SGLT2 Inhibition for CKD and Cardiovascular Disease in Type 2 Diabetes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation.

Diabetes is the most frequent cause of chronic kidney disease (CKD), leading to nearly half of all cases of kidney failure requiring replacement therapy. The principal cause of death among patients with diabetes and CKD is cardiovascular disease (CVD). Sodium/glucose cotransporter 2 (SGLT2) inhibitors were developed to lower blood glucose levels by inhibiting glucose reabsorption in the proximal tubule. In clinical trials designed to demonstrate the CVD safety of SGLT2 inhibitors in type 2 diabetes mellitus (T2DM), consistent reductions in risks for secondary kidney disease end points (albuminuria and a composite of serum creatinine doubling or 40% estimated glomerular filtration rate decline, kidney failure, or death), along with reductions in CVD events, were observed. In patients with CKD, the kidney and CVD benefits of canagliflozin were established by the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial in patients with T2DM, urinary albumin-creatinine ratio>300mg/g, and estimated glomerular filtration rate of 30 to<90mL/min/1.73m2. To clarify and support the role of SGLT2 inhibitors for treatment of T2DM and CKD, the National Kidney Foundation convened a scientific workshop with an international panel of more than 80 experts. They discussed the current state of knowledge and unanswered questions to propose therapeutic approaches and delineate future research. SGLT2 inhibitors improve glomerular hemodynamic function and are thought to ameliorate other local and systemic mechanisms involved in the pathogenesis of CKD and CVD. SGLT2 inhibitors should be used when possible by people with T2DM to reduce risks for CKD and CVD in alignment with the clinical trial entry criteria. Important risks of SGLT2 inhibitors include euglycemic ketoacidosis, genital mycotic infections, and volume depletion. Careful consideration should be given to the balance of benefits and harms of SGLT2 inhibitors and risk mitigation strategies. Effective implementation strategies are needed to achieve widespread use of these life-saving medications.

Experience with transplantation of human cryopreserved ovarian tissue to a sub-peritoneal abdominal site.

STUDY QUESTION: Is a sub-peritoneal abdominal site a suitable site for cryopreserved ovarian tissue transplantation? SUMMARY ANSWER: Live births have resulted from oocytes aspirated from follicles within cryopreserved ovarian tissue transplanted in a sub-peritoneal abdominal site with similar outcomes observed in terms of number of mature oocytes recovered and embryo development from tissue transplanted to sub-peritoneal abdominal, ovarian, and pelvic sites in our clinic. WHAT IS KNOWN ALREADY: Over 130 live births have been reported from cryopreservation of ovarian tissue and subsequent transplantation. In the majority of these, tissue was transplanted onto the remaining ovary. Although grafting to a non-ovarian, non-pelvic, sub-peritoneal abdominal site has resulted in births, it has been suggested that compromised outcomes may be expected from a non-pelvic site. STUDY DESIGN, SIZE, DURATION: The aim of the study was to assess the outcome from cryopreserved ovarian tissue transplanted to a site out of the pelvic area; a sub-peritoneal abdominal site. These outcomes were compared to transplantation to the ovary and peritoneal pelvic area in a cohort of 17 fertility preservation women where the individual sites of follicle aspiration were known and subsequent outcomes tracked. Ovarian tissue was slow frozen using the cryoprotectants propanediol and sucrose (n = 16 women) or using dimethyl sulfoxide and sucrose (n = 1 woman). Tissue was kept at 4°C overnight prior to freezing for 1 case. Tissue was thawed appropriately and prepared on 6.0 vicryl sutures for transplantation. Tissue was placed laparoscopically into a sub-peritoneal abdominal site, a pelvic side wall peritoneal pocket and the ovary. PARTICIPANTS/MATERIALS, SETTING, METHODS: Following resumption of cycling, gonadotrophin stimulation commenced with FSH, LH and antagonist and a trigger was given when one follicle was >13 mm in diameter. Abdominal follicles were aspirated under ultrasound guidance trans-abdominally; ovarian and pelvic follicles were aspirated trans-vaginally. Due to an inability to differentiate pelvic from ovarian follicles at the time of ultrasound-guided oocyte retrieval, both were classified as ovarian on the side where both were present. However, on the side, where no ovary was present, outcomes from pelvic follicles were reported. MAIN RESULTS AND THE ROLE OF CHANCE: Average time lapse between ovarian tissue harvest and graft was 6 years. Resumption of cycling occurred on average 4.2 months post first graft, regardless of graft site. Mean follicle diameter on the day of oocyte aspiration was 14 mm for all sites. Aspiration failed to retrieve an oocyte in 30% (36/120) of abdominal follicles which was similar to the other sites; ovarian 24% (21/87), pelvic 32% (31/97). A similar proportion of retrieved oocytes was mature from all sites (67% (50/75) abdominal, 68% (42/62) ovarian, 59% (34/58) pelvic). The proportion of embryos which developed on Day 2 from those fertilized was also similar in all groups (90% (34/38) abdominal, 76% (22/29) ovarian, 96% (22/23) pelvic). To our knowledge, this is the first report of outcomes from cryopreserved ovarian tissue transplanted to a sub-peritoneal abdominal site and the subsequent comparison to outcomes from the ovary and a sub-peritoneal pelvic graft, within the same cohort of patients, where tissue was slow frozen predominantly with the cryoprotectant propanediol and sucrose. LIMITATIONS, REASONS FOR CAUTION: The study reports outcomes from a small number of women following ovarian tissue transplantation. Follicle density is an estimate only and the amount of tissue grafted varied between patients. WIDER IMPLICATIONS OF THE FINDINGS: The demonstration of successful outcomes from cryopreserved ovarian tissue grafted to a sub-peritoneal abdominal site has significant implications for the management of women in which grafting to pelvic sites is contraindicated although it appears to be important to trigger follicle maturation at a lower than normal follicular diameter. The relative ease of oocyte retrieval at the sub-peritoneal abdominal site also has positive implications for the introduction of this approach into clinical practice. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was used. All authors have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Change in Albuminuria and GFR as End Points for Clinical Trials in Early Stages of CKD: A Scientific Workshop Sponsored by the National Kidney Foundation in Collaboration With the US Food and Drug Administration and European Medicines Agency.

The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) are currently willing to consider a 30% to 40% glomerular filtration rate (GFR) decline as a surrogate end point for kidney failure for clinical trials of kidney disease progression under appropriate conditions. However, these end points may not be practical for early stages of kidney disease. In March 2018, the National Kidney Foundation sponsored a scientific workshop in collaboration with the FDA and EMA to evaluate changes in albuminuria or GFR as candidate surrogate end points. Three parallel efforts were presented: meta-analyses of observational studies (cohorts), meta-analyses of clinical trials, and simulations of trial design. In cohorts, after accounting for measurement error, relationships between change in urinary albumin-creatinine ratio (UACR) or estimated GFR (eGFR) slope and the clinical outcome of kidney disease progression were strong and consistent. In trials, the posterior median R2 of treatment effects on the candidate surrogates with the clinical outcome was 0.47 (95% Bayesian credible interval [BCI], 0.02-0.96) for early change in UACR and 0.72 (95% BCI, 0.05-0.99) when restricted to baseline UACR>30mg/g, and 0.97 (95% BCI, 0.78-1.00) for total eGFR slope at 3 years and 0.96 (95% BCI, 0.63-1.00) for chronic eGFR slope (ie, the slope excluding the first 3 months from baseline, when there might be acute changes in eGFR). The magnitude of the relationships of changes in the candidate surrogates with risk for clinical outcome was consistent across cohorts and trials: a UACR reduction of 30% or eGFR slope reduction by 0.5 to 1.0mL/min/1.73m2 per year were associated with an HR of ∼0.7 for the clinical outcome in cohorts and trials. In simulations, using GFR slope as an end point substantially reduced the required sample size and duration of follow-up compared with the clinical end point when baseline eGFR was high, treatment effects were uniform, and there was no acute effect of the treatment. We conclude that both early change in albuminuria and GFR slope fulfill criteria for surrogacy for use as end points in clinical trials for chronic kidney disease progression under certain conditions, with stronger support for change in GFR than albuminuria. Implementation requires understanding conditions under which each surrogate is likely to perform well and restricting its use to those settings.

Treating Early-Stage CKD With New Medication Therapies: Results of a CKD Patient Survey Informing the 2020 NKF-FDA Scientific Workshop on Clinical Trial Considerations for Developing Treatments for Early Stages of Common, Chronic Kidney Diseases.

Rationale & Objective: With a growing number of medications and therapies available to treat chronic kidney disease (CKD), risk-versus-benefit discussions are increasingly critical. Balancing risks and benefits requires assessing patients' understanding of these, as well as incorporating patient preferences and tolerance for side effects into shared decision making. Study Design: A 26-question online survey was sent to people in the National Kidney Foundation patient email list and posted on associated social media pages to assess the respondents' willingness and comfort with taking preventative medications during earlier-stage CKD to inform a December 2020 scientific workshop co-sponsored by the National Kidney Foundation and the US Food and Drug Administration on clinical trial considerations in developing treatments for individuals with early stages of CKD. Setting & Population: Online survey of CKD patients, including broad demographic data and responses to risk-benefit scenarios, with surveys emailed to 20,249 people not identified as currently receiving kidney replacement therapy. Analytical Approach: Survey results are presented as descriptive data. Results: Of 1,029 respondents, 45 self-identified as at risk for CKD, 566 had CKD, 267 had received kidney transplants, 51 were receiving dialysis, and 100 replied other or did not answer. Respondents reported being willing to assume some risk with the goal of preventing the progression of CKD, with a greater willingness to assume risk and treatment burdens the closer they came to late-stage disease. Clinician recommendations regarding kidney therapies and clinician willingness to work with patients to address any side effects were important in respondents' willingness to initiate and persevere with a new medication. Limitations: Approximately 10% response rate with limited data on respondents. Conclusions: Risk-versus-benefit discussions appear key to patients and their care partners making well-informed decisions about taking a new medication that may or may not help the progression of their kidney disease. Future tools and strategies are needed to facilitate informed discussions of treatment in early-stage kidney disease.

SGLT2 Inhibition for CKD and Cardiovascular Disease in Type 2 Diabetes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation.

Diabetes is the most frequent cause of chronic kidney disease (CKD), leading to nearly half of all cases of kidney failure requiring replacement therapy. The principal cause of death among patients with diabetes and CKD is cardiovascular disease (CVD). Sodium/glucose cotransporter 2 (SGLT2) inhibitors were developed to lower blood glucose levels by inhibiting glucose reabsorption in the proximal tubule. In clinical trials designed to demonstrate the CVD safety of SGLT2 inhibitors in type 2 diabetes mellitus (T2DM), consistent reductions in risks for secondary kidney disease end points (albuminuria and a composite of serum creatinine doubling or 40% estimated glomerular filtration rate decline, kidney failure, or death), along with reductions in CVD events, were observed. In patients with CKD, the kidney and CVD benefits of canagliflozin were established by the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial in patients with T2DM, urinary albumin-creatinine ratio >300 mg/g, and estimated glomerular filtration rate of 30 to <90 mL/min/1.73 m2 To clarify and support the role of SGLT2 inhibitors for treatment of T2DM and CKD, the National Kidney Foundation convened a scientific workshop with an international panel of more than 80 experts. They discussed the current state of knowledge and unanswered questions in order to propose therapeutic approaches and delineate future research. SGLT2 inhibitors improve glomerular hemodynamic function and are thought to ameliorate other local and systemic mechanisms involved in the pathogenesis of CKD and CVD. SGLT2 inhibitors should be used when possible by people with T2DM to reduce risks for CKD and CVD in alignment with the clinical trial entry criteria. Important risks of SGLT2 inhibitors include euglycemic ketoacidosis, genital mycotic infections, and volume depletion. Careful consideration should be given to the balance of benefits and harms of SGLT2 inhibitors and risk mitigation strategies. Effective implementation strategies are needed to achieve widespread use of these life-saving medications.