Preemptive kidney transplantation: Has it come of age?

The benefits of preemptive kidney transplantation are manifold. By avoiding complications associated with dialysis, preemptive kidney transplantation offers significant benefits in terms of patient welfare and societal cost-saving. Patients transplanted preemptively also tend to enjoy better patient and graft survival, especially when done with a living-donor organ. While dialysis exposure limited to 6 to 12 months may not significantly impact post-transplant outcomes, longer period of dialysis has been shown to increase the risk of mortality, delayed graft function, acute rejection, and death-censored graft loss. The benefits of preemptive transplantation also extend to different age groups and end-stage kidney disease (ESKD) diagnoses. However, multiple barriers have prevented wider adoption of preemptive transplantation as the primary treatment of ESKD around the world. Timely preparation for ESKD and identification of living donors should be encouraged in all patients with advanced chronic kidney disease to increase the chance of preemptive transplantation.     

Cancers after renal transplantation

For patients with end-stage kidney failure, kidney transplantation improves both their quality of life and overall life expectancy compared with dialysis, but it is not without adverse effects. Cancer is second to cardiovascular disease as one of the major causes of morbidity and mortality in renal transplant recipients. Prolonged use of modern immunosuppression, which leads to alteration of immune function and immune surveillance, is associated with increased cancer risk. There is now convincing evidence from observational studies and registry data to confirm a 3- to 5-fold increase in overall cancer incidence, with viral-related neoplasia incurring the greatest risk when compare with the general population. Despite the increased risk, little is known about the overall cancer prognosis, screening, treatment strategies, and effectiveness in this population. Cancers can recur, occur de novo, and be transmitted from donor organs posttransplantation. Uncertainties exist as to how modern immunosuppressive agents impact on cancer management and outcomes in these patients, with some agents such as calcineurin inhibitors and azathioprine, being more carcinogenic than others. The newer agents, proliferation signal/mammalian target of rapamycin inhibitors and mycophenolate mofitil, may have some antiproliferative and antitumor activities demonstrated in preclinical and clinical studies, but long-term well-powered trial data are needed to determine whether they are either protective or curative for cancers in renal transplant recipients. In this review, the incidence, etiology, prognosis, and potential approaches to cancer screening and management post–renal transplantation are discussed.     

Incidence of cancer in kidney transplantation waiting list patients: a single center experience

Introduction

It is widely accepted that the risk of malignancies is significantly increased among patients with end-stage kidney disease (ESKD) and after kidney transplantation compared with the general population. Only a few data are available on kidney transplantation waiting list patients. The aim of this study was to investigate solid organ cancer incidence among subjects on the waiting list at a single center.

Materials and Methods

We retrospectively reviewed the records of all patients enrolled on our kidney transplantation waiting list between August 1, 2008 and July 31, 2010, seeking to evaluate the causes of withdrawal from the list, incidence of cancer, type of neoplasm, and its correlation with clinical features. We estimated the ratio of observed to expected numbers of cancers, the standardized incidence ratio (SIR).

Results

Among 1184 patients, we excluded 569 patients from the waiting list including 26 (4.56%) who displayed malignancies. The overall incidence of cancer was 0.11 events/person-months and the overall prevalence of cancer was 2.2%. In 97% of patients, the malignant disease was confined to the primitive organ of origin without secondary dissemination. We observed a prevalence of cancers related to ESKD (17; 65.38%). The SIR for all cancer types in our population compared with the general population was 2.22. The SIR for native kidney and thyroid cancers among our population compared with the general population was >10.

Conclusion

The incidence of cancer was significantly increased among kidney transplantation waiting list patients compared with the general population. Our study highlighted the importance of a careful, targeted neoplastic screening. It could be particularly important for ESKD-related malignancies like native kidney tumors or thyroid cancers.     

Screening for Prostate, Breast and Colorectal Cancer in Renal Transplant Recipients

American Society of Transplantation guidelines recommend screening renal transplant recipients for breast, colorectal and prostate cancer. However there is a lack of evidence to support this practice. Computer simulation modeling was used to estimate the years of life lost as a result of these cancers in 50-year-old renal transplant recipients and subjects in the general population. Renal transplant recipients lost fewer years of life to cancer than people in the general population largely because of reduced life expectancy. In nondiabetic transplant recipients, loss of life as a result of these cancers was comparable with that in the general population only under assumptions of increased cancer incidence and cancer-specific mortality risks. Even with two-fold higher cancer incidence and disease-specific mortality risks, diabetic transplant recipients lost considerably fewer life years to cancer than those in the general population. Recommended cancer screening for the general population may not yield the expected benefits in the average renal transplant recipient but the benefits will be considerably higher than for patients on dialysis. Transplanted patients at above-average cancer risk in good health may achieve the benefits of screening that are seen in the general population.     

Chronic kidney disease in the general population

End-stage kidney disease (ESKD), defined as the need for dialysis, receipt of a transplant, or death from chronic kidney failure, generally affects fewer than 1% of the population. However ESKD is the end result of chronic kidney disease (CKD), a widely prevalent but often silent condition with elevated risks of cardiovascular morbidity and mortality and a range of metabolic complications. A recently devised classification of CKD has facilitated prevalence estimates that reveal an "iceberg" of CKD in the community, of which dialysis and transplant patients are the tip. Hypertension, smoking, hypercholesterolemia, and obesity, currently among the World Health Organization's (WHO's) top 10 global health risks, are strongly associated with CKD. The factors, together with increasing diabetes prevalence and an aging population, will result in significant global increases in CKD and ESKD patients. Treatments now available effectively reduce the rate of progression of CKD and the extent of comorbid conditions and complications. The challenges are (1) to intervene effectively to reduce the excess burden of cardiovascular morbidity and mortality associated with CKD, (2) to identify those at greatest risk for ESKD and intervene effectively to prevent progression of early CKD, and (3) to ultimately introduce cost-effective primary prevention to reduce the overall burden of CKD. The vast majority of the global CKD burden will be in developing countries, and policy responses must be both practical and sustainable in these settings.     

High prevalence of colon adenomas in end‐stage kidney disease patients on hemodialysis undergoing renal transplant evaluation

The aim of this study was to determine whether patients with end‐stage kidney disease (ESKD) on hemodialysis (HD) undergoing kidney transplant evaluation are at higher risk for colonic neoplasia than the general population. This is a retrospective cohort study of patients with ESKD who underwent a first screening colonoscopy while undergoing kidney transplant evaluation. Data were collected on the prevalence of adenomatous polyps and advanced adenomas in 70 patients with ESKD and 70 controls, undergoing their first screening colonoscopy, matched for age, gender, and endoscopist. At the time of the colonoscopy, an average time on HD was 3.2 ± 2.9 yr. The prevalence of adenomatous polyps was significantly higher in ESKD on HD (54.3% vs. 32.9%, p = 0.008) than in controls. In a multivariate analysis controlling for other factors, ESKD on HD remained a risk factor for the presence of adenomas (OR 3.06, 95% CI 1.21, 7.73). No colonoscopy‐related complications were reported in the patients with ESKD on HD. We demonstrate a significantly higher prevalence of adenomatous polyps in patients with ESKD undergoing a first screening colonoscopy as part of kidney transplant evaluation. In addition, colonoscopy can be safely performed in this population.     

Clopidogrel Use in End‐Stage Kidney Disease

Clopidogrel irreversibly binds to the P2Y12 platelet receptor and acts as a potent inhibitor of platelet activation and aggregation. It is currently recommended for the prevention of cardiovascular events in patients with acute coronary syndromes, recent ischemic stroke, and peripheral arterial disease. Clopidogrel is a prodrug requiring hepatic conversion into its active metabolite. In the general population, genetic polymorphisms in the CYP2C19 gene interfering with hepatic conversion and the ABCB1 gene interfering with gut absorption of clopidogrel, account for the large interindividual response to clopidogrel and clopidogrel resistance. Chronic kidney disease (CKD) and ESKD are independent risk factors for clopidogrel resistance; 50–80% of patients with ESKD have high on‐treatment residual platelet reactivity when treated with clopidogrel. This may partially explain the abysmal outcomes for patients with kidney disease post coronary intervention. Several assays are used to determine residual on‐treatment platelet reactivity; however, their use in tailoring the suitability of clopidogrel treatment in patients with ESKD is unclear. Although clopidogrel decreased cardiovascular events in the general population after acute coronary syndromes and percutaneous intervention in the CURE and CREDO trials, a reanalysis of these studies in patients with CKD (eGFR <60 ml/minute) showed either a reduced or no benefit from clopidogrel treatment. ESKD patients were not represented in these two large trials; this is true for most of the trials that established clopidogrel as an integral part of the therapeutic armamentarium for cardiovascular disease. Furthermore, clopidogrel has been associated with an increased risk of death, death from bleeding, and hospitalization for bleeding in patients with ESKD. In conclusion, current evidence suggests that ESKD patients may not derive the same benefits from clopidogrel therapy as the general population and this therapy may be associated with harm. Properly designed observational studies and randomized controlled trials are needed to establish the role of clopidogrel in patients with ESKD, the use of platelet assays to tailor therapy, and the role of other antiplatelet agents such as prasugrel or ticagrelor in patients who exhibit high on‐treatment residual platelet reactivity.     

Assessment of kidney transplant suitability for patients with prior cancers: is it time for a rethink?

Kidney transplant recipients have up to a 100‐fold greater risk of incident cancer compared with the age/sex‐matched general population, attributed largely to chronic immunosuppression. In patients with a prior history of treated cancers, the type, stage and the potential for cancer recurrence post‐transplant of prior cancers are important factors when determining transplant suitability. Consequently, one of the predicaments facing transplant clinicians is to determine whether patients with prior cancers are eligible for transplantation, balancing between the accelerated risk of death on dialysis, the projected survival benefit and quality of life gains with transplantation, and the premature mortality associated with the potential risk of cancer recurrence post‐transplant. The guidelines informing transplant eligibility or screening and preventive strategies against cancer recurrence for patients with prior cancers are inconsistent, underpinned by uncertain evidence on the estimates of the incidence of cancer recurrence and the lack of stage‐specific outcomes data, particularly among those with multiple myeloma or immune‐driven malignancies such as melanomas. With the advent of newer anti‐cancer treatment options, it is unclear whether the current guidelines for those with prior cancers remain appropriate. This review will summarize the uncertainties of evidence informing the current recommendations regarding transplant eligibility of patients with prior cancers.     

Breaking the adherence barriers: Strategies to improve treatment adherence in dialysis patients

Nonadherence to therapy (dietary/fluid restrictions, medications, and dialysis treatment), is common in patients with end-stage kidney disease (ESKD) undergoing dialysis. It is associated with a higher risk of mortality and adverse outcomes. Clinical trials evaluating adherence improvement interventions have largely addressed patient-related factors by employing educational/cognitive, counselling/behavioral, psychological strategies, or combinations thereof. A major barrier to progress in addressing ESKD-related adherence is the difficulty in comparing these trials due to the highly diverse nature of interventions and adherence outcomes. Surrogate outcomes like changes in inter-dialysis weight gain or phosphate levels are frequently used without adjusting for confounders, with the potential for biased efficacy estimates. A majority of trials reported improvement in some adherence measures, but some of the same studies showed no improvement in other adherence markers, questioning the validity of outcome measurement. Among the interventions, cognitive/behavioral strategies, combination strategies, and individually delivered interventions may have some advantages. Relapse of nonadherence, which is common on follow-up, should be managed to sustain long-term adherence. Technology-based interventions hold great future potential for addressing ESKD nonadherence. Streamlining intervention strategies and standardizing outcome measures in future clinical trials will provide reliable guidance to manage nonadherence effectively, which may improve clinical outcomes in dialysis patients.     

Oncology in nephrology comes of age: A focus on chronic dialysis patients

Dialysis is the commonest modality of renal replacement therapy for patients suffering from end‐stage kidney disease. Different registry studies showed that the risks of overall cancer occurrence were significantly higher in chronic dialysis patients than in the age‐matched general population. However, the frequency and pattern of different cancers may vary among different geographical areas. Since chronic dialysis patients tend to have multiple comorbidities and a shorter life expectancy, routine cancer screening in all dialysis patients may not be cost‐effective; rather screening should be personalized according to the patient's expected survival, candidacy for kidney transplant together with patient preferences.     

Kidney cancer in the Swedish Family Cancer Database: familial risks and second primary malignancies

BACKGROUND: Familial risks in kidney cancer and association with second primary malignancies were studied using the nationwide Swedish Family Cancer Database. METHODS: Cancer data were retrieved from the Swedish Cancer Registry from years 1961 to 1998 and included 23,137 cases of kidney cancer. Standardized incidence ratios (SIRs) were used to measure the cancer risks. RESULTS: Seventy-one families were identified where both a parent and an offspring had kidney cancer, giving a familial risk for offspring of 1.56 (1.22 to 1.95) and population attributable proportion of 0.78%. A risk for kidney cancer from an affected sibling was considerably higher with a SIR of 4.72 (2.28 to 9.20), giving an attributable proportion of 0.77%. The discordant tumor site that was associated with kidney cancer between two generations was hemangioblastoma of central nervous system. Discordant cancer sites that were associated with kidney cancer in siblings were ovaries, endocrine glands and pancreas. There was an over threefold increase of second primary malignancies of the urinary bladder, nervous system and endocrine gland in kidney cancer patients. The risks for second primary hemangioblastoma following kidney cancer or familial kidney cancer was 21.19 (6.69 to 43.83) and 1206 (114 to 3456), respectively. CONCLUSIONS: The high ratio of sibling risk to offspring risk in kidney cancer may reflect a recessive susceptibility. The high risk for second primary cancers in the patients without family history is consistent with a polygenic model and variable degree of environmental modification.     

Surgical strategies for esophageal cancer associated with head and neck cancer

Esophageal cancer is frequently associated with squamous cell carcinoma in the head and neck. Both cigarette smoking and alcohol consumption are risk factors for multiple cancers of the head and neck, as well as the esophagus. Routine screening and close follow-up for second cancers are important in patients with esophageal cancer or head and neck cancer. For this purpose, endoscopy with Lugol’s staining, as well as narrow-band imaging combined with magnifying endoscopy, is a powerful tool for the early detection of esophageal cancer. Multimodal therapy is essential for patients with double cancers. When considering surgical treatment, the curability of both cancers must be carefully evaluated. If both tumors are potentially curable, each lesion should be treated individually. In patients with metachronous double cancers, the prior treatment of the first primary carcinoma often affects the treatment of the second cancer. Close cooperation among medical staff members is essential for complicated surgeries for double cancers. Techniques that are appropriate for each case must be adopted, such as careful dissection, staged operations, muscular flaps and microvascular anastomosis.     

Prostate Cancer Metastatic to the Renal Allograft: A Case Report

Malignancy is a leading cause of morbidity and mortality in organ transplant recipients who receive immunosuppression. Cancers associated with viruses such as nonmelanotic skin cancer and Kaposi sarcoma occur in allograft recipients at rates that far exceed that in the general population. The increased risk and tumor type may depend not only on degree of immune system modulation but also on the type of organ transplanted. In kidney transplant recipients, the risk of cancers such as prostate and breast does not seem to be increased. However, these cancers tend to be advanced and aggressive. The management of these cancers is similar to the general population with the additional consideration for reduction in immunosuppression and conversion to sirolimus. Given the increased survival of both transplanted organs as well as organ recipients along with the increased number of older recipients, the diagnosis of prostate cancer in the older male organ recipient is increasing. The long-term outcomes using current treatment guidelines for prostate cancer in these individuals are not clear. We report a case of known localized prostate cancer in a renal transplant recipient presenting with metastasis diagnosed as tumor infiltration of the allograft. Our patient, upon initial diagnosis of cancer, opted for radiation with eventual androgen-deprivation therapy. This unusual site of prostate cancer spread heightens the need for awareness among providers as well as the need for further studies of the outcomes in these patients undergoing treatments designed using guidelines developed for those with normally functioning immunity.     

Neoplasms in dialysis patients: a population-based study

Cancer incidence was assessed in 4,161 end-stage renal disease (ESRD) patients on dialysis to determine whether there was any excess risk of cancer in this population. Records from the Michigan Kidney Registry (MKR) for 1973 to 1984 were linked to those of the Michigan Cancer Foundation's Metropolitan Detroit Cancer Surveillance System (MDCSS) to identify cases in the dialysis cohort. The expected number of cancers in the ESRD population was calculated using the race-, sex-, age- and calendar year-specific incidence rates of the tricounty metropolitan Detroit region of 4 million residents. The standardized incidence ratio (observed:expected) was significantly increased for all in situ tumors combined, as well as for invasive tumors of the kidney, the corpus uteri, and the prostate. The four-fold to five-fold excess (P less than 0.005) observed for renal and endometrial cancers, in addition to the significantly elevated (P less than 0.05) risk of prostate cancer indicates that patients maintained on dialysis should be evaluated for these tumors when they experience even minor symptoms. Population-based cancer and renal disease registries provide excellent opportunities for investigating etiologic hypotheses and future studies should incorporate potential risk factors when analyzing these data.     

How ESKD complicates the management of diabetic foot ulcers: The vital role of the dialysis team in prevention,early detection,and support of multidisciplinary treatment to reduce lower extremity amputations

Diabetic foot ulcers do not heal as well in ESKD as in the absence of kidney failure, and rates of recurrent foot ulcers, as well as lower extremity amputation, are higher. This review of the literature highlights the vital role of the dialysis team in prevention, early detection, and support of treatment of diabetic foot ulcers. Our review has five goals—(a) increase nephrologists’ understanding of the high morbidity and mortality associated with chronic foot ulcers and (lower extrimity) LE amputations in ESKD; (b) promote nephrologists’ understanding of grading systems for diabetic foot ulcer severity, in order to expedite communication with local diabetic foot experts; (c) promote collaboration between nephrologists and infectious disease specialists regarding the dose, route, and delivery logistics of intravenous antibiotics for infected chronic foot ulcers, in particular in the presence of osteomyelitis and other deep-seated infections; (d) increase the awareness of dialysis nurses, technicians, dietitians, social workers and administrators regarding evidence-based and multidisciplinary approaches to patients’ diabetic foot ulcers; (e) encourage the application of published works integrating patient-centered diabetic foot education into the dialysis setting to reduce lower extremity amputations.     

Obesity as a barrier to kidney transplantation: Time to eliminate the body weight bias?

There is clear evidence that survival rates following transplantation far exceed those for remaining on dialysis, regardless of body size measured by body mass index (BMI). Studies over the past 15 years also suggest little to no difference in long‐term outcomes, including graft survival and mortality, irrespective of BMI, in contrast to earlier evidence. However, weight bias still exists, as access to kidney transplantation remains inequitable in centers using arbitrary BMI limits. Clinicians faced with the decision regarding listing based on body size are not helped by conflicting recommendations in national and international guidelines. Therefore, in clinical practice, obesity, and recommendations for weight loss, remain a controversial issue when assessing suitability for kidney transplantation. Obesity management interventions in end‐stage kidney disease (ESKD), whether for weight loss for transplantation listing or for slowing kidney disease progression, are under‐explored in trial settings. Bariatric surgery is the most successful treatment for obesity, but carries increased risk in the ESKD population, and the desired outcome of kidney transplant listing is not guaranteed. Centers that limit transplants to those meeting arbitrary levels of body mass, rather than adopting an individualized assessment approach, may be unfairly depriving many ESKD patients of the survival and quality of life benefits derived from kidney transplantation. However, robotic kidney transplantation surgery holds promise for reducing perioperative risks related to obesity, and may therefore represent an opportunity to remove listing criteria based on size.     

Prostate cancer: a serious disease suitable for prevention

Prostate cancer is among the most common causes of death from cancer in men, and accounts for 10% of all new male cancers worldwide. The diagnosis and treatment of prostate cancer place a substantial physical and emotional burden on patients and their families, and have considerable financial implications for healthcare providers and society. Given that the risk of prostate cancer continues to increase with age, the burden of the disease is likely to increase in line with population life‐expectancy. Reducing the risk of prostate cancer has gained increasing coverage in recent years, with proof of principle shown in the Prostate Cancer Prevention Trial with the type 2 5α‐reductase (5AR) inhibitor, finasteride. The long latency period, high disease prevalence, and significant associated morbidity and mortality make prostate cancer a suitable target for a risk‐reduction approach. Several agents are under investigation for reducing the risk of prostate cancer, including selenium/vitamin E and selective oestrogen receptors modulators (e.g. toremifene). In addition, the Reduction by Dutasteride of Prostate Cancer Events trial, involving >8000 men, is evaluating the effect of the dual 5AR inhibitor, dutasteride, on the risk of developing prostate cancer. A successful risk‐reduction strategy might decrease the incidence of the disease, as well as the anxiety, cost and morbidity associated with its diagnosis and treatment.     

Different kidney function trajectory patterns before dialysis in elderly patients: clinical implications and outcomes

Background. Identifying trajectories of kidney disease progression in chronic kidney disease (CKD) patients may help to deliver better care. We aimed to identify and characterize trajectories of renal function decline in CKD patients and to investigate their association with mortality after dialysis.Methods. This retrospective cohort study included 378 CKD patients who initiated dialysis (aged 65 years and over) between 2009 and 2016. Were considered mixed models using linear quadratic and cubic models to define the trajectories, and we used probabilistic clustering procedures. Patient characteristics and care practices at and before dialysis were examined by multivariable multinomial logistic regression. The association of these trajectories with mortality after dialysis was examined using Cox models.Results. Four distinct groups of eGFR trajectories decline before dialysis were identified: slower decline (18.3%), gradual decline (18.3%), early rapid decline (41.2%), and rapid decline (22.2%). Patients with rapid eGFR decline were more likely to have diabetes, more cognitive impairment, to have been hospitalized before dialysis, and were less likely to have received pre-dialysis care compared to the patients with a slower decline. They had a higher risk of death within the first and fourth year after dialysis initiation, and after being more than 4 years in dialysis.Conclusions. There are different patterns of eGFR trajectories before dialysis initiation in the elderly, that may help to identify those who are more likely to experience an accelerated decline in kidney function, with impact on pre ESKD care and in the mortality risk after dialysis.     

Outcome of dialysis in children with human immunodeficiency virus infection

Human immunodeficiency virus (HIV) infection accounts for an unknown percentage of children with end-stage kidney disease (ESKD). Our objective was to compare the outcome of renal replacement therapy (RRT) in subjects with ESKD due to HIV and other diagnoses and to examine the prevalence of ESKD due to HIV. We analyzed Kt/V, morbidity, mortality, echocardiography, nutritional, and transplant status in 12 dialysis patients with HIV and 32 without HIV followed at our center between February 2002 and February 2007. Body mass index (BMI) was lower and Kt/V higher in HIV than in non-HIV patients. Shortening fraction was significantly lower in HIV patients. There were six deaths in the HIV group and one in the non-HIV group over the study period. Hemodialysis (HD) is the prevalent mode of RRT in HIV in urban settings, and its adequacy as measured by Kt/V was higher in HIV patients than in non-HIV patients. Decreased BMI and cardiovascular disease may be associated with increased mortality in children with HIV on RRT.     

Anemia management in cancer patients with chronic kidney disease

Cancer and kidney disease are linked by causality and comorbidities. Observational data show an increased risk of malignancy as renal function declines. Erythropoietin stimulating agents (ESAs), which are the cornerstone therapy for anemia patients with chronic kidney disease and cancer, are associated with increased risks for cancer, cancer‐related mortality, progression of disease, and thromboembolic events. This article examines the recently published guidelines for ESA use in cancer patients from the American Society of Clinical Oncology and American Society of Hematology and attempts to contextualize them to the care of patients with coexistent CKD, cancer, and anemia.