Robert S. Rahimi M.D.

Cullaro, G., E. C. Verna, A. Duarte-Rojo, M. R. Kappus, D. R. Ganger, R. S. Rahimi, B. Boyarsky, D. L. Segev, M. McAdams-DeMarco, D. P. Ladner, M. L. Volk, C. Y. Hsu and J. C. Lai (2021). “Frailty and the Risk of Acute Kidney Injury Among Patients With Cirrhosis.” Hepatol Commun Oct 22. [Epub ahead of print].

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Acute kidney injury (AKI) and frailty are major drivers of outcomes among patients with cirrhosis. What is unknown is the impact of physical frailty on the development of AKI. We included adults with cirrhosis without hepatocellular carcinoma listed for liver transplantation at nine US centers (n = 1,033). Frailty was assessed using the Liver Frailty Index (LFI); “frail” was defined by LFI ≥ 4.2. Chronic kidney disease as a baseline estimated glomerular filtration rate <60 mL/min/1.73 m(2) . Our primary outcome, AKI, was defined as an increase in serum creatinine ≥0.3 mg/dL or a serum creatinine ≥1.5-fold increase. Wait-list mortality was defined as either a death on the wait list or removal for being too sick. We performed Cox regression analyses to estimate the hazard ratios (HRs) for AKI and wait-list mortality. Of 1,033 participants, 41% were frail and 23% had CKD. Twenty-one percent had an episode of AKI during follow-up. Frail versus nonfrail patients were more likely to develop AKI (25% vs. 19%) and wait-list mortality (21% vs. 13%) (P < 0.01 for each). In multivariable Cox regression, each of the following groups was associated with a higher risk of AKI as compared with not frail/no CKD: frail/no CKD (adjusted HR [aHR] = 1.87, 95% confidence interval [CI] = 1.29-2.72); not frail/CKD (aHR = 4.30, CI = 2.88-6.42); and frail/CKD (aHR = 4.85, CI = 3.33-7.07). We use a readily available metric, LFI, to identify those patients with cirrhosis most at risk for AKI. We highlight that serum creatinine and creatinine-based estimations of glomerular filtration rate may not fully capture a patient's vulnerability to AKI among the frail phenotype. Conclusion: Our work lays the foundation for implementing physical frailty in clinical practice to identify AKI earlier, implement reno-protective strategies, and expedite liver transplantation.

Xu, C.Q., Mohamad, Y., Kappus, M.R., Boyarsky, B., Ganger, D.R., Volk, M.L., Rahimi, R.S., Duarte-Rojo, A., McAdams-DeMarco, M., Segev, D.L., Ladner, D.P., Verna, E.C., Grab, J., Tincopa, M., Dunn, M.A. and Lai, J.C. (2021). “The relationship between frailty and cirrhosis etiology: From the Functional Assessment in Liver Transplantation (FrAILT) Study.” Liver Int Jul 5. [Epub ahead of print].

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BACKGROUND/AIMS: Cirrhosis leads to malnutrition and muscle wasting that manifests as frailty, which may be influenced by cirrhosis etiology. We aimed to characterize the relationship between frailty and cirrhosis etiology. METHODS: Included were adults with cirrhosis listed for liver transplantation (LT) at 10 U.S. centers who underwent ambulatory testing with the Liver Frailty Index (LFI; “frail”=LFI≥4.4). We used logistic regression to associate etiologies and frailty, and competing risk regression (LT as the competing risk) to determine associations with waitlist mortality (death/delisting for sickness). RESULTS: Of 1,623 patients, rates of frailty differed by etiology: 22% in chronic hepatitis C, 31% in alcoholic-associated (ALD), 32% in non-alcoholic fatty liver disease (NAFLD), 21% in autoimmune/cholestatic, and 31% in “other” (p<0.001). In univariable logistic regression, ALD (OR 1.53, 95% CI 1.12-2.09), NAFLD (OR 1.64, 95% CI 1.18-2.29) and "other" (OR 1.58, 95% CI 1.06-2.36) were associated with frailty. In multivariable logistic regression, only ALD (OR 1.40; 95% 1.01-1.94) and "other" (OR 1.59; 95% 1.05-2.40) remained associated with frailty. A total of 281 (17%) patients died/were delisted for sickness. In multivariable competing risk regression, LFI was associated with waitlist mortality (sHR 1.05, 95% CI 1.03-1.06), but etiology was not (p>0.05 for each). No interaction between frailty and etiology on the association with waitlist mortality was found (p>0.05 for each interaction term). CONCLUSIONS: Frailty is more common in patients with ALD, NAFLD, and “other” etiologies. However, frailty was associated with waitlist mortality independent of cirrhosis etiology, supporting the applicability of frailty across all cirrhosis etiologies.

Fallahzadeh, M.A., Hansen, D.J., Trotter, J.F., Everson, G.T., Saracino, G., Rahimi, R.S., Helmke, S., Boutte, J. and Asrani, S.K. (2021). “Predicting clinical decompensation in patients with cirrhosis using the Hepquant-SHUNT test.” Aliment Pharmacol Ther 53(8): 928-938.

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BACKGROUND: Early identification of risk for decompensation in clinically stable cirrhotic patients helps specialists target early interventions and supports effective referrals from primary care providers to specialty centres. AIMS: To examine whether the HepQuant-SHUNT test (HepQuant LLC, Greenwood Village, Colorado, USA) predicts decompensation and the need for liver transplantation, hospitalisation or liver-related death. METHODS: Thirty-five compensated and 35 subjects with a previous episode of decompensation underwent the SHUNT Test and were followed for a median of 4.2 years. The disease severity index (DSI) (range 0-50) was examined for association with decompensation in compensated patients; and liver transplantation, liver-related death, and the number and days of liver related hospitalisations in all. DSI prediction of decompensation was also evaluated in 84 subjects with compensated cirrhosis from the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis Trial (HALT-C) followed for a median of 5.8 years. RESULTS: At baseline, subjects with prior decompensation had significantly higher DSI than compensated subjects (32.6 vs 20.9, P < 0.001). DSI ≥24 distinguished the decompensated from the compensated patients and independently predicted adverse clinical outcomes (hazard ratio: 4.92, 95% confidence interval: 1.42-17.06). In the HALT-C cohort, 65% with baseline DSI ≥24 vs 19% with DSI <24 experienced adverse clinical outcomes (relative risk 3.45, P < 0.0001). CONCLUSIONS: The SHUNT test is a novel, noninvasive test that predicts risk of decompensation in previously compensated patients. DSI ≥24 is independently associated with risk for clinical decompensation, liver transplantation, death and hospitalisation.

Fallahzadeh, M.A., Hansen, D.J., Trotter, J.F., Everson, G.T., Saracino, G., Rahimi, R.S., Helmke, S., Boutte, J. and Asrani, S.K. (2021). “Predicting clinical decompensation in patients with cirrhosis using the Hepquant-SHUNT test.” Aliment Pharmacol Ther Feb 8. [Epub ahead of print].

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BACKGROUND: Early identification of risk for decompensation in clinically stable cirrhotic patients helps specialists target early interventions and supports effective referrals from primary care providers to specialty centres. AIMS: To examine whether the HepQuant-SHUNT test (HepQuant LLC, Greenwood Village, Colorado, USA) predicts decompensation and the need for liver transplantation, hospitalisation or liver-related death. METHODS: Thirty-five compensated and 35 subjects with a previous episode of decompensation underwent the SHUNT Test and were followed for a median of 4.2 years. The disease severity index (DSI) (range 0-50) was examined for association with decompensation in compensated patients; and liver transplantation, liver-related death, and the number and days of liver related hospitalisations in all. DSI prediction of decompensation was also evaluated in 84 subjects with compensated cirrhosis from the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis Trial (HALT-C) followed for a median of 5.8 years. RESULTS: At baseline, subjects with prior decompensation had significantly higher DSI than compensated subjects (32.6 vs 20.9, P < 0.001). DSI ≥24 distinguished the decompensated from the compensated patients and independently predicted adverse clinical outcomes (hazard ratio: 4.92, 95% confidence interval: 1.42-17.06). In the HALT-C cohort, 65% with baseline DSI ≥24 vs 19% with DSI <24 experienced adverse clinical outcomes (relative risk 3.45, P < 0.0001). CONCLUSIONS: The SHUNT test is a novel, noninvasive test that predicts risk of decompensation in previously compensated patients. DSI ≥24 is independently associated with risk for clinical decompensation, liver transplantation, death and hospitalisation.

Lai, J.C., Ganger, D.R., Volk, M.L., Dodge, J.L., Dunn, M.A., Duarte-Rojo, A., Kappus, M.R., Rahimi, R.S., Ladner, D.P., Boyarsky, B., McAdams-DeMarco, M., Segev, D.L., McCulloch, C.E. and Verna, E.C. (2020). “Association of Frailty and Sex With Wait List Mortality in Liver Transplant Candidates in the Multicenter Functional Assessment in Liver Transplantation (FrAILT) Study.” JAMA Surg DEc 30. [Epub ahead of print].

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IMPORTANCE: Female liver transplant candidates experience higher rates of wait list mortality than male candidates. Frailty is a critical determinant of mortality in patients with cirrhosis, but how frailty differs between women and men is unknown. OBJECTIVE: To determine whether frailty is associated with the gap between women and men in mortality among patients with cirrhosis awaiting liver transplantation. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study enrolled 1405 adults with cirrhosis awaiting liver transplant without hepatocellular carcinoma seen during 3436 ambulatory clinic visits at 9 US liver transplant centers. Data were collected from January 1, 2012, to October 1, 2019, and analyzed from August 30, 2019, to October 30, 2020. EXPOSURES: At outpatient evaluation, the Liver Frailty Index (LFI) score was calculated (grip strength, chair stands, and balance). MAIN OUTCOMES AND MEASURES: The risk of wait list mortality was quantified using Cox proportional hazards regression by frailty. Mediation analysis was used to quantify the contribution of frailty to the gap in wait list mortality between women and men. RESULTS: Of 1405 participants, 578 (41%) were women and 827 (59%) were men (median age, 58 [interquartile range (IQR), 50-63] years). Women and men had similar median scores on the laboratory-based Model for End-stage Liver Disease incorporating sodium levels (MELDNa) (women, 18 [IQR, 14-23]; men, 18 [IQR, 15-22]), but baseline LFI was higher in women (mean [SD], 4.12 [0.85] vs 4.00 [0.82]; P = .005). Women displayed worse balance of less than 30 seconds (145 [25%] vs 149 [18%]; P = .003), worse sex-adjusted grip (mean [SD], -0.31 [1.08] vs -0.16 [1.08] kg; P = .01), and fewer chair stands per second (median, 0.35 [IQR, 0.23-0.46] vs 0.37 [IQR, 0.25-0.49]; P = .04). In unadjusted mixed-effects models, LFI was 0.15 (95% CI, 0.06-0.23) units higher in women than men (P = .001). After adjustment for other variables associated with frailty, LFI was 0.16 (95% CI, 0.08-0.23) units higher in women than men (P < .001). In unadjusted regression, women experienced a 34% (95% CI, 3%-74%) increased risk of wait list mortality than men (P = .03). Sequential covariable adjustment did not alter the association between sex and wait list mortality; however, adjustment for LFI attenuated the mortality gap between women and men. In mediation analysis, an estimated 13.0% (IQR, 0.5%-132.0%) of the gender gap in wait list mortality was mediated by frailty. CONCLUSIONS AND RELEVANCE: These findings demonstrate that women with cirrhosis display worse frailty scores than men despite similar MELDNa scores. The higher risk of wait list mortality that women experienced appeared to be explained in part by frailty.