Aims
Post‐mortem imaging is a potential alternative to traditional medicolegal autopsy. We investigate the reduction in number of invasive autopsies required by use of post‐mortem CT ± coronary ...angiography.
Methods and results
A total of 120 adult deaths referred to the Coroner were investigated by CT, with coronary angiography employed only for the second series of 60 cases, in order to determine the added value of angiography. The confidence of imaging cause of death was classified as definite (no autopsy), probable, possible or unascertained. Invasive autopsy was not required in 38% of cases without coronary angiography and 70% of cases with angiography. Full autopsy, including brain dissection, was required in only 9% of cases. There was complete agreement between autopsy and radiological causes of death in the cases with a ‘probable’ imaging cause of death, indicating that cases for which imaging provides an accurate cause of death without autopsy were identified correctly. In two patients, CT demonstrated unsuspected fractures, not detected at subsequent autopsy.
Conclusions
A two‐thirds reduction in the number of invasive coronial autopsies can be achieved by use of post‐mortem CT plus coronary angiography. At the same time, use of post‐mortem CT may improve accuracy of diagnosis, particularly for traumatic deaths.
In a single-center, multiple-referral source study, 38 patients with progressive IgA nephropathy and controlled hypertension were randomized to treatment with prednisolone and cytotoxic agents, to ...therapy with low-dose cyclophosphamide then azathioprine, and to control groups. The follow-up period lasted 2 to 6 yr. Renal survival, as assessed by Kaplan-Meier analysis annually to 5 yr, showed significant preservation of function from 3 yr in the treatment group and 82, 82, 72, and 72% for 2, 3, 4, and 5 yr, respectively, compared with 68, 47, 26, and 6% in controls. Rate of loss of renal function, evaluated objectively by least-squares analyses of reciprocal serum creatinine, was reduced-and in one-third of the patients, arrested-during immunosuppressive treatment. Proteinuria, present in all patients at the time of entry into the trial, was reduced by treatment from 12 mo, compared with pretreatment levels or controls; erythrocyturia was reduced from 6 mo. Histologic activity and chronicity indexes were determined in renal biopsies performed at trial entry. Multivariate analysis demonstrated that mesangial cell proliferation and matrix scores were highest in those patients with more rapidly progressive disease. No morphologic variable or residual renal function predicted response to immunosuppressive therapy at entry. Mean arterial pressures did not differ significantly between treatment and control groups. There was thus no explanation other than treatment for the improved outcome in patients who received immunosuppressive therapy. Morbidity attributable to treatment or to renal failure occurred in both groups; an audit showed that benefits of therapy outweighed expected or minor side effects of drugs in this population at risk of end-stage renal failure. Patients selected for moderately progressive IgA nephropathy benefit from treatment with prednisolone and cytotoxic agents; results are consistent with modulation of systemic immune response or nephritic injury, thus explaining improved outcome, and indicate that this therapy has an acceptably low risk of side effects.
Focal segmental glomerulosclerosis (FSGS) is a common finding in IgA nephropathy (IgAN). Here we assessed FSGS lesions in the Oxford Classification patient cohort and correlated histology with ...clinical presentation and outcome to determine whether subclassification of the S score in IgAN is reproducible and of clinical value. Our subclassification of lesions in 137 individuals with segmental glomerulosclerosis or adhesion (S1) identified 38% with podocyte hypertrophy, 10% with hyalinosis, 9% with resorption droplets within podocytes, 7% with tip lesions, 3% with perihilar sclerosis, and 2% with endocapillary foam cells. Reproducibility was good or excellent for tip lesions, hyalinosis, and perihilar sclerosis; moderate for podocyte hypertrophy; and poor for resorption droplets, adhesion only, and endocapillary foam cells. Podocyte hypertrophy and tip lesions were strongly associated with greater initial proteinuria. During follow-up of patients without immunosuppression, those with these features had more rapid renal function decline and worse survival from a combined event compared to S1 patients without such features and those without FSGS. Also in individuals with podocyte hypertrophy or tip lesions, immunosuppressive therapy was associated with better renal survival. In IgA nephropathy, the presence of podocyte hypertrophy or tip lesions, markers of podocyte injury, were reproducible. These features are strongly associated with proteinuria and, in untreated patients, carry a worse prognosis. Thus, our findings support reporting podocytopathic features alongside the S score of the Oxford Classification.
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.
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.
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.
In the large VALIGA cohort of European subjects with IgAN, no significant correlation was found between tonsillectomy and renal function decline.
Accuracy of routinely collected information concerning cause of death is essential for public health and health systems planning. Since clinical examination has relatively low sensitivity for ...detection of valvular heart disease (VHD), mortality data based on clinical information alone might routinely underestimate the number of deaths due to VHD.
We compared autopsy findings against premortem clinical information for 8198 consecutive adult postmortems (mean age 69.1 years, 61.3% men), performed in a single UK tertiary referral centre with on-site cardiac surgical facilities over a 10-year period (2004-2013) during which 21% of the adult population underwent postmortem examination.
Following postmortem, VHD was the principal cause of death in 165 individuals (2.0%), a principal or contributory cause ('any cause') of death in 326 (4.0%) and an incidental (ie, non-causal) finding in a further 346 (4.2%). Clinical documentation of VHD before death was highly specific but relatively insensitive for postmortem identification of VHD as the principal (specificity 96.8%; 95% CI 96.4% to 97.2%; sensitivity 69.7%, 95% CI 62.1% to 76.6%) or any (specificity 98.1%; 95% CI 97.8% to 98.4%; sensitivity 68.4%, 95% CI 63.1% to 73.4%) cause of death. VHD (principally aortic stenosis, endocarditis and rheumatic heart disease) was newly noted at postmortem and listed as a cause of death in 142 individuals (1.7%).
Clinical information recorded premortem is highly specific but relatively insensitive for the cause of death established at autopsy. Population-based mortality statistics that depend on premortem clinical information are likely to routinely underestimate the mortality burden of VHD.
Aim
Interpretation of retrospective clinicopathological studies of IgA nephropathy (IgAN) has been confounded by immunosuppression bias. In published validation studies of the Oxford Classification ...of IgAN, an average of 33 % of patients received non-randomised steroid and/or cytotoxic therapy. In order to determine the true impact of proliferative lesions on the natural history of IgAN, analysis of patient cohorts that have received no immunosuppression is required.
Methods
We performed a retrospective single centre study of patients with IgAN managed without immunosuppressive therapy. Biopsies were scored according to the Oxford Classification. The primary outcomes were renal survival or a rapid loss of renal function defined as a decline in eGFR of >5 ml/min/year.
Results
237 patients with IgAN were identified with a mean follow-up of 82 months. 200 had biopsies available for review, of which 156 were adequate for scoring using the Oxford Classification. 9/156 patients (5.8 %) received some immunosuppressive therapy, mostly for unrelated conditions: these were excluded. In multivariate COX regression, including histological and clinical data, the only independent predictors of time to ESRD were baseline eGFR (HR 0.96 per ml/min increase, p = 0.018), baseline proteinuria (HR 1.36 per doubling, p = 0.004) and endocapillary hypercellularity (HR 4.75 for E1 compared to E0, p < 0.001). Independent predictors of a rapid decline in eGFR were proteinuria (OR 1.45 per doubling, p = 0.006), endocapillary hypercellularity (OR 3.41 for E1 compared to E0, p = 0.025) and tubular atrophy/interstitial fibrosis (OR 8.77 for T2 compared to T0, p = 0.006).
Conclusions
In a cohort of IgAN patients receiving no immunosuppression, endocapillary proliferation and tubular atrophy/interstitial fibrosis are independent predictors of rate of loss of renal function. The lack of predictive value of E score in other clinicopathological studies is most likely a result of immunosuppression-associated bias. Our findings provide evidence to support immunosuppressive treatment of endocapillary-pattern IgAN.
Reactivation of polyomavirus BK (BKV) after renal transplantation can lead to allograft dysfunction or loss with early detection improving outcomes. Current guidelines recommend quantitative ...polymerase chain reaction for surveillance; however, urinary decoy cell detection is a potentially cost-effective alternative. We present the outcomes from an early intensive BKV surveillance program using decoy cell detection for initial screening starting 2 weeks after transplantation.
Records for all recipients of kidney (n=211) or simultaneous kidney and pancreas (n=102) transplants performed over 2 years in a single center were reviewed. Follow-up was for a minimum of 1 year. Urine cytology screening was performed fortnightly from 0 to 3 months after transplantation, monthly from 3 to 6 months then every 2 months from 6 to 12 months.
Decoy cell positivity occurred in 56 of 313 patients (17.9%) with sustained decoy cell positivity (≥2 positive urine samples >2 weeks apart) present in 32 patients (10.2%). Twenty-four patients (7.6%) became viremic and three patients (1%) developed polyoma virus nephropathy. The median time after transplantation until decoy cell positivity was 78 days, decreasing to 67 days for patients with sustained positivity and 57 days for patients who developed polyoma virus nephropathy. No grafts were lost due to BKV during the study period. Decoy cell screening resulted in savings of approximately £135,000 over 2 years, when compared with routine surveillance by quantitative polymerase chain reaction.
Clinically significant BKV reactivation occurs early after transplantation and can be reliably detected by decoy cell screening. A surveillance strategy for detecting BKV reactivation based on urine cytology is cost-effective.
The demonstration of impaired C regulation in the thrombotic microangiopathy (TMA) atypical hemolytic uremic syndrome (aHUS) resulted in the successful introduction of the C inhibitor eculizumab into ...clinical practice. C abnormalities account for approximately 50% of aHUS cases; however, mutations in the non-C gene diacylglycerol kinase-
have been described recently in individuals not responsive to eculizumab. We report here a family in which the proposita presented with aHUS but did not respond to eculizumab. Her mother had previously presented with a post-renal transplant TMA. Both the proposita and her mother also had Charcot-Marie-Tooth disease. Using whole-exome sequencing, we identified a mutation in the inverted formin 2 gene (
) in the mutational hotspot for FSGS. Subsequent analysis of the Newcastle aHUS cohort identified another family with a functionally-significant mutation in
In this family, renal transplantation was associated with post-transplant TMA. All individuals with
mutations presenting with a TMA also had aHUS risk haplotypes, potentially accounting for the genetic pleiotropy. Identifying individuals with TMAs who may not respond to eculizumab will avoid prolonged exposure of such individuals to the infectious complications of terminal pathway C blockade.
Kidney transplant survival is shortened by chronic rejection and side effects of standard immunosuppressive drugs. Cell-based immunotherapy with tolerogenic dendritic cells has long been recognized ...as a promising approach to reduce general immunosuppression. Published trials report the safety and the absence of therapy-related adverse reactions in patients treated with tolerogenic dendritic cells suffering from several inflammatory diseases. Here, we present the first phase I clinical trial results using human autologous tolerogenic dendritic cells (ATDC) in kidney transplantation. Eight patients received ATDC the day before transplantation in conjunction with standard steroids, mycophenolate mofetil and tacrolimus immunosuppression with an option to taper mycophenolate mofetil. ATDC preparations were manufactured in a Good Manufacturing Practice–compliant facility and fulfilled cell count, viability, purity and identity criteria for release. A control group of nine patients received the same standard immunosuppression, except basiliximab induction replaced ATDC therapy and mycophenolate tapering was not allowed. During the three-year follow-up, no deaths occurred and there was 100% graft survival. No significant increase of adverse events was associated with ATDC infusion. Episodes of rejection were observed in two patients from the ATDC group and one patient from the control group. However, all rejections were successfully treated by glucocorticoids. Mycophenolate was successfully reduced/stopped in five patients from the ATDC group, allowing tacrolimus monotherapy for two of them. Regarding immune monitoring, reduced CD8 T cell activation markers and increased Foxp3 expression were observed in the ATDC group. Thus, our results demonstrate ATDC administration safety in kidney-transplant recipients.
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This review summarizes the recommendations for reporting immunoglobulin A (IgA) nephropathy biopsies and their evidence base, discusses the limitations of the Oxford Classification study and presents ...the findings of recent validation studies.
The Oxford Classification identified four histological lesions as independent prognostic factors: mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S) and tubular atrophy/interstitial fibrosis (T). The MEST criteria predicted outcome in some, but not all, of 13 recent validation studies. M is of independent prognostic value in four out of 13 studies, S in four out of 13 and T in 10 out of 13. Apparently contradictory findings reflect differences in patient selection criteria, treatment and outcome measures. The Oxford Classification study provided indirect evidence that endocapillary hypercellularity is responsive to immunosuppressive therapy. This is confirmed in two validation studies. One study, which included patients with rapidly progressive disease, found glomerular crescents to be a significant prognostic marker. Immunohistological findings correlate with proliferative glomerular lesions but are not of independent prognostic value.
The Oxford Classification is applicable to patients who were excluded from the original cohort, including those with rapidly progressive disease, and the prognostic value of proliferative glomerular lesions is influenced by immunosuppressive therapy. The Oxford schema will be reviewed in the light of recent findings.
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