Background Genome sequencing (GS) has revolutionised the diagnostic odyssey of patients with rare genetic diseases (RDs) and accelerated large-scale genome projects globally. However, the impact of GS on patients with RDs is yet to be investigated among genome projects in Asia. The Hong Kong Genome Project (HKGP) was implemented to benefit patients and families with RDs in Hong Kong, and to increase the inclusiveness of Chinese genomic data. This study evaluated the impact of short read GS (srGS), complemented by long read GS (lrGS) in a subset, on individuals recruited in the pilot phase of the HKGP. Methods GS was performed on a prospective cohort of patients with suspected genetic disease recruited by territory- wide referrals to the HKGP. All participants received srGS, while lrGS was applied to a subset to resolve technically challenging regions unclear from srGS and provide phasing information for potential compound heterozygous variants. A phenotypic-driven diagnostic workflow was implemented to filter and prioritise rare and likely disease- causing variants. The primary outcome was diagnostic yield. The impact on the diagnostic odyssey and clinical management was also assessed. Findings A total of 1264 individuals from 520 families with a broad spectrum of RDs were recruited, with 94% of probands being Chinese. srGS was performed for all individuals and lrGS was performed in 21 individuals. The use of srGS achieved a molecular diagnosis in 24% (125/520) of probands, and an additional 4% (21/520) with the assistance from lrGS. Approximately one-third of the identified diagnostic variants being novel. Diagnostic yield was found to be significantly higher among adult probands compared to paediatric probands (32% vs 24%; p = 0.025). The diagnostic yield was significantly higher in probands without prior genetic testing (37%; n = 185) compared to those previously tested, including exome and genome sequencing (23%; n = 335) (p = 0.001). GS ended diagnostic odysseys with an average length of 15 years (0.5-59), and potentially impacted clinical management in 77% (113/146) of diagnosed probands. Interpretation This population-based genome project shed light on the consideration of integrating srGS and lrGS in clinical workflows for RDs. The identification of unique and prevalent variants from Southeast Asia increased the inclusiveness of Chinese genomic data, contributing to greater representation and genomic diversity.

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.

Abstract Background and Aims Genetic testing has increasingly been employed to provide definitive diagnoses and prognostic information in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD). We aim to explore the genetic landscape of ADPKD in a Chinese cohort utilizing whole genome sequencing and study its real-world clinical utility. Method From 1st January 2022 to 31st March 2023, we recruited 50 adult Chinese patients who had the clinical diagnosis of ADPKD followed up at Queen Mary Hospital and consented to the study protocol. The study was approved by the University Institution Review Board and local ethics committees. Genomic DNA was isolated from samples obtained from patients per standard protocol. Whole-genome sequencing was performed and analysed through the germline analysis pipeline. Diagnostic analysis was performed per American College of Medical Genetics (ACMG) guidelines and ClinGen variant curation expert panel specifications. Diagnostic variants were defined as those classified as ‘pathogenic’ or ‘likely pathogenic’. Potential clinical utility of genetic findings were studied case-by-case based on the Kidney Disease Improving Global Outcomes (KDIGO) 2023 Clinical Practice Guideline for the Evaluation, Management and Treatment of ADPKD. Results Among the 50 unrelated probands with ADPKD, half were males and the mean age at presentation was 38. 38% patients had incidental finding of kidney cysts on abdominal imaging performed for unrelated symptoms or health screening, 32% presented for screening due to positive family history and only 30% presented with typical symptoms of ADPKD. Cystic complications were present in 30%, with cyst haemorrhage being the most common, followed by kidney stones, cyst rupture and infection. 80% patients also had liver cysts and none had a history of cerebral aneurysms. The majority of our cohort (72%) had a family history of ADPKD. We identified diagnostic variants in 35 individuals, reaching a diagnostic yield of 70%. Diagnostic variants were identified in PKD1 (20/35), PKD2 (11/35), IFT140 (3/35) and ALG9 (1/35). The majority of diagnostic variants were protein-truncating (32/35), while non-truncating variants consisted of 1 in-frame deletion and 2 missense variants in PKD1. We identified 3 copy number variation:NC_000016.10:g.2110587_2111851del,NC_000016.10:g.2132339_2137621del,NC_000016.10:g.2036427_2101117del. The genetic findings allowed physicians to make definitive diagnosis in 9 patients with negative family history of ADPKD. The genetic findings provided important prognostic information as protein-truncating variants in PKD1 or PKD2 were associated with more severe disease compared to non-truncating variants. For the 3 patients harbouring heterozygous pathogenic variants in IFT140 (NM_014714.4:c.2659G>T, NM_014714.4:c.3780del, NM_014714.4:c.1035_1036del), they demonstrated a milder PKD phenotype with stable kidney function, normal kidneys size and absence of liver cysts 10 years after the diagnosis. The patient with heterozygous likely pathogenic ALG9 variant (NM_024740.2:c.1225del) also had milder PKD phenotype with normal kidney function and normal sized kidneys on USG 5 years after the diagnosis. In another male patient with young hypertension who was classified as Mayo Class 1C according to kidney imaging, identifying the pathogenic protein-truncating variant in PKD1 (NM_001009944.3:c.7288C>T) would render him eligible to tolvaptan treatment in view of the high PROPKD score (7). Furthermore, the genetic findings enabled an earlier diagnosis in a number of family members by cascade testing and genetic results were important to identify suitable living-related kidney donors. Conclusion Genetic testing utilizing whole genome sequencing has multiple clinical utility in ADPKD patients. It could provide a definitive diagnosis in those with atypical presentation or without family history, inform prognosis, guide treatment, determine living-related donor suitability and allow earlier diagnosis in other family members.

Introduction It remains unclear how the presence of renal involvement will affect the cardiovascular (CV) risk factors and complications in patients with SLE.Methods We conducted a systematic review and meta-analysis using PubMed, EMBASE, MEDLINE and Scopus to identify studies published between 1947 and 2022 that evaluate the CV risk factors and complications in patients with SLE with or without lupus nephritis (LN).Results 58 studies were evaluated, with 22 two-arm studies (n=8675) included in two-arm meta-analysis and 45 studies (n=385 315) included in proportional meta-analysis. Patients with SLE with LN showed significantly higher risk of hypertension (HT) (OR=4.93, 95% CI=3.17 to 7.65, p<0.00001, I2=56%), hyperlipidaemia (OR=11.03, 95% CI=4.20 to 28.95, p<0.00001, I2=0%) and diabetes mellitus (DM) (OR=1.88, 95% CI=1.09 to 3.25, p=0.02, I2=32%) compared with those without LN. Patients with LN showed numerically higher prevalence of myocardial infarction (OR=1.35, 95% CI=0.53 to 3.45, p=0.52, I2=78%) and cerebrovascular accident (OR=1.64, 95% CI=0.79 to 3.39, p=0.27, I2=23%) than general patients with SLE. The incidence rates of CV mortality are also increased in patients with SLE with LN compared with those without LN (11.7/1000 patient-years vs 3.6/1000 patient-years).Conclusion Patients with SLE with LN show increased risk of CV risk factors including DM, HT and hyperlipidaemia. Early identification and optimal control of these CV risk factors may reduce the risk of CV disease and other non-CV complications.PROSPERO registration number CRD42022314682.

Background: Previous multinational studies of COVID-19 infections in kidney transplant recipients (KTX) from Asia suggest that the mortality rate is similar to that experienced in the West despite a younger population with lesser comorbidities. However, these studies were performed during the era where vaccination and better therapeutics for COVID-19 were not available. This multinational study from Asia seek to determine whether mortality of COVID-19 infected KTX have improved with different eras in vaccination and therapies. Method: Data of 657 KTX from 15 transplant centres in Singapore (n=196), Philippines (n=115), Mongolia (n=106), Malaysia (n=86), India (n=67), Bangladesh (n=53), Indonesia (n=21), Brunei (n=9), South Korea (n=3) and Hong Kong (n=1) were obtained to determine the effect of COVID-19 era (2022 vs. 2020-2021), country’s economic status according to the new World Bank country classification system, vaccination status (vaccinated vs. non-vaccinated), number of vaccine doses given (3 dose vs. 1-2 doses) and new COVID-19 therapeutics that are known to prevent disease progression (Remdesivir and SARS-CoV-2 monoclonal antibodies) on mortality from COVID-19 infection. Results: Mortality from COVID-19 infection in KTX has improved over the last 3 eras (30.3% in 2020 vs. 16.7% in 2021 vs. 0% for first 3 months of 2022; P<0.005) and was lowest among high income nations vs. lower income nations in Asia (0.5% vs. 20.9%; p<0.005). Mortality among vaccinated KTX was lower than non-vaccinated KTX (5.1% vs. 32.4%; p<0.005) as well as among those who received 3 doses versus those who received 0-2 doses of vaccine (3.2% vs. 21.4%; p<0.005). There was no significant difference in mortality in KTX who received Remdesivir vs. those who did not (16.9% vs. 12.7%; p=0.128) but mortality was lower among those received SARS-CoV2 monoclonal antibodies (0% vs. 16.8%; p<0.005). On multivariate analysis, low income nation status (OR 21.5; 95% CI 2.82-163.7) and 3 vaccine dose status (OR 0.24; 95% CI 0.11-0.53) were factors significantly associated with mortality. Conclusion: This multinational study suggest that mortality has improved over time and with the introduction of COVID-19 vaccines and SARS-CoV-2 monoclonal antibody therapies. Receiving 3 doses of COVID-19 vaccine was associated with lower mortality while lower income nation status was associated with higher mortality. These findings suggest that increasing vaccine doses and improving pandemic response capabilities of healthcare systems are important in reducing death from COVID-19. The Asian Transplant Registry Group include the leadership and support from Dr Romina Danguilan, Dr Rose Marie Liquete, Dr Lkhaakhuu Od-Erdene, Dr Rosnawati Yahya, Dr Devinder Singh Rana, Dr Harun Ur-Rashid, Dr Lim Soo Kun, Dr Maggie Ma Kam Man and Dr Curie Ahn from the Philippines, Mongolia, Malaysia, India, Bangladesh, Hong Kong and South Korea respectfully.

Hepatitis B virus (HBV), influenza, pneumococcus and herpes zoster are important infections which could result in significant morbidity and mortality in patients with chronic kidney disease (CKD). While seroconversion rates after vaccination are often lower in CKD patients compared with healthy adults due to impaired innate and adaptive immunity, vaccinations for HBV, influenza, pneumococcus and herpes zoster are generally effective in reducing the transmission and/or severity of these infections. Practical issues that have an impact on the efficacy of vaccination in the CKD population include the timing, dose, schedule of vaccination, the route of administration, and adjuncts applied at time of vaccination. This review discusses the vaccination regimens and the efficacy of HBV, influenza, pneumococcus and zoster vaccines in CKD patients, and highlights recent advances in enhancing vaccine seroconversion rates.

Background : Asia is the global epicenter of the coronavirus disease 2019 (COVID-19) pandemic; however, COVID-19-related mortality in Asia remains lower than in other parts of the world. It is uncertain whether the mortality of COVID-19-infected kidney transplant recipients (KTXs) from Asia follows the lower mortality trends of the younger Asian population. Methods : Specific transplant centers from countries in the Asian Society of Transplantation were invited to participate in a study to examine the epidemiology, clinical features, natural history, and outcomes of COVID-19 infections in KTXs. Data were analyzed and compared with those of large cohort studies from other countries. Results : The study population was 87 KTXs from nine hospitals in seven Asian countries. Within the study population, 9% were aged 60 years and older, and 79% had at least one comorbidity. The majority of patients (69%) presented with mild-to-moderate COVID-19 severity. Disease progression was more frequently encountered among those with moderate or severe infection (23%) and non-survivors (55%). The mortality rate was 23% (n=20) and differed according to the level of care: 12% (n=1/8), 15% (n=10/67), and 100% (n=9/9) of patients managed as outpatients, in the general ward, and in the intensive care unit, respectively. Disease severity at the time of presentation was an independent predictor of mortality. Compared with the mortality rates in other studies worldwide, mortality rates in the current study were comparable. Conclusions: Mortality in Asian KTXs who were infected with COVID-19 remains high and could be related to comorbidity burden and the constraints of the general healthcare system when the COVID-19 caseload is high.

Introduction: Chronotropic incompetence (CI) has been accepted as an independent predictor of cardiovascular event and overall mortality. We previously reported that CI was associated with poorer exercise tolerance and greater left ventricular mass in asymptomatic kidney transplant recipients. This study aimed to investigate the long-term outcome of kidney transplantation recipients with chronotropic incompetence Materials and Methods: All recruited patients underwent transthoracic echocardiogram and treadmill stress test using modified Bruce protocol. CI was defined by either a low percent heart rate reserve achieved or failure to achieve 85% maximal age-predicted heart rate. Left ventricular hypertrophy (LVH) was defined according to American Society of Echocardiography classification. Results and Discussion: 38 renal transplant recipients (21 male and 17 female, mean age 51.7±8.8 years), were followed for median of 9.2 years (interquartile range 8.7-9.3 years). 10 (47.4%) had CI alone (LVH-/CI+) and 7 (18.4%) had CI with commitment LVH (LVH+/CI+). 3 more (7.9%) had LVH alone but no CI (LVH+/CI-). 18 (47.4%) had neither CI nor LVH. 7 patients died during follow-up. Causes of death were infection (n=3), cardiovascular (n=1), malignancy (n=1) and unknown (n=2). The 5-year patient survival of LVH+/CI+, LVH-/CI+ were both 100%, whereas that of LVH+/CI- and LVH-/CI- were 66.7%, and 94% respectively (Figure 1A). 3 patients had graft failure during follow-up. Causes of graft failure were diabetic nephropathy (n=1), IgA nephropathy (n=1) and death with functional graft (n=1). The 5-year patient survival of LVH+/CI+, LVH-/CI+ were 85.7% and 90%, whereas that of LVH+/CI- and LVH-/CI- were 66.7% and 100% respectively (Figure 1B).Conclusion: Asymptomatic kidney transplantation recipients with chronotropic incompetence had excellent long-term graft and patient survival. Presence of LVH adversely impact on survival outcome. References: 1. Brubaker PH, Kitzman DW. Chronotropic incompetence: causes, consequences, and management. Circulation. 2011;123:1010-20. 2. Ma MK, Zuo ML, Yap DY, et al. Chronotropic incompetence, echocardiographic abnormalities and exercise intolerance in renal transplant recipients. J Nephrol. 2014;27:451-6. 3. Rao NN, Coates PT. Cardiovascular Disease After Kidney Transplant. Semin Nephrol. 2018;38:291-7. 4. Shirali AC, Bia MJ. Management of cardiovascular disease in renal transplant recipients. Clin J Am Soc Nephrol. 2008;3:491-504. 5. Kasiske BL, Chakkera HA, Roel J. Explained and unexplained ischemic heart disease risk after renal transplantation. J Am Soc Nephrol. 2000;11:1735-43. 6. Lauer MS, Okin PM, Larson MG, Evans JC, Levy D. Impaired heart rate response to graded exercise. Prognostic implications of chronotropic incompetence in the Framingham Heart Study. Circulation. 1996;93:1520-6. 7. Adabag AS, Grandits GA, Prineas RJ, et al. Relation of heart rate parameters during exercise test to sudden death and all-cause mortality in asymptomatic men. Am J Cardiol. 2008;101:1437-43. 8. Sacre JW, Franjic B, Jellis CL, Jenkins C, Coombes JS, Marwick TH. Association of cardiac autonomic neuropathy with subclinical myocardial dysfunction in type 2 diabetes. JACC Cardiovasc Imaging. 2010;3:1207-15.

Clinical outcomes of COVID‐19 vary considerably between patients. Little was known about the clinical course and optimal management of immunosuppressed patients infected with SARS‐CoV‐2. We report a kidney transplant recipient with COVID‐19 who presented with pneumonitis and acute kidney injury (AKI). She improved after reduction of immunosuppressive treatment and had two consecutive negative reverse transcription polymerase chain reaction (RT‐PCR) tests. Her respiratory tract samples turned positive again afterwards, and she was treated with lopinavir‐ritonavir. She had satisfactory virological and clinical response after a prolonged disease course. This case illustrates the risk of relapse or persisting shedding of SARS‐CoV‐2 in immunosuppressed patients, the important role of viral load monitoring in management, the challenges in balancing the risks of COVID‐19 progression and transplant rejection, and the pharmacokinetic interaction between immunosuppressive and antiviral medications.