Immunogenicity and Safety of the Three-Dose COVID-19 Vaccine Regimen in Patients Receiving Renal Replacement Therapy: A Systematic Review and Meta-Analysis.

Background: A three-dose regimen is the current standard for COVID-19 vaccination, but systematic data on immunogenicity and safety in chronic kidney disease patients remains limited. Objectives: We conducted a meta-analysis on the immunogenicity and safety of three-dose COVID-19 vaccination in patients on renal replacement therapy (RRT). Methods: Systematic literature search in four electronic databases yielded twenty eligible studies (2,117 patients, 94% of whom received mRNA vaccines) for meta-analysis. Results: The overall seropositivity rate of anti-SARS-CoV-2 was 74.2% (95% CI: 65.0-83.4%) after three-dose COVID-19 vaccination. The seropositivity rate of anti-SARS-CoV-2 in kidney transplant recipients (KTRs) was 64.6% (95% CI: 58.7-70.5%), and 43.5% (95% CI: 38.5-48.6%) of non-responders after second dose became seropositive after third dose. The seropositivity rate of anti-SARS-CoV-2 was 92.9% (95% CI: 89.5-96.2%) in dialysis patients, and 64.6% (95% CI: 46.8-82.3%) of non-responders after second dose became seropositive after third dose. In KTRs, each year increase in transplant vintage was associated with 35.6% increase in anti-SARS-CoV-2 seropositivity (95% CI: 15.9-55.4%, p = 0.01). There were no serious adverse events attributed to vaccination in KTRs, and the commonest local and systemic adverse events were injection site pain and fatigue, respectively. Conclusion: Three-dose COVID-19 vaccination regimen in patients on RRT is associated with reduced immunogenicity, especially in KTRs. There are no adverse events associated with third-dose COVID-19 vaccine in KTRs.

Effectiveness of Molnupiravir and Nirmatrelvir-Ritonavir in CKD Patients With COVID-19.

Introduction: Even with effective vaccines, patients with CKD have a higher risk of hospitalization and death subsequent to COVID-19 infection than those without CKD. Molnupiravir and nirmatrelvir-ritonavir have been approved for emergency use, but their effectiveness for the CKD population is still unknown. This study was conducted to determine the effectiveness of these drugs in reducing mortality and severe COVID-19 in the CKD population. Methods: This was a target trial emulation study using electronic health databases in Hong Kong. Patients with CKD aged 18 years or older who were hospitalized with COVID-19 were included. The per-protocol average treatment effect among COVID-19 oral antiviral initiators, including all-cause mortality, intensive care unit (ICU) admission, and ventilatory support within 28 days, were compared to noninitiators. Results: Antivirals have been found to lower the risk of all-cause mortality, with Molnupiravir at a hazard ratio (HR) of 0.85 (95% confidence interval [CI], 0.77 to 0.95] and nirmatrelvir-ritonavir at an HR of 0.78 [95% CI, 0.60 to 1.00]. However, they do not significantly reduce the risk of ICU admission (molnupiravir: HR, 0.88 [95% CI, 0.59 to 1.30]; nirmatrelvir-ritonavir: HR, 0.86 [95% CI, 0.56 to 1.32]) or ventilatory support (molnupiravir: HR, 1.00 [95% CI, 0.76 to 1.33]; nirmatrelvir-ritonavir: HR, 1.01 [95% CI, 0.74 to 1.37]). There was a greater risk reduction in males and those with higher Charlson Comorbidity Index (CCI). The nirmatrelvir-ritonavir trial also showed reduced risk for those who had antiviral treatment and received 3 or more vaccine doses. Conclusion: Both molnupiravir and nirmatrelvir-ritonavir reduced mortality rates for hospitalized COVID-19 patients with CKD.

Vaccine Effectiveness of BNT162b2 and CoronaVac against SARS-CoV-2 Omicron BA.2 in CKD.

BACKGROUND: The ongoing coronavirus disease 2019 (COVID-19) pandemic has posed increased risks of hospitalization and mortality in patients with underlying CKD. Current data on vaccine effectiveness of COVID-19 vaccines are limited to patients with CKD on dialysis and seroconversion in the non-dialysis population. METHODS: A case-control study was conducted of adults with CKD using data extracted from the electronic health record database in Hong Kong. Adults with CKD and COVID-19 confirmed by PCR were included in the study. Each case was matched with up to ten controls attending Hospital Authority services without a diagnosis of COVID-19 on the basis of age, sex, and index date (within three calendar days). The vaccine effectiveness of BNT162b2 and CoronaVac in preventing COVID-19 infection, hospitalizations, and all-cause mortality was estimated using conditional logistic regression adjusted by patients' comorbidities and medication history during the outbreak from January to March 2022. RESULTS: A total of 20,570 COVID-19 cases, 6604 COVID-19-related hospitalizations, and 2267 all-cause mortality were matched to 81,092, 62,803, and 21,348 controls, respectively. Compared with the unvaccinated group, three doses of BNT162b2 or CoronaVac were associated with a reduced risk of infection (BNT162b2: 64% [95% confidence interval (CI), 60 to 67], CoronaVac: 42% [95% CI, 38 to 47]), hospitalization (BNT162b2: 82% [95% CI, 77 to 85], CoronaVac: 80% [95% CI, 76 to 84]), and mortality (BNT162b2: 94% [95% CI, 88 to 97], CoronaVac: 93% [95% CI, 88 to 96]). Vaccines were less effective in preventing infection and hospitalization in the eGFR <15 and 15-29 ml/min per 1.73 m 2 subgroups as compared with higher GFR subgroups. However, receipt of vaccine, even for one dose, was effective in preventing all-cause mortality, with estimates similar to the higher eGFR subgroups, as compared with unvaccinated. CONCLUSIONS: A dose-response relationship was observed between the number of BNT162b2 or CoronaVac doses and the effectiveness against COVID-19 infection and related comorbidity in the CKD population.

Long-term post-acute sequelae of COVID-19 infection: a retrospective, multi-database cohort study in Hong Kong and the UK.

Background: Evidence on post-acute sequelae of SARS-CoV-2 (PASC) has shown inconsistent findings. This study aimed to generate coherent evidence on the post-acute sequelae of COVID-19 infection using electronic healthcare records across two regions. Methods: In this retrospective, multi-database cohort study, patients with COVID-19 aged 18 or above between April 1st 2020 and May 31st 2022 from the Hong Kong Hospital Authority (HKHA) and March 16th 2020 and May 31st 2021 from the UK Biobank (UKB) databases and their matched controls were followed for up to 28 and 17 months, respectively. Covariates between patients with COVID-19 and non-COVID-19 controls were adjusted using propensity score-based inverse probability treatment weighting. Cox proportional regression was used to estimate the hazard ratio (HR) of clinical sequelae, cardiovascular, and all-cause mortality 21 days after COVID-19 infection. Findings: A total of 535,186 and 16,400 patients were diagnosed with COVID-19 from HKHA and UKB, of whom 253,872 (47.4%) and 7613 (46.4%) were male, with a mean age (±SD) of 53.6 (17.8) years and 65.0 (8.5) years, respectively. Patients with COVID-19 incurred greater risk of heart failure (HR 1.82; 95% CI 1.65, 2.01), atrial fibrillation (1.31; 1.16, 1.48), coronary artery disease (1.32; 1.07, 1.63), deep vein thrombosis (1.74; 1.27, 2.37), chronic pulmonary disease (1.61; 1.40, 1.85), acute respiratory distress syndrome (1.89; 1.04, 3.43), interstitial lung disease (3.91; 2.36, 6.50), seizure (2.32; 1.12, 4.79), anxiety disorder (1.65; 1.29, 2.09), post-traumatic stress disorder (1.52; 1.23, 1.87), end-stage renal disease (1.76; 1.31, 2.38), acute kidney injury (2.14; 1.69, 2.71), pancreatitis (1.42; 1.10, 1.83), cardiovascular (2.86; 1.25, 6.51) and all-cause mortality (4.16; 2.11, 8.21) mortality during their post-acute phase of infection. Interpretation: The consistent greater risk of PASC highlighted the need for sustained multi-disciplinary care for COVID-19 survivors. Funding: Health Bureau, The Government of the Hong Kong Special Administrative Region, Collaborative Research Fund, The Government of the Hong Kong Special Administrative Region and AIR@InnoHK, administered by the Innovation and Technology Commission, The Government of the Hong Kong Special Administrative Region.

New insights into fibrotic signaling in renal cell carcinoma.

Fibrotic signaling plays a pivotal role in the development and progression of solid cancers including renal cell carcinoma (RCC). Intratumoral fibrosis (ITF) and pseudo-capsule (PC) fibrosis are significantly correlated to the disease progression of renal cell carcinoma. Targeting classic fibrotic signaling processes such as TGF-ß signaling and epithelial-to-mesenchymal transition (EMT) shows promising antitumor effects both preclinically and clinically. Therefore, a better understanding of the pathogenic mechanisms of fibrotic signaling in renal cell carcinoma at molecular resolution can facilitate the development of precision therapies against solid cancers. In this review, we systematically summarized the latest updates on fibrotic signaling, from clinical correlation and molecular mechanisms to its therapeutic strategies for renal cell carcinoma. Importantly, we examined the reported fibrotic signaling on the human renal cell carcinoma dataset at the transcriptome level with single-cell resolution to assess its translational potential in the clinic.

Long-term outcomes of add-on direct renin inhibition in igA nephropathy: a propensity score-matched cohort study.

INTRODUCTION: The long-term clinical outcomes in biopsy proven IgAN patients treated with aliskiren on top of a maximally tolerated dose of ACEi/ARB remain unknown. METHODS: Patients with IgAN treated with a direct renin inhibitor and ACEi/ARB for at least 6 months were compared with a 1:1 propensityscore-matched cohort (including MEST-C score and the 12-months pre-exposure slope of eGFR matching) who received ACEi/ARB without aliskiren exposure to compute the hazard ratio of reaching the primary endpoint of a composite of 40% reduction in eGFR, initiation of KRT and all-cause mortality. Secondary outcome measures included changes in mean UPCR, blood pressure, eGFR, incidence of hyperkalemia and other adverse events during follow-up. RESULTS: After a median follow-up of 2.5 years, 8/36 (22.2%) aliskiren-treated patients and 6/36 (16.7%) control patients reached the primary composite outcome (HR = 1.60; 95% CI 0.52-4.88; P = 0.412). Aliskiren treatment increased the risk of ≥ 40% eGFR decline (HR = 1.60; 95% CI 0.52-4.88; P = 0.412), and hyperkalemia (HR = 8.60; 95% CI 0.99-73.64; P = 0.050). At 10.8 years, renal composite outcome was reached in 69.4% vs 58.3% (HR = 2.16; 95% CI 1.18-3.98; P = 0.013) of patients in the aliskiren and control groups, respectively. The mean UPCR reduction between treatment and control was not statistically different (52.7% vs 42.5%; 95% CI 0.63-2.35; P = 0.556). The mean intergroup difference in eGFR decline over 60 months was 7.75 ± 3.95 ml/min/1.73 m2 greater in the aliskiren group (12.83 vs 5.08; 95% CI - 0.17 to 15.66; P = 0.055). CONCLUSION: Among patients with IgAN, add-on aliskiren was associated with less favorable long-term kidney outcomes despite an initial anti-proteinuric effect.

Risk of glomerular diseases, proteinuria and hematuria following mRNA (BNT162b2) and inactivated (CoronaVac) SARS-CoV-2 vaccines.

BACKGROUND: With accruing case reports on de novo or relapsing glomerular diseases (GD) following different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines, we evaluated the risk of GD following BNT162b2 and CoronaVac vaccines. METHODS: A modified self-controlled case series analysis was conducted using anonymized, territory-wide SARS-CoV-2 vaccination records in Hong Kong. All Hong Kong residents aged 18 years or above with outcomes of interest were included. Outcomes of interest were GD, proteinuria or hematuria within 42 days following each dose of SARS-CoV-2 vaccines. Incidence per 100 000 doses of SARS-CoV-2 vaccines administered was calculated, and incidence rate ratios (IRRs) were estimated using conditional Poisson regression with seasonality adjustment. RESULTS: Between 23 February 2021 and 31 March 2022, 4062 patients had an incident diagnosis of GD, proteinuria or hematuria, with 2873 of them being vaccinated during the observation period. The incidences of the composite events 1-41 days after vaccination were 3.7 (95% CI 3.1-4.4) per 100 000 doses of BNT162b2 administered, and 6.5 (95% CI 5.7-7.5) per 100 000 doses CoronaVac administered. There was no significant increase in the risks of composite events following the first (BNT162b2: IRR = 0.76, 95% CI 0.56-1.03; CoronaVac: IRR = 0.92, 95% CI 0.72-1.19), second (BNT162b2: IRR = 0.92, 95% CI 0.72-1.17; CoronaVac: IRR = 0.88. 95% CI 0.68-1.14) or third (BNT162b2: IRR = 0.39. 95% CI 0.15-1.03; CoronaVac: IRR = 1.18. 95% CI 0.53-2.63) dose of SARS-CoV-2 vaccines. CONCLUSIONS: There was no evidence of increased risks of de novo or relapsing GD with either BNT162b2 or CoronaVac vaccines.

Long-term spill-over impact of COVID-19 on health and healthcare of people with non-communicable diseases: a study protocol for a population-based cohort and health economic study.

INTRODUCTION: The COVID-19 pandemic has a significant spill-over effect on people with non-communicable diseases (NCDs) over the long term, beyond the direct effect of COVID-19 infection. Evaluating changes in health outcomes, health service use and costs can provide evidence to optimise care for people with NCDs during and after the pandemic, and to better prepare outbreak responses in the future. METHODS AND ANALYSIS: This is a population-based cohort study using electronic health records of the Hong Kong Hospital Authority (HA) CMS, economic modelling and serial cross-sectional surveys on health service use. This study includes people aged ≥18 years who have a documented diagnosis of diabetes mellitus, hypertension, cardiovascular disease, cancer, chronic respiratory disease or chronic kidney disease with at least one attendance at the HA hospital or clinic between 1 January 2010 and 31 December 2019, and without COVID-19 infection. Changes in all-cause mortality, disease-specific outcomes, and health services use rates and costs will be assessed between pre-COVID-19 and-post-COVID-19 pandemic or during each wave using an interrupted time series analysis. The long-term health economic impact of healthcare disruptions during the COVID-19 pandemic will be studied using microsimulation modelling. Multivariable Cox proportional hazards regression and Poisson/negative binomial regression will be used to evaluate the effect of different modes of supplementary care on health outcomes. ETHICS AND DISSEMINATION: The study was approved by the institutional review board of the University of Hong Kong, the HA Hong Kong West Cluster (reference number UW 21-297). The study findings will be disseminated through peer-reviewed publications and international conferences.

LncRNA-Dependent Mechanisms of Transforming Growth Factor-ß: From Tissue Fibrosis to Cancer Progression.

Transforming growth factor-ß (TGF-ß) is a crucial pathogenic mediator of inflammatory diseases. In tissue fibrosis, TGF-ß regulates the pathogenic activity of infiltrated immunocytes and promotes extracellular matrix production via de novo myofibroblast generation and kidney cell activation. In cancer, TGF-ß promotes cancer invasion and metastasis by enhancing the stemness and epithelial mesenchymal transition of cancer cells. However, TGF-ß is highly pleiotropic in both tissue fibrosis and cancers, and thus, direct targeting of TGF-ß may also block its protective anti-inflammatory and tumor-suppressive effects, resulting in undesirable outcomes. Increasing evidence suggests the involvement of long non-coding RNAs (lncRNAs) in TGF-ß-driven tissue fibrosis and cancer progression with a high cell-type and disease specificity, serving as an ideal target for therapeutic development. In this review, the mechanism and translational potential of TGF-ß-associated lncRNAs in tissue fibrosis and cancer will be discussed.

Adverse events of special interest and mortality following vaccination with mRNA (BNT162b2) and inactivated (CoronaVac) SARS-CoV-2 vaccines in Hong Kong: A retrospective study.

BACKGROUND: Safety monitoring of coronavirus disease 2019 (COVID-19) vaccines is crucial during mass vaccination rollout to inform the choice of vaccines and reduce vaccine hesitancy. Considering the scant evidence directly comparing the safety profiles of mRNA and inactivated SARS-CoV-2 vaccines, this territory-wide cohort study aims to compare the incidence of various adverse events of special interest (AESIs) and all-cause mortality between CoronaVac (inactivated vaccine) and BNT162b2 (mRNA-based vaccine). Our results can help vaccine recipients make an informed choice. METHODS AND FINDINGS: A retrospective, population-based cohort of individuals who had received at least 1 dose of BNT162b2 or CoronaVac from 23 February to 9 September 2021 in Hong Kong, and had data linkage to the electronic medical records of the Hong Kong Hospital Authority, were included. Those who had received mixed doses were excluded. Individuals were observed from the date of vaccination (first or second dose) until mortality, second dose vaccination (for first dose analysis), 21 days after vaccination, or 30 September 2021, whichever came first. Baseline characteristics of vaccinated individuals were balanced between groups using propensity score weighting. Outcome events were AESIs and all-cause mortality recorded during 21 days of post-vaccination follow-up after each dose, except anaphylaxis, for which the observation period was restricted to 2 days after each dose. Incidence rate ratios (IRRs) of AESIs and mortality comparing between CoronaVac and BNT162b2 recipients were estimated after each dose using Poisson regression models. Among 2,333,379 vaccinated individuals aged 18 years or above, the first dose analysis included 1,308,820 BNT162b2 and 955,859 CoronaVac recipients, while the second dose analysis included 1,116,677 and 821,560 individuals, respectively. The most frequently reported AESI among CoronaVac and BNT162b2 recipients was thromboembolism (first dose: 431 and 290 per 100,000 person-years; second dose: 385 and 266 per 100,000 person-years). After the first dose, incidence rates of overall AESIs (IRR = 0.98, 95% CI 0.89-1.08, p = 0.703) and mortality (IRR = 0.96, 95% CI 0.63-1.48, p = 0.868) associated with CoronaVac were generally comparable to those for BNT162b2, except for Bell palsy (IRR = 1.95, 95% CI 1.12-3.41, p = 0.018), anaphylaxis (IRR = 0.34, 95% CI 0.14-0.79, p = 0.012), and sleeping disturbance or disorder (IRR = 0.66, 95% CI 0.49-0.89, p = 0.006). After the second dose, incidence rates of overall AESIs (IRR = 0.97, 95% CI 0.87-1.08, p = 0.545) and mortality (IRR = 0.85, 95% CI 0.51-1.40, p = 0.516) were comparable between CoronaVac and BNT162b2 recipients, with no significant differences observed for specific AESIs. The main limitations of this study include residual confounding due to its observational nature, and the possibility of its being underpowered for some AESIs with very low observed incidences. CONCLUSIONS: In this study, we observed that the incidences of AESIs (cumulative incidence rate of 0.06%-0.09%) and mortality following the first and second doses of CoronaVac and BNT162b2 vaccination were very low. The safety profiles of the vaccines were generally comparable, except for a significantly higher incidence rate of Bell palsy, but lower incidence rates of anaphylaxis and sleeping disturbance or disorder, following first dose CoronaVac versus BNT162b2 vaccination. Our results could help inform the choice of inactivated COVID-19 vaccines, mainly administered in low- and middle-income countries with large populations, in comparison to the safety of mRNA vaccines. Long-term surveillance on the safety profile of COVID-19 vaccines should continue.

Potential Therapeutic Targets of Rehmannia Formulations on Diabetic Nephropathy: A Comparative Network Pharmacology Analysis.

Background: Previous retrospective cohorts showed that Rehmannia-6 (R-6, Liu-wei-di-huang-wan) formulations were associated with significant kidney function preservation and mortality reduction among chronic kidney disease patients with diabetes. This study aimed to investigate the potential mechanism of action of common R-6 variations in a clinical protocol for diabetic nephropathy (DN) from a system pharmacology approach. Study Design and Methods: Disease-related genes were retrieved from GeneCards and OMIM by searching "Diabetic Nephropathy" and "Macroalbuminuria". Variations of R-6 were identified from a published existing clinical practice guideline developed from expert consensus and pilot clinical service program. The chemical compound IDs of each herb were retrieved from TCM-Mesh and PubChem. Drug targets were subsequently revealed via PharmaMapper and UniProtKB. The disease gene interactions were assessed through STRING, and disease-drug protein-protein interaction network was integrated and visualized by Cytoscape. Clusters of disease-drug protein-protein interaction were constructed by Molecular Complex Detection (MCODE) extension. Functional annotation of clusters was analyzed by DAVID and KEGG pathway enrichment. Differences among variations of R-6 were compared. Binding was verified by molecular docking with AutoDock. Results: Three hundred fifty-eight genes related to DN were identified, forming 11 clusters which corresponded to complement and coagulation cascades and signaling pathways of adipocytokine, TNF, HIF-1, and AMPK. Five variations of R-6 were analyzed. Common putative targets of the R-6 variations on DN included ACE, APOE, CCL2, CRP, EDN1, FN1, HGF, ICAM1, IL10, IL1B, IL6, INS, LEP, MMP9, PTGS2, SERPINE1, and TNF, which are related to regulation of nitric oxide biosynthesis, lipid storage, cellular response to lipopolysaccharide, inflammatory response, NF-kappa B transcription factor activity, smooth muscle cell proliferation, blood pressure, cellular response to interleukin-1, angiogenesis, cell proliferation, peptidyl-tyrosine phosphorylation, and protein kinase B signaling. TNF was identified as the seed for the most significant cluster of all R-6 variations. Targets specific to each formulation were identified. The key chemical compounds of R-6 have good binding ability to the putative protein targets. Conclusion: The mechanism of action of R-6 on DN is mostly related to the TNF signaling pathway as a core mechanism, involving amelioration of angiogenesis, fibrosis, inflammation, disease susceptibility, and oxidative stress. The putative targets identified could be validated through clinical trials.

Personalized immunosuppression after kidney transplantation.

With advances in immunosuppressive therapy, there have been significant improvements in acute rejection rates and short-term allograft survival in kidney transplant recipients. However, this success has not been translated into long-term benefits by the same magnitude. Optimization of immunosuppression is important to improve the clinical outcome of transplant recipients. It is important to note that each patient has unique attributes and immunosuppression management should not be a one-size-fits-all approach. Elderly transplant patients are less likely to develop acute rejection but more likely to die from infectious and cardiovascular causes than younger patients. For those with post-transplant cancers and BK polyomavirus-associated nephropathy, reduction of immunosuppression can increase the risk of rejection. Therapeutic drug monitoring (TDM) is routinely used for dosage adjustment of several immunosuppressive drugs. It has been hoped that pharmacogenetics can be used to complement TDM in optimizing drug exposure. Among the various drug-genotype pairs being investigated, tacrolimus and CYP3A5 gives the most promising results. Different studies have consistently shown that CYP3A5 expressers require a higher tacrolimus dose and take longer time to achieve target blood tacrolimus levels than nonexpressers. However, for pharmacogenetics to be widely used clinically, further trials are necessary to demonstrate the clinical benefits of genotype-guided dosing such as reduction of rejection and drug-related toxicities. The development of different biomarkers in recent years may help to achieve true personalized therapy in transplant patients.

Effectiveness of Integrative Chinese-Western Medicine for Chronic Kidney Disease and Diabetes: A Retrospective Cohort Study.

Diabetes and chronic kidney disease (CKD) are pandemic, requiring more therapeutic options. This retrospective cohort evaluated the effectiveness, safety profile and prescription pattern of a pilot integrative medicine service program in Hong Kong. Data from 38 patients with diabetes and CKD enrolled to receive 48-week individualized add-on Chinese medicine (CM) were retrieved from the electronically linked hospital database. A 1:1 cohort was generated with patients from the same source and matched by propensity score. The primary outcomes are the change of estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) analyzed by analysis of covariance and mixed regression model adjusted for baseline eGFR, age, gender, duration of diabetes history, history of hypertension, diabetic retinopathy, and the use of insulin and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker. The rate of adverse events and the change of key biochemical parameters were analyzed. After a median of 51 weeks, patients who received add-on CM had stabilized eGFR (difference in treatment period: 0.74 ml/min/1.73m2, 95% CI: -1.01 to 2.50) and UACR (proportional difference in treatment period: 0.95, 95% CI: 0.67 to 1.34). Add-on CM was associated with significantly preserved eGFR (Inter-group difference: 3.19 ml/min/1.73m2, 95%CI: 0.32 to 6.06, [Formula: see text] 0.030) compared to standard care. The intergroup ratio of UACR was comparable (0.70, 95% CI: 0.45 to 1.08, [Formula: see text] 0.104). The result is robust in sensitivity analysis with different statistical methods, and there was no interaction with CKD stage and UACR. The rate of serious adverse events (8.1% vs. 18.9%, [Formula: see text] 0.174), moderate to severe hyperkalemia (8.1% vs. 2.7%, [Formula: see text] 0.304) and hypoglycemia (13.5% vs. 5.4%, [Formula: see text] 0.223), and the levels of key biochemical parameters were comparable between groups. The top seven most used CMs contained two classical formulations, namely Liu-wei-di-huang-wan and Si-jun-zi-tang. Individualized add-on CM was associated with significant kidney function preservation and was well tolerated. Further randomized controlled trials using CM prescriptions based on Liu-wei-di-huang-wan and Si-jun-zi-tang are warranted.

HLA-B*58:01 screening to prevent allopurinol-induced severe cutaneous adverse reactions in Chinese patients with chronic kidney disease.

Human leukocyte antigen (HLA)-B*58:01 allele is a significant risk factor for allopurinol-induced severe cutaneous adverse reactions (SCARs) which is potentially fatal. In some studies, chronic kidney disease (CKD) was also implicated to compound the risk of SCARs. We aim to investigate if pre-treatment HLA-B*58:01 screening can prevent allopurinol-induced SCARs in Chinese patients with CKD and its cost-effectiveness. We prospectively recruited Chinese CKD patients who required allopurinol during 2011-2015 and performed pre-treatment HLA testing (HLA screening group). Patients tested positive for HLA-B*58:01 were refrained from allopurinol while those tested negative were prescribed allopurinol. The incidence of SCARs in the HLA screening group was compared with the historical control in previous 5 years and the cost-effectiveness of HLA testing was analyzed. In the historical control (2006-2010), 3605 patients on allopurinol were screened, 22 out of 1027 (2.14%) CKD Chinese patients newly started on allopurinol developed SCARs, including 6 SJS/TEN. In the HLA screening group, 28 out of 192 patients (14.6%) tested HLA-B*58:01 positive were advised to avoid allopurinol; 156 out of 164 HLA-B*58:01-negative patients received allopurinol and none developed SCARs. The incidence rate of SCARs was significantly lower in the HLA screening group compared with controls (0% vs 2.14% respectively, p = 0.037*). The targeted HLA screening approach was associated with lower healthcare costs compared with no HLA screening (US$ 92,430 vs US$ 281,226). Pre-treatment HLA-B*58:01 screening is cost-effective to target on patients with CKD in Chinese to prevent allopurinol-induced SCARs.

PRAgmatic Clinical Trial Design of Integrative MediCinE (PRACTICE): A Focus Group Series and Systematic Review on Trials of Diabetes and Kidney Disease.

Background: Pragmatic trials inform clinical decision with better generalizability and can bridge different streams of medicine. This study collated the expectations regarding pragmatic trial design of integrative medicine (IM) for diabetes and kidney diseases among patients and physicians. Dissonance between users' perspective and existing pragmatic trial design was identified. The association between risk of bias and pragmatism of study design was assessed. Method: A 10-group semi-structured focus group interview series [21 patients, 14 conventional medicine (ConM) and 15 Chinese medicine (CM) physicians] were purposively sampled from private and public clinics in Hong Kong. Perspectives were qualitatively analyzed by constant comparative method. A systematic search of four databases was performed to identify existing IM pragmatic clinical trials in diabetes or kidney disease. Primary outcomes were the pragmatism, risk of bias, and rationale of the study design. Risk of bias and pragmatism were assessed based on Cochrane risk-of-bias tool and PRECIS-2, respectively. The correlation between risk of bias and pragmatism was assessed by regression models with sensitivity analyses. Results: The subtheme on the motivation to seek IM service was analyzed, covering the perceived limitation of ConM effect, perceived benefits of IM service, and assessment of IM effectiveness. Patients expected IM service to retard disease progression, stabilize concomitant drug dosage, and reduce potential side effects associated with ConM. In the systematic review, 25 studies from six countries were included covering CM, Korean medicine, Ayurvedic medicine, and western herbal medicine. Existing study designs did not include a detailed assessment of concomitant drug change and adverse events. Majority of studies either recruited a non-representative proportion of patients as traditional, complementary, and integrative medicine (TCIM) diagnosis was used as inclusion criteria, or not reflecting the real-world practice of TCIM by completely dropping TCIM diagnosis in the trial design. Consultation follow-up frequency is the least pragmatic domain. Increase in pragmatism did not associate with a higher risk of bias. Conclusion: Existing IM pragmatic trial design does not match the patients' expectation in the analysis of incident concomitant drug change and adverse events. A two-layer design incorporating TCIM diagnosis as a stratification factor maximizes the generalizability of evidence and real-world translation of both ConM and TCIM.

SYmptom-Based STratification of DiabEtes Mellitus by Renal Function Decline (SYSTEM): A Retrospective Cohort Study and Modeling Assessment.

Background: Previous UK Biobank studies showed that symptoms and physical measurements had excellent prediction on long-term clinical outcomes in general population. Symptoms and signs could intuitively and non-invasively predict and monitor disease progression, especially for telemedicine, but related research is limited in diabetes and renal medicine. Methods: This retrospective cohort study aimed to evaluate the predictive power of a symptom-based stratification framework and individual symptoms for diabetes. Three hundred two adult diabetic patients were consecutively sampled from outpatient clinics in Hong Kong for prospective symptom assessment. Demographics and longitudinal measures of biochemical parameters were retrospectively extracted from linked medical records. The association between estimated glomerular filtration rate (GFR) (independent variable) and biochemistry, epidemiological factors, and individual symptoms was assessed by mixed regression analyses. A symptom-based stratification framework of diabetes using symptom clusters was formulated by Delphi consensus method. Akaike information criterion (AIC) and Bayesian information criterion (BIC) were compared between statistical models with different combinations of biochemical, epidemiological, and symptom variables. Results: In the 4.2-year follow-up period, baseline presentation of edema (-1.8 ml/min/1.73m2, 95%CI: -2.5 to -1.2, p < 0.001), epigastric bloating (-0.8 ml/min/1.73m2, 95%CI: -1.4 to -0.2, p = 0.014) and alternating dry and loose stool (-1.1 ml/min/1.73m2, 95%CI: -1.9 to -0.4, p = 0.004) were independently associated with faster annual GFR decline. Eleven symptom clusters were identified from literature, stratifying diabetes predominantly by gastrointestinal phenotypes. Using symptom clusters synchronized by Delphi consensus as the independent variable in statistical models reduced complexity and improved explanatory power when compared to using individual symptoms. Symptom-biologic-epidemiologic combined model had the lowest AIC (4,478 vs. 5,824 vs. 4,966 vs. 7,926) and BIC (4,597 vs. 5,870 vs. 5,065 vs. 8,026) compared to the symptom, symptom-epidemiologic and biologic-epidemiologic models, respectively. Patients co-presenting with a constellation of fatigue, malaise, dry mouth, and dry throat were independently associated with faster annual GFR decline (-1.1 ml/min/1.73m2, 95%CI: -1.9 to -0.2, p = 0.011). Conclusions: Add-on symptom-based diagnosis improves the predictive power on renal function decline among diabetic patients based on key biochemical and epidemiological factors. Dynamic change of symptoms should be considered in clinical practice and research design.

Peritoneal dialysis: Status report in South and South East Asia.

BACKGROUND: Peritoneal dialysis (PD) as a modality of kidney replacement therapy (KRT) is largely underutilized globally. We analyzed PD utilization, impact of economic status, projected growth and impact of state policy(s) on PD growth in South Asia and Southeast Asia (SA&SEA) region. METHODS: The National Nephrology Societies of the region responded to a questionnaire on KRT practices. The responses were based on the latest registry data, acceptable community-based studies and societal perceptions. The representative countries were divided into high income and higher-middle income (HI & HMI) and low income and lower-middle income (LI & LMI) groups. RESULTS: Data provided by 15 countries showed almost similar percentage of GDP as health expenditure (4%-7%). But there was a significant difference in per capita income (HI & HMI -US$ 28 129 vs. LI & LMI - US$ 1710.2) between the groups. Even after having no significant difference in monthly cost of haemodialysis (HD) and PD in LI & LMI countries, they have poorer PD utilization as compared to HI & HMI countries (3.4% vs. 10.1%); the reason being lack of formal training/incentives and time constraints for the nephrologist while lack of reimbursement and poor general awareness of modalities has been a snag for the patients. The region expects ≥10% PD growth in the near future. Hong Kong and Thailand with 'PD first' policy have the highest PD utilization. CONCLUSION: Important deterrents to PD underutilization were lack of PD centric policies, lackadaisical patient/physician's attitude, lack of structured patient awareness programs, formal training programs and affordability.