Combining viral genomics and clinical data to assess risk factors for severe COVID-19 (mortality, ICU admission, or intubation) amongst hospital patients in a large acute UK NHS hospital Trust.

Throughout the COVID-19 pandemic, valuable datasets have been collected on the effects of the virus SARS-CoV-2. In this study, we combined whole genome sequencing data with clinical data (including clinical outcomes, demographics, comorbidity, treatment information) for 929 patient cases seen at a large UK hospital Trust between March 2020 and May 2021. We identified associations between acute physiological status and three measures of disease severity; admission to the intensive care unit (ICU), requirement for intubation, and mortality. Whilst the maximum National Early Warning Score (NEWS2) was moderately associated with severe COVID-19 (A = 0.48), the admission NEWS2 was only weakly associated (A = 0.17), suggesting it is ineffective as an early predictor of severity. Patient outcome was weakly associated with myriad factors linked to acute physiological status and human genetics, including age, sex and pre-existing conditions. Overall, we found no significant links between viral genomics and severe outcomes, but saw evidence that variant subtype may impact relative risk for certain sub-populations. Specific mutations of SARS-CoV-2 appear to have little impact on overall severity risk in these data, suggesting that emerging SARS-CoV-2 variants do not result in more severe patient outcomes. However, our results show that determining a causal relationship between mutations and severe COVID-19 in the viral genome is challenging. Whilst improved understanding of the evolution of SARS-CoV-2 has been achieved through genomics, few studies on how these evolutionary changes impact on clinical outcomes have been seen due to complexities associated with data linkage. By combining viral genomics with patient records in a large acute UK hospital, this study represents a significant resource for understanding risk factors associated with COVID-19 severity. However, further understanding will likely arise from studies of the role of host genetics on disease progression.

Incidence and survival of end-stage kidney disease due to polycystic kidney disease in Australia and New Zealand (1963-2014).

BACKGROUND: The aim of this study was to determine whether the incidence and survival of patients with end-stage kidney disease (ESKD) due to polycystic kidney disease (PKD) has changed in Australia and New Zealand. METHODS: Data for all PKD patients who developed ESKD and commenced renal replacement therapy (RRT) was assessed using the Australia and New Zealand Dialysis and Transplant Registry from 1963 to 2014. RESULTS: A total 4678 patients with ESKD due to PKD received RRT during the study period. The incidence rate of ESKD (per million population per year) due to PKD rose by 3.2-fold (1970-2010), but the percentage increase between each decade decreased (54.4, 43.8, 25.6 and 6.57%). The median age of onset of new patients developing ESKD has been stable since 1990. Haemodialysis was the most common initial mode of RRT (between 62 and 76% of patients) whereas 24-29% received peritoneal dialysis. The 5-year survival rate of PKD patients on RRT (censored for transplantation and adjusted for age) improved from 26 to 84%, with the percentage increase between each successive time period being 123, 7, 21, 19 and 7.4%. The percentage of deaths on RRT due to cerebrovascular disease declined from 15 to 6%. CONCLUSIONS: The incidence and age of onset of ESKD due to PKD has remained unchanged in the modern era though patient survival on RRT has continued to improve. These data suggest that the development and implementation of disease-specific treatments prior to RRT is needed to effectively diminish the incidence of ESKD due to PKD.

Renal replacement therapy in rural and urban Australia.

BACKGROUND: Australians living in rural regions have poorer health outcomes than city residents. This study compares rural and city patient access to and outcomes of renal replacement therapy (RRT) in Australia. METHODS: Non-indigenous Australians aged ≥16 years who commenced dialysis or underwent renal transplantation between 1996 and 2009 and were registered with the Australia and New Zealand Dialysis and Transplant Registry were included. Each patient's location was classified according to a remote area index as major city (MC), inner regional (IR), outer regional (OR) or remote/very remote (REM). RESULTS: A total of 24 068 commenced dialysis and 5399 received a renal transplant during the study period. Patient distribution by remote area index was 71.3 and 70.8% MC, 19.1 and 18.6% IR, 8.4 and 9.1% OR and 1.1 and 1.5% REM for dialysis and transplant patients, respectively. RRT incidence per million population after adjusting for age and gender was 124 [95% confidence interval (CI): 122-126] MC, 106 (95% CI: 103-110) IR, 100 (95% CI: 96-105) OR and 96 (95% CI: 84-109) REM. After controlling for demographic variables, comorbidities and other covariates, hazard ratios for dialysis survival compared to MC were 1.08 (95% CI: 1.03-1.14) IR, 1.19 (95% CI: 1.11-1.28) OR and 1.03 (95% CI: 0.84-1.25) REM. Transplant patient survival was not statistically different by remoteness. CONCLUSIONS: Rural Australians have lower incidence of RRT. Whether the causes of the lower RRT reflect lower disease rates or differential treatment access is not known. Differences in outcomes were seen for dialysis but not transplantation.

Acupuncture to treat primary dysmenorrhea in women: a randomized controlled trial.

We examined the effectiveness of acupuncture to reduce the severity and intensity of primary dysmenorrhea. A randomized controlled trial compared acupuncture with control acupuncture using a placebo needle. Eligible women were aged 14-25 years with a diagnosis of primary dysmenorrhea. Women received nine sessions of the study treatment over 3 months. The primary outcomes were menstrual pain intensity and duration, overall improvement in dysmenorrhea symptoms and reduced need for additional analgesia, measured at 3, 6 and 12 months from trial entry. A total of 92 women were randomly assigned to the intervention (acupuncture n = 46 and control n = 46). At 3 months although pain outcomes were lower for women in the acupuncture group compared with the control group, there was no significant difference between groups. Women receiving acupuncture reported a small reduction in mood changes compared with the control group, relative risk (RR) 0.72, 95% confidence interval (CI) 0.53-1.00, P = .05. Follow-up at 6 months found a significant reduction in the duration of menstrual pain in the acupuncture group compared with the control group, mean difference -9.6, 95% CI -18.9 to -0.3, P = .04, and the need for additional analgesia was significantly lower in the acupuncture group compared with the control group, RR 0.69, 95% CI 0.49-0.96, P = .03, but the follow-up at 12 months found lack of treatment effect. To conclude, although acupuncture improved menstrual mood symptoms in women with primary dysmenorrhea during the treatment phase, the trend in the improvement of symptoms during the active phase of treatment, and at 6 and 12 months was non-significant, indicating that a small treatment effect from acupuncture on dysmenorrhea may exist. In the study, acupuncture was acceptable and safe, but further appropriately powered trials are needed before recommendations for clinical practice can be made.

Donor human leukocyte antigen specific antibodies predict development and define prognosis in transplant glomerulopathy.

The pathogenesis of transplant glomerulopathy (TG) remains unclear, with evidence of human leukocyte antigen (HLA) antibodies as important contributors to the disease. We studied the risk factors and the associations of HLA antibodies in the development of TG. Sixty-one cases with morphologic features of TG were identified and compared with contemporaneous matched patients (without TG) from a 17-year period, all undergoing renal biopsy in a single center. Univariate risk factors for TG were previous glomerulitis [odds ratio (OR) 3.3, 95% confidence interval (95% CI) [1.2-9.4], p = 0.025), delayed graft function (OR 2.3 [1.0-5.1], p = 0.042), HLA class I presensitization defined by Luminex solid-phase immunoassays (OR 5.0 [2.3-11.0]. p < 0.001), and de novo posttransplant development of donor HLA specific antibody (DSA) (OR 4.7 [1.7-13.2], p = 0.002). Only DSA remained significantly associated with TG after adjustment (OR 3.8 [1.1-12.9], p = 0.032). DSA was detected in >50% of TG patients, suggesting HLA antibodies play a critical role in TG pathogenesis. TG patients with DSA had increased risk of graft loss (median graft survival 4.4-5.2 years), whereas patients with morphologic features of TG without DSA had similar graft survival compared with the non-TG group (median graft survival 15 years). Thus, DSA is a useful predictor for graft failure in TG patients.

Effect of donor-recipient age difference on graft function and survival in live-donor kidney transplantation.

BACKGROUND: Renal transplant recipients of older deceased-donor kidneys have reduced allograft survival. However, the impact of donor-recipient age difference on live-donor kidney transplant outcomes, where donors are older than recipients, remains unclear. METHODS: Using the Australia and New Zealand Dialysis and Transplant Registry, all primary live-donor kidney transplant recipients in Australia from 1991 to 2006 were studied. Donor-recipient age difference was divided into four categories (donor-recipient<-10, -10-20, 20-29 and ≥30 years). Outcome measures included serum creatinine, graft and patient survival. RESULTS: In the adjusted model, donor-recipient age difference of ≥30 years showed a trend towards increased risk of graft failure compared with a difference of -10-20 years during the first year post-transplant only (hazard ratio=2.11, 95% CI=1.00-4.47; P=0.05). However, in the multivariate competing risks Cox model, donor-recipient age difference was not associated with increased patient death, death-censored graft failure or serum creatinine at 5 or 10 years, nor was it associated with increased risk of acute rejection within the first 6 months. CONCLUSIONS: Recipients of kidney transplants donated by live donors who are significantly older than recipients have similar graft and patient survivals to recipients from organs of similar vintage. Thus, living kidney donors, who are up to 30 years older than their recipients, provide kidneys of excellent quality. These findings are of relevance when considering paired kidney donation programme because the chance of finding a suitable match should not be unnecessarily limited by unjustified restrictions on the perceived disadvantage of high donor-recipient age difference.

Haemodialysis outcomes of Aboriginal and Torres Strait Islander patients of remote Kimberley region origin.

OBJECTIVES: To compare the clinical outcomes and mortality rates of Aboriginal and Torres Strait Islander people of Kimberley origin receiving haemodialysis (HD) treatment with other subsets of Aboriginal and Torres Strait Islander HD patients (Northern Territory, Western Australia excluding the Kimberley region, the rest of Australia) and Australian non-Indigenous HD patients. DESIGN, PARTICIPANTS AND SETTING: Retrospective identification of Aboriginal and Torres Strait Islander patients of Kimberley origin and analysis of secondary data from the Australia and New Zealand Dialysis and Transplant Registry; this group was compared with other Australian patients receiving HD treatment from 1 January 2003 to 31 December 2007. MAIN OUTCOME MEASURES: Clinical outcome measures; comorbid conditions; death rates per 100 patient-years, unadjusted and adjusted (for age, sex, comorbid conditions, late referral to nephrologist treatment). RESULTS: Seventy per cent of HD treatments for Aboriginal and Torres Strait Islander patients of Kimberley origin was provided in the Kimberley. They had comparable adjusted mortality rates to non-Indigenous Australian patients (adjusted mortality rate ratio, 0.80; 95% CI, 0.51-1.23). CONCLUSIONS: This is the first report showing similar mortality rates for Aboriginal and Torres Strait Islander people exclusively from a remote area of Australia and non-Indigenous Australians receiving HD treatment. HD treatment delivered closer to home can be safe and effective in remote areas.

Donor-recipient age matching improves years of graft function in deceased-donor kidney transplantation.

BACKGROUND: Donor and recipient age in kidney transplantation are known to affect graft and patient survival. In deceased-donor (DD) transplantation, donor and recipient age matching are being increasingly accepted as part of the kidney allocation programme. The aims of this study are to evaluate the effect of donor and recipient age on transplant outcomes and to determine the effect of changing existing allocation criteria to allocation based on age matching of donors and recipients on total graft years of function. METHODS: Using the Australia and New Zealand Dialysis and Transplant Registry, all DD kidney transplant recipients in Australia and New Zealand between 1991 and 2006 were analysed (n = 4616). Outcomes analysed were overall graft failure, death with functioning graft and serum creatinine. We calculated the mean time to graft loss ('years of graft function') for donor and recipient age cut-offs as 60 and 55 years, respectively, over up to 16 years follow-up. We then examined the gain in graft years if all older kidneys were allocated to older recipients. RESULTS: Older donors were associated with higher risk of overall graft failure [adjusted hazard ratio (HR) = 1.79, 95% confidence interval (95% CI) = 1.45, 2.21 and HR = 1.29, 95% CI = 1.09, 1.53, respectively] at 1-8 years post-transplant and higher serum creatinine at 1 and 5 years post-transplant (mean differences 32.74 micromol/L, 95% CI 27.60, 37.89 and 38.17 micromol/L, 95% CI 27.58, 48.77, respectively). Overall, young and old recipients with young donor kidneys have an additional two to three mean graft years compared to those receiving older donor kidneys. CONCLUSION: Donor and recipient age matching is an effective method of organ allocation to improve total graft years.

Effect of interleukin-2 receptor antibody therapy on acute rejection risk and severity, long-term renal function, infection and malignancy-related mortality in renal transplant recipients.

In renal transplantation, the use of interleukin-2 receptor antibody (IL-2Ra) has been associated with reduced rejection rates, but the effect of this agent on rejection severity and type, long-term graft function and risk of infection and malignancy-related mortality remains unclear. Using Australia and New Zealand Dialysis and Transplant Registry, all live- and deceased-donor renal transplant recipients in Australia between 2000 and 2006 were included. Of the 3344 renal transplant recipients, 1874 (56.0%) received no induction and 1470 (44.0%) had received IL-2Ra. Compared with no induction, IL-2Ra was associated with reduced rejection risk (relative risk 0.70, 95% CI 0.60, 0.81) and higher estimated glomerular filtration rate at 5 years (difference in means 3.51, 95% CI 0.83, 6.19). Severity and type of rejection were similar in both the groups. The adjusted rate of death attributed to malignancy for no induction and IL-2Ra per 1000 patient-years was 1.48 and 1.63, respectively, whereas death attributed to infection was 2.42 and 2.16 respectively. This registry analysis demonstrates that IL-2Ra induction in kidney transplantation is associated with substantial clinical benefits of reduced risk of acute rejection and improved long-term graft function without an increase in adverse events.

Interleukin-2 receptor antibody does not reduce rejection risk in low immunological risk or tacrolimus-treated intermediate immunological risk renal transplant recipients.

AIM: The use of interleukin-2 receptor antibody (IL-2Ra) induction has been associated with reduced rejection rates in renal transplant recipients. However, the effect of IL-2Ra induction on graft and patient outcomes in renal transplant recipients with differing immunological risk remains unclear. METHODS: Using Australia and New Zealand Dialysis and Transplant Registry, renal transplant recipients in Australia between 1995 and 2005 were included. Recipients were stratified into low immunological risk (primary grafts with < or = 2 human leucocyte antigen (HLA)-mismatches and panel-reactive antibody (PRA) < 10%) or intermediate immunological risk (subsequent grafts or >2 HLA-mismatches or PRA > 25%) recipients. Recipients receiving T-cell depletive induction therapy or steroid and/or calcineurin-free inhibitor regimens were excluded. Outcomes analysed included the presence of rejection at 6 months, estimated glomerular filtration rate at 1 and 5 years, graft and patient survival. RESULTS: 218 of 1220 (18%) low-risk and 883 of 3204 (28%) intermediate-risk recipients received IL-2Ra. In intermediate-risk recipients, IL-2Ra induction was associated with a 26% reduction in the incidence of acute rejection; but this benefit was restricted only to recipients initiated on cyclosporine-based immunosuppressive regimens. In contrast, the use of IL-2Ra in low-risk recipients was not associated with reduced rejection risk. There was no association between IL-2Ra induction and other graft or patient outcomes in both low- and intermediate-risk recipients. CONCLUSION: This registry analysis suggests that IL-2Ra induction may be associated with a reduction in rejection risk in cyclosporine-treated intermediate immunological risk recipients, but not in low-risk renal transplant recipients.

Reduction in cardiovascular death after kidney transplantation.

BACKGROUND: Cardiovascular (CVS) disease is the commonest cause of death after kidney transplantation. In the general population, CVS mortality has reduced significantly over the last two decades; however, this trend has not been specifically examined in the kidney transplant population. METHODS: We studied all patients in Australia and New Zealand with a functioning kidney transplant between 1980 and 2007 and examined trends in the cause and timing of all 2195 deaths recorded after kidney transplantation in the Australia and New Zealand Dialysis and Transplant registry. Poisson regression was used to compare death rates over the time periods. RESULTS: CVS events were the commonest cause of death throughout all the time points examined; however, CVS death rates significantly decreased with an adjusted risk ratio of 0.61 (95% confidence interval, 0.38-0.96; P=0.034) for 2005 to 2007 era. In comparison, death rates due to malignancy have increased significantly over this period. Decreased CVS death rates have occurred despite increasing comorbidity at the time of transplantation. Factors associated with CVS death were older recipient age, preexisting CVS disease, and diabetes mellitus. There was a significantly lower CVS death rate in patients with a glomerular filtration rate >48 mL/min compared with those with poor renal function (risk ratio, 0.66; 95% confidence interval, 0.45-0.95; P=0.024). CONCLUSIONS: These trends suggest improvements in CVS risk management and outcomes in the kidney transplant population in Australia and New Zealand.

Interleukin-2 receptor antibody reduces rejection rates and graft loss in live-donor kidney transplant recipients.

BACKGROUND: The use of interleukin-2 receptor antibody (IL-2Ra) induction has been associated with reduced rejection rates in both live and deceased donor kidney transplantation. However, the longer term effect of IL-2Ra induction on estimated glomerular filtration rates and graft and patient survival remains unclear. METHODS: Using Australia and New Zealand Dialysis and Transplant Registry, live donor renal transplant recipients in Australia between 2001 and 2005 were studied (n=1106). Multiple organ graft recipients and those receiving T-cell depletive induction therapy or steroid- or calcineurin-free inhibitor regimens were excluded. Outcomes analyzed included the presence of rejection at 6 months, estimated glomerular filtration rate at 1 and 3 years, 5 years graft and patient survival. RESULTS: A total of 41.7% of live donor renal transplant recipients received IL-2Ra induction. Recipients of IL-2Ra experienced a 51% reduction in the incidence of acute rejection (odds ratio 0.49, 95%CI 0.36-0.67; P<0.001). In addition, the use of IL-2Ra was associated with reduced overall graft loss (hazard ratio 0.58, 95%CI 0.35-0.96; P=0.03) and higher mean estimated glomerular filtration rate at 1 year but not 3 years. There was no association between IL-2Ra induction and death-censored graft loss or death with functioning graft. CONCLUSION: This registry analysis demonstrates that IL-2Ra induction in live donor kidney transplantation is associated with substantial clinical benefits of reduced risk of acute rejection, improved short-term graft function, and reduced graft loss.

Association of dialysis modality and cardiovascular mortality in incident dialysis patients.

BACKGROUND AND OBJECTIVES: The aim of the investigation presented here was to compare the rates, causes, and timing of cardiovascular (CV) death in incident peritoneal dialysis (PD) and hemodialysis (HD) patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The study included all adult Australian and New Zealand patients commencing dialysis between January 1, 1997 and December 31, 2007. Rates of and times to CV death were compared by incident rate ratios, cumulative incidence, and multivariable Cox proportional hazards model analyses. Dialysis modality was included in the model as a time-varying covariate, and a competing risks approach was used to obtain cause-specific hazard ratios. RESULTS: Of the 24,587 patients who commenced dialysis (first treatment PD n = 6521; HD n = 18,066) during the study, 5669 (21%) died from CV causes [PD 2044 (28%) versus HD 3625 (21%)]. The incidence rates of CV mortality in PD and HD patients were 9.99 and 7.96 per 100 patient-years, respectively (incidence rate ratio PD versus HD, 1.25; 95% confidence interval 1.12 to 1.32). PD was consistently associated with an increased hazard of CV death compared with HD after 1 yr of treatment. This increased risk in PD patients was largely accounted for by an increased risk of death due to myocardial infarction. CONCLUSIONS: Dialysis modality is significantly associated with the risk, causes, and timing of CV death experienced by ESRD patients in Australia and New Zealand.

Frequencies of hepatitis B and C infections among haemodialysis and peritoneal dialysis patients in Asia-Pacific countries: analysis of registry data.

BACKGROUND: The impact of dialysis modality on the rates and types of infectious complications has not been well studied. The aim of the present investigation was to evaluate the rates of hepatitis C virus (HCV) and hepatitis B virus (HBV) infections in peritoneal dialysis (PD) and haemodialysis (HD) patients in the Asia-Pacific region. METHODS: The study included the most recent period-prevalent data recorded in the national or regional dialysis registries of the 10 Asia-Pacific countries/areas (Australia, New Zealand, Japan, China, Taiwan, Korea, Thailand, Hong Kong, Malaysia and India), where such data were available. Longitudinal data were also available for all incident Australian and New Zealand patients commencing dialysis between 1 April 1995 and 31 December 2005. Rates of HCV and HBV infections were compared by chi-square, Poisson regression and Kaplan-Meier survival analyses, as appropriate. RESULTS: Data were obtained on 201,590 patients (HD 173,788; PD 27,802). HCV seroprevalences ranged between 0.7% and 18.1% across different countries and were generally higher in HD versus PD populations (7.9% +/- 5.5% versus 3.0% +/- 2.0%, P = 0.01). Seroconversion rates on dialysis were also significantly higher in HD patients (incidence rate ratio PD versus HD 0.33, 95% CI 0.13-0.75). HCV infection was highly predictive of mortality in Japan (relative risk 1.37, 95% CI 1.15-1.62, P = 0.003) and in Australia and New Zealand (adjusted hazards ratio 1.29, 95% CI 1.05-1.58). HBV infection data were limited, but less clearly influenced by dialysis modality. CONCLUSIONS: Dialysis modality selection significantly influences the risk of HCV infection experienced by end-stage renal failure patients in the Asia-Pacific region. No such association could be identified for HBV infection.

Associations of dialysis modality and infectious mortality in incident dialysis patients in Australia and New Zealand.

BACKGROUND: The aim of the present investigation is to compare rates, types, causes, and timing of infectious death in incident peritoneal dialysis (PD) and hemodialysis (HD) patients in Australia and New Zealand. STUDY DESIGN: Observational cohort study using the Australian and New Zealand Dialysis and Transplant Registry data. SETTING & PARTICIPANTS: The study included all patients starting dialysis therapy between April 1, 1995, and December 31, 2005. PREDICTOR: Dialysis modality. OUTCOMES & MEASUREMENTS: Rates of and time to infectious death were compared by using Poisson regression, Kaplan-Meier, and competing risks multivariate Cox proportional hazards model analyses. RESULTS: 21,935 patients started dialysis therapy (first treatment PD, n = 6,020; HD, n = 15,915) during the study period, and 1,163 patients (5.1%) died of infectious causes (PD, 529 patients; 7.6% versus HD, 634 patients; 4.2%). Incidence rates of infectious mortality in PD and HD patients were 2.8 and 1.7/100 patient-years, respectively (incidence rate ratio PD versus HD, 1.66; 95% confidence interval [CI], 1.47 to 1.86). After performing competing risks multivariate Cox analyses allowing for an interaction between time on study and modality because of identified nonproportionality of hazards, PD consistently was associated with increased hazard of death from infection compared with HD after 6 months of treatment (<6 months hazard ratio [HR], 1.08; 95% CI, 0.76 to 1.54; 6 months to 2 years HR, 1.31; 95% CI, 1.09 to 1.59; 2 to 6 years HR, 1.51; 95% CI, 1.26 to 1.80; >6 years HR, 2.76; 95% CI, 1.76 to 4.33). This increased risk of infectious death in PD patients was largely accounted for by an increased risk of death caused by bacterial or fungal peritonitis. LIMITATIONS: Patients were not randomly assigned to their initial dialysis modality. Residual confounding and coding bias could not be excluded. CONCLUSIONS: Dialysis modality selection significantly influences risks, types, causes, and timing of fatal infections experienced by patients with end-stage kidney disease in Australia and New Zealand.