Granulomatosis with polyangiitis presenting as a solitary renal mass: a case report.

BACKGROUND: Granulomatosis with polyangiitis (GPA) is characterized by necrotizing granulomatous vasculitis involving small-sized vessels in the upper airways, lower airways, and kidneys. Renal pathology is usually characterized by focal segmental necrotizing glomerulonephritis, which often leads to rapidly progressive renal failure. This type of renal involvement is usually unapparent on radiography. The presence of a renal mass in a patient with GPA, although extremely rare, is recognizable. Herein, we report a rare case of GPA presenting as a solitary renal mass and present a review of the literature. CASE PRESENTATION: A 75-year-old woman presented with a solitary right kidney mass measuring 4 × 3.5 cm detected by enhanced computed tomography. There was no history of sinusitis, rhinitis, cough, or pneumonia suggestive of systemic GPA. Nephrectomy was performed based on the suspicion of renal cell carcinoma or malignant lymphoma. Three months later, she was admitted because her serum creatinine levels increased from 54.81 µmol/L to 405.76 µmol/L accompanied by a high C-reactive protein level of 159 mg/L. Anti-neutrophil cytoplasmic antibodies against myeloperoxidase and anti-proteinase 3 were negative. Histological examinations of the solitary renal mass revealed necrotizing granulomatous arteritis in the cortex and medullary vasa recta, surrounded by interstitial fibrosis, and focal segmental necrotizing glomerulonephritis in the localized lesion; however, signs of vasculitis were not observed in areas other than the solitary mass. Therefore, the patient was diagnosed with granulomatosis with polyangiitis (GPA). Despite treatment with prednisolone (30 mg/day), the patient developed oliguria with an elevation of her serum creatinine level to 583.44 µmol/L, which required hemodialysis within one month after the initiation of steroid therapy. The patient could successfully discontinue hemodialysis 21 months later, following a decrease in her serum creatinine level to 251.06 µmol/L. CONCLUSIONS: GPA should be considered as one of the differential diagnoses of a solitary renal mass. Furthermore, patients with solitary renal masses associated with GPA may exhibit a favorable response to steroid or immunosuppressive treatment.

Tubulointerstitial nephritis: a biopsy case series of 139 Japanese patients.

BACKGROUND: Tubulointerstitial nephritis (TIN) is an important cause of acute kidney injury (AKI) and advanced CKD. Only a limited number of studies have reported etiology-based differences in the clinical and/or histopathological properties and kidney outcomes of the biopsy-proven TIN. METHODS: Patients with biopsy-proven TIN identified from 2005 to 2016 in five hospitals were categorized based on the etiologies and were retrospectively analyzed in relation to the clinicopathological findings and kidney outcomes. RESULTS: Among 4815 biopsy cases screened, 153 Japanese TIN patients were identified, of whom 139 patients with ≥ 6 months of follow-up data (median 58 years old, 45.3% female, median 31.5 months follow-up) were further analyzed. TIN was drug-induced in 32.4%, autoimmune-related in 24.5%, of unknown etiology in 27.3% and other disease-related in 15.8%. Non-steroidal anti-inflammatory drugs and antibiotics were major causative drugs in drug-induced TIN, and IgG4-related disease, Sjögren's syndrome and sarcoidosis were common in autoimmune-related TIN. Among etiology groups, drug-induced TIN showed advanced AKI with elevated serum creatinine (sCr) and increased C-reactive protein levels at the diagnosis. TIN patients with autoimmune diseases showed less-severe AKI, but were more frequently treated with corticosteroids than others. Tubulointerstitial injury expansion in biopsy specimens was comparable among the groups. Complete or partial kidney function recovery at 6 months was more frequent in drug-induced and autoimmune-related TIN than in others. sCr levels at 6 months were similar among the groups. CONCLUSIONS: This largest case series study of the biopsy-proven TIN in Japan provides detailed information regarding both etiology-based clinicopathological properties and kidney outcomes.

Indirect podocyte injury manifested in a partial podocytectomy mouse model.

In progressive glomerular diseases, segmental podocyte injury often expands, leading to global glomerulosclerosis by unclear mechanisms. To study the expansion of podocyte injury, we established a new mosaic mouse model in which a fraction of podocytes express human (h)CD25 and can be injured by the immunotoxin LMB2. hCD25+ and hCD25- podocytes were designed to express tdTomato and enhanced green fluorescent protein (EGFP), respectively, which enabled cell sorting analysis of podocytes. After the injection of LMB2, mosaic mice developed proteinuria and glomerulosclerosis. Not only tdTomato+ podocytes but also EGFP+ podocytes were decreased in number and showed damage, as evidenced by a decrease in nephrin and an increase in desmin at both protein and RNA levels. Transcriptomics analysis found a decrease in the glucocorticoid-induced transcript 1 gene and an increase in the thrombospondin 4, heparin-binding EGF-like growth factor, and transforming growth factor-ß genes in EGFP+ podocytes; these genes may be candidate mediators of secondary podocyte damage. Pathway analysis suggested that focal adhesion, integrin-mediated cell adhesion, and focal adhesion-phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin signaling are involved in secondary podocyte injury. Finally, treatment of mosaic mice with angiotensin II receptor blocker markedly ameliorated secondary podocyte injury. This mosaic podocyte injury model has distinctly demonstrated that damaged podocytes cause secondary podocyte damage, which may be a promising therapeutic target in progressive kidney diseases.NEW & NOTEWORTHY This novel mosaic model has demonstrated that when a fraction of podocytes is injured, other podocytes are subjected to secondary injury. This spreading of injury may occur ubiquitously irrespective of the primary cause of podocyte injury, leading to end-stage renal failure. Understanding the molecular mechanism of secondary podocyte injury and its prevention is important for the treatment of progressive kidney diseases. This model will be a powerful tool for studying the indirect podocyte injury.

Remission of proteinuria under therapeutic intervention and the renal outcomes in Japanese patients with lupus nephritis class III and IV.

AbstractsBackground: Recent studies have identified the significance of proteinuria levels after initial induction therapies on the renal outcomes in patients with proliferative lupus nephritis, but the issue has not been evaluated in Japanese patients.Methods: Based on the ISN/RPS classification, only patients diagnosed with lupus nephritis class III or IV were included. The remission of proteinuria 12 months after diagnosis, as well as the clinicopathological features at diagnosis, on renal outcomes was examined retrospectively. Renal progression was defined as a 50% decrease in the estimated glomerular filtration rate or the development of end-stage renal disease.Results: This study included 82 Japanese patients with a median follow-up period of seven years. Although all patients received intensive induction therapy, 15 patients (18%) showed progression. Proteinuric remission 12 months after diagnosis predicted a good renal outcome by multivariate analysis. A receiver-operating characteristic analysis of 38 patients whose quantitative urinary protein excretion levels at 12 months were available for analysis showed that a cut-off value of 0.8 g/day predicted renal progression most effectively. Neither the renal function nor proteinuria level at diagnosis were associated with the renal outcomes.Conclusion: In Japanese patients with lupus nephritis class III or IV, proteinuria levels after 12 months under intensive therapy predicted renal outcomes more accurately than did factors identified at diagnosis.

Global polysome analysis of normal and injured podocytes.

Podocyte injury is a key event for progressive renal failure. We have previously established a mouse model of inducible podocyte injury (NEP25) that progressively develops glomerulosclerosis after immunotoxin injection. We performed polysome analysis of intact and injured podocytes utilizing the NEP25 and RiboTag transgenic mice, in which a hemagglutinin tag is attached to ribosomal protein L22 selectively in podocytes. Podocyte-specific polysomes were successfully obtained by immunoprecipitation with an antihemagglutinin antibody from glomerular homogenate and analyzed using a microarray. Compared with glomerular cells, 353 genes were highly expressed and enriched in podocytes; these included important podocyte genes and also heretofore uncharacterized genes, such as Dach1 and Foxd2. Podocyte injury by immunotoxin induced many genes to be upregulated, including inflammation-related genes despite no infiltration of inflammatory cells in the glomeruli. MafF and Egr-1, which structurally have the potential to antagonize MafB and WT1, respectively, were rapidly and markedly increased in injured podocytes before MafB and WT1 were decreased. We demonstrated that Maff and Egr1 knockdown increased the MafB targets Nphs2 and Ptpro and the WT1 targets Ptpro, Nxph3, and Sulf1, respectively. This indicates that upregulated MafF and Egr-1 may promote deterioration of podocytes by antagonizing MafB and WT1. Our systematic microarray study of the heretofore undescribed behavior of podocyte genes may open new insights into the understanding of podocyte pathophysiology.

A grading system that predicts the risk of dialysis induction in IgA nephropathy patients based on the combination of the clinical and histological severity.

Histological classification is essential in the clinical management of immunoglobulin A nephropathy (IgAN). However, there are limitations in predicting the prognosis of IgAN based on histological information alone, which suggests the need for better prognostic models. Therefore, we defined a prognostic model by combining the grade of clinical severity with the histological grading system by the following processes. We included 270 patients and explored the clinical variables associated with progression to end-stage renal disease (ESRD). Then, we created a predictive clinical grading system and defined the risk grades for dialysis induction by a combination of the clinical grade (CG) and the histological grade (HG). A logistic regression analysis revealed that the 24-h urinary protein excretion (UPE) and the estimated glomerular filtration rate (eGFR) were significant independent variables. We selected UPE of 0.5 g/day and eGFR of 60 ml/min/1.73 m2 as the threshold values for the classification of CG. The risk of progression to ESRD of patients with CG II and III was significantly higher than that of patients with CG I. The patients were then re-classified into nine compartments based on the combination of CG and HG. Furthermore, the nine compartments were grouped into four risk groups. The risk of ESRD in the moderate, high, and super-high-risk groups was significantly higher than that in the low-risk group. Herein, we are giving a detailed description of our grading system for IgA nephropathy that predicted the risk of dialysis based on the combination of CG and HG.

Forced expression of vascular endothelial growth factor-A in podocytes decreases mesangial cell numbers and attenuates endothelial cell differentiation in the mouse glomerulus.

BACKGROUND: Glomerular podocyte-derived vascular endothelial growth factor (VEGF) is indispensable for the migration and proliferation of glomerular endothelial cells. In contrast, podocyte-specific Vegf overexpression leads to the collapse of glomerular tufts; however, the mechanisms underlying this outcome have not yet been reported. METHODS: To further clarify the effects of elevated levels of Vegf expression on glomerular cells, we established a dual transgenic mouse line in which Vegf was exclusively and inducibly expressed in podocytes under the control of the "Tet-on system" (Podocin-rtTA/TetO-Vegf164 mice). RESULTS: Macroscopic and microscopic examination of Podocin-rtTA/TetO-Vegf164 animals following Vegf induction identified the presence of prominent red bloody spots. In addition, the endothelial cell number was increased along with enlargement of the subendothelial spaces. We also observed impaired endothelial fenestrations and aberrant plasmalemmal vesicle-associated protein-1 (PV-1) expression. In contrast, the mesangial cell number markedly decreased, resulting in a glomerular tuft intussusceptive splitting defect. Furthermore, whereas platelet-derived growth factor-B (PDGF-B) expression in the glomerular cells of Podocin-rtTA/TetO-Vegf164 mice was not decreased, phospho-PDGF receptor immunoreactivity in the mesangial cells was significantly decreased when compared to wild-type animals. CONCLUSION: Taken together, the results of this study indicated that the upregulation of podocyte VEGF decreased the number of mesangial cells, likely owing to inhibition of PDGF-B-mediated signaling.

Maternally inherited diabetes and deafness complicated by mesangial galactose-deficient IgA1 deposits: a case report.

BACKGROUND: Maternally inherited diabetes and deafness (MIDD), a mitochondrial genetic disorder, typically affects the kidneys and results in end-stage renal disease. Early diagnosis of MIDD is challenging when renal manifestations precede other key clinical features such as diabetes and deafness and/or when the disease is complicated by other renal pathologies. CASE PRESENTATION: Here, we present the case of a 33-year-old Japanese woman who had initially been diagnosed with IgA nephropathy but was found to have MIDD 6 years later. Two renal biopsies were conducted six years apart. While assessment of the first biopsy specimen with the monoclonal antibody (KM55) revealed mesangial IgA deposits (containing the galactose-deficient IgA1 variant [Gd-IgA1]), examination of the second specimen showed no mesangial IgA deposits and newly-developed glomerular global scleroses and tubular damage. Granular swollen epithelial cells (GSECs), characterised by abnormal mitochondria, were observed among the tubules and collecting ducts in both biopsy specimens. Mitochondrial DNA analysis revealed an m.3243A > G mutation. CONCLUSIONS: We rediscovered the usefulness of GSECs as a pathologically distinctive feature of mitochondrial nephropathy and reviewed the literature regarding MIDD complicated by mesangial IgA deposition. Furthermore, we demonstrate that the mesangial IgA deposits in this patient consisted of the galactose-deficient IgA1 variant. The monoclonal antibody (KM55) might be a useful tool to distinguish IgAN from latent IgA deposits.

Circadian blood pressure abnormalities in patients with primary nephrotic syndrome.

BACKGROUND: Only a few studies have evaluated the abnormalities of ambulatory blood pressure (ABP) in patients with nephrotic syndrome (NS). METHODS: The 24-h ABPs were measured in primary NS patients with acute onset of disease and analyzed in relation to the clinical variables. RESULTS: Our subjects comprised 21 patients: 17 with minimal change disease and 4 with focal segmental glomerulosclerosis. Of these patients, 8 (38%) had daytime hypertension, 13 (62%) had nighttime hypertension, and 13 (62%) were non-dippers (nighttime-to-daytime ratio of ABP: NDR > 0.9). The serum sodium level was correlated with the average 24-h ABP and NDR, after adjustment for other clinical variables, such as the increase in body weight, serum albumin level, and urinary protein excretion. The data from repeated ABP measurements, before and after the achievement of remission, showed a marked decrease in the average 24-h ABP after remission. Furthermore, change in the serum sodium level was significantly correlated with the change in NDR. CONCLUSION: These results suggest that alteration in renal handling of sodium and water, which might be reflected in serum sodium level, is involved in the abnormality of circadian blood pressure in primary NS patients.

Pathological sub-analysis of a multicenter randomized controlled trial of tonsillectomy combined with steroid pulse therapy versus steroid pulse monotherapy in patients with immunoglobulin A nephropathy.

BACKGROUND: The IgA nephropathy (IgAN) Study Group in Japan conducted a multicenter, randomized, controlled trial of tonsillectomy with steroid pulse therapy (TSP) versus steroid pulse monotherapy in patients with IgAN (UMIN Clinical Trial Registry Number; C000000384). The effects of therapies in relation to pathological severity were analyzed in this study. METHODS: The patients with IgAN, urinary protein 1.0-3.5 g/day, serum creatinine of 1.5 mg/dl or less were randomly assigned to receiving TSP (Group A) or steroid pulses alone (Group B). The primary endpoint was the disappearance of proteinuria and/or hematuria. Twenty-six biopsies in Group A and 33 in Group B were available. The histological grades (HG) according to the percentage of glomeruli with crescent or sclerosis and the Oxford classification were analyzed. RESULTS: The patients in Group A had a 4.32- to 12.1-fold greater benefit of disappearance of proteinuria and 3.61- to 8.17-fold greater benefit of clinical remission (disappearance of proteinuria and hematuria) than those in Group B in patients with HG2-3, acute lesions (cellular or fibrocellular crescent) affecting more than 5 % of glomeruli, chronic lesions (fibrous crescents or sclerosis) affecting more than 20 % and S1. In contrast, odds ratios for disappearance of proteinuria or clinical remission in Group A to Group B were not significant in patients with HG 1, acute lesion in 5 % or less of glomeruli, chronic lesion in 20 % or less and S0. The disappearance of hematuria showed no relation to pathological severity. CONCLUSION: TSP might be better employed according to the pathological severity.

Clinicopathological characteristics of patients with immunoglobulin A nephropathy showing acute exacerbations after favorable long-term clinical courses.

BACKGROUND: Sometimes, acute and progressive proteinuria increases occur in patients with IgA nephropathy (IgAN) after favorable long-term clinical courses of >10 years, but their clinical and histological characteristics are not well understood. METHODS: We retrospectively selected 20 IgAN patients who had been followed for >10 years after their initial biopsies ((1st)Bx) and underwent second biopsies ((2nd)Bx), because their proteinuria increased to >1 g/day. Eight patients with acute exacerbations (Group A) showed acute proteinuria increases after long periods of mild proteinuria. Their clinicopathological characteristics were analyzed as a case series and were compared with those in Group B that comprised 12 patients with persistent proteinuria. RESULTS: Group A experienced acute proteinuria increases and significant hematuria increases compared with the -1-year (P = 0.006) and -3-year (P = 0.010) time points before the (2nd)Bx, which contrasted to the clinical course in Group B. In Group A, glomerulosclerosis (GS) and the arteriosclerosis score did not differ between the (2nd)Bx and the (1st)Bx, and most patients (88 %) showed cellular and/or fibrocellular crescents within the (2nd)Bx. Compared with Group B, the (2nd)Bx revealed that the percentage of cellular and/or fibrocellular crescents (P = 0.001) was significantly higher, whereas the percentage of GS (P = 0.012) and the arteriosclerosis score (P = 0.020) were significantly lower in Group A. CONCLUSION: Rapid proteinuria and hematuria increases, and acute histological lesions characterize acute exacerbations in IgAN after favorable long-term clinical courses.

Reduction of proteinuria by therapeutic intervention improves the renal outcome of elderly patients with IgA nephropathy.

BACKGROUND: The number of elderly patients with IgA nephropathy (IgAN) is increasing in parallel with the increased longevity in the general population. However, information is limited regarding the characteristics of such patients. METHODS: IgAN patients who were ≥60 years of age at diagnosis were retrospectively analyzed. The clinicopathological features at biopsy, therapies during the follow-up period, renal outcomes and extrarenal complications were evaluated. RESULTS: The characteristics of a total of 87 patients were as follows (mean values): 65 years of age, an eGFR of 47 mL/min/1.73 m2, and urinary protein excretion (UPE) of 1.9 g/day. In the initial 1-year follow-up period, UPE decreased from 2.4 to 0.4 g/day in patients treated with corticosteroids and 1.4 to 0.8 g/day in patients treated with conservative therapies, including renin-angiotensin system blockade. During the observation period, 26 % of the patients who received corticosteroids and 38 % of the patients treated with conservative therapies showed a ≥30 % decrease in their eGFR or reached end-stage renal disease. In the analysis of all patients, UPE at 1 year after the diagnosis was identified to be an independent predictor of the subsequent loss of renal function. However, neither corticosteroid therapy nor conservative therapies was identified to be an independent valuable. There was no significant difference in the incidence of the extrarenal complications between patients treated with corticosteroids and those with conservative therapies. CONCLUSION: In elderly IgAN patients, the reduction of proteinuria by therapeutic interventions may lead to better renal outcomes without causing severe extrarenal complications.

Tonsillectomy reduces recurrence of IgA nephropathy in mesangial hypercellularity type categorized by the Oxford classification.

BACKGROUND: In patients with IgA nephropathy (IgAN), recurrence after steroid pulse therapy is associated with reduced renal survival. However, the predictors of recurrence have not yet been clarified. METHODS: All patients who received 6-month steroid pulse therapy from 2004 to 2010 in our four affiliated hospitals and achieved a reduction of proteinuria to <0.4 g/day 1 year after treatment were retrospectively evaluated. The primary outcome was proteinuria ≥1.0 g/day during follow-up or additional antiproteinuric therapy. Two histological classifications were evaluated, the Oxford Classification with a split system and Japanese histological grades (HGs) with a lumped system. RESULTS: During a median follow-up of 3.4 years, 27 (26.7 %) of the 101 patients showed recurrence. Multivariate analysis showed that HG was the only significant predictor of recurrence, with HG 2+3+4 vs HG 1 having a hazard ratio of 7.38 (95 % confidence interval 1.52-133). Furthermore, in patients with mesangial hypercellularity according to the Oxford Classification, cumulative rate of recurrence-free survival was greater in patients with steroid therapy plus tonsillectomy compared with those who received steroid therapy alone (Log-rank test, P = 0.022). However, this association was not observed in patients without mesangial hypercellularity. CONCLUSIONS: HG is a novel predictor of recurrence after steroid pulse therapy in patients with IgAN. Moreover, the combination of steroid pulse therapy plus tonsillectomy may indicate a lower risk of recurrence in patients with mesangial hypercellularity, as defined by the Oxford Classification.

Unilateral ureteral obstruction attenuates intrarenal angiotensin II generation induced by podocyte injury.

The renal tissue renin-angiotensin system is activated in chronic kidney diseases. We previously demonstrated that intrarenal ANG II is synthesized primarily from liver-derived angiotensinogen filtered through the glomerulus and that podocyte injury increases the passage of angiotensinogen into the tubular lumen and generation of ANG II. In the present study, we tested the effect of cessation of glomerular filtration by ureteral obstruction on renal ANG II generation in kidneys with podocyte injury under two experimental conditions. Ureteral obstruction is known to activate the renin-angiotensin system in nonproteinuric kidneys. Transgenic mice expressing hCD25 in podocyte (NEP25) were injected with 1.25 or 10 ng/g body wt of LMB2, a hCD25-targeted immunotoxin, subjected to unilateral ureteral ligation on the following day, and euthanized 7 and 4 days later, respectively. In both experiments, compared with the kidney in untreated wild-type mice, renal angiotensinogen protein, as assessed by immunostaining and Western blot analysis, was increased in the contralateral unobstructed kidney. However, it was markedly decreased in the obstructed kidney. Whereas intrarenal ANG II content was increased in the contralateral kidney compared with the untreated kidney (248 ± 83 vs. 106 ± 21 and 298 ± 185 vs. 64.8 ± 20 fmol/g kidney, respectively), this increase was suppressed in the obstructed kidney (161 ± 75 and 113 ± 34 fmol/g kidney, respectively), a pattern opposite to what we expected in obstructed kidneys without podocyte injury. Thus, our study indicates that the major source of increased renal ANG II in podocyte injury is filtered angiotensinogen.

Mice are unable to endogenously regenerate podocytes during the repair of immunotoxin-induced glomerular injury.

BACKGROUND: Recent studies have reported that podocytes are postnatally generated from progenitor cells localized in Bowman's capsule or in the bone marrow. In the present study, we investigated whether or not podocyte regeneration is important in the repair of injured glomeruli after mild podocyte injury in mice. METHODS: Mild podocyte injury was induced in NEP25 mice (n = 8) by injecting an immunotoxin, LMB2 (0.625 ng/g body weight). Control mice, not injured by LMB2 injection (n = 7) was used as a comparison. Proliferating cells were labeled by continuous infusion of bromodeoxyuridine (BrdU). Podocytes, identified by nephrin, WT1 or podocin staining, that had incorporated BrdU were enumerated 4 weeks later. RESULTS: A total of 742 corpuscles were inspected in serial sections stained for BrdU and nephrin; 19% showed sclerosis. BrdU(+) cells were observed in both the glomeruli and Bowman's capsules, averaging 2.5 ± 3.1 in non-sclerotic corpuscles and 7.0 ± 5.8 in sclerotic corpuscles. Only one BrdU(+) cell was also positive for nephrin. Another cell, localized at a position consistent with its potential identification as a podocyte, was nephrin negative but had incorporated BrdU. WT1 staining similarly revealed that only two nuclei were doubly positive for BrdU and WT1. Additional 1676 corpuscles were inspected by double staining for BrdU and podocin; none were doubly positive. CONCLUSIONS: Podocytes are not replenished by proliferation of endogenous progenitor cells in mice with glomerular injury.

Keap1 inhibition attenuates glomerulosclerosis.

BACKGROUND: NFE2-related factor 2 (Nrf2) is a master regulatory transcription factor for antioxidant genes. Inhibition of its adaptor protein, Kelch-like ECH-associated protein 1 (Keap1), activates Nrf2. Podocyte injury triggers the progressive deterioration of glomerular damage toward glomerulosclerosis. We examined whether modulation of the Keap1-Nrf2 system has an impact on this process. METHODS: Nrf2 null-mutant (KO) and Keap1 hypomorphic knockdown (KD) mice were crossed with NEP25 mice, in which podocyte-specific injury can be induced by an immunotoxin. RESULTS: Thiobarbituric acid reactive substances, 8-hydroxydeoxyguanosine and phosphorylated JNK were increased in the injured NEP25 kidney. Real-time PCR revealed that Keap1 KD upregulated Nrf2 target genes, including Gclc, Gclm, Gstp1, Gstp2 and Nqo1 in the glomerulus. However, podocyte injury did not upregulate these genes in Keap1 wild-type mice, nor did it further increase the expression of those genes in Keap1 KD mice. Three weeks after the induction of podocyte injury, glomerulosclerosis was considerably more attenuated in Keap1 KD mice than in control mice (median sclerosis index, 0.27 versus 3.03, on a 0-4 scale). Keap1 KD mice also showed considerably preserved nephrin staining (median index, 6.76 versus 0.91, on a 0-8 scale) and decreased glomeruli containing desmin-positive injured podocytes (median percentage, 24.5% versus 85.8%), along with a decrease in mRNAs for Fn1, Tgfb1, Col4a4 and Col1a2. CONCLUSIONS: Thus, podocyte injury cannot effectively activate Nrf2, but Nrf2 activation by Keap1 knockdown attenuates glomerulosclerosis. These results indicate that the Nrf2-Keap1 system is a promising drug target for the treatment of chronic kidney diseases.

A multicenter randomized controlled trial of tonsillectomy combined with steroid pulse therapy in patients with immunoglobulin A nephropathy.

BACKGROUND: The study aim was, for the first time, to conduct a multicenter randomized controlled trial to evaluate the effect of tonsillectomy in patients with IgA nephropathy (IgAN). METHODS: Patients with biopsy-proven IgAN, proteinuria and low serum creatinine were randomly allocated to receive tonsillectomy combined with steroid pulses (Group A; n = 33) or steroid pulses alone (Group B; n = 39). The primary end points were urinary protein excretion and the disappearance of proteinuria and/or hematuria. RESULTS: During 12 months from baseline, the percentage decrease in urinary protein excretion was significantly larger in Group A than that in Group B (P < 0.05). However, the frequency of the disappearance of proteinuria, hematuria, or both (clinical remission) at 12 months was not statistically different between the groups. Logistic regression analyses revealed the assigned treatment was a significant, independent factor contributing to the disappearance of proteinuria (odds ratio 2.98, 95% CI 1.01-8.83, P = 0.049), but did not identify an independent factor in achieving the disappearance of hematuria or clinical remission. CONCLUSIONS: The results indicate tonsillectomy combined with steroid pulse therapy has no beneficial effect over steroid pulses alone to attenuate hematuria and to increase the incidence of clinical remission. Although the antiproteinuric effect was significantly greater in combined therapy, the difference was marginal, and its impact on the renal functional outcome remains to be clarified.

The role of a low glomerular density and being overweight in the etiology of proteinuria in CKD patients without known glomerular diseases.

BACKGROUND: Among the proteinuric patients with chronic kidney disease (CKD) who undergo a renal biopsy, we sometimes encounter those who cannot be classified as having a known primary or secondary glomerular disease. The pathogenesis and pathophysiology of these CKD patients have not been sufficiently elucidated. METHODS: We recruited 34 proteinuric patients without known glomerular diseases. The glomerular volumes (GV) of the biopsy specimens from those patients were determined by a morphometric analysis. Glomerular hypertrophy (GH) was defined as having more than 3.6 × 10(6) µm(3). The patients were divided in two groups: those with GH (Group 1) and those without GH (Group 2). We compared the clinical and pathological parameters between Group 1 and Group 2, and among the three groups of patients: non-obese, overweight and obese group. RESULTS: The patients with Group 1 had significantly higher values for the proportion of males, the body mass index (BMI), uric acid and significantly lower values for the glomerular density (GD). Of note, a multivariate regression analysis revealed that sex, the BMI and GD were significant factors correlated with the mean GV. The values for the mean GV were significantly higher in the overweight and obese groups as compared to the non-obese group, and the values for the GD were significantly lower in the obese group than in the non-obese group. CONCLUSIONS: We identified a subgroup of patients who were characterized as having a high BMI and GV, and a low GD among the proteinuric CKD patients without known glomerular diseases.