KCTD1 and Scalp-Ear-Nipple ('Finlay-Marks') syndrome may be associated with myopia and Thin basement membrane nephropathy through an effect on the collagen IV α3 and α4 chains.

INTRODUCTION: Scalp-Ear-Nipple syndrome is caused by pathogenic KCTD1 variants and characterised by a scalp defect, prominent ears, and rudimentary breasts. We describe here further clinical associations in the eye and kidney. METHODS: Fifteen affected members from two unrelated families with p.(Ala30Glu) or p.(Pro31Leu) in KCTD1 were examined for ocular and renal abnormalities. The relevant proteins were studied in the eye and kidney, and the mutation consequences determined from mouse knockout models. RESULTS: Five males and 10 females with a median age of 40 years (range 1-70) with pathogenic variants p.(Ala30Glu) (n = 12) or p.(Pro31Leu) (n = 3) in KCTD1 were studied. Of the 6 who underwent detailed ophthalmic examination, 5 (83%) had low myopic astigmatism, the mean spherical equivalent of 10 eyes was 2.38D, and one (17%) had hypermetropic astigmatism. One female had a divergent strabismus.Five individuals had renal cysts (5/15, 33%), with renal biopsy in one demonstrating a thinned glomerular basement membrane identical to that seen in Thin basement membrane nephropathy (AD Alport syndrome).In the eye, KCTD1 and its downstream targets, TFAP2, and the collagen IV α3 and α4 chains localised to the cornea and near the retinal amacrine cells. In the kidney, all these proteins except TFAP2 were expressed in the podocytes and distal tubules. TFAP2B and COL4A4 knockout mice also had kidney cysts, and COL4A3 and COL4A4 knockout mice had myopia. CONCLUSION: Individuals with a pathogenic KCTD1 variant may have low myopic astigmatism and represent a further rare genetic cause for a thinned glomerular basement membrane.

Assessment of Restored Kidney Transplantation Including the Use of Wider Criteria for Accepting Renal Donors After Cancer Excision.

The transplantation of kidneys after cancer excision (restored kidney transplantation, RKT) warrants further evaluation as a source of kidneys for transplantation. We determined whether larger cancers can be safely transplanted, the risks of adverse events from RKT, and whether RKT confers a survival advantage for patients waiting for transplantation. METHODS: In a retrospective cohort study, 23 dialysis patients awaiting transplant underwent RKT at John Hunter Hospital, Australia between 2008 and 2015. Patients were >60 years old and accepted onto the National Organ Matching Service. This RKT Group was divided into donor renal cancers ≤30 mm and >30-≤50 mm. Adverse event profiles for RKT recipients were compared with 22 standard live donor recipients using logistic regression analyses. Recipient and transplant survivals for RKT were compared with 2050 controls from Australian New Zealand Dialysis Transplant Registry using Cox regression models. To increase statistical power for survival analyses, data from 25 RKT recipients from Princess Alexandra Hospital, Brisbane were added, thus creating 48 RKT recipients. RESULTS: There were no significant differences in mortality, transplant failure nor AEs between the 2 cancer Groups. RKT increased the risks of Adverse event profiles (odds ratio: 6.48 [2.92-15.44]; P < 0.001). RKT reduced mortality risk by 30% (hazard ratio [HR]: 0.70 [0.36-1.07]; P = 0.299) compared with those continuing on the transplant list who may or may not be transplanted. RKT significantly reduced mortality risk for those remaining on dialysis (HR: 2.86 [1.43-5.72]; P = 0.003). Transplant survival for RKT was reduced compared with control deceased donor (HR: 0.42 [0.21-0.83]; P = 0.013) and live donor transplants (HR: 0.33 [0.02-0.86]; P =0.023). CONCLUSIONS: The use of larger carefully selected cancer-resected kidneys for transplantation appears safe and effective. RKT confers a possible survival advantage compared with waiting for transplantation, an increased survival compared with those remaining on dialysis but reduced transplant survival.

Metastatic lung adenocarcinoma- associated thrombotic microangiopathy in a renal transplant recipient.

Thrombotic microangiopathy (TMA) after renal transplantation can be a diagnostic challenge. TMA can occur with calcineurin inhibitors, allograft rejection, infection, mutations in complement regulatory proteins and autoimmunity. A 52-year-old male renal transplant recipient presented with extensive deep vein thrombosis. He developed transfusion-dependent microangiopathic haemolytic anaemia with thrombocytopenia. He did not respond calcineurin inhibitor cessation, eculizumab or plasma exchange. ADAMTS13 and complement levels were normal. Infection and autoimmune screens were negative. A diagnosis of metastatic adenocarcinoma was made on bone marrow biopsy. This represents a rare case of malignancy-associated TMA in a renal transplant recipient. Early diagnosis can facilitate the prompt initiation of chemotherapy which is the only treatment option.

Functional significance and risk factors for lymphocele formation after renal transplantation.

BACKGROUND: Lymphocele development following renal transplantation is a significant adverse event. It may cause acute graft dysfunction or venous obstruction. There are no consistent risk factors reported in literature. Perioperative fluid balance may lead to increased lymphocele formation and has never been studied. We aimed to analyse incidence and risk factors for lymphocele formation. We hypothesized that overhydration in perioperative period is a risk factor. METHODS: We analysed 250 consecutive renal transplant recipients from 2006 to 2014. All recipients had undergone protocol screening by computerized tomography and ultrasound scan at 3 months post-transplant. We analysed risk factors for lymphocele formation. Comparisons between lymphocele and no-lymphocele groups were made with binary logistic regression analyses. Renal function was compared between treated, untreated and no-lymphocele groups with linear regression analyses. RESULTS: Thirty-one of 250 (12.4%) transplant recipients developed lymphocele. Fourteen of 31 (45.4%) recipients required intervention due to symptoms (venous obstruction being the most common). Surgical drainage was done in all symptomatic patients (11 laparoscopic and three open). Two of 11 (18%) recipients had recurrence after laparoscopic drainage. There were no significant differences in risk factors between the lymphocele and no-lymphocele groups. Renal function was comparable between no-lymphocele and treated lymphocele groups. Untreated lymphocele group trended towards better graft function at 1 year (P = 0.051). CONCLUSION: Post-transplant lymphocele developed one in eight transplant recipients and tended to occur in those with good renal function. Around half of the recipients with lymphocele required intervention with good recovery of long-term renal function. No risk factor for lymphocele development was established.

Anti-PD-1-induced high-grade hepatitis associated with corticosteroid-resistant T cells: a case report.

Effective treatment or prevention of immune side effects associated with checkpoint inhibitor therapy of cancer is an important goal in this new era of immunotherapy. Hepatitis due to immunotherapy with antibodies against PD-1 is uncommon and generally of low severity. We present an unusually severe case arising in a melanoma patient after more than 6 months uncomplicated treatment with anti-PD-1 in an adjuvant setting. The hepatitis rapidly developed resistance to high-dose steroids, requiring anti-thymocyte globulin (ATG) to achieve control. Mass cytometry allowed comprehensive phenotyping of circulating lymphocytes and revealed that CD4+ T cells were profoundly depleted by ATG, while CD8+ T cells, B cells, NK cells and monocytes were relatively spared. Multiple abnormalities in CD4+ T cell phenotype were stably present in the patient before disease onset. These included a population of CCR4-CCR6- effector/memory CD4+ T cells expressing intermediate levels of the Th1-related chemokine receptor CXCR3 and abnormally high multi-drug resistance type 1 transporter (MDR1) activity as assessed by a rhodamine 123 excretion assay. Expression of MDR1 has been implicated in steroid resistance and may have contributed to the severity and lack of a sustained steroid response in this patient. The number of CD4+ rhodamine 123-excreting cells was reduced > 3.5-fold after steroid and ATG treatment. This case illustrates the need to consider this form of steroid resistance in patients failing treatment with corticosteroids. It also highlights the need for both better identification of patients at risk and the development of treatments that involve more specific immune suppression.

Enteric-coated mycophenolate sodium in combination with full dose or reduced dose cyclosporine, basiliximab and corticosteroids in Australian de novo kidney transplant patients.

AIM: Cyclosporine (CsA), dosed to achieve C2 targets, has been shown to provide safe and efficacious immunosuppression when used with a mycophenolate and steroids for de novo kidney transplant recipients. This study examined whether use of enteric-coated mycophenolate sodium (EC-MPS) together with basiliximab and steroids would enable use of CsA dosed to reduced C2 targets in order to achieve improved graft function. METHODS: Twelve-month, prospective, randomized, open-label trial in de novo kidney transplant recipients in Australia. Seventy-five patients were randomized to receive either usual exposure (n = 33) or reduced exposure (n = 42) CsA, EC-MPS 720 mg twice daily, basiliximab and corticosteroids. RESULTS: There was no significant difference in mean Cockcroft-Gault CrCl (creatinine clearance) (60.2 ± 17.6 mL/min per 1.73 m(2) vs 63.2 ± 24.3, P = 0.64 for usual versus reduced exposure respectively) at 6 months. There was no significant difference between treatment groups in the incidence of treatment failure defined as biopsy proven acute rejection, graft loss or death (secondary endpoint: 30.3% full exposure vs 35.7% reduced exposure). At 12 months the incidence of overall adverse events was the same in both groups. CONCLUSION: This exploratory study suggests de novo renal transplant patients can safely receive a treatment regimen of either full or reduced exposure CsA in combination with EC-MPS, corticosteroids and basiliximab, with no apparent difference in efficacy or graft function during the first year after transplant.

Effect of immunosuppression for primary renal disease on the risk of cancer in subsequent renal transplantation: a population-based retrospective cohort study.

BACKGROUND: To measure the risk of cancer in renal transplantation for recipients who had previously been treated with immunosuppressive agents for primary renal disease. METHODS: A retrospective population-based cohort study of 5970 renal transplant recipients in Australia registered on the Australia and New Zealand Dialysis and Transplant Registry between 1982 and 1997 and followed until 2007. Data about the incidence of a range of cancer types from this Registry were compared with cancer incidence data for the general population matched for cancer type, year of incidence, age, and gender derived from national cancer records. Outcome measures for each cancer group with or without pretransplantation immunosuppression were cancer-specific standardized incidence ratios and a multivariate hazard ratio (HR) standardized to 1. RESULTS: For those treated with pretransplantation immunosuppression, the risks for four cancer groups during renal transplantation were significantly increased: anogenital cancer (HR, 3.13; confidence interval [CI], 1.92-5.11; P<0.0001), non-Hodgkin's lymphoma (HR, 2.37; CI, 1.53-3.68; P=0.0001), breast cancer (HR, 2.52; CI, 1.13-5.61; P=0.024), and urinary tract cancer (excluding kidney) (HR, 1.84; CI, 1.13-3.01; P=0.015). However, the risks of cancer in the oral cavity and pharynx, kidney, thyroid, colon, leukemia, lung, melanoma, prostate, and stomach were not significantly increased. CONCLUSIONS: Pretransplantation immunosuppression for primary renal disease increases the risks of four cancer types in renal transplantation while sparing the others. Patients in whom this treatment is being considered should be informed of these risks.

Monoclonal gammopathy and glomerulopathy associated with chronic lymphocytic leukemia.

BACKGROUND: A 42-year-old previously healthy man was referred to hospital with an 8-week history of fevers, night sweats, fatigue, and unintentional weight loss. There was no past history of medical illness or any medication use. Physical examination was unremarkable. On urinalysis, the patient had hematuria (grade 4+) and proteinuria (grade 4+). INVESTIGATIONS: Urine phase-contrast microscopy, full blood count, renal function tests, 24-h urine collection for protein, serum immune electrophoresis, renal biopsies, phase-contrast microscopy, serological tests for antinuclear antibodies, extractable nuclear antigens, antineutrophil cytoplasmic antibodies, hepatitis B, hepatitis C and HIV, cryoglobulin test, complement testing, flow cytometry of the peripheral blood, and bone marrow biopsy. DIAGNOSIS: Monoclonal gammopathy and a glomerulopathy, with microtubular deposits, associated with chronic lymphocytic leukemia. MANAGEMENT: Treatment with prednisone and cyclophosphamide did not improve proteinuria, although lymphocyte count returned to normal. The patient did not tolerate high-dose cyclophosphamide and was started on rituximab. His proteinuria completely resolved and there was complete disappearance of the microtubules.

Association between cytokine gene polymorphisms and outcomes in renal transplantation: a meta-analysis of individual patient data.

BACKGROUND: Cytokine gene polymorphisms have been associated with poor outcomes after renal transplantation such as chronic allograft nephropathy (CAN), graft rejection (GR) and graft failure (GF), but the effects of these polymorphisms are still controversial. We therefore conducted a systematic review, with individual patient data (IPD) where possible, to determine the association between cytokine polymorphisms (TGF-beta1, TNF-alpha and IL-10) and outcomes after renal transplantation. METHODS: Five investigators were willing to participate and provided IPD. The outcomes of interest were GF, GR and CAN. Subjects with at least one of these were classified as having poor outcomes. Heterogeneity of gene effects was assessed. Multiple logistic regression was applied to assess gene effects, adjusting for clinical variables such as HLA matching and age. RESULTS: One-thousand and eighty-seven subjects were included in the IPD meta-analysis. Pooled results showed no evidence of heterogeneity and indicated that the strongest variables determining poor outcomes are HLA mismatching (OR = 1.6-1.8 for >/=3 HLA-A, -B, -DR mismatches compared with those with <3 mismatches) and age (OR = 1.2-1.4 for age 45 years or more). Incremental information on risk of a poor outcome is provided by the TGF-beta1c10 polymorphism (OR = 1.5, P = 0.034, 95% CI: 1.0-2.2 for TC genotype compared to TT genotype). Haplotypes of TGF-beta1 at c10 and c25 were inferred and the C-C haplotype was a marker of a poor outcome (OR = 1.3, P = 0.177, 95% CI: 1.0-2.3). Three polymorphisms of the IL-10 gene at -1082, -819, -592 are in strong linkage disequilibrium with each other (correlation coefficients: 0.6-1) and inferred haplotypes between these three loci show some association, with ACC increasing the risk of poor events compared to GCC (OR = 1.3, P = 0.044, 95% CI: 0.9-1.6). CONCLUSION: Pooled results to date suggest possible association between both the TGF-beta1 c10 polymorphism and a 3-SNP-haplotype of IL-10 and poor outcomes in renal transplantation, but this needs to be confirmed in larger studies.

alpha(v)beta(6) Integrin expression in diseased and transplanted kidneys.

BACKGROUND: Integrins have been implicated in the pathogenesis of a diverse range of kidney diseases. Herein, we provide the first detailed description of an epithelial restricted integrin, alpha(v)beta(6), in kidney biopsies from patients suffering acute and chronic renal diseases and after transplantation. METHODS: Immunoperoxidase staining for beta(6) was performed on 267 selected biopsy specimens from native (N= 126) and transplanted kidneys (N= 141) and scored semiquantitatively. The site of beta(6) expression in tubules was determined using haematoxylin counterstaining and by colocalization with Tamm-Horsfall protein. Comparisons were made between subcategories of diseases of native kidneys and between "service" and "protocol" biopsies of transplanted kidneys. RESULTS: beta(6), when present, is largely confined to the distal tubules and collecting ducts, colocated with Tamm-Horsfall protein. When sparsely present, it was often restricted to the tubular segment associated with the juxtaglomerular apparatus. It was found in tubular cells shed into the urine. beta(6) was not expressed in thin membrane nephropathy, or in nonproliferative forms of glomerulonephritis, with the exception of focal and segmental glomerulosclerosis (FSGS). It was diffusely expressed where there was glomerular necrosis or thrombosis and in most forms of acute or chronic tubulointerstitial disease. beta(6) was diffusely up-regulated in allografts biopsied for delayed function, in almost all kidneys that have clinical or subclinical rejection episodes and was prominent in chronic allograft nephropathy. CONCLUSION: beta(6) integrin is not normally expressed in adult native or transplanted kidneys but is commonly up-regulated in the distal tubule in disease. Our descriptive study suggests that it is a molecule worthy of further study.