The liver changes with age leading to an impaired ability to respond to hepatic insults and increased incidence of liver disease in the elderly. Therefore, there is critical need for rapid model systems to study aging-related liver changes. One potential opportunity is murine models of human progerias, or diseases of accelerated aging. Ercc1−/Δ mice model a rare human progeroid syndrome caused by inherited defects in DNA repair. To determine if hepatic changes that occur with normal aging occur prematurely in Ercc1−/Δ mice, we systematically compared liver from 5 month-old, progeroid Ercc1−/Δ mice to old (24–36 month) wild-type (WT) mice. Both displayed areas of necrosis, foci of hepatocellular degeneration and acute inflammation. Loss of hepatic architecture, fibrosis, steatosis, pseudocapillarization, and anisokaryosis were more dramatic in Ercc1−/Δ mice than in old WT mice. Liver enzymes were significantly elevated in serum of Ercc1−/Δ mice and old WT mice, while albumin was reduced, demonstrating liver damage and dysfunction. The regenerative capacity of Ercc1−/Δ liver following partial hepatectomy was significantly reduced. There was evidence of increased oxidative damage in Ercc1−/Δ and old WT liver, including lipofuscin, lipid hydroperoxides and acrolein as well as increased hepatocellular senescence. There was a highly significant correlation in genome-wide transcriptional changes between old WT and 16 but not 5 week-old Ercc1−/Δ mice emphasizing that the Ercc1−/Δ mice acquire an aging profile in early adulthood. Conclusion There are strong functional, regulatory and histopathological parallels between accelerated aging driven by a DNA repair defect and normal aging. This supports a role for DNA damage in driving aging and validates a murine model for rapidly testing hypotheses about causes and treatment for aging-related hepatic changes.

Background and objectives The rate of progression to ESKD is variable, and prognostic information helps patients and physicians plan for future ESKD. We assessed the estimations of ESKD risk of patients with CKD and physicians and compared them with risk calculators and outcomes at 2 years. Design, setting, participants, & measurements This prospective observational study assessed 257 adult patients with CKD stages 3-5 and their nephrologists at University of California, San Diego and Veterans Affairs San Diego CKD clinics. Patients' and nephrologists' estimations of 2-year ESKD risk were evaluated, and objective estimation of 2-year risk was determined using kidney failure risk equations; actual incidence rates of ESKD and death were ascertained by chart review. Participants' baseline characteristics were compared across kidney failure risk equation risk levels and according to whether patients' estimations were more optimistic or pessimistic than physicians' estimations. We examined correlations between estimations and compared estimations with outcomes using c statistics and calibration plots. Results Average age was 65 (613) years old, and eGFR was 34 (613) ml/min per 1.73 m 2. Overall, 13% reached ESKD, and 9% died. About one quarter of patients gave estimates that were .20% more optimistic than physicians, and more than one in ten gave estimates that were .20% more pessimistic. Physicians' and kidney failure risk equation estimations had the strongest correlation (r=0.72; P,0.001) compared with 0.50 (P,0.001) between physicians and patients and 0.47 (P,0.001) between patients and kidney failure risk equation. Although all three estimations provided reasonable risk rankings (c statistics .0.8), physicians and patients overestimated risk compared with actual outcomes; no patient whose physician estimated a risk of ESKD ,15% reached ESKD at 2 years. The kidney failure risk equation was best calibrated to actual ESKD risk. Conclusions Compared with actual ESKD incidence, the kidney failure risk equation outperformed patients' and physicians' estimations of ESKD incidence. Patients and physicians overestimated risk compared with the kidney failure risk equation.

Rationale & Objective Excess morbidity and mortality are associated with both high and low serum bicarbonate levels in epidemiologic studies of patients with end-stage kidney disease (ESKD) receiving hemodialysis. The Kidney Disease Outcomes Quality Initiative (KDOQI) recommends modifying dialysate bicarbonate concentration to achieve a predialysis serum bicarbonate level ≥ 22 mmol/L, measured as total carbon dioxide (CO 2 ). This practice assumes that total CO 2 is an adequate surrogate for acid-base status, yet its surrogacy performance is unknown in ESKD. We determined acid-base status at the beginning and end of hemodialysis using total CO 2 and pH and tested whether total CO 2 is an appropriate surrogate for acid-base status. Study Design Pilot study. Setting & Participants 25 veterans with ESKD receiving outpatient hemodialysis. Tests Compared pH, calculated bicarbonate level, and total CO 2 . Outcomes The proportion of paired samples for which total CO 2 misclassified acid-base status according to pH was determined. Bias of total CO 2 was evaluated using Bland-Altman plots, comparing it to calculated bicarbonate. Results Among 71 samples, mean pH was 7.41 ± 0.03 predialysis and 7.48 ± 0.05 postdialysis. Compared with interpretation of full blood gas profiles, 9 of 25 (36%) participants were misclassified as acidemic using predialysis total CO 2 measures alone (total CO 2 < 22 mmol/L but pH ≥ 7.38); 1 (4%) participant was misclassified as alkalemic (total CO 2 > 26 mmol/L but pH ≤ 7.42). Among paired samples in which predialysis total CO 2 was < 22 mmol/L, the corresponding pH was acidemic (< 7.38) in just 3 of 13 (23%) instances. Limitations Small, single-center, entirely male cohort. Conclusions A majority of participants became alkalemic during routine hemodialysis despite arriving with normal pH. 10 of 25 (40%) participants’ acid-base status was misclassified using total CO 2 measurements alone; the majority of predialysis total CO 2 values that would trigger therapeutic modification according to practice guidelines did not have acidemia when assessed using pH. Efforts to improve dialysis prescription require recognition that total CO 2 may not be reliable for interpreting acid-base status in hemodialysis patients.

Among CKD patients, there is substantial variation in sodium intake but no predictable relationship between dietary sodium and blood pressure in individuals. The frequent dismissal of elevated blood pressure readings as related to recent sodium intake in clinic may be a misapplication of large-scale population data to explain individual variability and may contribute to clinical inertia regarding high blood pressure treatment.

OBJECTIVES To determine the relationship between chronic kidney disease (measured by cystatin C-based eGFR) and abnormal ambulatory blood pressure (including nocturnal dipping) in healthy older adults. Further, to assess agreement between clinic and ambulatory blood pressure monitoring. METHODS Serum cystatin C levels were measured to calculate eGFR. Participants underwent clinic and 24-hour ambulatory blood pressure measurement. Multiple linear regression, was performed to examine the association between reduced cystatin C-based eGFR (CKDcys) and blood pressure parameters. Bland-Altman analysis was performed to evaluate agreement between clinic and ambulatory measurements. RESULTS Average age was 72. There were 60 individuals with CKDcys (eGFR < 60 ml/min/1.73m2). Compared to those without CKDcys, individuals with CKDcys were older, more likely to have hypertension and less likely to have normal dipping patterns. After multivariate analysis, the presence of CKDcys was significantly associated with lower mean ambulatory diastolic blood pressure (DBP) (−2 mm Hg, p = 0.048), but not with nocturnal dipping or other blood pressure parameters. Clinic systolic blood pressure (SBP) significantly overestimated mean wake time ambulatory SBP; mean difference was 11 mmHg for those without CKDcys (95% limits of agreement −14 to 35 mmHg) and 14 mmHg for those with CKDcys (95% limits of agreement −13 to 41 mmHg); there was no statistically significant effect modification by CKD status. CONCLUSION In older, seemingly healthy adults, mild CKD was associated with lower ambulatory DBP. The presence of CKD did not affect interpretation of clinic vs. ambulatory blood pressure monitoring, although accuracy of clinic SBP was poor.