Cancer mortality after kidney transplantation: A multicenter cohort study in Italy.

Kidney transplant (KT) recipients are known to be at risk of developing several cancer types; however, cancer mortality in this population is underinvestigated. Our study aimed to assess the risk of cancer death among Italian KT recipients compared to the corresponding general population. A cohort study was conducted among 7373 individuals who underwent KT between 2003 and 2020 in 17 Italian centers. Date and cause of death were retrieved until 31 December 2020. Indirect standardization was used to estimate standardized mortality ratios (SMRs) and corresponding 95% confidence intervals (CIs). Cancer was the most common cause of death among the 7373 KT recipients, constituting 32.4% of all deaths. A 1.8-fold excess mortality (95% CI: 1.59-2.09) was observed for all cancers combined. Lymphomas (SMR = 6.17, 95% CI: 3.81-9.25), kidney cancer (SMR = 5.44, 95% CI: 2.97-8.88) and skin melanoma (SMR = 3.19, 95% CI: 1.03-6.98) showed the highest excess death risks. In addition, SMRs were increased about 1.6 to 3.0 times for cancers of lung, breast, bladder and other hematopoietic and lymphoid tissues. As compared to the general population, relative cancer mortality risk remained significantly elevated in all age groups though it decreased with increasing age. A linear temporal increase in SMR over time was documented for all cancers combined (P < .01). Our study documented significantly higher risks of cancer death in KT recipients than in the corresponding general population. Such results support further investigation into the prevention and early detection of cancer in KT recipients.

The impact of cancer on the risk of death with a functioning graft of Italian kidney transplant recipients.

This study assessed the impact of cancer on the risk of death with a functioning graft of kidney transplant (KT) recipients, as compared to corresponding recipients without cancer. A matched cohort study was conducted using data from a cohort of 13 245 individuals who had undergone KT in 17 Italian centers (1997-2017). Cases were defined as subjects diagnosed with any cancer after KT. For each case, two controls matched by gender, age, and year at KT were randomly selected from cohort members who were cancer-free at the time of diagnosis of the index case. Overall, 292 (20.5%) deaths with a functioning graft were recorded among 1425 cases and 238 (8.4%) among 2850 controls. KT recipients with cancer had a greater risk of death with a functioning graft (hazard ratio, HR = 3.31) than their respective controls. This pattern was consistent over a broad range of cancer types, including non-Hodgkin lymphoma (HR = 33.09), lung (HR = 20.51), breast (HR = 8.80), colon-rectum (HR = 3.51), and kidney (HR = 2.38). The survival gap was observed throughout the entire follow-up period, though the effect was more marked within 1 year from cancer diagnosis. These results call for close posttransplant surveillance to detect cancers at earlier stages when treatments are more effective in improving survival.

Variation in Post-Transplant Cancer Incidence among Italian Kidney Transplant Recipients over a 25-Year Period.

This cohort study examined 25-year variations in cancer incidence among 11,418 Italian recipients of kidney transplantation (KT) from 17 Italian centers. Cancer incidence was examined over three periods (1997-2004; 2005-2012; and 2013-2021) by internal (Incidence rate ratio-IRR) and external (standardized incidence ratios-SIR) comparisons. Poisson regression was used to assess trends. Overall, 1646 post-transplant cancers were diagnosed, with incidence rates/1000 person-years ranging from 15.5 in 1997-2004 to 21.0 in 2013-2021. Adjusted IRRs showed a significant reduction in incidence rates across periods for all cancers combined after exclusion of nonmelanoma skin cancers (IRR = 0.90, 95% confidence interval-CI: 0.76-1.07 in 2005-2012; IRR = 0.72, 95% CI: 0.60-0.87 in 2013-2021 vs. 1997-2004; Ptrend < 0.01). In site-specific analyses, however, significant changes in incidence rates were observed only for Kaposi's sarcoma (KS; IRR = 0.37, 95% CI: 0.24-0.57 in 2005-2012; IRR = 0.09, 95% CI: 0.04-0.18 in 2013-2021; Ptrend < 0.01). As compared to the general population, the overall post-transplant cancer risk in KT recipients was elevated, with a decreasing magnitude over time (SIR = 2.54, 95% CI: 2.26-2.85 in 1997-2004; SIR = 1.99, 95% CI: 1.83-2.16 in 2013-2021; Ptrend < 0.01). A decline in SIRs was observed specifically for non-Hodgkin lymphoma and KS, though only the KS trend retained statistical significance after adjustment. In conclusion, apart from KS, no changes in the incidence of other cancers over time were observed among Italian KT recipients.

[Indications for apheresis in kidney transplant recipients: apheresis in the hyperimmune patient]. / Indicazioni all'aferesi nel trapianto di rene: aferesi nel paziente iperimmune.

Patients who are sensitized through pregnancy, previous blood transfusions, or organ transplantation produce donor-specific anti-HLA antibodies (DSA) that can result in an important obstacle in kidney transplantation. Sensitized patients wait longer on the cadaver donor transplant list, may not receive a transplant, and may have greater morbidity and mortality. Sensitized patients may have living donor candidates but transplantation cannot be performed because of cross-match positivity. Kidney transplant recipients with DSA are at higher risk of developing early acute antibody-mediated rejection (AMR) despite negative complement-dependent cytotoxicity (CDC) T-cell cross-match, and thus require desensitization. Desensitization protocols using the combination of apheresis (PE) or immunoadsorption to remove DSA and/or intravenous Ig (Iv-Ig) and rituximab to downregulate antibody-mediated immune responses have made kidney transplantation feasible by abrogating CDC T-cell cross-match positivity. All sensitized patients should be studied for DSA by sensitive methods and followed over time. The presence of DSA should be documented, and also the strength or titers of the alloantibodies should be determined to decide on the type of desensitization protocol. High-dosage Iv-Ig alone does not prevent AMR in patients with strong DSA, and the addition of peritransplantation PE as unselective plasma exchange, semiselective double filtration, or selective immunoadsorption significantly decreases the incidence of AMR. The effect of addition of monoclonal antibodies such as rituximab to desensitization protocols or of PE to patients with strong anti-HLA-II DSA on allograft outcomes requires further prospective studies.

[Kidney transplant and cancer risk: an epidemiological study in Northern and Central Italy]. / Trapianto di rene e rischio di cancro: studio epidemiologico in Nord e Centro Italia.

OBJECTIVE: This investigation aimed at highlighting the cancer risk of recipients of kidney transplant in northern and central Italy. METHODS: Data on 2,120 kidney transplant recipients from Niguarda Ca' Granda Hospital Milan, or from Policlinico "A. Gemelli", Rome, were analyzed The period at risk of developing cancer (person-years, PY) was computed from 30 days after transplant to date of cancer diagnosis, or date of death, or date of re-entering dialysis, or date of last follow-up. Observed and expected numbers of cancer were compared through sex- and age-standardized incidence ratios (SIRs) and 95% confidence intervals (CIs). The transplant attributable fraction (AF) of cancer cases and incidence rate ratios (IRR) were also computed. RESULTS: After 16.594 PY of follow-up (median flow-up: 6.8 years), 121 cancer cases were diagnosed (729.2 cases/10(5) PY). The SIR for all cancers was 1.9. Kaposi's sarcoma (KS) (27 cases observed, SIR = 82) and non-Hodgkins lymphoma (NHL) (18 cases observed a SIR = 6.4 were the most common cancers. Significantly increased SIRs were also noted for native kidney (11 cases observed SIR = 4.9), corpus uteri (6 cases observed SIR = 4.6), and liver (6 cases observed, SIR = 3.1). The transplant AF was 46.9%, largely due to KS (98.8%) and NHL (84.3%). Since SIRs decreased with increasing age, the transplant AF ranged from 73.2% below 45 years of age to 30.4% after 54. Among risk factors, area of birth strongly influenced the risk of KS, with a 3-fold higher risk in those born in the South of Italy as compared to those born in the northern part. CONCLUSIONS: Immune depression after kidney transplantation entails a two-fold increased overall risk of cancer, mainly related to cancers associated to a viral aetiology. Furthermore, our findings suggest the need to adopt a specific serological screening for the prevention of post-transplant KS in individuals born in southern Italy.

Risk of cancer following immunosuppression in organ transplant recipients and in HIV-positive individuals in southern Europe.

This investigation highlighted the risk of cancer in 8074 HIV-infected people and in 2875 transplant recipients in Italy and France. Observed and expected numbers of cancer were compared through sex- and age-standardised incidence ratios (SIRs) and 95% confidence intervals (CIs). After 15 years of follow-up, the cumulative probability of cancer was 14.7% in transplant recipients and 13.3% in HIV-positives. The SIRs for all cancers were 9.8 in HIV-positives and 2.2 in transplants. Kaposi's sarcoma (SIR=451 in HIV-positives, 125 in transplants) and non-Hodgkin lymphoma (SIR=62 and 11.1, respectively) were the most common cancers. A significantly increased SIR for liver cancer also emerged in both groups. The risk of lung cancer was significantly elevated in heart transplant recipients (SIR=2.8), and of borderline statistical significance in HIV-positive people (95% CI:0.9-2.8). Immune depression entails a two-fold increased overall risk of cancers, mainly related to cancers associated with a viral aetiology.

Incidence of second primary cancer in transplanted patients.

BACKGROUND: Solid organ transplanted patients have a three- to fourfold higher lifetime risk of developing a cancer than the general population. However, the incidence of a second primary cancer in transplanted patients has never been studied, despite the fact that the presence of regular follow-ups and the increased survival of these patients make them a very attractive model. METHODS: We investigated the incidence of a second primary cancer (SPC) in 7,636 patients who underwent a kidney, liver, lung or heart transplant between 1970 and 2004, and were followed-up for 51,819 person-years. RESULTS: During the follow-up, 499 subjects developed a first cancer (annual incidence: 98.6 x 10,000 PY), and 22 of them developed a SPC (annual incidence: 3.9 x 10,000 PY). The annual incidence of a SPC in the transplanted patients who developed a first cancer was 107.8 x 10,000 PY, giving a standardized incidence ratio of 1.1 (95% CI: 0.83-1.41). CONCLUSIONS: This result shows that the incidence of the SPC was the same as the incidence of a first cancer. Our study does not indicate an increased risk of SPC in transplanted subjects who already suffered a first malignancy.

The molecular basis of lecithin:cholesterol acyltransferase deficiency syndromes: a comprehensive study of molecular and biochemical findings in 13 unrelated Italian families.

OBJECTIVE: To better understand the role of lecithin:cholesterol acyltransferase (LCAT) in lipoprotein metabolism through the genetic and biochemical characterization of families carrying mutations in the LCAT gene. METHODS AND RESULTS: Thirteen families carrying 17 different mutations in the LCAT gene were identified by Lipid Clinics and Departments of Nephrology throughout Italy. DNA analysis of 82 family members identified 15 carriers of 2 mutant LCAT alleles, 11 with familial LCAT deficiency (FLD) and 4 with fish-eye disease (FED). Forty-four individuals carried 1 mutant LCAT allele, and 23 had a normal genotype. Plasma unesterified cholesterol, unesterified/total cholesterol ratio, triglycerides, very-low-density lipoprotein cholesterol, and pre-beta high-density lipoprotein (LDL) were elevated, and high-density lipoprotein (HDL) cholesterol, apolipoprotein A-I, apolipoprotein A-II, apolipoprotein B, LpA-I, LpA-I:A-II, cholesterol esterification rate, LCAT activity and concentration, and LDL and HDL3 particle size were reduced in a gene-dose-dependent manner in carriers of mutant LCAT alleles. No differences were found in the lipid/lipoprotein profile of FLD and FED cases, except for higher plasma unesterified cholesterol and unesterified/total cholesterol ratio in the former. CONCLUSIONS: In a large series of subjects carrying mutations in the LCAT gene, the inheritance of a mutated LCAT genotype causes a gene-dose-dependent alteration in the plasma lipid/lipoprotein profile, which is remarkably similar between subjects classified as FLD or FED.

Kaposi's sarcoma in transplant and HIV-infected patients: an epidemiologic study in Italy and France.

BACKGROUND: A follow-up study was conducted in Italy and in France to compare the epidemiology of Kaposi's sarcoma (KS) between human immunodeficiency virus (HIV)-infected people and transplant recipients. METHODS: In all, 8,074 HIV-positive individuals (6,072 from France and 2,002 HIV-seroconverters from Italy) and 2,705 Italian transplant recipients (1,844 kidney transplants, 702 heart transplants, and 159 liver transplants) were followed-up between 1970 and 2004. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were computed to estimate the risk of KS, as compared to sex- and age-matched Italian and French populations. Incidence rate ratios (IRRs) were used to identify risk factors for KS. RESULTS: A 451-fold higher SIR for KS was recorded in HIV-infected subjects and a 128-fold higher SIR was seen in transplant recipients. Significantly increased KS risks were observed in HIV-infected homosexual men (IRR=9.7 in France and IRR=6.7 in Italy vs. intravenous drug users), and in transplant recipients born in southern Italy (IRR=5.2 vs. those born in northern Italy). HIV-infected patients with high CD4+ cell counts and those treated with antiretroviral therapies had reduced KS risks. In relation to duration of immunosuppression, KS occurred earlier in transplant patients than in HIV-seroconverters. CONCLUSIONS: This comparison highlighted that the risk of KS was higher among HIV-infected individuals than in transplant recipients, and that different co-factors are likely to influence the risk of KS. Moreover, the early KS occurrence in transplant recipients could be associated with different patterns of progressive impairment of the immune function.

Epidemiology of de novo malignancies after solid-organ transplantation: immunosuppression, infection and other risk factors.

Organ transplantation is an increasingly used medical procedure for treating otherwise fatal end-stage organ diseases, and a large number of anti-rejection drugs have been developed to prolong long-term survival of both the individual and the transplanted organ. However, the prolonged use of immunosuppressive drugs is well known to increase the risk of opportunistic diseases, particularly infections and virus-related malignancies. Although transplant recipients experience a nearly twofold elevated risk for all types of de novo cancers, persistent infections with oncogenic viruses are associated with up to hundredfold increased risks. Women of the reproductive age are growing in number among the recipients of solid-organ transplants, but specific data on cancer outcomes are lacking. This article updates evidences linking iatrogenic immunosuppression, persistent infections with oncogenic viruses, other risk factors and post-transplant malignancies. Epidemiological aspects, tumourigenesis related to oncogenic viruses, clinical implications, as well as primary and secondary prevention issues are discussed to offer clinicians and researchers alike an update of an increasingly important topic.

Risk of de novo cancers after transplantation: results from a cohort of 7217 kidney transplant recipients, Italy 1997-2009.

To assess incidence and risk factors for de novo cancers (DNCs) after kidney transplant (KT), we carried out a cohort investigation in 15 Italian KT centres. Seven thousand two-hundred seventeen KT recipients (64.2% men), transplanted between 1997 and 2007 and followed-up until 2009, represented the study group. Person years (PY) were computed from 30 days after transplant to cancer diagnosis, death, return to dialysis or to study closure. The number of observed DNCs was compared to that expected in the general population of Italy through standardised incidence ratios (SIR) and 95% confidence intervals (CI). To identify risk factors, incidence rate ratios (IRR) were computed. Three-hundred ninety five DNCs were diagnosed during 39.598PYs, with Kaposi's sarcoma (KS), post-transplant lymphoproliferative disorders (PTLD), particularly non-Hodgkin' lymphoma (NHL), lung, kidney and prostate as the most common types. The overall IR was 9.98/1.000PY, with a 1.7-fold augmented SIR (95% CI: 1.6-1.9). SIRs were particularly elevated for KS (135), lip (9.4), kidney carcinoma (4.9), NHL (4.5) and mesothelioma (4.2). KT recipients born in Southern Italy were at reduced risk of kidney cancer and solid tumors, though at a higher KS risk, than those born in Northern Italy. Use of mTOR inhibitors (mTORi) exerted, for all cancers combined, a 46% significantly reduced risk (95% CI: 0.4-0.7). Our study findings confirmed, in Italy, the increased risks for cancer following KT, and they also suggested a possible protective effect of mTORi in reducing the frequency of post transplant cancers.

Everolimus with very low-exposure cyclosporine a in de novo kidney transplantation: a multicenter, randomized, controlled trial.

BACKGROUND: In combination with everolimus (EVL), cyclosporine A (CsA) may be used at low exposure, so reducing the risk of renal dysfunction in renal transplant recipients (RTR). We evaluated whether higher exposure of EVL could allow a further reduction of CsA. METHODS: De novo RTR were randomized to standard exposure EVL (C0 3-8 ng/mL) with low-concentration CsA (C2 maintenance levels 350-500 ng/mL, group A) or higher EVL exposure (C0 8-12 ng/mL) with very low-concentration CsA (C2 maintenance levels 150-300 ng/mL, group B). The primary endpoints were 6-month creatinine clearance (CrCl) and biopsy-proven acute rejection (BPAR) rate. After 6 months, patients were followed up (observational extension) to 12 months. RESULTS: Two hundred eighty-five RTR (97% from deceased donors) were enrolled. Two patients per group died (1.4%). The 6-month death-censored graft survival was 90.2% in group A and 97.9% in group B and was unchanged at 12 months (P=0.007). There was no significant difference between groups at 6 months in CrCl (59.9 vs. 57.8 mL/min) and BPAR rates (14.7% vs. 11.9%) and also at 12 months (CrCl 62.5+/-20.7 vs. 61.3+/-22.0 mL/min, BPAR 14.7% vs. 14.1%). No significant differences were seen in treated acute rejections, steroid-resistant acute rejections, treatment failures, or delayed graft function, although there was a trend to better results in group B. CONCLUSIONS: EVL given at higher exposure for 6 months plus very low CsA concentration may obtain low acute rejection rate and good graft survival in De novo renal transplantation. However, there was no difference between groups in CrCl.

Long-term follow-up of simultaneous heart and kidney transplantation with single donor allografts: report of nine cases.

BACKGROUND: Combined heart-kidney transplantation is an accepted therapeutic option for patients with end-stage heart disease associated with severely impaired renal function. We report our single-institutional experience with this combined procedure and long-term follow-up. METHODS: Between April 1989 and August 2006, 9 patients underwent combined simultaneous heart-kidney transplantation at our center. Seven patients were male (mean age, 45.2 +/- 10.12 years); 7 patients were on dialysis at transplantation. Whenever possible, donors were selected on the basis of ABO identity, weight (ratio > or = 0.9), on-site or short-distance procurement, young age, low inotropic support, and normal renal function. RESULTS: Mean ischemic time was 132.2 +/- 57.0 minutes for the cardiac allograft and 6.0 +/- 1.0 hours for the kidney. Surgical procedure was uneventful in all patients. One patient died in the intensive care unit 41 days after transplantation. Three patients died during follow-up, 1 of lung neoplasm after 6 years, 1 of cerebral stroke after 34 months, and 1 of infection and multiorgan failure after 148 months. The mortality rates led to an overall actuarial survival of 88.9% +/- 10.4% at 1 year, 77.8% +/- 13.6% at 5 years, and 64.8% +/- 16.5% at 10 years. Seven patients lived beyond 5 years, 4 beyond 10 years, and the patient who has longest survival is patient no. 1, with 17 years of follow-up. One patient lost kidney function after 113 months. CONCLUSIONS: In selected patients, with coexisting end-stage cardiac and renal failure, combined heart-kidney transplantation with allograft from the same donor proved to have satisfactory short- and long-term results, with a low incidence of both cardiac and renal allograft rejection.

The Italian Registry for Therapeutic Apheresis. A report from the Apheresis Study Group of the Italian Society of Nephrology.

Many clinical indications and different technical issues have been reported on therapeutic apheresis: much criticism has also been recorded in several instances, mainly due to the lack of large clinical trials to validate collected data. A Registry where all the available data can be organized and analyzed therefore becomes a priority for all the professionals involved in apheresis. The purpose of this report is to describe the data submitted from 1994 to 2004 from 15,285 treatments on 1,477 patients from 44 Centers, including mainly, but not exclusively, Nephrological Units, collected by the Apheresis Study Group of the Italian Society of Nephrology in 15 Italian regions. Plasma exchange accounted for 56.2% of the procedures, and of these 50.4% were performed by filtration. Plasma treatment was used in 40.1% of procedures, namely with Protein A immunoadsorption (14.6%), LDL-Cholesterol dextran sulfate adsorption (9.7%), and semiselective cascade or double filtration (12.6%). Cell apheresis, limited to photopheresis, was used in 0.85% of cases, and whole blood treatment (direct adsorption lipoprotein, and molecular adsorption recirculating system) in 2.7%. The procedures analyzed here account for less than 20% of estimated therapeutic apheresis performed in Italy, according to the national survey of activity performed for year 2000 by the Italian Apheresis Society. Notwithstanding that the data are largely incomplete, they are sufficiently informative for a definite trend: plasma treatment with filtration on fractionation filters and adsorption must be used as often as possible, instead of plasma exchange, thus obtaining the most selective removals.