Impaired 11ß-hydroxysteroid dehydrogenase type 2 activity in kidney disease disrupts 11-oxygenated androgen biosynthesis.

CONTEXT: 11-oxygenated androgens are a group of adrenal-derived steroids that require peripheral activation. In vitro data highlight a putative role for 11ß-hydroxysteroid dehydrogenase type 2 (HSD11B2) in 11-oxygenated androgen biosynthesis, converting 11ß-hydroxyandrostenedione (11OHA4) to 11-ketoandrostenedione (11KA4), the direct precursor of the potent androgen 11-ketotestosterone (11KT). As the kidney is the major site of HSD11B2 expression, we hypothesized that patients with chronic kidney disease (CKD) would have reduced 11-oxygenated androgen biosynthesis due to impaired HSD11B2 activity. OBJECTIVE: To determine the role of HSD11B2 in 11-oxygenated androgen biosynthesis using a human CKD cohort alongside complementary cell culture and computational modeling approaches. DESIGN: Cross-sectional observational study of patients with CKD (n=85) and healthy controls (n=46) measuring serum and urinary concentrations of glucocorticoids, classic and 11-oxygenated androgens by liquid chromatography-tandem mass spectrometry. A computational model of peripheral 11-oxygenated androgen biosynthesis was fitted to the serum data to calculate relative HSD11B2 expression levels for each participant. RESULTS: HSD11B2 activity declined with eGFR, evidenced by higher cortisol (F)/cortisone (E) ratios in CKD patients compared to controls (p<0.0001). Serum concentrations of E, 11KA4, 11KT and 11ß-hydroxytestosterone were lower in patients with CKD compared to controls (p<0.0001 for each). A computational model based on enzyme kinetic parameters of HSD11B2, 11ß-hydroxysteroid dehydrogenase type 1, 17ß-hydroxysteroid dehydrogenase type 2 and aldo-keto reductase 1C3 confirmed HSD11B2 as the key enzyme responsible for reduced 11-oxygenated androgen biosynthesis in CKD. Predicted HSD11B2 expression correlated with eGFR. CONCLUSION: This is the first in vivo study to confirm a central role for renal HSD11B2 in 11-oxygenated androgen biosynthesis. Determining the clinical implications of this observation for patients with CKD requires further research.

A case of mediastinal hyperparathyromatosis.

Recurrent hyperparathyroidism (HPT) after initial parathyroid surgery occurs rarely in an ectopic location. The rare phenomenon of parathyromatosis may be the cause of this. We present the case of a 59-year-old woman with recurrent HPT, which presented as a new ectopic mediastinal parathyroid gland 13 years after initial 3.5 gland parathyroidectomy. A 1.5 × 1.3 cm lesion was discovered as an incidental finding in the pretracheal region, closely abutting the aortic arch. An aspirate revealed oncocytic cells, which were positive for parathyroid hormone, confirming a mediastinal parathyroid nodule. Sestamibi scan confirmed an avid nodule in the mediastinum. This patient had multiple co-morbidities but was asymptomatic of HPT. It was therefore decided at multi-disciplinary team discussion that she should undergo surveillance. To our knowledge, no such presentations have been reported in the literature. Thus, our case report is a unique addition of an atypical presentation of HPT.

Adrenal insufficiency is common amongst kidney transplant recipients receiving maintenance prednisolone and can be predicted using morning cortisol.

BACKGROUND: Long-term glucocorticoid therapy is a key component of immunosuppression for kidney transplant recipients (KTRs), leading to significant cumulative glucocorticoid exposure. The aims of this study are to investigate the prevalence of adrenal insufficiency (AI) in KTRs taking prednisolone and to develop a screening algorithm to identify patients at the highest risk of AI. METHODS: In this cross-sectional cohort study, 67 KTRs receiving prednisolone underwent a short synacthen test (SST) and measurement of cumulative glucocorticoid exposure. RESULTS: A total of 72% (n = 48) of participants failed the SST. Participants with AI had a higher daily prednisolone dose (4.9 versus 4.2 mg/day; P = .002) and greater cumulative glucocorticoid exposure (289 versus 111 mg/kg; P = .03) than those with intact adrenal function. Participants with AI had lower baseline cortisol than participants with intact adrenal function (143 versus 303 nmol/L; P < .001). Morning cortisol of >288 nmol/L predicted a normal SST with 100% specificity [95% confidence interval (CI) 92-100] and 70% sensitivity (95% CI 56-78%), therefore excluding AI. CONCLUSIONS: Our results suggest KTRs are at a higher risk for AI than previously reported. A morning serum cortisol measurement is a useful screening tool in this cohort, reducing the need for stimulatory testing by 44%. KTRs with AI need education regarding glucocorticoid sick rules, similar to patients with other forms of AI.

Pacemaker-related Candida parapsilosis fungaemia in an immunosuppressed renal transplant recipient.

Renal transplant recipients are at risk for opportunistic infections due to their immunosuppressed state. We describe the case of a 59-year-old renal transplant recipient who presented with sepsis and bilateral pulmonary emboli due to Candida parapsilosis She was treated with intravenous caspofungin and had a transoesophageal echocardiogram, which revealed vegetations on her pacemaker leads. She then underwent surgery to replace her pacemaker; however, her blood cultures remained positive for C. parapsilosis postoperatively. Her antifungal was switched to liposomal amphotericin B and flucytosine for 6 weeks, which yielded sterile blood cultures, and she was then initiated on lifelong fluconazole. Her recovery was complicated by tacrolimus toxicity 1 month after discharge due to fluconazole-induced CYP3A inhibition.

Progressive survival improvement of incident dialysis patients in a tertiary center, Ireland.

BACKGROUND: The survival of incident dialysis patients' end-stage kidney disease in some European and American has been reported to improve in modern era compared to earlier periods. However, in Ireland, this has not been well documented. AIM: To investigate the survival outcomes of incident end-stage kidney failure dialysis patients in a tertiary center over a 24-year period, 1993-2017. METHODS: A retrospective analysis was carried out utilizing the Beaumont Hospital Renal Database. Consecutive adults with incident dialysis were analyzed. Kaplan-Meier methods and the estimated mean survival times were used to evaluate survival at successive 4-year periods of time. RESULTS: In total, 2106 patients were included, of whom 830 underwent subsequent renal transplantation during follow-up. During the study period, from 1993 up to 2017, the mean patients' age increased from 56.3 ± 17.4 in 1993-1996 to 60.6 ± 18.3 in 2014-2017. There was an overall decrement in mortality over successive time intervals which were mirrored by the improvements in median survival after commencement of dialysis treatment from 6.14 years during 1993-1996 to 8.01 years during 2009-2012. Patients' survival has steadily improved, with the 5-year survival has risen over time, by almost 15%. This positive signal persisted and became more pronounced after adjusting Kaplan-Meier curve to age, where the 5-year survival estimates were exceeding 80% in 2014-2017. CONCLUSION: Survival rates among incident dialysis patients have improved progressively between 1993 and 2017 in Beaumont Hospital in Dublin, Ireland. The factors which led to this improvement are not entirely clear, but likely to be multifactorial.

Surveillance of common infections in the early period after renal transplantation in a national center: 2014-2017.

BACKGROUND: Infection prevention and timely and effective treatment are among the major aims of care in kidney transplant recipients. Pre-transplant vaccination and pre-transplant viral screening have been extensively studied and are now considered standard practice. Early post-operative infection surveillance is mandatory in other vulnerable cohorts, but has not been extensively studied in this population. We hypothesized that surveillance of the most common bacterial infection types in the post-transplant setting would be beneficial and identify key areas for improvement. METHODS: All adult kidney transplant recipients whose surgeries were performed in the Irish national kidney transplant unit over a 1-year period had prospective early post-transplant (first 30 days) infection surveillance in 2014 for surgical site infection, urinary tract infection, and secondary bloodstream infections (Group T0). Several key changes were implemented following scrutiny of infection patterns and clinical practice. Subsequently, infection surveillance was undertaken for 2016 and 2017 (Group T1) to assess the impact of these changes. RESULTS: Between 2014 and 2017, the number of kidney transplants increased by 32%. The following aspects of clinical practice were the focus of change following analysis of Group T0 data: timing of surgical antimicrobial prophylaxis (SAP) administration, choice of SAP antimicrobial agent, and routine microbiological testing in the peri-operative period. Following implementation of these changes, the timing of SAP administration was greatly improved (45%-100% of cases appropriately timed). The infection rate decreased from 8.9% to 7.4% in 2016, with a further decrease to 4% in 2017 (OR 0.42 (95% CI: 0.16-1.10); P = .08). Compliance with pre-operative microbiological screening improved in Group T1. CONCLUSIONS: Simple clinical practice changes, implemented upon analysis of common bacterial infection surveillance data in the first 30 days after kidney transplantation resulted in more effective SAP administration and improved compliance with routine microbiological testing in the peri-operative period. These interventions have potentially contributed to reduced early post-operative infection rates, despite increased transplant activity in the unit. Infection surveillance is an important and under-utilized way of reducing infections in this vulnerable patient cohort.

Assessing the discrimination of the Kidney Donor Risk Index/Kidney Donor Profile Index scores for allograft failure and estimated glomerular filtration rate in Ireland's National Kidney Transplant Programme.

BACKGROUND: The Kidney Donor Risk Index (KDRI)/Kidney Donor Profile Index (KDPI) is relied upon for donor organ allocation in the USA, based on its association with graft failure in time-to-event models. However, the KDRI/KDPI has not been extensively evaluated in terms of predictive metrics for graft failure and allograft estimated glomerular filtration rate (eGFR) outside of the USA. METHODS: We performed a retrospective analysis of outcomes in the Irish National Kidney Transplant Service Registry for the years 2006-13. Associations of the KDRI/KDPI score with eGFR at various time points over the follow-up and ultimate graft failure were modelled. RESULTS: A total of 772 patients had complete data regarding KDRI/KDPI calculation and 148 of these allografts failed over the follow-up. The median and 25-75th centile for KDRI/KDPI was 51 (26-75). On repeated-measures analysis with linear mixed effects models, the KDRI/KDPI (fixed effect covariate) associated with eGFR over 5 years: eGFR = -0.25 (standard error 0.02; P < 0.001). The variability in eGFR mathematically accounted for by the KDRI/KDPI score was only 21%. The KDRI/KDPI score did not add significantly to graft failure prediction above donor age alone (categorized as > and <50 years of age) when assessed by the categorical net reclassification index. CONCLUSIONS: In this cohort, while the KDRI/KDPI was predictive of eGFR over the follow-up, it did not provide additive discrimination above donor age alone in terms of graft failure prediction. Therefore it is unlikely to help inform decisions regarding kidney organ allocation in Ireland.

Progressive improvement in short-, medium- and long-term graft survival in kidney transplantation patients in Ireland - a retrospective study.

It is often quoted that while short-term graft survival in kidney transplantation has improved in recent years, it has not translated into a commensurate improvement in long-term graft survival. We considered whether this was true of the entire experience of the national kidney transplant program in Ireland. A retrospective analysis of the National Kidney Transplant Service (NKTS) database was undertaken to investigate patient and graft survival for all adult first deceased donor kidney transplant recipients in Ireland, 1971-2015. Three thousand two hundred and sixty recipients were included in this study. Kaplan-Meier methods were used to estimate survival at each time period post transplant for the various eras of transplantation. Uncensored graft survival has improved over the course of the program in Ireland at various time points despite risk factors for graft failure progressively increasing over successive eras. For example the graft survival at 15 years post transplant has increased from 10% in 1971-1975 to 45% by 1996-2000. Ireland has experienced a progressive improvement in long-term graft survival following kidney transplantation. Whether these trends are attributable to biological or nonbiological factors is unclear but likely involves a combination of both.

Monogenic causes of chronic kidney disease in adults.

Approximately 500 monogenic causes of chronic kidney disease (CKD) have been identified, mainly in pediatric populations. The frequency of monogenic causes among adults with CKD has been less extensively studied. To determine the likelihood of detecting monogenic causes of CKD in adults presenting to nephrology services in Ireland, we conducted whole exome sequencing (WES) in a multi-centre cohort of 114 families including 138 affected individuals with CKD. Affected adults were recruited from 78 families with a positive family history, 16 families with extra-renal features, and 20 families with neither a family history nor extra-renal features. We detected a pathogenic mutation in a known CKD gene in 42 of 114 families (37%). A monogenic cause was identified in 36% of affected families with a positive family history of CKD, 69% of those with extra-renal features, and only 15% of those without a family history or extra-renal features. There was no difference in the rate of genetic diagnosis in individuals with childhood versus adult onset CKD. Among the 42 families in whom a monogenic cause was identified, WES confirmed the clinical diagnosis in 17 (40%), corrected the clinical diagnosis in 9 (22%), and established a diagnosis for the first time in 16 families referred with CKD of unknown etiology (38%). In this multi-centre study of adults with CKD, a molecular genetic diagnosis was established in over one-third of families. In the evolving era of precision medicine, WES may be an important tool to identify the cause of CKD in adults.

Direct-Acting Oral Anticoagulants as Prophylaxis Against Thromboembolism in the Nephrotic Syndrome.

We report 2 cases of apixaban use as prophylaxis against thromboembolism in the nephrotic syndrome (NS), and review the existing literature on direct-acting oral anticoagulant (DOAC) use in this scenario. Our cases appear to be the first reported use of apixaban as prophylaxis against thromboembolism in NS. We report our systematic review of the existing literature on direct-acting oral anticoagulant (DOAC) use in NS, and discuss theoretical issues relevant to their therapeutic use in this clinical scenario. We searched electronic databases such as OVID, EMBASE, PubMed, and CENTRAL, DARE. The search to identify studies and the application of inclusion and exclusion criteria was performed in duplicate independently. We identified 1 pilot randomized study, 3 case reports, and 3 conference proceedings abstracts relating to DOAC use in NS. These reports all pertain to the treatment of clinically evident thrombosis in NS with rivaroxaban, edoxaban, and dabigatran rather than prophylaxis against thrombosis. Although the existing literature on DOAC use in NS is limited, initial preliminary experience appears promising.

The impact of donor and recipient weight incompatibility on renal transplant outcomes.

BACKGROUND: Donor/recipient size mismatching and correlation to allograft outcome remains poorly defined. This study assessed the impact of donor body weight (DBW) to recipient body weight (RBW) ratio on allograft function and survival. METHODS: A total of 898 deceased donor renal transplant recipients were included in the study. Patients were divided into quartiles depending on the ratio of DBW/RBW: Q1 (≤ 0.88), Q2 (0.89-1.00), Q3 (1.01-1.22) and Q4 (> 1.22). Donor and recipient characteristics were obtained from the national kidney transplant service database. Serum creatinine and estimated glomerular filtration rate (eGFR) at 1 and 5 years after transplant were compared. RESULTS: Q4 patients had a higher eGFR 1 year post-transplant (median 59.5 ml/min, IQR 46.8-76.2) compared to Q1-Q3 which had median eGFRs of 54.3, 54.8 and 55.3 ml/min, respectively (p < 0.001). At 5 years post-transplant, there were modest differences in the eGFR across the four quartiles, Q1-4 with median eGFRs of 56.9, 61.1, 61.2 and 58.6 ml/min, respectively (p = 0.02). However, there were no significant differences in 1- and 5-year allograft survival between groups. CONCLUSIONS: In the setting of deceased donor renal transplantation, mismatching of donor to recipient weight had no impact on 5-year allograft survival, but a low DBW/RBW ratio is modestly associated with lower eGFR.

IVIG Associated Aseptic Meningitis in a Renal Transplant Patient.

The management of antibody-mediated rejection in renal transplant recipients involves plasmapheresis with IVIG. Aseptic meningitis is a rare adverse effect of IVIG therapy and is a diagnosis of exclusion. We report a case of a renal transplant patient who developed IVIG associated aseptic meningitis in the context of management of antibody-mediated rejection, four years after transplantation.

The epidemiology of Clostridium difficile infection in a national kidney transplant center.

BACKGROUND: We aimed to describe the epidemiology and outcomes of CDI in a national kidney transplant center from 2008 to 2015. METHODS: Adult kidney and kidney-pancreas transplant recipients were included for analysis if they met the surveillance CDI case definition. Rates of new healthcare-associated CDI (HA-CDI) were expressed per 10 000 KTR/KTPR bed days used (BDU) to facilitate comparisons. RESULTS: Fifty-two cases of CDI were identified in 42 KTRs and KPTRs. This corresponded to an average annual rate of 9.6 per 10 000 BDU, higher than that seen among general hospital inpatients locally, nationally, and internationally. Of the 45 cases (87%) that were considered HA-CDI, nine (20%) had symptom onset in the community. Recent proton-pump inhibitor (PPI) and broad-spectrum antimicrobial exposure preceded the majority of cases. KTRs and KPTRs with CDI had a longer mean length of hospital stay (35 days) than those KTR and KPTRs admitted during the same period that did not have CDI (8 days). CONCLUSIONS: Education regarding CDI must be extended to transplant recipients and their general practitioners. Other targets for future CDI rate reduction must include stringent antimicrobial stewardship (both in hospital and in the community) and judicious PPI prescribing.

The Irish living kidney donor program - why potential donors do not proceed to live kidney donation?

BACKGROUND: Living donation is not only a method to increase access to kidney transplantation but can also offer superior outcomes. We report the experience of the living donor (LD) program in the Republic of Ireland and explore reasons why potential donors do not proceed to live donation. METHODS: Retrospective cohort study of all potential donors from January 2000 to March 2014 who presented wishing to undergo donor work-up and their subsequent outcomes. RESULTS: A total of 956 donors for 496 recipients contacted the live kidney donation program of which 883 potential donors proceeded to the initial stage of assessment. The donor dropout rate at this stage was 64.2% (614/956 potential donors did not proceed to further evaluation). Thereafter, 269 (28.1%) donors underwent further assessment by the multidisciplinary team. In total, 93 (9.7%) donors were declined following this assessment with 176 (18.4%) donors ultimately proceeding to live kidney donation. The major reason for declining a donor was a medical contraindication (n = 63, 67.7%). In term of recipients, 54.2% (n = 269/496) had a potential donor proceed for further assessment of which 65.4% (n = 176/269) ultimately proceeding to live donation. CONCLUSION: Further evaluation of the declined donor group is warranted to allow for expansion of the LD program.

Factors affecting eGFR 5-year post-deceased donor renal transplant: analysis and predictive model.

AIM: Long-term survival of renal allografts has improved over the last 20 years. However, less is known about current expectations for long-term allograft function as determined by estimated glomerular filtration rate (eGFR). The aim of this study was to investigate factors which affect graft function at 5 years' post-renal transplantation. The statistically significant factors were then used to construct a predictive model for expected eGFR at five years' post-transplant. METHODS: We retrospectively reviewed all adult patients who received a renal transplant in the Republic of Ireland between 1990 and 2004. Data collected included era of transplantation (1990-1994, 1995-1999, 2000-2004), donor and recipient age and gender, number of human leucocyte antigen mismatches, cold ischemia time (CIT), number of prior renal transplants, immunosuppressive regimen used and acute rejection episodes. Estimated GFR was calculated at 5 years after transplantation from patient data using the Modified Diet in Renal Disease (MDRD) equation. Consecutive sampling was used to divide the study population into two equal unbiased groups of 489 patients. The first group (derivation cohort) was used to construct a predictive model for eGFR five years' post-transplantation, the second (validation cohort) to test this model. RESULTS: Nine hundred and seventy eight patients were analyzed. The median age at transplantation was 43 years (range 18-78) and 620 (63.4%) were male. One hundred and seventy five patients (17.9%) had received a prior renal transplant. Improved eGFR at five years' post-transplantation was associated with tacrolimus-based combination immunosuppression, younger donor age, male recipient, absence of cytomegalovirus disease and absence of acute rejection episodes as independently significant factors (p < 0.05). The predictive model developed using these factors showed good correlation between predicted and actual median eGFR at five years. The model explained 20% of eGFR variability. The validation model findings were consistent with the derivation model (21% variability of eGFR explained by model using same covariates on new data). CONCLUSION: The predictive model we have developed shows good correlation between predicted and actual median eGFR at five years' post-transplant. Applications of this model include comparison of current and future therapy options such as new immunosuppressive regimens.

Long-term outcomes of kidney transplantation across a positive complement-dependent cytotoxicity crossmatch.

BACKGROUND: More than 30% of potential kidney transplant recipients have pre-existing anti-human leukocyte antigen antibodies. This subgroup has significantly lower transplant rates and increased mortality. Desensitization has become an important tool to overcome this immunological barrier. However, limited data is available regarding long-term outcomes, in particular for the highest risk group with a positive complement-dependent cytotoxicity crossmatch (CDC XM) before desensitization. METHODS: Between 2002 and 2010, 39 patients underwent living-kidney transplantation across a positive CDC XM against their donors at our center. The desensitization protocol involved pretransplant immunosuppression, plasmapheresis, and low-dose intravenous immunoglobulin±rituximab. Measured outcomes included patient survival, graft survival, renal function, rates of rejection, infection, and malignancy. RESULTS: The mean and median follow-up was 5.2 years. Patient survival was 95% at 1 year, 95% at 3 years, and 86% at 5 years. Death-censored graft survival was 94% at 1 year, 88% at 3 years, and 84% at 5 years. Uncensored graft survival was 87% at 1 year, 79% at 3 years, and 72% at 5 years. Twenty-four subjects (61%) developed acute antibody-mediated rejection of the allograft and one patient lost her graft because of hyperacute rejection. Infectious complications included pneumonia (17%), BK nephropathy (10%), and CMV disease (5%). Skin cancer was the most prevalent malignancy in 10% of patients. There were no cases of lymphoproliferative disorder. Mean serum creatinine was 1.7±1 mg/dL in functioning grafts at 5 years after transplantation. CONCLUSION: Despite high rates of early rejection, desensitization in living-kidney transplantation results in acceptable 5-year patient and graft survival rates.