Phase 2 Trial of Cemdisiran in Adult Patients with IgA Nephropathy: A Randomized Controlled Trial.

BACKGROUND: IgA nephropathy is the most common primary GN. Clinical features of IgA nephropathy include proteinuria, which is the strongest known surrogate of progression to kidney failure. Complement pathway activation is a critical driver of inflammation and tissue injury in IgA nephropathy. Cemdisiran is an investigational RNA interference therapeutic that suppresses hepatic production of complement component 5 (C5), thereby potentially reducing proteinuria in IgA nephropathy. We evaluated the efficacy and safety of cemdisiran in adult patients with IgA nephropathy at high risk of kidney disease progression. METHODS: In this phase 2, 36-week, double-blind study, adult patients with IgA nephropathy and urine protein ≥1 g/24 hours were randomized (2:1) to subcutaneous cemdisiran 600 mg or placebo every 4 weeks in combination with the standard of care. The primary end point was percentage change from baseline at week 32 in urine protein-to-creatinine ratio (UPCR) measured by 24-hour urine collection. Additional end points included change from baseline in UPCR measured by spot urine, serum C5 level, and safety assessments. RESULTS: Thirty-one patients were randomized (cemdisiran, N =22; placebo, N =9). Cemdisiran-treated patients had a placebo-adjusted geometric mean change in 24-hour UPCR of -37.4% (cemdisiran-adjusted geometric mean ratio to baseline [SEM], 0.69 [0.10]) at week 32. Spot UPCR was consistent with 24-hour UPCR placebo-adjusted change of -45.8% (cemdisiran-adjusted geometric mean ratio to baseline [SEM], 0.73 [0.11]). Mean (SD) change in serum C5 level from baseline at week 32 was -98.7% (1.2) with cemdisiran and 25.2% (57.7) with placebo. Over 36 weeks, most adverse events were mild or moderate and transient; the most common adverse event after cemdisiran treatment was injection-site reaction (41%). CONCLUSIONS: These findings indicate that treatment with cemdisiran resulted in a reduction of proteinuria at week 32 and was well tolerated.

Translating the efficacy of dapagliflozin in chronic kidney disease to lower healthcare resource utilization and costs: a medical care cost offset analysis.

AIMS: Dapagliflozin was approved for use in patients with chronic kidney disease (CKD) based on results of the DAPA-CKD trial, demonstrating attenuation of CKD progression and reduced risk of cardio-renal outcomes and all-cause mortality (ACM) versus placebo, in addition to standard therapy. The study objective was to assess the potential medical care cost offsets associated with reduced rates of cardio-renal outcomes across 31 countries and regions. MATERIALS AND METHODS: A comparative cost-determination framework estimated outcome-related costs of dapagliflozin plus standard therapy versus standard therapy alone over a 3-year horizon based on the DAPA-CKD trial. Incidence rates of end-stage kidney disease (ESKD), hospitalizations for heart failure (HHF), acute kidney injury (AKI), and ACM were estimated for a treated population of 100,000 patients. Associated medical care costs for non-fatal events were calculated using sources from a review of publicly available data specific to each considered setting. RESULTS: Patients treated with dapagliflozin plus standard therapy experienced fewer incidents of ESKD (7,221 vs 10,767; number needed to treat, NNT: 28), HHF (2,370 vs 4,684; NNT: 43), AKI (4,110 vs. 5,819; NNT: 58), and ACM (6,383 vs 8,874; NNT: 40) per 100,000 treated patients versus those treated with standard therapy alone. Across 31 countries/regions, reductions in clinical events were associated with a 33% reduction in total costs, or a cumulative mean medical care cost offset of $264 million per 100,000 patients over 3 years. LIMITATIONS AND CONCLUSIONS: This analysis is limited by the quality of country/region-specific data available for medical care event costs. Based on the DAPA-CKD trial, we show that treatment with dapagliflozin may prevent cardio-renal event incidence at the population level, which could have positive effects upon healthcare service delivery worldwide. The analysis was restricted to outcome-associated costs and did not consider the cost of drug treatments and disease management.

Chronic kidney disease (CKD) has a high clinical, economic, and societal burden and it affects approximately 8-16% of the global population. The progressive nature of CKD may lead to complications, co-morbidities, and mortality, costing healthcare systems millions and consuming a large proportion of healthcare resources. Dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, has been demonstrated to slow CKD progression and reduce cardio-renal complications, as demonstrated in the DAPA-CKD trial. With the emergence of dapagliflozin as a treatment for CKD, it is important for clinicians and healthcare providers to understand how effective treatment can positively affect short-term healthcare service delivery and associated costs. This medical care cost offset modelling analysis considers a scalable population of 100,000 patients in 31 countries/regions worldwide. The analysis estimates treatment with dapagliflozin plus standard therapy to be offset by a 33% reduction in costs associated with key cardio-renal outcomes, translating to an average $264 million in cost offsets per 100,000 treated patients. This modelling analysis of pivotal trial data shows dapagliflozin could have considerable benefits to healthcare systems worldwide that are under strain from the rising burden of CKD.

Coding practice in national and regional kidney biopsy registries.

BACKGROUND: Kidney biopsy registries all over the world benefit research, teaching and health policy. Comparison, aggregation and exchange of data is however greatly dependent on how registration and coding of kidney biopsy diagnoses are performed. This paper gives an overview over kidney biopsy registries, explores how these registries code kidney disease and identifies needs for improvement of coding practice. METHODS: A literature search was undertaken to identify biopsy registries for medical kidney diseases. These data were supplemented with information from personal contacts and from registry websites. A questionnaire was sent to all identified registries, investigating age of registries, scope, method of coding, possible mapping to international terminologies as well as self-reported problems and suggestions for improvement. RESULTS: Sixteen regional or national kidney biopsy registries were identified, of which 11 were older than 10 years. Most registries were located either in Europe (10/16) or in Asia (4/16). Registries most often use a proprietary coding system (12/16). Only a few of these coding systems were mapped to SNOMED CT (1), older SNOMED versions (2) or ERA-EDTA PRD (3). Lack of maintenance and updates of the coding system was the most commonly reported problem. CONCLUSIONS: There were large gaps in the global coverage of kidney biopsy registries. Limited use of international coding systems among existing registries hampers interoperability and exchange of data. The study underlines that the use of a common and uniform coding system is necessary to fully realize the potential of kidney biopsy registries.

Impact of Age Difference, Sex Matching, and Body Mass Index Matching Between Donor and Recipient in Renal Transplant.

BACKGROUND: Various factors influence kidney transplant (KT) outcome. The impact of age difference between donor and recipient on long- and short-term graft and patient survival in living donor KT remains unclear. OBJECTIVE: We aim to determine whether age difference, sex matching, and body mass index (BMI) matching between donor and recipient affect the 12-month patient and graft survival in KT. METHOD: We studied a retrospective cohort of 804 patients 18 years or older with primary KT from January 2010 to December 2014. Patient renal function and patient survival were followed up for 12 months post KT. Repeated analysis of variance measurement determined if there was a significant difference in the mean creatinine levels when the sample was grouped according to the matching groups for sex, age difference, and BMI classification. Odds ratios were computed to ascertain graft loss and graft rejection. Results were considered statistically significant if P < .05. RESULTS: Male donor-female recipient had the lowest creatinine levels over time compared with male donor-male recipient (P < .001) and female donor-male recipient (P < .001). Older donor-younger recipient with age difference of ≥ 15 years had the highest overall creatinine (P < .001). For BMI matching, a normal donor and an underweight recipient combination resulted in the lowest mean creatinine levels over the course of 12 months (P < .001). In terms of graft rejection, odds ratio was highest for a female donor and a male recipient (P < .00a) compared with a male donor and a female recipient. For graft loss, older donors (≥ 15 years) had the highest risk (P < .001) vs those older by 11 to 15 years. CONCLUSION: There was significant difference in the 12-month graft function of patients when grouped according to their matching for age difference, sex, and BMI. The risk for graft rejection increases when the combination for donor-recipient is female donor-male recipient. For graft loss, this is most significant for donors who are older by ≥ 15 years than their recipients.

Caught in the crosshairs: identity and cultural authority within chiropractic.

In this paper the discourse over identity and cultural authority within the profession of chiropractic in the United States has been analyzed using critical discourse analysis. As the profession struggles to construct one singular image, versions of self must be internally debated and also shaped in consideration of larger, external forces. The dilemma of remaining tied to a marginal professional status must be balanced against considerations of integration. Written texts from chiropractic journals and newspapers are analyzed in a multidimensional approach that considers the rhetorical devices and thematic issues of identity construction; the representation of various voices within the discourse (both heard and unheard); and the extent to which external pressures affect the projection of cultural authority for the profession. A heterogeneous discourse characterized by conflict was found, with discrepancies between everyday chiropractors in actual practice versus academic chiropractors and leaders particularly over the idea, practice and significance of science for the profession.

Evidence-based medicine and its implications for the profession of chiropractic.

Evidence-based medicine (EBM) has grown in popularity and prominence in the world of orthodox medicine since the 1980s. The focus of this article is on the process of developing practice guidelines (one type of EBM) and its effects upon chiropractic, a profession with a "philosophy, science and art" that is constructed upon divergent epistemological and methodological tenets (namely, the idea of "vitalism"). The EBM movement is conceptualized as part of a larger political economy surrounding the health care environment that creates a new set of imperatives for orthodox medicine, and also branches of alternative medicine that are in the process of professionalization. The quantitative, positivist and empiricist assumptions of EBM dictate which approaches to treatment and which clinical procedures are legitimate and perhaps reimbursable under systems of managed care. The ramifications of practice guidelines and its effects upon the intraprofessional segments of the chiropractic profession are also discussed.