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OBJECTIVES To analyze the prevalence of systemic de novo thrombotic microangiopathy in ABO-incompatible kidney transplantation and risk factors associated with this condition. METHODS A total of 201 patients who received living-donor kidney transplantation (114 patients with ABO-identical kidney transplantation and 87 patients with ABO-incompatible kidney transplantation) were retrospectively analyzed. Systemic de novo thrombotic microangiopathy was diagnosed clinically according to the presence of thrombocytopenia with microangiopathic hemolytic anemia and pathological findings of thrombotic microangiopathy. Anti-A and anti-B antibodies were purified from human plasma, and these antibodies' bindings to human kidney were investigated in vitro. RESULTS ABO-incompatible kidney transplantation was a significant risk factor of systemic de novo thrombotic microangiopathy (odds ratio 55.9, 95% CI 1.8-8.9, P

Plasma cell-rich acute rejection (PCAR) and antibody-mediated rejection (ABMR), for which a standard treatment has not yet been established, are associated with poor graft survival after kidney transplantation. Here, we report a case series of 3 Japanese patients diagnosed with PCAR accompanied by ABMR. Steroid pulse therapy and rabbit antithymocyte globulin, plasma exchange, intravenous immunoglobulin, and rituximab therapies were sequentially performed in the first case. A graft biopsy after each treatment showed that plasma cell infiltration persisted. Five months after the initiation of rejection therapy, the patient was subjected to bortezomib therapy, which led to the partial elimination of plasma cells from the graft. However, the graft function gradually deteriorated, and hemodialysis treatment was warranted. In the other 2 cases, the patients received the same combination of therapy including bortezomib within a short period. Graft biopsies performed subsequently showed a marked decrease in the number of infiltrated plasma cells, and stabilization of renal graft function was achieved in both cases. Bortezomib, which targets plasma cells, is a potent drug that eliminates infiltrated plasma cells from the graft in PCAR. Thus, in addition to conventional therapy comprising plasma exchange, intravenous immunoglobulin, and rituximab against ABMR, bortezomib may be necessary to administer without any delay to control PCAR.

(Background) The standard treatment for recurrent immunoglobulin A nephropathy (rIgAN) after kidney transplantation (KTx) has not been established. (Methods) The results of treatment consisting of tonsillectomy and steroid pulse therapy in 20 recipients who were diagnosed as rIgAN were retrospectively analyzed. (Results) The level of proteinuria significantly decreased from 0.84±0.81 g/day to 0.27±0.31 g/day after treatment (P=0.007). Microscopic hematuria disappeared or improved in 58.3% and 66.6% of recipients 6 and 12 months after treatment, respectively. Serum creatinine levels remained stable for 5 years by the treatment, except for 3 cases of graft loss. Sixteen recipients received renal graft biopsies before and after treatment. Mesangial IgA deposition were dramatically decreased in 7 recipients (43.75%). The degree of mesangial hypercellularity, endocapillary hypercellularity, and crescents formation improved in 3 (18.8%), 6 (37.5%), and 4 (25%) recipients after treatment. (Conclusion) Steroid pulse therapy combined with tonsillectomy may be clinically and histopathologically effective treatment for rIgAN after KTx.

Heavy chain deposition disease (HCDD) is a rare complication of plasma cell dyscrasias, characterized by nonamyloid tissue deposits of incomplete monoclonal heavy chains in renal tissues. We report the case of a 78-year-old female with HCDD who was successfully treated with bortezomib and dexamethasone (BD); histopathological improvements were confirmed by kidney biopsy after 2 years of chemotherapy. She presented with renal insufficiency, proteinuria, hematuria, hypogammaglobulinemia, and hypocomplementemia. Renal biopsy showed diffuse global nodular glomerulopathy with the deposition of IgG1 and C3 in the glomeruli and on the tubular basement membrane. Kappa and lambda light chains were not detected. Staining for the constant regions of the gamma heavy chain revealed the absence of the CH1 domain. These findings are consistent with those of gamma 1 HCDD. Results of liquid chromatography-tandem mass spectrometric analysis were consistent with the immunohistochemical results. Two years after weekly BD therapy, normalization of the kappa/lambda ratio and reduction of urinary protein excretion were achieved. A follow-up biopsy showed remarkable diminution of nodular lesions of glomeruli and deposits of IgG and C3. Keywords: Heavy chain deposition disease, Bortezomib, Liquid chromatography-tandem mass spectrometry

A 60-year-old male presented with accelerated hypertension, renal insufficiency, proteinuria, and hematuria. Percutaneous kidney biopsy revealed membranoproliferative glomerulonephritis (MPGN) without any immunoglobulin and complement deposition. On performing electron microscopy, deposits with a tubular, organized structure and approximately 60 nm in diameter were detected in the glomerular subendothelial spaces and mesangial areas. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) demonstrated the significantly increased deposition of fibrinogen and fibronectin in glomeruli. Immunohistochemistry and immunoelectron microscopy demonstrated that the deposits were composed of fibrinogen. Here we report a case of cryofibrinogen -associated GN in which LC-MS/MS and immunoelectron microscopy were useful for diagnosis. When MPGN with organized deposits without the deposition of immunoglobulins and complements is diagnosed, we considered the cryofibrinogen-associated GN in one of the differential diagnosis, and even skin symptoms cannot be detected. Keywords: Cryofibrinogen-related kidney disease, Liquid chromatography-tandem mass spectrometry, Immunoelectron microscopy

Objective Understanding the long-term prognosis of preeclampsia (PE) is important. Proteinuria and poor renal function persist in some PE patients, but the relationship between their histopathological findings of kidney and renal prognosis is unknown. Our objective was to clarify the relationship between clinicopathological features and renal prognosis in PE patients. Study design Retrospective observational study. Main outcome measures Seventy patients who had been referred to the Niigata University Hospital between 1977 and 2014 and were diagnosed with PE were classified into unimproved and improved groups. The unimproved group included patients whose serum creatinine level had doubled and/or whose proteinuria had persisted until the end of observation, which included three patients with end-stage kidney disease (ESKD). The improved group included patients whose serum creatinine level did not double and whose proteinuria had disappeared until the last observation. We examined and compared these patients’ characteristics, clinical and laboratory findings, and renal histopathological findings from percutaneous kidney biopsies. Results There were no significant differences in the clinical backgrounds and clinical findings between the two groups during pregnancy. However, light microscopy findings of their kidney biopsies were able to identify significantly more severe duplications of the capillary loop, interstitial cell infiltration, and interstitial fibrosis in the unimproved group. Conclusions Histopathological examination of the kidney may be a valid method for predicting the long-term prognosis of renal function and for histological a risk assessment of poor renal recovery in PE patients.

Scleroderma renal crisis (SRC) is a severe complication of systemic sclerosis characterised by abrupt onset of arterial hypertension and rapid progression to renal failure. Angiotensin-converting e...

(Backgrounds) The efficacy of bortezomib for chronic antibody mediated rejection (CAMR) after kidney transplantation is still obscure. (Materials and methods) CAMR were persisted in 5 recipients who were treated with plasma exchange, low dose of IVIG, steroid pulse therapy, and rituximab. 1.3 mg/m2 of bortezomib was administered on days 1, 4, 8, 11. Serum creatinine (sCr) levels, anti-HLA antibodies, and histology were analyzed. (Results) Stable sCr levels were obtained in 3 out of 5 recipients. No one lost renal graft function during follow-up periods. Anti-HLA class I antibodies were significantly decreased after bortezomib treatment, however anti-HLA class II antibodies were not changed. Histology showed no improvement at 6 months after bortezomib administration. Two recipients whose sCr levels increased during follow-up had already had interstitial fibrosis and tubular atrophy (IF/TA) in histology before bortezomib treatment. (Conclusions) The use of bortezomib after IF/TA could be detected in histology may not contribute to stabilize renal graft function in CAMR.

A main feature of Fabry disease is nephropathy, with polyuria an early manifestation; however, the mechanism that underlies polyuria and affected tubules is unknown. To increase globotriaosylceramide (Gb3) levels, we previously crossbred asymptomatic Glatm mice with transgenic mice that expressed human Gb3 synthase (A4GALT) and generated the GlatmTg(CAG-A4GALT) symptomatic Fabry model mice. Additional analyses revealed that these mice exhibit polyuria and renal dysfunction without remarkable glomerular damage. In the present study, we investigated the mechanism of polyuria and renal dysfunction in these mice. Gb3 accumulation was mostly detected in the medulla; medullary thick ascending limbs (mTALs) were the most vacuolated tubules. mTAL cells contained lamellar bodies and had lost their characteristic structure ( i.e., extensive infolding and numerous elongated mitochondria). Decreased expression of the major molecules-Na+-K+-ATPase, uromodulin, and Na+-K+-2Cl- cotransporter-that are involved in Na+ reabsorption in mTALs and the associated loss of urine-concentrating ability resulted in progressive water- and salt-loss phenotypes. GlatmTg(CAG-A4GALT) mice exhibited fibrosis around mTALs and renal dysfunction. These and other features were consistent with pathologic findings in patients with Fabry disease. Results demonstrate that mTAL dysfunction causes polyuria and renal impairment and contributes to the pathophysiology of Fabry nephropathy.-Maruyama, H., Taguchi, A., Nishikawa, Y., Guili, C., Mikame, M., Nameta, M., Yamaguchi, Y., Ueno, M., Imai, N., Ito, Y., Nakagawa, T., Narita, I., Ishii, S. Medullary thick ascending limb impairment in the GlatmTg(CAG-A4GALT) Fabry model mice.

(Background) Long-term care is necessary for normal growth and development of pediatric recipients of kidney transplants. We report on our experience with pediatric kidney transplantation (KTx) during the past 19 years. (Methods) We retrospectively analyzed the data from 26 recipients who received KTx between 1996 and 2014 at Niigata University Hospital (one patient underwent two consecutive KTx during the designated period). All recipients were 16 years old or younger at the time of KTx. (Results) The graft survival rates at 1, 5, and 10 years after transplantation were 96%, 96%, and 88%, respectively. Three recipients lost the renal graft function due to graft thrombosis, antibody mediated rejection and steroid resistant rejection. Drug non-adherence was associated with rejection episodes, which led to the increasing of estimated glomerular filtration rate (eGFR) level. In addition, renal graft function was related to the growth after KTx. Eighteen recipients graduated from high school during follow-up periods and 17 recipients obtained employment. (Conclusion) Interventions promoting adherence should be implemented among pediatric recipients and parents to optimize graft survival and growth after KTx. Successful KTx contributed the high rate of social participation and employment after pediatric KTx.

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.

Background Although most cases of tubulointerstitial nephritis in paraproteinemia are monoclonal light chain deposition-mediated, interstitial nephritis as neoplastic interstitial cell infiltration has rarely been described. On the other hand, lympho-plasma-cell-rich tubulointerstitial nephritis, in which the infiltrative cells are usually polytypic, is often evident in primary Sjögren’s syndrome (pSS). Herein we present a rare case of pSS in a patient who had been diagnosed as having IgA kappa-type monoclonal gammopathy of undetermined significance (MGUS) and developed tubulointerstitial nephritis with monotypic (IgA kappa) lympho-plasmacytic infiltrates. Case presentation A 74-year-old Japanese woman with pSS who had been diagnosed as having IgA kappa-type MGUS developed progressive renal dysfunction. Renal biopsy revealed tubulointerstitial nephritis with abundant plasma cell-rich mononuclear cell infiltrates without atypia. Immunohistochemical staining for immunoglobulins and light chains showed that most infiltrates were positive for IgA and kappa. Most of the infiltrative cells were positive for CD38 and CD138, and cells positive for CD 19 and CD 45 were also widely evident. Electron microscopy and immunofluorescence studies revealed no apparent immunological deposits in the glomeruli and tubules. Bone marrow and whole-body radiological examinations revealed no findings suggestive of multiple myeloma or lymphoma. Renal function improved rapidly with prednisolone 40 mg daily and has been maintained at the same level on low-dose prednisolone and azathioprine for 18 months. Conclusion Tubulointerstitial nephritis with monotypic cell infiltrates, without immunological deposits, is a quite rare histological picture in MGUS, and might be a unique renal manifestation in patients with pSS.

We previously described the relationship between clinical manifestations and amount of amyloid deposition in the renal biopsy specimens of amyloid A (AA) and light-chain (AL) amyloidosis. The amoun...

Most of the adult population are infected with Epstein-Barr virus (EBV), but as EBV replication is usually under immune system control, the majority of individuals remain asymptomatic. On the other hand, some individuals continuously retain a high EBV antibody titer and a high EBV DNA load in their blood, suggesting a defect of EBV replication control. To date, only a limited number of reports have addressed the relationship between this chronic form of EBV infection and renal involvement. Here, we describe an 80-year-old woman who developed acute kidney injury shortly after an episode of mosquito bites, accompanied by a severe skin rash, which raised a suspicion of chronic EBV infection. She was subsequently diagnosed as having chronic replicative EBV infection. Renal biopsy revealed a diagnosis of IgA nephropathy with crescent formation. Although the relationship between IgA nephropathy and EBV infection has been discussed, no substantial understanding has yet emerged. The patient's characteristic clinical course suggested that the renal failure may have been partly attributable to chronic EBV infection. This case suggests that physicians may need to consider the possibility that chronic EBV infection may affect the clinical course of IgA nephropathy, or exacerbate the disease.

The mechanism of long-term B cell immunity against donor blood group antigens in recipients who undergo ABO-incompatible (ABOi) living-donor kidney transplantation (LKTx) is unknown. To address this question, we evaluated serial anti-A and anti-B antibody titers in 50 adult recipients. Donor-specific antibody titers remained low (≤1:4) in 42 recipients (84%). However, antibodies against nondonor blood group antigens were continuously produced in recipients with blood type O. We stimulated recipients' peripheral blood mononuclear cells in vitro to investigate whether B-cells produced antibodies against donor blood group antigens in the absence of graft adsorption in vivo. Antibodies in cell culture supernatant were measured using specific enzyme-linked immunosorbent assays (ELISA). Thirty-five healthy volunteers and 57 recipients who underwent ABO-compatible LKTx served as controls. Antibody production in vitro against donor blood group antigens by cells from ABOi LKTx patients was lower than in the control groups. Immunoglobulin deposits were undetectable in biopsies of grafts of eight recipients with low antibody titers (≤1:4) after ABOi LKTx. One patient with blood type A1 who received a second ABOi LKTx from a type B donor did not produce B-specific antibodies. These findings suggest diminished donor-specific antibody-production function in the setting of adult ABOi LKTx. This article is protected by copyright. All rights reserved.

We describe a 53-year-old woman with primary Sjögren's syndrome and tubulointerstitial nephritis showing distal renal tubular acidosis and Fanconi syndrome. The patient showed high serum IgM levels and positivity for antimitochondrial antibodies, although her liver function was in normal range. According to our literature review, 75% of patients with tubulointerstitial nephritis who were positive for antimitochondrial antibodies showed Fanconi syndrome, suggesting that these antibodies may directly be associated with the pathophysiology of Fanconi syndrome.

A main feature of Fabry disease is nephropathy, with polyuria an early manifestation; however, the mechanism that underlies polyuria and affected tubules is unknown. To increase globotriaosylceramide (Gb3) levels, we previously crossbred asymptomatic Glatm mice with transgenic mice that expressed human Gb3 synthase (A4GALT) and generated the GlatmTg(CAG-A4GALT) symptomatic Fabry model mice. Additional analyses revealed that these mice exhibit polyuria and renal dysfunction without remarkable glomerular damage. In the present study, we investigated the mechanism of polyuria and renal dysfunction in these mice. Gb3 accumulation was mostly detected in the medulla; medullary thick ascending limbs (mTALs) were the most vacuolated tubules. mTAL cells contained lamellar bodies and had lost their characteristic structure (i.e., extensive infolding and numerous elongated mitochondria). Decreased expression of the major molecules—Na+-K+-ATPase, uromodulin, and Na+-K+-2Cl− cotransporter—that are involved in Na+ reabsorption in mTALs and the associated loss of urine-concentrating ability resulted in progressive water- and salt-loss phenotypes. GlatmTg(CAG-A4GALT) mice exhibited fibrosis around mTALs and renal dysfunction. These and other features were consistent with pathologic findings in patients with Fabry disease. Results demonstrate that mTAL dysfunction causes polyuria and renal impairment and contributes to the pathophysiology of Fabry nephropathy.—Maruyama, H., Taguchi, A., Nishikawa, Y., Guili, C., Mikame, M., Nameta, M., Yamaguchi, Y., Ueno, M., Imai, N., Ito, Y., Nakagawa, T., Narita, I., Ishii, S. Medullary thick ascending limb impairment in the GlatmTg(CAG-A4GALT) Fabry model mice.

The Oxford classification of IgA nephropathy consists of four markers as prognosticators. We retrospectively examined the relevance of extracapillary proliferation involving cellular and fibrocellular crescents (Ex) and arteriolar hyalinosis (A) on the long-term outcome of renal function. A total of 314 Japanese patients who were diagnosed with IgA nephropathy, with 12 months or more of follow-up period were included in this study. A total of 186 patients were with UP ≥ 0.5 g/day. Patients with diabetes mellitus or severe kidney injury (eGFR

Background Acute tubulointerstitial nephritis (ATIN) has been increasingly recognized as an important manifestation of kidney injury associated with the use of immune checkpoint inhibitors (anti-PD-1 and anti-CTLA-4). While the exact pathophysiology remains unknown, corticosteroids are the mainstay of management. Case presentation We describe a 67-year-old man with stage IV non-small-cell lung cancer who developed kidney injury during treatment with the anti-PD-1 antibody nivolumab. A kidney biopsy showed ATIN without granuloma formation. Considering their mechanism of action, immune checkpoint inhibitors can alter immunological tolerance to concomitant drugs that have been safely used for a long time. For more than 4 years before the initiation of nivolumab therapy, the patient had been receiving the proton pump inhibitor lansoprazole, known to cause drug-induced ATIN, without significant adverse events including kidney injury. He showed rapid improvement in kidney function in 3 days (creatinine decreased from 2.74 to 1.82 mg/dl) on discontinuation of lansoprazole. He then received 500 mg intravenous methylprednisolone for 3 days followed by 1 mg/kg/day oral prednisolone and his creatinine levels eventually stabilized around 1.7 mg/dl. Drug-induced lymphocyte stimulation test (DLST) for lansoprazole was positive. Conclusions The rapid improvement of kidney function after discontinuation and DLST positivity indicate that lansoprazole contributed to the development of ATIN during nivolumab therapy. Considering the time course, it is plausible that nivolumab altered the long-lasting immunological tolerance against lansoprazole in this patient. To the best of our knowledge, this is the first case report of DLST positivity for a drug that had been used safely before the initiation of an immune checkpoint inhibitor. Although corticosteroid therapy is recommended, the recognition and discontinuation of concomitant drugs, especially those known to induce ATIN, is necessary for the management of kidney injury associated with anti-PD-1 therapy.

Objective Ultrastructural studies of IgG4-related kidney disease (IgG4-RKD) characterized by tubulointerstitial nephritis (TIN) are limited in previous reports due to the rarity of the condition. In the present report, we performed ultrastructural examinations and assessed the pathogenesis of this disease. Patients Clinicopathological studies were conducted in eight patients diagnosed with IgG4-RKD. Routine light, immunofluorescence and electron microscopy examinations and immunohistochemical assessments of IgG4 were performed using renal biopsy samples. Results Hypocomplementemia, positive anti-nuclear antibodies and eosinophilia were confirmed in more than half of the cases. Electron dense deposits (EDDs) were frequently found in the glomeruli and interstitium. The rate of deposition was 62.5% in both mesangial areas and Bowman's capsule. EDDs were frequently detected on the tubular basement membrane (TBM) (87.5% of patients). The interstitium also contained EDDs on collagen fibers in 87.5% of the cases and on basement membrane-like materials in areas of fibrosis in 37.5% of the cases. The creatinine clearance levels were significantly lower in the patients with the latter pattern. Meanwhile, the rate of immunoglobulin and/or complement deposition on the TBM was observed in less than 37.5% of patients, and these findings were not entirely coincident with the cases of EDDs on the TBM. Conclusion EDDs are frequently found in the glomeruli and interstitium in patients with IgG4-RKD; however, immunohistological studies do not provide evidence that IgG4-RKD involves TIN with immune complex nephropathy. The presence of interstitial EDDs may be related to the progression of interstitial fibrosis in the setting of IgG4-RKD.

The kidney is a major target organ for systemic amyloidosis, which results in proteinuria and an elevated serum creatinine level. The clinical manifestations and precursor proteins of amyloid A (AA) and light-chain (AL) amyloidosis are different, and the renal damage due to amyloid deposition also seems to differ. The purpose of this study was to clarify haw the difference in clinical features between AA and AL amyloidosis are explained by the difference in the amount and distribution of amyloid deposition in the renal tissues. A total of 119 patients participated: 58 patients with an established diagnosis of AA amyloidosis (AA group) and 61 with AL amyloidosis (AL group). We retrospectively investigated the correlation between clinical data, pathological manifestations, and the area occupied by amyloid in renal biopsy specimens. In most of the renal specimens the percentage area occupied by amyloid was less than 10%. For statistical analyses, the percentage area of amyloid deposition was transformed to a common logarithmic value (Log10%amyloid). The results of sex-, age-, and Log10%amyloid-adjusted analyses showed that systolic blood pressure (SBP) was higher in the AA group. In terms of renal function parameters, serum creatinine, creatinine clearance (Ccr) and estimated glomerular filtration rate (eGFR) indicated significant renal impairment in the AA group, whereas urinary protein indicated significant renal impairment in the AL group. Pathological examinations revealed amyloid was predominantly deposited at glomerular basement membrane (GBM) and easily transferred to the mesangial area in the AA group, and it was predominantly deposited at in the AL group. The degree of amyloid deposition in the glomerular capillary was significantly more severe in AL group. The frequency of amyloid deposits in extraglomerular mesangium was not significantly different between the two groups, but in AA group, the degree amyloid deposition was significantly more severe, and the deposition pattern in the glomerulus was nodular. Nodular deposition in extraglomerular mesangium leads to renal impairment in AA group. There are significant differences between AA and AL amyloidosis with regard to the renal function, especially in terms of Ccr, eGFR and urinary protein, even after Log10%amyloid was adjusted; showing that these inter-group differences in renal function would not be depend on the amount of renal amyloid deposits. These differences could be explained by the difference in distribution and morphological pattern of amyloid deposition in the renal tissue.

We previously described the relationship between clinical manifestations and amount of amyloid deposition in the renal biopsy specimens of amyloid A (AA) and light-chain (AL) amyloidosis. The amoun...

Multiple myeloma (MM) is a plasma-cell neoplasm that can cause renal disorders. Renal lesions in MM can present with a very rare pathological manifestation involving a specific monoclonal immunoglobulin (Ig). We report the case of a 33-year-old woman who had edema, fatigue, elevated serum creatinine levels, hypoalbuminemia, and hypercholesterolemia. She had persistent hematuria and proteinuria lasting 3 years. Serum protein electrophoresis showed an M-spike, and serum immunofixation demonstrated the presence of monoclonal IgG λ. She had proteinuria in the nephrotic range, and a monoclonal λ fragment was present on urine immunofixation. Renal biopsy showed proliferative glomerulonephritis with λ light chain and C3c deposition and inflammatory cell infiltration with CD68. Macrophage lysosomes contained λ light chains, suggesting their partial phagocytosis. She was diagnosed with symptomatic MM and was treated with bortezomib and dexamethasone and an autologous peripheral stem cell transplant conditioned with intravenous melphalan. She achieved a partial response with decreased serum monoclonal protein and improved renal function. This case may be categorized as a monoclonal gammopathy-associated proliferative glomerulonephritis. The biopsy finding of partially phagocytosed Ig λ light chains by macrophages is very rare; this pathological condition is similar to crystal-storing histiocytosis.

Background Patient and graft survival after successful kidney transplantation (KT) have improved despite an increase in the number of challenging cases. Various factors have evolved during the long history of kidney transplantation. Methods Between 1988 and 2012, a total of 292 living donor and 56 deceased donor KTs were performed at Niigata University Hospital. Long-term patient and graft survival and changes in background during a 20-year period in a single center were retrospectively analyzed. Results Excellent patient survival rates of 95.1% at 20 years for living donor KT and 96.2% at 15 years for deceased donor KT were observed. Graft survival rates at 1, 5, 10, 15, and 20 years were 96.8%, 95.4%, 83.1%, 61.8%, and 56.2% in living donor KT, respectively. In contrast, graft survival rates at 1, 5, 10, and 15 years in deceased donor KT were 89.0%, 80.3%, 77.3%, and 33.8%, respectively. These survival rates have dramatically improved since 2002 (91.7% for living and 80.9% for deceased donor KT at 10 years post-transplantation). The number of elderly recipients (older than 60 years) and the percentage of grafts donated from spouses have increased. The rejection rate decreased and the cytomegalovirus antigenemia–positive rate increased during the 20-year period assessed. The percentage of pre-emptive KTs progressively increased, with graft survival in this group tending to be better than non-preemptive KTs. The causes of graft loss were chronic allograft dysfunction (54.7%), acute rejection (11.1%), and malignancies (9.4%). After living donor KT, the principal predictors of graft loss were if the recipient was younger than 30 years, if the donor was older than 50 years, and if the rejection episodes occurred after living donor KT. In contrast, the only risk factor in the case of deceased donor KT occurred after transplantation from donors who were older than 50 years. Conclusions A summary of the long-term outcome of KT over 20 years in a single center has been reported. Along with the changes in patient backgrounds, immunosuppressive drugs, and our knowledge of transplantation, patient and graft survival outcomes have also changed. Investigation into such outcomes during a different transplantation era is required to fully appreciate advances in KT.

We aimed to examine the influence of donor age on living-donor kidney transplantation (KTx), particularly with regard to long-term graft survival in young recipients with aged kidney grafts. Between 1988 and 2012, 287 living-donor KTxs were performed in our center. The recipients were divided into 3 groups according to age in years: under 30 (young), 30–49 (middle-aged), and over 50 (old). The data regarding the influence of kidneys from donors aged over 50 years were retrospectively analyzed. Graft survival at 1, 5, 10, and 15 years was 94.7, 94.7, 90.2, and 75.2 %, respectively, in young recipients who received grafts from donors aged under 50 years, and 96.4, 91.9, 65.4, and 41.4 %, respectively, in young recipients who received grafts from donors aged over 50 years (P = 0.023). In contrast, there were no significant differences regarding graft survival and donor age in the middle-aged and old recipient groups. Multivariate analysis revealed that young recipient and rejection episode were significant predictors of graft loss in transplantation from older donors. Histological examination revealed significant age-related changes in the grafts before transplant and a significant higher rate of glomerular hypertrophy at the 1-month protocol biopsy in young recipients with aged kidney grafts. Kidney grafts from older living donors affected long-term graft survival in young recipients. In addition to the damage from rejection, aged kidney grafts, which have less nephron mass, may have a limited capacity to appropriately respond to increases in physiological or metabolic demands of young recipients, leading to a greater reduction in renal function.

A 47-year-old Japanese man was admitted to our hospital for evaluation of proteinuria, which was detected when he was 37 years of age. His creatinine clearance levels had fallen to 76.3 mL/min/1.73 m2. A kidney biopsy was conducted, and the patient’s low plasma α-galactosidase A levels suggested Fabry disease. After genetic counseling, GLA analysis revealed a novel mutation p.L387P. Interview with the patient revealed that both his younger brother and mother suffered from cardiomyopathy and were undergoing cardiological treatment. They also were positive for proteinuria. About 30 years ago, the patient’s cousin (aged 25) was diagnosed with Fabry disease. He underwent hemodialysis for 9 years until his death at 42. At that time, the patient and his brother had not been investigated for Fabry disease so their cousin could not act as a proband for the brothers. Eventually, the patient, his mother, and his brother were put on enzyme replacement therapy with agalsidase beta. As this series of cases shows, medical interviews to collate both medical and family history were essential for the discovery of Fabry disease in these patients. In addition, being a treatable genetic disorder, Fabry disease should be listed in the standard differential diagnoses of systemic and familial diseases, including unknown cause of nephropathy or cardiomyopathy, for early detection of the disorder.

A 36-year-old female received protocol biopsy at 1 month after living donor kidney transplantation. At 3 months post-transplantation, presence of a growing cystic mass in the kidney graft which had not been detected preoperatively, was demonstrated by ultrasound and computed tomography. The patient had an abdominal pain around the graft. Percutaneous drainage and sclerotherapy with minocyclin were performed twice, but the cystic mass, nevertheless, became enlarged and the abdominal pain recurred again. Laparoscopic fenestration was then performed. Immunohistochemistry of the cystic mass wall showed that it was CD34 (-), EMA (-), Megalin (-), but D2-40 (+). These results suggested that the cystic mass was derived from lymphatic vessels, which developed into lymphocele in the graft. We concluded that lymphatic vessels could have been injured and obstructed by the protocol biopsy. This is the first report of successful laparoscopic fenestration for lymphocele in the kidney graft.

We detected an increase in small arterioles around glomeruli, particularly adjacent to tuft adhesive lesions in immunoglobulin A nephropathy (IgAN), for the 1 st time, as far as we know. We labeled these as periglomerular microarterioles (PGMAs). This study aimed to clarify the pathological significance of PGMAs. Sixty-two patients with IgAN and 19 controls with minor glomerular abnormalities without proteinuria were evaluated in this study. The number of PGMAs located between the Bowman's capsule and the adjoining tubules was counted for each glomerulus. The mean number of PGMAs per glomerulus in cases of IgAN was significantly higher than those of the controls (0.530 ± 0.477 vs. 0.240 ± 0.182, P

A 31-year-old woman with proteinuria, hypocomplementemia, rheumatoid factor, and high serum polyclonal IgM concentration was admitted to our hospital for renal biopsy. She had a past history of two renal biopsies. When she was 12 years old, she developed proteinuria, microscopic hematuria, and hypocomplementemia. She was diagnosed as having ‘IgM nephropathy’ based on minor glomerular abnormalities as determined by light microscopy and IgM and C3 deposition in the mesangial region by immunofluorescence microscopy at the first biopsy. Despite corticosteroid treatment, her proteinuria did not improve and she discontinued regular outpatient checkups. When she was 29 years old and pregnant, she developed preeclampsia and, after delivery, a second renal biopsy was implemented. She was diagnosed as having progressed ‘IgM nephropathy’ with endotheliosis induced by preeclampsia. She was treated with angiotensin II receptor blocker and her proteinuria diminished; however, 1 year after the delivery, she developed proteinuria again, along with microscopic hematuria and hypocomplementemia. A third renal biopsy was conducted at 31 years of age and she was diagnosed as having membranoproliferative glomerulonephritis (MPGN) type I on the basis of diffuse mesangial proliferation, endocapillary hypercellularity with double contour of the capillary wall, and lobular formation in glomeruli, as determined by light microscopy. Immunofluorescence staining demonstrated deposits of C3, C4, C1q, and IgM in the mesangial region and capillary wall. She underwent corticosteroid therapy followed by normalization of urinalysis and serum complement level. Although she had initially been diagnosed with ‘IgM nephropathy’, she was finally diagnosed with secondary MPGN and was successfully treated by corticosteroid therapy.

Pentraxin-3 (PTX3) is an acute phase reactant produced by a variety of cell types at sites of local inflammation. We examined by immunohistochemistry renal biopsies from patients with acute rejection (n = 10), protocol biopsies without rejection (n = 37), and peri-operative donor biopsies of the same transplant patients (n = 94) for intra-renal expression of PTX3, and its correlation with clinical, laboratory, and histopathologic parameters. PTX3 was mainly expressed in the interstitium of renal allograft. In the non-rejection biopsies (pre- and post-reperfusion and protocol biopsies), PTX3 expression area (PTX3%) was equally maintained at a low level, whereas in the rejection biopsies, PTX3% was significantly higher (p

Immunoglobulin (Ig) G4-related kidney disease characterizing tubulointerstitial nephritis (TIN) is an organ complication recognized in IgG4-related systemic diseases that has some unique aspects compared to other types of TIN. TIN lesions in the kidney can be tumor-like, focal or diffuse. Abnormal urinalysis is usually mild or absent even in the cases with deteriorated renal dysfunction. Some cases are accidentally diagnosed from radiological findings without renal dysfunction and/or abnormal urinalysis. The typical pathological findings of TIN are unique fibrosis and infiltration of massive lymphocytes and IgG4-positive plasma cells. Glomerular lesions are rare but the complication of mesangial proliferative glomerulonephritis and membranous nephropathy is occasionally reported. Pathogenic mechanisms are unclear until now; however, auto-immune and allergic mechanisms have been suspected from laboratory data. The initial response to steroid agents is generally favorable; however, recurrence is possible after the discontinuation of steroid treatment. Long-term follow-up is necessary with continuous systemic checks for organ disorders due to IgG4-related systemic diseases.

Ikezumi Y, Suzuki T, Karasawa T, Hasegawa H, Yamada T, Imai N, Narita I, Kawachi H, Polkinghorne K R, Nikolic-Paterson D J & Uchiyama M (2011) Histopathology 58, 198–210 Identification of alternatively activated macrophages in new-onset paediatric and adult immunoglobulin A nephropathy: potential role in mesangial matrix expansion Aims: New onset of the clinical symptoms of immunoglobulin A (IgA) nephropathy (IgAN) manifests with proliferative glomerular lesions in children, whereas adults exhibit mesangial matrix expansion and interstitial fibrosis. Alternatively, activated (M2) macrophages have been implicated in promoting tissue fibrosis in some settings. Therefore, the aim of this study was to investigate whether M2 macrophages are present in new-onset IgAN and if they are related to pathological differences between paediatric and adult disease. Methods and results: Biopsy specimens from paediatric ( 12 years, n = 15) and adult (n = 27) IgAN showed a significant infiltrate of CD68+ macrophages. M2 macrophages, identified by CD163 or CD204 expression, were detected in glomeruli and the interstitium, being more prominent in adults versus young children. CD163+ and CD204+ macrophages were present in areas of fibrosis containing myofibroblasts, and double staining showed that CD163+ cells produced the profibrotic molecule, connective tissue growth factor. In young children, total CD68+ macrophages, but not M2 macrophages, correlated with glomerular hypercellularity. In contrast, in adults and older children, mesangial matrix expansion correlated with M2 macrophages but not with the total CD68+ macrophage infiltrate. Conclusions: Alternatively activated M2 macrophages are present in new-onset paediatric and adult IgAN, and this population may promote the development of fibrotic lesions.

IgG4-related disease is a recently recognized multi-organ disorder characterized by high levels of serum IgG4 and dense infiltration of IgG4-positive cells into several organs. Although the pancreas was the first organ recognized to be affected by IgG4-related disorder in the syndrome of autoimmune pancreatitis, we present here clinico-pathological features of 23 patients diagnosed as having renal parenchymal lesions. These injuries were associated with a high level of serum IgG4 and abundant IgG4-positive plasma cell infiltration into the renal interstitium with fibrosis. In all patients, tubulointerstitial nephritis was the major finding. Although 14 of the 23 patients did not have any pancreatic lesions, their clinicopathological features were quite uniform and similar to those shown in autoimmune pancreatitis. These included predominance in middle-aged to elderly men, frequent association with IgG4-related conditions in other organs, high levels of serum IgG and IgG4, a high frequency of hypocomplementemia, a high serum IgE level, a patchy and diffuse lesion distribution, a swirling fibrosis in the renal pathology, and a good response to corticosteroids. Thus, we suggest that renal parenchymal lesions actually develop in association with IgG4-related disease, for which we propose the term 'IgG4-related tubulointerstitial nephritis.'

Background Recessive inherited disorder lecithin-cholesterol acyltransferase (LCAT) deficiency causes severe hypocholesterolemia and nephrotic syndrome. Characteristic lipoprotein subfractions have been observed in familial LCAT deficiency (FLD) with renal damage. Objective We described a case of acquired LCAT deficiencies with literature review. Methods The lipoprotein profiles examined by gel permeation–high-performance liquid chromatography (GP-HPLC) and native 2-dimensional electrophoresis before and after prednisolone (PSL) treatment. Results Here we describe the case of a 67-year-old man with severely low levels of cholesterol. The serum LCAT activity was undetectable, and autoantibodies against it were detected. The patient developed nephrotic syndrome at the age of 70 years. Renal biopsy revealed not only membranous glomerulonephritis but also lesions similar to those seen in FLD. We initiated PSL treatment, which resulted in remission of the nephrotic syndrome. In GP-HPLC analysis, lipoprotein profile was similar to that of FLD although lipoprotein X level was low. Acquired LCAT deficiencies are extremely rare with only 7 known cases including ours. Patients with undetectable LCAT activity levels develop nephrotic syndrome that requires PSL treatment; cases whose LCAT activity levels can be determined may also develop nephrotic syndrome, but spontaneously recover. Conclusion Lipoprotein X may play a role in the development of renal impairment in individuals with FLD. However, the effect might be less significant in individuals with acquired LCAT deficiency.

The phenomenon of accommodation in recipients of blood group ABO incompatible kidney transplantation (iKTx), in which grafts survive despite the presence of blood group A or B antigen in the graft and the presence of corresponding antibodies in the recipient's blood, is not uncommon. alpha1,3-N-Acetylgalactosaminyltransferase and alpha1,3galactosyltransferase associated with the synthesis of blood group A and B antigen (A and B enzymes), respectively, were measured by a highly specific enzyme-linked immunosorbent assay in the sera and transplanted tissues of patients who underwent an ABO iKTx. Allogeneic A and B enzymes were present in the sera and tissues as well as A and B antigens in the tissues for a long period, which hitherto have never been seen in recipients prior to an iKTx. However, activities of these enzymes in the sera after an iKTx decreased in patients who experienced a serious acute antibody-mediated rejection and disappeared in patients who had an unrepairable rejection, leading to graft loss without establishment of accommodation. Our observations on the presence of allogeneic A and B enzymes in the recipients' sera should have implications in decision making for a successful iKTx.

Recently, a new clinical entity, IgG4-positive multi-organ lymphoproliferative syndrome (IgG4+ MOLPS), characterized by hyper-IgG4 gammaglobulinemia and IgG4-positive plasma cell tissue infiltration, has been proposed. It includes autoimmune pancreatitis (AIP), Mikulicz's disease, and many other inflammatory conditions affecting multiple organs. However, diagnosis is difficult if the disease is not suspected because serum IgG subclasses are not measured routinely and the affected organs vary. Because hypocomplementemia is often observed in this condition, we investigated the serum subclasses of IgG in patients with hypocomplementemia, especially of unknown etiology. We found 6 patients with high serum IgG4 levels among 10 patients with hypocomplementemia of unknown etiology who visited our hospital between December 2004 and September 2007. The results of additional pathological and imaging examinations in the 6 patients with high serum IgG4 levels were compatible with IgG4+ MOLPS. Our results suggest that hypocomplementemia of unknown etiology offers an opportunity to find cases of IgG4+ MOLPS.

We present here two cases of kidney transplantation from a non-heart beating deceased donor after long cold-ischemic time (CIT) more than 24 h. The donor was a young male who died of severe subarachnoid hemorrhage. Grafts were transplanted into two different patients one after another in our hospital. Their total ischemic times were 24 and 43 h because they were the fourth and fifth candidates on the waiting list. Although the anuric phase continued for more than three wk in both cases, finally their grafts functioned well with the nadir serum creatinine of 2.2 and 1.8 mg/dL, respectively. We evaluated protocol biopsies after 50 d from the transplantation. Both biopsy specimens revealed diffuse interstitial fibrosis, particularly more severe in the second recipient. The expression of 8-OHdG, one of the histochemical markers of oxidative stress, was more strongly expressed in the biopsy specimens of pre-perfusion and protocol biopsy in the same case. From these results, it was suspected that the interstitial fibrosis was induced by oxidative stress derived from the longer CIT and the following reperfusion.

Systemic lupus erythematosus (SLE) and IgG4-related disease (IgG4-RD) both result from altered inflammatory and immunological responses. They also present with similar clinical and renal histological findings. In both conditions, the urinalysis can appear normal despite the presence of active nephritis. The serological examination demonstrates positive anti-nuclear antibodies and hypocomplementemia, and the serum levels of IgG and IgG4 are elevated in both SLE and IgG4-RD. Although polyclonal gammopathies are found in both conditions, the frequent finding of an IgG4 predominance is characteristic of IgG4-related kidney disease (IgG4-RKD). Increases in IgE are also typical of IgG4-RKD. Tubulointerstitial nephritis (TIN) and the infiltration of IgG4-bearing plasma cells into the interstitium observed using light microscopy are common to both. Thus, careful examination with immunofluorescence and electron microscopy are essential to establishing the correct diagnosis. The “full-house” pattern of immunoglobulin and complement deposition in the tubular basement membranes are distinguishing features of TIN in lupus nephritis. In contrast, storiform fibrosis, often observed most easily with periodic acid-methenamine silver staining, is the pathognomonic feature of IgG4-RKD.