Academic literature on the topic 'Kidney Cancer'

Kidney cancer is a malignant disease that affects a large number of adults around the world. The kidneys are paired organs, extremely important for the normal functioning of the body. Each person has two kidneys, left and right, located along the spine and below the ribs. The kidneys are the main filters in the human body and perform multiple functions. They are responsible for fluid control, excretion of toxins, mineral salts, production of the hormone erythropoietin which stimulates the production of red blood cells. Each kidney works independently and a person can live with one kidney. When the kidneys are severely damaged, this leads to the need for dialysis. Kidney tumor refers to abnormal tissue growth within the kidney, and can be benign or malignant. This disease affects men more often than women aged 55 to 75 years. The disease develops within one or both kidneys, while in an advanced stage it spreads to the lymph nodes and bloodstream. It is important to know that early diagnosis and effective methods can help treat this type of cancer.

Kidney cancer is a very dangerous and lethal cancerous disease caused by kidney tumors or by genetic renal disease, and very few patients survive because there is no method for early prediction of kidney cancer. Early prediction of kidney cancer helps doctors start proper therapy and treatment for the patients, preventing kidney tumors and renal transplantation. With the adaptation of artificial intelligence, automated tools empowered with different deep learning and machine learning algorithms can predict cancers. In this study, the proposed model used the Internet of Medical Things (IoMT)-based transfer learning technique with different deep learning algorithms to predict kidney cancer in its early stages, and for the patient’s data security, the proposed model incorporates blockchain technology-based private clouds and transfer-learning trained models. To predict kidney cancer, the proposed model used biopsies of cancerous kidneys consisting of three classes. The proposed model achieved the highest training accuracy and prediction accuracy of 99.8% and 99.20%, respectively, empowered with data augmentation and without augmentation, and the proposed model achieved 93.75% prediction accuracy during validation. Transfer learning provides a promising framework with the combination of IoMT technologies and blockchain technology layers to enhance the diagnosing capabilities of kidney cancer.

Kidney cancer is a disease in which kidney cells become malignant and grow uncontrollably, forming a mass or tumor. Before discussing further kidney cancer, it is important to briefly know the kidneys. The kidneys are two bean-shaped organs located in the lower abdomen on the left and right of the spine. The primary function of the kidneys is to excrete and excrete water, salt, and other unnecessary substances and turn them into urine. The urine collects in the renal pelvis (the funnel-shaped part of each kidney), then travels to the ureters (the tube between the kidneys and bladder), and finally to the bladder, where it is stored before urination. Another function of the kidneys is to help control blood pressure by making the renin hormone and forming red blood cells by forming the hormone erythropoietin. In the United States, an estimated 76,080 adults were diagnosed with kidney cancer, and 13,780 of them died from the disease in 2021. Meanwhile, a total of 2,394 new cases of kidney cancer were found in Indonesia with 1,358 total deaths in 2020. More than half of patients with kidney cancer are diagnosed at an advanced stage.

The 2022 ASCO Genitourinary Cancers Symposium took place in San Francisco between February 17-19th. As always, the scientific program contained several exciting abstracts with a focus on prostate cancer, bladder cancer, and kidney cancer. Here we will highlight key abstracts related to kidney cancer/renal cell carcinoma presented at this year’s symposium.

An estimated 38,890 Americans will be diagnosed with kidney cancer and 12,840 will die of this disease in the United States in 2006. Renal cell carcinoma (RCC) constitutes approximately 2% of all malignancies, with a median age at diagnosis of 65 years. Smoking and obesity are among the risk factors for RCC development, and tumor grade, local extent of the tumor, presence of regional nodal metastases, and evidence of metastatic disease at presentation are the most important prognostic determinants of 5-year survival. These guidelines discuss evaluation, staging, treatment, and management after treatment. For the most recent version of the guidelines, please visit NCCN.org

Introduction Chronic kidney disease (CKD) is a common and important public health problem, with significant impact on the person’s quality of life and chances of survival. Cardiovascular disease is major cause of morbidity and mortality among people with CKD. Cancer is also a well-recognised complication in people on dialysis and with kidney transplants, but has not been adequately assessed in people with mild to moderately reduced kidney function. It is uncertain whether the basis of such increased risk in the end-stage kidney and transplant populations is solely related to their immunocompromised health states, or there are plausible biological reasons to explain the association beyond current knowledge. Screening, which allows early detection and subsequent treatment, is effective in reducing cancer-related deaths for common cancer such as breast, colorectal and cervical cancers in the general population. Given the inherent differences in the overall cancer risk and life expectancy among people with CKD, it is plausible that the effects, costs, and harms of routine population cancer screening may be different to the general population. This thesis is presented as published work on the theme of cancer and chronic kidney disease. The first chapter summarises the existing epidemiological evidence of association between cancer and kidney transplantation. The second chapter, uses data from the Blue Mountain Eyes Study cohort and linkage with the New South Wales Central Cancer Registry, explores the hypothesis of increased cancer risk in people with mild to moderately reduced kidney function. The work presented in the last five chapters of this thesis have extrapolated, critically appraised, and synthesized the available evidence for cancer screening in the general, end-stage kidney disease and kidney transplant populations.

Cancer impacts people with kidney failure in multiple ways, however, we still do not fully understand the epidemiology of cancer mortality, feasibility of cancer screening and probability of cancer transmission in organ donation and transplant. This thesis aims to understand the impact of cancer on outcomes for people with kidney failure, utilising existing clinical and health administrative datasets in novel ways. Where existing data is unavailable, it generates new information. Methods: Chapters 2 and 3 estimate cancer mortality in people on dialysis and kidney transplant recipients, compared to the general population, in a bi-national data-linkage study, 1980-2013. Chapters 4 and 5, estimate the prevalence of anal cytological abnormalities and HPV DNA in kidney transplant recipients and, evaluates the acceptability of anal cancer screening intervention, in a cross-sectional study. Chapter 6 and 7 describe a population-based data-linkage study that aims to improve estimates of disease transmission risk in solid organ donation. They explore how real-time data access could support decision making at referral by comparing agreement between suspected and verified risk of melanoma in solid organ donor referrals and tabulated them against donation outcomes, to identify potential missed opportunities for donation. Results: People with on dialysis for kidney failure and kidney transplant recipients experience two- and three-times excess deaths from all-site cancer, respectively, compared to the general population. The relative risk of cancer death was highest for urinary related cancers in people on dialysis and immune related cancers in kidney transplant recipients. Although relative mortality has decreased over time for people on dialysis, this has not reached general population levels. Relative mortality in kidney transplant recipients, remains unchanged. Prevalence of anal cancer precursors in kidney transplant recipients was higher than other immune-compromised populations. An anal cancer screening intervention may be well received in this population. Less than 1% of solid organ donor were suspected of melanoma at referral, however over two-thirds were not verified. Acceptance of these donors would have increased the donor pool by 2%. Conclusion: The impact of cancer in people with kidney failure is reflected in their increased risk of cancer mortality compared to the general population and the limitation of deceased donor kidneys available due to misclassified cancer transmission risk. Concerted efforts at an individual, risk-based approach to cancer prevention, including targeted screening programs, and guideline-based assessment of deceased donor cancers may improve cancer outcomes in this population.

Based on figure from American Association for Cancer Research (2010) & Global Cancer Statistics (2011), Liver cancer (HCC) is the sixth most frequently diagnosed cancer globally and third leading cause of cancer death (Jemal, A. et al., 2011; Jemal, A., Center, M. M., DeSantis, C. et al., 2010). In Hong Kong, Liver Cancer caused 1488 deaths in 2009 in total; it is 2nd and 4th leading killer of cancer death among Hong Kong male and female respectively (Hong Kong Cancer Registry, 2010). However, surgical resection for HCC remains as mainstream treatment modality and extensive studies on post-operative surgical outcomes for different HCC treatment modalities have been published. Nevertheless, the influence of kidney function on surgical outcomes on HCC patient stays novel and it emerges a need to explore on the relation. This study aims to compare the surgical outcomes of post hepatectomy HCC patients between reduced kidney function and normal kidney function in terms of (1) Length of hospital stay, (2) Survival rate, (3) Hospital Mortality and (4) Overall post operative complications. The kidney function can be reflected by the glomerular filtration rate (Thomas, R., Stanley, B. & Datta, S., 2007; Daugirdas, J. T., 2011). The direct measurement of GFR is a complicated and expensive procedure, which is not clinical possible to screen every patient. Thus this study adopted modified Cockcroft- Gault (CG) Formula, one type of creatinine based glomerular filtration rate estimation formulas with normalization to body surface area. Modified CG formula calculate the estimated glomerular filtration rate (eGFR) based on age, body weight, body height, gender and serum creatinine level (Himmelfarb, J. & Sayegh, M. H., 2010; Daugirdas, J. T., 2011; Joanna, Q. H. & Heather A. N., 2011). The eGFR of 452 HCC patients with major hepatectomy was evaluated and categorized into different kidney function groups according to the chronic kidney disease staging system suggested by K/DOQI, National Kidney Foundation. Hence, the surgical outcomes from different kidney function groups are analyzed and compared. Length of hospital stay was analyzed by Kruskal-Wallis Test. Hospital mortality and incidences of post-op complication are analyzed by Chi-square test. Lastly, the survival rate is analyzed by Kaplan-Meier Log rank test; the result is presented in form of survival curve, then 5-year survival rate of different group of samples are obtained and compared. Result of the study shows no evidence that patients with chronic kidney disease will have a longer hospital stay and more prone to surgical complications post operatively. However, it is indicated that the hospital mortality is associated with the severity of kidney function reduction and suggested that patients with chronic kidney disease are at higher risk of post-operative death than those with normal kidney. Patient with severe reduction of kidney function should be aware of high foreseeable chance of death after the surgery and special caution need to be taken. Surprisingly, the result revealed that the overall survival improves with the severity of kidney function reduction and the patients with worse kidney function are more likely to have a better survival. Nevertheless, the result on survival rate suspected to be biased by possible confounders and underlying co-morbidities of samples. In conclusion, eGFR formula is recommended in clinical estimation of kidney function for the patients. Also, it is suggested that HCC patients with reduced kidney function are more susceptible to hospital death after hepatectomy than normal individuals. Thus, cautious consideration and risk analysis before operation is particularly crucial for HCC patient with chronic kidney disease.
published_or_final_version
Medicine
Master
Master of Medical Sciences

Thesis (Ph. D.)--University of Sydney, 2006.
Title from title screen (viewed 21 May 2007). Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the School of Public Health, Faculty of Medicine. Includes bibliographical references. Also available in print form.

Background: Prostate cancer is the most common cancer in Sweden with around 10,000 new cases every year. Kidney and bladder cancer are less common with 1,000 and 2,000 new cases annually, respectively. The incidence of these cancer sites is higher in developed, than in developing countries, suggesting an association between lifestyle and cancer risk. The aims of this thesis were to investigate body mass index (BMI), blood pressure, and blood levels of glucose, total cholesterol, and triglycerides as risk factors for prostate, kidney, and bladder cancer. Furthermore, we aimed at assess probabilities of prostate cancer and competing events, all-cause death, for men with normal and high levels of metabolic factors. Material and methods: This thesis was conducted within the Metabolic Syndrome and Cancer project (Me-Can), a pooled cohort study with data from 578,700 participants from Norway, Sweden, and Austria. Data from metabolic factors were prospectively collected at health examinations and linked to the Cancer and Cause of Death registers in each country.  Results: High levels of metabolic factors were not associated with increased risk of prostate cancer, but high levels of BMI and blood pressure were associated with risk of prostate cancer death. The probability of prostate cancer was higher for men with normal levels of metabolic factors compared to men with high levels, but the probability of all-cause death, was higher for men with high levels than for those with normal levels. For both men and women, high levels of metabolic factors were associated with increased risk of kidney cancer (renal cell carcinoma). Furthermore, blood pressure for men and BMI for women were found as independent risk factors of kidney cancer. High blood pressure was associated with an increased risk of bladder cancer for men. Conclusions: High levels of metabolic factors were associated to risk of kidney and bladder cancer and to death from kidney, bladder, and prostate cancer. Compared to men with normal levels, men with high levels of metabolic factors had a decreased probability of prostate cancer but an increased probability of all-cause death.

Ytterligare forskningsfinansiärer: World Cancer Research Fund (2007/09) och Wereld Kanker Onderzoek Fonds (R2010/247)

Me-Can

Les progrès thérapeutiques ont conduit à une augmentation de la survie à 5 ans des enfants traités pour un un cancer et qui dépasse actuellement 80%. En France il a été estimé que 50 000 adultes guéris d’un cancer pédiatrique, mais la prévalence des complications à long terme causées par la maladie et par ses traitement dépasse 60% après un suivi de 30 ans. L’objectif général de cette thèse était de faire avancer les connaissances actuelles sur la mortalité et la morbidité à long terme liées aux cancers pédiatriques.Avec les données de la cohorte FCCSS (French Childhood Cancer Survivor Study) qui inclut des sujets ayant été traités pour entre 1946 et 2000 pour un cancer pédiatrique solide, nous avons observé que le risque de mortalité chez ces patients demeure plus élevé que la population générale même à plus de 40 ans après le diagnostic de leur premier cancer. D’autre part, la mortalité liée plus aux effets à long terme des traitements anticancéreux, plus spécifiquement les seconds cancers et maladies circulatoires, a significativement baissé parmi les sujets traités plus récemment.Par ailleurs, nous avons aussi confirmé le rôle des anthracyclines dans la survenue de l’insuffisance cardiaque et montré que la fraction du volume médian du cœur ayant reçu 30 Gray était beaucoup plus élevés chez les sujets ayant développé une insuffisance cardiaque par rapport aux autres. Nous avons aussi observé que des faibles volumes du cœur (10% du volume du ventricule gauche) ayant reçus ≥30 Gy sont associés à un risque élevé de développer une insuffisance cardiaque. Cette étude est la première à rapporter une relation dose-effet basée sur des indicateurs dose-volume et ces résultats peuvent être utilisés dans la pratique clinique couranteNos travaux ont aussi montré que les patients ayant subi une néphrectomie unilatérale étaient à risque de développer une maladie rénale chronique à très long terme. L’effet de la dose de radiation reçue aux reins différait selon si les patients ayant subi une néphrectomie unilatérale ou non . En effet, une dose au seul rein même <5Gy était associée à un risque élevé de dysfonctionnement rénal. Par ailleurs, grâce aux données du registre REIN, nous avons pu montrer que l’incidence de l’insuffisance rénale terminale liée aux anticancéreux était en train d’augmenter au fil des années. Cependant ces patients étaient moins inscrits en liste d'attente comparés à d’autres malades rénaux et avaient par conséquent un accès très limité à la transplantation rénale.En conclusion, le travail effectué courant cette thèse pourrait aider à identifier les patients à risque accru de complications tardives majeures liées aux traitements anticancéreux. Nos résultats pourraient être utilisés dans la pratique clinique courante pour l’adaptation de la prise en charge thérapeutique des enfants atteints de cancer et pour les recommandations de leurs suivi à long terme
Advances in treatment have increased the overall 5-year survival rate for childhood cancers to approximately 80%. In France, it estimated that about 50,000 adults have survived childhood cancer. However, previous studies have demonstrated that by the second decade of life, more than 60% of survivor of childhood malignancies (CCS) will suffer from at least one chronic disease related to the treatment they have received.The general objective of this thesis was to advance knowledge about the very long morbidity associated with childhood cancer, with the ultimate target to improve both the long term outcome and quality of life of survivors.Using data from the French Childhood Cancer Survivor Study (FCCSS) cohort, which includes patients treated for a solid pediatric malignancy between 1942 and 2000, we found that that mortality among CCS remained higher than the general population even after more than 40 years of the primary cancer diagnosis. A major finding of this study was that mortality attributed to adverse effects of cancer treatments (secondary primary neoplasm and circulatory disease) declined among patients treated in more recent treatment periods. We also conducted a case control study nested in the FCCSS cohort and further affirmed the role of anthracycline in the occurrence of heart failure. We demonstrated that the median heart volume that received at least 30Gy was higher among heart failure cases and that exposing small volumes of the heart (10% of the volume of the left ventricle) to at least 30Gy was associated with an elevated risk of cardiac failure. This study was the first to derive a dose response relationship based on dose-volume metrics which can be used in current clinical practice.Our results also showed that unilateral nephrectomy was associated with a high risk of renal impairment. The effect of radiation dose to the kidneys was also different among nephrectomized patients for whom any exposure to radiation was associated with an elevated risk of chronic kidney disease even at doses less than 5 Gy.Furthermore, data from the renal epidemiology and information network (REIN) registry allowed us to investigated ESKD (end stage kidney disease) related to nephrotoxic chemotherapy and/or radiation. Our registry-based study showed that ESKD related to nephrotoxic cancer treatment has been steadily increasing over the past decade in the French population. These patients experienced a much lower rate of wait-listing than matched controls with other causes of ESKD, despite similar survival on dialysis.To conclude the results of this thesis are useful to identify survivors of childhood malignancies who are at risk of developing severe long term adverse effects related to the treatment of their primary cancer. Our results could be applied in current clinical practice to help adapt current treatment strategies and improve the long-term follow-up recommendations of childhood cancer survivors

Introduction Kidney transplantation confers both survival and quality of life advantages over dialysis for most people with end-stage kidney disease (ESKD). The mortality rate on dialysis is 10-15% per year, compared with 2-4% per year post-transplantation. Short-term graft survival is related to control of the acute rejection process, requiring on-going immunosuppression. Most current immunosuppressive algorithms include one of the calcineurin inhibitors (CNI: cyclosporin or tacrolimus), an anti-metabolite (azathioprine or mycophenolate) and corticosteroids, with or without antibody induction agents (Ab) given briefly peri-transplantation. Despite this approach, between 15-35% of recipients undergo treatment for an episode of acute rejection (AR) within one year of transplantation. Transplantation is not without risk, and relative mortality rates for kidney recipients after the first post-transplant year remain 4-6 times that of the general population. Longer-term transplant and recipient survival are related to control of chronic allograft nephropathy (rooted in the interplay of AR, non-immunological factors, and the chronic nephrotoxicity of CNI) and limitation of the complications of chronic ESKD and long-term immunosuppression: cardiovascular disease, cancer and infection, which are responsible for 22%, 39% and 21% of deaths respectively. This thesis is presented as published works on the theme of immunosuppression and cancer after kidney transplantation. The work presented in the first chapters of this thesis has striven to identify, evaluate, synthesise and distil the entirety of evidence available of new and established immunosuppressive drug agents through systematic review of randomised trial data, with particular emphasis on quantifying harms of treatment. The final chapters use inception cohort data from the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA), which is first validated then used to explore the risk of cancer in more detail than was possible from trial data alone. Interleukin 2 receptor antagonists Interleukin-2 receptor antagonists (IL2Ra, commercially available as basiliximab and daclizumab) are humanised or chimeric IgG monoclonal antibodies to the alpha subunit of the IL2 receptor present only on activated T lymphocytes, and the rationale for their use has been as induction agents peri-transplantation. Introduced in the mid-1990s, IL2Ra use has increased globally, and by 2003 38% of new kidney transplant recipients in the United States and 25% in Australasia received an IL2Ra. This study aimed to systematically identify and synthesise the evidence of effects of IL2Ra as an addition to standard therapy, or as an alternative to other induction agents. We identified 117 reports from 38 randomised trials involving 4893 participants. Where IL2Ra were compared with placebo (17 trials; 2786 patients), graft loss was not different at one (Relative Risk -RR 0.84; 0.64 to 1.10) or 3 years (RR 1.08; 0.71 to1.64). AR was reduced at 6 months (RR 0.66; 0.59 to 0.74) and at 1 year (RR 0.66; 0.59 to 0.74) but cytomegalovirus (CMV) disease (RR 0.82; CI 0.65 to 1.03) and malignancy (RR 0.67; 0.33 to1.36) were not different. Where IL2Ra were compared with other antibody therapy no significant differences in treatment effects were demonstrated, but IL2Ra had significantly fewer side effects. Given a 40% risk of rejection, 7 patients would need treatment with IL2Ra in addition to standard therapy, to prevent 1 patient having rejection, with no definite improvement in graft or patient survival. There was no apparent difference between basiliximab and daclizumab. Tacrolimus versus cyclosporin for primary immunosuppression There are pronounced global differences in CNI use; 63% of new kidney transplant recipients in the USA but only 22% in Australia receive tacrolimus as part of the initial immunosuppressive regimen. The side effects of CNI differ: tacrolimus is associated more with diabetes and neurotoxicity, but less with hypertension and dyslipidaemia than cyclosporin, with uncertainty about equivalence of nephrotoxicity or how these relate to patient and graft survival, or impact on patient compliance and quality of life. This study aimed to systematically review and synthesise the positive and negative effects of tacrolimus and cyclosporin as initial therapy for renal transplant recipients. We identified 123 reports from 30 randomised trials involving 4102 participants. At 6 months graft loss was reduced in tacrolimus-treated recipients (RR 0•56; 0•36 to 0•86), and this effect persisted for 3 years. The relative reduction in graft loss with tacrolimus diminished with higher levels of tacrolimus (P=0.04), but did not vary with cyclosporin formulation (P=0.97) or cyclosporin level (P=0.38). At 1 year, tacrolimus patients suffered less AR (RR 0•69; 0•60 to 0•79), and less steroid-resistant AR (RR 0•49; 0•37 to 0•64), but more insulin-requiring diabetes (RR 1•86; 1•11 to 3•09), tremor, headache, diarrhoea, dyspepsia and vomiting. The relative excess in diabetes increased with higher levels of tacrolimus (P=0.003). Cyclosporin-treated recipients experienced significantly more constipation and cosmetic side-effects. We demonstrated no differences in infection or malignancy. Treating 100 recipients with tacrolimus instead of cyclosporin for the 1st year post-transplantation avoids 12 suffering acute rejection and 2 losing their graft but causes an extra 5 to become insulin dependent diabetics, thus optimal drug choice may vary among patients. Target of rapamycin inhibitors for primary immunosuppression Target of rapamycin inhibitors (TOR-I) are among the newest immunosuppressive agents and have a novel mode of action but uncertain clinical role. Sirolimus is a macrocyclic lactone antibiotic and everolimus is a derivative of sirolimus. Both prevent DNA synthesis resulting in arrest of the cell cycle. Animal models suggested TOR-I would provide synergistic immunosuppression when combined with CNI, but early clinical studies demonstrated synergistic nephrotoxicity. Since then diverse trials have explored strategies that avoid this interaction and investigated other potential benefits. The aim of this study was to systematically identify and synthesise available evidence of sirolimus and everolimus when used in initial immunosuppressive regimens for kidney recipients. We identified 142 reports from 33 randomised trials involving 7114 participants, with TOR-I evaluated in four different primary immunosuppressive algorithms: as replacement for CNI, as replacement for antimetabolites, in combination with CNI at low and high dose, and with variable dose of CNI. When TOR-I replaced CNI (8 trials, 750 participants), there was no difference in AR (RR 1.03; 0.74 to 1.44), but creatinine was lower (WMD -18.31 umol/l; -30.96 to -5.67), and bone marrow more suppressed (leucopoenia RR 2.02; 1.12 to 3.66, thrombocytopenia RR 6.97; 2.97 to 16.36, anaemia RR 1.67; 1.27 to 2.20). When TOR-I replaced antimetabolites (11 trials, 3966 participants), AR and CMV were reduced (RR 0.84; 0.71 to 0.99 and RR 0.49; 0.37 to 0.65) but hypercholesterolaemia was increased (RR 1.65; 1.32 to 2.06). When low was compared to high-dose TOR-I, with equal CNI dose (10 trials, 3175 participants), AR was increased (RR 1.23; 1.06 to 1.43) but GFR higher (WMD 4.27 ml/min; 1.12 to 7.41). When low-dose TOR-I and standard-dose CNI were compared to higher-dose TOR-I and reduced CNI AR was reduced (RR 0.67; 0.52 to 0.88), but GFR also reduced (WMD -9.46 ml/min; -12.16 to -6.76). There was no significant difference in mortality, graft loss or malignancy risk demonstrated for TOR-I in any comparison. Generally surrogate endpoints for graft survival favoured TOR-I (lower risk of acute rejection and higher GFR) and surrogate endpoints for patient outcomes were worsened by TOR-I (bone marrow suppression, lipid disturbance). Long-term hard-endpoint data from methodologically robust randomised trials are still needed. Monoclonal and polyclonal antibody therapy for treating acute rejection Strategies for treating AR include pulsed steroids, an antibody (Ab) preparation, the alteration of background immunosuppression, or combinations of these options. In 2002, in the USA 61.4% of patients with AR received steroids, 20.4% received Ab and 18.2% received both. The Ab available for AR are not new: horse and rabbit derived polyclonal antibodies (ATG and ALG) have been used for 35 years, and a mouse monoclonal antibody (muromonab-CD3) became available in the late 1980s. These preparations remove the functional T-cell population from circulation, producing powerful saturation immunosuppression which is useful for AR but which may be complicated by immediate toxicity and higher rates of infection and malignancy. The aim of this study was to systematically evaluate and synthesise all evidence available to clinicians for treating AR in kidney recipients. We identified 49 reports from 21 randomised trials involving 1394 participants. Outcome measures were inconsistent and incompletely defined across trials. Fourteen trials (965 patients) compared therapies for 1st AR episodes (8 Ab versus steroid, 2 Ab versus another Ab, 4 other comparisons). In treating first rejection, Ab was better than steroid in reversing AR (RR 0.57; CI 0.38 to 0.87) and preventing graft loss (RR 0.74; CI 0.58 to 0.95) but there was no difference in preventing subsequent rejection (RR 0.67; CI 0.43 to 1.04) or death (RR 1.16; CI 0.57 to 2.33) at 1 year. Seven trials (422 patients) investigated Ab treatment of steroid-resistant rejection (4 Ab vs another Ab, 1 different doses Ab, 1 different formulation Ab, 2 other comparisons). There was no benefit of muromonab-CD3 over ATG or ALG in reversing rejection (RR 1.32; CI 0.33 to 5.28), preventing subsequent rejection (RR 0.99; CI 0.61 to 1.59), graft loss (RR 1.80; CI 0.29 to 11.23) or death (RR 0.39; CI 0.09 to 1.65). Given the clinical problem caused by AR, comparable data are sparse, and clinically important differences in outcomes between widely used interventions have not been excluded. Standardised reproducible outcome criteria are needed. Validity of cancer data in an end stage kidney disease registry Registries vary in whether the data they collect are given voluntarily or as a requirement of law, the completeness of population coverage, the breadth of data collected and whether data are assembled directly or indirectly through linkage to other databases. Data quality is crucial but difficult to measure objectively. Formal audit of ANZDATA cancer records has not previously taken place. The aim of this study was to assess agreement of records of incident cancer diagnoses held in ANZDATA (voluntary reporting system) with those reported under statute to the New South Wales (NSW) state Central Cancer Registry (CCR), to explore the strengths and weaknesses of both reporting systems, and to measure the impact of any disagreement on results of cancer analyses. From 1980-2001, 9453 residents received dialysis or transplantation in NSW. Records from ANZDATA registrants were linked to CCR using probabilistic matching and agreement between registries for patients with 1 or more cancers, all cancers and site-specific cancer was estimated using the kappa-statistic (κ). ANZDATA recorded 867 cancers in 779 (8.2%) registrants; CCR 867 cancers in 788 (8.3%), with κ =0.76. ANZDATA had sensitivity 77.3% (CI 74.2 to 80.2), specificity 98.1% (CI 97.7 to 98.3) if CCR records were regarded as the reference standard. Agreement was similar for diagnoses whilst receiving dialysis (κ =0.78) or after transplantation (κ =0.79), but varied by cancer type. Melanoma (κ =0.61) and myeloma (κ =0.47) were less good; lymphoma (κ =0.80), leukaemia (κ =0.86) and breast cancer (κ =0.85) were very good. Artefact accounted for 20.8% non-concordance but error and misclassification did occur in both registries. Cancer risk did not differ in any important way whether estimated using ANZDATA or CCR records. Quality of cancer records in ANZDATA are high, differences largely explicable, and seem unlikely to alter results of analyses. Risk of cancer after kidney transplantation Existing data on the magnitude of excess risk of cancer across different kidney recipient groups are sparse. Quantifying an individual transplant candidate’s cancer risk informs both pre-transplant counselling, treatment decisions and has implications for monitoring, screening and follow-up after transplantation. The aims of this study were firstly to establish the risk of cancer in the post-transplant population compared to that experienced by the general population, and secondly to quantify how excess risk varied within the transplanted population, seeking to establish meaningful absolute risk estimates for post-transplant cancer based on unalterable recipient characteristics known a priori at the time of transplantation. 15,183 residents of Australia and New Zealand had a transplant between 1963 and 2004, and were followed for a median of 7.2 years (130,186 person-years), with 1642 (10.8%) developing cancer. Overall, kidney recipients had 3 times the cancer risk, with risk inversely related to age (Standardised Incidence Ratio of 15 to 30 in children reducing to 2 in people > 65 years). Female recipients aged 25 -29 had rates of cancer (779.2/100,000) equivalent to women aged 55 - 59 from the general population. The risk pattern of lymphoma, colorectal and breast cancer was similar to the overall age trend, melanoma showed less variability across ages and prostate cancer showed no risk increase. Within the transplanted population cancer risk was affected by age differently for each sex (P=0.007), and was elevated for recipients with prior non-skin malignancy (Hazard Ratio: HR 1.40; 1.03 to 1.89), of white race (HR 1.36; 1.12 to 1.89), but reduced for those with diabetic ESKD (HR 0.67; 0.50 to 0.89) Rates of cancer in kidney recipients were similar to non-transplanted people 20 -30 years older, but risk differed across patient groups. Men aged 45 - 54 at transplantation with graft function at 10 years had a risk of cancer that varied from 1 in 13 (non-white, diabetic ESKD, no prior cancer) to 1 in 5 (white, prior cancer, ESKD from other causes).

PhD
Introduction Kidney transplantation confers both survival and quality of life advantages over dialysis for most people with end-stage kidney disease (ESKD). The mortality rate on dialysis is 10-15% per year, compared with 2-4% per year post-transplantation. Short-term graft survival is related to control of the acute rejection process, requiring on-going immunosuppression. Most current immunosuppressive algorithms include one of the calcineurin inhibitors (CNI: cyclosporin or tacrolimus), an anti-metabolite (azathioprine or mycophenolate) and corticosteroids, with or without antibody induction agents (Ab) given briefly peri-transplantation. Despite this approach, between 15-35% of recipients undergo treatment for an episode of acute rejection (AR) within one year of transplantation. Transplantation is not without risk, and relative mortality rates for kidney recipients after the first post-transplant year remain 4-6 times that of the general population. Longer-term transplant and recipient survival are related to control of chronic allograft nephropathy (rooted in the interplay of AR, non-immunological factors, and the chronic nephrotoxicity of CNI) and limitation of the complications of chronic ESKD and long-term immunosuppression: cardiovascular disease, cancer and infection, which are responsible for 22%, 39% and 21% of deaths respectively. This thesis is presented as published works on the theme of immunosuppression and cancer after kidney transplantation. The work presented in the first chapters of this thesis has striven to identify, evaluate, synthesise and distil the entirety of evidence available of new and established immunosuppressive drug agents through systematic review of randomised trial data, with particular emphasis on quantifying harms of treatment. The final chapters use inception cohort data from the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA), which is first validated then used to explore the risk of cancer in more detail than was possible from trial data alone. Interleukin 2 receptor antagonists Interleukin-2 receptor antagonists (IL2Ra, commercially available as basiliximab and daclizumab) are humanised or chimeric IgG monoclonal antibodies to the alpha subunit of the IL2 receptor present only on activated T lymphocytes, and the rationale for their use has been as induction agents peri-transplantation. Introduced in the mid-1990s, IL2Ra use has increased globally, and by 2003 38% of new kidney transplant recipients in the United States and 25% in Australasia received an IL2Ra. This study aimed to systematically identify and synthesise the evidence of effects of IL2Ra as an addition to standard therapy, or as an alternative to other induction agents. We identified 117 reports from 38 randomised trials involving 4893 participants. Where IL2Ra were compared with placebo (17 trials; 2786 patients), graft loss was not different at one (Relative Risk -RR 0.84; 0.64 to 1.10) or 3 years (RR 1.08; 0.71 to1.64). AR was reduced at 6 months (RR 0.66; 0.59 to 0.74) and at 1 year (RR 0.66; 0.59 to 0.74) but cytomegalovirus (CMV) disease (RR 0.82; CI 0.65 to 1.03) and malignancy (RR 0.67; 0.33 to1.36) were not different. Where IL2Ra were compared with other antibody therapy no significant differences in treatment effects were demonstrated, but IL2Ra had significantly fewer side effects. Given a 40% risk of rejection, 7 patients would need treatment with IL2Ra in addition to standard therapy, to prevent 1 patient having rejection, with no definite improvement in graft or patient survival. There was no apparent difference between basiliximab and daclizumab. Tacrolimus versus cyclosporin for primary immunosuppression There are pronounced global differences in CNI use; 63% of new kidney transplant recipients in the USA but only 22% in Australia receive tacrolimus as part of the initial immunosuppressive regimen. The side effects of CNI differ: tacrolimus is associated more with diabetes and neurotoxicity, but less with hypertension and dyslipidaemia than cyclosporin, with uncertainty about equivalence of nephrotoxicity or how these relate to patient and graft survival, or impact on patient compliance and quality of life. This study aimed to systematically review and synthesise the positive and negative effects of tacrolimus and cyclosporin as initial therapy for renal transplant recipients. We identified 123 reports from 30 randomised trials involving 4102 participants. At 6 months graft loss was reduced in tacrolimus-treated recipients (RR 0•56; 0•36 to 0•86), and this effect persisted for 3 years. The relative reduction in graft loss with tacrolimus diminished with higher levels of tacrolimus (P=0.04), but did not vary with cyclosporin formulation (P=0.97) or cyclosporin level (P=0.38). At 1 year, tacrolimus patients suffered less AR (RR 0•69; 0•60 to 0•79), and less steroid-resistant AR (RR 0•49; 0•37 to 0•64), but more insulin-requiring diabetes (RR 1•86; 1•11 to 3•09), tremor, headache, diarrhoea, dyspepsia and vomiting. The relative excess in diabetes increased with higher levels of tacrolimus (P=0.003). Cyclosporin-treated recipients experienced significantly more constipation and cosmetic side-effects. We demonstrated no differences in infection or malignancy. Treating 100 recipients with tacrolimus instead of cyclosporin for the 1st year post-transplantation avoids 12 suffering acute rejection and 2 losing their graft but causes an extra 5 to become insulin dependent diabetics, thus optimal drug choice may vary among patients. Target of rapamycin inhibitors for primary immunosuppression Target of rapamycin inhibitors (TOR-I) are among the newest immunosuppressive agents and have a novel mode of action but uncertain clinical role. Sirolimus is a macrocyclic lactone antibiotic and everolimus is a derivative of sirolimus. Both prevent DNA synthesis resulting in arrest of the cell cycle. Animal models suggested TOR-I would provide synergistic immunosuppression when combined with CNI, but early clinical studies demonstrated synergistic nephrotoxicity. Since then diverse trials have explored strategies that avoid this interaction and investigated other potential benefits. The aim of this study was to systematically identify and synthesise available evidence of sirolimus and everolimus when used in initial immunosuppressive regimens for kidney recipients. We identified 142 reports from 33 randomised trials involving 7114 participants, with TOR-I evaluated in four different primary immunosuppressive algorithms: as replacement for CNI, as replacement for antimetabolites, in combination with CNI at low and high dose, and with variable dose of CNI. When TOR-I replaced CNI (8 trials, 750 participants), there was no difference in AR (RR 1.03; 0.74 to 1.44), but creatinine was lower (WMD -18.31 umol/l; -30.96 to -5.67), and bone marrow more suppressed (leucopoenia RR 2.02; 1.12 to 3.66, thrombocytopenia RR 6.97; 2.97 to 16.36, anaemia RR 1.67; 1.27 to 2.20). When TOR-I replaced antimetabolites (11 trials, 3966 participants), AR and CMV were reduced (RR 0.84; 0.71 to 0.99 and RR 0.49; 0.37 to 0.65) but hypercholesterolaemia was increased (RR 1.65; 1.32 to 2.06). When low was compared to high-dose TOR-I, with equal CNI dose (10 trials, 3175 participants), AR was increased (RR 1.23; 1.06 to 1.43) but GFR higher (WMD 4.27 ml/min; 1.12 to 7.41). When low-dose TOR-I and standard-dose CNI were compared to higher-dose TOR-I and reduced CNI AR was reduced (RR 0.67; 0.52 to 0.88), but GFR also reduced (WMD -9.46 ml/min; -12.16 to -6.76). There was no significant difference in mortality, graft loss or malignancy risk demonstrated for TOR-I in any comparison. Generally surrogate endpoints for graft survival favoured TOR-I (lower risk of acute rejection and higher GFR) and surrogate endpoints for patient outcomes were worsened by TOR-I (bone marrow suppression, lipid disturbance). Long-term hard-endpoint data from methodologically robust randomised trials are still needed. Monoclonal and polyclonal antibody therapy for treating acute rejection Strategies for treating AR include pulsed steroids, an antibody (Ab) preparation, the alteration of background immunosuppression, or combinations of these options. In 2002, in the USA 61.4% of patients with AR received steroids, 20.4% received Ab and 18.2% received both. The Ab available for AR are not new: horse and rabbit derived polyclonal antibodies (ATG and ALG) have been used for 35 years, and a mouse monoclonal antibody (muromonab-CD3) became available in the late 1980s. These preparations remove the functional T-cell population from circulation, producing powerful saturation immunosuppression which is useful for AR but which may be complicated by immediate toxicity and higher rates of infection and malignancy. The aim of this study was to systematically evaluate and synthesise all evidence available to clinicians for treating AR in kidney recipients. We identified 49 reports from 21 randomised trials involving 1394 participants. Outcome measures were inconsistent and incompletely defined across trials. Fourteen trials (965 patients) compared therapies for 1st AR episodes (8 Ab versus steroid, 2 Ab versus another Ab, 4 other comparisons). In treating first rejection, Ab was better than steroid in reversing AR (RR 0.57; CI 0.38 to 0.87) and preventing graft loss (RR 0.74; CI 0.58 to 0.95) but there was no difference in preventing subsequent rejection (RR 0.67; CI 0.43 to 1.04) or death (RR 1.16; CI 0.57 to 2.33) at 1 year. Seven trials (422 patients) investigated Ab treatment of steroid-resistant rejection (4 Ab vs another Ab, 1 different doses Ab, 1 different formulation Ab, 2 other comparisons). There was no benefit of muromonab-CD3 over ATG or ALG in reversing rejection (RR 1.32; CI 0.33 to 5.28), preventing subsequent rejection (RR 0.99; CI 0.61 to 1.59), graft loss (RR 1.80; CI 0.29 to 11.23) or death (RR 0.39; CI 0.09 to 1.65). Given the clinical problem caused by AR, comparable data are sparse, and clinically important differences in outcomes between widely used interventions have not been excluded. Standardised reproducible outcome criteria are needed. Validity of cancer data in an end stage kidney disease registry Registries vary in whether the data they collect are given voluntarily or as a requirement of law, the completeness of population coverage, the breadth of data collected and whether data are assembled directly or indirectly through linkage to other databases. Data quality is crucial but difficult to measure objectively. Formal audit of ANZDATA cancer records has not previously taken place. The aim of this study was to assess agreement of records of incident cancer diagnoses held in ANZDATA (voluntary reporting system) with those reported under statute to the New South Wales (NSW) state Central Cancer Registry (CCR), to explore the strengths and weaknesses of both reporting systems, and to measure the impact of any disagreement on results of cancer analyses. From 1980-2001, 9453 residents received dialysis or transplantation in NSW. Records from ANZDATA registrants were linked to CCR using probabilistic matching and agreement between registries for patients with 1 or more cancers, all cancers and site-specific cancer was estimated using the kappa-statistic (κ). ANZDATA recorded 867 cancers in 779 (8.2%) registrants; CCR 867 cancers in 788 (8.3%), with κ =0.76. ANZDATA had sensitivity 77.3% (CI 74.2 to 80.2), specificity 98.1% (CI 97.7 to 98.3) if CCR records were regarded as the reference standard. Agreement was similar for diagnoses whilst receiving dialysis (κ =0.78) or after transplantation (κ =0.79), but varied by cancer type. Melanoma (κ =0.61) and myeloma (κ =0.47) were less good; lymphoma (κ =0.80), leukaemia (κ =0.86) and breast cancer (κ =0.85) were very good. Artefact accounted for 20.8% non-concordance but error and misclassification did occur in both registries. Cancer risk did not differ in any important way whether estimated using ANZDATA or CCR records. Quality of cancer records in ANZDATA are high, differences largely explicable, and seem unlikely to alter results of analyses. Risk of cancer after kidney transplantation Existing data on the magnitude of excess risk of cancer across different kidney recipient groups are sparse. Quantifying an individual transplant candidate’s cancer risk informs both pre-transplant counselling, treatment decisions and has implications for monitoring, screening and follow-up after transplantation. The aims of this study were firstly to establish the risk of cancer in the post-transplant population compared to that experienced by the general population, and secondly to quantify how excess risk varied within the transplanted population, seeking to establish meaningful absolute risk estimates for post-transplant cancer based on unalterable recipient characteristics known a priori at the time of transplantation. 15,183 residents of Australia and New Zealand had a transplant between 1963 and 2004, and were followed for a median of 7.2 years (130,186 person-years), with 1642 (10.8%) developing cancer. Overall, kidney recipients had 3 times the cancer risk, with risk inversely related to age (Standardised Incidence Ratio of 15 to 30 in children reducing to 2 in people > 65 years). Female recipients aged 25 -29 had rates of cancer (779.2/100,000) equivalent to women aged 55 - 59 from the general population. The risk pattern of lymphoma, colorectal and breast cancer was similar to the overall age trend, melanoma showed less variability across ages and prostate cancer showed no risk increase. Within the transplanted population cancer risk was affected by age differently for each sex (P=0.007), and was elevated for recipients with prior non-skin malignancy (Hazard Ratio: HR 1.40; 1.03 to 1.89), of white race (HR 1.36; 1.12 to 1.89), but reduced for those with diabetic ESKD (HR 0.67; 0.50 to 0.89) Rates of cancer in kidney recipients were similar to non-transplanted people 20 -30 years older, but risk differed across patient groups. Men aged 45 - 54 at transplantation with graft function at 10 years had a risk of cancer that varied from 1 in 13 (non-white, diabetic ESKD, no prior cancer) to 1 in 5 (white, prior cancer, ESKD from other causes).

Review question / Objective: 1) In humans, how does environmental and/or occupational exposure to uranium affect the risk of mortality due to primary kidney disease compared to unexposed individuals? (2) In humans, how does environmental and/or occupational exposure to uranium affect the risk of developing kidney failure compared to unexposed individuals? Eligibility criteria: We included cohort studies that evaluate the risk of CKD/ESKD due to uranium exposure. We also included cohort studies that evaluate standardized mortality due to all-cause mortality, kidney cancer, chronic kidney disease, diabetes, and cardiovascular disease in humans with exposure to uranium. We also included cross sectional studies that evaluate renal function in humans exposed to uranium via biomarkers and hard clinical measures (such as creatinine clearance) compared to humans with low/no uranium exposure. In order to not include the same cohort multiple times in the statistical analyses, we selected studies that evaluated an outcome of interest for a given cohort for the longest follow-up period. When this was not possible (due to multiple studies using different combinations of cohorts with varying lengths of follow up), the study with the largest study population size was selected.

Objectives. To examine the evidence on whether and how healthcare algorithms (including algorithm-informed decision tools) exacerbate, perpetuate, or reduce racial and ethnic disparities in access to healthcare, quality of care, and health outcomes, and examine strategies that mitigate racial and ethnic bias in the development and use of algorithms. Data sources. We searched published and grey literature for relevant studies published between January 2011 and February 2023. Based on expert guidance, we determined that earlier articles are unlikely to reflect current algorithms. We also hand-searched reference lists of relevant studies and reviewed suggestions from experts and stakeholders. Review methods. Searches identified 11,500 unique records. Using predefined criteria and dual review, we screened and selected studies to assess one or both Key Questions (KQs): (1) the effect of algorithms on racial and ethnic disparities in health and healthcare outcomes and (2) the effect of strategies or approaches to mitigate racial and ethnic bias in the development, validation, dissemination, and implementation of algorithms. Outcomes of interest included access to healthcare, quality of care, and health outcomes. We assessed studies’ methodologic risk of bias (ROB) using the ROBINS-I tool and piloted an appraisal supplement to assess racial and ethnic equity-related ROB. We completed a narrative synthesis and cataloged study characteristics and outcome data. We also examined four Contextual Questions (CQs) designed to explore the context and capture insights on practical aspects of potential algorithmic bias. CQ 1 examines the problem’s scope within healthcare. CQ 2 describes recently emerging standards and guidance on how racial and ethnic bias can be prevented or mitigated during algorithm development and deployment. CQ 3 explores stakeholder awareness and perspectives about the interaction of algorithms and racial and ethnic disparities in health and healthcare. We addressed these CQs through supplemental literature reviews and conversations with experts and key stakeholders. For CQ 4, we conducted an in-depth analysis of a sample of six algorithms that have not been widely evaluated before in the published literature to better understand how their design and implementation might contribute to disparities. Results. Fifty-eight studies met inclusion criteria, of which three were included for both KQs. One study was a randomized controlled trial, and all others used cohort, pre-post, or modeling approaches. The studies included numerous types of clinical assessments: need for intensive care or high-risk care management; measurement of kidney or lung function; suitability for kidney or lung transplant; risk of cardiovascular disease, stroke, lung cancer, prostate cancer, postpartum depression, or opioid misuse; and warfarin dosing. We found evidence suggesting that algorithms may: (a) reduce disparities (i.e., revised Kidney Allocation System, prostate cancer screening tools); (b) perpetuate or exacerbate disparities (e.g., estimated glomerular filtration rate [eGFR] for kidney function measurement, cardiovascular disease risk assessments); and/or (c) have no effect on racial or ethnic disparities. Algorithms for which mitigation strategies were identified are included in KQ 2. We identified six types of strategies often used to mitigate the potential of algorithms to contribute to disparities: removing an input variable; replacing a variable; adding one or more variables; changing or diversifying the racial and ethnic composition of the patient population used to train or validate a model; creating separate algorithms or thresholds for different populations; and modifying the statistical or analytic techniques used by an algorithm. Most mitigation efforts improved proximal outcomes (e.g., algorithmic calibration) for targeted populations, but it is more challenging to infer or extrapolate effects on longer term outcomes, such as racial and ethnic disparities. The scope of racial and ethnic bias related to algorithms and their application is difficult to quantify, but it clearly extends across the spectrum of medicine. Regulatory, professional, and corporate stakeholders are undertaking numerous efforts to develop standards for algorithms, often emphasizing the need for transparency, accountability, and representativeness. Conclusions. Algorithms have been shown to potentially perpetuate, exacerbate, and sometimes reduce racial and ethnic disparities. Disparities were reduced when race and ethnicity were incorporated into an algorithm to intentionally tackle known racial and ethnic disparities in resource allocation (e.g., kidney transplant allocation) or disparities in care (e.g., prostate cancer screening that historically led to Black men receiving more low-yield biopsies). It is important to note that in such cases the rationale for using race and ethnicity was clearly delineated and did not conflate race and ethnicity with ancestry and/or genetic predisposition. However, when algorithms include race and ethnicity without clear rationale, they may perpetuate the incorrect notion that race is a biologic construct and contribute to disparities. Finally, some algorithms may reduce or perpetuate disparities without containing race and ethnicity as an input. Several modeling studies showed that applying algorithms out of context of original development (e.g., illness severity scores used for crisis standards of care) could perpetuate or exacerbate disparities. On the other hand, algorithms may also reduce disparities by standardizing care and reducing opportunities for implicit bias (e.g., Lung Allocation Score for lung transplantation). Several mitigation strategies have been shown to potentially reduce the contribution of algorithms to racial and ethnic disparities. Results of mitigation efforts are highly context specific, relating to unique combinations of algorithm, clinical condition, population, setting, and outcomes. Important future steps include increasing transparency in algorithm development and implementation, increasing diversity of research and leadership teams, engaging diverse patient and community groups in the development to implementation lifecycle, promoting stakeholder awareness (including patients) of potential algorithmic risk, and investing in further research to assess the real-world effect of algorithms on racial and ethnic disparities before widespread implementation.