Non-resolution of acute kidney injury in the first week portends the development of chronic kidney disease in critically ill patients with cirrhosis.

BACKGROUND: Renal tubular epithelial cells (RTECs) cause maladaptive repair and perpetuate renal fibrosis. AIM: To evaluate urinary neutrophil gelatinase-associated lipocalin (NGAL) and RTEC as risk factors for non-resolution of acute kidney injury (AKI-NR) at day seven and chronic kidney disease (CKD) in critically ill patients with cirrhosis. METHODS: We performed urinary NGAL and microscopy at enrolment and day 7 in all patients. We assessed 17 renal injury, endothelial injury and repair markers, genes for mitochondrial biogenesis by qRT-PCR in RTEC, and post-mortem renal biopsies for understanding mechanisms of AKI non-resolution (n = 30). RESULTS: We enrolled 310 patients, aged 48.1 ± 11.6 years, 87% male, 90% alcoholic. Of these, 36% had RTEC at enrolment, and 53% had AKI-NR on day 7. On mean follow-up of 136 days (range 43-365), 150 (48.3%) developed CKD. The presence of RTEC or granular casts, NGAL and AKI-NR were independent predictors of CKD development on competing risk analysis. Higher MCP-1, renal endothelial injury, decrease in tubular repair markers and failure of mitochondrial biogenesis in RTEC were seen in patients with AKI-NR compared with AKI-R (p < 0.05). Renal biopsies showed infiltration with monocyte-macrophage, increased α-SMA, and tubulointerstitial fibrosis. CONCLUSION: Almost two-thirds of critically ill patients with cirrhosis have AKI, which resolves in only one-half at day seven and predicts the development of CKD. Higher NGAL, RTEC, or granular casts were independent predictors of AKI-NR and CKD development. Enhanced tubular and endothelial injury, decreased repair, monocyte-macrophage infiltration and mitochondrial dysfunction in RTEC are associated with AKI non-resolution and risk of renal fibrosis.

AARC score determines outcomes in patients with alcohol-associated hepatitis: a multinational study.

BACKGROUND AND AIM: Acute-on-chronic liver failure (ACLF) is a severe form of alcoholic hepatitis (SAH). We aimed to study the natural course, response to corticosteroids (CS), and the role of the Asian Pacific Association for the Study of Liver (APASL) research consortium (AARC) score in determining clinical outcomes in AH patients. METHODS: Prospectively collected data from the AARC database were analyzed. RESULTS: Of the 1249 AH patients, (aged 43.8 ± 10.6 years, 96.9% male, AARC score 9.2 ± 1.9), 38.8% died on a 90 day follow-up. Of these, 150 (12.0%) had mild-moderate AH (MAH), 65 (5.2%) had SAH and 1034 (82.8%) had ACLF. Two hundred and eleven (16.9%) patients received CS, of which 101 (47.87%) were steroid responders by day 7 of Lille's model, which was associated with improved survival [Hazard ratio (HR) 0.15, 95% CI 0.12-0.19]. AARC-ACLF grade 3 [OR 0.28, 0.14-0.55] was an independent predictor of steroid non-response and mortality [HR 3.29, 2.63-4.11]. Complications increased with degree of liver failure [AARC grade III vs. II vs I], bacterial infections [48.6% vs. 37% vs. 34.7%; p < 0.001); extrahepatic organ failure [66.9% vs. 41.8% vs. 35.4%; p < 0.001] respectively. The AARC score better discriminated 90-day mortality. Harrell's C-index was 0.72 compared to other scores. CONCLUSION: Nearly 4 of 5 patients with AH present with ACLF. Such patients have a higher risk of infections, organ failures, lower response to CS, and higher mortality. Patients with AH and ACLF with AARC grade 3 should be considered for an early liver transplant.

PIRO-CIC model can predict mortality and futility of care in critically ill cirrhosis patients in the intensive care unit.

BACKGROUND: Dynamic assessment of critically ill patients with cirrhosis (CICs) is required for accurate prognostication. OBJECTIVE: Development of a dynamic model for prediction of mortality and decision on futility of care in CICs. DESIGN AND SETTING: In a prospective cohort study, we developed the PIRO-CIC model (predisposition, injury, response, organ failure for critically ill cirrhotics)] in a derivative cohort (n = 360) and validated it (n = 240) for patients admitted to the Liver ICU. PATIENTS: Decompensated cirrhosis admitted to ICU. The model was developed using Cox-regression analysis, and futility was performed by decision-curve analysis. RESULTS: CICs aged 48 ± 11.5 years, 87% males, majority being alcoholics, were enrolled, of which 73.5% were alive at one month. Factors significant for P component were INR [hazard ratio 1.12, 95% confidence interval 1.07-1.18] and CystatinC [2.25, 1.70-2.97]; for I component were sepsis [4.69, 1.90-11.57], arterial lactate[1.40, 1.02-1.93] and alcohol as etiology [2.78, 1.85-4.18]; for R component-systemic inflammatory response syndrome [1.97, 1.14-3.42] and urine neutrophil-gelatinase-associated lipocalin [HR 2.37, 1.59-3.53]; for O component-low PaO2/FiO2 ratio and need of mechanical ventilation [7.41, 4.63-11.86]. The PIRO-CIC model predicted one-month mortality with a C-index of 0.83 in the derivation and 0.80 in the validation cohorts. It predicted futility of care better than other prognostic scores. The immediate risk of mortality increased by 39% with each unit increase in PIRO-CIC score. LIMITATIONS: Not applicable for acute-on-chronic liver failure and patients requiring emergency liver transplant. CONCLUSIONS: Assessment and stratification of CICs with the dynamic PIRO-CIC model could determine one-month mortality and futility in the first week. Targeted and aggressive management of coagulation, kidneys, sepsis, and severe systemic inflammation may improve outcomes of CICs.

Impact of Living Donor Liver Transplantation on COVID-19 Clinical Outcomes from a Quaternary Care Centre in Delhi.

Background and Aims: The anticipated fear of serious outcomes in coronavirus infected liver transplant recipients led to disruption of transplant services globally. The aim of our study was to analyze COVID-19 severity in transplant recipients and to compare the difference of COVID-19 clinical outcomes in early (<1 year) vs. late (>1 year) post-transplant period. Methods: 41 post-living donor liver transplant recipients with COVID-19 infection were studied retrospectively from 1st April 2020 to 28th February 2021. Results: The median age was 49.00 years with a male preponderance (80.49%). Fifteen patients had infection within 1 year of transplant and 26 were infected after 1 year of transplant. The overall median interval between transplantation and COVID-19 diagnosis was 816.00 days. Fever and malaise were the common presenting symptoms. The most common associated comorbidities were diabetes mellitus (65.85%) and hypertension (46.34%). The severity of illness was mild in 28 (68.29%), moderate in 4 (9.76%), severe in 6 (14.63%) and critical in 3 (7.32%). To identify associated risk factors, we divided our patients into less severe and more severe groups. Except for lymphopenia, there was no worsening of total bilirubin, transaminases, alkaline phosphatase, and gamma-glutamyl transferase in the more severe group. Eight (19.51%) patients required intensive care unit admission and three (7.32%) died, while none suffered graft rejection. In recipients with early vs. late post-transplant COVID-19 infection, there were similar outcomes in terms of severity of COVID-19 illness, intensive care unit care need, requirement of respiratory support, and death. Conclusion: Living donor liver transplantation can be performed during the COVID-19 pandemic without the fear of poor recipient outcome in cases of unfortunate contraction of severe acute respiratory syndrome coronavirus-2.

A randomized-controlled trial comparing 20% albumin to plasmalyte in patients with cirrhosis and sepsis-induced hypotension [ALPS trial].

BACKGROUND & AIMS: The choice of resuscitation fluid in patients with cirrhosis and sepsis-induced hypotension is unclear. 5% albumin was superior to normal saline in the FRISC study. We compared the efficacy and safety of 20% albumin, which has greater oncotic properties, to plasmalyte in reversing sepsis-induced hypotension. METHODS: Critically ill patients with cirrhosis underwent open-label randomization to receive either 20% albumin (0.5-1.0 g/kg over 3 hours; n = 50) or plasmalyte (30 ml/kg over 3 hours, n = 50). The primary endpoint of the study was the attainment of mean arterial pressure (MAP) above 65 mmHg at 3 hours. RESULTS: Baseline characteristics were comparable in albumin and plasmalyte groups; arterial lactate (6.16±3.18 mmol/L vs. 6.38±4.77 mmol/L; p = 0.78), MAP (51.4±6.52 mmHg vs. 49.9±4.45 mmHg; p = 0.17) and SOFA score (10.8±2.96 vs. 11.1±4.2; p = 0.68), respectively. Most patients were alcoholics (39%) and had pneumonia (40%). In the intention-to-treat analysis, albumin was superior to plasmalyte in achieving the primary endpoint (62% vs. 22%; p <0.001). A faster decline in arterial lactate (p = 0.03), a reduced need for dialysis (48% vs. 62%; p = 0.16), and a longer time to initiation of dialysis (in hours) (68.13±47.79 vs. 99.7± 63.4; p = 0.06) were seen with albumin. However, the 28-day mortality rate was not different (58% vs. 62%, p = 0.57) and treatment had to be discontinued in 11 (22%) patients in the albumin group due to adverse effects compared to no discontinuations in the plasmalyte group. CONCLUSION: In patients with cirrhosis and sepsis-induced hypotension, 20% albumin leads to a faster improvement in hemodynamics and lactate clearance than plasmalyte, while 28-day survival was similar. However, patients on 20% albumin need to be closely monitored as it was more often associated with pulmonary complications. CLINICAL TRIAL REGISTRATION: NCT02721238. LAY SUMMARY: The current randomized-controlled trial performed in critically ill patients with cirrhosis and sepsis-induced hypotension highlights that 20% albumin restores arterial pressure more quickly but causes more pulmonary complications than plasmalyte. The impact on renal functions was also modest. These effects did not result in improvement in survival at 28 days. Plasmalyte is safer and well-tolerated and can be considered for volume resuscitation in patients with cirrhosis and sepsis-induced hypotension.

Health and economic burden due to alcohol-associated liver diseases in the Union Territory of Delhi: A Markov probabilistic model approach.

BACKGROUND: Nearly one-fifth of all deaths attributable to alcohol are due to liver diseases. METHODS: The study employs a Markov Probabilistic Modeling approach considering various clinical spectrum of alcohol-associated liver diseases (ALD), to gauge the health and economic burden due to ALD for the national capital territory of Delhi, from March 2017 to February 2018. The health impact was estimated through Disability Adjusted Life Years (DALYs), years of life lost (YLL), and total deaths due to ALD. The economic burden of ALD was assessed assuming the current health-seeking preferences and assuming that all the diseased individuals are cared for in the public health systems. Sensitivity analysis was done by Monte Carlo simulations. RESULTS: Total number of estimated deaths due to ALD in the national capital territory of Delhi for one year period from March 2017 was 8367. The DALYs due to ALD were estimated to be 0.247 million life years; this includes 0.178 million YLL and 0.069 million life years lost due to disability. The total cost of treating ALD was estimated to be 92.94 billion Indian rupees, if patients sought care based on current preferences and 55.52 billion Indian rupees if all diseased individuals were cared for in public health systems. The total excise revenue due to alcohol to the Government is being Indian rupees 43.1 billion in the said year. CONCLUSION: The high burden of ALD in terms of lives lost, DALYs lost, and more than two times higher estimated expense for care than the revenue generation due to alcohol clearly indicates that it would be prudent to initiate social engineering and preventive strategies to lessen the growing burden of ALD in India. The Delhi model for health and economic burden of ALD could help the country develop policies for better health outcomes of these patients.

Effect of positive cumulative fluid balance on postoperative complications after living donor liver transplantation: A retrospective analysis.

BACKGROUND AND AIMS: Fluid administration during liver transplant (LT) surgery is controversial. Although adverse outcomes following positive intraoperative fluid balance have been reported, studies presenting the influence of cumulative postoperative fluid balance (CFB) on complications following LT are sparse. Patients with chronic liver disease tend to receive more fluid during and after surgery due to their unique physiological disease state. The aim of this study was to evaluate the influence of 48-hour CFB on the development of acute kidney injury (AKI) and pulmonary complications on day 4 after live donor LT. METHODS: This retrospective study included 230 patients undergoing live donor LT. The effect of CFB on day 2 on AKI and pulmonary complications was analysed. Chi-square test, Fisher's exact test, samples t-test, Mann-Whitney U-test were used. RESULTS: Bivariate analysis showed a lower graft vs recipient weight ratio (GRWR), sepsis (P < 0.001) and a higher 48-hour CFB after surgery significantly increased the development of AKI. For pulmonary complications, higher Model for End- stage Liver Disease-Na(MELD-Na) score, higher peak arterial lactate, higher 48-hour CFB (P = 0.016) and sepsis (P = 0.003) were found to be statistically significant. Upon multivariate analysis, CFB at 48 hours was significantly higher in patients suffering from pulmonary complications, and GRWR and sepsis were significant for AKI. For every one litre increase in CFB on day 2, the odds of pulmonary complications increased by 37%. CONCLUSION: A more positive CFB on day 2 increased the development of pulmonary complications and lower GRWR and sepsis increased the development of AKI.

Degree of Portal and Systemic Hemodynamic Alterations Predict Recurrent AKI and Chronic Kidney Disease in Patients With Cirrhosis.

The relevance of hemodynamic derangements on the incidence of recurrent acute kidney injury (AKI) and chronic kidney disease (CKD) in patients with cirrhosis is largely unknown. Consecutive patients with cirrhosis with a complete record of baseline hemodynamics were followed for identifying risk factors for the development of recurrent AKI and CKD by using negative binomial regression and competing risk analysis, respectively. Consecutive patients with cirrhosis (n = 2013, age 50.1 ± 11.8 years, 80% male, Child A:B:C percentage 13.7:52.9:33.4, and mean Child-Turcotte-Pugh score 8.6 ± 1.8) were enrolled, 893 (44.3%) of whom received beta-blockers, with 44.2% responders. Prior AKI was noted in 12.4% at enrollment. At a median follow-up of 379 (interquartile range: 68-869) days, AKI developed at a rate of 0.37 episodes per person-year, and 26% patients developed CKD. A lower mean number of AKI episodes (0.05 ± 0.25 vs. 0.42 ± 0.868; P < 0.001), CKD (subdistribution hazard ratio 0.74 [0.54-1.02]), and mortality (hazard ratio 0.21 [0.06-0.73]) were observed in beta-blocker responders. Albuminuria was an independent risk factor for recurrent AKI, CKD, and mortality (P < 0.05). Lower systemic vascular resistance index predicted hemodynamic response (odds ratio 2.04 [1.29-3.22]), cumulative AKI episodes (ratio of means 0.10 [0.08-0.14]), and development of CKD (subdistribution hazard ratio 0.70 [0.58-0.83]). Higher hepatic venous pressure gradient (≥17 mm Hg) predicted AKI episodes (ratio of means 1.76 [1.32-2.35]) but not CKD. Conclusion: High portal pressure and severe vasodilatation predispose patients with cirrhosis to repeated AKI episodes and development of CKD. Response to beta-blockers and therapies targeting the vasodilatory state could prevent frequent AKI and the risk of CKD development. Albuminuria could serve as an early marker of renal dysfunction in patients with cirrhosis.

A novel, bedside, etiology specific prognostic model (Peds-HAV) in hepatitis A induced pediatric acute liver failure.

BACKGROUND: Hepatitis A virus (HAV) is the commonest cause of pediatric acute liver failure (PALF) in developing countries. Our objective was to develop and validate a HAV-etiology specific prognostic model in PALF. METHODS: All children with HAV induced PALF (IgM HAV reactive) were included. Outcome was defined at day 28. Only those with death or native liver survival were included. The model (Peds-HAV) was derived using the independent predictors of outcome and validated in a prospective independent cohort. RESULTS: Hepatitis A accounted for 131 (45.9%) of total 285 PALF. After excluding 11 children who underwent liver transplant, 120 children (74 survivors and 46 death) were included. The first 75 patients formed the derivation cohort and the next 45 patients formed the prospective validation cohort. In the derivation cohort, INR: OR 2.208, (95% CI 1.321-3.690), p = 0.003, grade of hepatic encephalopathy (HE): OR 3.078, (95% CI 1.017-9.312), p = 0.047 and jaundice-to-HE interval: OR 1.171, (95% CI 1.044-1.314), p = 0.007 were independent predictors of death. The final model comprised three criteria: (1) presence of grade 3-4 HE, (2) INR greater than 3.1, and (3) jaundice to HE interval more than 10 days. Presence of 2 or more of these criteria predicted death with 90% sensitivity, 81.4% specificity and 84.9% accuracy. Peds-HAV model was superior to existing prognostic models. In the validation cohort, Peds-HAV model predicted death with 83.3% sensitivity and 92.6% specificity. CONCLUSION: Peds-HAV model is a simple, bedside, dynamic, etiology (HAV) specific prognostic model based on 3 objective parameters with optimum sensitivity and specificity, hence should be used as liver transplant listing criteria in HAV induced PALF.

Incidence, Risk Factors, and Outcomes of Transition of Acute Kidney Injury to Chronic Kidney Disease in Cirrhosis: A Prospective Cohort Study.

Transition to chronic kidney disease (CKD) after an episode of acute kidney injury (AKI) is known in patients without cirrhosis. We studied the incidence and risk factors for development of CKD in patients with cirrhosis. Competing risk analysis was performed to identify risk factors for CKD development. Of 818 patients with cirrhosis (age, 50.4 ± 11.8 years; 84% males; Model for End-Stage Liver Disease [MELD], 19.9 ± 9.9), 36% had AKI at enrollment, 27% had previous AKI, and 61% developed new episodes of AKI during the follow-up period. CKD developed in 269 (33%) patients. Serum cystatin C (CysC; subdistribution hazard ratio [SHR], 1.58; 1.07-2.33), episodes of previous AKI (SHR, 1.26; 1.02-1.56), and AKI stage at enrollment (no AKI [SHR, 1] vs. stage 1 [SHR, 3.28; 1.30-8.25] vs. stage 2 [SHR, 4.33; 1.76-10.66] vs. stage 3 [SHR, 4.5; 1.59-12.73]) were identified as baseline risk factors for CKD development. On time-varying competing risk analysis, MELD (SHR, 1.01; 1.00-1.03), number of AKI episodes (SHR, 1.25; 1.15-1.37), and CysC (SHR, 1.38; 1.01-1.89) predicted CKD development. Development of CKD was associated with higher risk of death. Reduction in glomerular filtration rate (GFR) not meeting CKD criteria was observed in 66% of patients with cirrhosis, more so in those with previous AKI episodes and a high CysC level and MELD score. Renal histology, available in 55 patients, showed tubulointerstitial injury in 86%, cholemic nephrosis in 29%, and glomerular changes in 38%. Conclusion: Almost two-thirds of patients with cirrhosis develop episodes of AKI and reduction in GFR; one-third progress to CKD, resulting in adverse outcomes. Higher MELD and CysC levels and number of AKI episodes predict development of CKD in patients with cirrhosis.

Investigating the Dynamics of Migration and Health in Australia: A Longitudinal Study.

There have been few longitudinal studies investigating the immigrant health and changes in their health with longer residency in the host country. Additionally, the pathways and mechanisms by which transition of health over time occurs are poorly understood, limiting the ability to implement policies that will result in improved health for all, including immigrants. We assessed differences in health outcomes among foreign-born people from English speaking countries and non-English speaking countries relative to native-born Australians over a 10-year period using a large representative longitudinal dataset. We also explored English language proficiency, socio-economic factors and health behaviour factors as possible mechanisms through which health outcomes change over time post-migration. Conventional multilevel mixed and hybrid regression models were used to evaluate health outcomes in 9558 native-born and 3067 foreign-born people from the Household, Income and Labour Dynamics in Australia survey. There were clear differences in physical health, mental health and self-assessed health between foreign-born subgroups in comparison with native-born Australians. Foreign-born people from English speaking countries typically had a health advantage relative to native-born people, and foreign-born people from non-English speaking countries had a health disadvantage with respect to native-born people for all health outcomes. There was no evidence that these differences changed by duration of residence except for self-assessed health amongst foreign-born people from non-English speaking countries when duration of residence exceeded 20 years. English language proficiency mediated the relationship between duration of residence and health for foreign-born people from non-English speaking countries.

HINDU-MUSLIM FERTILITY DIFFERENTIAL IN INDIA: A COHORT APPROACH.

Hindus and Muslims together account for 94% of the population of India. The fertility differential between these two religious groups is a sensitive and hotly debated issue in political and academic circles. However, the debate is mostly based on a period approach to fertility change, and there have been some problems with the reliability of period fertility data. This study investigated cohort fertility patterns among Hindus and Muslims and the causes of the relatively higher level of fertility among Muslims. Data from the three National Family Health Surveys conducted in India since the early 1990s were analysed using a six-parameter special form of the Gompertz model and multiple linear regression models. The results show a gap of more than 1.3 children per woman between those Muslim and Hindu women who ended/will end their reproductive period in the calendar years 1993 to 2025. The socioeconomic and demographic characteristics of Muslims explain 31.2% of the gap in fertility between Muslims and Hindus, while the desire for more children among Muslims explains an additional 18.2% of the gap in fertility.

EFFECT OF NATIVITY AND DURATION OF RESIDENCE ON CHRONIC HEALTH CONDITIONS AMONG ASIAN IMMIGRANTS IN AUSTRALIA: A LONGITUDINAL INVESTIGATION.

This study examined the effect of Asian nativity and duration of residence in Australia on the odds of reporting a chronic health condition (cancer, respiratory problems, cardiovascular disease (CVD) and diabetes mellitus). Data were from waves 3, 7 and 9 of the Household Income and Labour Dynamics in Australia (HILDA) longitudinal survey, and multi-level group-mean-centred logistic regression models were used for the analysis. After covariate adjustment, Asian immigrants were less likely to report cancer and respiratory problem compared with native-born Australians. While there was no significant difference in reporting CVD, they were more likely to report diabetes than native-born people. Asian immigrants maintained their health advantage with respect to cancer regardless of duration of residence. However, after 20 years of stay, Asian immigrants lost their earlier advantage and were not significantly different from native-born people in terms of reporting a respiratory problem. In contrast, Asian immigrants were not measurably different from native-born Australians in reporting diabetes if their length of stay in Australia was less than 20 years, but became disadvantaged after staying for 20 years or longer. There was no measurable difference in the odds of reporting CVD between Asian immigrants and native-born Australians for any duration of residence. On the whole this study found that health advantage, existence of healthy immigrant effect and subsequent erosion of it with increasing duration of residence among Asian immigrants depends upon the chronic health condition.

Nativity, duration of residence and chronic health conditions in Australia: do trends converge towards the native-born population?

Using data from waves 3, 7 and 9 of the Household, Income and Labour Dynamics in Australia (HILDA) survey, a group-mean-centred multilevel mixed model and self-reported chronic conditions, this study contributes to the limited longitudinal evidence on the nativity health gap in Australia. We investigated whether differences exist in the reporting of any chronic condition (including cancer, cardiovascular disease (CVD), arthritis, diabetes and respiratory disease), and in the total number of chronic conditions, between foreign-born (FB) from English speaking (ES) and non-English speaking (NES) countries and native-born (NB) Australians. We also investigated differences between these groups in the reporting of any chronic condition, and the total number of chronic conditions, by duration of residence. After adjusting for time varying and time invariant covariates, we found a significant difference by nativity status in the reporting of chronic condition, with immigrants from both ES and NES countries less likely to report a chronic condition and having fewer chronic conditions compared with the NB. Immigrants from both ES and NES countries living in Australia for less than 20 years were significantly less likely to report a chronic condition compared with the NB. However, the health of both these groups converged to that of the NB population in terms of reporting a chronic condition after 20 years of stay in Australia.