Anthony Dorman

C3 Glomerulopathy: Clinicopathologic Features and Predictors of Outcome

BACKGROUND AND OBJECTIVES The term C3 glomerulopathy describes renal disorders characterized by the presence of glomerular deposits composed of C3 in the absence of significant amounts of Ig. On the basis of electron microscopy appearance, subsets of C3 glomerulopathy include dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). The full spectrum of histologic change observed in C3 glomerulopathy has yet to be defined and pathologic predictors of renal outcome within this patient population remain largely unknown. This study thus characterized a large C3 glomerulopathy cohort and identified clinicopathologic predictors of renal outcome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS All patients with kidney biopsies fulfilling criteria for C3 glomerulopathy from two quaternary renal centers within the United Kingdom and Ireland between 1992 and 2012 were retrospectively reviewed. We recorded histologic, demographic, and clinical data and determined predictors of ESRD using the Cox proportional hazards model. RESULTS Eighty patients with C3 glomerulopathy were identified: 21 with DDD and 59 with C3GN. Patients with DDD were younger, more likely to have low serum C3 levels, and more likely to have crescentic GN than patients with C3GN. Patients with C3GN were older and had more severe arteriolar sclerosis, glomerular sclerosis, and interstitial scarring than patients with DDD. Of 70 patients with available follow-up data, 20 (29%) progressed to ESRD after a median of 28 months. Age >16 years, DDD subtype, and crescentic GN were independent predictors of ESRD within the entire cohort. Renal impairment at presentation predicted ESRD only among patients with DDD. CONCLUSIONS Although detailed serologic and genetic data are lacking, this study nevertheless identifies important clinicopathologic distinctions between patients with DDD and C3GN. These include independent predictors of renal outcome. If replicated in other cohorts, these predictors could be used to stratify patients, enabling application of emerging mechanism-based therapies to patients at high risk for poor renal outcome.

Pathogenesis of acute renal failure associated with the HELLP syndrome: a case report and review of the literature

Acute renal failure is a rare but serious complication of pregnancy. We describe a 31-year-old woman with haemolytic anemia, elevated liver enzymes, low platelets (HELLP syndrome) who developed acute peripartum renal failure. Renal biopsy performed 2 weeks later because of persistent oliguria revealed thrombotic microangiopathy and acute tubular necrosis. This case highlights the probable pathogenesis of acute renal failure in HELLP patients and explains why it resolves in the majority of cases. A review of the literature that describes renal histology in HELLP patients is presented.

Mesangioproliferative glomerulonephritis with IgM deposition: clinical characteristics and outcome.

The significance of IgM on immunofluorescence in renal biopsy specimens remains unclear. This retrospective case study was conducted to define the clinical features, response to therapy and outcome of patients with Mesangioproliferative Glomerulonephritis (MGN) with diffuse IgM deposition. Of 1919 native renal biopsies performed over a ten-year period, 139 (7.2%) had light microscopic features of MGN and manifested IgM as the dominant immunoglobulin. When exclusion criteria (more than a trace of IgA or IgG, segmental IgM, evidence of SLE, vasculitis, FSGS or Alports syndrome and pregnant patients) were applied, 60 patients (3.1%) remained. Follow-up data were available for 54 cases with a mean age of 26.5 years (range 1.7–63). Mean follow-up period was 7.4 years (range 4.7–22.2). Forty-one per cent presented with nephrotic syndrome (NS), 26% with asymptomatic proteinuria (>250mg/24hr), 18% with macroscopic hematuria and 15% with isolated microscopic hematuria. Twenty-one percent of patients were hypertensive at presentation. Creatinine was initially <120(mol/L in all but one patient. Only four patients (7.4%), all nephrotic, suffered a decline in renal function despite treatment; all 4 developed ESRF after a mean of 5.6 years (range 2–8.3). Two of these were subsequently re-biopsied and found to have FSGS. No patients with isolated microscopic / macroscopic hematuria or asymptomatic proteinuria suffered a decline in renal function. Protein excretion rate fell into the normal range in 63% of those receiving steroids, with 82% becoming steroid dependent. Of those treated with cyclosporine (48%) or cyclophosphamide (52%) only 9.5% and 14.5% respectively remained in prolonged remission after discontinuing treatment. It is concluded that MGN with IgM deposition carries a very favorable prognosis except in patients with NS who develop FSGS. However there is a high incidence of steroid dependence and resistance in the proteinuric group.

Higher tacrolimus trough levels on days 2-5 post-renal transplant are associated with reduced rates of acute rejection

Abstract:  We analyzed the association between whole‐blood trough tacrolimus (TAC) levels in the first days post‐kidney transplant and acute cellular rejection (ACR) rates. Four hundred and sixty‐four consecutive, deceased‐donor kidney transplant recipients were included. All were treated with a combination of TAC, mycophenolate mofetil and prednisolone. Patients were analyzed in four groups based on quartiles of the mean TAC on days 2 and 5 post‐transplant: Group 1: median TAC 11 ng/mL (n = 122, range 2–13.5 ng/mL), Group 2: median 17 ng/mL (n = 123, range 14–20 ng/mL), Group 3: median 24 ng/mL (n = 108, range 20.5–27 ng/mL) and Group 4: median 33.5 ng/mL (n = 116, range 27.5–77.5 ng/mL). A graded reduction in the rates of ACR was observed for each incremental days 2–5 TAC. The one‐yr ACR rate was 24.03% (95% CI 17.26–32.88), 22.20% (95% CI 15.78–30.70), 13.41% (95% CI 8.15–21.63) and 8.69% (95% CI 4.77–15.55) for Groups 1–4, respectively (p = 0.003). This study suggests that higher early TACs are associated with reduced rates of ACR at one yr.

Adenosquamous carcinoma of the prostate : a case report

Mixed types of carcinoma of the prostate are rare. The majority of those described (22 cases) are examples of mixed adenocarcinoma and transitional cell carcinoma. Much more unusual is the mixed adenosquamous carcinoma, of which only three cases have been described. This report presents an additional case of the rare adenosquamous carcinoma of the prostate. It discusses the clinicopathologic features and the possible histogenesis of this tumor and suggests a role for stilbestrol in its development.

Improved graft survival in highly sensitized patients undergoing renal transplantation after the introduction of a clinically validated flow cytometry crossmatch.

Background. Flow cytometric techniques are increasingly used in pretransplant crossmatching, although there remains debate regarding the clinical significance and predictive value of donor-specific antibodies detected by flow cytometry. At least some of the discrepancies between published studies may arise from differences in cutoffs used and lack of standardization of the test. Methods. We selected cut-off values for pretransplant flow cytometric crossmatching (FCXM) based on the correlation of retrospective results with the occurrence of antibody-mediated rejection. The impact on long-term renal graft survival of prospective FCXM was determined by comparing graft survival between patients crossmatched with complement-dependent cytotoxicity (CDC) only with those prospectively crossmatched with both CDC and FCXM. Results. Chosen cut-off values gave a positive predictive value of FCXM for antibody-mediated rejection of 83%, and a negative predictive value of 90%. After the introduction of prospective B- and T-cell crossmatching by flow cytometry in addition to CDC in our center, there was a significant improvement in renal graft survival in highly sensitized patients (P=0.017). Four-year graft survival in highly sensitized patients after the introduction of FCXM was 89%, which did not differ significantly from that seen in nonsensitized patients (93%; P=0.638). Conclusions. Our data demonstrate that prospective FCXM improves renal transplant outcome in highly sensitized patients, provided that cut-off values are carefully validated and results interpreted in the context of sensitization history and antibody screening results.

Renal histology in the elderly: indications and outcomes.

BACKGROUND Renal disease is being increasingly diagnosed in the elderly. However, reports on biopsy-confirmed renal disease in this population are limited. The aim of this study was to give an overview of the most important indications, diagnoses and outcomes of renal biopsies in the elderly in our center. METHODS This was a retrospective review of all elderly renal biopsies over 5 years. Patients were eligible for inclusion if they were aged ≥65 years and had had a native kidney biopsy performed. The data recorded included age, sex, indications for biopsy, histological diagnoses and outcomes. RESULTS During this time, 1,372 native renal biopsies were performed. Of these, 236 (17%) were in patients aged ≥65 years; 150 male (64%) and 86 female (36%). The most common indications for biopsy were acute renal failure and nephrotic syndrome. Common diagnoses included pauci-immune crescentic glomerulonephritis, tubulointerstitial nephritis, membranous nephropathy, IgA nephropathy and chronic thrombotic microangiopathy. Long-term follow-up of 3 years was available for 102 patients; median serum creatinine at the time of biopsy was 427 µmol/L (interquartile range 204-702) and at 3 years post biopsy had fallen to 192 µmol/L (interquartile range 152-408). CONCLUSIONS In our center, 17% of native kidney biopsies are performed in elderly patients aged ≥65 years. In our experience, this procedure was safe and had a 97% diagnostic rate. The available follow-up data of patients suggest that renal histology is not only of benefit in diagnosis but also of potential value in terms of prognosis and treatment.

Clinical and pathologic characteristics of hereditary apolipoprotein A-I amyloidosis in Ireland.

Apolipoprotein A‐I amyloidosis is a rare, autosomal dominant disorder characterized by progressive accumulation of amyloid fibrils in tissues, leading to renal and hepatic disease. We describe the clinical manifestations and pathologic features of kidney disease in three Irish families.

Spatial and Temporal Clustering of Anti-Glomerular Basement Membrane Disease

BACKGROUND AND OBJECTIVES An environmental trigger has been proposed as an inciting factor in the development of anti-GBM disease. This multicenter, observational study sought to define the national incidence of anti-GBM disease during an 11-year period (2003-2014) in Ireland, investigate clustering of cases in time and space, and assess the effect of spatial variability in incidence on outcome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We ascertained cases by screening immunology laboratories for instances of positivity for anti-GBM antibody and the national renal histopathology registry for biopsy-proven cases. The population at risk was defined from national census data. We used a variable-window scan statistic to detect temporal clustering. A Bayesian spatial model was used to calculate standardized incidence ratios (SIRs) for each of the 26 counties. RESULTS Seventy-nine cases were included. National incidence was 1.64 (95% confidence interval [95% CI], 0.82 to 3.35) per million population per year. A temporal cluster (n=10) was identified during a 3-month period; six cases were resident in four rural counties in the southeast. Spatial analysis revealed wide regional variation in SIRs and a cluster (n=7) in the northwest (SIR, 1.71; 95% CI, 1.02 to 3.06). There were 29 deaths and 57 cases of ESRD during a mean follow-up of 2.9 years. Greater distance from diagnosis site to treating center, stratified by median distance traveled, did not significantly affect patient (hazard ratio, 1.80; 95% CI, 0.87 to 3.77) or renal (hazard ratio, 0.76; 95% CI, 0.40 to 1.13) survival. CONCLUSIONS To our knowledge, this is the first study to report national incidence rates of anti-GBM disease and formally investigate patterns of incidence. Clustering of cases in time and space supports the hypothesis of an environmental trigger for disease onset. The substantial variability in regional incidence highlights the need for comprehensive country-wide studies to improve our understanding of the etiology of anti-GBM disease.

Deoxyribonucleic Acid Ploidy Studies in Choroidal Melanomas

In several tumors of different organ sites, the amount of DNA in a cell (ploidy) is associated with malignancy. We performed DNA quantitation in 21 choroidal melanomas and compared flow cytometry with image analysis in 11 of these melanomas. We modified our preparation technique to overcome problems with pigment and control cell populations in the image analysis group. Fifteen tumors were diploid and two tumors were tetraploid. Four tumors were unprocessable by flow cytometry, but two of these tumors were diploid by image analysis. Image analysis also detected tetraploidy in two tumors that were diploid by flow cytometry. During image analysis, cells were classified according to the Callendar classification and histograms were plotted for each cell type. All spindle A cells were diploid and most tetraploid peaks were formed by epithelioid cells. The use of image analysis on small samples of choroidal melanomas may be of value both in confirmation of diagnosis and prognosis of these lesions, and perhaps therapeutically, for example, in the monitoring of radiation treatment.