Genetic approaches to human renal agenesis/hypoplasia and dysplasia

Congenital abnormalities of the kidney and urinary tract are frequently observed in children and represent a significant cause of morbidity and mortality. These conditions are phenotypically variable, often affecting several segments of the urinary tract simultaneously, making clinical classification and diagnosis difficult. Renal agenesis/hypoplasia and dysplasia account for a significant portion of these anomalies, and a genetic contribution to its cause is being increasingly recognized. Nevertheless, overlap between diseases and challenges in clinical diagnosis complicate studies attempting to discover new genes underlying this anomaly. Most of the insights in kidney development derive from studies in mouse models or from rare, syndromic forms of human developmental disorders of the kidney and urinary tract. The genes implicated have been shown to regulate the reciprocal induction between the ureteric bud and the metanephric mesenchyme. Strategies to find genes causing renal agenesis/hypoplasia and dysplasia vary depending on the characteristics of the study population available. The approaches range from candidate gene association or resequencing studies to traditional linkage studies, using outbred pedigrees or genetic isolates, to search for structural variation in the genome. Each of these strategies has advantages and pitfalls and some have led to significant discoveries in human disease. However, renal agenesis/hypoplasia and dysplasia still represents a challenge, both for the clinicians who attempt a precise diagnosis and for the geneticist who tries to unravel the genetic basis, and a better classification requires molecular definition to be retrospectively improved. The goal appears to be feasible with the large multicentric collaborative groups that share the same objectives and resources

Calcineurin inhibitors in renal transplantation still needed but in reduced doses: a review.

Despite their contribution in the success of organ transplantation, calcineurin inhibitors (CNIs) may be responsible for frequent and severe side effects that can affect graft survival and life expectancy. In this article, we have reviewed registry studies and randomized controlled trials (RCTs) that seek to avoid, withdraw, or minimize CNIs in renal transplant recipients. Attempts to completely avoid CNIs by administering mycophenolate mofetil (MMF) and/or sirolimus (SRL) have resulted in increased risks of rejection and side effects, with small advantage to improve renal graft function. Early withdrawal of CNIs after transplantation using administration of MMF can improve graft function but may be associated with a greater risk of acute or chronic rejection and graft failure. RCTs in which CNIs were replaced a few months after transplantation by SRL reported improved graft function among SRL-treated patients, but such a treatment was complicated by iatrogenic toxicity. Late replacement of CNIs with SRL did not produce a particular advantage and again was complicated by more frequent side effects. On the basis of these trials, it seems that CNI elimination can trigger rejection or side effects. Recent RCTs showed that minimization of CNI doses in association with everolimus does not increase the risk of rejection, allows one to obtain good graft function, and is well tolerated. Such an approach seems therefore preferable to complete elimination of CNIs with substitution of the current immunosuppressive drugs

Hyperimmunized patients awaiting cadaveric kidney graft: is there a quick desensitization possible?

On all kidney waiting lists the 10% to 20% of patients who have antibodies against more than 80% of a panel of HLA antigens (panel reactive antibody [PRA] >80%) are difficult to transplant. The best solution for these patients is to find a compatible donor, ideally a full match, who yields a negative crossmatch test (CMX). If this is not possible, desensitization treatment (high-dose) intravenous immunoglobulin (IVIG) or plasmapheresis (PP) + low-dose IVIG is possible with good results in living donor kidney transplantation mainly if the antibody titer is low. It may also be offered to patients awaiting cadaveric donors too after a long waiting time; however, when applied for several months, it has the obvious disadvantage of giving the patient the risk for long-lasting immunologic weakness without the certitude of finding a kidney. In one of our recent cases of combined liver plus kidney transplantation, a positive CMX became negative 8 hours after the liver operation; the kidney was transplanted with a good result which lasted over 3 years. This observation suggested the possibility of a quick desensitization protocol in selected patients with a large (but not strong) immunization who probably are the majority. Patients sensitized to IVIG and with low titer PRA could be given a single PP + low-dose IVIG (what can be done within the time limit of cadaveric donor kidney transplantation) with good probability of turning an initial positive CMX to negative with the possibility of performing the operation and the advantage of giving the immunosuppression only when the kidney is present

Trapianto di rene a Bologna

Presso il Centro Trapianti di Rene del Policlinico S. Orsola di Bologna nel corso del 2011 sono stati sottoposti a trapianto 62 pazienti di cui 51 da donatore cadavere (43 singoli reni, 3 doppi trapianti di rene, 4 trapianti combinati rene/fegato, 1 trapianto combinato rene/cuore) e 11 da donatore vivente; per la realizzazione dell\u2019attivit\ue0 sono stati utilizzati complessivamente 65 reni. Complessivamente si \ue8 registrata una riduzione dell\u2019attivit\ue0 trapiantologica rispetto al 2010 (-10%); in linea con la media Nazionale che risulta in calo di circa il 10%. Si \ue8 assistito ad un incremento dell\u2019attivit\ue0 di trapianto da donatore vivente del 30% rispetto ai dati del 2010 e al continuo sviluppo di programmi di trapianto combinato. Anche nel 2011 si \ue8 confermata una buona collaborazione con il Centro Regionale Trapianto, con il Centro Interregionale AIRT e con le altre strutture trapiantologiche nazionali (NITp, OCST); non si sono registrati rifiuti di organi per motivi di carattere organizzativo o logistico. Anche nel 2011 le strutture logistiche e le procedure operative utilizzate dal Centro Trapianti di Bologna sono stati sottoposti a verifiche dei requisiti di qualit\ue0; nel corso dell\u2019anno il Dipartimento di cui fa parte il Centro Trapianti ha superato la fase di accreditamento regionale. Nel corso dell\u2019anno \ue8 stata divulgata ai pazienti candidati a trapianto renale la guida al trapianto che fornisce informazioni sugli aspetti gestionali e pratici delle diverse fasi del Programma del Trapianto (lista di attesa, trapianto, follow-up post-trapianto) con l\u2019intento di rispondere ai pi\uf9 frequenti quesiti dei pazienti. L\u2019esperienza del Centro Trapianto di Rene del S. Orsola nelle diverse fasi (inserimento in lista di attesa, terapia immunosoppressiva, follow-up post trapianto) \ue8 stata oggetto di pubblicazione su riviste Nazionali ed Internazionali e di comunicazione in Congressi di Nefrologia, Chirurgia ed Immunologia. L\u2019Unit\ue0 Operativa di Nefrologia Dialisi e Trapianto del Policlinico S. Orsola \ue8 sede della Lista Unica Regionale per il trapianto di rene (circolare dell\u2019Assessorato alla Sanit\ue0 della Regione Emilia-Romagna n. 12 del 30 maggio 2001); coordina, in collaborazione con i colleghi dei Centri Trapianto di Modena e di Parma, la valutazione di idoneit\ue0 al trapianto dei reni proposti dal Centro Regionale Trapianti e, in collaborazione con la Unit\ue0 Operativa di Genetica Medica di Parma, l\u2019allocazione degli stessi. L\u2019attivit\ue0 complessiva attinente alla Lista Unica \ue8 riportata in dettaglio in una specifica sezione del presente report regionale. Gli obiettivi del Centro per l\u2019anno 2012 sono costituiti dal mantenimento di un\u2019attivit\ue0 di trapianto da donatore cadavere in linea con i dati storici del Centro, dall\u2019incremento dei Trapianti da donatore vivente con lo sviluppo di programmi di informazione sul territorio regionale, dalla periodica rivalutazione dei pazienti con comorbidit\ue0 note (in particolare patologia cardiovascolare) o da pi\uf9 tempo inseriti in lista e dal consolidamento dei programmi di trapianto combinato

Tacrolimus-associated myositis: a case report in a renal transplant patient.

A 55-year-old Caucasian man who had received a second kidney graft in July 1993, was switched from cyclosporine to tacrolimus in June 2000 due to deterioration of renal function. Thereafter, he began to complain of muscle cramps in both quadriceps with an increased CPK and EMG findings of polyneuropathy. A muscle biopsy demonstrated acute myositis. Prednisone was administered with amelioration of the patient's symptoms, but with persistently increased CPK and myoglobin levels. In February 2001, mycophenolate mofetil was introduced and tacrolimus tapered to 3 mg daily to seek a toxic role of this immunosuppressant, since there was no other cause of myositis. A sudden decrease in CPK was observed, but the complete normalization took place only after its withdrawal in September 2002. This case represents a tacrolimus-associated myositis

Metabolic syndrome after kidney transplantation.

BACKGROUND: Metabolic syndrome (MS) includes some risk factors for development of diabetes and cardiovascular disease, obesity (BMI > 30), high triglycerides, low HDL cholesterol, hypertension and impaired glucose tolerance. Following the definition of the Adult Treatment Panel III criteria, a diagnosis of MS was established when 3 or more factors were present. In renal transplant patients MS has been reported to negatively influence both patient and graft survivals. The present study sought to verify the effect of MS among our cases. METHODS: 298 cadaveric renal transplant recipients operated between January 1, 1996 and December 31, 2001 with absence of diabetes before transplantation, stable renal function 1 year posttransplantation and at least 4 years follow up were retrospectively evaluated from the end of the first post-operative year. RESULTS: 50 patients out of 298 (16,7%) had MS at the beginning of the study, including 37 of them with 3 and 13 with 4 risk factors. Only one patient with MS died of cardiovascular disease. Graft failure was observed in 23.5% MS patients versus 9,7% patients without the Syndrome (p:n.s.) Only Creatinine and the incidence of Cardiovascular Diseases at 4 years were statistically higher in MS patients (P < .001). CONCLUSIONS: These results suggested that MS is a risk factor for increasing CVD morbidity and decreased graft function, but early treatment of risk factors as soon as they become apparent can limit the adverse effects on patient and graft survival

Expression of metanephric differentiation markers in human mesenchymal stem cells. [Marker di differenziamento metanefrico espressi in cellule staminali mesenchimanli umane].

Stem cells are a potential source for the regeneration of many tissues, including damaged kidneys. The present study describes the adoption of hyaluronic- butyric acid monoesters (HB) to induce expression of nephrogenic genes by mesenchymal cells isolated from human placental membranes. HB at a concentration of 1 mg/mL induces chromatin opening and increases the expression of the observed markers (cadherin 11, CD24, RAR-alpha, stearoyl-CoA desaturase 2, 14-3-3 0, Ewing sarcoma homolog.). These results open new routes toward cell regeneration after kidney injury