Sean J. Barbour

Disease-specific risk of venous thromboembolic events is increased in idiopathic glomerulonephritis

The risk of venous thromboembolic events is thought to be highest in patients with membranous nephropathy. This association has been recently questioned, and it is not known whether this simply reflects the severity of proteinuria. To better understand the relationship between histologic diagnosis and the risk of venous thromboembolic events we evaluated patients in the Toronto Glomerulonephritis Registry. Of 1313 patients with idiopathic glomerulonephritis, 395 were diagnosed with membranous nephropathy, 370 with focal segmental glomerulosclerosis (FSGS), and 548 with immunoglobulin-A nephropathy (IgAN). Risk factors were evaluated by Cox proportional hazards for 53 image-confirmed venous thromboembolic events in 44 patients during a median follow-up of 63 months. The risk was highest in patients with membranous nephropathy and FSGS (hazard ratios of 22 and 7.8, respectively) referenced to patients with IgAN. Following adjustment for gender, cancer history, proteinuria, and serum albumin by multivariable analysis, the histologic subtype remained an independent risk for venous thromboembolic events. This risk was still highest in patients with membranous nephropathy followed by FSGS with adjusted hazard ratios of 10.8 and 5.9, respectively. Thus, in this large cohort, histologic diagnosis was an independent risk factor for venous thromboembolic events. Further studies are needed to discover mechanisms responsible for this high risk in patients with membranous nephropathy.

Risk Stratification of Patients With IgA Nephropathy

In this review, we summarize recent advances in the risk stratification of patients with immunoglobulin A (IgA) nephropathy. Several clinical variables have consistent and independent associations with worse kidney prognosis, including blood pressure, proteinuria, and baseline kidney function. Although one-time cross-sectional assessments of blood pressure and proteinuria are important, a more thorough understanding of risk can be achieved when these variables are considered over a follow-up period. IgA nephropathy is unique compared with other glomerular diseases in that a much lower threshold of proteinuria (protein excretion, 1 g/d) is associated with glomerular filtration rate (GFR) loss. Controlling proteinuria and blood pressure over time is important to reduce the risk of future loss of kidney function. The recently described Oxford classification has helped standardize the pathologic characterization of IgA nephropathy using a scoring system that is readily reproducible and associated with increased risk of GFR loss independent of clinical variables. We suggest an approach to risk stratification in IgA nephropathy when considering potential treatment with immunosuppression. Despite our current understanding of risk stratification in IgA nephropathy, the ability to accurately predict individual patient-level risk currently is limited, and further research into additional biomarkers or risk prediction tools is needed to improve the care of patients with IgA nephropathy.

Oxford Classification of IgA nephropathy 2016: an update from the IgA Nephropathy Classification Working Group

Since the Oxford Classification of IgA nephropathy (IgAN) was published in 2009, MEST scores have been increasingly used in clinical practice. Further retrospective cohort studies have confirmed that in biopsy specimens with a minimum of 8 glomeruli, mesangial hypercellularity (M), segmental sclerosis (S), and interstitial fibrosis/tubular atrophy (T) lesions predict clinical outcome. In a larger, more broadly based cohort than in the original Oxford study, crescents (C) are predictive of outcome, and we now recommend that C be added to the MEST score, and biopsy reporting should provide a MEST-C score. Inconsistencies in the reporting of M and endocapillary cellularity (E) lesions have been reported, so a web-based educational tool to assist pathologists has been developed. A large study showed E lesions are predictive of outcome in children and adults, but only in those without immunosuppression. A review of S lesions suggests there may be clinical utility in the subclassification of segmental sclerosis, identifying those cases with evidence of podocyte damage. It has now been shown that combining the MEST score with clinical data at biopsy provides the same predictive power as monitoring clinical data for 2 years; this requires further evaluation to assess earlier effective treatment intervention. The IgAN Classification Working Group has established a well-characterized dataset from a large cohort of adults and children with IgAN that will provide a substrate for further studies to refine risk prediction and clinical utility, including the MEST-C score and other factors.

Effect of Oral Methylprednisolone on Clinical Outcomes in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial

Importance Guidelines recommend corticosteroids in patients with IgA nephropathy and persistent proteinuria, but the effects remain uncertain. Objective To evaluate the efficacy and safety of corticosteroids in patients with IgA nephropathy at risk of progression. Design, Setting, and Participants The Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) study was a multicenter, double-blind, randomized clinical trial designed to recruit 750 participants with IgA nephropathy (proteinuria greater than 1 g/d and estimated glomerular filtration rate [eGFR] of 20 to 120 mL/min/1.73 m2 after at least 3 months of blood pressure control with renin-angiotensin system blockade] and to provide follow-up until 335 primary outcomes occurred. Interventions Patients were randomized 1:1 to oral methylprednisolone (0.6-0.8 mg/kg/d; maximum, 48 mg/d) (n = 136) or matching placebo (n = 126) for 2 months, with subsequent weaning over 4 to 6 months. Main Outcomes and Measures The primary composite outcome was end-stage kidney disease, death due to kidney failure, or a 40% decrease in eGFR. Predefined safety outcomes were serious infection, new diabetes, gastrointestinal hemorrhage, fracture/osteonecrosis, and cardiovascular events. The mean required follow-up was estimated to be 5 years. Results After randomization of 262 participants (mean age, 38.6 [SD, 11.1] years; 96 [37%] women; eGFR, 59.4 mL/min/1.73 m2; urine protein excretion, 2.40 g/d) and 2.1 years’ median follow-up, recruitment was discontinued because of excess serious adverse events. Serious events occurred in 20 participants (14.7%) in the methylprednisolone group vs 4 (3.2%) in the placebo group (P = .001; risk difference, 11.5% [95% CI, 4.8%-18.2%]), mostly due to excess serious infections (11 [8.1%] vs 0; risk difference, 8.1% [95% CI, 3.5%-13.9%]; P < .001), including 2 deaths. The primary renal outcome occurred in 8 participants (5.9%) in the methylprednisolone group vs 20 (15.9%) in the placebo group (hazard ratio, 0.37 [95% CI, 0.17-0.85]; risk difference, 10.0% [95% CI, 2.5%-17.9%]; P = .02). Conclusions and Relevance Among patients with IgA nephropathy and proteinuria of 1 g/d or greater, oral methylprednisolone was associated with an increased risk of serious adverse events, primarily infections. Although the results were consistent with potential renal benefit, definitive conclusions about treatment benefit cannot be made, owing to early termination of the trial. Trial Registration clinicaltrials.gov Identifier: NCT01560052

Individuals of Pacific Asian origin with IgA nephropathy have an increased risk of progression to end-stage renal disease.

IgA nephropathy (IgAN) accounts for a far higher proportion of end-stage renal disease (ESRD) in Asia compared with North America. It is not known whether this is entirely because of differences in disease prevalence or a higher risk of disease progression. The lack of a racially diverse population cohort followed longitudinally has previously precluded the ability to address this question. To determine whether Asians in North America with IgAN are at higher risk for ESRD, we analyzed a cohort of 202 patients of self-reported Pacific Asian origin and 467 of other origin from the Toronto GN Registry followed up for a median of 46.4 months. The primary outcome of ESRD (dialysis, transplantation, or eGFR below 15) was analyzed using Cox regression analysis. Baseline eGFR was 59.6 ml/min/1.73 m(2), and median proteinuria was 1.8 g/day. ESRD occurred in 213 patients. By univariable analysis, the risk of ESRD was similar between the two groups (hazard ratio 0.98, 95% CI 0.73, 1.31); however, after adjusting for age, gender, eGFR, medication use, blood pressure, and proteinuria, the risk of ESRD was significantly higher in Pacific Asian individuals (hazard ratio 1.56, 95% CI 1.10, 2.22). This was supported by a significant 1.62 ml/min/1.73 m(2)/year faster rate of eGFR decline (95% CI -3.19, -0.5) and an increased risk of a reduction in eGFR by half (hazard ratio 1.81, 95% CI 1.25, 2.62). Thus, in a large multiracial cohort of patients with IgAN, individuals of Pacific Asian origin have a higher risk of progression to ESRD.

A systematic review of ethnic differences in the rate of renal progression in CKD patients

Chronic kidney disease (CKD) is a public health problem of increasing importance, consuming a growing proportion of health care resources. It is estimated that, in the United States, there are 19.2 million individuals with CKD [1], and this figure is expected to increase in parallel to the rising prevalence of hypertension and diabetes. By 2010, the projected number of end-stage renal disease (ESRD) patients will climb to over 650 000 [2], with a further predicted increase to 2.24 million by 2030 [3]. Therefore, improved understanding of the predictors of GFR decline is essential. Information about predictors would allow nephrologists to accurately predict those CKD patients at risk of progressing to ESRD, which would help to individualize patient care, allowing for optimal planning for renal replacement therapy (RRT), reduce the need for urgent dialysis and ultimately allow for more efficient allocation of scarce health care resources. In addition, the recognition of novel risk factors for progression may lead to the development of new therapies capable of altering the trajectory of the disease. It has been recognized that the incidence of ESRD is higher in ethnic minorities; however, the reasons for this have not been well defined. For example, American blacks are four times more likely to require dialysis than whites [4]. An increased burden of ESRD has also been shown to affect Hispanics and Asians [5]. Conversely, ethnic minorities tend, paradoxically, to have improved outcomes once started on haemodialysis [5,6]. Several mechanisms have been suggested to explain such differences, though these have not been proven. For example, a higher prevalence of co-morbidities, lower socioeconomic status and comparatively worse access to health care among ethnic minorities have been cited as reasons for the higher incidence of ESRD [7–9]. Such reasoning holds that the incidence of ESRD is dependent on the number of CKD patients at risk of progressing, and the higher prevalence of diabetes and hypertension in blacks may result in greater CKD [4]. Similarly, lower socioeconomic status in minorities may create inequalities in access to health care resources and thus reduce delivery of medical management known to slow the progression of renal dysfunction [10,11]. A second explanation is that a higher death rate amongst CKD patients in one ethnic group would leave fewer patients alive to require RRT, thus affecting the observed incidence rate of ESRD. Different thresholds for starting RRTwould also affect the measured incidence of ESRD. Finally, the higher incidence of ESRD amongst ethnic minorities may in fact be due to a faster rate of GFR decline and more rapid progression of renal disease. The purpose of this review is to summarize the available evidence on ethnic differences in the rates of CKD progression towards ESRD. Ideally, available studies would directly observe rates of GFR decline in CKD cohorts of different races. This would avoid such confounders as CKD prevalence, the competing risk of death and varying thresholds for starting RRT. Alternatively, in studies examining the incidence rates of ESRD, inferences can be made regarding progression rates only if attempts are made to account for differences in the baseline prevalence of CKD and in longitudinal mortality rates.

Proliferative glomerulonephritis with monoclonal IgG deposits secondary to chronic lymphocytic leukemia. Report of two cases

Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) is a recently described entity that is only rarely associated with a hematological or lymphoproliferative malignancy. We describe the cases of two men with preexisting chronic lymphocytic leukemia (CLL) who developed endocapillary proliferative glomerulonephritis with nonorganized monoclonal IgG(1) deposits. One biopsy also showed CLL infiltration of the cortex. Both patients were treated with rituximab in addition to cyclophosphamide in one case and fludarabine in the other with significant improvement of their renal disease and CLL. This report provides additional evidence to support the use of rituximab in the therapy of CLL-associated PGNMID.

Increased tidal volume variability in children is a better marker of opioid-induced respiratory depression than decreased respiratory rate

Objective. During opioid administration, decreasing respiratory rate is typically used as a predictor of respiratory depression. Prior to opioid-induced apnea, progressively irregular breathing patterns have been noticed. We hypothesize that opioid administration to children will increase tidal volume variability (TVvar) and that this will be a better predictor of respiratory depression than a decrease in respiratory rate. Methods. We recruited 32 children aged 2–8 years scheduled to undergo surgery. During spontaneous ventilation, flow rates and respiratory rates were continuously recorded, while remifentanil was infused at stepwise increasing doses each lasting 10 min. The infusion was continued until the patient showed signs of respiratory depression. Flow data from each dose was used to calculate tidal volumes, from which TVvar was calculated. The respiratory rate and TVvar during the last (Dlast), second to last (D−2), and third to last (D−3), administered doses were compared to those during baseline (fourth to last dose). We chose a threshold of TVvar increase and compared it to a decrease in respiratory rate below 10 breaths per min as predictors of respiratory depression. Results. Compared to baseline, the TVvar increased by 336% and 668% during D−2 and Dlast, respectively, whereas respiratory rate decreased by 14.3%, 31.7%, and 55.5% during D−3, D−2, and Dlast, respectively. A threshold increase in TVvar of 150% over baseline correctly predicted respiratory depression in 41% of patients, compared to a drop in respiratory rate correctly predicting 22% of patients. Conclusions.TVvar increases as children approach opioid-induced respiratory depression. This is a more useful predictor of respiratory depression than a fall in respiratory rate because the TVvar increase is 10 times the drop in respiratory rate. A TVvar increase also correctly predicts respiratory depression twice as often as decreased respiratory rate and is independent of age-related alterations in physiologic respiratory rates.

Identifying the ideal metric of proteinuria as a predictor of renal outcome in idiopathic glomerulonephritis

The majority of our insight about glomerulonephritis (GN) is from observational research. Because proteinuria is an important element of outcome in GN, the validity of observational analyses is dependent on the metric used to model proteinuria. Previous metrics of proteinuria included the value at baseline, the average of all values over the entire follow-up (time-averaged), the instantaneous value at each time point (time-varying), or the average of all values prior to each time point, and each of these standardized to body surface area. It was not known which of these metrics best accounts for the risk of renal outcome and should be used in GN research. To address this, we studied 1351 adult patients with IgA nephropathy, focal segmental glomerulosclerosis, and membranous nephropathy from the Toronto GN Registry. Cox regression models for the risk of end-stage renal disease or a halving of estimated glomerular filtration rate included each proteinuria metric and were compared using model fit and discrimination. Proteinuria did not need to be standardized to body surface area. Time-varying proteinuria was the best metric to account for the prognostic effects of proteinuria over time, especially in focal segmental glomerulosclerosis and IgA nephropathy over the majority of follow-up, and in membranous nephropathy earlier in the disease course. Using alternate proteinuria metrics biased analyses up to 30.3%. These findings can improve the validity and design of future observational and prediction modeling studies in GN.

The need for improved uptake of the KDIGO glomerulonephritis guidelines into clinical practice in Canada: a survey of nephrologists

Background The lack of glomerulonephritis (GN) guidelines has historically contributed to substantial variability in the treatment of GN. We hypothesize that there are barriers to GN guideline implementation leading to incomplete translation of the 2012 KDIGO GN guidelines into patient care, and that current practice patterns deviate from guideline recommendations. Methods Adult nephrologists in Canada (N = 390) were surveyed using a web-based tool. The survey of 40 questions captured physician demographics, self-reported GN case load, treatment approaches and barriers to guideline implementation. Results The response rate was 44%. Physicians report seeing six (IQR 4,10) new cases of idiopathic GN every 6 months. The majority treat ANCA GN according to guidelines, but 9–37% treat nephrotic focal segmental glomerulosclerosis or membranous nephropathy with non-recommended immunosuppression and 6–9% do not treat with any immunotherapy, whereas 26% treat subnephrotic disease with immunosuppression. The majority indicated that standardized care tools would improve patient care, but they were only available to 25–44%. Patient education tools and nursing support are unavailable to 87 and 67%, respectively; insurance coverage for immune therapies is poorly accessible to 84%, yet 86% feel this would improve care and 96% of physicians support comparing their practice with benchmarks from provincial GN registries. Conclusions We show that 2 years after the publication of the KDIGO GN guidelines, 15–46% of Canadian nephrologists report treatment strategies not in keeping with guideline recommendations. We identify barriers to guideline implementation and widespread physician support for initiatives that address these barriers to improve patient care.