Nontargeted Native Renal Biopsy Adequacy: Preintervention Data From a Province-Wide, Multicentre, and Interdepartmental Audit.

Background: Nontargeted renal biopsy is essential to diagnosis, classification, and prognostication of medical renal disease. Inadequate biopsies delay diagnosis, expose the patient to repeated biopsy, and increase costs. Objective: The purpose of this project is to characterize nontargeted renal biopsy specimen adequacy and identify areas for improvement. Design: This project was designed as a clinical audit of specimen adequacy rates of nontargeted renal biopsies from 13 hospitals, as well as a questionnaire of radiology and pathology department staff regarding current practices surrounding renal biopsies. Setting: Retrospective analysis of 2188 adult native renal biopsies was performed from January 1, 2018, to September 9, 2021, across 13 hospitals. Patients: Adult patients with medical renal disease undergoing a nontargeted renal biopsy were included. Methods: Retrospective analysis of 2188 adult native renal biopsies was performed from January 1, 2018, to September 9, 2021, across 13 hospitals. Adequacy was divided into 4 categories based on number of glomeruli received: ideally adequate (≥25 glomeruli), minimally adequate (15-24), suboptimal (<15 and diagnosis rendered), and inadequate (<15 and no diagnosis rendered). Two targets were chosen; target 1, to achieve a combined suboptimal and inadequate rate ≤ 10%, and target 2, to attain an ideally adequate rate ≥80%. Radiology department heads in the province were surveyed on biopsy equipment, technique, technologist support, and feasibility of possible interventions to enhance biopsy adequacy. Pathology department staff were surveyed on their education and experience. Results: Adequacy was as follows: ideally adequate 64.7%, minimally adequate 26.0%, suboptimal 7.9%, and inadequate 1.4%. The province (and 8/13 hospitals) met target 1 for native biopsies (9.3%). Two hospitals achieved target 2 for native biopsies. A key finding was that the 2 hospitals with the lowest target 1 scores did not have a technologist present at biopsy. Limitations: Survey data was used to assess biopsy technique at each hospital, and specific technique for each biopsy was not recorded. As such, a multivariate statistical analysis of specimen adequacy rates was not feasible. Data on complications was not collected. Conclusions: Preintervention the province was at target for limiting inadequate and suboptimal native biopsies. There was a substantial shortfall in the ideally adequate rate from the proposed target. Using insight from survey data, interventions with the greatest expected impact were identified and those that are feasible given limited resources will be implemented to improve sample adequacy. Trial Registration: Not registered.

Contexte: La biopsie rénale non ciblée est essentielle au diagnostic, à la classification et au pronostic d'une néphropathie. Les biopsies inadéquates retardent le diagnostic, exposent le patient à des biopsies répétées et coûtent plus cher au système de santé. Objectif: L'objectif de cette étude était de caractériser l'adéquation des échantillons des biopsies rénales non ciblées et de dégager les domaines d'amélioration. Conception: Cet essai a été conçu comme un audit clinique du taux d'adéquation des échantillons de biopsies rénales non ciblées provenant de 13 hôpitaux. Il comporte également un questionnaire destiné au personnel des services de radiologie et de pathologie portant sur les pratiques actuelles entourant les biopsies rénales. Cadre: Analyze rétrospective de 2 188 biopsies rénales natives réalisées chez des patients adultes dans 13 hôpitaux entre le 1er janvier 2018 et le 9 septembre 2021. Sujets: Ont été inclus les adultes atteints d'une pathologie rénale médicale ayant subi une biopsie rénale non ciblée. Méthodologie: Nous avons procédé à une analyze rétrospective de 2 188 biopsies rénales natives réalisées chez des patients adultes dans 13 hôpitaux entre le 1er janvier 2018 et le 9 septembre 2021. L'adéquation a été classée en 4 catégories en fonction du nombre de glomérules reçus: parfaitement adéquate (25 glomérules et plus), minimalement adéquate (15 à 24 glomérules), sous-optimale (moins de 15 glomérules + diagnostic rendu), inadéquate (moins de 15 glomérules sans diagnostic rendu). Deux objectifs ont été établis: obtenir un taux d'adéquation combiné « sous-optimale + inadéquate ¼ de 10 % ou moins (objectif 1) et obtenir au moins 80 % d'adéquation « parfaite ¼ (objectif 2). Les chefs des services de radiologie de la province ont été interrogés sur l'équipement de biopsie, la technique, le soutien des technologues et la faisabilité des interventions possibles visant à améliorer l'adéquation des biopsies. Le personnel des services de pathologie a été interrogé sur sa formation et son expérience. Résultats: Les taux d'adéquation étaient les suivants: parfaitement adéquate = 64,7 %; minimalement adéquate = 26,0 %; sous-optimale = 7,9 %; inadéquate = 1,4 %. Pour les biopsies natives, avec un taux de 9,3 %, la province (et 8 des 13 hôpitaux) a atteint l'objectif 1. Deux hôpitaux ont atteint l'objectif 2. Une des principales observations a été qu'il n'y avait aucun technologue présent lors de la biopsie dans les deux hôpitaux qui avaient obtenu les moins bons résultats pour l'objectif 1. Limites: Les données de l'enquête ont été utilisées pour évaluer la technique de biopsie dans chaque hôpital; la technique précise utilisée pour chaque biopsie n'a pas été consignée. Par conséquent, il n'était pas possible de réaliser une analyze statistique multivariée des taux d'adéquation des échantillons. Les données sur les complications n'ont pas été recueillies. Conclusion: Avant l'intervention la province atteignait déjà l'objectif de limiter des biopsies natives inadéquates et sous-optimales. Le taux d'adéquation jugé « parfaitement adéquat ¼ était nettement inférieur à l'objectif proposé. Les données de l'enquête ont permis d'identifier les interventions dont l'impact escompté est le plus important; celles qui sont réalisables compte tenu des ressources limitées seront mises en œuvre afin d'améliorer l'adéquation des échantillons.

Semaglutide-Associated Acute Interstitial Nephritis: A Case Report.

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are being investigated to slow the decline of kidney function in type 2 diabetics with chronic kidney disease (CKD). These agents have proven benefits on cardiac outcomes and all-cause mortality as well as in reducing the incidence of macroalbuminuria. Ours is a case of drug-associated acute interstitial nephritis requiring hemodialysis temporally related to a semaglutide dose increase. This case is unique as the index patient had no underlying CKD. Limited cases of acute kidney injury, superimposed on underlying CKD, in patients taking the GLP-1RA semaglutide have been reported. To our knowledge, there are no existing case reports in the literature of GLP-1RA-associated acute interstitial nephritis in a patient with baseline normal kidney function. Because our prescription of these agents is increasing and is anticipated to increase further with growing scientific evidence for their benefit, we sought to highlight this possible, important serious adverse effect of semaglutide.

Clinical evaluation of performance, biocompatibility, and safety of vitamin E-bonded polysulfone membrane hemodialyzer compared to non-vitamin E-bonded hemodialyzer.

The vitamin E-bonded polysulfone membrane hemodialyzer (ViE™-21) was evaluated in a clinical study for regulatory submission. Seventeen patients on hemodialysis were treated with conventional high-flux hemodialyzers for 2 weeks (Pre-ViE phase) and switched to the ViE-21 for 36 sessions (ViE phase) followed by an additional 2 weeks on conventional hemodialyzers (Post-ViE phase). Reduction ratios of urea, creatinine, beta-2-microglobulin, albumin, and ultrafiltration coefficients (KUF) were measured once during the Pre-ViE phase and twice during the ViE phase. Moreover, biocompatibility markers [leucocyte count, platelet count, and activated complement factor (C3a) levels] were evaluated pre-dialysis, 15 min after initiation, and post-dialysis. During the study, type and number of adverse events (AEs), and device malfunctions were recorded. ViE-21 reduction ratios and KUF were not noticeably different than those of conventional hemodialyzers. Fluctuations of leucocyte counts and C3a concentrations were similar using ViE-21 and conventional hemodialyzers; however, the platelet count fluctuation was lower in ViE-21 sessions. The frequency of episodes of hypotension occurring during the ViE phase was lower than that occurring during the Pre- and Post-ViE phases. In conclusion, this study provided performance and safety data of the ViE-21 for regulatory application. The data suggest that vitamin E-bonded hemodialyzers are beneficial in lowering platelet activation and frequency of intradialytic hypotension. Larger randomized controlled trials are needed to confirm these findings.

Multi-intervention management of calcific uremic arteriolopathy in 24 patients.

BACKGROUND: Calcific uremic arteriolopathy (CUA), also known as calciphylaxis, is a rare but life-threatening condition predominately occurring in patients with end-stage renal disease on dialysis. In the absence of randomized clinical trials to guide management, clinicians must rely on observational data. We have previously reported the outcomes of our multi-intervention management in seven patients and now present a larger series of patients with extended follow-up. METHODS: We performed a retrospective analysis of all patients diagnosed with CUA at a single academic center between 2008 and 2017. We identified 24 patients including 13 hemodialysis, 8 peritoneal dialysis and 3 predialysis Stage 5 chronic kidney disease patients. RESULTS: Mean age at diagnosis was 60.5 years (range 35-83) and mean follow-up 30.5 months (range <1-99). Patients were predominately female (71%) and Caucasian (83%) with diabetes mellitus diagnosed in 16 of 24 patients. Fifteen of 24 patients had ulcerating lesions suggestive of advanced disease and 20 of 24 had extensive involvement (bilateral disease or lesion size >5 cm). Treatment consisted of intensive hemodialysis (>20 h per week), sodium thiosulfate, wound care, analgesics and discontinuation of trigger medications including warfarin. Hyperbaric oxygen, cinacalcet, bisphosphonates and vitamin K were used in some cases. Overall 1 year mortality was 41% (9/22) and overall mortality at the end of follow-up was 64% (14/24). Cause of death was felt to be attributable to CUA in only four cases (16.7%). Complete or partial resolution of lesions occurred in 17 of 24 patients. One patient had recurrence of CUA 20 months after initial diagnosis. CONCLUSIONS: Although mortality remains high in this group, direct CUA-attributable mortality is lower than historic reports. We conclude that a multi-intervention approach can be successful in treating a group of patients with severe CUA lesions.

Plasmapheresis for the treatment of kidney diseases.

The purpose of this review is to examine the evidence supporting the application of plasma exchange in renal disease. Our review focuses on the following 6 most common renal indications for plasma exchange based on 2014 registry data from the Canadian Apheresis Group: (i) thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome; (ii) renal transplantation, (iii) anti-neutrophil cytoplasm antibodies-associated vasculitis, (iv) cryoglobulinemia, (v) focal segmental glomerulosclerosis, and (vi) Goodpasture syndrome. The rarity of these diseases and their rapid, often fatal course mean that randomized controlled studies of plasma exchange are rarely conducted. Although evidence from an adequately powered randomized controlled trial supports the use of plasma exchange to treat thrombotic thrombocytopenic purpura, the use of plasma exchange to treat other renal diseases is only supported by observational and mechanistic studies. Larger well-designed trials are needed to clarify the potential role of plasma exchange in renal disease. Growing international collaboration will improve the quality of future studies in this area.

Combination hemodialysis and centrifugal therapeutic plasma exchange: 18 years of Canadian experience.

Hemodialysis (HD) and therapeutic plasma exchange (TPE) are extracorporeal treatments that may both be required in the same patient. When provided separately, 7-8 hours of therapy time is required. Simultaneous administration of both therapies can reduce time and personnel requirements. We report our 18-year institutional experience with combination HD and centrifugal TPE therapy. During combination therapy, the TPE circuit is attached to the HD circuit through an extension blood line connected to the HD venous return line, allowing simultaneous operation of both circuits. The HD circuit is anticoagulated with heparin and the TPE circuit with regional citrate. Blood flow rates through the HD circuit can reach 350 mL/min with plasma removal rates in the TPE circuit up to 60 mL/min. Ninety-two patients received a total of 621 treatments between December 1993 and July 2011. All treatments were completed within 4 hours. No major treatment-related adverse events occurred and less than 10% of treatments were complicated by minor events. Main indications for treatment were ANCA (anti-neutrophilic cytoplasmic antibody) vasculitis (n = 25), Goodpasture's/antiglomerular basement membrane disease (n = 24), adult thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (n = 24), and acute antibody-mediated renal transplant rejection (n = 8). Overall rates of renal recovery, in-hospital mortality, and overall mortality at 18-year follow-up were 45% (41/ 92), 2% (2/92), and 21% (19/ 92), respectively, compatible with published literature. Combination HD and TPE is safe, efficient, and requires less human resources and time than conventional sequential therapy. It should be considered in patients whose treatment regimen includes HD and TPE.

Use of electron-beam sterilized hemodialysis membranes and risk of thrombocytopenia.

CONTEXT: Thrombocytopenia is not widely recognized as a potential dialyzer-related complication. Following the observation of significant thrombocytopenia among 20 patients undergoing hemodialysis in a single dialysis unit after the introduction of dialyzers sterilized by electron beam (e-beam), a larger investigation was undertaken. OBJECTIVE: To determine the prevalence and etiology of thrombocytopenia in hemodialysis populations of 2 Canadian provinces (British Columbia and Alberta). DESIGN, SETTING, AND PARTICIPANTS: A cohort study of patients undergoing hemodialysis in British Columbia (n = 1706) and southern Alberta (n = 425) between April 1, 2009, and November 30, 2010. Retrospective analyses of historical patient, laboratory, and dialyzer data predating conversion to e-beam dialyzers were undertaken, with prospective collection of predialysis and postdialysis platelet counts before and after the change from e-beam to non-e-beam sterilized dialyzers in September 2009. MAIN OUTCOME MEASURE: Significant thrombocytopenia, defined a priori as postdialysis treatment platelet count of less than 100 × 10(3)/µL and a postdialysis decrease in platelet count of more than 15%. RESULTS: Among 1706 patients undergoing hemodialysis in British Columbia, 1411 (83%) were undergoing hemodialysis with e-beam sterilized dialyzers. Of 1706 patients, 194 (11.4%; 95% CI, 9.9%-12.9%) had postdialysis platelet counts of less than 100 × 10(3)/µL; 400 (23.4%; 95% CI, 21.5%-25.5%) had postdialysis decreases in platelet counts of more than 15%; and 123 (7.2%; 95% CI, 6.0%-8.6%) met both criteria. Among 425 patients in Alberta undergoing dialysis with polysulfone, e-beam sterilized dialyzers made by a different manufacturer, 46 (10.8%; 95% CI, 8.1%-14.3%) had platelet counts of less than 100 × 10(3)/µL; 156 (32.0%; 95% CI, 27.6%-36.7%) had decreases in platelet counts of more than 15%; and 31 (7.3%; 95% CI, 5.1%-10.3%) met both criteria. In multivariable analysis adjusting for patient and dialysis history characteristics, a significant association was observed between using an e-beam sterilized dialyzer and risk of significant thrombocytopenia (odds ratio [OR], 2.52; 95% CI, 1.20-5.29; P = .02). Compared with use of e-beam sterilized dialyzers, following the change to use of non-e-beam sterilized dialyzers, among 1784 patients, significant reductions were observed in postdialysis thrombocytopenia (120 patients [6.7%; 95% CI, 5.6%-8.0%; P < .001] had platelet counts of <100 × 10(3)/µL; 167 patients [9.4%; 95% CI, 8.1%-10.8%; P < .001] had decreases in platelet counts of >15%; and 38 patients [2.1%; 95% CI, 1.5%-2.9%; P < .001] met both criteria). Using generalized estimating equation modeling for repeated data with binary outcome, after adjusting for patient characteristics, the odds of significant thrombocytopenia were higher during the use of e-beam sterilized dialyzers than with use of non-e-beam sterilized dialyzers (OR, 3.57; 95% CI, 2.54-5.04; P < .001). CONCLUSION: In this cohort of patients undergoing hemodialysis in 2 Canadian provinces in 2009-2010, the use of e-beam sterilized dialyzers was associated with significant thrombocytopenia following dialysis.

Multi-intervention management of calciphylaxis: a report of 7 cases.

Calcific uremic arteriolopathy (calciphylaxis) is a devastating but rare complication seen predominantly in dialysis patients that often is fatal. Because of the rarity of the disease and the multifactorial nature of its cause, no clinical trials have been conducted to date to determine the best therapy for the condition. We report a case series of 7 patients at a single institution in whom a systematic multi-interventional treatment strategy was implemented, consisting of trigger-agent cessation (calcium-based phosphate binders, alphacalcidol, and warfarin), wound management, and antibiotic therapy, supplemented by intensified hemodialysis (4 hours daily for 7 days followed by 5-6 times weekly), intravenous sodium thiosulfate (12.5-25 g intravenously 3 times a week), and attempted oxygen therapy (given through a face mask or hyperbaric chamber as tolerated by patient circumstance). Treatments selected were based on literature review, consensus discussion, and attempts to address the physiologic disturbances that underlie the condition. All 7 patients identified with biopsy-proven calcific uremic arteriolopathy were treated with this regimen in 2007-2010, with 6 of 7 showing complete recovery. We suggest that consistent implementation of a multi-interventional approach may alter the course of this devastating disease. Further studies are needed to confirm and extend these findings.

Calciphylaxis in the current era: emerging 'ironic' features?

BACKGROUND: Calcific uraemic arteriolopathy (CUA), previously known as calciphylaxis, is a condition of microvascular calcification and thrombosis with resultant tissue necrosis. Due to the rarity of this disease, our understanding of its pathogenesis remains speculative. Iron has emerged as a potential pathogenic contributor to the development of CUA, but investigation into this link is lacking. The purpose of our study was to explore the clinical characteristics of patients diagnosed with CUA at our institution to allow for comparison to available literature. In addition, we wanted to pursue the possibility of iron being a pathogenic contributor to CUA development. We hypothesized that iron would have to be present in areas of microvascular calcification in order to play a contributing pathogenic role and, therefore, wished to establish whether iron deposition was present within available diagnostic CUA skin biopsy specimens. METHODS: This study included all patients diagnosed with CUA at our institution between 1997 and 2009 whose tissue was available for further analysis. All available diagnostic skin biopsy specimens were reviewed and further analysed by a dermatopathologist. As the goal was to explore the potential pathogenic role of iron, staining for iron deposition within biopsy specimens was undertaken. All available medical and biochemical information about patients was also collated for analytic purposes and related to the biopsy specimen findings. RESULTS: Tissue blocks from 12 patients diagnosed with CUA at our institution were available for further analysis. In this CUA cohort, the average age at diagnosis was 61 years (range, 36-83 years), with six (50%) patients being female. Of these patients, 8 (67%) had diabetes, 8 (67%) had coronary artery disease and 10 (83%) had dyslipidaemia. At the time of diagnosis, eight (67%) were on peritoneal dialysis, two (17%) on haemodialysis and two (17%) were pre-dialysis. Our patients had short dialysis vintage times prior to diagnosis (average, 2.1 years). Iron deposition was detected in areas of microvascular calcification in all diagnostic specimens and was absent in unaffected microvasculature within the same biopsy specimens. CONCLUSIONS: The findings of iron deposition in affected microvasculature lend support to the potential role of iron in the complex pathophysiologic cascade of CUA. The implications for iron therapy in high-risk patients and the possible rationale for the use of sodium thiosulphate, a metal chelator, in the treatment of CUA are explored.

Endoscopic retrograde cholangiopancreatography in the management of benign biliary strictures.

Several conditions may cause benign biliary stricture formation. Intraoperative bile duct injury, most often sustained during laparoscopic cholecystectomy, is the leading cause. Although surgical bypass procedure was the traditional treatment of choice for benign extrahepatic biliary strictures, therapeutic endoscopic retrograde cholangiopancreatography has recently come into favor; however, success rates have been variable and largely dependent on the underlying etiology. Because endoscopic therapy may be unsuccessful, a multidisciplinary approach to management, with surgical or radiological intervention if necessary, should be considered.

Granulomatous hepatitis associated with etanercept therapy.

Etanercept has recently been implicated in the induction of granulomatous reactions. We describe a patient with rheumatoid arthritis who developed granulomatous hepatitis after taking etanercept. Infectious and metabolic causes of liver disease had been excluded and the liver biopsy was not typical of sarcoidosis. Liver enzyme abnormalities improved after etanercept was discontinued. We suggest that etanercept was responsible for the development of granulomatous hepatitis. This has not been previously described and adds to the increasing reports of rare granulomatous reactions induced by etanercept therapy.

5,6-Dichloro-ribifuranosylbenzimidazole- and apigenin-induced sensitization of colon cancer cells to TNF-alpha-mediated apoptosis.

Tumor necrosis factor-alpha (TNF-alpha) is a multifunctional cytokine involved in the expression of many genes integral to the inflammatory response. In addition, it activates both apoptotic and survival pathways, the latter being mediated through the activation of the transcription factor nuclear factor-kappaB (NF-kappaB). Protein kinase CK2, a serine-threonine kinase that is universally upregulated in human malignancies, may be involved at multiple levels in this process. However, its role in mediating a survival response within colon cancer cells remains incompletely understood. Here we report that inhibition of CK2 in HCT-116 and HT-29 cells with the use of two specific CK2 inhibitors, 5,6-dichloro-ribifuranosylbenzimidazole (DRB) and apigenin, effected a synergistic reduction in cell survival when used in conjunction with TNF-alpha. Furthermore, there was a demonstrable synergistic reduction in colony formation in soft agar with the use of the same combinations. Western blot analysis showed that poly-ADP ribose polymerase and procaspase-3 cleavage complemented the fluorescence-activated cell sorter analysis findings of significantly increased subdiploid DNA-containing cell populations using these conditions. Remarkably, these events occurred in the absence of any reduction in the expression of the Bcl-2 family members Bcl-2, Mcl-1, and Bcl-xL or any change in the proapoptotic molecules Bad or Bax. One-hybrid NF-kappaB promoter assays utilizing a Gal4-p65 transactivation domain construct revealed that the TNF-induced transactivation was inhibited by both DRB and apigenin. This was associated with a concomitant reduction in the expression of a recognized anti-apoptotic NF-kappaB target, manganese superoxide dismutase, demonstrated by Q-PCR. Our findings indicate a potentially novel strategy for the treatment of colon cancer, one that targets CK2 simultaneous with TNF-alpha administration.