Nephrophobia: a retrospective study of medical students' attitudes towards nephrology education.

BACKGROUND: Nephrology is a subject which is challenged by a lack of applicants for trainee places. This study addresses the attitudes of medical students towards the subject and explores the causes of this lack of interest amongst potential specialty trainees. METHODS: Students were asked to complete a survey ranking their attitudes towards nephrology and other specialties. This data was collated and analysed to show trends and allow comparison of the attitudes towards each specialty. RESULTS: Students felt that along with geriatrics, their least favourite subject was nephrology. Students felt unconfident in diagnosing, managing and understanding chronic conditions more so than acute conditions. Nephrology was consistently amongst the least popular subject for all areas of diagnosis, management and pathophysiology. Renal anatomy was the only area of nephrology that students felt confident in. The less popular specialties of nephrology and geriatrics had the greatest room for improvement when directly instructed in specialty medical training. CONCLUSIONS: Nephrology remains a problematic and unpopular specialty for medical students, driving their unwillingness to consider it as a future career route. This study identifies areas of misconception amongst medical students toward the specialty and highlights areas for improvement in renal training for students.

Predicting 5-year risk of kidney transplant failure: a prediction instrument using data available at 1 year posttransplantation.

BACKGROUND: Accurate prediction of kidney transplant failure remains imperfect. The objective of this study was to develop and validate risk scores predicting 5-year transplant failure, based on data available 12 months posttransplantation. STUDY DESIGN: Development and then independent multicenter validation of risk scores predicting death-censored and overall transplant failure. SETTING & PARTICIPANTS: Outcomes of kidney transplant recipients (n=651) alive with transplant function 12 months posttransplantation in Birmingham, United Kingdom, were used to develop models predicting transplant failure risk 5 years posttransplantation. The resulting risk scores were evaluated for prognostic utility (discrimination, calibration, and risk reclassification) in independent cohorts from Tours, France (n=736); Leeds, United Kingdom (n=787); and Halifax, Canada (n=475). PREDICTORS: Weighted regression coefficients for baseline and 12-month demographic and clinical predictor characteristics. OUTCOMES: Death-censored and overall transplant failure 5 years posttransplantation. MEASUREMENTS: Baseline data and time to transplant failure. RESULTS: Following model development, variables included in separate scores for death-censored and overall transplant failure included recipient age, sex, and race; acute rejection; transplant function; serum albumin level; and proteinuria. In the validation cohorts, these scores showed good to excellent discrimination for death-censored transplant failure (C statistics, 0.78-0.90) and moderate to good discrimination for overall transplant failure (C statistics, 0.75-0.81). Both scores demonstrated good calibration (Hosmer-Lemeshow P>0.05 in all cohorts). Compared with estimated glomerular filtration rate in isolation, application of the scores resulted in statistically significant and clinically relevant risk reclassification for death-censored transplant failure (net reclassification improvement [NRI], 36.1%-83.0%; all P<0.001) and overall transplant failure (NRI, 38.7%-53.5%; all P<0.001). Compared with the previously described US Renal Data System-based risk calculator, significant and relevant risk reclassification for overall transplant failure was seen (NRI, 30.0%; P<0.001). LIMITATIONS: Validation is required in further populations. CONCLUSIONS: These validated risk scores may be of prognostic utility in kidney transplantation, accurately identifying at-risk transplants, and informing clinicians and patients.

Impaired direct priming of CD8 T cells by donor-derived cytomegalovirus following kidney transplantation.

Cytomegalovirus (CMV) infection increases the risk of complications after renal transplantation, but the mechanisms controlling donor-derived infection are not adequately characterized. Here, we assessed the risk of clinically significant CMV disease in donor-seropositive, recipient-seropositive (D+R+) renal transplantation and examined recipients' CMV antigen-specific cellular immune responses primed directly by donor cells. In a retrospective cohort of 569 patients administered standardized basiliximab-tacrolimus-mycophenolate-corticosteroid immunosuppressive therapy, CMV disease rates increased in D+R+ serostatus pairings compared with D-R+ pairings (hazard ratio [HR], 2.61; 95% confidence interval [CI], 1.36 to 5.01; P=0.004) and associated with increased donor-recipient HLA mismatch in the D+R+ group (HR [per class 1 mismatch], 1.43; 95% CI, 1.12 to 1.82]; P=0.02). D+R+ and D+R- transplants in which the donor and recipient differentially expressed at least one HLA class I allele were followed prospectively from the time of transplantation. During the first year after transplantation, four of eight seropositive recipients and one of three seronegative recipients displayed peripheral blood CD8+ T cell responses to CMV presented by recipient-specific HLA. Notably, no recipients mounted responses to CMV presented by donor-specific HLA, despite the detection of CMV antigen expression in all seropositive donor organs examined (n=10), suggesting that the allograft of Class I HLA-mismatched seropositive donors is inaccessible to CD8+ T cell responses. Finally, pretransplant assays of anti-CMV cellular immunity predicted post-transplant CMV replication less accurately in D+R+ pairings than in D-R+ pairings, possibly reflecting in vitro assay specificity for recipient, rather than donor, HLA. These findings are relevant to the clinical management and immunologic understanding of donor-transmitted viral infection.

Validity of glycated haemoglobin to diagnose new onset diabetes after transplantation.

Diagnosing new onset diabetes after transplantation (NODAT) by glycated haemoglobin (HbA1c) has not been validated against the gold-standard oral glucose tolerance test (OGTT). We analysed the predictive and optimum value of HbA1c to diagnose NODAT amongst nondiabetic renal transplant recipients. Assessment of glucose metabolism (OGTT and HbA1c) was prospectively undertaken at 3 and 12 months post-transplantation in 71 nondiabetic renal transplant recipients. Receiver operator characteristic (ROC) curve analyses were performed to determine accuracy, sensitivity, specificity and area under curve (c-statistic). Incidence of NODAT at 3 and 12 months post-transplantation was 14.3% and 9.5% respectively. At 3 months, optimum HbA1c cut-off value for predicting NODAT based on fasting glucose was 7.35 [AUC 1.00 (sensitivity 100.0%, specificity 100.0%, P = 0.004)] and for postprandial glucose-defined NODAT was 6.20 [AUC 0.98 (sensitivity 100.0%, specificity 88.9%, P < 0.001)]. At 12 months, optimum HbA1c cut-off value for both fasting- and postprandial glucose-defined NODAT was 6.45 [AUC 0.92 (sensitivity 100.0%, specificity 87.5%, P = 0.048) and AUC 0.84 (sensitivity 75.0%, specificity 89.5%, P = 0.026) respectively]. Concordance between diagnosis of NODAT (OGTT+, HbA1c+) and nondiagnosis of NODAT (OGTT-, HbA1c-) was 88.9% and 98.7% respectively. To conclude, HbA1c (≥6.5%) can be utilized to diagnose NODAT beyond 3 months post-transplantation but the OGTT remains the gold-standard tool.

Meta-analysis of calcineurin-inhibitor-sparing regimens in kidney transplantation.

Calcineurin-inhibitor-sparing strategies in kidney transplantation may spare patients the adverse effects of these drugs, but the efficacy of these strategies is unknown. Here, we conduct a meta-analysis to assess outcomes associated with reducing calcineurin inhibitor exposure from the time of transplantation. We search Medline, Embase, and Cochrane Register of Controlled Trials for randomized controlled trials published between 1966 and 2010 that compared de novo calcineurin-inhibitor-sparing regimens to calcineurin-inhibitor-based regimens. In this analysis, we include 56 studies comprising data from 11337 renal transplant recipients. Use of the contemporary agents belatacept or tofacitinib, in combination with mycophenolate, decreased the odds of overall graft failure (OR 0.61; 95% CI 0.39-0.96; P = 0.03). Similarly, minimization of calcineurin inhibitors in combination with various induction and adjunctive agents reduces the odds of graft failure (OR 0.73; 95% CI 0.58-0.92; P = 0.009). Conversely, the use of inhibitors of mammalian target of rapamycin (mTOR), in combination with mycophenolate, increases the odds of graft failure (OR 1.43; 95% CI 1.08-1.90; P = 0.01). Calcineurin-inhibitor-sparing strategies are associated with less delayed graft function (OR 0.89; 95% CI 0.80-0.98; P = 0.02), improved graft function, and less new-onset diabetes. The more contemporary protocols did not seem to increase rates of acute rejection. In conclusion, this meta-analysis suggests that reducing exposure to calcineurin inhibitors immediately after kidney transplantation may improve clinical outcomes.

Development and evaluation of a composite risk score to predict kidney transplant failure.

BACKGROUND: Although risk factors for kidney transplant failure are well described, prognostic risk scores to estimate risk in prevalent transplant recipients are limited. STUDY DESIGN: Development and validation of risk-prediction instruments. SETTING & PARTICIPANTS: The development data set included 2,763 prevalent patients more than 12 months posttransplant enrolled into the LOTESS (Long Term Efficacy and Safety Surveillance) Study. The validation data set included 731 patients who underwent transplant at a single UK center. PREDICTOR: Estimated glomerular filtration rate (eGFR) and other risk factors were evaluated using Cox regression. OUTCOME: Scores for death-censored and overall transplant failure were based on the summed hazard ratios for baseline predictor variables. Predictive performance was assessed using calibration (Hosmer-Lemeshow statistic), discrimination (C statistic), and clinical reclassification (net reclassification improvement) compared with eGFR alone. RESULTS: In the development data set, 196 patients died and another 225 experienced transplant failure. eGFR, recipient age, race, serum urea and albumin levels, declining eGFR, and prior acute rejection predicted death-censored transplant failure. eGFR, recipient age, sex, serum urea and albumin levels, and declining eGFR predicted overall transplant failure. In the validation data set, 44 patients died and another 101 experienced transplant failure. The weighted scores comprising these variables showed adequate discrimination and calibration for death-censored (C statistic, 0.83; 95% CI, 0.75-0.91; Hosmer-Lemeshow χ(2)P = 0.8) and overall (C statistic, 0.70; 95% CI, 0.64-0.77; Hosmer-Lemeshow χ(2)P = 0.5) transplant failure. However, the scores failed to reclassify risk compared with eGFR alone (net reclassification improvements of 7.6% [95% CI, -0.2 to 13.4; P = 0.09] and 4.3% [95% CI, -2.7 to 11.8; P = 0.3] for death-censored and overall transplant failure, respectively). LIMITATIONS: Retrospective analysis of predominantly cyclosporine-treated patients; limited study size and categorization of variables may limit power to detect effect. CONCLUSIONS: Although the scores performed well regarding discrimination and calibration, clinically relevant risk reclassification over eGFR alone was not evident, emphasizing the stringent requirements for such scores. Further studies are required to develop and refine this process.

Effects of fasting on solid organ transplant recipients during Ramadan - a practical guide for healthcare professionals.

Fasting in the month of Ramadan is an obligatory act for healthy adult Muslims. It requires abstinence from food and drink from dawn to sunset. Although there are exemptions from fasting, many patients are keen to fulfil what they see as a religious obligation, even if this may be against medical advice in some cases. Solid organ transplant (SOT) recipients often ask healthcare professionals for advice on fasting. Studies on the effect of fasting in transplant patients have all been done in the Middle East and North Africa where the average fasting duration is between 12 and 14 hours. In comparison, in temperate regions in the summer, fasting duration can be as long as 20 hours. Fasting when patients have to take immunosuppression 12 hours apart with little time variation poses unique challenges. In this review, current literature is reviewed, and a decision-making tool has been developed to assist clinicians in discussing the risks of fasting in transplant recipients, with consideration also given to circumstances such as the COVID-19 pandemic.Our review highlights that SOT recipients wishing to fast should undergo a thorough risk assessment, ideally 3 months before Ramadan. They may require medication changes and a plan for regular monitoring of graft function and electrolytes in order to fast safely. Recommendations have been based on risk tiers (very high risk, high risk and low/moderate risk) established by the International Diabetes Federation and the Diabetes and Ramadan International Alliance. Patients in the 'very high risk' and 'high risk' categories should be encouraged to explore alternative options to fasting such as winter fasting or Fidyah. Those in the 'low/moderate' category may be able to cautiously fast with guidance from their clinician. Prior to the commencement of Ramadan, all patients must receive up-to-date education on sick-day rules, instructions on when to terminate their fast or abstain from fasting.

Prediction of ESRD in pauci-immune necrotizing glomerulonephritis: quantitative histomorphometric assessment and serum creatinine.

BACKGROUND: Clinical and pathologic features that predict outcome have important potential application in patients with pauci-immune necrotizing glomerulonephritis (usually antineutrophil cytoplasmic antibody-associated vasculitis). This study examines the predictive value of simple quantitative renal histologic measurements in a large cohort with extended follow-up. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: 390 consecutive patients with pauci-immune necrotizing glomerulonephritis at a single hospital (1983-2002); 90 patients underwent repeated kidney biopsy during follow-up. PREDICTORS: Age and serum creatinine concentration at biopsy, antineutrophil cytoplasmic antibody specificity, percentage of normal glomeruli, percentage of glomeruli with active lesions, and index of chronic damage (quantitative measurement of established cortical damage) in the initial kidney biopsy for all patients. The same factors were assessed in both biopsy specimens for patients undergoing an additional biopsy. OUTCOMES & MEASUREMENTS: End-stage renal disease and patient survival. RESULTS: Mortality at 1 and 5 years was 23% and 40%, respectively: standardized mortality ratio, 4.74 (95% CI, 3.62-6.32). End-stage renal disease was reached by 14% and 18% at 1 and 5 years, respectively. In multivariable analysis, serum creatinine level at biopsy and percentage of normal glomeruli in the initial biopsy specimen were the best predictors of kidney survival. C Statistics were 0.80 for creatinine level alone and 0.83 for creatinine level with normal glomeruli. In patients undergoing an additional biopsy, rapid progression in the index of chronic damage and serum creatinine level at the second biopsy were associated with kidney survival in multivariable analysis. LIMITATIONS: Retrospective analysis. External validity of the index of chronic damage requires further assessment. Selection bias may influence repeated biopsy analyses. CONCLUSIONS: Serum creatinine level at biopsy best predicts kidney survival in patients with pauci-immune necrotizing glomerulonephritis overall.

Drug-eluting stent insertion in the treatment of in-stent renal artery restenosis in three renal transplant recipients.

Percutaneous transluminal angioplasty (PTA) with or without stent insertion is the treatment of choice in transplant renal artery stenosis. However, in-stent restenosis occurs in as many as 13% of patients after PTA and stent insertion. This article describes three patients with recurrent transplant renal artery in-stent stenosis who were treated with paclitaxel-eluting stents. In two patients, the transplant renal artery remained patent after insertion of the drug-eluting stent (DES), and one patient required balloon angioplasty 7 months after the DES was inserted.

HLA incompatible combined liver-kidney transplantation: dynamics of antibody modulation revealed by a novel approach to HLA antibody characterisation.

This case report confirms the utility of simultaneous liver transplantation in allowing successful kidney transplantation in the face of preformed, high levels of DSA, which would under normal circumstances be associated with hyperacute rejection and kidney graft failure. Antibody characterisation in terms of epitope specificity is more accurate and informative than antibodies described as "antigen-specific" and we suggest a method for identifying and tracking these antibodies; i.e. follow the epitope reaction not the antigen reactions. We consider that this will give a better insight into the behaviour and pathogenicity of HLA-specific sera. In the case presented here this approach has revealed some novel features of the post transplant antibody response in a sensitised recipient. These illustrate three phenomena which challenge current dogmas; an early resynthesis of DSA does not necessarily cause AMR, high levels of DSA can spontaneously modulate, and measurement of antibodies in terms of antigen specificity can give misleading results.

Mortality prediction after kidney transplantation: comparative clinical use of 7 comorbidity indices.

OBJECTIVES: Despite comorbidity associated with chronic kidney disease, little data exist applying comorbidity scoring systems to renal transplant recipients. This study compared the performance of 7 established comorbidity scores in predicting mortality after kidney transplantation. MATERIALS AND METHODS: We retrospectively analyzed prospectively collected data from 2033 incident renal transplant recipients. Comorbidity was assessed at baseline, and the following scores were derived: Recipient Risk Score, Charlson Comorbidity Index, Age-adjusted Charlson Comorbidity Index, Modified End-Stage Renal Disease Charlson Comorbidity Index, Foley Score, Wright-Khan Index, and Davies Index. Cox models investigated the association of each comorbidity score with mortality; performance characteristics were tested using receiver operating characteristic curve analysis. RESULTS: Age-stratified Cox analyses showed the Recipient Risk Score-based model displayed the best fit, and receiver operating characteristic curve analysis showed the Recipient Risk Score demonstrated greatest predictive use (5-year mortality c-statistic: 0.787). The independent effect of age on mortality was demonstrated after analysis of scores not containing age as a component (the Charlson Comorbidity Index, the Modified End-Stage Renal Disease Charlson Comorbidity Index, the Davies Index); addition of age to these scores improved fit. CONCLUSIONS: Of the currently available comorbidity scores, the Recipient Risk Score demonstrated greatest use. This has implications for deceased-donor allocation algorithms, assessment of confounders in clinical research, and potentially, individual patient management.

T Lymphocyte responses to nonpolymorphic HLA-derived peptides are associated with chronic renal allograft dysfunction.

BACKGROUND: The routine assessment of cellular alloimmunity to guide therapy is of perennial interest because this limb of the immune system is the main target of current transplant immunosuppression. That this has not as yet been realized in clinical practice reflects the difficulty of developing a standardized assay that accounts for the high degree of polymorphism exhibited by histocompatibility antigens. METHODS: We have investigated whether immune responses to peptides derived from nonpolymorphic regions of human leukocyte antigen arise after transplantation, in particular in those with chronic allograft dysfunction. RESULTS: Peripheral blood mononuclear cell γ-interferon production to peptides derived from the nonpolymorphic α3 domain of class 1 human leukocyte antigen occurred more frequently in long-term renal transplant recipients than healthy controls (51/110 vs. 1/18, 46.3% vs. 5.5%; P<0.001). These responses were associated with chronic allograft dysfunction manifested by a reduced and decreasing estimated glomerular filtration rate (responders vs. nonresponders: 39.5 vs. 48.8 mL/min, P=0.015 and -4.1 vs. -1.3 mL/min/year, P=0.008). Responses occurred mostly to autologous, "cryptic self-epitopes" and arose from CD4CD25CD127 T lymphocytes, which have been previously implicated in chronic rejection. CONCLUSION: These findings suggest a strategy for assessing cellular immune responses to transplantation antigens with potential for generalization.

Assessing and comparing rival definitions of delayed renal allograft function for predicting subsequent graft failure.

BACKGROUND: The traditional definition of delayed graft function (DGF) rests on dialysis requirement during the first postoperative week. Subsequently, a more objective and "functional" definition of DGF (fDGF) has been proposed as an alternative to this dialysis-based definition of DGF (dDGF) and defined as a failure of the serum creatinine to decrease by at least 10% daily on 3 successive days during the first week posttransplantation, irrespective of dialysis requirement. However, an association between fDGF and long-term graft failure has not been fully established, and it is unknown whether fDGF is a better marker of subsequent outcomes than dDGF. METHODS: We studied 750 adult deceased donor kidney transplant recipients (1996-2006) and analyzed the association between these two DGF definitions and long-term graft outcome. RESULTS: Univariable associations with death-censored graft failure were seen for both dDGF and fDGF (hazard ratio [HR] 1.59; 95% confidence interval [CI] 1.16-2.18; P=0.004 and HR 1.72; 95% CI 1.26-2.36; P=0.001, respectively). On bivariable analysis (dDGF vs. fDGF), dDGF lost significance, whereas the effect of fDGF persisted (HR 1.52; 95%CI 1.03-2.25; P=0.04). This was also the case in a multivariable model, where fDGF but not dDGF was significantly associated with graft failure (HR 1.47; 95%CI 1.06-2.03; P=0.02). Results were similar for overall graft failure. CONCLUSIONS: This study confirms the utility of fDGF as an early marker of subsequent inferior allograft outcomes, suggesting superiority over the traditional (often subjective) dialysis-based definition. Wider adoption of the fDGF definition should be considered, both as a risk-stratification tool in clinical practice and a clinical trial endpoint.

Comparison of the predictive performance of eGFR formulae for mortality and graft failure in renal transplant recipients.

BACKGROUND: To date, efforts have focused on assessing estimated glomerular filtration rate (eGFR) formulae against measured GFR. However, a more appropriate clinical gold standard is one conveying a defined clinical disadvantage. In renal transplantation, these measures are mortality and graft failure. METHODS: The Long Term Efficacy and Safety Surveillance database was used to analyze 1344 renal transplant recipients. eGFR was assessed 6 months posttransplantation with the following formulae: Cockcroft-Gault; Walser; Nankivell; abbreviated modification of diet in renal disease (aMDRD); MDRD7; Rule's refitted MDRD; and Mayo Clinic. The outcome measures were mortality and graft failure. RESULTS: Although eGFR was statistically associated with subsequent mortality and graft failure in the Cox model (irrespective of which eGFR formula was used), the clinical utility of eGFR was moderate at best in predicting subsequent mortality and graft failure. No clinically relevant or statistically significant difference was discernable between formulae, with a maximum area under the receiver operating characteristic curve of 0.63 and 0.61 for 3- and 5-year mortality, respectively, and 0.66 and 0.60 for 3- and 5-year graft failure, respectively. Serum creatinine used in isolation displayed similar predictive utility, and no improvement was seen by investigating the change in creatinine or eGFR between 6 and 12 months. CONCLUSIONS: In summary, seven eGFR equations showed similar and limited utility in predicting mortality and graft failure after renal transplantation. This has important implications for the management of renal transplant recipients and the use of an eGFR as a surrogate endpoint in clinical trials.