The increasing success of organ transplantation has significantly improved survival for patients with end-stage diseases, yet it introduces a complex dilemma: the elevated risk for the development of de novo gastrointestinal (GI) tumors. The sustained immunosuppression required to maintain graft function paradoxically undermines the body's natural defenses against cancer, leading to a higher incidence, aggressive progression, and atypical presentations of GI tumors among transplant recipients compared with the general population. This presents a pressing challenge: balancing the dual imperatives of preventing graft rejection and effectively managing malignancies. Current treatment paradigms, including surgical approaches, chemotherapy, radiation therapy, and the emerging role of immunotherapy, are fraught with complexities due to the altered immune landscape in these patients. This review underscores the critical need to understand the multifaceted relationship between post-transplantation immunosuppression and tumorigenesis, providing a comprehensive exploration of epidemiologic shifts, pathophysiologic insights, and the intricacies of the tumor microenvironment in this unique patient population. Understanding and managing GI tumors in transplant recipients is not only a clinical challenge, but also a necessary frontier in transplant oncology, promising to refine therapeutic strategies and improve the longevity and quality of life for this growing patient cohort.

Late kidney allograft loss occurs through one of two mechanisms: ( 1 ) deterioration of kidney function leading to retransplantation or dialysis (death-censored graft loss) and ( 2 ) premature death with a normally functioning transplant (death with graft function)-each accounting for approximately 50% of late kidney graft losses. Late death-censored graft loss typically results from a combination of immune and nonimmune events leading to common nonspecific end points ( e.g ., tubular atrophy, interstitial fibrosis, and glomerulosclerosis). Conversely, leading causes of death with graft function typically include cardiovascular events, malignancy, and infection. With an improved understanding of the multiple mechanism by which late graft dysfunction develops, there is an opportunity to identify patients at greatest risk and institute novel strategies to quell the process. Newer cardiometabolic agents with proven benefit in the general population have not been well-studied in kidney transplant recipients. However, in addition to their potential benefits in reducing cardiovascular, infectious, and malignancy end points (thus minimizing death with graft function risk), many novel agents may have additional anti-inflammatory and/or antifibrotic benefit (minimizing death-censored graft loss risk) in the kidney transplant population. In this review, we summarize existing literature regarding major causes of death-censored graft loss and death with graft function and discuss the potential roles of new cardiorenal metabolic agents including sodium-glucose cotransport 2 inhibitors, nonsteroidal mineralocorticoid receptor antagonists, glucagon-like peptide 1 receptor agonists, and dual endothelin and angiotensin receptor antagonists in the kidney transplant population, including potential mechanisms to improve death with graft function and death-censored graft loss outcomes.

Kidney transplant (KT) patients have higher risks of developing de novo colorectal cancer (CRC) compared to the general population. However, there is still a knowledge gap in their clinical characteristics, as most single- or multi-center efforts are underpowered and lack generalizability.

PubMed, Web of Science, Cochrane CENTRAL, and Scopus databases were queried for studies published until July 22nd, 2024. Studies reporting the clinicopathologic characteristics and outcomes of de novo CRC among KT recipients were included.

There were 49 articles included involving 1855 KT patients who developed CRC. The mean time from transplantation to CRC diagnosis was 8·7 years (95%CI 7·2, 10·3 years; I2 = 98·3%). De novo CRC was most commonly located in the ascending colon (43·6%; 95%CI 29·5%, 58·9%; I2 = 55·3%), and 37·1% had advanced CRC at diagnosis (95%CI 22·3%, 54·8%; I2 = 64·1%). Although 68·8% underwent curative intent treatment (95%CI 45·4%, 85·4%; I2 = 65·4%), pooled 5-year survival rate was 31·8% (95%CI 10·5%, 65·1%; I2 = 82·5%).

De novo CRC was diagnosed in under 10 years after KT, and nearly 40% of patients already have advanced stage disease at diagnosis. The pooled rate of 5-year survival was 31.8%. However, there was wide heterogeneity between studies and further research is required. PROSPERO Registration: CRD42023415767.

People with kidney failure have a higher risk of cancer compared with age- and sex-matched individuals in the general population, yet data from southern Europe are limited. This study explores cancer incidence in the kidney failure population in Catalonia.

We identified cancer cases through linkage of the Catalan Kidney Registry with Catalan cancer databases. Standardized incidence ratios (SIRs) were calculated for all-site and site-specific cancers in people on dialysis and kidney transplant recipients.

We described the epidemiology of cancer in 21 595 people on dialysis and 8037 kidney transplant recipients in Catalonia (2003-21). Cancer risk was more than two times higher in people on dialysis (SIR 2.11, 95% CI 2.02-2.19) and nearly four times higher in kidney transplant recipients (SIR 3.82, 95% CI 3.65-3.99) compared with the general population. Risks varied by cancer site, with a significantly higher incidence of kidney and thyroid cancers in the dialysis cohort, and skin cancer in the transplant cohort. The highest cancer risks were observed in the youngest, those with glomerular diseases, and those with the longest time since transplantation.

People with kidney failure face a high burden of cancer, particularly after kidney transplantation. Understanding the epidemiology of cancer in the kidney failure population is crucial for shaping health policies.

Kidney transplant (KT) recipients are at an elevated risk of developing de novo cancers. However, penile (PeCa) and testis cancers have received limited attention in this setting.

To summarize the epidemiology, treatment options, and oncological outcomes of penile and testis cancer in KT recipients.

We conducted a systematic review of prospective, retrospective and national transplant registries studies published up to December 2023. Data on the incidence of penile and testis cancers among KT recipients, diagnostic protocols, screening recommendations, and therapeutic strategies tailored for KT recipients were collected. The risk of bias (RoB) of included studies was determined using the Newcastle and Ottawa scale.

Overall, 21 studies involving 67924 KT male recipients were included. PeCa was diagnosed in 33 patients, yielding an incidence ranging from 0.04% to 0.3%. Additionally, 67 cases of testicular cancer were recorded, with an incidence ranging from 0.03% to 0.55%. Most tumors were localized, and histology variants were uncommon. While the surgical treatment of the primary tumor remains consistent with that of the general population, the use of radiotherapy and cytotoxic treatments are less frequently reported in this setting. These therapies should be considered on an individualized basis to minimize the risk of graft injury.

Penile and testis cancers are relatively uncommon among KT recipients. General screening protocols and deviation from current treatment guidelines are not recommended in localized diseases. Given the risk of graft damage, any non-cytotoxic option should be preferred in locally advanced cases.

Renal cell carcinoma (RCC) is the most common solid-organ malignancy in Western countries, and upper tract urothelial carcinoma (UTUC) is the most common malignancy in Asian countries. The management of RCC/UTUC in kidney transplant recipients is complex and clinically challenging due to post-transplant modifications associated with immunosuppressive treatment. This retrospective study evaluated the incidence, risk factors, treatment outcomes, and oncological implications of RCC and UTUC in kidney transplant recipients from 2008 to 2023. Data were collected from clinical records, and follow-up calls for 20 patients diagnosed with RCC and UTUC among 2,283 kidney transplant recipients, revealing an incidence rate of 0.78% for RCC (18 patients) and 0.087% (two patients) for UTUC. Most patients presented localized disease at diagnosis. Surgical interventions included radical nephrectomy for the native kidney's RCC, radical or partial nephrectomy for allograft RCC, and radical nephroureterectomy for UTUC in the native kidney and allograft. Oncological outcomes indicated a mean follow-up of 51.29 months, during which five patients (25%) developed metastases, which achieved prolonged survival through surgical management, adjuvant therapy, and immunosuppression adjustments. The study highlights the increased cancer risk in this population and underscores the necessity for established screening protocols and individualized treatment strategies to optimize patient outcomes while preserving kidney function. These findings contribute to the ongoing research on managing malignancies in transplant recipients, with implications for further research and clinical guidelines.

Organ transplantation is a lifesaving procedure, with 50,000 transplants happening every year in the United States. However, many patients harbor antibodies and B cells directed against allogeneic human leukocyte antigen (HLA) molecules, notably HLA-A2, greatly decreasing their likelihood of receiving a compatible organ. Moreover, antibody-mediated rejection is a significant contributor to chronic transplant rejection. Current strategies to desensitize patients non- specifically target circulating antibodies and B cells, resulting in poor efficacy and complications. Regulatory T cells (Tregs) are immune cells dedicated to suppressing specific immune responses by interacting with both innate and adaptive immune cells. Here, we genetically modified human Tregs with a chimeric anti-HLA antibody receptor (CHAR) consisting of an extracellular HLA-A2 protein fused to a CD28-CD3zeta intracellular signaling domain, driving Treg activation upon recognition of anti-HLA-A2 antibodies on the surface of alloreactive B cells. We find that HLA-A2 CHAR Tregs get activated specifically by anti-HLA-A2 antibody-producing cells. Of note, HLA-A2 CHAR activation does not negatively affect Treg stability, as measured by expression of the Treg lineage transcription factors FOXP3 and HELIOS. Interestingly, HLA-A2 CHAR Tregs are not cytotoxic towards anti-HLA-A2 antibody-producing cells, unlike HLA-A2 CHAR modified conventional CD4 + T cells. Importantly, HLA-A2 CHAR Tregs recognize and significantly suppress high affinity IgG antibody production by B cells from HLA-A2 sensitized patients. Altogether, our results provide proof-of-concept of a new strategy to specifically inhibit alloreactive B cells to desensitize transplant recipients.

Kidney transplantation is considered the best long-term option for patients with end-stage renal disease; however, immunosuppression increases the risk of developing malignancies. Approximately 0.2-0.5% of kidney transplant recipients experience renal cell carcinoma (RCC) in their allografts. Recently, nephron-sparing surgery has become widely accepted because of its favorable survival outcomes and low risk of recurrence.

In this study, we retrospectively evaluated the peri- and postoperative outcomes of robot-assisted partial nephrectomy (RAPN) and open partial nephrectomy (OPN) for allograft RCC, analyzing five and six patients who underwent OPN and RAPN, respectively, from 1998 to 2023.

The estimated blood loss was significantly lower in the RAPN group than in the OPN group (6.5 mL [interquartile range (IQR): 1-15] vs. 350 mL [IQR: 139-560], P = 0.006), whereas the operative and renal arterial clamping times were similar. Additionally, the perioperative complication rate and severity were lower in the RAPN group, resulting in a significantly shorter postoperative hospital stay than the OPN group (3 days [IQR: 2-5] vs. 10 days [IQR: 8-12], P = 0.01). Postoperative renal function and oncological outcomes were similar between the two groups.

RAPN for allograft RCC demonstrated advantages in terms of estimated blood loss and postoperative hospital stay compared with OPN, even though the patients' backgrounds were not adjusted. Therefore, RAPN may be a viable option for managing T1 allograft tumors.

There are conflicting results regarding survival in preemptive versus non-preemptive kidney transplant recipients. The present study aimed to estimate the risk of death in preemptive versus non-preemptive kidney transplant recipients.

In the present retrospective cohort study, all end-stage renal disease (ESRD) patients who underwent kidney transplantation between 1996 and 2021 in referral kidney transplantation centers in Isfahan province were investigated. In total, 499 patients who received dialysis before kidney transplantation (non-preemptive) and 168 patients who received no dialysis before kidney transplantation (preemptive) were included in the final analysis. Data regarding demographic and clinical variables including sex, age, body mass index (BMI), follow-up duration, immunosuppressive regimen change, kidney donor type, underlying causes of ESRD, and comorbidities before and after kidney transplantation were collected.

The mean age was 55.47 ± 15.53 years in preemptive and 54.87 ± 14.69 years in non-preemptive patients (P = 0.65). Mortality rates were 24.44/1000 person-years of follow-up for preemptive and 18.25/1000 person-years of follow-up for non-preemptive patients (P = 0.013). In the crude model of Cox regression analysis, preemptive kidney transplant recipients had a significantly higher risk of mortality compared to non-preemptive kidney transplant recipients (hazard ratio [HR] = 1.59; 95% confidence interval [CI]: 1.09-2.33; P = 0.015). However, the association attenuated and became insignificant after adjustment for confounders, including age, BMI, immunosuppressive regimen change, kidney donor type, and comorbidities (HR = 1.35; 95% CI: 0.92-1.99; P = 0.12).

The results of the present study indicated that there is no independent association between preemptive kidney transplantation and increased risk of mortality.

Because of the risk of tumor implantation, a kidney with a small renal mass is not accepted as a donor in the kidney transplant program. Here, we evaluated the long-term outcomes of transplantation of kidneys with small renal mass.

We reviewed 14 donors who had been incidentally diagnosed with a small renal mass during standard donor evaluation. All donors underwent laparoscopic donor nephrectomy followed by bench resection of the mass. The negative margins were confirmed on the frozen section.

On histopathological examination, 6 masses were reported as renal cell carcinoma, 4 were angiomyolipomas, 2 were oncocytoma, and 2 were papillary adenoma. After a median follow-up of 30 months, no recurrences were shown in the recipients. All recipients showed stable graft function.

When no other donor is available, a kidney with a small renal mass can be considered for living related kidney transplant. Bench excision of the mass was oncologically safe, with recipients having good long-term outcomes.

End-stage renal failure has negative effects on sexual life, and solid kidney transplantation helps to recovery in sexuality. However, recovery in sexual life progresses slowly, and female recipients may need spousal support during this process. To examine the perceived spousal support and sexual lives of female kidney recipients in the aim of this study.

The study was conducted as a descriptive and cross-sectional research. 158 female kidney recipients were included in the study. In data collection, Personal Information Form, Spousal Support Scale, and Arizona Sexual Experience Scale were used. The study data were analyzed through descriptive statistics, Mann-Whitney U test, Kruskal-Wallis test, Dunn-Bonferroni post-hoc test, and Spearman correlation analysis.

In this study 47.5 % of the female recipients were within the age range of 28-40 years. 43.7 % had university education and above. 60.1 % had their income equal to their expenses. 38 % of the female kidney recipients suffered from diabetes mellitus and endocrine problems. In this study, sexual dysfunction of female kidney recipients was found to be slightly above average. The spouse support perceived by the female recipients was well above average. As a result of this study was determined that as the economic status of the female recipients improved, perceived spousal support increased (p < 0.05). It was also determined that the female kidney recipients who were 40 years old and above, had poor economic status, used Tacrolimus and Cyclosporine, and had a comorbid chronic disease were under more risk in terms of poor sexual life, and their perceived spousal support was above moderate level.

The sexual life of female kidney recipients is affected by their clinical situation (concomitant diseases, advanced age, medication use). On the other hand, strong spouse support can make significant contributions to improving sexual life. A correlation was found in the study between sexual life and perceived spousal support in the female kidney recipients. The findings of the study point to the importance of spousal support in terms of improving sexual lives in female kidney recipients. Studies should be conducted on these two important concepts in planning care interventions and training programs.

Renal cell carcinoma (RCC) is one of the most prevalent cancers in kidney transplant recipients (KTR). The hereditary background of RCC in native kidneys has been determined, implicating its clinical importance.

This retrospective single-center pilot study aimed to identify a potential genetic predisposition to RCC of the transplanted kidney and outcome in KTR who underwent single kidney transplantation between January 2000 and December 2020 and manifested RCC of the transplanted kidney. Next-generation sequencing (NGS) based germline genetic analysis from peripheral blood-derived genomic DNA (gDNA) was performed in both the recipient and donor using a gene panel targeting 226 cancer predisposition genes.

The calculated incidence of RCC of the transplanted kidney among 4146 KTR was 0.43%. In fifteen KTR and donors, NGS was performed. The mean KTR age at transplantation and the diagnosis of RCC was 50.3 years (median 54; 5-67 years) and 66 years (median 66; 24-79 years), respectively. The mean donor age at transplantation and graft age at RCC diagnosis was 39.7 years (median 42; 7-68 years) and 50.2 years (median 46; 20-83 years), respectively. The mean follow-up after RCC diagnosis was 47 months (median 39.1; 0-112 months). Papillary RCC was the most prevalent (n = 8), followed by clear cell RCC (n = 6) and unspecified RCC (n = 1). Thirteen RCCs were low-stage (pT1a/b) diseases, one was pT3, and one was of unknown stage. Most RCC was higher graded. No germline pathogenic cancer-predisposition variant was found in either KTR or donors except for several variants of uncertain significance.

RCC of the transplanted kidney is very rare. Germline cancer-predisposition testing has identified several variants of uncertain significance, but no germline genetic predisposition to graft RCC in KTR. Further research is needed to assess the clinical relevance of genetic testing for cancer risk in KTR.

Limited data are available on the adverse effects of new-onset diabetes after transplantation (NODAT) in solid organ transplantation (TPL) other than kidney. This study aimed to identify the risk of complications associated with NODAT in recipients of kidney, liver, or heart TPL.

Using the Korean National Health Insurance Service database, recipients of kidney, liver, or heart TPL between 2009 and 2015 were identified. The incidence of coronary artery disease (CAD), cerebrovascular accident (CVA), and malignancy was compared across groups with NODAT, pretransplant diabetes mellitus (DM), and without DM using Cox regression analysis.

A total of 9,632 kidney, liver, or heart TPL recipients were included. During the median follow-up of 5.9 years, NODAT independently increased the incidence of CAD (hazard ratio [HR], 2.46; 95% confidence interval [CI], 1.39 to 4.30) and overall mortality (HR, 1.48; 95% CI, 1.14 to 1.95) compared to the reference group even after adjustment for confounders; this was more prominent in kidney TPL than in liver TPL. The risk of CVA was significantly increased by pretransplant DM but not by NODAT in both kidney and liver TPL (HR, 2.47; 95% CI, 1.68 to 3.65; and HR, 3.18; 95% CI, 1.07 to 9.48, respectively). NODAT increased the risk of malignancy in the crude model, which lost its statistical significance after confounder adjustment.

NODAT independently increases the risk of CAD and mortality after TPL, which is more evident in kidney recipients. There was no additional increased risk of CVA or malignancy with NODAT in solid organ TPL.

De novo renal transplant carcinoma, especially in the context of bilateral renal carcinoma, is rare and often presents as small, low-grade papillary renal cell carcinoma (RCC). There is currently no consensus or effective treatment for advanced metastatic RCC after kidney transplantation. A 40-year-old man developed de novo renal transplant carcinoma with venous thrombus and lung metastases 13 years after transplantation. The patient underwent cytoreductive nephrectomy followed by sequential treatment with tyrosine kinase inhibitors (TKI) and anti-PD-1 monoclonal antibodies. After 2 years, the patient showed excellent graft function with no evidence of cancer progression. Despite subsequent graft failure, the disease remained controlled for more than 2 years and the patient survived for more than 3 years, which was significantly longer than the typical survival of 10 to 20 months in patients with advanced kidney cancer. The results suggest that combining cytoreductive nephrectomy with TKI and anti-PD-1 therapy may significantly prolong survival in patients with renal allograft carcinoma.

Advances in immunosuppressive therapy and postoperative management have greatly improved the graft and patient survival rates after kidney transplantation; however, the incidence of post-transplant malignant tumors is increasing. Post-renal transplantation malignant tumors are associated with renal failure, immunosuppression, and viral infections. Moreover, the risk of developing cancer is higher in kidney transplant recipients than in the general population, and the tendency to develop cancer is affected by the background and environment of each patient. Recently, cancer after kidney transplantation has become the leading cause of death in Japan. Owing to the aggressive nature and poor prognosis of genitourinary malignancies, it is crucial to understand their epidemiology, risk factors, and best practices in kidney transplant recipients. This review has a special emphasis on the epidemiology, risk factors, and treatment protocols of genitourinary malignancies in kidney transplant recipients to enhance our understanding of the appropriate management strategies. Optimal immunosuppressive therapy and cancer management for these patients remain controversial, but adherence to the general guidelines is recommended.

Patients treated with kidney replacement therapy experience a 1.5- to 2-fold increased risk of cancer and cancer mortality compared with the general population. Whether this excess risk extends to people with earlier stage chronic kidney disease and whether reduced kidney function is causally related to cancer is unclear.

Two-sample Mendelian randomization (MR).

Genome-wide association study (GWAS) summary statistics for estimated glomerular filtration rate (eGFR) (n=567,460) and urinary albumin-creatine ratio (UACR) (n=127,865) from the CKDGen consortium and cancer outcomes from the UK Biobank (n = 407,329).

eGFR and UACR.

Overall cancer incidence, cancer-related mortality and site-specific colorectal, lung, and urinary tract cancer incidence.

Univariable and multivariable MR conducted for all outcomes.

The mean eGFR and median UACR were 91.4mL/min/1.73m2 and 9.32mg/g, respectively, in the CKDGen, and 90.4mL/min/1.73m2 and 9.29mg/g, respectively, in the UK Biobank. There were 98,093 cases of cancer, 15,850 cases of cancer-related death, 6,664 colorectal, 3584 lung, and 3,271 urinary tract cancer cases, respectively. The genetic instruments for eGFR and UACR comprised 34 and 38 variants, respectively. Genetically predicted kidney function (eGFR and UACR) was not associated with overall cancer risk or cancer death. The association between genetically predicted eGFR and UACR and overall cancer incidence had an odds ratio of 0.88 ([95% CI, 0.40-1.97], P=0.8) and 0.90 ([95% CI, 0.78-1.04], P=0.2) respectively, using the inverse-variance weighted method. An adjusted generalized additive model for eGFR and cancer demonstrated evidence of nonlinearity. However, there was no evidence of a causal association between eGFR and cancer in a stratified MR.

To avoid overlapping samples a smaller GWAS for UACR was used, which reduced the strength of the instrument and may introduce population stratification.

Our study did not show a causal association between kidney function, overall cancer incidence, and cancer-related death.

Does reduced kidney function cause cancer? Patients with chronic kidney disease have been shown to have an increased risk of cancer and cancer-related death. However, it is not clear whether kidney disease is causally related to cancer or the association is due to other factors such as immune suppression and inflammation or a result of distortion of the analyses from unidentified variables (confounding). We used large, published genetic studies as well a database including 407,329 people in the United Kingdom in a series of Mendelian randomization analysis. Mendelian randomization uses the random assignment of genetic variants at birth to investigate causal relationships without confounding from measured and unmeasured confounders. We found that there is no evidence of a causal relationship between reduced kidney function and cancer.

To evaluate the cancer mortality risk among solid organ transplant recipients through a systematic review and meta-analysis.

Systematic searches were conducted in PubMed (starting from 1965), ISI Web of Science (starting from 1900), MEDLINE (starting from 1976), and Scopus (starting from 1968) from the inception of each database until July 15, 2024. Studies published in English reporting at least one type of cancer mortality risk among recipients of any type of solid organ transplantation were included. The main outcomes were the standardized mortality ratio (SMR) for cancer mortality in transplant recipients compared to the general population, and the hazard ratio (HR) for cancer mortality in transplant recipients versus cancer patients without prior transplantation.

Solid organ transplant recipients had a 2.06-fold increased cancer mortality risk (SMR, 2.06 [95 % CI, 1.56-2.71]) than the general population. Risks were higher in kidney (SMR 1.92 [95 % CI: 1.30-2.84]), liver (SMR 3.07 [95 % CI: 1.80-5.24]), and lung/heart (SMR 4.87 [95 % CI: 3.33-7.12]) transplant recipients. Cancer patients with prior transplantation had a 1.47-fold increased cancer mortality risk (HR 1.47 [95 % CI: 1.29-1.68]) than those without. East Asia female transplant recipients exhibited higher mortality risks from breast, ovarian, cervix and uterus cancers than those from other regions (SMR 3.13 [95 % CI: 1.93-5.07] vs. 1.16 [95 % CI: 0.88-1.53], P < 0.01).

Solid organ transplant recipients face significantly higher cancer mortality risks than the general population, highlighting the need for targeted cancer screening and interventions, especially for female solid organ transplant recipients from East Asia.

Cancer is a major cause of morbidity and mortality in kidney transplant patients. Unfortunately, the use of new anti-cancer therapies such as immune checkpoint inhibitors (ICPIs) in this population has been associated with rejection rates up to 40%, in retrospective studies. The main challenge is to maintain the patient in a delicate immunologic balance in which, while antitumor therapy defeats cancer the graft is safely protected from rejection. Recent clinical trials with ICPI have included kidney transplant recipients (KTRs) and the results advocate for a paradigm shift in the management of basal immunosuppression. This suggests that downward adjustments should be avoided or, even better, that this adjustment should be "dynamic." This review summarizes the latest scientific evidence available in renal transplantation under ICPI treatment: case series, prospective studies, histopathologic diagnosis, immunosuppression regimens and new biomarkers. This article will provide the latest information in on this specific field, allowing nephrologists to gain valuable knowledge and to be aware of new approaches to immunosuppression management in oncological kidney transplant patients.

The TWO Study (Transplantation Without Overimmunosuppression) aimed to investigate a novel approach to regulatory T-cell (Treg) therapy in renal transplant patients, using a delayed infusion protocol at 6 mo posttransplant to promote a Treg-skewed lymphocyte repopulation after alemtuzumab induction. We hypothesized that this would allow safe weaning of immunosuppression to tacrolimus alone. The COVID-19 pandemic led to the suspension of alemtuzumab use, and therefore, we report the unique cohort of 7 patients who underwent the original randomized controlled trial protocol. This study presents a unique insight into Treg therapy combined with alemtuzumab and is therefore an important proof of concept for studies in other diseases that are considering lymphodepletion.

Living donor kidney transplant recipients were randomized to receive autologous polyclonal Treg at week 26 posttransplantation, coupled with weaning doses of tacrolimus, (Treg therapy arm) or standard immunosuppression alone (tacrolimus and mycophenolate mofetil). Primary outcomes were patient survival and rejection-free survival.

Successful cell manufacturing and cryopreservation until the 6-mo infusion were achieved. Patient and transplant survival was 100%. Acute rejection-free survival was 100% in the Treg-treated group at 18 mo after transplantation. Although alemtuzumab caused a profound depletion of all lymphocytes, including Treg, after cell therapy infusion, there was a transient increase in peripheral Treg numbers.

The study establishes that delayed autologous Treg therapy is both feasible and safe, even 12 mo after cell production. The findings present a new treatment protocol for Treg therapy, potentially expanding its applications to other indications.

Use of antihypertensive medications could be associated with an increased risk of kidney cancer. Despite their various mechanisms of action, whether this association differs between different classes of medications remains unclear.

The objective of this study is to compare the risk of kidney cancer between first-line treatment options of antihypertensive medications in a hypertensive population.

In this retrospective cohort study, we used the MarketScan Databases (2007-2021). We included individuals older than 30 years of age with a diagnosis of hypertension who received first-line medications for hypertension, which included three classes: angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), and dihydropyridine calcium channel blockers (dCCB). We applied a propensity score matching method and created three separate cohorts: (1) ARB versus ACEI, (2) dCCB versus ACEI, and (3) dCCB versus ACEI. For non-dCCB, we repeated the analyses. The primary outcome was kidney cancer incidence. To assess kidney cancer risk, we applied multivariable conditional Cox proportional hazards models.

In the first cohort, ARB use was associated with an increased risk of kidney cancer compared to ACEI use (hazard ratio [HR] 1.10, 95% confidence interval [CI] 1.02-1.18). In the second cohort, dCCB use was associated with an increased risk of kidney cancer compared to ACEI use (HR 1.29, 95% CI 1.18-1.40). In the third cohort, dCCB use was associated with a higher risk of kidney cancer compared to ARB use (HR 1.17, 95% CI 1.08-1.28). Null association was shown when comparing non-dCCB with ACEI or ARB use.

Use of dCCB showed a higher risk of kidney cancer compared to ACEI or ARB use in patients with hypertension.

As the population ages and post-transplant survival improves, pretransplant and post-transplant malignancy are becoming increasingly common. In addition, rapid advances in cancer therapies and improving outcomes prompt us to rethink pretransplant cancer-free wait time and screening strategies. Although kidney transplant recipients (KTRs) are at higher risk of developing cancer, epidemiological data on how to best screen and treat cancers in KTRs are incomplete. Thus, current recommendations are still largely on the basis of studies in the general population, and their validity in KTRs is uncertain. Kidney transplant candidates without prior cancer should be evaluated for latent malignancies even in the absence of symptoms. Conversely, individuals with a history of malignancy require thorough monitoring to detect potential recurrences or de novo malignancies. When treating KTRs with cancer, reducing immunosuppression can enhance antitumor immunity, yet this also increases the risk of graft rejection. Optimal treatment and immunosuppression management remains undefined. As the emergence of novel cancer therapies adds complexity to this challenge, individualized risk-benefit assessment is crucial. In this review, we discuss up-to-date data on pretransplant screening and cancer-free wait time, as well as post-transplant cancer screening, prevention strategies, and treatment, including novel therapies such as immune checkpoint inhibitors and chimeric antigen receptor T-cell therapies.

Number of organ transplant recipients continues to rise worldwide with increasing accessibility and growing advancements in transplant medicine. Transplant patients have at least a two-to-four fold higher risk of developing cancer compared to the general population. As the prevalence of transplant patients increases, a growing number of these patients are expected to present with concurrent conditions such as cancer, requiring more complex and interdisciplinary care.

A 44-year-old patient with an intraperitoneal pelvic renal transplant, found to have high-grade ovarian adenocarcinoma most likely arising from endometriosis, successfully underwent surgical staging, adjuvant chemotherapy, and subsequent pelvic radiation for recurrence. Her kidney function and graft viability were preserved throughout her treatment with careful monitoring.

Management of reproductive tract cancers in kidney transplant recipients is complex. Current practices largely rely on evidence from observational studies and case reports for these cancers and more research is needed in this area.

The population with kidney failure is at increased risk of cancer and associated mortality. Relative survival can provide insight into the excess mortality, directly or indirectly, attributed to cancer in the population with kidney failure.

We estimated relative survival for people all ages receiving dialysis (n = 4089) and kidney transplant recipients (n = 3253) with de novo cancer, and for the general population with cancer in Australia and New Zealand (n = 3 043 166) over the years 1980-2019. The entire general population was the reference group for background mortality, adjusted for sex, age, calendar year and country. We used Poisson regression to quantify excess mortality ratios.

Five-year relative survival for all-site cancer was markedly lower than that for the general population for people receiving dialysis [0.25, 95% confidence interval (CI) 0.23-0.26] and kidney transplant recipients (0.55, 95% CI 0.53-0.57). In dialysis, excess mortality was more than double (2.16, 95% CI 2.08-2.25) that of the general population with cancer and for kidney transplant recipients 1.34 times higher (95% CI 1.27-2.41). There was no difference in excess mortality from lung cancer between people with kidney failure and the general population with cancer. Comparatively, there was a significant survival deficit for people with kidney failure, compared with the general population with cancer, for melanoma, breast cancer and prostate cancers.

Decreased cancer survival in kidney failure may reflect differences in multi-morbidity burden, reduced access to treatment, or greater harm from or reduced efficacy of treatments. Our findings support research aimed at investigating these hypotheses.

Previous solid organ transplantation has been associated with worse survival among colorectal cancer (CRC) patients. This study investigates the contribution of CRC characteristics and treatment-related factors to the differential survival. Using the Swedish register-linkage CRCBaSe, all patients with solid organ transplantation before CRC diagnosis were identified and matched with non-transplanted CRC patients. Associations between transplantation history and clinical CRC factors and survival were estimated using the Kaplan-Meier estimator and logistic, multinomial, and Cox regression, respectively. Ninety-eight transplanted and 474 non-transplanted CRC patients were followed for 5 years after diagnosis. Among patients with stage I-III cancer, transplanted patients had lower odds of treatment with abdominal surgery [odds ratio (OR):0.27, 95% confidence interval (CI):0.08-0.90], than non-transplanted patients. Among those treated with surgery, transplanted colon cancer patients had lower odds of receiving adjuvant chemotherapy (OR:0.31, 95% CI:0.11-0.85), and transplanted rectal cancer patients had higher rate of relapse (hazard ratio:9.60, 95% CI:1.84-50.1), than non-transplanted patients. Five-year cancer-specific and overall survival was 56% and 35% among transplanted CRC patients, and 68% and 57% among non-transplanted. Accordingly, transplanted CRC patients were treated less intensely than non-transplanted patients, and had worse cancer-specific and overall survival. These patients might benefit from multidisciplinary evaluation including transplantation specialists.

Improving access to kidney transplants remains a priority for the transplant community. However, many medical, psychosocial, geographic, and socioeconomic barriers exist that prevent or delay transplantation for candidates with certain conditions. There is a lack of consensus regarding how to best approach many of these issues and barriers, leading to heterogeneity in transplant centers' management and acceptance practices for a variety of pretransplant candidate issues. In this review, we address several of the more common contemporary patient medical and psychosocial barriers frequently encountered by transplant programs. The barriers discussed here include kidney transplant candidates with obesity, older age, prior malignancy, cardiovascular disease, history of nonadherence, and cannabis use. Improving understanding of how to best address these specific issues can empower referring providers, transplant programs, and patients to address these issues as necessary to progress toward eventual successful transplantation.

The management of noninfectious complications in kidney transplant recipients includes a broad spectrum of conditions, including metabolic issues, cardiovascular diseases, and malignancies, each presenting unique challenges for nephrologists managing these patients. Unlike infectious complications, these noninfectious issues require nuanced, multidisciplinary approaches for prevention, diagnosis, and management, emphasizing the need for personalized care plans. Cardiovascular disease is particularly significant, standing as the primary cause of death post-transplantation, with recent data indicating an overtaking of cancer death rates over infections among kidney transplant recipients. The intricacies of managing these patients, influenced by the burden of kidney disease and immunosuppression, highlight the importance of a collaborative care model. Although nephrologists may not directly treat all these conditions, their understanding of the unique aspects of transplant recipients is crucial. They play a pivotal role in coordinating care with specialists such as cardiologists, endocrinologists, hematologists, and oncologists, ensuring comprehensive management that addresses these specific post-transplant complications. This review discusses the epidemiology, underlying mechanisms, clinical manifestations, and management strategies of various noninfectious complications post-kidney transplant, with a focus on cardiovascular, metabolic, oncologic, and hematologic complications.

Post-transplantation cancer is a significant cause of mortality among kidney transplant recipients (KTR). The incidence of post-transplantation cancer varies based on geographic region and ethnicity. However, data on KTR from South East Asia, where characteristics differ from other parts of Asia, is lacking. We conducted a retrospective cohort study at a transplant center in Thailand to investigate the incidence of post-transplantation cancer and mortality rates. Factors associated with post-transplantation cancer and patient outcomes were analyzed using competing-risks regression. The study included 1156 KTR with a post-transplant follow-up duration of 5.1 (2.7-9.4) years. The age- and sex-adjusted incidence rate of post-transplant cancer was highest for urothelial cancer (6.9 per 1000 person-years), which also resulted in the highest standardized incidence ratio (SIR) of 42.5 when compared to the general population. Kidney cancer had the second-highest SIR of 24.4. Increasing age was the factor associated with an increased risk of post-transplant cancer (SHR 1.03; 95% CI 1.01-1.05). Human leukocyte antigen (HLA) DR mismatch was associated with a decreased risk of post-transplant cancer (SHR 0.72; 95% CI 0.52-0.98). Post-transplantation cancer was significantly associated with patient mortality (HR 3.16; 95% CI 2.21-4.52). Cancer significantly contributes to KTR mortality, and the risk profile for cancer development in Thai KTRs differs from that of Western and most Asian counterparts. Further research is essential to explore appropriate screening protocols for countries with high rates of urothelial and kidney cancer, including Thailand.

We describe the epidemiology of cancer after kidney transplantation (KTx), investigating its risk factors and impact on therapeutic management and survival in KTx recipients (KTRs). The association between modification of immunosuppressive (IS) therapy after cancer and survival outcomes was analyzed. We collected data from 930 KTRs followed for 7 [1-19] years. The majority of KTRs received KTx from a deceased donor (84%). In total, 74% of patients received induction therapy with basiliximab and 26% with ATG. Maintenance therapy included steroids, calcineurin inhibitors, and mycophenolate. Patients with at least one cancer (CA+) amounted to 19%. NMSC was the most common tumor (55%). CA+ were older and had a higher BMI. Vasculitis and ADPKD were more prevalent in CA+. ATG was independently associated with CA+ and was related to earlier cancer development in survival and competing risk analyses (p = 0.01 and <0.0001; basiliximab 89 ± 4 vs. ATG 40 ± 4 months). After cancer diagnosis, a significant prognostic impact was derived from the shift to mTOR inhibitors compared to a definitive IS drug suspension (p = 0.004). Our data confirm the relevance of cancer as a complication in KTRs with ATG as an independent risk factor. An individualized choice of IS to be proposed at the time of KTx is crucial in the prevention of neoplastic risk. Finally, switching to mTORi could represent an important strategy to improve patient survival.

Posttransplant malignancies are an important complication of solid organ transplantation. Kidney transplant recipients are at particularly high risk of cancer development. The most relevant risk factors of carcinogenesis are the use of immunosuppressive agents and oncogenic viral infections. Additionally, immune dysregulation caused by these factors may predispose to various types of organ damage. Paraneoplastic glomerular diseases are one of the most interesting and understudied cancer manifestations. The appropriate diagnosis of paraneoplastic glomerular damage can be challenging in kidney transplant recipients, due to factors inherent to concomitant medication and common comorbidities. Recent advances in the field of molecular and clinical nephrology led to a significant improvement in our understanding of glomerular diseases and their more targeted treatment. On the other hand, introduction of novel anticancer drugs tremendously increased patients' survival, at the cost of kidney-related side effects. Our review aims to provide insights into diagnosis and treatment of paraneoplastic glomerular diseases, with a special attention to kidney transplant recipients.

The interplay of onco-immunology and kidney transplantation heralds a transformative era in medical science. This integration, while promising, presents significant challenges. Chief among these is the dichotomy of immunosuppression-boosting immunity against malignancies while suppressing it for graft survival. Additionally, limited clinical data on novel therapies, genetic variations influencing responses, economic concerns, and the narrow therapeutic window for post-transplant malignancies necessitate strategic addressal. Conversely, opportunities abound, including personalized immune monitoring, targeted therapies, minimized immunosuppression, and improved patient quality of life. Emphasizing collaborative research and interdisciplinary cooperation, the merging of these fields offers the potential for enhanced graft survival and reduced post-transplant malignancy risks. As we harness modern technology and promote patient-centric care, the vision for the future of kidney transplantation becomes increasingly hopeful, paving the way for more personalized and effective treatments. The article aims to elucidate the critical challenge of balancing immunosuppression to simultaneously combat malignancies and ensure graft survival. It addresses the scarcity of clinical data on novel therapies, the impact of genetic variations on treatment responses, and the economic and therapeutic concerns in managing post-transplant malignancies. Furthermore, it explores the opportunities precision medicine offers, such as personalized immune monitoring, targeted therapies, and reduced immunosuppression, which could significantly improve patient outcomes. Highlighting the importance of collaborative research and interdisciplinary efforts, the article seeks to demonstrate the potential for enhanced graft survival and reduced post-transplant malignancy risks. By leveraging modern technology and prioritizing patient-centric care, it envisions a future where kidney transplantation is more personalized and effective, offering hope for advancements in this field.

This study investigates the incidence and clearance of cervical and anal high-risk human papillomavirus (hrHPV) infection in kidney transplant recipients (KTRs) compared to immunocompetent controls. During 2016-2017, we enrolled 125 female KTRs and 125 female controls. Liquid-based cervical and anal cytology samples collected at enrollment and follow-up were tested for human papillomavirus (HPV) DNA using the CLART HPV2 test. All participants answered a questionnaire on lifestyle and sexual behavior at both examinations. KTRs had an increased age-adjusted risk of incident cervical hrHPV infection compared to controls (hazard ratio [HR] = 3.6, 95% CI = 1.2-11.2). Probability of cervical hrHPV clearance at 18 months was lower among KTRs (8.3%) than controls (66.7%). There was no statistically significant difference in anal hrHPV incidence between KTRs and controls (HR = 0.9, 95% CI = 0.4-2.0). Clearance of anal hrHPV was similar between KTRs and controls at 18 months. During the total follow-up, a lower anal hrHPV clearance, although not statistically significant, was observed among KTRs (HR = 0.3, 95% CI = 0.06-1.2). KTRs had higher incidence of cervical hrHPV and lower probability of clearance, especially of cervical hrHPV infections, than controls. Our findings support that KTRs are at increased risk of HPV infection and point to the need for targeted HPV prevention strategies, such as cervical cancer screening.

Homoharringtonine (HHT) is an effective anti-inflammatory, anti-viral, and anti-tumor protein synthesis inhibitor that has been applied clinically. Here, we explored the therapeutic effects of HHT in a mouse heart transplant model.

Healthy C57BL/6 mice were used to observe the toxicity of HHT in the liver, kidney, and hematology. A mouse heart transplantation model was constructed, and the potential mechanism of HHT prolonging allograft survival was evaluated using Kaplan-Meier analysis, immunostaining, and bulk RNA sequencing analysis. The HHT-T cell crosstalk was modeled ex vivo to further verify the molecular mechanism of HHT-induced regulatory T cells (Tregs) differentiation.

HHT inhibited the activation and proliferation of T cells and promoted their apoptosis ex vivo . Treatment of 0.5 mg/kg HHT for 10 days significantly prolonged the mean graft survival time of the allografts from 7 days to 48 days ( P <0.001) without non-immune toxicity. The allografts had long-term survival after continuous HHT treatment for 28 days. HHT significantly reduced lymphocyte infiltration in the graft, and interferon-γ-secreting CD4 + and CD8 + T cells in the spleen ( P <0.01). HHT significantly increased the number of peripheral Tregs (about 20%, P <0.001) and serum interleukin (IL)-10 levels. HHT downregulated the expression of T cell receptor (TCR) signaling pathway-related genes ( CD4 , H2-Eb1 , TRAT1 , and CD74 ) and upregulated the expression of IL-10 and transforming growth factor (TGF)-β pathway-related genes and Treg signature genes ( CTLA4 , Foxp3 , CD74 , and ICOS ). HHT increased CD4 + Foxp3 + cells and Foxp3 expression ex vivo , and it enhanced the inhibitory function of inducible Tregs.

HHT promotes Treg cell differentiation and enhances Treg suppressive function by attenuating the TCR signaling pathway and upregulating the expression of Treg signature genes and IL-10 levels, thereby promoting mouse heart allograft acceptance. These findings may have therapeutic implications for organ transplant recipients, particularly those with viral infections and malignancies, which require a more suitable anti-rejection medication.

We assessed whether contemporary immunosuppression agents were associated with cancer among kidney transplant recipients (KTR), and if this association varied by age and sex. We studied a retrospective province-wide cohort of primary KTR (1997-2016). Employing multivariable Cox models, we estimated associations of cumulative doses of prednisone, mycophenolate and tacrolimus administered over the past 10 years, lagged by 2 years, with the incidence of primary malignant neoplasms (PMN). We assessed interactions with age and sex. To assess the impact of exposure recency, we used weighted cumulative exposure (WCE) modeling. Among 1064 KTR, 108 (10.2%) developed PMN over median follow-up of 73 months (interquartile range: 32-120). Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) of 0.96 (0.64-1.43), 1.34 (0.96-1.86), and 1.06 (0.88-1.29) were estimated for cumulative daily doses of prednisone (5 mg), mycophenolate (1000 mg), and tacrolimus (2 mg) administered continuously over the past 10 years, respectively. PMN risk associated with cumulative tacrolimus exposure was modified by age (interaction p = .035) and was more pronounced in 15-year and 30-year-old KTR (aHRs of 1.57 [1.08-2.28] and 1.31 [1.03-1.66], respectively) in comparison to older KTR. PMN risk increase associated with higher cumulative mycophenolate dose was more pronounced in females (aHR = 1.86 [1.15-3.00]) than in males (aHR = 1.16 [0.74-1.81]; interaction p = .131). WCE analyses suggested increased PMN risk the higher the mycophenolate doses taken 5-10 years ago. A trend toward increased PMN risk with long-term mycophenolate exposure, particularly in females, and more pronounced risk with long-term tacrolimus exposure in younger KTR, identify opportunities for tailored immunosuppression to mitigate cancer risk.

This systematic review and meta-analysis aims to investigate the prevalence of cervical high-risk human papillomavirus (hrHPV) among kidney transplant recipients (KTRs) and, furthermore to compare it to that in immunocompetent controls.

A systematic literature search was conducted in PubMed, EMBASE, and Cochrane Library databases from January 2000 to February 2023, to identify studies investigating the prevalence of cervical hrHPV in KTRs. Pooled cervical hrHPV prevalences, odds ratios (ORs) comparing KTRs to controls and corresponding confidence intervals (CIs) were estimated using random effects logistic regression models. Heterogeneity between studies was assessed through the I2 statistic, and the significance was evaluated by the Cochrane's Q test.

Altogether, 16 studies covering >1200 KTRs were included. The prevalence of cervical hrHPV in KTRs was 27.7% (95% CI 21.3-35.1) with substantial interstudy heterogeneity. Stratification indicated a higher prevalence in recent years (2019-2023) and in Asia (39% (95% CI 11.2-61.4)). The prevalence of HPV16 and HPV18 in KTRs was 8.0% (95% CI 3.9-15.9) and 1.7% (95% CI 0.8-3.7), respectively. Comparing hrHPV prevalence in KTRs and controls based on six studies including >500 KTRs and 1000 controls, the OR for hrHPV was 2.0 (95% CI 1.1-3.6).

This meta-analysis establishes an increased cervical hrHPV prevalence in KTRs compared to controls. The increased risk may be associated with immunosuppressive therapy post-transplantation. Further research is needed to explore the potential benefits of HPV vaccination, including potential revaccination strategies in KTRs.

Cancer is a common complication after kidney transplantation. Kidney transplant recipients (KTR) have a 2- to 4-fold higher risk of developing cancer compared to the general population and post-transplant malignancy is the third most common cause of death in KTR. Moreover, it is well known that certain cancer types are overrepresented after transplantation, especially non-melanoma skin cancer. Immune checkpoint inhibitors (ICI) have revolutionized the treatment of cancer, with remarkable survival benefit in a subgroup of patients. ICI are monoclonal antibodies that block the binding of specific co-inhibitory signaling molecules. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1), and its ligand programmed cell death ligand 1 (PD-L1) are the main targets of ICI. Solid organ transplant recipients (SOTR) have been excluded from clinical trials owing to concerns about tumor response, allo-immunity, and risk of transplant rejection. Indeed, graft rejection has been estimated as high as 48% and represents an emerging problem. The underlying mechanisms of organ rejection in the context of treatment with ICI are poorly understood. The search for restricted antitumoral responses without graft rejection is of paramount importance. This review summarizes the current knowledge of the use of ICI in KTR, the potential mechanisms involved in kidney graft rejection during ICI treatment, potential biomarkers of rejection, and how to deal with rejection in clinical practice.