SUMMARYChronic kidney disease (CKD) represents a major health burden1. Its central feature of renal fibrosis is not well understood. By whole exome resequencing in a model disorder for renal fibrosis, nephronophthisis (NPHP), we identified mutations of Fanconi anemia-associated nuclease 1 (FAN1) as causing karyomegalic interstitial nephritis (KIN). Renal histology of KIN is indistinguishable from NPHP except for the presence of karyomegaly2. FAN1 has nuclease activity, acting in DNA interstrand crosslinking (ICL) repair within the Fanconi anemia pathway of DNA damage response (DDR)3–6. We demonstrate that cells from individuals with FAN1 mutations exhibit sensitivity to the ICL agent mitomycin C. However, they do not exhibit chromosome breakage or cell cycle arrest after diepoxybutane treatment, unlike cells from patients with Fanconi anemia. We complement ICL sensitivity with wild type FAN1 but not mutant cDNA from individuals with KIN. Depletion of fan1 in zebrafish revealed increased DDR, apoptosis, and kidney cysts akin to NPHP. Our findings implicate susceptibility to environmental genotoxins and inadequate DNA repair as novel mechanisms of renal fibrosis and CKD.

Amplification of chromosomal regions leads to an increase of DNA copy numbers and expression of oncogenes in many human tumors. The identification of tumor-specific oncogene targets has potential diagnostic and therapeutic implications. To identify distinct spectra of oncogenic alterations in ovarian carcinoma, metaphase comparative genomic hybridization (mCGH), array CGH (aCGH), and ovarian tumor tissue microarrays were used in this study. Twenty-six primary ovarian carcinomas and three ovarian carcinoma cell lines were analyzed by mCGH. Frequent chromosomal overrepresentation was observed on 2q (31%), 3q (38%), 5p (38%), 8q (52%), 11q (21%), 12p (21%), 17q (21%), and 20q (52%). The role of oncogenes residing in gained chromosomal loci was determined by aCGH with 59 genetic loci commonly amplified in human tumors. DNA copy number gains were most frequently observed for PIK3CA on 3q (66%), PAK1 on 11q (59%), KRAS2 on 12p (55%), and STK15 on 20q (55%). The 11q13-q14 amplicon, represented by six oncogenes (CCND1, FGF4, FGF3, EMS1, GARP, and PAK1) revealed preferential gene copy number gains of PAK1, which is located at 11q13.5-q14. Amplification and protein expression status of both PAK1 and CCND1 were further examined by fluorescence in situ hybridization and immunohistochemistry using a tissue microarray consisting of 268 primary ovarian tumors. PAK1 copy number gains were observed in 30% of the ovarian carcinomas and PAK1 protein was expressed in 85% of the tumors. PAK1 gains were associated with high grade (P < 0.05). In contrast, CCND1 gene alterations and protein expression were less frequent (10.6% and 25%, respectively), suggesting that the critical oncogene target of amplicon 11q13-14 lies distal to CCND1. This study demonstrates that aCGH facilitates further characterization of oncogene candidates residing in amplicons defined by mCGH.

Urinary CXCL10 is a promising noninvasive biomarker for tubulo-interstitial allograft inflammation, but its diagnostic characteristics have not been assessed in a real-life setting. We investigated urinary CXCL10 in 213 consecutive renal allograft recipients having 362 surveillance biopsies at 3/6 months and 80 indication biopsies within the first year posttransplant. Allograft histology results were classified as (i) acute Banff score zero, (ii) interstitial infiltrates only, (iii) tubulitis t1, (iv) tubulitis t2-3 and (v) isolated vascular compartment inflammation. For clinical and subclinical pathologies, urinary CXCL10 correlated well with the extent of tubulo-interstitial inflammation. To determine diagnostic characteristics of urinary CXCL10, histological groups were separated into two categories: no relevant inflammation (i.e. acute Banff score zero and interstitial infiltrates only) versus all other pathologies (i.e. tubulitis t1-3 and isolated vascular compartment inflammation). For subclinical pathologies, AUC was 0.69 (sensitivity 61%, specificity 72%); for clinical pathologies, AUC was 0.74 (sensitivity 63%, specificity 80%). A urinary CXCL10-guided biopsy strategy would have reduced performance of surveillance and indication biopsies by 61% and 64%, respectively. Missed (sub)clinical pathologies were mostly tubulitis t1 and isolated vascular compartment lesions. In real life, urinary CXCL10 had clinically useful diagnostic properties making it a candidate biomarker to guide allograft biopsies.

In recent decades, improvements in immunosuppressive medication have considerably increased the shortterm life expectancy of transplanted kidneys by reducing the incidence of acute rejections, primarily in the first year post-transplant. However, over the same period, long-term patient survival curves have been relatively flat [1,2]. Extending the perspectives of kidney transplant recipients is therefore a profound challenge and an important research priority [3][4][5].A major limiter of long-term survival is the gradual deterioration of kidney graft function [3][4][5][6], resulting from a range of function-impairing problems known collectively as chronic kidney dysfunction. Among the possible cause of chronic kidney dysfunction are behavioural aspects of the medication regimen, such as non adherence to the immunosuppressive prescription [5,7,8]. Next to the observation that non adherence has been linked to increased serum creatinine levels, a marker of decreased kidney function [9], the microscopic morphology of transplanted kidney tissue in non adherent patients shows a greater number of histological lesions than in those who adhere closely [10]. As surveys have shown that at least 28% of kidney transplant patients are non adherent to their regimens, non adherence may be a significant contributor to long-term kidney dysfunction [11].One common disadvantage of existing studies exploring the associations between non adherence and clinical outcomes is that they were based predominantly on the older azathioprine-and cyclosporine-based regimens, which are no longer considered state-of-the-art. How far their conclusions can be applied to regimens using subsequent generations of medications, such as tacrolimus, mycophenolate mofetil or sirolimus is an issue that has previously only been investigated in a retrospective study of SummaryLittle is known of the long-term clinical effects of non adherence on transplanted kidneys, especially regarding newer immunosuppressive regimens. In a study of 356 adult Swiss kidney transplant patients, non adherence was measured at inclusion by means of self-reporting, electronic monitoring, collateral reporting and blood assay. Long-term clinical outcomes regarding graft loss and creatinine levels were collected prospectively over a period of 5 years. A Cox proportional hazards model and mixed regression analysis were used, respectively, to examine the effects of non adherence on kidney survival and kidney function. The majority of patients (62%) were on immunosuppressive regimens that included mycophenolate mofetil, tacrolimus or sirolimus. No associations were found between non adherence and kidney graft survival or graft function. Notwithstanding weaknesses of this study, this negative result suggests that high adherence may protect patients against detrimental clinical outcomes, and/or that immunosuppressive regimens containing newer drugs allow wider non adherence margins than those based on previous generation medications such as cyclosporine, azathioprine and corticosteroids.

BackgroundAlthough, Pseudomonas exit-site infection (ESI) is recognized as a major complication of peritoneal dialysis (PD) with high risk of catheter loss due to refractory/recurrent infection or peritonitis, there is remarkably little literature about treatment outcomes. International Society for Peritoneal Dialysis guidelines advise the use of one to two antibiotics; in addition, we change standard exit-site care by stopping prophylactic mupirocin and starting regular use of gentamicin 1% cream.MethodsRetrospective review of outcomes of Pseudomonas ESI from January 2012 to March 2015.ResultsDuring the study period, a total of 135 patients were on PD with an overall incidence of any ESI of 0.36/patient-year. There were 14 patients with ESI episodes with Pseudomonas with a rate of 0.12/patient-year. In total, 13 of 14 patients with ESI episodes were treated with oral ciprofloxacin and/or intraperitoneal (IP) gentamicin or ceftazidime, plus topical gentamicin, with a success rate of 38% (5/13). One patient had gentamicin-resistant Pseudomonas species and was treated successfully with topical polymyxin/bacitracin cream. Median follow-up time in cured patients was 385 days (range 74–1107). Six patients had associated with Pseudomonas peritonitis, four during follow-up and two at initial presentation. Three patients had recurrent ESI with Pseudomonas, with one successfully re-treated with topical and IP gentamicin. In total, in only 50% of the patients was Pseudomonas ESI successfully treated. Five of the patients (36%) changed modality to permanent haemodialysis following catheter removal.ConclusionEradication of Pseudomonas ESI remains difficult even with the addition of topical gentamicin to the exit site. There should be a low threshold for catheter replacement.

Our data show a high prevalence of CKD and traditional risk factors, and their association with CKD in Haiti. These findings have now to be confirmed in other regions in longitudinal analyses as a basic step to build up screening and prevention programmes for CKD.

BackgroundInduction treatment with rabbit polyclonal antithymocyte globulins (ATGs) is frequent used in kidney transplant recipients with donorspecific HLA antibodies and shows acceptable outcomes. The two commonly used ATGs, Thymoglobulin and ATG-F have slightly different antigen profile and antibody concentrations. The two compounds have never been directly compared in a prospective trial in immunological high-risk recipients. Therefore we performed a prospective randomized controlled study comparing the two compounds in immunological high-risk kidney recipients in terms of safety and efficacy.MethodsImmunological high-risk kidney recipients, defined as the presence of HLA DSA but negative CDC-B and T-cell crossmatches were randomized 1:1 to receive ATG-F or Thymoglobulin. Maintenance immunosuppressive therapy consisted of tacrolimus, mycophenolate mofetil and steroids.ResultsThe per-protocol analysis included 35 patients. There was no immediate infusion reaction observed with both compounds. No PTLD or malignancy occurred during the follow-up in both groups. The incidence of viral and bacterial infections was similar in both groups (p = 0.62). The cumulative incidence of clinical and subclinical antibody mediated allograft rejection as well as T-cell mediated allograft rejection during the first year between ATG-F and Thymoglobulin was similar (35% versus 19%; p = 0.30 and 11% versus 18%; 0.54 respectively). The two-year graft function was similar with a median eGFR of 56 ml/min/1.73m2 (range 21–128) (ATG-F-group) and 51 ml/min/1.73m2 (range 22–132) (Thymo-group) (p = 0.69).ConclusionWe found no significant differences between the compared study drugs for induction treatment in immunological high-risk patients regarding safety and efficacy during follow-up with good allograft function at 2 years after transplantation.

BackgroundBesides ‘definitive rejection’, the Banff classification includes categories for ‘suspicious for rejection’ phenotypes. The aim of this study was to determine the frequency and phenotypes of rejection episodes in 316 consecutive renal transplants from 2009 to 2014 grouped into patients without/with pretransplant HLA-DSA (ptDSAneg, n = 251; ptDSApos, n = 65).MethodsAll adequate indication (n = 125) and surveillance biopsies (n = 538) performed within the first year posttransplant were classified according to the current Banff criteria.Results‘Suspicious for rejection’ phenotypes were 3 times more common than ‘definitive rejection’ phenotypes in biopsies from ptDSAneg patients (35% vs 11%) and equally common in biopsies from ptDSApos patients (25% vs 27%). In both groups, ‘suspicious for rejection’ phenotypes were more frequent in surveillance than in indication biopsies (28% vs 16% in ptDSAneg patients, and 37% vs 29% in ptDSApos patients). ‘Borderline changes: ‘Suspicious' for acute T-cell mediated rejection’ (91%) were the dominant ‘suspicious for rejection’ phenotype in ptDSAneg patients, whereas ‘borderline changes’ (58%) and ‘suspicious for acute/active antibody-mediated rejection’ (42%) were equally frequent in biopsies from ptDSApos patients. Inclusion of ‘suspicious for rejection’ phenotypes increased the 1-year incidence of clinical (ptDSAneg patients: 18% vs 8%, P = 0.0005; ptDSApos patients: 24% vs 18%, P = 0.31) and (sub)clinical rejection (ptDSAneg patients: 59% vs 22%, P < 0.0001; ptDSApos patients: 68% vs 40%, P = 0.004).Conclusions‘Suspicious for rejection’ phenotypes are very common in the current era and outnumber the frequency of ‘definitive rejection’ within the first year posttransplant.