Stem cells for end stage liver disease: How far have we got?

End stage liver disease (ESLD) is a health problem worldwide. Liver transplantation is currently the only effective therapy, but its many drawbacks include a shortage of donors, operative damage, risk of rejection and in some cases recidivism of the pre-transplant disease. These factors account for the recent growing interest in regenerative medicine. Experiments have sought to identify an optimal source of stem cells, sufficient to generate large amounts of hepatocytes to be used in bioartificial livers or injected in vivo to repair the diseased organ. This update aims to give non-stem cell specialists an overview of the results obtained to date in this fascinating field of biomedical research.

Epistaxis in end stage liver disease masquerading as severe upper gastrointestinal hemorrhage

AIM: To describe the prevalence, diagnosis, treatment, and outcomes of end stage liver disease (ESLD) patients with severe epistaxis thought to be severe upper gastrointestinal hemorrhage (UGIH).

Quality of life in end stage renal disease patients

AIM： To understand factors associated with quality of life （QOL）, examine types of QOL instruments, and determine need for further improvements in QOL assessment.METHODS： The method used databases （Pubmed, Google scholar） and a bibliographic search using key words QOL, end stage renal disease, Hemodialysis, Peritoneal dialysis, instruments to measure QOL, patients and qualitative/quantitative analysis published during 1990 to June 2014. Each article was assessed for sample size, demographics of participants, study design and type of QOL instruments used. We used WHO defnition of QOL. RESULTS： For this review, 109 articles were screened, out of which 65 articles were selected. Out of 65 articles, there were 19 reports/reviews and 12 question-naire manuals. Of the 34 studies, 82% were quantita-tive while only 18% were qualitative. QOL instruments measured several phenomenon such as physical/psychological health, effects and burdens of kidney dis-ease, social support etc. those are associated with QOL. Few studies looked at spiritual beliefs, cultural beliefs, personal concerns, as per the WHO defnition. Telemedicine and Palliative care have now been successfully used however QOL instruments seldom addressed those in the articles reviewed. Also noticed was that longitudinal studies were rarely conducted. Existing QOL instruments only partially measure QOL. This may limit validity of predictive power of QOL. CONCLUSION： Culture and disease specific QOL in-struments that assess patients’ objective and subjective experiences covering most aspects of QOL are urgently needed.

Prognostic utility of NT-proBNP greater than 70,000 pg/mL in patients with end stage renal disease

Natriuretic peptides are synthesized in ventricular myocytes and released into the circulation in response to increased myocardial wall stress, Causes of myocardial wall stress include pulmonary hypertension, ventricular dilatation, as well as heart failure with reduced or preserved left ventricular function.

A retrospective study on use of palliative care for patients with alcohol related end stage liver disease in United States

BACKGROUND Palliative care(PC)has been shown to be beneficial in end stage liver disease(ESLD),yet the hospitalization data for PC utilization is unknown.AIM To identify the trend of PC utilization for the special population of alcoholassociated ESLD patients,factors affecting its use and ascertain its impact on healthcare utilization.METHODS We analyzed around 78 million discharges from the 2007-2014 national inpatient sample and 2010-2014 national readmission database including adult patients admitted for decompensated alcohol-associated cirrhosis.We identified patients with PC consultation as a secondary diagnosis.Odds ratios(OR)and means were adjusted for confounders using multivariate regression analysis models.RESULTS Out of the total 1421849 hospitalizations for decompensated liver cirrhosis,62782(4.4%)hospitalizations had a PC consult,which increased from 0.8%(1258)of all alcohol-associated ESLD hospitalizations in 2007 to 6.6%in 2014(P<0.01).Patient and hospital characteristics associated with increased odds of PC utilization were advanced age,lower income,Medicaid coverage,teaching institution,urban location,length of stay>3 d,prolonged ventilation,and administration of total parenteral nutrition(all P<0.01).Palliative encounters in alcohol-associated ESLD and acute-onchronic liver failure(ACLF)score were associated with increased odds of discharge to a rehabilitation facility,but significantly lower odds of 30-d readmissions(aOR:0.35,95%CI:0.31-0.41),lower total hospitalization charges and lower mean hospitalization days(all P<0.01).CONCLUSION Inpatient PC is sparingly used for patients with decompensated alcohol related liver disease,however it has increased over the past decade.PC consultation is associated with lower 30-d readmission rates on multivariate analysis,and lower hospitalization cost and length of stay in patients with ACLF score≥2.

Mortality rate of COVID-19 infection in end stage kidney disease patients on maintenance hemodialysis:A systematic review and meta-analysis

BACKGROUND Coronavirus disease 2019(COVID-19)has been the most talked-about disease of the past few years.Patients with significant comorbidities have been at particular risk of adverse outcomes.This study looked at the outcomes and risk factors for adverse outcomes among patients on chronic hemodialysis for end-stage renal disease,a group of patients known to be particularly susceptible to infectious complications.AIM To assess outcomes and risk factors for adverse outcomes of COVID-19 infection among patients on chronic hemodialysis.METHODS We searched PubMed/MEDLINE,EMBASE,Reference Citation Analysis(https://www.referencecitationanalysis.com/)and Web of Science databases for relevant terms and imported the results into the Covidence platform.From there,studies were assessed in two stages for relevance and quality,and data from studies that satisfied all the requirements were extracted into a spreadsheet.The data was then analyzed descriptively and statistically.RESULTS Of the 920 studies identified through the initial database search,only 17 were included in the final analysis.The studies included in the analysis were mostly carried out during the first wave.We found that COVID-19 incidence among patients on hemodialysis was significant,over 10%in some studies.Those who developed COVID-19 infection were most likely going to be hospitalized,and over 1 in 5 died from the infection.Intensive care unit admission rate was lower than the infection lethality rate.Biochemical abnormalities and dyspnea were generally reported to be associated with adverse outcomes.CONCLUSION This systematic review confirms that patients on chronic hemodialysis are very high-risk individuals for COVID-19 infections,and a significant proportion was infected during the first wave.Their prognosis is overall much worse than in the general population,and every effort needs to be made to decrease their exposure.

Efficacy of remdesivir for hospitalized COVID-19 patients with end stage renal disease

BACKGROUND Since the beginning of corona virus disease 2019(COVID-19)pandemic,there has been a widespread use of remdesivir in adults and children.There is little known information about its outcomes in patients with end stage renal disease who are on dialysis.AIM To assess the clinical outcomes with use of remdesivir in adult patients with end stage kidney failure on hemodialysis.METHODS A retrospective,multicenter study was conducted on patients with end stage renal disease on hemodialysis that were discharged after treatment for COVID-19 between April 1,2020 and December 31,2020.Primary endpoints were oxygen requirements,time to mortality and escalation of care needing mechanical ventilation.RESULTS A total of 45 patients were included in the study.Twenty patients received remdesivir,and 25 patients did not receive remdesivir.Most patients were caucasian,females with diabetes mellitus and hypertension being the commonest comorbidities.There was a trend towards reduced oxygen requirement(beta=-25.93,X^(2)(1)=6.65,P=0.0099,probability of requiring mechanical ventilation(beta=-28.52,X^(2)(1)=22.98,P<0.0001)and mortality(beta=-5.03,X^(2)(1)=7.41,P=0.0065)in patients that received remdesivir compared to the control group.CONCLUSION Larger studies are justified to study the effects of remdesivir in this high-risk population with end stage kidney disease on dialysis.

Unicentric Castleman's disease associated with end stage renal disease caused by amyloidosis

Castleman's disease(CD), also known as angiofolicular lymph node hyperplasia, is a rare heterogenous group of lymphoproliferative disorders. Histologically, it can be classified as hyaline vascular type, plasma cell type, or mixed type. Clinically two different subtypes of the CD are present: Unicentric and multicentric. Unicentric CD is generally asymptomatic and associated with hyaline vascular type, and its diagnoses depend on the localized lymphadenopathy on examination or imaging studies. However, multicentric CD presents with generalized lymphadenopathy and systemic symptoms including malaise, fever, night sweats, weight loss, and it is associated with the plasma cell type and mix type. Herein, we report a patient with unicentric CD of the plasma cell type without systemic symptoms, who developed end stage renal failure caused by amyloidosis 6 years after onset of CD.

Study the Effect of High Dialysate Potassium Solution in Comparison to Low Potassium Dialysate Solution in End Stage Renal Disease Patients

Background: Nowadays cardiovascular diseases remain as the single most common cause of death in chronic dialysis patients;the aim of this study was to evaluate the effects of two different regimens of dialysis potassium removal in patients with a tendency to develop arrhythmias during haemodialysis (HD). Methods and Materials: There were 88 (36 men and 52 women) end stage renal disease (ESRD) patients recruited for the study. They received regular haemodialysis three times per week at the haemodialysis units of a university medical centre (Golestan hospital) during year 2011. We compared the arrhythmogenic effects of two dialysis techniques. Results: There was a tendency in the HD solution with constant (3 mEq/l) K for premature ventricular complex (PVC) appearance in to be reduced as compared with constant (2 mEq/l) K in the time of dialysis period, although this reduction was not statistically significant(P = 0.09). There was a significant reduction in SVC in the HD solution with constant (3 mEq/l) K as compared with constant (2 mEq/l) K. Discussion: In conclusion, the use of a model of intra-HD potassium that is more close to potassium serum concentration of ESRD patients can reduce the arrhythmogenic effect of HD in patients on regular HD treatment.

Contrast induced neurotoxicity following coronary angiogram with Iohexol in an end stage renal disease patient

Neurotoxicity is an infrequent adverse reaction to iodinated contrast agents. Contrast induced neurotoxicity following coronary angiogram is very rare. Renal disease is a risk factor for contrast induced neurotoxicity. We report a case of contrast induced neurotoxicity following coronary angiogram and intervention using Iohexol(Omnipaque 350) in an end stage renal disease patient on peritoneal dialysis who had prior exposure to iodinated contrast without any adverse reaction. Hemodialysis had to be initiated for rapid removal of the contrast agent with subsequent complete resolution of neurological deficits. This case highlights the need for interventionalists to be aware of an important adverse reaction to iodinated contrast agents, especially in individuals with renal dysfunction, and that neurotoxicity is a possibility even with prior uneventful exposures. The role and timing of hemodialysis in contrast induced neurotoxicity in patients with chronic kidney disease and in those without chronic kidney disease needs further deliberation.

Endothelin-1 Antagonist in the Management of Refractory Systemic Hypertension in Children with End Stage Kidney Disease: A Case Series

Uncontrolled hypertension is a significant problem in children with end stage kidney disease. We studied 10 children on chronic hemodialysis who received the endothelin-1 receptor antagonist, bosentan as adjunctive therapy in refractory systemic hypertension. Data were retrospectively analyzed on systolic (SBP) and diastolic blood pressure (DBP), antihypertensive medications and hospitalization days per patient per year, at baseline and 3 months after initiation of bosentan. The standard deviation (Z) score of BP for age, height and gender was calculated. Mean age and weight of these children were 11.4 ± 4.8 years (range 1 - 17.5 years) and 32.9 ± 14.4 kg (range 7.4 - 57 kg) respectively and 90% were African American. Seven were on hemodialysis ≥4 times weekly. The average inter-dialytic weight gain was 4.7% ± 1.8%. The pre-dialysis SBP and DBP Z scores were 4.9 ± 1.8 and 4.0 ± 1.0 at baseline and decreased to 1.3 ± 0.4 and 1.3 ± 0.8, 3 months after initiation of bosentan (p < 0.0001). Similarly, anti-hypertensive medications were decreased from 5 ± 1.5 to 2.1 ± 2.6 (p < 0.01). Hospitalization days decreased from 35.6 ± 52.4 days to 1.5 ± 3.3 days (p < 0.0001). This preliminary report indicates bosentan may be beneficial in the management of children with severe refractory hypertension.

Prognostic value of neutrophil-to-lymphocyte ratio in end-stage liver disease:A meta-analysis

BACKGROUND The neutrophil-to-lymphocyte ratio(NLR)is commonly utilized as a prognostic indicator in end-stage liver disease(ESLD),encompassing conditions like liver failure and decompensated cirrhosis.Nevertheless,some studies have contested the prognostic value of NLR in ESLD.AIM To investigate the ability of NLR to predict ESLD.METHODS Databases,such as Embase,PubMed,Web of Science,Cochrane Library,China National Knowledge Infrastructure,Weipu,and Wanfang,were comprehensively searched to identify studies published before October 2022 assessing the prognostic ability of NLR to predict mortality in patients with ESLD.Effect sizes were calculated using comprehensive meta-analysis software and SATAT 15.1.RESULTS A total of thirty studies involving patients with end-stage liver disease(ESLD)were included in the evaluation.Among the pooled results of eight studies,it was observed that the Neutrophil-to-Lymphocyte Ratio(NLR)was significantly higher in non-survivors compared to survivors(random-effects model:standardized mean difference=1.02,95%confidence interval=0.67-1.37).Additionally,twenty-seven studies examined the associations between NLR and mortality in ESLD patients,reporting either hazard ratios(HR)or odds ratios(OR).The combined findings indicated a link between NLR and ESLD mortality(randomeffects model;univariate HR=1.07,95%CI=1.05-1.09;multivariate HR=1.07,95%CI=1.07-1.09;univariate OR=1.29,95%CI=1.18-1.39;multivariate OR=1.29,95%CI=1.09-1.49).Furthermore,subgroup and meta-regression analyses revealed regional variations in the impact of NLR on ESLD mortality,with Asian studies demonstrating a more pronounced effect.CONCLUSION Increased NLR in patients with ESLD is associated with a higher risk of mortality,particularly in Asian patients.NLR is a useful prognostic biomarker in patients with ESLD.

Palliative care for end-stage liver disease and acute on chronic liver failure:A systematic review

BACKGROUND End stage liver disease(ESLD)represents a growing health concern characterized by elevated morbidity and mortality,particularly among individual ineligible for liver transplantation.The demand for palliative care(PC)is pronounced in patients grappling with ESLD and acute on chronic liver failure(ACLF).Unfortunately,the historical underutilization of PC in ESLD patients,despite their substantial needs and those of their family caregivers,underscores the imperative of seamlessly integrating PC principles into routine healthcare practices across the entire disease spectrum.AIM To comprehensively investigate the evidence surrounding the benefits of incorporating PC into the comprehensive care plan for individuals confronting ESLD and/or ACLF.METHODS A systematic search in the Medline(PubMed)database was performed using a predetermined search command,encompassing studies published in English without any restrictions on the publication date.Subsequently,the retrieved studies were manually examined.Simple descriptive analyses were employed to summarize the results.RESULTS The search strategies yielded 721 references.Following the final analysis,32 fulllength references met the inclusion criteria and were consequently incorporated into the study.Meticulous data extraction from these 32 studies was undertaken,leading to the execution of a comprehensive narrative systematic review.The review found that PC provides significant benefits,reducing symptom burden,depressive symptoms,readmission rates,and hospital stays.Yet,barriers like the appeal of transplants and misconceptions about PC hinder optimal utilization.Integrating PC early,upon the diagnosis of ESLD and ACLF,regardless of transplant eligibility and availability,improves the quality of life for these patients.CONCLUSION Despite the substantial suffering and poor prognosis associated with ESLD and ACLF,where liver transplantation stands as the only curative treatment,albeit largely inaccessible,PC services have been overtly provided too late in the course of the illness.A comprehensive understanding of PC's pivotal role in treating ESLD and ACLF is crucial for overcoming these barriers,involving healthcare providers,patients,and caregivers.

Bone marrow derived stem cells for the treatment of end-stage liver disease

End-stage disease due to liver cirrhosis is an important cause of death worldwide. Cirrhosis results from progressive, extensive fibrosis and impaired hepatocyte regeneration. The only curative treatment is liver transplantation, but due to the several limitations of this procedure, the interest in alternative therapeutic strategies is increasing. In particular, the potential of bone marrow stem cell(BMSC) therapy in cirrhosis has been explored in different trials. In this article, we evaluate the results of 18 prospective clinical trials, and we provide a descriptive overview of recent advances in the research on hepatic regenerative medicine. The main message from the currently available data in the literature is that BMSC therapy is extremely promising in the context of liver cirrhosis. However, its application should be further explored in randomized, controlled trials with large cohorts and long follow-ups.

Extra-pulmonary tuberculosis infection in the dialysis patients with end stage renal diseases:case reports and literature review

The diagnosis of extra-pulmonary tuberculosis(TB) seems relatively difficult due to the absence of specific symptoms and signs in patients on peritoneal dialysis or hemodialysis.We report four cases of extra-pulmonary tuberculosis on dialysis,with two cases on peritoneal dialysis and two cases on hemodialysis.The presentations,therapy,and outcomes of TB infection in these patients were reviewed.Otherwise,the English literature published in the PubMed database associating extra-pulmonary tuberculosis on dialysis over the last three decades is reviewed.A total of 61 studies containing 70 cases were included.The most common primary disease was diabetic nephropathy(22.86%,16/70).The peritoneum(31.42%,22/70),bone(21.42%,15/70),and lymph node(20%,14/70) were the most frequently infected.Single organ infection was common(90%,63/70).Fever(58.57%,41/70),pain(35.71%,25/70),and enlarged lymph node(20%,14/70) were the most common symptoms.Biopsy(67.14%,47/70) and culture(40%,28/70) provided most reliable methods for clear diagnosis of tuberculosis.The combined treatment of isoniazid,rifampicin,pyrazinamide,and ethambutol(44.29%,31/70) was the most common therapy.The majority of patients improved(82.86%,58/70);however,12 cases got worse(17.14%),with 10 of them dying(14.29%).Physicians should be aware of the non-specific symptoms and location of infection,and consider tuberculosis in their differential diagnoses in dialysis patients presenting with symptoms such as fever,pain,and weight loss.

Association between Helicobacter pylori and end-stage renal disease: A meta-analysis

To investigate the prevalence and association of Helicobacter pylori (H. pylori) with end-stage renal disease (ESRD).METHODSSA comprehensive literature search was completed from inception until October 2016. Studies that reported prevalence, relative risks, odd ratios, hazard ratios or standardized incidence ratio of H. pylori among ESRD patients were included. Participants without H. pylori were used as comparators to assess the association between H. pylori infection and ESRD. Pooled risk ratios and 95%CI was calculated using a random-effect model. Adjusted point estimates from each study were combined by the generic inverse variance method of DerSimonian and Laird.RESULTSOf 4546 relevant studies, thirty-seven observational studies met all inclusion criteria. Thirty-five cross-sectional studies were included in the analyses to assess the prevalence and association of H. pylori with ESRD. The estimated prevalence of H. pylori among ESRD patients was 44% (95%CI: 40%-49%). The pooled RR of H. pylori in patients with ESRD was 0.77 (95%CI: 0.59-1.00) when compared with the patients without ESRD. Subgroup analysis showed significantly reduced risk of H. pylori in adult ESRD patients with pooled RR of 0.71 (95%CI: 0.55-0.94). The data on the risk of ESRD in patients with H. pylori were limited. Two cohort studies were included to assess the risk of ESRD in patients with H. pylori. The pooled risk RR of ESRD in patients with H. pylori was 0.61 (95%CI: 0.03-12.20).CONCLUSIONThe estimated prevalence of H. pylori in ESRD patients is 44%. Our meta-analysis demonstrates a decreased risk of H. pylori in adult ESRD patients.

Good news for end stage renal disease patients

End stage renal disease （ESRD）, with a prevalence in China of about 200-250 cases per million, is one of the major diseases that seriously threaten human health and cause poverty. Recently, with the advancement of healthcare system reform in China, basic medical insurance now covers over 95% of urban and rural residents, and a high-reimbursement system for the catastrophic diseases including ESRD has been established. The improvement of healthcare policy calls on the medical community to strengthen healthcare service capability for severe illness,

Interleukin-10 genotype protects end stage renal disease patients from microinflammation and arteriosclerosis

End stage renal disease （ ESRD ） and cardiovascular disease are induced by arteriosclerosis （AS）. The latest investigation shows that AS is a special inflammatory state. The constant inflammation,which has been defined as a micro inflammatory state is related to the decline of renal function and blood purification, but not the result of infections caused by external pathogenic microorganisms or internal opportunistic pathogenic microorganisms. We investigated the mechanism of interleukin-10 （IL-10） gene-1082 A/G protection effect to keep ESRD patients away from micro inflammation and AS.

Bioengineered functional humanized livers： An emerging supportive modality to bridge the gap of organ transplantation for management of end-stage liver diseases

End stage liver diseases （ESLD） represent a major, neglected global public health crisis which requires an urgent action towards fnding a proper cure. Orthotro-pic liver transplantation has been the only definitive treatment modality for ESLD. However, shortage of donor organs, timely unavailability, post-surgery related complications and financial burden on the patients li-mits the number of patients receiving the transplants. Since last two decades cell-based therapies have revolu-tionized the feld of organ/tissue regeneration. However providing an alternative organ source to address the donor liver shortage still poses potential challenges. The developments made in this direction provide useful futuristic approaches, which could be translated into preclinical and clinical settings targeting appropriate applications in specific disease conditions. Earlier studies have demonstrated the applicability of this particular approach to generate functional organ in rodent system by connecting them with portal and hepatic circulatory networks. However, such strategy requires very high level of surgical expertise and also poses the technical and financial questions towards its future applicability. Hence, alternative sites for generating secondary organs are being tested in several types of disease conditions. Among different sites, omentum has been proved to be more appropriate site for implanting several kinds of functional tissue constructs without eliciting much immunological response. Hence, omentum may be con-sidered as better site for transplanting humanized bio-engineered ex vivo generated livers, thereby creating a secondary organ at intra-omental site. However, the expertise for generating such bioengineered organs are limited and only very few centres are involved for inve-stigating the potential use of such implants in clinical practice due to gap between the clinical transplant surgeons and basic scientists working on the concept evolution. Herein we discuss the recent advances and challenges to create functional secondary organs thr-ough intra-omental transplantation of ex vivo genera-ted bioengineered humanized livers and their further application in the management of ESLD as a supportive bridge for organ transplantation.

Indocyanine green clearance test and model for end-stage liver disease score of patients with liver cirrhosis

BACKGROUND: The indocyanine green (ICG) clearance test (clearance rate (K) and retention rate at 15 minutes (R(15))) is a sensitive indicator to evaluate liver function. The model for end-stage liver disease (MELD) score has emerged as a useful tool for estimating the mortality of patients awaiting liver transplantation and has recently been validated on patients with liver diseases of various etiologies and severity. In this study, we investigated the correlation between the ICG clearance test and MELD score of patients with liver cirrhosis. METHODS: From June 2007 to March 2008, 52 patients with liver cirrhosis admitted to our center were classified into Child-Pugh class A (8 patients), B (14) and C (30). The ICG clearance test (K value and R(15)) was performed by ICG pulse spectrophotometry (DDG-3300K), and the MELD scores of patients were calculated. RESULTS: As the Child-Pugh classification of liver function gradually deteriorated, the K value decreased, while R(15) and MELD score increased. There were significant statistical differences in K value, R(15) and MELD score in patients with different Child-Pugh classifications. Significant correlations were found between the parameters of the ICG clearance test (K value and R(15)) and MELD score. A negative correlation was observed between K value and MELD score (r=-0.892, P < 0.05), while a positive correlation was observed between R(15) and MELD score (r=0.804, P < 0.05). CONCLUSIONS: The ICG clearance test and MELD score are good parameters for evaluating liver function. Moreover, K value and R(15) have significant correlations with MELD score, especially the K value, which may be a convenient and appropriate indicator to evaluate liver function of patients with liver cirrhosis.