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Access to reliable contraception is a pillar of modern society. The burden of unintended pregnancy has fallen disproportionately on the mother throughout human history; however, recent legal developments surrounding abortion have sparked a renewed interest in male factor contraceptives beyond surgical sterilization and condoms. Modern efforts to develop reversible male birth control date back nearly a century and initially focused on altering the hypothalamic-pituitary-testes axis. These hormonal contraceptives faced multiple barriers, including systemic side effects, challenging dosing regimens, unfavorable routes of delivery, and the public stigma surrounding steroid use. Novel hormonal agents are seeking to overcome these barriers by limiting the side effects and simplifying use. Non-hormonal contraceptives are agents that target various stages of spermatogenesis; such as inhibitors of retinoic acid, Sertoli cell–germ cell interactions, sperm ion channels, and other small molecular targets. The identification of reproductive tract–specific genes associated with male infertility has led to more targeted drug development, made possible by advances in CRISPR and proteolysis targeting chimeras (PROTACs). Despite multiple human trials, no male birth control agents have garnered regulatory approval in the United States or abroad. This narrative review examines current and emerging male contraceptives, including hormonal and non-hormonal agents.

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Objectives To evaluate effects of worsening surgically induced chronic kidney disease (CKD‐S) on oncological and non‐oncological survival outcomes in renal cell carcinoma (RCC). Patients and Methods We performed a retrospective analysis of patients who underwent partial (PN) or radical nephrectomy (RN) and were free of preoperative CKD (estimated glomerular filtration rate [eGFR] ≥60 mL/min/1.73 m2). Patients were stratified by CKD stage at last follow‐up: no CKD‐S (eGFR ≥60 mL/min/1.73 m2), de novo CKD‐S 3a (eGFR 45–59 mL/min/1.73 m2), CKD‐S 3b (eGFR <45 and ≥30 mL/min/1.73 m2) and CKD‐S 4 (eGFR <30 and ≥15 mL/min/1.73 m2). The primary outcome was all‐cause mortality (ACM). Secondary outcomes included non‐cancer mortality (NCM), cancer‐specific mortality (CSM) and de novo CKD‐S Stage 3/4. Multivariable analysis (MVA) was utilised to identify risk factors for outcomes. Kaplan–Meier analysis (KMA) was utilised to evaluate overall (OS), non‐cancer (NCS), and cancer‐specific survival with respect to CKD‐S categories. Results We analysed 3239 patients. The mean preoperative and last‐follow‐up eGFRs were 87.4 and 69.5 mL/min/1.73 m2, respectively. On last follow‐up, 57.9% (n = 1876) had no CKD‐S, 18.7% (n = 606) had CKD‐S 3a, 15.1% (n = 489) had CKD‐S 3b and 8.3% (n = 268) had CKD‐S 4. On MVA, de novo CKD‐S 3b and 4 were independently associated with ACM (hazard ratios [HRs] 1.3–2.1, P = 0.003–0.001) and NCM (HRs 1.5–2.8, P = 0.021–0.001), but not CSM (P = 0.219–0.909); de novo CKD‐S 3a was not predictive for any mortality outcomes (P = 0.102–0.81). RN was independently associated with CKD‐S 3–4 (HRs 1.78–1.99, P < 0.001–0.035). Comparing no CKD‐S, CKD‐S 3a, CKD‐S 3b and CKD‐S 4, KMA demonstrated worsening outcomes with progressive CKD‐S stage: 5‐year OS 84% vs 78% vs 71% vs 60% (P < 0.001) and 5‐year NCS 93% vs 87% vs 83% vs 72% (P < 0.001). Conclusion Development of CKD‐S Stage 3b and 4, but not 3a, was associated with worsened ACM and NCM. The decision to proceed with nephron preservation via PN should be individualised based on oncological risk and risk of functional decline to CKD‐S 3b or 4, and not CKD‐S 3a.

736 Background: Lymph node positivity in Renal Cell Carcinoma (RCC) is associated with worsened oncologic outcomes. However, the actual prognostic significance of node positivity is poorly understood. Currently, American Joint Committee on Cancer (AJCC) Stage III RCC includes both node-positive pN1 and node-negative pN0 disease. We hypothesize that (1) there is a threshold in number of pathologic node positivity that distinguishes favorable risk from poor risk nodal disease, and (2) current categorization of pN1 can be subdivided into pN1 and pN2 based this threshold. We tested our hypothesis using the National Cancer Database (NCDB). Methods: From 2004-2019, all cases of RCC were queried in patients age ≥18. Patients with pathologic node positive disease and without synchronous metastasis were selected for analysis to minimize confounding from metastatic burden. Multivariable Cox Proportional-Hazards regression tested association between number of pathologically positive lymph nodes and all-cause mortality (ACM), adjusting for clinical and pathologic co-variables. Receiver Operator Characteristic (ROC) Curve analyses employing the concordance probability method evaluated performance of potential cut-points for pN2 node-positivity. Kaplan-Meier analyses (KMA) compared these thresholds against overall survival (OS) in non-metastatic Stage IV RCC. Results: 28,590 patients with above criteria were identified, of which 13.6% had pN1. On multivariable analyses, increased pathologic node positivity was associated with increased hazard of ACM (HR 1.19, 95% Confidence Interval [CI] 1.17-1.20, p<0.001). ROC mapping of all possible lymph node thresholds from ≥2 to ≥10, with stage IV as the highest point, showed comparable concordance probability among these cutoffs 0.26-0.33, AUC=0.656. On KMA, when threshold was set at ≥3, 5-year OS was no longer significantly different from non-metastatic Stage IV RCC as illustrated by overlapping confidence intervals. We designated pN1 as 1-2 pathologic positive nodes, and pN2 as ≥3 pathologic positive nodes. 5-year OS for Stage III pN0 was 69.4% (95% CI 68.4-70.5), for Stage III pN1 was 41.4% (95% CI 39.0-43.8), for Stage III pN2 was 31.8% (95% CI 28.2-35.9%), and for non-metastatic Stage IV was (30.0%, 95% CI 28.2-32.0%). On multivariable analyses, pN2 exhibited 38% greater hazard of ACM (HR 3.31, 95% CI 2.24-2.54, p<0.001) compared to pN1 (HR 2.39, 95% CI 2.24-2.54, p<0.001). Conclusions: These findings represent one of the largest characterizations of impact of positive nodal counts on prognostic stratification in RCC. Pathologic node positivity could be stratified to pN1 and pN2, with pN2 conferring poor prognostic risk comparable to non-metastatic Stage IV pN0 disease. Although further validation studies are warranted, consideration should be given towards stratifying Stage III pN2 patients to a higher risk group.