Citations

ABSTRACT No treatment until now has directly targeted the mechanisms responsible for the development and growth of cysts in autosomal dominant polycystic kidney disease (ADPKD). Strong rationale and preclinical studies using in vitro and in vivo models justified the launching of two large phase 3 clinical trials of tolvaptan in early and later stages of ADPKD. Their design was based on preliminary studies informing on the pharmacokinetics, pharmacodynamics, short-term safety and self-reported tolerability in patients with ADPKD. Tolvaptan slowed kidney growth in the early stage and estimated glomerular filtration rate decline in early and later stages of the disease. All participants had the opportunity to enroll in open-label extension trials to ascertain long-term safety and efficacy. In a single-center analysis of long-term outcomes, the effect of tolvaptan was sustained and cumulative over time supporting a disease-modifying effect of tolvaptan in ADPKD. In the countries where tolvaptan has been approved by regulatory agencies, patients with rapidly progressive ADPKD should be informed about the option of treatment including possible benefits and risks. If a decision to initiate treatment is made, prescribing physicians should educate the patients on the prevention of aquaresis-related adverse events and should be vigilant in the surveillance and management of the potential tolvaptan hepatotoxicity. Other vasopressin V2 receptor antagonists, possibly without potential hepatotoxicity, alternative strategies targeting vasopressin and combination with other drugs able to enhance the efficacy or reduce the aquaresis associated with tolvaptan, deserve further study.

Mayo Clinic, Mayo Foundation, Rochester, MinnesotaPlatelets are believed to play an important role in the pathogenesis of atherosclerosis and thrombotic occlusive arterial disease. As part of a prospective study of peripheral occlusive arterial disease in diabetes mellitus, platelet survival half-life (PS) was determined in years 1 and 2 from the disappearance pattern of 51cr-labeled platelets obtained by measuring radioactivity in serial samples over 8 days in four groups of patients age 50-70. Using computer assisted least-square analysis, a single exponent is fitted to the data and half-life determined.Groups included (1) normal subjects (NC); (2) subjects with clinical and objective evidence (transcutaneous doppler ultrasound and treadmill exercise) of peripheral arterial occlusive disease (AS0); (3) subjects with diabetes mellitus without AS0 (DM); (A) subjects with both diabetes mellitus and AS0 (DM+AS0). 112 subjects were tested in year 1 and 75 of these were available for retesting in year 2.In year 1, there is a difference in the distribution of platelet survival (PS) for the four groups (p=.002). PS is significantly short in groups AS0 and DM+AS0 compared with controls (NC), Year 2 values for PS (75 subjects) were compared to year 1. Using the t test on mean differences PS for each group was not significantly different year 2 vs year 1; mean percent differences year 2 vs year 1 were 1.2% (NC), 0.2% (ASO), 3.2% (DM), and -9.3% (9-3% lower than year 1 for DM+ ASO).Platelet survival half-life (PS) does distinguish popula tion groups and is reproducible when repeated.

Background and objectives In the 3-year Tolvaptan Efficacy and Safety in Management of ADPKD and Its Outcomes (TEMPO) 3:4 and 1-year Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) trials, tolvaptan slowed the decline of eGFR in patients with autosomal dominant polycystic kidney disease at early and later stages of CKD, respectively. Our objective was to ascertain whether the reduction associated with the administration of tolvaptan is sustained, cumulative, and likely to delay the need for kidney replacement therapy. Design, setting, participants, & measurements One hundred and twenty-eight patients with autosomal dominant polycystic kidney disease participated in clinical trials of tolvaptan at the Mayo Clinic. All had the opportunity to enroll into open-label extension studies. Twenty participated in short-term studies or received placebo only. The remaining 108 were analyzed for safety. Ninety seven patients treated with tolvaptan for ≥1 year (mean±SD, 4.6±2.8; range, 1.1–11.2) were analyzed for efficacy using three approaches: ( 1 ) comparison of eGFR slopes and outcome (33% reduction from baseline eGFR) to controls matched by sex, age, and baseline eGFR; ( 2 ) Stability of eGFR slopes with duration of follow-up; and ( 3 ) comparison of observed and predicted eGFRs at last follow-up. Results Patients treated with tolvaptan had lower eGFR slopes from baseline (mean±SD, −2.20±2.18 ml/min per 1.73 m 2 per year) and from month 1 (mean±SD, −1.97±2.44 ml/min per 1.73 m 2 per year) compared with controls (mean±SD, −3.50±2.09 ml/min per 1.73 m 2 per year; P <0.001), and lower risk of a 33% reduction in eGFR (risk ratio, 0.63; 95% confidence interval, 0.38 to 0.98 from baseline; risk ratio, 0.53; 95% confidence interval, 0.31 to 0.85 from month 1). Annualized eGFR slopes of patients treated with tolvaptan did not change during follow-up and differences between observed and predicted eGFRs at last follow-up increased with duration of treatment. Conclusions Follow-up for up to 11.2 years (average 4.6 years) showed a sustained reduction in the annual rate of eGFR decline in patients treated with tolvaptan compared with controls and an increasing separation of eGFR values over time between the two groups.

Abstract Background Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10−8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods We conducted a GWAS in European descent CRC cases and control subjects using a discovery–replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10−8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10−8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

Acute on chronic liver failure (ACLF) is the culmination of chronic liver disease and extrahepatic organ failures, which is associated with a high short‐term mortality and immense health care expenditure. There are varying definitions for organ failures and ACLF in Europe, North America, and Asia. These differing definitions need to be reconciled to enhance progress in the field. The pathogenesis of ACLF is multifactorial and related to interactions between the immunoinflammatory system, microbiota, and the various precipitating factors. Individual organ failures related to the kidney, brain, lungs, and circulation have cumulative adverse effects on mortality and are often complicated or precipitated by infections. Strategies to prevent and rapidly treat these organ failures are paramount in improving survival. With the aging population and paucity of organs for liver transplant, the prognosis of ACLF patients is poor, highlighting the need for novel therapeutic strategies. The role of liver transplant in ACLF is evolving and needs further investigation across large consortia. A role for early palliative care and management of frailty as approaches to alleviate disease burden and improve patient‐reported outcomes is being increasingly recognized. Conclusion: ACLF is a clinically relevant syndrome that is epidemic worldwide and requires a dedicated multinational approach focused on prognostication and management; investigations are underway worldwide to prepare ACLF for prime time. (Hepatology 2018; 00:000‐000)

New antiviral therapies cure most patients with hepatitis C and prevent the development of cirrhosis and hepatocellular carcinoma. The major challenges for global hepatitis C virus eradication are the identification of patients with chronic hepatitis C, referrals to treatment, and elevated drug prices. See also pages 1644‐46.