DEVELOPING THERAPIES FOR C3G: REPORT OF THE KIDNEY HEALTH INITIATIVE C3G TRIAL ENDPOINTS WORK GROUP.

Randomized clinical trials are underway to evaluate the efficacy of novel agents targeting the alternative complement pathway in patients with C3G, a rare glomerular disease. The Kidney Health Initiative (KHI) convened a panel of experts in C3G to: (1) assess the data supporting the use of the prespecified trial endpoints as measures of clinical benefit; and (2) opine on efficacy findings they would consider compelling as treatment(s) for C3G in native kidneys. Two subpanels of the C3G Trial Endpoints Work group reviewed the available evidence and uncertainties for the association between the three prespecified endpoints -- (1) proteinuria; (2) estimated glomerular filtration rate (eGFR); and (3) histopathology -- and anticipated outcomes. The full work group provided feedback on the summaries provided by the subpanels and on what potential treatment effects on the proposed endpoints they would consider compelling to support evidence of an investigational product's effectiveness for treating C3G. Members of the full work group agreed with the characterization of the data, the evidence, and uncertainties, supporting the endpoints. Given the limitations of the available data, the workgroup was unable to define a minimum threshold for change in any of the endpoints that might be considered clinically meaningful. The workgroup concluded that a favorable treatment effect on all three endpoints would provide convincing evidence of efficacy in the setting of a therapy that targeted the complement pathway. A therapy might be considered effective in the absence of complete alignment in all three endpoints if there was meaningful lowering of proteinuria and stabilization or improvement in eGFR. The panel unanimously supported efforts to foster data sharing between academic and industry partners to address the gaps in the current knowledge identified by the review of the endpoints in the aforementioned trials.

Executive summary of the KDIGO 2021 guideline for the management of glomerular diseases

The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Management of Glomerular Diseases is an update to the KDIGO 2012 guideline. The aim is to assist clinicians caring for individuals with glomerulonephritis (GN), both adults and children. The scope includes various glomerular diseases, including IgA nephropathy and IgA vasculitis, membranous nephropathy, nephrotic syndrome, minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), infection-related GN, antineutrophil cytoplasmic antibody (ANCA) vasculitis, lupus nephritis, and anti­glomerular basement membrane antibody GN. In addition, this guideline will be the first to address the subtype of complement-mediated diseases. Each chapter follows the same format providing guidance related to diagnosis, prognosis, treatment, and special situations. The goal of the guideline is to generate a useful resource for clinicians and patients by providing actionable recommendations based on evidence syntheses, with useful infographics incorporating views from experts in the field. Another aim is to propose research recommendations for areas where there are gaps in knowledge. The guideline targets a broad global audience of clinicians treating GN while being mindful of implications for policy and cost. Development of this guideline update followed an explicit process whereby treatment approaches and guideline recommendations are based on systematic reviews of relevant studies, and appraisal of the quality of the evidence and the strength of recommendations followed the "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) approach. Limitations of the evidence are discussed, with areas of future research also presented

A Comparison of Pulsatile Hypothermic and Normothermic Ex Vivo Machine Perfusion in a Porcine Kidney Model.

BACKGROUND: Hypothermic machine perfusion (HMP) is a well-established method for deceased donor kidney preservation. Normothermic machine perfusion (NMP) might offer similar or greater advantages. We compared the 2 methods in an ex vivo perfusion model using 34 porcine kidneys. METHODS: Thirty kidneys were stored on ice for 24 h before undergoing 4 h of HMP (n = 15) or NMP (n = 15) followed by 2 h of normothermic ex vivo reperfusion with whole blood. Four kidneys underwent 28 h of cold static storage followed by 2 h of normothermic ex vivo reperfusion. During the 2 h of normothermic ex vivo reperfusion, perfusate flow rates, urinary output, and oxygen consumption rates were compared between all groups. RESULTS: Porcine kidneys after HMP showed significantly higher urinary output (5.31 ± 2.06 versus 2.44 ± 1.19 mL/min; P = 0.002), oxygen consumption (22.71 ± 6.27 versus 11.83 ± 1.29 mL/min; P = 0.0016), and perfusate flow rates (46.24 ± 12.49 versus 26.16 ± 4.57 mL/min; P = 0.0051) than kidneys after NMP. TUNEL staining of tissue sections showed significantly higher rates of apoptosis in kidneys after NMP (P = 0.027). CONCLUSIONS: In our study, the direct comparison of HMP and NMP kidney perfusion in a translational model demonstrated superiority of HMP; however, further in vivo studies would be needed to validate those results.

Is there long-term value of pathology scoring in immunoglobulin A nephropathy? A validation study of the Oxford Classification for IgA Nephropathy (VALIGA) update.

BACKGROUND: It is unknown whether renal pathology lesions in immunoglobulin A nephropathy (IgAN) correlate with renal outcomes over decades of follow-up. METHODS: In 1130 patients of the original Validation Study of the Oxford Classification for IgA Nephropathy (VALIGA) cohort, we studied the relationship between the MEST score (mesangial hypercellularity, M; endocapillary hypercellularity, E; segmental glomerulosclerosis, S; tubular atrophy/interstitial fibrosis, T), crescents (C) and other histological lesions with both a combined renal endpoint [50% estimated glomerular filtration rate (eGFR) loss or kidney failure] and the rate of eGFR decline over a follow-up period extending to 35 years [median 7 years (interquartile range 4.1-10.8)]. RESULTS: In this extended analysis, M1, S1 and T1-T2 lesions as well as the whole MEST score were independently related with the combined endpoint (P < 0.01), and there was no effect modification by age for these associations, suggesting that they may be valid in children and in adults as well. Only T lesions were associated with the rate of eGFR loss in the whole cohort, whereas C showed this association only in patients not treated with immunosuppression. In separate prognostic analyses, the whole set of pathology lesions provided a gain in discrimination power over the clinical variables alone, which was similar at 5 years (+2.0%) and for the whole follow-up (+1.8%). A similar benefit was observed for risk reclassification analyses (+2.7% and +2.4%). CONCLUSION: Long-term follow-up analyses of the VALIGA cohort showed that the independent relationship between kidney biopsy findings and the risk of progression towards kidney failure in IgAN remains unchanged across all age groups and decades after the renal biopsy.

Successful management of post-transplant focal segmental glomerulosclerosis with therapeutic plasma exchange and rituximab.

BACKGROUND: Post-transplant focal segmental glomerulosclerosis (FSGS) is associated with renal allograft loss. Currently, optimal treatment remains controversial. METHODS: The aim of our study was to examine the efficacy and safety of therapeutic plasma exchange (TPE), and rituximab (RTX), in the management of post-transplant FSGS. The treatment protocol consisted of RTX and monthly cycles of 5 plasma exchanges for 6 months. We treated 10 transplant recipients with biopsy-proven post-transplant FSGS. Lastly, we compared the studied group to a historic control group of nine patients with post-transplant FSGS. RESULTS: 9 out of 10 patients achieved remission after the conclusion of treatment (4 complete and 5 partial), while 1 patient did not respond to treatment. During the follow-up period, there was one graft loss and one patient died while in remission from unrelated complications. There was a significant reduction in mean uPCR between diagnosis (517.4 ± 524.2 mg/mmol) and last follow-up (87 ± 121.6 mg/mmol) in the patients with sustained remission (p = 0.026). There was no significant decline in eGFR in the eight relapse-free responders at the end of follow-up. (54.4 ± 16.7 from 49.8 ± 20.4 ml/min) (p = 0.6) An increased response rate to the combined TPE and RTX treatment was demonstrated, when compared to a historic control group of nine patients with post-transplant FSGS, as only five out of nine patients achieved remission (two complete and three partial) in that group. CONCLUSIONS: In this study, treatment with TPE and RTX appears to be safe, well tolerated and effective in the management of patients with post-transplant FSGS.

Dual-hormone regulation of psychopathy: Evidence from mass spectrometry.

Previous work suggests that testosterone and cortisol interactively predict psychopathy. This effect represents a reversal of the established dual-hormone hypothesis, whereby testosterone is positively correlated with psychopathic traits, but only among individuals with elevated cortisol concentrations. This study aims to replicate the dual-hormone moderation of psychopathy in two independent samples. Enzyme-linked immunoassays (ELISAs) were used to assess cortisol across both samples and testosterone in Sample 1 (n = 165, 100% males). To address recent criticism of ELISAs and potentially extend these findings to women, testosterone concentrations were determined by liquid chromatography tandem mass spectrometry (LC-MS/MS) in Sample 2 (n = 213, 44.1% males). We found conflicting evidence of the dual-hormone moderation of psychopathic traits. Although results were non-significant in Sample 1, a reversal of the dual-hormone hypothesis was found in Sample 2, in which testosterone was positively correlated with psychopathic traits, but only among individuals with high cortisol. This replication provides mixed support for less common reversals to the dual-hormone hypothesis. These findings emphasize the importance of using LC-MS/MS to measure testosterone and adds to the growing body of work on the relationship between hormones and psychopathology in general.

Protocol and rationale for the first South Asian 5-year prospective longitudinal observational cohort study and biomarker evaluation investigating the clinical course and risk profile of IgA nephropathy: GRACE IgANI cohort.

Background: IgA nephropathy (IgAN) is the most common primary glomerulonephritis and an important cause of end-stage kidney disease. Unlike the slowly progressive course seen among Caucasian and East Asian subjects (actuarial survival 80-85% over 10 years), in India about 30-40% of patients have nephrotic syndrome and renal dysfunction at presentation and a 10-year renal survival of 35%, as reported from a retrospective registry. These observations cannot be entirely attributed to a lack of uniform screening protocols or late referral and attest to the probability that IgAN may not be the same disease in different parts of the world. Methods: We will prospectively recruit 200 patients with IgAN (the GRACE IgANI- Glomerular Research And Clinical Experiments- Ig A Nephropathy in Indians-cohort) and stratify them into low and high risk of progression based on published absolute renal risk scores. We will test the validity of this risk score in an unselected Indian IgAN population over a 5-year follow-up period. In parallel, we will undertake extensive exploratory serum, urine, renal and microbiome biomarker studies, firstly, to determine if the underlying pathogenic pathways are the same in Indian IgAN compared to those reported in Caucasian and East Asian IgAN. Secondly, we will systematically assess the value of measuring selected biomarkers and adding this data to traditional measures of risk in IgAN to predict kidney failure. We ultimately hope to generate a composite IgAN risk score specific for the Indian population. Ethics and data dissemination: Approval was obtained from the Institutional Review Board (Silver, Research and Ethics Committee) of the Christian Medical College, Vellore, India (Ref. No. IRB Min. No. 8962 [Other] dated 23.07.2014 and IRB Min. No. 9481 [Other] dated 24.06.2015). It is anticipated that results of this study will be presented at national and international meetings, with reports being published from late 2018.

Crescentic glomerulonephritis with anti-GBM antibody but no glomerular deposition.

BACKGROUND: Anti-glomerular basement membrane (GBM) antibodies are highly specific for Goodpasture's or anti-GBM disease, in which they are generally directed against the non-collagenous (NC1) domain of the alpha 3 chain of type IV collagen(α3(IV)), and less commonly, toward the α 4(IV) or α 5(IV) chains, which form a triple helical structure in GBM and alveolar basement membrane (ABM). Alterations in the hexameric structure of the NC1 (α3 (IV)), allows novel epitopes to be exposed and an immune response to develop, with subsequent linear antibody deposition along the GBM, leading to a crescentic glomerulonephritis. Positive anti-GBM antibodies are assumed to be pathogenic and capable of binding GBM in vivo, especially in the context of rapidly progressive glomerulonephritis. We have investigated patients with circulating anti-GBM antibodies, reactive to α3 (IV) and human GBM by immunoassays and Western blotting respectively, with focal necrotising crescentic glomerulonephritis but no linear GBM antibody deposition on immunohistochemistry. Three out of four were also ANCA positive. Despite not binding native GBM, patients' sera showed linear binding to primate glomeruli by indirect immunofluorescence, in the 2 cases tested. Following treatment, significant improvements in kidney function were found in 3/4 patients. CASE PRESENTATION: We present four patients with crescentic glomerulonephritis and circulating anti-GBM antibodies, but no glomerular binding. CONCLUSIONS: These novel findings, demonstrate that in some patients anti-GBM antibodies may not bind their own GBM. This has important implications for clinical diagnosis, suggesting that histological confirmation of kidney injury by anti-GBM antibodies should be obtained, as non-binding GBM antibodies may be associated with significant renal recovery.

Tonsillectomy in a European Cohort of 1,147 Patients with IgA Nephropathy.

BACKGROUND: Tonsillectomy has been considered a treatment for IgA nephropathy (IgAN). It is aimed at removing a source of pathogens, reducing mucosa-associated lymphoid tissue and decreasing polymeric IgA synthesis. However, its beneficial effect is still controversial. In Asia, favorable outcomes have been claimed mostly in association with corticosteroids. In Europe, small, single-center uncontrolled studies have failed to show benefits. METHODS: The European validation study of the Oxford classification of IgAN (VALIGA) collected data from 1,147 patients with IgAN over a follow-up of 4.7 years. We investigated the outcome of progression to end-stage renal disease (ESRD) and/or 50% loss of estimated glomerular filtration rate (eGFR) and the annual loss of eGFR in 61 patients who had had tonsillectomy. RESULTS: Using the propensity score, which is a logistic regression model, we paired 41 patients with tonsillectomy and 41 without tonsillectomy with similar risk of progression (gender, age, race, mean blood pressure, proteinuria, eGFR at renal biopsy, previous treatments and Oxford MEST scores). No significant difference was found in the outcome. Moreover, we performed an additional propensity score pairing 17 patients who underwent tonsillectomy after the diagnosis of IgAN and 51 without tonsillectomy with similar risk of progression at renal biopsy and subsequent treatments. No significant difference was found in changes in proteinuria, or in the renal end point of 50% reduction in GFR and/or ESRD, or in the annual loss of eGFR. CONCLUSION: In the large VALIGA cohort of European subjects with IgAN, no significant correlation was found between tonsillectomy and renal function decline.

Tubuloreticular Inclusions in Renal Allografts Associate with Viral Infections and Donor-Specific Antibodies.

The presence of tubuloreticular inclusions (TRIs) in native glomerular endothelial cells associates with viral infections and lupus nephritis. However, the associations of TRIs in renal transplant biopsy specimens are not known. We analyzed data from 316 patients who had a transplant biopsy with electron microscopy examination; 41 of 316 (13.0%) patients had TRIs. Patients with TRIs had significantly lower allograft survival rates (50.9%) than patients without TRIs (74.3%; P=0.03). Transplant glomerulopathy-free survival was also inferior in the TRI-positive group (57.5%) compared with the TRI-negative group (87.3%; P=0.002). Serologically, hepatitis C associated with the presence of TRIs (P=0.04) along with donor-specific antibodies (P=0.01). Furthermore, patients who were TRI positive were more likely than patients who were TRI negative to have had a previous rejection episode (P=0.02). On multivariate analysis, TRIs associated with prior rejection, viral infections, and class 1 HLA donor-specific antibodies. These results show that the presence of TRIs in renal allograft biopsy specimens associates with poor allograft outcomes and serologic evidence of viral infections and alloimmunity. The association with alloimmunity is a novel finding that warrants additional investigation.

Local IL-17 Production Exerts a Protective Role in Murine Experimental Glomerulonephritis.

IL-17 is a pro-inflammatory cytokine implicated in the pathogenesis of glomerulonephritis and IL-17 deficient mice are protected from nephrotoxic nephritis. However, a regulatory role for IL-17 has recently emerged. We describe a novel protective function for IL-17 in the kidney. Bone marrow chimeras were created using wild-type and IL-17 deficient mice and nephrotoxic nephritis was induced. IL-17 deficient hosts transplanted with wild-type bone marrow had worse disease by all indices compared to wild-type to wild-type bone marrow transplants (serum urea p<0.05; glomerular thrombosis p<0.05; tubular damage p<0.01), suggesting that in wild-type mice, IL-17 production by renal cells resistant to radiation is protective. IL-17 deficient mice transplanted with wild-type bone marrow also had a comparatively altered renal phenotype, with significant differences in renal cytokines (IL-10 p<0.01; IL-1ß p<0.001; IL-23 p<0.01), and macrophage phenotype (expression of mannose receptor p<0.05; inducible nitric oxide synthase p<0.001). Finally we show that renal mast cells are resistant to radiation and produce IL-17, suggesting they are potential local mediators of disease protection. This is a novel role for intrinsic cells in the kidney that are radio-resistant and produce IL-17 to mediate protection in nephrotoxic nephritis. This has clinical significance as IL-17 blockade is being trialled as a therapeutic strategy in some autoimmune diseases.

Macrophage epoxygenase determines a profibrotic transcriptome signature.

Epoxygenases belong to the cytochrome P450 family. They generate epoxyeicosatrienoic acids, which are known to have anti-inflammatory effects, but little is known about their role in macrophage function. By high-throughput sequencing of RNA in primary macrophages derived from rodents and humans, we establish the relative expression of epoxygenases in these cells. Zinc-finger nuclease-mediated targeted gene deletion of the major rat macrophage epoxygenase Cyp2j4 (ortholog of human CYP2J2) resulted in reduced epoxyeicosatrienoic acid synthesis. Cyp2j4(-/-) macrophages have relatively increased peroxisome proliferator-activated receptor-γ levels and show a profibrotic transcriptome, displaying overexpression of a specific subset of genes (260 transcripts) primarily involved in extracellular matrix, with fibronectin being the most abundantly expressed transcript. Fibronectin expression is under the control of epoxygenase activity in human and rat primary macrophages. In keeping with the in vitro findings, Cyp2j4(-/-) rats show upregulation of type I collagen following unilateral ureter obstruction of the kidney, and quantitative proteomics analysis (liquid chromatography-tandem mass spectrometry) showed increased renal type I collagen and fibronectin protein abundance resulting from experimentally induced crescentic glomerulonephritis in these rats. Taken together, these results identify the rat epoxygenase Cyp2j4 as a determinant of a profibrotic macrophage transcriptome that could have implications in various inflammatory conditions, depending on macrophage function.

Long-term outcome of anti-neutrophil cytoplasm antibody-associated glomerulonephritis: evaluation of the international histological classification and other prognostic factors.

BACKGROUND: Anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis with renal involvement requires treatment with potentially toxic drugs to reduce morbidity and mortality, and there is a major challenge to determine clinical and histological features predictive of renal prognosis. The aim of our study was to evaluate the use of the 2010 international histological classification for ANCA-associated glomerulonephritis (AAGN) as a predictor of renal outcome when used in conjunction with other prognostic factors. METHODS: One hundred and four patients with AAGN treated at our centre were included: 23 were classified as focal, 26 as crescentic, 48 as mixed and 7 as sclerotic. Renal outcomes were based on estimated glomerular filtration rate (eGFR) at 1 and 5 years, and on renal survival. RESULTS: By univariate analysis, patients in the focal class had the best renal outcome, those in the sclerotic class the worst outcome, and those in the mixed and crescentic classes had intermediate renal survival. There was no significant difference in outcome between the mixed and crescentic classes. In multivariate models, histological class did not improve model fit or associate with renal outcome after adjusting for established prognostic factors. Lower percentage of normal glomeruli, greater degree of tubular atrophy (TA), MPO-ANCA positivity, increasing age and lower starting eGFR, all correlated with poorer renal outcomes. CONCLUSIONS: We conclude that, in our cohort of patients, the international histological classification is predictive of renal outcome in AAGN, but did not appear to be additionally informative over other established prognostic factors in multivariate analysis. However, it may be of value to combine the current histological classification with other established parameters, such as TA and percentage normal glomeruli.

Adenocarcinoma of the seminal vesicles complicated by antineutrophil cytoplasmic antibody vasculitis: a case report and review of the literature.

INTRODUCTION: Adenocarcinoma of the seminal vesicles is a very rare malignancy, with less than 100 cases reported worldwide. It is documented to have a poor prognosis, with the majority of patients developing metastatic disease, most commonly in the prostate, bladder and rectum. Currently there is no standard treatment for metastatic disease and the limited reports of treatment with radiotherapy, chemotherapy and hormonal (anti-androgenic) therapy show that they are generally of modest benefit. The association between malignancy and an increased risk of autoimmune vasculitis has been demonstrated in a number of malignancies, but to date there have been no documented cases of adenocarcinoma of the seminal vesicles associated with anti-neutrophil cytoplasmic antibody vasculitis. CASE PRESENTATION: In this report we describe the case of a 55-year-old Caucasian man with metastatic adenocarcinoma of the seminal vesicles. He previously had received chemotherapy treatment for advanced testicular cancer and later presented with hemospermia. He subsequently developed c-antineutrophil cytoplasmic antibody vasculitis requiring intensive immunosuppression and renal dialysis. CONCLUSION: Adenocarcinoma of the seminal vesicles is a rare diagnosis and our case is more unusual in that our patient previously had chemotherapy treatment for advanced testicular cancer and went on to develop severe antineutrophil cytoplasmic antibody vasculitis when diagnosed with metastatic seminal vesicle cancer. This case illustrates that autoimmune vasculitis can occur in any patient with malignancy and an early referral to the renal team combined with renal biopsy can assist in the earlier diagnosis and more successful management of these rare events. This case should be of interest to oncologists, renal physicians, urologists and general physicians who encounter patients presenting with hemospermia or vasculitis.

C3 glomerulonephritis/CFHR5 nephropathy is an endemic disease in Cyprus: clinical and molecular findings in 21 families.

Microscopic haematuria is the presenting symptom of several conditions, either heritable or acquired. A well-recognized familial condition is Alport syndrome, either of X-linked or autosomal recessive inheritance, as well as thin basement membrane nephropathy (TBMN) because of heterozygous collagen IV mutations. Even though microscopic haematuria of TBMN was long considered as a benign disease with excellent prognosis, more recent data suggest that development of chronic kidney disease (CKD) and even end-stage kidney disease (ESKD) is not a rare finding, perhaps owing to the cofounding role of modifier genes and other factors. Recent investigations in London and Cyprus culminated in the identification of another autosomal dominant condition that presents with microscopic haematuria because of heterozygous mutations in the CFHR5 gene, which apparently plays a pivotal role in the regulation of the alterative pathway of complement system, which constitutes a significant part of innate immunity in humans. Histologically, the hallmark observation is the isolated glomerular deposition of C3 complement in the absence of immune complexes. It is considered one of the C3 glomerulopathies, and it may or may not be accompanied by mild membranoproliferative glomerulonephritis. Interestingly, a single mutation has been identified so far, a duplication of exons 2-3 of the CFHR5 gene, and it has been described in patients of Greek-Cypriot descend only, perhaps originating on the Troodos mountains of Cyprus. Thus far, no patient with a mutation in this gene has been diagnosed in any other population. In Cyprus, it has been found in clusters of families in neighbouring villages in a total of 136 patients, and it constitutes a strong founder phenomenon. About 50% of patients over 50 years have progressed to CKD, and 14% of all patients progressed to ESKD. It is not quite well understood why males run a much higher risk to progress to CKD, compared to women.

Loss of properdin exacerbates C3 glomerulopathy resulting from factor H deficiency.

Complement factor H (CFH) is a negative regulator of the alternative pathway of complement, and properdin is the sole positive regulator. CFH-deficient mice (CFH(-/-)) develop uncontrolled C3 activation and spontaneous renal disease characterized by accumulation of C3 along the glomerular basement membrane, but the role of properdin in the pathophysiology is unknown. Here, we studied mice deficient in both CFH and properdin (CFH(-/-).P(-/-)). Although CFH(-/-) mice had plasma depleted of both C3 and C5, CFH(-/-).P(-/-) animals exhibited depletion of C3 predominantly, recapitulating the plasma complement profile observed in humans with properdin-independent C3 nephritic factors. Glomerular inflammation, thickening of the capillary wall, and glomerular C3 staining were significantly increased in CFH(-/-).P(-/-) compared with CFH(-/-) mice. We previously reported that exogenous CFH ameliorates C3 staining of the glomerular basement membrane and triggers the appearance of mesangial C3 deposits in CFH(-/-) mice; here, we show that these effects require properdin. In summary, during uncontrolled activation of C3 driven by complete CFH deficiency, properdin influences the intraglomerular localization of C3, suggesting that therapeutic inhibition of properdin would be detrimental in this setting.

Recognizing isolated IgG4-related nephropathy.

IgG4-related tubulointerstitial nephritis is an uncommon cause of renal impairment. It has been associated with dysfunction in a number of other organs giving rise to the term IgG4-related systemic disease; organ involvement can occur metachronously, hence, making it more difficult to identify patients. The exact cause of this condition remains unknown. Here, we present a case of isolated renal involvement which demonstrates how particular biochemical, radiological and histopathological changes should raise the suspicion of IgG4-related nephropathy, especially when there is an absence of clues from any other organ.

De novo DQ donor-specific antibodies are associated with a significant risk of antibody-mediated rejection and transplant glomerulopathy.

BACKGROUND: The importance of human leukocyte antigen (HLA) matching in renal transplantation is well recognized, with HLA-DR compatibility having the greatest influence. De novo DQ donor-specific antibodies (DSAbs) are the predominant HLA class II DSAb after transplantation. The aim of this study was to establish the incidence and outcomes after the development of DQ DSAbs along with the impact of class II HLA mismatch on their development. METHODS: We retrospectively analyzed 505 patients who received a renal-alone transplant between 2005 and 2010. We excluded patients who received an ABO- and HLA-incompatible allograft, which we defined as those with a positive crossmatch or preformed DSAbs detected by single-antigen beads only. RESULTS: Of 505 patients, 92 (18.2%) developed DSAbs, with 50 (54.3%) of these 92 patients having DQ DSAbs. Patients who developed DQ DSAbs were at significant risk for antibody-mediated rejection, transplant glomerulopathy, and allograft loss (P<0.0001). Of 505 patients, 108 (21.4%) were matched at both the DR and DQ loci, 284 (56.2%) were mismatched at both loci, 38 (7.5%) were matched at DR alone, and 75 (14.9%) were matched at DQ alone. Patients mismatched at both DR and DQ were at risk for developing class II DSAbs when compared with those mismatched at either DR or DQ alone, P=0.001, and were at risk for antibody-mediated rejection, P=0.001. CONCLUSIONS: DQ DSAbs are associated with inferior allograft outcomes. This study shows the importance of establishing the DQ match before transplantation to define immunologic risk.

Hyperglycemia causes renal cell damage via CCN2-induced activation of the TrkA receptor: implications for diabetic nephropathy.

CCN2, a secreted profibrotic protein, is highly expressed in diabetic nephropathy (DN) and implicated in its pathogenesis; however, the actions of CCN2 in DN remain elusive. We previously demonstrated that CCN2 triggers signaling via tropomyosin receptor kinase A (TrkA). Trace expression of TrkA is found in normal kidneys, but its expression is elevated in several nephropathies; yet its role in DN is unexplored. In this study we show de novo expression of TrkA in human and murine DN. We go on to study the molecular mechanisms leading to TrkA activation and show that it involves hypoxia, as demonstrated by ischemia-reperfusion injury and in vitro experiments mimicking hypoxia, implicating hypoxia as a common pathway leading to disease. We also expose renal cells to hyperglycemia, which led to TrkA phosphorylation in mesangial cells, tubular epithelial cells, and podocytes but not in glomerular endothelial cells and renal fibroblasts. In addition, we report that hyperglycemia caused an induction of phosphorylated extracellular signal-related kinase 1/2 and Snail1 that was abrogated by silencing of TrkA or CCN2 using small interfering RNA. In conclusion, we provide novel evidence that TrkA is activated in diabetic kidneys and suggest that anti-TrkA therapy may prove beneficial in DN.