[Clinical study of the month: depressive pseudo-dementia]. / Le cas clinique du mois. Pseudo-démence dépressive.

We report the case of a man aged 62 suffering from a known type I bipolar disorder and referred by his attending psychiatrist because of a state of spatiotemporal disorientation, confusion and prostration evoking significant neurologic impairment. The interest of this case report is in the use of the 18-FDG PET-Scanner, which is increasingly widespread in clinical psychiatry, to support the differential diagnosis between a psycho-organic pathology like dementia or a functional psychiatric pathology like depressive pseudo-dementia (also named melancholic dementia), in which some patterns of dysfunction can now be identified by functional imaging.

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.

Ischemia-reperfusion injury-induced abnormal dendritic cell traffic in the transplanted kidney with delayed graft function.

Delayed graft function (DGF) in kidney transplantation is associated with an increased risk of acute rejection. Myeloid dendritic cells (DCs) are involved in graft rejection, whereas plasmacytoid DCs may play a role in inducing tolerance. We evaluated the presence and phenotype of the DCs in renal graft biopsies of 15 patients with DGF collected before and 7-15 days after transplantation. Biopsies taken from normal patients and from transplant recipients with acute calcineurin inhibitors (CNIs) nephrotoxicity served as a control group. Specific markers of myeloid, plasmacytoid, and mature DCs were imaged by confocal microscopy and immunohistochemistry. In normal kidneys and pre-transplant biopsies, sparse niches of myeloid and plasmacytoid cells were found but these were significantly increased with few mature cells during DGF. This same pattern was seen in acute rejection but with overall higher cell numbers. In CNI nephrotoxicity, myeloid cells were slightly increased but plasmacytoid cells were significantly higher than in DGF. Using a pig model, we found that a short period of warm ischemia followed by reperfusion led to myeloid cell infiltration of the kidney. Our data suggest that ischemia-reperfusion injury may cause an imbalance between intragraft myeloid and plasmacytoid DCs, which might be related to DGF and acute rejection.

[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.

Double J stent with antireflux device in the prevention of short-term urological complications after cadaveric kidney transplantation: single-center prospective randomized study.

The placement of a double J stent to protect a uretero-vesical anastomosis in a kidney transplant is a widespread procedure performed to reduce the incidence of fistula and stenosis at the anastomosis. However, the presence of a double J stent may cause vesicoureteral reflux (VUR), predisposing one to urinary tract infections (UTIs), which may be a significant source of morbidity for the graft. We evaluated whether a ureteral stent incorporating an antireflux device can reduce the incidence of ureteral reflux and UTIs. From January to December 2003, 44 kidney transplant recipients were randomized to receive a 14-cm 4.8-F double J stent with (group A) or without an anti-reflux device (group B). Primary end points were the reduction of the incidence of VUR and of UTIs. The secondary end point was the graft function, on the basis of mean serum creatinine level at 3, 6, and 12 months. We failed to observe statistically significant differences in terms of either the incidence of VUR and UTIs, or the short-term outcomes of the grafts. We concluded that the anti-reflux device does not have an impact on the incidence of stent-related side effects.

[Cardiovascular risk and renal transplantation]. / Il rischio cardiovascolare nel paziente con trapianto renale.

Cardiovascular disease after renal transplantation is often the expression of a disease process that first started with the onset of renal dysfunction many years before, and its prevention starts with the early predialysis phase of chronic renal failure and with the aggressive treatment of hypertension and dyslipidemia. The evidence that dialysis treatment itself accelerates arterial damage is poor. After transplantation, however, many patients are restored to a state not of normal renal function but of chronic renal impairment and have drug-induced hypertension and dyslipidemia, resulting in a vastly increased risk of atherosclerosis. Further research is required on optimal strategies to prevent or ameliorate cardiovascular disease, to establish the roles of lipid-lowering and antihypertensive therapies after transplantation and to define immunosuppressive ad hoc treatments for each kind of patient.

Rare phenotype and transplantability in cadaveric kidney transplant.

The waiting list for kidney transplants in the Apulia region contains recipients (about 30%) who were never selected for transplant due to the rare HLA antigen phenotypes and homozygosis. Therefore, an algorithm was selected to equilibrate the chance for patients to be selected despite a rare phenotype. We calculated for each patient, the sum (%) of the A, B, DR antigen frequency (total phenotypic frequency; TPF). All the potential recipients were grouped into five classes in increasing order of TPF. The number transplanted depended on the phenotype frequency. The selection index was the quotient of the number selected and the total number of patients. The selection index was 0.28 to 0.43 to 0.79 to 1.34 to 2.38 from class 1 to 5. To equilibrate the transplantability of rare phenotype recipients on the waiting list, a bonus was introduced for the most disadvantageous frequency class. Adding the bonus modified the selection index as follows: 1.0 to 1.25 to 1.5 to 1.34 to 2.38, which appears more equilibrated except for the class 5. In conclusion, if a bonus is applied for rare phenotypes, the chance to be transplanted becomes similar between patients with other parameters the same.

Kidney transplants from infected donors: our experience.

Organ procurement from infected donors may transmit a disease to the recipient that could cause a graft loss and/or recipient morbidity. Retrospectively, all kidney transplants from infected donors at our center in the last 4 years were reviewed. A donor was considered infected in the presence of at least one positive culture before procurement. From January 1999 to 2003, 23 of 160 donors (14.5%) were infected: in 10 donors a positive blood culture; in 3, a urine culture; and in 13, a bronchial culture. In a further 12 (7%) donors, only the preservation solution was contaminated. Organisms isolated were: Staphylococcus coagulase.neg. (n = 7); Staphylococcus epidermidis (n = 3); Staphylococcus aureus (n = 6); Klebsiella pneumoniae (n = 3); Pseudomonas aeruginosa (n = 4); Acinetobacter (n = 1); Candida albicans (n = 13); Aspergillus (n = 1); and Escherichia coli (n = 1). All except 2 kidneys were transplanted with positivity in all cultures. All recipients received general, nonspecific, antibacterial and antifungal prophylaxis until the antibiotic and antifungal spectrum was ready. Patient and graft survival rates at 6 months were 94% and 93%, respectively. Two deaths occurred due to bacterial arteritis (P aeruginosa), and 2 acute graft losses due to fungal arteritis. Kidneys from infected donors seem suitable for transplants. Only grafts infected by vasculotropic agents (S aureus, P aeruginosa, and C albicans) should be discarded.

Medical and surgical complications after kidney transplantation from "suboptimal donors": one centre's experience.

To overcome the organ shortage, the pool of donors can be expanded to include aged donors (>55 years old) or patients with diabetes and long-standing hypertension, the so-called "suboptimal donors." Our experience on medical and surgical complications in kidney recipients from such donors and their impact on the graft and patient survival rates is reported. From January 1998 to April 2003, 276 kidney transplantation were performed: 107 from suboptimal donors (group A) and 169 from optimal ones (group B). After a mean follow-up of 26.8 months (range, 1-63 months), the 1-year graft survival rate was 89.3% and 97% for groups A and B, respectively. Medical complications were observed in 18.8% of group A and 6% of group B and surgical complications in 34.5% and 20%, respectively. In conclusion, even if the complication rate is higher among the suboptimal donor group, the patient and graft survival rates appear to be only slightly affected, therefore, validating the use of marginal donors.

Experience with cyclosporine: approaching the therapeutic window for C2 levels in maintenance kidney transplant recipients.

This study was aimed to evaluate the clinical benefit of C2 monitoring in 191 stable renal transplant patients previously monitored by C0. All patients had been transplanted for at least 1 year and received cyclosporine (CsA)-based immunosuppression since the start. At the inceptions C0 levels were significantly correlated with C2 values (P<.0001). Patients with starting C2 levels >1000 ng/mL showed significantly higher levels of serum creatinine (sCr) both at inception (1.66 +/- 0.50 vs 1.44 +/- 0.41 mg/dL; P=.0021) and at the end of a 2-year follow-up (1.84 +/- 0.80 vs 1.46 +/- 0.51 mg/dL; P=.005). C2 monitoring revealed that a high percentage of patients were overexposed to CsA, mainly in the subgroup with most recent renal engraftments (12 to 24 months). The switch to C2 monitoring was associated with a slower deterioration of graft function (P=.02). Further, the mean values of C2 over a 2-year follow-up were inversely correlated with sCr at the end of follow-up (P=.0005). Finally, patients with mean threshold C2 levels above 720 ng/mL, roughly corresponding to the median value of C2, showed significantly lower levels of sCr at the end of follow-up (P=.0004). In conclusion, C2 monitoring of maintenance renal transplant patients allows one to identify a significant percentage of overexposed subjects, possibly limiting the rate of progression of chronic graft dysfunction. Target range values between 700 and 900 ng/mL appear to be associated with better long-term kidney graft function.

[Recurrent and de novo glomerular disease after renal transplantation]. / Recidive della nefropatia di base e nefropatie "de novo" in pazienti portatori di trapianto renale.

The development and progression or recurrent and de novo renal disease does not seem to have been influenced by the use of newer immunosuppressive agents. The rate of development of recurrent and de novo renal disease has been variable and is perhaps related to pre-existing immunological and/or haematological factors. The diagnosis of recurrent glomerulonephritis requires an accurate diagnosis of both primary renal disease and subsequent disease in the transplant kidney. Published data suggest that recurrent glomerulonephritis occurs in 6 to 19.4% of all renal transplant recipients, and causes the loss of 1.1 to 4.4% of all renal allografts. However, the propensity for glomerulonephritis to recur seems to be time dependent. Consequently, as grafts survival increases, so, too, does the likelihood of disease recurrence. In conclusion, currently available data on recurrence patterns of the less common nephropathies are unfortunately inadequate and our practice is therefore guided by small series, case reports, and local experience. It is to be hoped for that this deficit be addressed in the near future through the use of powerful database and registries, some of which are prospectively collecting data on specific disorders. Prospective studies on the treatment of recurrent glomerulonephritis are lacking. As grafts last longer and recurrent glomerulonephritis becomes a more significant entity, affecting greater numbers of patients, the opportunity to study management prospectively will be possible. This will probably require a cooperative, multicentre approach but it is clearly the only way forward, remembering that renal transplantation is a treatment, not a cure.

[Double renal transplant. Retrospective analysis of data on the patient population with double kidney transplantation in the setting of the AIRT]. / Trapianto di rene doppio. Analisi retrospettiva dei dati relativi alla popolazione dei pazienti portatori di trapianto renale doppio in ambito AIRT.

BACKGROUND: The number of patients on the waiting list for renal transplantation has progressively increased in the last decade, while the number of potential donors have remained the same. The expansion of the donor pool using marginal donors may represent a possible, although partial solution to this problem. Thus, the aim of the present analysis was to evaluate the graft survival of double renal transplant from marginal donors performed within the Associazione InterRegionale Trapianti (AIRT) and to assess whether this procedure is characterized by an increase in surgical complications. PATIENTS: 79 double renal transplants were performed from January 1st 1999 to December 31st 2002 in three AIRT transplant centers (Bari, Bologna, Torino). Immunosuppressive therapy for all patients included anti-IL-2 receptor antibodies, corticosteroids, tacrolimus and mofetil micophenolate. RESULTS: Graft survival was 90% at 36 months. Acute rejection incidence was 6.4%, while the incidence of surgical complications was 16.6%. CONCLUSIONS: The present study opens new perspectives to overcome the actual shortage of donor kidneys. Indeed, the use of marginal organs for double renal transplantation not suitable for single transplantation may create an additional pool of potential donors and significantly increase the number of kidney transplants.

[HCV+ patients on the waiting list for kidney transplantation. Retrospective analysis of data on the patient population with hepatitis C on the waiting list for kidney transplantation in the setting of the AIRT]. / Pazienti HCV+ in lista d'attesa per trapianto renale. Analisi retrospettiva dei dati relativi alla popolazione dei pazienti affetti da epatite C in lista d'attesa per trapianto di rene in ambito AIRT.

BACKGROUND: HCV infection in hemodialysis is still a matter of debate from an epidemiological and clinical point of view. Evaluation criteria for HCV-infected patients as transplant candidates are still not adequately standardized. Aims of the present study were to investigate: 1. the percentage of HCV positive patients on the waiting list of three Italian regions belonging to the Associazione InterRegionale Trapianti (AIRT); 2. to analyze the clinical approach in the evaluation of these patients in the attempt to define national guidelines for their pre- and post-transplant management. PATIENTS: We evaluated 2045 uremic patients on the waiting lists of four transplant centers (Bari, Bologna, Modena, Novara) belonging to AIRT at 31/12/2002. RESULTS: The overall prevalence of HCV positive patients was 14.2%, with a peak in the Puglia waiting list. The most common screening tests were AST and ALT serum levels and viral load (HCV RNA). Although there is a clear evidence that histological parameters are the main diagnostic and prognostic markers, a liver biopsy was performed in only 9.5% of patients. An even smaller percentage of HCV-infected patients underwent anti-viral therapy. CONCLUSIONS: Our retrospective analysis evidenced the need to improve common clinical strategies in approaching HCV-infected canditates to renal transplantation in the attempt to improve their post-transplant outcome.

[Malignant neoplasia and kidney transplantation. Retrospective analysis of data on the population having kidney transplantation with de novo neoplasia in the setting of the AIRT]. / Trapianto renale e neoplasie. Analisi retrospettiva dei dati relativi alla popolazione dei trapiantati di rene affetti da neoplasie de novo in ambito AIRT.

BACKGROUND: In transplanted patients undergoing immunossuppressive therapy the incidence of malignant neoplasia is 3-4 times higher than in the general population. Aim of the present study was to evaluate the prevalence of different tumours and the links between modulation of immunosuppressive therapy and patient and graft survival. PATIENTS: We evaluated 2029 kidney-transplanted patients from four Transplant Centres (Bari, Bologna, Modena, Novara) belonging to the Associazione InterRegionale Trapianti (AIRT). RESULTS: The incidence of neoplastic disease after transplantation was 3.9% in our population with a median time between transplantation and clinical onset of 23 months. We demonstrated a significant difference in the geographical distribution of different tumours. We did not observe any correlation with specific immunosuppressive drugs. Finally, dramatic reduction of the immunosuppression levels did not modify either the patients' or the graft's survival. CONCLUSIONS: Several factors can influence the post-transplant onset of neoplastic diseases with immunosuppressive therapy playing a pivotal role. The implementation of a National Registry would be the first step in an attempt to optimise immunosuppression in this particular group of patient's.

[Correlation between the onset of early proteinuria and the outcome of renal transplantation. Experience of a single centre]. / Correlazione tra insorgenza di proteinuria precoce e decorso clinico del rene trapiantato. Esperienza di un singolo centro.

BACKGROUND: Proteinuria is associated with an increased risk of renal failure. In chronic kidney transplant failure it is associated with poorer graft outcome. MATERIALS AND METHODS: In our Unit 405 renal transplants were performed between April 1992 and December 2001. We analysed 1) the main causes of post-transplant proteinuria and 2) the prognostic significance for graft outcome in patients with a minimum follow-up of 6 months. RESULTS: Early proteinuria was associated with a higher incidence of chronic allograft nephropathy (CAN) and de novo/recurrent nephropathies. Graft outcome was poorer in patients with early persistent proteinuria. CONCLUSIONS: Proteinuria after renal transplantation increases the risk of graft failure. We can, therefore, hypothesize that a graft biopsy is the best way to reveal the causes of proteinuria so that therapeutic interventions, which have been shown to reduce proteinuria, can be applied immediately.

[Herpetic viruses and renal transplantation]. / Virus erpetici e trapianto renale.

Over the last few years emerging evidence indicate the involvement of herpes viruses in the pathogenesis of several medical complications in transplanted patients. Herpes viruses are transmitted via inter-human contact and cause a primary infection, which commonly fails to give clinical signs and may persist even for years in a latent state in healthy subjects. In transplanted patients, herpes viruses may be transmitted through the transplanted organ or may be reactivated because of the use of powerful immunosuppressive drugs. Moreover, the persistence of immunosuppression greatly favours the clinical expression and severity of virus infection. Thus, herpes viruses seem to be involved in both acute and chronic deterioration of graft function, in the pathogenesis of post-transplant lymphoproliferative disorders and Kaposi sarcoma, and even in vessel atherosclerosis. This review will focus on relevant clinical aspects of herpes-virus infection, namely cytomegalovirus, EBV, herpes simplex 1 and 2, varicella zoster virus, HHV-6, HHV-7 and HHV-8, in kidney transplanted patients.

Pregnancy in renal transplantation: immunologic evaluation of neonates from mothers with transplanted kidney.

The occurrence of pregnancy in young female organ transplant recipients may sustain a high risk for prematurity and low rate of malformations in neonates. Therefore, it is necessary to counsel couples who want a child. In case of pregnancy, strict guidelines must be observed. Continuous exposure to CsA in utero seems to impair T-, B- and NK-cell development and function in neonates. This effect is prolonged throughout the first year of life. In addition, low levels of serum immunoglobulins occur at the same time. This leads to suggest a delayed administration of classical vaccinations (after the first 6 months of life) in view of the potential risks of both sub-optimal immunologic responses, and adverse events after the administration of live, attenuated vaccines in infants born from young female organ transplant recipients.

Immunologic evaluation during the first year of life of infants born to cyclosporine-treated female kidney transplant recipients: analysis of lymphocyte subpopulations and immunoglobulin serum levels.

BACKGROUND: In rodents, CsA has been shown to affect T-cell development, giving rise to an abnormal production of mature T cells and the absence of many T-cell subsets as well as to autoimmunity. Surprisingly, only a few studies investigated the effect of the immunosuppressive drug on the immune system of the human fetus. METHODS: We examined six infants born to female kidney transplant recipients who had received cyclosporine and methylprednisolone throughout their pregnancies. Peripheral blood was obtained 1 day and 2, 4, 6, and 12 months after birth, and two-color flow cytometric immunophenotyping of lymphocytes was performed. RESULTS: Total T cells, as well as CD4+ and CD8+ T cells, were low at birth, but normalized thereafter. Among T-cell activation markers, the expression of CD25, the alpha chain of the interleukin-2 receptor, was below the normal range or low range throughout the study period, and HLA-DR expression was extremely low at birth and failed to increase up to 12 months. The number of total B cells was lower than normal at birth, but steeply increased over time. In contrast, B-cell subset bearing CD5 antigen was severely depleted throughout the first year of life. Total IgG concentration was significantly lower than in controls at 2 months, mainly because of subnormal levels of IgG1 and IgG3 subclasses, which remained in the low range up to 6 months. Finally, infants showed normal numbers of true natural killer (NK) cells (CD3-CD16+CD56+), whereas the expression of CD57 antigen, defining non-MHC-restricted cytotoxic lymphocytes, was barely detectable at birth and failed to increase over time, in both CD8+ and CD8- subsets. Of note, none of the infants had clinical evidence of an immunodeficient state. CONCLUSIONS: continuous exposure to CsA in utero seemingly impairs T-, B-, and NK-cell development and/or maturation, and most of its effects are still apparent at 1 year, which might suggest that conventional vaccinations should be delayed in these infants.

Are lipid-dependent indicators of cardiovascular risk affected by renal transplantation?

Hyperlipoproteinemia has been reported to frequently occur in kidney transplanted patients, thus possibly explaining, at least in part, the increased incidence of cardiovascular disease in this population. To evaluate the impact of renal transplantation (Tx), and related immunosuppressive therapy, on plasma lipoprotein and Lp(a) profile, we selected a cohort of kidney transplanted patients (36 M/14 F; age 33.8 + 12.0 yr, range 13-62) lacking significant causes of hyperlipidemia. All patients received a triple immunosuppressive regimen and showed a stable renal function after Tx (plasma creatinine: 1.36 +/- 0.35 mg/dL). One year after Tx, we found a significant increase of total cholesterol (TC), LDL, HDL, ApoB and ApoA-I (p < 0.005), while plasma triglyceride levels remained unmodified. Lp(a) plasma levels after Tx were within the normal range and displayed a significant inverse relationship with apo(a) size. Noteworthy, LDL/HDL ratio and ApoB/ ApoA-I ratio in kidney transplanted patients were almost superimposable with those of normal controls. Specifically, LDL/HDL ratio significantly decreased in 64% of patients after Tx, due to a prevalent increase of HDL, and was associated with a moderate amelioration of plasma TG. In a multiple linear regression model, post-Tx HDL level was significantly related to recipient's age, gender, BMI and cyclosporine (CyA) trough levels (Adj-R2 = 0.35, p = 0.0002), with gender and CyA trough levels being the better predictors of HDL. In conclusion, immunosuppressive regimens, in themselves, do not appear to significantly increase the atherogenic risk related to lipoproteins. Rather, other factors can affect the lipoprotein profile and its vascular effects in renal transplant recipients.