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.

Long-term, prolonged-release tacrolimus-based immunosuppression in de novo kidney transplant recipients: 5-year prospective follow-up of the ADHERE study patients.

The objectives of this study were to assess long-term graft survival, patient survival, renal function, and acute rejections in de novo kidney transplant recipients, treated with once-daily prolonged-release tacrolimus-based therapy. The study was a 5-year non-interventional prospective follow-up of patients from the ADHERE study, a Phase IV 12-month open-label assessment of patients randomized to receive prolonged-release tacrolimus in combination with mycophenolate mofetil (MMF) (Arm 1) or sirolimus (Arm 2). From 838 patients in the randomized study, 587 were included in the long-term follow-up, of whom 510 completed the study at year 5. At 1 year post-transplant, graft and patient survival rates were 93.0% and 97.8%, respectively, and at 5 years were 84.0% and 90.8%, respectively. Cox proportional hazards analysis showed no association between graft loss, initial randomized treatment arm, donor age, donor type, or sex. The 5-year acute rejection-free survival rate was 77.4%, and biopsy-confirmed acute rejection-free survival rate was 86.0%. Renal function remained stable over the follow-up period: mean ± SD eGFR 4-variable modification diet in renal disease formula (MDRD4) was 52.3 ± 21.6 ml/min/1.73 m2 at 6 months and 52.5 ± 23.0 ml/min/1.73 m2 at 5 years post-transplant. These findings support the role of long-term once-daily prolonged-release tacrolimus-based immunosuppression, in combination with sirolimus or MMF, for renal transplant recipients in routine clinical practice.

Are there any relations among transplant centre volume, surgical technique and anatomy for donor graft selection? Ten-year multicentric Italian experience on mini-invasive living donor nephrectomy.

BACKGROUND: Selection of the right or left living donor kidney for transplantation is influenced by many variables. In the present multi centric study including 21 Italian transplant centres, we evaluated whether centre volume or surgical technique may influence the selection process. METHODS: Intra- and perioperative donor data, donor kidney function, and recipient and graft survival were collected among 693 mini-invasive living donor nephrectomies performed from 2002 to 2014. Centre volume (LOW, 1-50 cases; HIGH, >50 cases) and surgical technique (FULL-LAP, full laparoscopic and robotic; HA-LAP, hand-assisted laparoscopy; MINI-OPEN, mini-lumbotomy) were correlated with selection of right or left donor kidney and with donor and recipient outcome. RESULTS: HIGH-volume centres retrieved a higher rate of donor right kidneys (29.3% versus 17.6%, P < 0.01) with single artery (83.1% versus 76.4%, P < 0.05) compared with LOW-volume centres. Surgical technique correlated significantly with rate of donor right kidney and presence of multiple arteries: MINI-OPEN (53% and 13%) versus HA-LAP (29% and 22%) versus FULL-LAP (11% and 23%), P < 0.001 and P < 0.05, respectively. All donors had an uneventful outcome; donor bleeding was more frequent in LOW-volume centres (4% versus 0.9%, P < 0.05). CONCLUSIONS: Centre volume and surgical technique influenced donor kidney side selection. Donor nephrectomy in LOW-volume centres was associated with higher risk of donor bleeding.

Pregnancy outcomes after kidney graft in Italy: are the changes over time the result of different therapies or of different policies? A nationwide survey (1978-2013).

BACKGROUND: Kidney transplantation is the treatment of choice to restore fertility to women on renal replacement therapy. Over time, immunosuppressive, support therapies and approaches towards high-risk pregnancies have changed. The aim of this study was to analyse maternal-foetal outcomes in two cohorts of transplanted women who delivered a live-born baby in Italy in 1978-2013, dichotomized into delivery before and after January 2000. METHODS: A survey involving all the Italian transplant centres was carried out, gathering data on all pregnancies recorded since the start of activity at each centre; the estimated nationwide coverage was 75%. Data on cause of ESRD, dialysis, living/cadaveric transplantation, drug therapy, comorbidity, and the main maternal-foetal outcomes were recorded and reviewed. Data were compared with a low-risk cohort of pregnancies from two large Italian centres (2000-14; Torino and Cagliari Observational Study cohort). RESULTS: The database consists of 222 pregnancies with live-born babies after transplantation (83 before 2000 and 139 in 2000-13; 68 and 121 with baseline and birth data, respectively), and 1418 low-risk controls. The age of the patients significantly increased over time (1978-99: age 30.7 ± 3.7 versus 34.1 ± 3.7 in 2000-13; P < 0.001). Azathioprine, steroids and cyclosporine A were the main drugs employed in the first time period, while tacrolimus emerged in the second. The prevalence of early preterm babies increased from 13.4% in the first to 27.1% in the second period (P = 0.049), while late-preterm babies non-significantly decreased (38.8 versus 33.1%), thus leaving the prevalence of all preterm babies almost unchanged (52.2 and 60.2%; P = 0.372). Babies below the 5th percentile decreased over time (22.2 versus 9.6%; P = 0.036). In spite of high prematurity rates, no neonatal deaths occurred after 2000. The results in kidney transplant patients are significantly different from controls both considering all cases [preterm delivery: 57.3 versus 6.3%; early preterm: 22.2 versus 0.9%; small for gestational age (SGA): 14 versus 4.5%; P < 0.001] and considering only transplant patients with normal kidney function [preterm delivery: 35 versus 6.3%; early preterm: 10 versus 0.9%; SGA: 23.7 versus 4.5% (P < 0.001); risks increase across CKD stages]. Kidney function remained stable in most of the patients up to 6 months after delivery. Multiple regression analysis performed on the transplant cohort highlights a higher risk of preterm delivery in later CKD stages, an increase in preterm delivery and a decrease in SGA across periods. CONCLUSIONS: Pregnancy after transplantation has a higher risk of adverse outcomes compared with the general population. Over time, the incidence of SGA babies decreased while the incidence of 'early preterm' babies increased. Although acknowledging the differences in therapy (cyclosporine versus tacrolimus) and in maternal age (significantly increased), the decrease in SGA and the increase in prematurity may be explained by an obstetric policy favouring earlier delivery against the risk of foetal growth restriction.

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.

[Pulmonary fibrosis associated with anti-neutrophil cytoplasmic antibody positive vasculitis]. / Fibrosis pulmonar asociada a vasculitis con anticuerpos anticitoplasmáticos positivos.

The most frequently observed pulmonary complications of vasculitis (AAV) with anti-neutrophil cytoplasmic positive antibodies (ANCA) are alveolar hemorrhage, granulomas and airway stenosis. In recent years, some reports have been published that show the association of vasculitis with pulmonary fibrosis (PF), suggesting that it may be another complication of AAV. We report and describe here two cases with such association, and their clinical, tomographic and immunological characteristics. Given that in the association between PF and AAV, as reported in the last years, PF could be the first manifestation of AAV, the search for ANCA in patients with PF may be necessary, as a cause of it and for the possible subsequent development of vasculitis.

[Home hemodialysis and peritoneal dialysis compared]. / Dialisi domiciliare sì, ma quale? Emodialisi domiciliare e dialisi peritoneale a confronto: una controversia non controversa.

The evolution of home dialysis marked the main steps in the progress of renal replacement therapy. From the origins when home hemodialysis was often the only alternative to death, to the advent and widespread use of peritoneal dialysis, the dream of kidney transplant as a solution to all problems (at least in the young), and ultimately the profound social and organizational changes that have led to a drastic reduction of home hemodialysis, we arrive at the present with the rediscovery of the clinical, rehabilitative and economic advantages of home dialysis. Seven experts from five different centers with different expertise in home dialysis report their opinions on the future of home dialysis in a ''noncontroversial controversy''. Beyond the sterile competition between peritoneal dialysis and home hemodialysis, the shared opinion is that the two methods may complement each other, allowing a tailored treatment for each patient and a tailored organization in each setting. The organizational solutions are many; the authors underline the importance of longer survival and better rehabilitation, and the ethical need of offering each patient a choice among all available treatments. Add to this the importance of dedicated educational programs targeted to physicians, nurses and patients alike and focused on self-care and patient empowerment. A new generation of dialysis machines, easier technical solutions, and financial incentives may strengthen motivations and simplify problems; all these elements may in the near future be combined in a joint effort to increase peritoneal dialysis and revive home hemodialysis in Italy.

Efficacy and safety of sevelamer hydrochloride and calcium acetate in patients on peritoneal dialysis.

BACKGROUND: Inadequate phosphorus control is associated with increased morbidity and mortality in patients with CKD stage 5. Although phosphate binders are often used in patients on peritoneal dialysis (PD), no large randomized controlled studies evaluating their use solely in this population have previously been reported. METHODS: In this multicentre, open-label study, adult patients on PD with serum phosphorus >5.5 mg/dl were randomized (2:1) to 12 weeks of treatment with sevelamer hydrochloride or calcium acetate. Doses were titrated to achieve serum phosphorus of 3.0-5.5 mg/dl. Changes in serum phosphorus, calcium, intact parathyroid hormone (iPTH), lipids and plasma biomarkers were assessed. RESULTS: A total of 253 patients were screened, 143 of whom were randomized (sevelamer hydrochloride, n = 97; calcium acetate, n = 46). Treatment groups were well balanced with regard to baseline demographics. Serum phosphorus levels were significantly reduced after 12 weeks with both sevelamer hydrochloride and calcium acetate (P < 0.001). Serum PTH was also reduced in both groups while serum calcium increased in the calcium acetate group (P = 0.001) but not in the sevelamer hydrochloride group. Sevelamer hydrochloride was also associated with decreases in total cholesterol, low-density lipoprotein cholesterol and uric acid and an increase in bone-specific alkaline phosphatase (all P < 0.001 versus baseline). Both treatments were well tolerated and safety profiles were consistent with previous reports in haemodialysis patients. Hypercalcaemia was experienced by more calcium acetate-treated patients (18 versus 2%; P = 0.001). CONCLUSIONS: In summary, sevelamer hydrochloride provides a reduction in serum phosphorus compared to that obtained with calcium-based binders in PD patients. The effects of sevelamer hydrochloride appear similar in both PD and haemodialysis populations.

Takayasu's disease effects on the kidneys: current perspectives.

Takayasu arteritis (TA) is a chronic vasculitis disease of unknown etiology. Clinically significant renal disease is relatively common, and renovascular hypertension is the major renal problem. The assessment of TA activity is usually challenging because vascular inflammation may progress to fixed vascular injury without findings of active disease. Until now, the best therapeutic options have not been identified. This review highlights the current perspectives of renal involvement in TA.

Clinical management of patients on peritoneal dialysis in Italy: results from the ATENA study.

BACKGROUND: In Italy, few studies have examined the clinical management of peritoneal dialysis (PD) patients, resulting in a lack of information and awareness. METHODS: A total of 378 PD patients (64.7 ± 14.3 years, 58.9% males) were enrolled across 15 centres in a 12-month retrospective and 6-month prospective study. The primary objective was to evaluate the achievement of Kidney Disease Outcomes Quality Initiative and Kidney Disease Improving Global Outcomes guidelines on recommended target values for anaemia, high blood pressure and mineral metabolism. Comorbidities, hospitalizations, treatment and quality of life were also assessed. RESULTS: Frequent comorbidities included hypertension (87.8%) and cardiovascular disease (39.7%). Peritonitis was the leading cause of hospitalization [12 admissions per 100 person-years (95% confidence interval 9.3-15.2)]. At 6 months, anaemia corrected by erythropoiesis-stimulating agents was observed in 30% of patients and 73% received erythropoiesis-stimulating agents. Systolic and diastolic blood pressures were recorded in 50% and 20% of patients, respectively. Sixty-four percent of echocardiograms revealed left ventricular hypertrophy and 30% of patients had vitamin D <10 ng/mL. Medication to treat intact parathyroid hormone (PTH) included calcitriol (36.3%), paricalcitol (29.2%), cholecalciferol (23.6%) and cinacalcet (21.5%). In a subgroup of patients matched for baseline PTH treated for 1 year, a significant reduction in PTH with paricalcitol (-41%; P < 0.001) but not cinacalcet (+2%; P = 0.63) was observed. Comparison of quality of life domains revealed significant differences for symptoms (P = 0.049), cognitive function (P = 0.019) and social support (P = 0.04) (baseline versus 6 months). CONCLUSIONS: Hypertension and cardiovascular diseases were frequent comorbidities and peritonitis was the leading cause of hospitalization. Secondary hyperparathyroidism and anaemia were common, thus necessitating frequent monitoring of PTH, calcium, phosphorus and haemoglobin.

Outcomes of Pregnancies After Kidney Transplantation: Lessons Learned From CKD. A Comparison of Transplanted, Nontransplanted Chronic Kidney Disease Patients and Low-Risk Pregnancies: A Multicenter Nationwide Analysis.

BACKGROUND: Kidney transplantation (KT) may restore fertility in chronic kidney disease (CKD). The reasons why maternofetal outcomes are still inferior to the overall population are only partially known. Comparison with the CKD population may offer some useful insights for management and counselling.Aim of this study was to analyse the outcomes of pregnancy after KT, compared with a large population of nontransplanted CKD patients and with low-risk control pregnancies, observed in Italy the new millennium. METHODS: We selected 121 live-born singletons after KT (Italian study group of kidney in pregnancy, national coverage about 75%), 610 live-born singletons in CKD, and 1418 low-risk controls recruited in 2 large Italian Units in the same period (2000-2014). The following outcomes were considered: maternal and fetal death; malformations; preterm delivery; small for gestational age (SGA) baby; need for the neonatal intensive care unit; doubling of serum creatinine or increase in CKD stage. Data were analyzed according to kidney diseases, renal function (staging according to CKD-epidemiology collaboration), hypertension, maternal age, parity, ethnicity. RESULTS: Maternofetal outcomes are less favourable in CKD and KT as compared with the low-risk population. CKD stage and hypertension are important determinants of results. Kidney transplantation patients with estimated glomerular filtration rate greater than 90 have worse outcomes compared with CKD stage 1 patients; the differences level off when only CKD patients affected by glomerulonephritis or systemic diseases ("progressive CKD") are compared with KT. In the multivariate analysis, risk for preterm and early-preterm delivery was linked to CKD stage (2-5 vs 1: relative risk 3.42 and 3.78) and hypertension (RR 3.68 and 3.16) while no difference was associated with being a KT or a CKD patient. CONCLUSIONS: The maternofetal outcomes in patients with kidney transplantation are comparable with those of nontransplanted CKD patients with similar levels of kidney function impairment and progressive and/or immunologic kidney disease.

Microscopic polyangiitis associated with pulmonary fibrosis.

Microscopic polyangiitis (MPA) is a systemic necrotizing vasculitis characterised by inflammation of the small blood vessels, the absence of granulommas on histopathological specimens, with few or no immune deposits and the presence of circulating anti-neutrophil cytoplasmic antibodies (ANCAs). The classic pulmonary manifestation is diffuse alveolar haemorrhage (DAH), but its association with pulmonary fibrosis (PF) has been increasingly reported and may be the first manifestation of MPA. Our aim was to evaluate MPA patients with PF and compare their characteristics and evolution to those of MPA patients without PF. We conducted a retrospective review of MPA patients followed in our hospital over a 15-year period. They were divided into two subgroups, with PF (MPA-PF) and without PF (MPA-non PF), and their clinical and functional features were compared. Nine of the 28 patients were classified as MPA-PF (32%). This subgroup showed significantly more respiratory symptoms and higher mortality than MPA-non PF subgroup. The most frequent chest computed tomographic pattern of PF was usual interstitial pneumonia. PF preceded other manifestations of vasculitis in five patients and occurred simultaneously in the remaining four. During the follow-up period, four deaths were reported in the MPA-PF subgroup. No deaths were registered in the MPA-non PF subgroup. We found a high prevalence of MPA-PF patients (32%), most of whom had a poor outcome and PF was often the first manifestation of the disease.

Can peritoneal dialysis be used as a long term therapy for end stage renal disease?

Over the last 25 years, since the introduction of CAPD, the use of PD has increased greatly and over this period many advances in technique have been made. As is well known, that home and self-dialysis, such as PD, cost less than in-center HD and can provide excellent survival and a high level of patient rehabilitation. To date however, the demonstration that PD can provide long term dialysis has been limited to a small number of patients. The next few decades will see a marked increase in the worldwide dialysis population, particularly as older and sicker patients are accepted into dialysis. It is likely that worldwide pressures related to cost containment will favour the use of cost effective therapies, such as PD. However, the increased use of PD will continue, only if we continue to improve its efficacy and do not waste the economic benefits gained over HD. We are challenged to improve and develop PD in a way that optimises patient medical and psychosocial outcomes while minimizing costs. This may be achieved by using more biocompatible solutions, hopefully inexpensive, that will maintain the peritoneal membrane intact for long periods, will better preserve the membrane's transport characteristics over time, and thus reduce the main causes of drop out from dialysis.