Multiple rare genetic variants co-segregating with familial IgA nephropathy all act within a single immune-related network.

BACKGROUND: IgA nephropathy (IgAN) is a common complex disease with a strong genetic involvement. We aimed to identify novel, rare, highly penetrant risk variants combining family-based linkage analysis with whole-exome sequencing (WES). METHODS: Linkage analysis of 16 kindreds of South Italian ancestry was performed using an 'affected-only' strategy. Eight most informative trios composed of two familial cases and an intrafamilial control were selected for WES. High-priority variants in linked regions were identified and validated using Sanger sequencing. Custom TaqMan assays were designed and carried out in the 16 kindreds and an independent cohort of 240 IgAN patients and 113 control subjects. RESULTS: We found suggestive linkage signals in 12 loci. After sequential filtering and validation of WES data, we identified 24 private or extremely rare (MAF <0.0003) linked variants segregating with IgAN status. These were present within coding or regulatory regions of 23 genes that merged into a common functional network. The genes were interconnected by AKT, CTNNB1, NFKB, MYC and UBC, key modulators of WNT/ß-catenin and PI3K/Akt pathways, which are implicated in IgAN pathogenesis. Overlaying publicly available expression data, genes/proteins with expression notably altered in IgAN were included in this immune-related network. In particular, the network included the glucocorticoid receptor gene, NR3C1, which is the target of corticosteroid therapy routinely used in the treatment of IgAN. CONCLUSION: Our findings suggest that disease susceptibility could be influenced by multiple rare variants acting in a common network that could provide the starting point for the identification of potential drug targets for personalized therapy.

MicroRNAs in kidney diseases: new promising biomarkers for diagnosis and monitoring.

A series of microRNAs (miRNAs) have a critical role in many cellular and physiological activities such as cell cycle, growth, proliferation, apoptosis and metabolism. miRNAs are also important in the maintenance of renal homeostasis and kidney diseases. In vitro and in vivo animal models have shown a critical role of miRNAs in the development of diabetic nephropathy (DN) and in the progression of renal fibrosis. Specific miRNAs in renal tissue and peripheral blood mononuclear cells (PBMCs) are up and downregulated in different kidney diseases. They represent new potential biomarkers for diagnosis and targeted therapy. In addition, urinary miRNAs may be considered non-invasive biomarkers for monitoring the progression of renal damage. The activity of miRNAs can be modified by different approaches such as the use of antisense oligonucleotide inhibitors (antagomirs), tandem miRNA-binding site repeats manufactured by Decoy or Sponge technologies and miRNA mimics. The use of miRNA blockers or antagonists as therapeutic agents is very attractive but new information will be necessary considering their role in other systems.

IgA nephropathy, the most common cause of glomerulonephritis, is linked to 6q22-23.

End-stage renal disease (ESRD) is a major public health problem, affecting 1 in 1,000 individuals and with an annual death rate of 20% despite dialysis treatment. IgA nephropathy (IgAN) is the most common form of glomerulonephritis, a principal cause of ESRD worldwide; it affects up to 1.3% of the population and its pathogenesis is unknown. Kidneys of people with IgAN show deposits of IgA-containing immune complexes with proliferation of the glomerular mesangium (Fig. 1). Typical clinical features include onset before age 40 with haematuria and proteinuria (blood and protein in the urine), and episodes of gross haematuria following mucosal infections are common; 30% of patients develop progressive renal failure. Although not generally considered a hereditary disease, striking ethnic variation in prevalence and familial clustering, along with subclinical renal abnormalities among relatives of IgAN cases, have suggested a heretofore undefined genetic component. By genome-wide analysis of linkage in 30 multiplex IgAN kindreds, we demonstrate linkage of IgAN to 6q22-23 under a dominant model of transmission with incomplete penetrance, with a lod score of 5.6 and 60% of kindreds linked. These findings for the first time indicate the existence of a locus with large effect on development of IgAN and identify the chromosomal location of this disease gene.

Rapamycin-induced hypophosphatemia and insulin resistance are associated with mTORC2 activation and Klotho expression.

Rapamycin, an immunosuppressive drug used to prevent rejection after kidney transplantation, influences phosphate homeostasis, induces insulin resistance and has been shown to prolong lifespan in animal models. Because Klotho is an aging-suppressor gene controlling phosphate metabolism and insulin sensitivity, we investigated the influence of rapamycin on Klotho expression. A total of 100 kidney transplant recipients, 50 chronically treated with rapamycin and 50 with calcineurin inhibitors, were enrolled; 20 healthy subjects were employed as control. In the rapamycin group, serum phosphate was lower than in the CNI group with an increase in phosphate excretion and a reduction in its reabsorption. In addition, rapamycin increased insulin resistance as shown by HOMA index. Rapamycin treatment of an immortalized proximal tubular cell line induced the expression of Klotho, the phosphorylation of AKT in Ser473, downstream target of mTORC2 and the expression of RICTOR, mTORC2 main component. AKT inhibition reduced the rapamycin-induced expression of Klotho. In vivo rapamycin treatment induced higher degree of RICTOR and AKT Ser(473) expression directly correlating with long-term rapamycin exposure, FE(PO4) and HOMA index. In conclusion, our data would suggest that rapamycin may influence phosphate homeostasis and insulin resistance modulating Klotho expression through mTORC2 activation.

IL-17 expression by tubular epithelial cells in renal transplant recipients with acute antibody-mediated rejection.

Acute rejection is still a common complication of kidney transplantation. IL-17 is known to be associated with allograft rejection but the cellular source and the role of this cytokine remains unclear. We investigated IL-17 graft expression in renal transplant recipients with acute antibody-mediated rejection (ABMR), acute T-cell-mediated rejection (TCMR), interstitial fibrosis and tubular atrophy (IFTA) and acute tubular damage due to calcineurin-inhibitor toxicity (CNI). In acute ABMR, tubular IL-17 protein expression was significantly increased compared to TCMR, where most of the IL-17⁺ cells were CD4⁺ graft infiltrating lymphocytes, IFTA and CNI control groups. The tubular expression of IL-17 in acute ABMR colocalized with JAK2 phosphorylation and peritubular capillaries C4d deposition. In addition, IL-17 tubular expression was directly and significantly correlated with the extension of C4d deposits. In cultured proximal tubular cells, C3a induced IL-17 gene and protein expression along with an increased in JAK2 phosphorylation. The inhibition of JAK2 abolished C3a-induced IL-17 expression. The use of steroids and monoclonal antibodies reduced IL-17 expression, JAK2 phosphorylation and C4d deposition in acute ABMR patients. Our data suggest that tubular cells represent a significant source of IL-17 in ABMR and this event might be mediated by the complement system activation featuring this condition.

Cryoglobulinemic membranoproliferative glomerulonephritis: beyond conventional therapy.

Membranoproliferative glomerulonephritis associated with Type II cryoglobulinemia is the predominant type of HCV-related glomerulonephritis. Immunosuppressive and anti-viral therapy is alternately used to treat it, but the results are not always satisfactory or lasting. In this paper we report 3 cases of cryoglobulinemic membranoproliferative glomerulonephritis, treated with different and personalized therapeutic approaches by using conventional therapy and new drugs such as mycophenolate mofetil and rituximab. Our case series report emphasizes the importance of choosing the treatment for each patient, taking into account many factors: age, severity of liver and renal involvement, extra-renal manifestations, any previous treatment, contraindications or adverse events and last but not least the balance between immunosuppression and virus activity.

NMR-based metabolomic study of Apulian Coratina extra virgin olive oil extracted with a combined ultrasound and thermal conditioning process in an industrial setting.

The innovative combination of ultrasound (Us) with a thermal exchanger to produce high quality extra virgin olive oil (EVOO) was studied using Nuclear Magnetic Resonance (NMR) spectroscopy and multivariate analysis (MVA). Major and minor metabolomic components of Apulian Coratina EVOO obtained using the two methods were compared. Early and late olive ripening stages were also considered. An increased amount of polyphenols was found for EVOOs obtained using the Us with respect to the conventional method for both early and late ripening stages (900.8 ± 10.3 and 571.9 ± 9.9 mg/kg versus 645.1 ± 9.3 and 440.8 ± 10.4 mg/kg). NMR spectroscopy showed a significant increase (P < 0.05) in polyunsaturated fatty acids (PUFA) as well as in the tyrosol and hydroxytyrosol derivatives, such as oleocanthal, oleacein, and elenolic acid, for both ripening stages. In conclusion, NMR spectroscopy provides information about the metabolomic components of EVOOs to producers, while the Us process increases the levels of healthy bioactive components.

Pharmacogenomics: a new paradigm to personalize treatments in nephrology patients.

Although notable progress has been made in the therapeutic management of patients with chronic kidney disease in both conservative and renal replacement treatments (dialysis and transplantation), the occurrence of medication-related problems (lack of efficacy, adverse drug reactions) still represents a key clinical issue. Recent evidence suggests that adverse drug reactions are major causes of death and hospital admission in Europe and the United States. The reasons for these conditions are represented by environmental/non-genetic and genetic factors responsible for the great inter-patient variability in drugs metabolism, disposition and therapeutic targets. Over the years several genetic settings have been linked, using pharmacogenetic approaches, to the effects and toxicity of many agents used in clinical nephrology. However, these strategies, analysing single gene or candidate pathways, do not represent the gold standard, being the overall pharmacological effects of medications and not typically monogenic traits. Therefore, to identify multi-genetic influence on drug response, researchers and clinicians from different fields of medicine and pharmacology have started to perform pharmacogenomic studies employing innovative whole genomic high-throughput technologies. However, to date, only few pharmacogenomics reports have been published in nephrology underlying the need to enhance the number of projects and to increase the research budget for this important research field. In the future we would expect that, applying the knowledge about an individual's inherited response to drugs, nephrologists will be able to prescribe medications based on each person's genetic make-up, to monitor carefully the efficacy/toxicity of a given drug and to modify the dosage or number of medications to obtain predefined clinical outcomes.

Emotional symptoms, quality of life and cytokine profile in hemodialysis patients.

BACKGROUND: Mental disorders are frequent in hemodialysis (HD) patients. Depression and anxiety along with physical co-morbidity affect quality of life (QOL). Uremia is associated with inflammation and release of cytokines by lymphomonocytes. Inflammatory cytokines are relevant in depression. The aim of this study was to assess the psychological alterations and QOL in HD patients, and to correlate them with pattern of cytokine production. PATIENTS: 30 HD patients and 20 subjects with CKD Stage I-II K-DOQI. Psychometric tests were administered: 1) Hospital Anxiety and Depression Scale (HADS) composed of an anxiety subscale (HADS-A) and a depression subscale (HADS-D); 2) Kidney Disease Quality of Life (KDQOL) modified, including a cognitive function subscale (KDQOL-CF). Whole blood samples collected at beginning of HD session were diluted with RPMI/heparin and incubated for 24 h in presence of lipopolysaccharide (LPS). IL-1Gamma, IL-6, TNF-alpha and IL-10 were assayed on supernatants and results were normalized per number of lymphomonocytes (ng/106 cells). RESULTS: A depressive mood was more frequent in HD patients (50%) than controls (20%, p < 0.0001). No difference for anxiety (HD = 43%, controls = 45%) was observed. QOL score was significantly lower in HD than controls (p = 0.006) and correlated inversely with HADS total, HADS-A and HADS-D (p < 0.0001). Albumin, Kt/V and phosphate were comparable in patients with or without anxiety or depression. Cytokine production was significantly higher in HD patients than controls (IL-1beta p = 0.05; IL-6 p = 0.010; TNF-alpha p < 0.0001; IL-10, p = 0.0019). HD patients with the HADS-A positive for anxiety showed higher IL-6 production (p = 0.026), while IL-1beta levels were not associated with symptoms of depression. KDQOL-CF correlated inversely with levels of IL-6, TNF-alpha and IL-10. CONCLUSIONS: HD patients have symptoms of depression and anxiety that negatively affect QOL. These symptoms are independent of the efficiency of dialysis and nutritional status. On the contrary, IL-6 is linked to the presence of psychological discomfort in these patients.

ID2-VEGF-related pathways in the pathogenesis of Kaposi's sarcoma: a link disrupted by rapamycin.

The Id-proteins are a family of four related proteins implicated in the control of differentiation and cell-cycle progression. Down-regulation of Id-gene expression is essential for the differentiation of several cell types. In addition, deregulated Id2 activity inhibits the Rb tumor suppressor pathway and promotes the expression of vascular endothelial growth factor (VEGF). Several members of VEGF family could be involved in Kaposi's sarcoma (KS) development and progression. Lymphatic vascular endothelial hyaluronan receptor-1 (LYVE-1) is the first marker of lymphatic endothelial competence during development in the mature vasculature, and is also expressed on KS spindle cells. Rapamycin (RAPA), an immunosuppressive drug, has been shown to reverse KS growth and to reduce tumor angiogenesis. We evaluate, in transplantation-associated KS and in cultured KS-cells the RAPA effect on Id2 and on de novo lymphangiogenesis. Markers of lymphatic-endothelial-cells (VEGFR-3, LYVE-1) and Id2, expressed at low levels within the normal skin, were up-regulated in KS and returned to normal levels after RAPA introduction. The association between Id2 and lymphangiogenesis is suggested by co-localization of Id2, VEGFR-3 and LYVE-1. RAPA inhibition on Id2 expression was confirmed in vitro in KS-cells, both in basal conditions and upon stimulation with VEGF. In conclusion, our data would suggest a novel molecular mechanism for the antineoplastic effects of RAPA in posttransplant KS.

Immunological and non-immunological mechanisms of proteinuria.

Proteinuria as a general symptom of a broad range of different diseases can result from gene mutations of molecules building up the glomerular sieve, from immune-mediated, haemodynamic or metabolic disturbances of the glomerular filter. This filter is not a static barrier but consists of a highly dynamic interacting podocyte foot process to foot process to glomerular basement membrane complex. Its function is to prevent leakage of macromolecules and blood cells into the urine. Molecules like nephrin and podocin are directly involved in the formation of the slit diaphragm located at the end of the foot processes. Other molecules, i.e. CD2AP, play a role in organizing the correct position of the podocytes and its foot processes via controlling intra-cellular actin filaments. Gene mutations coding for these molecules directly cause proteinuric diseases. Autoantibodies or circulating immune complexes can destroy this fragile network of cells and the basement membrane via accumulation of inflammatory cells, cytokines and generation of oxygen radicals. Hemodynamic and metabolic changes as seen in diabetic nephropathy are associated with increased TGF-ss expression and extra-cellular matrix expansion in the mesangium and a decrease of podocyte numbers. Thus, proteinuria is the result of a disturbance of the highly fragile network of cells and the basement membrane on the micro-anatomical and molecular level.

The dynamics of kidney donation: viewpoints from the donor, the recipients, and the transplant team.

Living kidney transplantation has become increasingly widespread to reduce organ shortage. Very few studies have prospectively investigated the donor's long-term risks. Living donation is a complex medical decision in which different actors are involved. This therapeutic option needs educational programs for potential donors, recipients, and transplant professionals to make them aware of the possible risks and benefits. It is important to fully exploit living-donor kidney transplantation.

A randomized, multicenter study of steroid avoidance, early steroid withdrawal or standard steroid therapy in kidney transplant recipients.

In a randomized, open-label, multicenter study, de novo renal transplant patients received no steroids (n = 112), steroids to day 7 (n = 115), or standard steroids (n = 109) with cyclosporine microemulsion (CsA-ME), enteric-coated mycophenolate sodium (EC-MPS) and basiliximab. The primary objective, to demonstrate noninferiority of 12-month GFR in the steroid-free or steroid-withdrawal groups versus standard steroids, was not met in the intent-to-treat population. However, investigational groups were not inferior to standard steroids in the observed-case analysis. Median 12-month GFR was not significantly different in the steroid-free or steroid-withdrawal groups (58.6 mL/min/1.73 m(2) and 59.1 mL/min/1.73 m(2)) versus standard steroids (60.8 mL/min/1.73 m(2)). The 12-month incidence of biopsy-proven acute rejection (BPAR), graft loss or death was 36.0% in the steroid-free group (p = 0.007 vs. standard steroids), 29.6% with steroid withdrawal (N.S.) and 19.3% with standard steroids. BPAR was significantly less frequent with standard steroids than either of the other two regimens. Reduced de novo use of antidiabetic and lipid-lowering medication, triglycerides and weight gain were observed in one or both steroid-minimization group versus standard steroids. For standard-risk renal transplant patients receiving CsA-ME, EC-MPS and basiliximab, steroid withdrawal by the end of week 1 achieves similar 1-year renal function to a standard-steroids regimen, and may be more desirable than complete steroid avoidance.

[The mechanisms of chronic kidney damage in renal transplant and their possible reversibility]. / I meccanismi del danno cronico nel trapianto renale e la loro possibile reversibilita'

Chronic allograft dysfunction (CAD) represents the main cause of delayed graft loss. Several mechanisms, immunological and not, are involved in the pathogenesis of CAD, some of which are modifiable. Suboptimal immunosuppression may induce subclinical acute rejections, identifiable by histology and influencing graft survival. Typical transplant recipients' comorbidities such as hypertension, diabetes and dyslipidemia accelerate CAD progression. Calcineurin inhibitors, which are known to be nephrotoxic, play a key role in the onset of CAD through several mechanisms. Therapeutic interventions to stop or at least slow down CAD progression involve all these modifiable factors by means of comorbidity correction, tailored immunosuppression and, in some cases, withdrawal of calcineurin inhibitors.

[Evidence-based guidelines and nephrological clinical practice: the GRADE system for rating of evidence]. / Applicabilità delle Linee Guida basate sull'evidenza e alla comune pratica clinica: il sistema GRADE.

It has become widely accepted that decision-making should be based on the best available evidence. The preparation of evidence-based guidelines in the interest of improving long-term outcomes has been a challenging task for many societies. Although nephrology is a relatively young medical discipline and therefore presumably well-disposed towards evidence-based decision making, many problems exist and evidence-based approaches to guidelines have also been widely criticized. One key issue has been the availability of only few and suboptimal randomized trials in this discipline. Considerable variation in the grading systems used to assess existing evidence in nephrology guidelines highlights the need for a better tool. Tools that rigidly assess existing evidence need to also explore the applicability to current practice. The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system, developed and implemented in 2004 by the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines panel, is the most advanced tool in this direction.

Expression of platelet-derived growth factor receptors in normal and diseased human kidney. An immunohistochemistry and in situ hybridization study.

We studied the expression of PDGF-alpha and -beta receptors in 10 normal and 40 pathologic human kidneys (five minimal change disease, five membranous nephropathy, 25 IgA nephropathy, five lupus nephritis), by both immunohistochemistry and in situ hybridization techniques. In normal-appearing kidneys, both PDGF-alpha and -beta receptors were expressed at the glomerular and interstitial level, the latter receptor more intensely than the former. The distribution and degree of expression of both receptors in nonproliferative glomerulonephritides were comparable with those found in normal-appearing kidneys. PDGF-beta receptor gene and protein expression were upregulated in proliferative nephritides both at the glomerular and the interstitial level and strictly correlated with the grade of histologic lesions. Finally, PDGF beta receptor expression was observed at a low level in normal-appearing renal vessels, and strikingly increased in injured arteries. Diseased kidneys displayed only a slight increase of PDGF-alpha receptor expression, chiefly at the interstitial level. Noteworthy, a few cases of lupus nephritis showed a moderate increase of PDGF-alpha receptor also at the glomerular level. These data establish PDGF-beta receptor activation as a candidate for driving glomerular and interstitial proliferation and, probably, expansion of extracellular matrix in proliferative glomerulonephritis, while the role of PDGF-alpha receptor activation at the renal level remains to be elucidated.

PDGF-B gene single-nucleotide polymorphisms are not predictive for disease onset or progression of IgA nephropathy.

BACKGROUND: Few genetic factors have been identified that determine susceptibility to and progression of IgA-nephropathy (IgAN). Given that IgAN is usually characterized by mesangioproliferative glomerulonephritis and that PDGF-B is of central pathophysiological relevance in this process, we analyzed four single-nucleotide polymorphisms (SNPs) of the PDGF-B gene to evaluate a possible association of these SNPs with disease onset and progression, histological grading and responses to ACE inhibitor (ACEi) therapy. METHODS: The total study population consisted of 195 IgAN patients (127 from southern Italy and 68 from northern Germany) and 200 healthy controls (100 from each region). All four SNPs were in Hardy-Weinberg equilibrium and genotype distributions did not differ between patients and controls in either region. RESULTS: SNP distribution in Italian patients reaching end-stage renal disease (n=45) also was not significantly different from patients maintaining a serum creatinine below 1.2 mg/dl (n=60) during 5.6 +/- 5.5 years of follow-up. Furthermore, we failed to detect significant effects of any SNP on the slope of 1/serum creatinine, proteinuria level or the antiproteinuric response to ACEi. Additionally, particular PDGF-B genotypes did not correlate with histological grading using the Lee classification. CONCLUSION: We conclude that none of the four PDGF-B SNPs is related to the onset of IgAN in two different populations and that none of them has a major influence on the course of IgAN.

[2004 census of the Italian nephrology and dialysis units]. / Censimento 2004 dei Centri di Nefrologia e Dialisi Italiani.

The Italian Society of Nephrology (SIN) promoted a census of the renal and dialysis units to analyze structural and human resources, organizational aspects, activities and epidemiological data. An online 158-item questionnaire for the year 2004 was used. Three hundred sixty-three public renal units, 303 satellite dialysis centers and 295 private dialysis centers were identified, resulting in a total of 961 dialysis centers (16.4 per million population, pmp). The inpatient renal beds were 2,742 (47 pmp). Renal and dialysis activity was performed by 3,728 physicians (64 pmp), of whom 2,964 (80%) were nephrologists. There was no permanent medical assistance in 41% of the satellite dialysis centers. Renal admissions (1,800 pmp) and renal biopsies (99 pmp) were done. The management of the acute renal failure was one of the most relevant activities in the public renal units (13,456 cases, 230 pmp). In 2004 9,858 new cases of end-stage renal disease (169 pmp) were diagnosed. On December 31st 2004, 43,293 patients (741 pmp) were on renal replacement therapy, of whom 89.7% on hemodialysis and 10.3% on peritoneal dialysis. Renal transplant recipients were 16,765 (287 pmp). The benchmark data derived from this census show interesting comparisons between centers, regions and groups of regions. These data realised the clinical management of renal disease in Italy.

Confocal laser scanning microscope study of terminal villi vessels in normal term and pre-eclamptic placentas.

The aim of this study was to compare immunocytochemical confocal scanning laser microscopy measures of villus capillarization in control placentas with pre-eclamptic ones. Accordingly, placentas from normal term pregnancies (n=3) and cases of late-onset pre-eclampsia without intrauterine growth retardation (IUGR) featuring normal uterine artery Doppler (n=3) were analyzed by confocal scanning laser microscopy (CSLM), which is a powerful technique for obtaining three-dimensional reconstructions of any kind of blood vessels (arteries, veins, capillaries). A laser light beam is used in order to detect CD34 antibody-related immunofluorescence, which is a marker of endothelial cells. Villus capillarization was assessed by estimating the following parameters: number of pixels, mean, maximum and minimum immunofluorescence amplitude. Our results show a significant hyper-ramification of the capillary loop in pre-eclamptic placentas, featuring irregular profile and narrow lumina. Such findings support the hypothesis that several agents causing angiogenesis and vasoconstriction affect villus vessels in pre-eclamptic placentas, thus promoting a lasting condition of fetal hypoxia by decreasing endothelial surface and materno-fetal exchanges.

[Pro and anti-neoplastic effects of immunosuppressive drug in renal transplantation]. / Effetti pro ed anti-neoplastici dei principali farmaci immunosoppressori usati nella pratica clinica trapiantologica.

The increased efficiency of immunosuppressive drugs obtained in the last few years has significantly reduced the incidence of acute rejection, prolonging transplant survival rates. The inevitable trade-off was however an increased rate of post-transplant infections and malignancies. Furthermore, this problem might get more and more serious in the next future due to the increasing incidence of cancer in immunosuppressed transplant recipients; the introduction of new immunosuppressive strategies is expected to extend significantly allograft survival. The inclusion of older recipients in transplant programs will also likely increase this problem. Thus, cancer may represent a serious cause of morbidity and mortality in patients otherwise successfully treated by organ transplantation. Nevertheless, effective approaches to deal with malignancies in immunosuppressed patients are still far from the clinical arena. Therefore, once cancer occurs in a transplant recipient, clinicians only have two options: to reduce or withdraw the immunosuppression eventually causing acute or chronic allograft rejection, or to continue the standard immunosuppressive therapy while beginning specific therapy for the malignancy. Several clinical studies suggest that the use of immunosuppressive drugs may result in increased cancer incidence, in transplant as well as autoimmune disease patients. This clinical observation is supported by experimental data showing that these drugs enhance cancer cell growth characteristics and inhibit DNA repair mechanisms, clearly suggesting that the increased incidence of neoplastic disease in patients treated with several immunosuppressive drugs is at least partially independent of their immunosuppressive action. In this scenario it is of particular interest the fact that some immunosuppressive drugs have both an anti-rejection and anti-neoplastic activity. In this review we focus our attention on this potential dual role of immunosuppressive therapy in the development of neoplasia in transplanted patients.