of these markers need to be clarified in further studies.

Age differences in the relationships between risk factors and loss of kidney function: a general population cohort study.

BACKGROUND: Annual decline in kidney function is a widely applied surrogate outcome of renal failure. It is important to understand the relationships between known risk factors and the annual decline in estimated glomerular filtration rate (eGFR) according to baseline age; however, these remain unclear. METHODS: A community-based retrospective cohort study of adults who underwent annual medical examinations between 1999 and 2013 was conducted. The participants were stratified into different age groups (40-49, 50-59, 60-69, 70-79, and ≥ 80 years) to assess the risk for loss of kidney function. A mixed-effects model was used to estimate the association between risk factors and annual changes in eGFR. RESULTS: In total, 51,938 participants were included in the analysis. The age group of ≥80 years included 8127 individuals. The mean annual change in eGFR was - 0.39 (95% confidence interval: - 0.41 to - 0.37) mL/min/1.73 m2 per year. Older age was related to faster loss of kidney function. In the older age group, higher systolic blood pressure, proteinuria, and current smoking were related to faster loss of kidney function (p trend < 0.01, 0.03, and < 0.01, respectively). Conversely, each age group showed similar annual loss of kidney function related to lower hemoglobin levels and diabetes mellitus (p trend 0.47 and 0.17, respectively). CONCLUSIONS: Higher systolic blood pressure, proteinuria, and smoking were related to faster loss of kidney function, and a greater effect size was observed in the older participants. More risk assessments for older people are required for personalized care.

Trehalose ameliorates peritoneal fibrosis by promoting Snail degradation and inhibiting mesothelial-to-mesenchymal transition in mesothelial cells.

Peritoneal fibrosis (PF) is a severe complication of peritoneal dialysis, but there are few effective therapies for it. Recent studies have revealed a new biological function of trehalose as an autophagy inducer. Thus far, there are few reports regarding the therapeutic effects of trehalose on fibrotic diseases. Therefore, we examined whether trehalose has anti-fibrotic effects on PF. PF was induced by intraperitoneal injection of chlorhexidine gluconate (CG). CG challenges induced the increase of peritoneal thickness, ColIα1 mRNA expression and hydroxyproline content, all of which were significantly attenuated by trehalose. In addition, CG challenges induced a marked peritoneal accumulation of α-SMA+ myofibroblasts that was reduced by trehalose. The number of Wt1+ α-SMA+ cells in the peritoneum increased following CG challenges, suggesting that a part of α-SMA+ myofibroblasts were derived from peritoneal mesothelial cells (PMCs). The number of Wt1+ α-SMA+ cells was also suppressed by trehalose. Additionally, trehalose attenuated the increase of α-SMA and ColIα1 mRNA expression induced by TGF-ß1 through Snail protein degradation, which was dependent on autophagy in PMCs. These results suggest that trehalose might be a novel therapeutic agent for PF through the induction of autophagy and the suppression of mesothelial-to-mesenchymal transition in PMCs.

A case of minimal change disease after the administration of anti receptor activator of nuclear factor kappa B ligand (RANKL) monoclonal antibody: a case report.

BACKGROUND: Minimal change disease (MCD) is one of the causes of idiopathic nephrotic syndrome in adults. The pathogenesis of proteinuria in MCD has not been fully understood. Recently, it has been reported that the receptor activator of nuclear factor-kappa B (RANK)/RANK ligand (RANKL) may contribute to the podocyte biology in kidney diseases. Denosumab is a human anti-RANKL monoclonal antibody used to treat osteoporosis. Here we report a case of MCD after denosumab administration. CASE PRESENTATION: A 59-year-old male without any episodes of proteinuria was given denosumab to treat osteoporosis. Two weeks after its administration, he noticed a foamy urine and bilateral pretibial edema. Laboratory tests revealed that he had severe proteinuria (15g/g Cr), hypoproteinemia (4.0g/dL), and hypoalbuminemia (1.5g/dL). Based on the results, he was diagnosed with nephrotic syndrome. The proteinuria selectivity index was 0.05, indicating selective proteinuria. Renal biopsy showed minor glomerular abnormality with less tubulointerstitial damage, and electron microscopy showed extensive foot process effacement, indicating MCD. With all these results, glucocorticoid therapy of 50mg/day prednisolone was started. After 4weeks of treatment, the urinary protein level remains high (3.1g/g Cr). Prednisolone therapy was continued, and the levels of proteinuria decreased gradually to the range of partial remission (1.2g/g Cr) with another 7weeks of prednisolone treatment, but complete remission was not achieved. CONCLUSIONS: This might be a case wherein RANKL inhibition is associated with the pathogenesis of MCD. Further studies will be needed to elucidate the causal relationship of RANK-RANKL signaling to the pathogenesis of MCD.

Association between Unhealthy Dietary Habits and Proteinuria Onset in a Japanese General Population: A Retrospective Cohort Study.

The relationship between dietary habits and development of chronic kidney disease (CKD) is unclear. This retrospective cohort study was conducted to examine the association between unhealthy dietary habits and proteinuria onset, a key prognostic factor of CKD, among a Japanese general population aged ≥40 years. The risks of proteinuria onset were estimated based on the status of baseline unhealthy dietary habits (quick eating, late dinner, late evening snack, and skipping breakfast) compared with the status without these habits. A total of 26,764 subjects were included, with a mean follow-up period of 3.4 years. The most frequent unhealthy dietary habit was quick eating (29%), followed by late dinner (19%), late evening snack (16%), and skipping breakfast (9%). During the follow-up period, 10.6% of participants developed proteinuria. Late dinner and skipping breakfast showed an increased adjusted risk of proteinuria onset (hazard ratio (HR) 1.12, 95% confidence interval (CI) 1.02 to 1.22, and HR 1.15, 95% CI 1.01 to 1.31, respectively). Unhealthy dietary habits were not associated with changes in body mass index or waist-to-height ratio during the follow-up period. Our results suggest that late dinner and skipping breakfast are associated with higher risks for proteinuria onset.

Clinicopathological features of fast eGFR decliners among patients with diabetic nephropathy.

INTRODUCTION: The speed of declining kidney function differs among patients with diabetic nephropathy. This study was undertaken to clarify clinical and pathological features that affect the speed of declining kidney function in patients with diabetic nephropathy. RESEARCH DESIGN AND METHODS: This study was design as multicenter retrospective study. The subjects (377 patients with diabetic nephropathy diagnosed by kidney biopsy at 13 centers in Japan) were classified into three groups based on the estimated glomerular filtration rate (eGFR) declining speed. The eGFR increasing group, the control group, and the eGFR declining group were divided at 0 and 5 mL/min/1.73 m2/year, respectively. Characteristics of clinicopathological findings of declining kidney function were evaluated. RESULTS: The mean observation period of this study was 6.9 years. The control group, the eGFR increasing group, and the eGFR declining group included 81, 66, and 230 patients, respectively. The incidences of composite kidney events represented by 100 persons/year were 25.8 in the eGFR declining group and 2.0 in the eGFR increasing group. After adjustment for age, sex, systolic blood pressure, hemoglobin, and urinary albumin levels, three clinicopathological findings (urinary albumin levels, presence of nodular lesion, and mesangiolysis) were risk factors for inclusion in the eGFR declining group (the ORs were 1.49, 2.18, and 2.08, respectively). In contrast, the presence of subendothelial space widening and polar vasculosis were characteristic findings for inclusion in the eGFR increasing group (the ORs were 0.53 and 0.41, respectively). CONCLUSIONS: As well as urinary albumin elevation, nodular lesion and mesangiolysis were characteristic pathological features of patients with fast declining kidney function.

Relationship between anti-erythropoietin receptor autoantibodies and responsiveness to erythropoiesis-stimulating agents in patients on hemodialysis: a multi-center cross-sectional study.

BACKGROUND: A decreased response to erythropoiesis-stimulating agents (ESAs) leads to refractory anemia and worse prognosis in patients with chronic kidney disease. We examined the association between autoantibodies to the erythropoietin receptor (EPOR) and responsiveness to ESAs in patients on maintenance hemodialysis. METHODS: A total of 108 Japanese patients on maintenance hemodialysis at three institutions were enrolled. Sera from these patients were screened for anti-EPOR antibodies using an enzyme-linked immunosorbent assay. An ESA resistance index (ERI) was calculated, and patients in the highest ERI quartile were defined as ESA hyporesponsive. RESULTS: Anti-EPOR antibodies were detected in 11 patients (10%). Body mass index and hemoglobin, platelet, magnesium, and ferritin levels decreased with higher ERI levels. On the other hand, C-reactive protein (CRP) levels and the prevalence of anti-EPOR antibodies increased with higher ERI levels. In multivariate analysis, the presence of anti-EPOR antibodies together with CRP was a significant risk factor for ESA hyporesponsiveness. CONCLUSIONS: Anti-EPOR antibodies were detected in patients on maintenance hemodialysis, and these autoantibodies were independent factors for hyporesponsiveness to ESAs in these patients.