Monoclonal and polyclonal immunoglobulin G deposits on tubular basement membranes of native and pretransplant kidneys: A retrospective study.

Monoclonal tubular basement membrane immune deposits (TBMID) are associated with progression of interstitial injury in renal allograft. However, the significance of monoclonal and polyclonal TBMID in the native kidney remains unclear. We retrospectively analyzed 1894 native kidney biopsies and 1724 zero-hour biopsies performed between 2008 and 2018 in our institution. The rate of immunoglobulin G (IgG) TBMID was found to be 8.4% among native kidney biopsies and 0.4% among zero-hour biopsies. Polyclonal TBMID is common in IgG4-related tubulointerstitial nephritis (37.5%), diabetic nephropathy (31.3%) and lupus nephritis (25.5%). Monoclonal IgG TBMID was identified in seven cases, including three zero-hour biopsies. The combination of IgG1κ was observed in two cases, IgG1λ in three, and IgG2κ in two. Electron microscopy revealed powdery electron-dense deposits in all cases. Monoclonal gammopathy of undetermined significance was diagnosed in one case. Although one patient with focal segmental glomerulosclerosis developed renal failure, all others exhibited stable renal function. Monoclonal IgG TBMID in the native kidney is not associated with renal prognosis. However, this may be an interesting immunopathological finding that would help clarify the pathogenesis of TBM immune deposits. Further study for both monoclonal and polyclonal TBMID is required in the future.

Deletion in the Cobalamin Synthetase W Domain-Containing Protein 1 Gene Is associated with Congenital Anomalies of the Kidney and Urinary Tract.

BACKGROUND: Researchers have identified about 40 genes with mutations that result in the most common cause of CKD in children, congenital anomalies of the kidney and urinary tract (CAKUT), but approximately 85% of patients with CAKUT lack mutations in these genes. The anomalies that comprise CAKUT are clinically heterogenous, and thought to be caused by disturbances at different points in kidney development. However, identification of novel CAKUT-causing genes remains difficult because of their variable expressivity, incomplete penetrance, and heterogeneity. METHODS: We investigated two generations of a family that included two siblings with CAKUT. Although the parents and another child were healthy, the two affected siblings presented the same manifestations, unilateral renal agenesis and contralateral renal hypoplasia. To search for a novel causative gene of CAKUT, we performed whole-exome and whole-genome sequencing of DNA from the family members. We also generated two lines of genetically modified mice with a gene deletion present only in the affected siblings, and performed immunohistochemical and phenotypic analyses of these mice. RESULTS: We found that the affected siblings, but not healthy family members, had a homozygous deletion in the Cobalamin Synthetase W Domain-Containing Protein 1 (CBWD1) gene. Whole-genome sequencing uncovered genomic breakpoints, which involved exon 1 of CBWD1, harboring the initiating codon. Immunohistochemical analysis revealed high expression of Cbwd1 in the nuclei of the ureteric bud cells in the developing kidneys. Cbwd1-deficient mice showed CAKUT phenotypes, including hydronephrosis, hydroureters, and duplicated ureters. CONCLUSIONS: The identification of a deletion in CBWD1 gene in two siblings with CAKUT implies a role for CBWD1 in the etiology of some cases of CAKUT.

Renal hypoplasia can be the cause of membranous nephropathy-like lesions.

BACKGROUND: Renal hypoplasia (RH) is the most common cause of chronic kidney disease in children. In cases of RH, proteinuria is often induced by glomerular hypertrophy and hyperfiltration that is commonly associated with focal segmental glomerulosclerosis. This study reports the first case series of a possible association between RH and membranous nephropathy (MN). METHODS: Of the 168 children with RH who visited our department between 1999 and 2017, five with overt proteinuria (≥ 1 g/gCr) underwent renal biopsy. We retrospectively reviewed the medical charts and analyzed biopsy specimens using light microscopy (LM), immunofluorescence (IF), and electron microscopy. RESULTS: The five children (four boys and one girl) had a median age of 5.5 years at the time of renal biopsy. The median proteinuria was 4.23 g/gCr (range 1.46-14.25), median serum albumin, 2.9 g/dL (range 2.3-3.7), and median estimated glomerular filtration rate, 59.7 mL/min/1.73 m2 (range 36.7-103.6). LM showed segmental spike formation and mesangial hypercellularity and IF study showed segmental granular immunoglobulin G (IgG) staining (IgG1 and IgG3 dominant) along the capillary loops in all five patients. Electron-dense deposits were observed in the subepithelial and mesangial areas. Thus, the pathological studies showed MN-like lesions in all patients. CONCLUSION: Our study suggests that RH can be the cause of MN-like lesions.

Monoclonal immunoglobulin G deposits on tubular basement membrane in renal allograft: is this significant for chronic allograft injury?

BACKGROUND: Tubular basement membrane immune deposits (TBMID) has rarely been observed in renal allografts. It is usually found in BK virus nephropathy and immune complex glomerulonephritis; however, its significance is not well understood. We conducted a retrospective clinicopathological study on monoclonal immunoglobulin G (IgG) TBMID. METHODS: We studied 7177 renal allograft biopsy specimens obtained from Tokyo Women's Medical University from 2007 to 2015 and performed light microscopic, electron microscopic and immunofluorescence studies. RESULTS: Tubular basement membrane (TBM) deposits of IgG were found in 73 biopsies from 61 patients and the IgG subclass was obtained in 31 biopsies. There were no cases of monoclonal IgA or IgM TBMID. In total, 13 biopsies from 10 patients showed monoclonal IgG TBMID. Of these, seven showed monoclonal IgG1κ TBMID and one each showed monoclonal IgG2κ, IgG2λ and IgG3κ TBMID. Conversely, eight patients showed polyclonal IgG TBMID. In electron microscopy, large granular electron-dense deposits (EDDs) in the TBM were detected in all patients with monoclonal IgG1κ TBMID. EDDs were absent in TBM in patients with monoclonal IgG2κ, IgG2λ or IgG3κ TBMID. Progression of interstitial fibrosis and tubular atrophy (IFTA) was significantly higher in patients with monoclonal IgG1κ TBMID than in those with polyclonal IgG TBMID (P < 0.05). There were no significant differences in the other clinical parameters between monoclonal IgG1κ and polyclonal IgG TBMID. CONCLUSIONS: This is the first study of patients with monoclonal IgG TBMID in renal allografts. We found that monoclonal IgG1κ TBMID was associated with EDD formation in TBM and IFTA progression.

Fate of full-house immunofluorescence staining in renal allograft: A case report.

Here, we report the case of a patient with renal allograft with full-house immunofluorescence staining in the zero-hour biopsy. Full-house immunofluorescence staining is a well-known characteristic of lupus nephritis. Previous studies have reported patients with full-house immunofluorescence staining, but without other symptoms or serological findings; this condition is referred to as full-house nephropathy. We identified only one case out of 2203 zero-hour biopsies over 13 years. Zero-hour biopsy presented no glomerular changes but showed full-house immunofluorescence staining. Electron microscopy revealed a nonorganized electron-dense deposit mainly in the mesangial lesion. Systemic lupus erythematosus (SLE)-associated antibodies were negative, and complement deficiency was not observed in the donor patients. Deposition of immunoglobulin and complement levels markedly decreased within 1-3 years post transplantation. Neither donor nor recipient developed clinical or biological features of SLE; they showed good renal prognosis.

A case of recurrent proliferative glomerulonephritis with monoclonal IgG deposits or de novo C3 glomerulonephritis after kidney transplantation.

Proliferative glomerulonephritis with monoclonal immunoglobulin (Ig)G deposits (PGNMID) is a rare disease with a treatment that is not well established. Several cases of recurrent PGNMID after kidney transplantation have been documented, but almost all cases reported symptoms such as elevated serum creatinine and/or urinary protein levels; subsequently, episode biopsies were performed and a diagnosis was made. This is the case of a 27-year-old man who underwent living-donor kidney transplantation. The aetiology of renal failure was membranoproliferative glomerulonephritis type III, which had been diagnosed at the age of 9 years. Protocol biopsy performed on postoperative day 62 revealed isolated granular C3 deposits in the glomerular capillaries and mesangium. We reviewed the native kidney biopsy and confirmed IgG3 deposition alone, with strong glomerular staining for lambda light chains and negative staining for kappa light chains. Accordingly, we re-diagnosed the aetiology of his renal failure as PGNMID and suspected recurrent PGNMID in the early stage; therefore, we administered plasma exchange therapy. Thereafter, protocol biopsies were performed twice, which revealed persistent isolated C3 deposition; therefore, we made a diagnosis of recurrent PGNMID or C3 glomerulonephritis. Currently, the patient has normal renal function, with negative urine findings for >1 year. Here, we present the histological findings of consecutive allograft biopsies performed in this patient.

Clinicopathological study of de novo membranous nephropathy of 'stage 0' after kidney transplantation.

AIM: De novo membranous nephropathy (dnMN) contributes to graft failure, but the pathophysiology of the disease remains poorly understood. We defined cases exhibiting granular Immunoglobulin G (IgG) immunofluorescence staining but lacking dense deposits on electron microscopy as being of 'dnMN stage 0'; we studied the associated clinicopathological features. METHODS: We studied 4653 allograft biopsy specimens (from 1747 cases treated in the Department of Urology, Tokyo Women's Medical University) and found 42 cases of allograft membranous nephropathy, of which 28 (1.6%) were diagnosed as dnMN. Of these, five cases (0.06%) fulfilled the criteria for dnMN stage 0. RESULTS: All five cases were diagnosed based on biopsies indicating increased serum levels of creatinine. Proteinuria status varied from negative to 2+. The median period from transplantation to allograft biopsy was 4068 days. Four of the five cases exhibited suspicious antibody-mediated rejection together with dnMN. The glomerular capillaries of all cases were C4d-positive, as were the peritubular capillaries of three of the four ABO-compatible transplants. In terms of IgG subclass, IgG1 and IgG3 predominated in all cases, and phospholipase A2 receptor status (evaluated via immunoreactivity) was negative in all cases. We examined two cases by immunoelectron microscopy using anti-IgG and anti-C4d antibodies. We found subendothelial and intramembranous deposits expressing both IgG and C4d, corresponding to positivity in immunofluorescence analysis. CONCLUSION: We confirmed the existence of dnMN stage 0 by focusing on granular IgG immunofluorescence positivity.

Long-term survival in Japanese renal transplant recipients with Alport syndrome: a retrospective study.

BACKGROUND: Patients with Alport syndrome (AS) develop progressive kidney dysfunction due to a hereditary type IV collagen deficiency. Survival of the kidney allograft in patients with AS is reportedly excellent because AS does not recur. However, several studies have implied that the type IV collagen in the GBM originates from podocytes recruited from the recipient's bone marrow-derived cells, suggesting the possibility of AS recurrence. Limited data are available regarding AS recurrence and graft survival in the Japanese population; the vast majority were obtained from living related kidney transplantation (LRKTx). METHODS: In this retrospective study, twenty-one patients with AS were compared with 41 matched patients without AS from 1984 to 2015 at two centers using propensity scores. Nineteen of the 21 patients with AS underwent LRKTx. The mean post-transplant follow-up period was 83 months in the AS group and 110 months in the control group. Histopathological AS recurrence was assessed by immunoreactivity of α5 (type IV collagen) antibody and electron microscopy. RESULTS: The graft survival rate was equivalent between patients with and without AS (86.7% vs. 77.1% and 69.3% vs. 64.2% at 5 and 10 years; p = 0.16, log-rank test). Immunoreactivity to α5 antibody showed strong linear positivity with no focal defect in six patients. Electron microscopy showed no GBM abnormalities in two patients who were exhibiting long-term kidney allograft survival. CONCLUSIONS: We confirmed that α5 and the GBM structure were histopathologically maintained in the long term after kidney transplantation. The patient and graft survival rates were equivalent between Japanese patients with and without AS.

M-type phospholipase A2 receptor (PLA2R) glomerular staining in pediatric idiopathic membranous nephropathy.

BACKGROUND: Identifying M-type phospholipase A2 receptor (PLA2R) is a landmark breakthrough for understanding adult idiopathic membranous nephropathy (iMN). However, potential roles for PLA2R in pediatric iMN have not been well investigated. METHODS: A total of 34 pediatric iMN patients who underwent kidney biopsy between 1972 and 2015 were enrolled in this study. The study cohort consisted of 15 children aged from 3 to 9 years and 19 aged from 10 to 15 years. In all cases, secondary causes of MN, including infections, autoimmune diseases, and others, were ruled out. We examined PLA2R glomerular staining in stored, formalin-fixed, paraffin-embedded kidney biopsy samples. Kidney biopsy specimens obtained from an adult patient with iMN and an adult patient with lupus-associated MN were also examined to assess our PLA2R staining procedure. RESULTS: Granular staining of PLA2R along glomerular capillary loops was present in two patients: an 11-year-old girl and 12-year-old boy identified during a school urine screening test and who presented with mild proteinuria at the time of biopsy. Interestingly, the intensity of PLA2R glomerular staining in these patients was weaker than that of a PLA2R-positive adult iMN patient. There were no PLA2R-positive patients among our cohort of children younger than 10 years. CONCLUSIONS: This preliminary study suggests PLA2R may play a role in some adolescent and preteen iMN patients but may be less frequently associated with iMN during childhood.

Recurrence and graft loss after renal transplantation in adults with IgA vasculitis.

BACKGROUND: IgA vasculitis, a rare condition resulting in end-stage renal disease, is a small-vessel vasculitis that affects the kidney in 49-83 % of adults. The reported recurrence rate of IgA vasculitis in renal transplant recipients is 11.5-60 %, leading to graft loss in 0-50 % of these patients. However, limited data are available on recurrence and graft loss after renal transplantation. METHODS: We evaluated renal transplant recipients seen from 1987 to 2015 at the Jikei University School of Medicine and the Department of Urology, Tokyo Women's Medical University. Using a 1:2 match, 21 patients with IgA vasculitis and 42 controls were selected. The mean post-transplant follow-up was 121 ± 69 months for IgA vasculitis and 147 ± 66 months for the controls. RESULTS: The 15-year patient survival was 100 % in IgA vasculitis and 97.6 % in the controls (p = 0.22). The 5-, 10-, and 15-year graft survival rates were 95.2, 90.5, and 81 % in IgA vasculitis and 100, 90.5, and 88.1 % in the controls, respectively (p = 0.63). The recurrence rate was 28.6 % (6 of 21 cases) and half of them (3 of 6 cases) showed histological activity (ISKDC III). We treated them with methylprednisolone pulse therapy and/or tonsillectomy. None of the recurrence cases lost the allograft. CONCLUSION: The long-term patient and graft survival of IgA vasculitis in renal transplantation were comparable with the previous reports. The recurrence rate was 28.6 %, but none of the recurrent cases showed allograft loss in this study. We speculate that methylprednisolone pulse therapy and/or tonsillectomy prevent the progression of recurrent IgA vasculitis.

Afadin is localized at cell-cell contact sites in mesangial cells and regulates migratory polarity.

In kidney glomeruli, mesangial cells provide structural support to counteract for expansile forces caused by pressure gradients and to regulate the blood flow. Glomerular injury results in proliferation and aberrant migration of mesangial cells, which is the pathological characteristic of mesangial proliferative glomerulonephritis. To date, molecular changes that occur in mesangial cells during glomerular injury and their association with the pathogenesis of glomerulonephritis remain largely unclear. During the search for proteins regulating the morphology of mesangial cells, we found that afadin, a multi-domain F-actin-binding protein, and ß-catenin are expressed in cell-cell contact sites of cultured mesangial cells and mesangial cells in vivo. Afadin forms a protein complex with ß-catenin in glomeruli and in cultured mesangial cells. Protein expression of afadin at mesangial intercellular junctions was dramatically decreased in mesangial proliferative nephritis in rats and in patients with glomerulonephritis. RNA interference-mediated depletion of afadin in cultured mesangial cells did not affect proliferation rate but resulted in delayed directional cell migration. Furthermore, reorientation of the Golgi complex at the leading edges of migrating cells in wound-healing assay was disturbed in afadin-depleted cells, suggesting the role of aberrant migratory polarity in the pathogenesis of proliferative glomerulonephritis. These data shed light on glomerulonephritis-associated changes in cell-cell adhesion between mesangial cells, which might be related to migratory polarity.

The prognostic values of caveolin-1 immunoreactivity in peritubular capillaries in patients with kidney transplantation.

The low sensitivity of C4d immunoreactivity in peritubular capillaries (PTCs) hinders its use in the diagnosis of chronic active antibody-mediated rejection (CAAMR). C4d-negative CAAMR was defined in the 2013 Banff classification, which included the expression of endothelial-associated transcripts (ENDATs). We previously showed that the ENDAT caveolin-1 (CAV-1) is a distinct feature of CAAMR. In this study, we investigated the prognostic value of CAV-1 immunoreactivity in PTCs in kidney transplant patients. Ninety-eight kidney transplant recipients were included in this study. The prognostic value of CAV-1 immunoreactivity in PTCs was evaluated by double immunostaining for CAV-1 and pathologische Anatomie Leiden endothelium (PAL-E, a PTC marker) in the PTCs of kidney allograft biopsy samples. The patients were divided into two groups: CAV-1/PAL-E<50% and CAV-1/PAL-E≥50%. Kaplan-Meier curves showed that CAV-1/PAL-E≥50% patients had a significantly worse prognosis than that of CAV-1/PAL-E<50% patients (log-rank; P<.001). C4d staining of PTCs was not associated with the development of graft failure (log-rank; P=.345), whereas in a multivariate Cox regression analysis, CAV-1 immunoreactivity in PTCs was independently associated with graft failure (hazard ratio: 11.1; P=.0324). CAV-1 immunoreactivity in PTCs may serve as a prognostic marker for kidney allograft survival.

Proliferative glomerulonephritis with monoclonal immunoglobulin G deposits complicated by immunoglobulin A nephropathy in the renal allograft.

Immunoglobulin (Ig) A nephropathy (IgAN) is a known autoimmune disease due to abnormal glycosylation of IgA1, and occasionally, IgG co-deposition occurs. The prognosis of IgG co-deposition with IgAN is adverse, as shown in the previous studies. However, in the clinical setting, monoclonality of IgG co-deposition with IgAN has not been observed. We describe a case of proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) combined with IgAN in a renal allograft. A-21-year-old man developed end-stage renal failure with unknown aetiology and underwent living-donor kidney transplantation from his mother 2 years after being diagnosed. One year after kidney transplantation, proteinuria 2+ and haematuria 2+ were detected; allograft biopsy revealed mesangial IgA and C3 deposits, indicating a diagnosis of IgAN. After tonsillectomy and steroid pulse therapy, proteinuria and haematuria resolved. However, 4 years after transplantation, pedal oedema, proteinuria (6.89 g/day) and allograft dysfunction (serum creatinine (sCr) 203.3 µmol/L) appeared. A second allograft biopsy showed mesangial expansion and focal segmental proliferative endocapillary lesions with IgA1λ and monoclonal IgG1κ depositions. Electron microscopic analysis revealed a massive amount of deposits, located in the mesangial and subendothelial lesions. A diagnosis of PGNMID complicated with IgAN was made, and rituximab and plasmapheresis were added to steroid pulse therapy. With this treatment, proteinuria was alleviated to 0.5 g/day, and the allograft dysfunction recovered to sCr 132.6 µmol/L. This case suggests a necessity for investigation of PGNMID and IgA nephropathy in renal allografts to detect monoclonal Ig deposition disease.

Recurrence of diabetic kidney disease in a type 1 diabetic patient after kidney transplantation.

Post-transplant hyperglycaemia of diabetic patients may cause recurrent diabetic kidney disease (DKD) in kidney allografts. We report a patient with slowly progressive DKD with calcineurin inhibitor toxicity (CNI) toxicity after the kidney transplantation. A 28-year-old female with type 1 diabetes mellitus underwent successful kidney transplantation from her mother in April 2003, and the kidney graft survived for more than 10 years. She was treated with combined immunosuppressive therapy consisting of cyclosporine and mycophenolate mofetil. After transplantation, she continued to take insulin injection four times per day, but her glycosylated haemoglobin (HbA1c) was above 10%. Protocol allograft kidney biopsies performed 5 and 10 years after transplantation revealed the recurrence of slowly progressive diabetic kidney disease. In addition, arteriolar hyalinosis partly associated with calcineurin inhibitor toxicity (CNI) was detected with progression. Post-transplant hyperglycaemia causes recurrent diabetic kidney disease (DKD) in kidney allografts, but its progression is usually slow. For long-term management, it is important to prevent the progression of the calcineurin inhibitor arteriolopathy, as well as maintain favourable glycaemic control.

A case of recurrent focal segmental glomerulosclerosis after kidney transplantation associated with variant conversion in the Columbia classification.

Focal segmental glomerulosclerosis commonly recurs following kidney transplantation. A 33-year-old man underwent living donor kidney transplantation. Proteinuria appeared two months after transplantation, and an episode biopsy on postoperative day 66 revealed recurrent focal segmental glomerulosclerosis lesions of the cellular variant by Columbia classification. We reviewed the native kidney biopsy and confirmed collapsing variant focal segmental glomerulosclerosis. Plasma exchange therapy was performed, and his proteinuria temporarily resolved. A second allograft biopsy performed on postoperative day 200 showed no evidence of focal segmental glomerurosclerosis. He experienced incomplete remission with a proteinuria of 0.5 g/day during the subsequent three years until his urinary protein level rose to 1.3 g/day. A third biopsy performed on postoperative day 1248 showed focal segmental glomerulosclerosis cellular variant lesions. Plasma exchange was resumed in combination with additional rituximab, but his proteinuria persisted. Intermittent plasma exchange was performed 42 times in total. However, his proteinuria continued, and his renal function gradually worsened. A fourth biopsy performed on postoperative day 2540 showed focal segmental glomerulosclerosis collapsing variant lesions with severe interstitial fibrosis and tubular atrophy. He ultimately required hemodialysis seven years after transplantation. Intensive therapy with long-term intermittent plasma exchange and rituximab suppressed proteinuria and preserved graft function for seven years, at which time graft failure occurred. We here present the clinical course and histological findings from consecutive allograft biopsies.

Epithelial protein lost in neoplasm modulates platelet-derived growth factor-mediated adhesion and motility of mesangial cells.

Mesangial cell migration, regulated by several growth factors, is crucial after glomerulopathy and during glomerular development. Directional migration requires the establishment of a polarized cytoskeletal arrangement, a process regulated by coordinated actin dynamics and focal adhesion turnover at the peripheral ruffles in migrating cells. Here we found high expression of the actin cross-linking protein EPLIN (epithelial protein lost in neoplasm) in mesangial cells. EPLIN was localized in mesangial angles, which consist of actin-containing microfilaments extending underneath the capillary endothelium, where they attach to the glomerular basement membrane. In cultured mesangial cells, EPLIN was localized in peripheral actin bundles at focal adhesions and formed a protein complex with paxillin. The MEK-ERK (extracellular signal-regulated kinase) cascade regulated EPLIN-paxillin interaction and induced translocalization of EPLIN from focal adhesion sites to peripheral ruffles. Knockdown of EPLIN in mesangial cells enhanced platelet-derived growth factor-induced focal adhesion disassembly and cell migration. Furthermore, EPLIN expression was decreased in mesangial proliferative nephritis in rodents and humans in vivo. These results shed light on the coordinated actin remodeling in mesangial cells during restorative remodeling. Thus, changes in expression and localization of cytoskeletal regulators underlie phenotypic changes in mesangial cells in glomerulonephritis.

LMX1B mutation with residual transcriptional activity as a cause of isolated glomerulopathy.

BACKGROUND: Nail-patella syndrome (NPS) is a rare autosomal-dominant disorder caused by LMX1B mutation. In patients with the renal lesions typical of NPS without skeletal or nail findings, it is described as nail-patella-like renal disease (NPLRD). However, the pathogenesis of NPLRD is largely unknown. METHODS: A 6-year-old girl with microscopic haematuria and mild proteinuria was diagnosed with NPLRD because of an aberrantly thickened glomerular basement membrane (GBM) and deposition of Type III collagen in the GBM observed by electron microscopy. Immunohistological analyses of podocyte protein expression were performed on biopsy tissues. Sequence analysis of LMX1B was performed, and the functional consequences of the detected mutation were analysed by luciferase reporter assay. RESULTS: When analysing molecules that are important for podocyte development, maintenance and maturation, CD2AP expression was found to be altered in the podocytes. A novel LMX1B missense mutation (R246Q) was identified. Functional analyses revealed partial but significant impairment of R246Q transcriptional activity. However, no dominant-negative effect of R246Q was detected, which suggests that NPLRD is caused by LMX1B haploinsufficiency. CONCLUSIONS: This is the first report on LMX1B mutation identified in a patient with NPLRD. Residual transcriptional activity would account for normality of the nails and patella in this case. Genetic and pathological analyses of additional cases would clarify the role of LMX1B in glomerulopathy without systemic symptoms, which, together with nephropathy in NPS, can be designated as 'LMX1B nephropathy'.

Proliferative glomerulonephritis with monoclonal immunoglobulin A light-chain deposits in the renal allograft.

We herein describe the unique case of a 59-year-old man who underwent living kidney transplantation for IgA nephropathy (IgAN) and developed progressive kidney failure associated with the appearance of proliferative glomerulonephritis. An early protocol biopsy revealed recurrent IgAN with mesangial IgA2 deposits restricted to a single immunoglobulin λ light-chain isotype. Despite treatment with tonsillectomy and rituximab, the patient eventually lost his allograft 31 months after transplantation. Serum electrophoresis showed a monoclonal IgA pattern. This case might share common pathological characteristics with the newly described entity referred to as proliferative glomerulonephritis with monoclonal IgG deposits.

Sequential analysis of donor-specific antibodies and pathological findings in acute antibody-mediated rejection in a rat renal transplantation model.

Alloantibodies contribute significantly to renal transplant rejection by activation of complement and various cytokines with a variety of effector cells, and are a major cause of allograft loss. Although there is clinical evidence of antibody- and complement-mediated injury in renal transplantation, the mechanism of antibody-mediated rejection remains largely unknown. In order to understand the sequential production of antibodies and complement components, we presensitized recipient rats by skin transplantation. Anti-donor-specific IgG levels reached a maximum 2 weeks following presensitization after which the rats underwent renal transplantation from the same donor strain. We then evaluated sequential pathological findings based on the Banff classification and several factors related to graft rejection. In this presensitized model, peritubular capillaries were already dilated and stained for C4d. Neutrophil and mononuclear cell infiltration in these capillaries was detected beginning 2 h after transplantation. Donor-specific antibody IgG levels decreased rapidly and anti-IgG antibody stained glomerular and peritubular capillaries in the grafts beginning 2 h after transplantation. Additionally, several cytokines and complement components showed marked changes in the presensitized group. Thus, in the donor-specific presensitized recipient, alloantibodies and complement were activated immediately after transplant. C4d deposition in peritubular capillaries appears to be a key factor for the diagnosis of antibody-associated rejection.