Comparative proteomic analysis of glomerular proteins in IgA nephropathy and IgA vasculitis with nephritis.

BACKGROUND: IgA nephropathy (IgAN) and IgA vasculitis with nephritis (IgAVN) are related glomerular diseases characterized by marked similarities in immunological and histological findings. We herein performed a comparative proteomic analysis of glomerular proteins in IgAN and IgAVN. METHODS: We used renal biopsy specimens from 6 IgAN patients without nephrotic syndrome (NS) (IgAN-I subgroup), 6 IgAN patients with NS (IgAN-II subgroup), 6 IgAVN patients with 0-8.0% of glomeruli with crescent formation (IgAVN-I subgroup), 6 IgAVN patients with 21.2-44.8% of glomeruli with crescent formation (IgAVN-II subgroup), 9 IgAVN patients without NS (IgAVN-III subgroup), 3 IgAVN patients with NS (IgAN-IV subgroup), and 5 control cases. Proteins were extracted from laser microdissected glomeruli and analyzed using mass spectrometry. The relative abundance of proteins was compared between groups. An immunohistochemical validation study was also performed. RESULTS: More than 850 proteins with high confidence were identified. A principal component analysis revealed a clear separation between IgAN and IgAVN patients and control cases. In further analyses, 546 proteins that were matched with ≥ 2 peptides were selected. The levels of immunoglobulins (IgA, IgG, and IgM), complements (C3, C4A, C5, and C9), complement factor H-related proteins (CFHR) 1 and 5, vitronectin, fibrinogen chains, and transforming growth factor-ß inducible gene-h3 were higher (> 2.6 fold) in the IgAN and IgAVN subgroups than in the control group, whereas hornerin levels were lower (< 0.3 fold). Furthermore, C9 and CFHR1 levels were significantly higher in the IgAN group than in the IgAVN group. The abundance of some podocyte-associated proteins and glomerular basement membrane (GBM) proteins was significantly less in the IgAN-II subgroup than in the IgAN-I subgroup as well as in the IgAVN-IV subgroup than in the IgAVN-III subgroup. Among the IgAN and IgAVN subgroups, talin 1 was not detected in the IgAN-II subgroup. This result was supported by immunohistochemical findings. CONCLUSIONS: The present results suggest shared molecular mechanisms for glomerular injury in IgAN and IgAVN, except for enhanced glomerular complement activation in IgAN. Differences in the protein abundance of podocyte-associated and GBM proteins between IgAN and IgAVN patients with and without NS may be associated with the severity of proteinuria.

Advanced Tertiary Lymphoid Tissues in Protocol Biopsies are Associated with Progressive Graft Dysfunction in Kidney Transplant Recipients.

BACKGROUND: Tertiary lymphoid tissues (TLTs) are ectopic lymphoid tissues found in chronically inflamed organs. Although studies have documented TLT formation in transplanted kidneys, the clinical relevance of these TLTs remains controversial. We examined the effects of TLTs on future graft function using our histologic TLT maturity stages and the association between TLTs and Banff pathologic scores. We also analyzed the risk factors for the development of TLTs. METHODS: Serial protocol biopsy samples (0 hour, 1, 6, and 12 months) without rejection were retrospectively analyzed from 214 patients who underwent living donor kidney transplantation. TLTs were defined as lymphocyte aggregates with signs of proliferation and their stages were determined by the absence (stage I) or presence (stage II) of follicular dendritic cells. RESULTS: Only 4% of patients exhibited TLTs at the 0-hour biopsy. Prevalence increased to almost 50% at the 1-month biopsy, and then slightly further for 12 months. The proportion of advanced stage II TLTs increased gradually, reaching 19% at the 12-month biopsy. Presence of stage II TLTs was associated with higher risk of renal function decline after transplantation compared with patients with no TLT or stage I TLTs. Stage II TLTs were associated with more severe tubulitis and interstitial fibrosis/tubular atrophy at 12 months and predicted poorer graft function independently from the degree of interstitial inflammation. Pretransplantation rituximab treatment dramatically attenuated the development of stage II TLTs. CONCLUSIONS: TLTs are commonly found in clinically stable transplanted kidneys. Advanced stage II TLTs are associated with progressive graft dysfunction, independent of interstitial inflammation.

Comparative proteomic analysis of glomerular proteins in primary and bucillamine-induced membranous nephropathy.

BACKGROUND: Anti-phospholipase A2 receptor autoantibody (PLA2R Ab)-associated membranous nephropathy (MN) is the most common form of primary MN (pMN). On the other hand, bucillamine (BCL), an antirheumatic drug developed in Japan, was reported to cause a rare form of secondary MN (sMN). Between these MN forms, comparative proteomic analysis of glomerular proteins has not been performed. METHODS: We used renal biopsy specimens from 6 patients with PLA2R Ab (+) pMN, 6 patients with PLA2R Ab (‒) pMN, 6 patients with BCL-induced sMN, and 5 control cases (time 0 transplant biopsies). Proteins were extracted from laser-microdissected glomeruli and analyzed using mass spectrometry. The quantification values of protein abundance in each MN group were compared with those in the control group. RESULTS: More than 800 proteins with high confidence were identified. Principal component analysis revealed a different distribution between the pMN and sMN groups. For further analysis, 441 proteins matched with ≥ 3 peptides were selected. Among the pMN and sMN groups, we compared the profiles of several protein groups based on the structural and functional characteristics, such as immunoglobulins, complements, complement-regulating proteins, podocyte-associated proteins, glomerular basement membrane proteins, and several proteins that are known to be associated with kidney diseases, including MN. In all MN groups, increased levels of immunoglobulins (IgG, IgA, and IgM), complements (C3, C4, and C9), complement factor H-related protein 5, type XVIII collagen, calmodulin, polyubiquitin, and ubiquitin ligase were observed. For some proteins, such as type VII collagen and nestin, the fold-change values were significantly different between the pMN and sMN groups. CONCLUSIONS: Between the pMN and BCL-induced sMN groups, we observed common and different alterations in protein levels such as known disease-associated proteins and potential disease marker proteins.

Long-term prognosis of monoclonal immunoglobulin-associated glomerular diseases with non-organized deposits: A report of 38 cases from a Japanese single center.

Monoclonal immunoglobulin (MIg)-associated glomerular diseases with non-organized deposits are rare disorders. They have recently been categorized into light chain deposit disease (LCDD), light and heavy chain deposit disease (LHCDD), heavy chain deposit disease (HCDD), proliferative glomerulonephritis with MIg deposits (PGNMID) and its light chain only variant (PGNMID-LC), and membranous glomerulopathy with light chain-restricted deposits (MG-LC). In our Japanese cohort of more than 9,500 patients who underwent renal biopsy (1979 - 2020), we evaluated clinicopathological features and long-term outcomes in 38 patients with MIg-associated glomerular diseases with non-organized deposits: LCDD (n = 9), LHCDD (n = 8), HCDD (n = 5), PGNMID-membranoproliferative glomerulonephritis (MPGN) (n = 7), PGNMID-LC (n = 2), and MG-LC (n = 7). In patients with LCDD, a low estimated glomerular filtration rate (eGFR) at biopsy, a high detection rate of urinary MIgs, a high incidence rate of multiple myeloma, and sever tubulointerstitial and vascular lesions were significant clinicopathological characteristics. Median duration of follow-up in each group was 42 - 114 months. Most patients were treated with steroid-based therapy. Patients with LCDD, LHCDD, HCDD, and MG-LC were recently treated with bortezomib-based therapy. Renal survival rate was significantly shorter for LCDD than of PGNMID and MG-LC. Patient survival rate was significantly longer for MG-LC than HCDD and PGNMID. Major causes of death were pulmonary and cardiovascular complications. Among disease groups, significant differences were observed in eGFR at biopsy, detection rates of urinary MIgs, incidence rates of multiple myeloma, severities of tubulointerstitial and vascular lesions, and long-term outcomes.

Evaluation of a newly proposed renal risk score for Japanese patients with ANCA-associated glomerulonephritis.

BACKGROUND: We determined the usefulness and prognostic ability of the renal risk score (RRS), proposed in Europe, for Japanese patients with antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (AAGN) and high myeloperoxidase (MPO)-ANCA positivity; these aspects remain to be verified. METHODS: This retrospective study was conducted on 86 Japanese patients with new, biopsy-confirmed AAGN. We calculated the RRS and analyzed the relationship between this classification, and clinicopathological features and prognosis. We also compared the predictive values between RRS for endpoints including renal death and conventional prognostic tools for patients with AAGN. RESULTS: There were 33, 37, and 16 patients in the low-, medium-, and high-risk groups, respectively. All patients were MPO-ANCA positive. The median follow-up period was 33 months; 16 (18.6%) patients progressed to end-stage renal disease (ESRD). In the high-risk group, 9/16 (56.3%) patients progressed to ESRD, and renal prognosis was significantly poorer than that in other groups (low-risk group, P < 0.001; medium-risk group, P = 0.004). In Cox multivariate regression analysis, RRS was an independent, poor renal prognostic factor (hazard ratio 5.22; 95% confidence interval 2.20-12.40; P < 0.001). The receiver-operating characteristic curves of the RRS for each endpoint were comparable with those of the 2010 histological classification and those of the severity classification of Japanese rapidly progressive glomerulonephritis. CONCLUSIONS: This is the first study to report the usefulness of the RRS for predicting renal outcomes among Japanese patients with AAGN. Our predictive value of the RRS was comparable with that of conventional prognostic tools.

VEGF-VEGFR2 inhibitor-associated hyaline occlusive glomerular microangiopathy: a Japanese single-center experience.

BACKGROUND: Inhibitors of vascular endothelial growth factor (VEGF)-VEGF receptor 2 (VEGFR2) signaling, such as bevacizumab (Bmab), are used for the treatment of various advanced cancers. However, these inhibitors induce renal thrombotic microangiopathy (TMA). Recently, two European cohort studies showed a distinctive histopathological pseudothrombotic pattern different from TMA in Bmab-treated patients. METHODS: We analyzed 9 renal biopsies from proteinuric cancer patients treated with VEGF-VEGFR2 inhibitors in our Japanese cohort. Clinical and laboratory features were also assessed in these patients. RESULTS: All 9 patients had moderate to heavy proteinuria with normal or slightly elevated serum creatinine levels. On light microscopy, a patchy pattern of hemispherical/spherical lesions along glomerular capillary walls was a characteristic finding. On immunofluorescence microscopy, staining for immunoglobulins (IgM dominant) at varying intensities was observed mainly along glomerular capillary walls. Especially, hemispherical/spherical positive staining for immunoglobulins was a characteristic pattern. Immunohistochemical studies showed positive staining for immunoglobulins and negative staining for CD61-positive platelets in capillary hemispherical/spherical lesions and positive VEGF staining in podocytes. On electron microscopy, variably electron-dense material in dilated glomerular capillaries and partial effacement of podocyte foot processes were observed. After the withdrawal of VEGF-VEGFR2 inhibitors, proteinuria improved without any specific treatment in 8 patients. CONCLUSIONS: Histopathological findings in our patients treated with VEGF-VEGFR2 inhibitors were consistent with those observed in the recently described new form of Bmab-associated hyaline occlusive glomerular microangiopathy. This form should be considered in proteinuric cancer patients treated with VEGF-VEGFR2 inhibitors. Discontinuing VEGF-VEGFR2 inhibitors may lead to improvement of glomerular microangiopathy induced by these drugs.

Clinicopathological features and outcomes of diabetic kidney disease with extracapillary hypercellularity: a Japanese single-center experience.

BACKGROUND: The prognostic significance of glomerular extracapillary hypercellularity (EXHC) in diabetic kidney disease (DKD) is unclear. The aim of this study was to investigate the clinicopathological features and outcomes of DKD patients with EXHC. METHODS: We studied 70 cases of renal biopsy-confirmed type 2 DKD that were diagnosed between 2004 and 2014 and compared the clinicopathological features and outcomes of 22 patients with EXHC (EXHC group) with those of 48 patients without EXHC (control group). All of the patients were Japanese. We assessed the renal biopsy specimens based on the Renal Pathology Society classification system. Clinical and laboratory data were collected at the time of the renal biopsy, and renal outcomes were assessed based on progression to end-stage renal disease (ESRD) requiring renal replacement therapy. The median duration of the observation period was 3 years. RESULTS: In pathological features, nodular sclerosis (Kimmelstiel-Wilson lesions) was observed more frequently in the EXHC group than in the control group (63.6% vs. 35.4%, P = 0.027). There were no significant intergroup differences in clinical features or renal outcomes. Univariate and multivariate Cox regression analyses of all patients showed that a high level of proteinuria, a low initial eGFR, and severe interstitial inflammation were poor prognostic factors. CONCLUSIONS: EXHC is related to nodular sclerosis, which is a known risk factor for ESRD. Careful observation is needed during the follow-up of DKD patients with EXHC, although there were no significant differences in renal outcomes between the EXHC and control groups.

Comparative proteomic analysis of renal proteins from IgA nephropathy model mice and control mice.

BACKGROUND: High-IgA ddY (HIGA) mice, an animal model of human IgA nephropathy (IgAN), spontaneously develop nephropathy with glomerular IgA deposition and markedly elevated serum IgA levels from 25 weeks of age. METHODS: We performed a comparative proteomic analysis of the renal proteins collected from HIGA mice and control C57BL/6 mice at 5 or 38 weeks of age (the H5, H38, C5, and C38 groups) (n = 4 in each group). Proteins were extracted from the left whole kidney of each mouse and analyzed using nano-liquid chromatography-tandem mass spectrometry. The right kidneys were used for histopathological examinations. RESULTS: Immunohistochemical examinations showed glomerular deposition of IgA and the immunoglobulin joining (J) chain, and increased numbers of interstitial IgA- and J-chain-positive plasma cells in the H38 group. In the proteomic analysis, > 5000 proteins were identified, and 33 proteins with H38/H5 ratios of > 5.0, H38/C38 ratios of > 5.0, and C38/C5 ratios of < 1.5 were selected. Among them, there were various proteins that are known to be involved in human IgAN and/or animal IgAN models. Immunohistochemical examinations validated the proteomic results for some proteins. Furthermore, two proteins that are known to be associated with kidney disease displayed downregulated expression (H38/H5 ratio: 0.01) in the H38 group. CONCLUSIONS: The results of comparative proteomic analysis of renal proteins were consistent with previous histopathological and serological findings obtained in ddY and HIGA mice. Various proteins that are known to be involved in kidney disease, including IgAN, and potential disease marker proteins exhibited markedly altered levels in HIGA mice.

Comparison of measurements of anti-PLA2R antibodies in Japanese patients with membranous nephropathy using in-house and commercial ELISA.

BACKGROUND: The prevalence of antibodies against M-type anti-phospholipase A2 receptor (PLA2R) was reported to be ~ 70-80% in early studies on idiopathic membranous nephropathy (iMN) cohorts from Western countries, China, and Korea, and ~ 50% in recent studies on two Japanese iMN cohorts. METHODS: We developed an in-house enzyme-linked immunosorbent assay (ELISA) for the detection of anti-PLA2R antibodies, and examined sera from 217 patients with iMN, 22 patients with secondary MN (sMN), and 50 healthy individuals. All patients and healthy individuals were Japanese. The relationships between levels of anti-PLA2R antibodies and clinical parameters were analyzed. Serum samples were also tested using a standardized commercial ELISA (Euroimmun, Germany). RESULTS: In our ELISA, OD values greater than the mean + 3 standard deviation of healthy subjects were considered to be positive for anti-PLA2R antibodies. Of the patients with iMN, 33.6% (73/217) were positive, but all sMN patients were negative. Our ELISA and the Euroimmun ELISA had a high concordance (93.5%). The proportion of patients with nephrotic syndrome was significantly higher in anti-PLA2R antibody-positive patients than in antibody-negative patients (65.8 vs. 37.5%, P < 0.001). Levels of anti-PLA2R antibodies were significantly correlated with levels of urinary protein and serum albumin (P = 0.004 and P < 0.001, respectively). CONCLUSIONS: The prevalence of anti-PLA2R antibodies in our Japanese iMN cohort was lower than that in the previous studies from other countries and other Japanese institutes. The low prevalence of antibodies may be related with the characteristics of enrolled patients with mild proteinuria and undetectable antibody levels.

Hospital-based screening to detect patients with cadmium nephropathy in cadmium-polluted areas in Japan.

BACKGROUND: In health examinations for local inhabitants in cadmium-polluted areas, only healthy people are investigated, suggesting that patients with severe cadmium nephropathy or itai-itai disease may be overlooked. Therefore, we performed hospital-based screening to detect patients with cadmium nephropathy in two core medical institutes in cadmium-polluted areas in Akita prefecture, Japan. METHODS: Subjects for this screening were selected from patients aged 60 years or older with elevated serum creatinine levels and no definite renal diseases. We enrolled 35 subjects from a hospital in Odate city and 22 from a clinic in Kosaka town. Urinary ß2-microglobulin and blood and urinary cadmium levels were measured. RESULTS: The criteria for renal tubular dysfunction and the over-accumulation of cadmium were set as a urinary ß2-microglobulin level higher than 10,000 µg/g cr. and a blood cadmium level higher than 6 µg/L or urinary cadmium level higher than 10 µg/g cr., respectively. Subjects who fulfilled both criteria were diagnosed with cadmium nephropathy. Six out of 57 patients (10.5% of all subjects) had cadmium nephropathy. CONCLUSIONS: This hospital-based screening is a very effective strategy for detecting patients with cadmium nephropathy in cadmium-polluted areas, playing a complementary role in health examinations for local inhabitants. REGISTRATION NUMBER: No. 6, date of registration: 6 June, 2010 (Akita Rosai Hospital), and No. 1117, date of registration: 26 December, 2013 (Akita University).

Membranoproliferative glomerulonephritis with unusual deposits of parallel arrangement striated structure: a new pathological entity?
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A 71-year-old male with a past history of lower limb arteriosclerosis obliterans developed nephrotic syndrome and renal dysfunction. Renal biopsy showed diffuse global endocapillary proliferative lesions with infiltration of mononuclear cells and occasional foam cells. An irregular double contour of the glomerular basement membrane and global mild-to-moderate mesangial proliferative lesions were observed, indicating membranoproliferative glomerulonephritis. Congo red staining was negative. Routine immunofluorescence studies showed no obvious immunoglobulin or complement depositions. Electron microscopy showed endocapillary proliferative lesions and infiltration of macrophages with abundant lysosomes. Irregular subepithelial, subendothelial, and mesangial electron-dense deposits were observed in glomeruli. In these electron-dense deposits, parallel arrangement striated structures were detected. All known disease entities with Congo red-negative and immunoglobulin-negative glomerular deposits were pathologically excluded. The glomerular lesion in our case might be a new disease entity.
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Analysis of PLA2R1 and HLA-DQA1 sequence variants in Japanese patients with idiopathic and secondary membranous nephropathy.

BACKGROUND: Several recent studies in patients with idiopathic membranous nephropathy (iMN) from Western and Asian counties showed that some single nucleotide polymorphisms (SNPs) within the PLA2R1 and HLA-DQA1 genes are significantly associated with iMN. However, there is only 1 report on analysis of PLA2R1 and HLA regions in Japanese patients with iMN. METHODS: A total of 58 patients with iMN, 26 patients with secondary MN (sMN), and 50 patients with other diseases were enrolled. All patients were Japanese. We selected 6 SNPs within PLA2R1 and 1 SNP within HLA-DQA1, which were significantly associated with iMN in reported white European cohorts, and sequenced these exons using genomic DNA prepared from peripheral mononuclear cells from each patient. We then analyzed differences in PLA2R1 and HLA-DQA1 sequence variants among the 3 groups. RESULTS: Genotypic and allelic frequency distributions for 3 out of 6 SNPs within PLA2R1, rs3749117, rs35771982, and rs2715918 were significantly different between the iMN and control groups. Allelic frequency distributions for SNP rs2187668 within HLA-DQA1 were significantly different between the iMN and control groups. There were no correlations between PLA2R1 and HLA-DQA1 sequence variants and clinical parameters in patients with iMN. There were no significant differences in genotypic or allelic frequency distributions for examined SNPs between the sMN and control groups. CONCLUSIONS: There are some differences in PLA2R1 SNP distributions between previously reported cohorts from other countries and our Japanese cohort of patients with iMN, while there is a significant association between SNP rs35771982 and iMN in most of reported cohorts.

Clinicopathological and long-term prognostic features of membranous nephropathy with crescents: a Japanese single-center experience.

BACKGROUND: Three recent studies from the United States and China reported the clinicopathological features and short-term prognosis in patients with membranous nephropathy (MN) and crescents in the absence of secondary MN, anti-glomerular basement membrane (GBM) antibodies, and anti-neutrophil cytoplasmic antibodies (ANCA). METHODS: We compared clinicopathological and prognostic features in 16 MN patients with crescents (crescent group) and 38 MN patients without crescents (control group), in the absence of secondary MN, anti-GBM antibodies, and ANCA. Median follow-up periods in the crescent and control groups were 79 and 50 months, respectively. RESULTS: Decreased estimated glomerular filtration rates (<50 mL/min/1.73 m2), glomerulosclerosis, and moderate-to-severe interstitial fibrosis were more frequently observed in the crescent group than in the control group (P = 0.043, P = 0.004, and P = 0.035, respectively). Positive staining rates for glomerular IgG2 and IgG4 were significantly different between the 2 groups (P = 0.032, P = 0.006, respectively). Doubling of serum creatinine during follow-up was more frequently observed in the crescent group than in the control group (P = 0.002), although approximately two-thirds of patients in the crescent group were treated with immunosuppressive therapy. Crescent formation and interstitial fibrosis were risks for doubling of serum creatinine [hazard ratio (HR) = 10.506, P = 0.012; HR = 1.140, P = 0.009, respectively]. CONCLUSIONS: This is the first Japanese study demonstrating significant differences in clinicopathological and prognostic features between the 2 groups. Most patients in the crescent group may develop a long-term decline in renal function despite immunosuppressive therapy.

Tubulointerstitial Nephritis with IgM-Positive Plasma Cells.

Infiltration by IgG-positive plasma cells is a common finding in tubulointerstitial nephritis. Indeed, it has been thought that CD138-positive mature plasma cells secrete mainly IgG, and the occurrence of tubulointerstitial nephritis with CD138-positive plasma cells secreting IgM has rarely been reported. Routine immunofluorescence of fresh frozen sections is considered the gold standard for detection of immune deposits. However, the immunoenzyme method with formalin-fixed, paraffin-embedded sections is superior for detecting IgM- or IgG-positive cells within the renal interstitium, thus histologic variants may often go undetected. We recently discovered a case of tubulointerstitial nephritis showing IgM-positive plasma cell accumulation within the interstitium. To further explore the morphologic and clinical features of such cases, we performed a nationwide search for patients with biopsy-proven tubulointerstitial nephritis and high serum IgM levels. We identified 13 patients with tubulointerstitial nephritis and IgM-positive plasma cell infiltration confirmed with the immunoenzyme method. The clinical findings for these patients included a high prevalence of distal renal tubular acidosis (100%), Fanconi syndrome (92%), and anti-mitochondrial antibodies (82%). The pathologic findings were interstitial nephritis with diffusely distributed CD3-positive T lymphocytes and colocalized IgM-positive plasma cells, as well as tubulitis with CD3-positive T lymphocytes in the proximal tubules and collecting ducts. Additionally, levels of H+-ATPase, H+, K+-ATPase, and the HCO3--Cl- anion exchanger were markedly decreased in the collecting ducts. We propose to designate this group of cases, which have a common histologic and clinical form, as IgM-positive plasma cell-tubulointerstitial nephritis.

Quantification of Interstitial Fibrosis in Renal Allografts and Clinical Correlates of Long-Term Graft Function.

BACKGROUND: The present study investigated interstitial fibrosis (IF) in 144 kidney recipients 0 h and 1 year post transplantation and assessed relationships with Banff code scores, clinical parameters, and long-term graft function. METHODS: A quantitative analysis of IF was performed using the computer-assisted imaging of Sirius red-stained biopsy samples. Percent IF (%IF) in the cortical region was assessed at 0 h and 1 year, and an increase in the ratio of %IF from 0 h to 1 year was calculated. The relationship between %IF and Banff code scores was analyzed. Demographics and trough concentrations of tacrolimus were tested as risk factors in the top 20 patients with increases in %IF. The influence of increases in the ratio of %IF at 1 year on long-term graft function and survival was also assessed in these 20 patients. RESULTS: Median %IF at 0 h and 1 year were 1.55 and 2.80%, respectively. No correlation was found between %IF and Banff code scores. The mean increase in the ratio of %IF from 0 h to 1 year was 4.31-fold. The increase in %IF in the top 20 patients correlated with diabetes mellitus. Graft function, but not graft survival, was lower in the top 20 patients for 10 years post transplantation. CONCLUSIONS: A correlation was not found between %IF and Banff code scores. Greater increases in %IF within 1 year post transplantation may influence long-term graft survival. Computer-analyzed increases in %IF at 1 year may be a surrogate marker for long-term graft function.

Long-term prognosis of AL and AA renal amyloidosis: a Japanese single-center experience.

BACKGROUND: Few studies have been conducted on the long-term prognosis of patients with amyloid light chain (AL) and amyloid A (AA) renal amyloidosis in the same cohort. METHODS: We retrospectively examined 68 patients with biopsy-proven renal amyloidosis (38 AL and 30 AA). Clinicopathological findings at the diagnosis and follow-up data were evaluated in each patient. We analyzed the relationship between clinicopathological parameters and survival data. RESULTS: Significant differences were observed in several clinicopathological features, such as proteinuria levels, between the AL and AA groups. Among all patients, 84.2 % of the AL group and 93.3 % of the AA group received treatments for the underlying diseases of amyloidosis. During the follow-up period (median 18 months in AL and 61 months in AA), 36.8 % of the AL group and 36.7 % of the AA group developed end-stage renal failure requiring dialysis, while 71.1 % of the AL group and 56.7 % of the AA group died. Patient and renal survivals were significantly longer in the AA group than in the AL group. eGFR of >60 mL/min/1.73 m2 at biopsy and an early histological stage of glomerular amyloid deposition were identified as low-risk factors. A multivariate analysis showed that cardiac amyloidosis and steroid therapy significantly influenced patient and renal survivals. CONCLUSIONS: Our results showed that heart involvement was the major predictor of poor outcomes in renal amyloidosis, and that the prognosis of AA renal amyloidosis was markedly better than that in previously reported cohorts. Therapeutic advances in inflammatory diseases are expected to improve the prognosis of AA amyloidosis.

Long-term renal survival of γ3-heavy chain deposition disease: a case report.

BACKGROUND: Monoclonal immunoglobulin deposition disease (MIDD) is characterized by the non-amyloid deposition of monoclonal immunoglobulin fragments in the basement membranes. Heavy chain deposition disease (HCDD) is a type of MIDD. HCDD is an extremely rare disease, and only three cases have been reported in Japan up to the present. The prognosis of HCDD is very poor, and optimal treatment has not been established. Only a few cases of HCDD with favorable long-term renal prognosis have been reported to date. CASE PRESENTATION: The authors describe a 61-year-old woman who presented with massive proteinuria, progressive kidney impairment, and hypocomplementemia. Kidney biopsy was performed for a precise diagnosis. On light microscopy, glomerules were lobulated and presented with nodular sclerosing glomerulopathy with membranoproliferative glomerulonephritis-like features. Immunofluorescence studies were positive for IgG, C3, and C1q within the mesangial nodules and in a linear distribution along the capillary walls without associated deposition of light chains. Staining for IgG showed the presence of linear deposits along tubular basement membranes. The analysis of the IgG subclass stain demonstrated intense positivity for IgG3 only. Electron microscopy revealed non-organized electron-dense deposits in the expanded mesangial area and inner aspect of the glomerular basement membranes. In accordance with the histological findings, we diagnosed γ3-HCDD. There was no evidence of plasma cell dyscrasia as a result of bone marrow aspiration. Serum and urine monoclonal proteins were not detected by immunoelectrophoresis and immunofixation electrophoresis. The serum free light chain ratio was within normal range. At first, prednisolone was administrated at a dose of 40 mg/day. However, a therapeutic effect was not observed. Urinary protein was not decreased and renal function further deteriorated. Therefore, melphalan plus prednisolone (MP) therapy was initiated. After 4 courses of MP therapy, the clinical parameters, including proteinuria, serum creatinine, albumin, and complement level (C3 and C4) were ameliorated. To date, the patient has been followed for 28 months, and long-term renal survival has been observed. CONCLUSIONS: In this case, hematologic disease such as multiple myeloma was not detected; however, MP therapy was effective. Recently, the novel concept of monoclonal gammopathy of renal significance (MGRS) has been reported. MIDD, which includes HCDD, is one category of MGRS. In MGRS, aggressive chemotherapy may induce favorable renal outcomes.

Different Expression Patterns of Toll-Like Receptor mRNAs in Blood Mononuclear Cells of IgA Nephropathy and IgA Vasculitis with Nephritis.

Mucosal immunity may play a key role in IgA nephropathy (IgAN) and IgA vasculitis with nephritis (IgAVN). IgAVN is characterized by the presence of non-thrombocytopenic palpable purpura, associated with glomerulonephritis with IgA-dominant immune deposits. Recent studies have shown the up-regulation of Toll-like receptors (TLRs) in patients with IgAN or IgAVN. Among TLRs that mediate innate immune reactions, TLR2, TLR4, and TRL5 recognize bacterial components, while TLR3, TLR7, and TLR9 recognize viral components. Here we compared the expression levels of TLR mRNAs in peripheral blood mononuclear cells (PBMCs) from 49 IgAN patients, 20 IgAVN patients, and 20 patients with thin basement membrane nephropathy (TBMN), unrelated to immune-mediated pathogenesis, as a control. The real-time RT-PCR analysis revealed the significantly higher expression levels of TLR2, TLR3, TLR5, TLR7, and TLR9 mRNAs in PBMCs of IgAN and IgAVN patients, compared to TBMN patients. Importantly, TLR4 mRNA levels were significantly higher in IgAN patients than in IgAVN patients, while its expression levels were comparable in IgAVN patients and TBMN patients. In contrast, TLR5 and TLR9 mRNA levels were significantly higher in IgAVN patients than in IgAN patients. In IgAN patients, expression levels of TLR2, TLR3, TLR5, or TLR9 mRNA were correlated with proteinuria levels, and TLR4 mRNA levels were correlated with serum IgA levels. In IgAVN patients, however, there was no such correlation. The up-regulated expression of TLR mRNAs in PBMCs may be related to the development of IgAN and IgAVN. The distinct expression patterns between these two diseases may reflect their different pathogenetic mechanisms.

Clinical and structural remission rates increased annually and radiographic progression was continuously inhibited during a 3-year administration of tocilizumab in patients with rheumatoid arthritis: A multi-center, prospective cohort study by the Michinoku Tocilizumab Study Group.

OBJECTIVE: To evaluate the clinical and structural efficacy of tocilizumab (TCZ) during its long-term administration in patients with rheumatoid arthritis (RA). METHODS: In total, 693 patients with RA who started TCZ therapy were followed for 3 years. Clinical efficacy was evaluated by DAS28-ESR and Boolean remission rates in 544 patients. Joint damage was assessed by calculating the modified total Sharp score (mTSS) in 50 patients. RESULTS: When the reason for discontinuation was limited to inadequate response or adverse events, the 1-, 2-, and 3-year continuation rates were 84.0%, 76.8%, and 72.2%, respectively. The mean DAS28-ESR was initially 5.1 and decreased to 2.5 at 6 months and to 2.2 at 36 months. The Boolean remission rate was initially 0.9% and increased to 21.7% at 6 months and to 32.2% at 36 months. The structural remission rates (ΔmTSS/year ≤ 0.5) were 68.8%, 78.6%, and 88.9% within the first, second, and third years, respectively. The structural remission rate at 3 years (ΔmTSS ≤ 1.5) was 66.0%, and earlier achievement of swollen joint count (SJC) of 1 or less resulted in better outcomes. CONCLUSIONS: TCZ was highly efficacious, and bone destruction was strongly prevented. SJC was an easy-to-use indicator of joint destruction.

Effect of CYP3A5 and ABCB1 polymorphisms on the interaction between tacrolimus and itraconazole in patients with connective tissue disease.

PURPOSE: The aim of this study was to investigate the effect of itraconazole (ITCZ), a potent inhibitor of CYP3A4 and P-glycoprotein, on the blood concentration 12 h after tacrolimus administration (C 12h) in relation to CYP3A5 6986A>G and ABCB1 3435C>T genotype status in patients with connective tissue disease (CTD). METHODS: Eighty-one CTD patients taking tacrolimus (Prograf®) once daily at night (2100 hours) were enrolled in this study. Whole blood samples were collected 12 h after tacrolimus administration at steady state. RESULTS: The dose-adjusted tacrolimus C 12h with or without ITCZ co-administration was significantly higher in patients with CYP3A5*3/*3 than in those with the CYP3A5*1 allele [CYP3A5 *1/*1 vs. *1/*3 vs. *3/*3 = 1.67 vs. 2.70 vs. 4.83 ng/mL/mg (P = 0.003) and 0.68 vs. 0.97 vs. 2.20 ng/mL/mg (P < 0.001), respectively], but differences were not observed for ABCB1 genotypes. However, there was no difference in the increase rate of the dose-adjusted C 12h of tacrolimus between CYP3A5 or ABCB1 genotypes (P = 0.378 and 0.259). On the other hand, reduction of the estimated glomerular filtration rate exhibited a correlation with the C 12h of tacrolimus after ITCZ co-administration (r = -0.482, P = 0.009). CONCLUSIONS: In CYP3A5*3/*3 patients, because the metabolic pathway for tacrolimus occurs only through CYP3A4, the combination with ITCZ seems to lead to a higher risk of acute renal dysfunction. Therefore, we suggest that the target blood tacrolimus concentration be set as low as possible through dose-adjustment for patients with the CYP3A5*3/*3 allele.