Biomedical subjects

Luisa Murer

Publications and source records attributed to Luisa Murer.

9 recordsLinked to original sources

PubMed2005

One-year results of basiliximab induction and tacrolimus associated with sequential steroid and MMF treatment in pediatric kidney transplant recipient.

We report the 1-year results with a triple immunosuppressive regimen in pediatric recipients of a first kidney transplant, in order to evaluate its safety and efficacy in the prevention of acute rejection and in the reduction of steroid side effects. The immunosuppression is as follows: (i) basiliximab (20 mg if body weight >30 kg; 10 mg if < 30 kg) is given pretransplant and at day 4; (ii) tacrolimus (Tac) is administered in order to obtain blood trough levels of 10-20 and 5-10 ng/ml during and after the first 2 months post-transplant, respectively; (iii) steroids are tapered during the first 6 months and then replaced by mycophenolate mofetil (depending on previous rejection episodes, infection status and the result of a routine biopsy) at a dosage of 4-600 mg/m(2) body surface area. Fifty-three children (median age 13 years, range 2-20) have entered this protocol. One-year patient and kidney survival are 100% and 94% respectively. During the first year a total of nine rejections in seven patients (13% of the cohort study) occurred, all but one responsive to steroids. Renal function was satisfactory throughout the first year (mean CrCl was 63.8 +/- 18 and 60.9 +/- 15.5 ml/min/1.73 m(2) at 6 and 12 months respectively). Subclinical signs of rejection were absent in more than 80% of biopsies (grade I Banff) at 6 months (n = 47); at the 12th month biopsy (n = 42) score I was stable in 20 patients (16 after stopping steroids) and had worsened in eight biopsies (six after stopping steroids). Major complications were insulin-dependent diabetes in three (5.6%) children with the need of insulin for a mean of 3 months; transient hyperglycemia (11 patients), treated with a dietary regimen, symptomatic viral infections (in 11 patients: two parvovirus B19, three cytomegalovirus and two Epstein-Barr virus systemic infections, three interstitial pneumonia, two BK nephritis). Tac doses more than 0.3-0.4 mg/kg/day are at significantly higher risk of viral infection. In conclusion, this immunosuppressive regimen is associated with a low percentage of clinical (13%) and subclinical rejections, but with a relatively high number of infections, prevented by a reduction in Tac doses (<0.3 mg/kg/day) during the first 2 months after transplantation. The assessment of steroid withdrawal needs a longer follow-up.

Adolescent↗

PubMed2004

Selective decrease in urinary aquaporin 2 and increase in prostaglandin E2 excretion is associated with postobstructive polyuria in human congenital hydronephrosis.

This study was undertaken to determine the role of aquaporin 2 (AQP2) in the impaired urinary concentrating capacity observed in patients who underwent pyeloplasty because of congenital unilateral hydronephrosis as a result of pyeloureteral junction disease. Twelve children (mean age, 8 +/- 2 mo) were examined in the study. From day 1 to day 5 after surgery, the urine was collected separately from pyelostomy draining only from the postobstructed kidney and from the bladder catheter draining mostly from the contralateral kidney used as internal control. After pyeloplasty, the postobstructed kidney was characterized by a reduced urinary excretion of AQP2 (approximately 54%) associated with polyuria that persisted from day 1 to day 5 (433 +/- 58 versus 310 +/- 74 ml/24 h at day 1; 326 +/- 44 versus 227 +/- 26 ml/24 h at day 5). In parallel, urine osmolality from the postobstructed kidney was significantly reduced compared with the contralateral kidney (111 +/- 12 versus 206 +/- 49 at day 1; 136 +/- 24 versus 235 +/- 65 mOsm/kg at day 5). Creatinine clearance from the postobstructed kidney was not significantly different compared with the contralateral kidney throughout the 4 d after surgery. However, on day 5, creatinine clearance from the postobstructed kidney became significantly lower. Prostaglandin E2 in the urine from postobstructed kidneys was found to be twofold higher than in the contralateral samples (26.0 +/- 6.7 versus 13.5 +/- 2.5 at day 5). It is concluded that (1) the selective downregulation of AQP2 in postobstructed kidney may account for the higher excretion of hypotonic urine, and (2) the local increase in prostaglandin E2 synthesis in postobstructed kidney may be involved in AQP2 downregulation and in maintaining a GFR similar to that of the contralateral kidney.

Adolescent↗

PubMed2003

Recurrence of focal segmental glomerulosclerosis after renal transplantation in patients with mutations of podocin.

BACKGROUND: Posttransplant recurrence of focal segmental glomerulosclerosis (FSGS) occurs in a relevant proportion of FSGS patients and represents an important clinical emergency. It is taken as a proof of the existence of circulating permeability plasma factor(s) that are also putative effectors of original proteinuria in these patients. Familial forms of FSGS do not recur, but the discovery of numerous patients with sporadic FSGS and mutations of podocin (NPHS2, that is actually an inherited disease) who received a renal graft require a re-evaluation of the problem. METHODS: To evaluate the incidence of posttransplant recurrence of FSGS in patients with NPHS2, the authors screened for podocin mutations in 53 patients with the clinical and pathologic stigmata of FSGS who had renal failure and who had undergone renal transplantation.Results. Twelve children were found to carry a homozygous (n9) or a heterozygous (n4) mutation of podocin and were classified, according to current criteria, as patients with inherited FSGS. In 5 patients of this group (38%), proteinuria recurred after renal graft and in 2, renal biopsy results showed recurrence of FSGS. Prerecurrence serum of 3 patients of this cohort was tested for antipodocin antibodies with indirect immuno-Western utilizing human podocyte extracts and were found negative. The rate of FSGS recurrence was comparable in non-NPHS2-FSGS children (12 of 27) and adults (3 of 13). Also clinical outcome of recurrence and response to plasmapheresis and immunosuppressors were comparable, suggesting a common mechanism. CONCLUSION: These data show a high rate of FSGS recurrence in patients with NPHS2 mutations that is comparable with idiopathic FSGS and describe the successful therapeutic approach. Recurrence of an apparently inherited disease should stimulate a critical review of the mechanisms of recurrence and of original proteinuria in these cases.

Adolescent↗

PubMed2003

Mutational spectrum of the CTNS gene in Italy.

Classic nephropathic or infantile cystinosis (NC) is an autosomal recessive disorder; the gene coding for the integral membrane protein cystinosin, which is responsible for membrane transport of cystine (CTNS), was cloned. Mutation analysis of the CTNS gene of Caucasian patients revealed a common 57-kb deletion, and several other mutations spread throughout the entire gene. In the present study, we report the CTNS mutations identified in 42 of 46 Italian families with NC. The percentage of mutations characterized in this study is 86%. The mutational spectrum of the Italian population is different from that of populations of North European origin: the 57-kb deletion is present in a lower percentage, while the splicing mutations represent 30% of mutation detected in our sample. In all, six novel mutations have been identified, and the origin of one recurrent mutation has been traced.

Adolescent↗

PubMed2003

Broadening the spectrum of diseases related to podocin mutations.

A total of 179 children with sporadic nephrotic syndrome were screened for podocin mutations: 120 with steroid resistance, and 59 with steroid dependence/frequent relapses. Fourteen steroid-resistant patients presented homozygous mutations that were associated with early onset of proteinuria and variable renal lesions, including one case with mesangial C3 deposition. Single mutations of podocin were found in four steroid-resistant and in four steroid-dependent; five patients had the same mutation (P20L). Among these, two had steroid/cyclosporin resistance, two had steroid dependence, and one responded to cyclosporin. The common variant R229Q of podocin, recently associated with late-onset focal segmental glomerulosclerosis, had an overall allelic frequency of 4.2% versus 2.5% in controls. To further define the implication of R229Q, a familial case was characterized with two nephrotic siblings presenting the association of the R229Q with A297V mutation that were inherited from healthy mother and father, respectively. Immunohistochemistry with anti-podocin antibodies revealed markedly decreased expression of the protein in their kidneys. All carriers of heterozygous coding podocin mutation or R229Q were screened for nephrin mutation that was found in heterozygosity associated with R229Q in one patient. Finally, podocin loss of heterozygosity was excluded in one heterozygous child by characterizing cDNA from dissected glomeruli. These data outline the clinical features of sporadic nephrotic syndrome due to podocin mutations (homozygous and heterozygous) in a representative population with broad phenotype, including patients with good response to drugs. The pathogenetic implication of single podocin defects per se in proteinuria must be further investigated in view of the possibility that detection of a second mutation could have been missed. A suggested alternative is the involvement of other gene(s) or factor(s).

Actinin↗

PubMed2002

Extracorporeal photochemotherapy: a new therapeutic approach for allograft rejection.

Photopheresis (ECP) is a new immunomodulatory therapy in which recipient lymphocytes are treated extracorporeally with 8-methoxypsoralen (8-MOP) and ultraviolet light. The treatment seems to induce an inhibition of both umoral and cellular rejections after transplantation. More than 160 transplanted patients have been treated with ECP (107 heart, 30 kidney, 24 lung and I liver) in different studies. Indication for ECP included acute rejection, recurrent/refractory rejection, prophilaxis of rejection, need of reducing standard immunosuppression. Patient survival is satisfactory. Only one study where ECP was used as the last therapeutic resource in very compromised patients shows a high rate of mortality. On the contrary, when ECP was used earlier after the failure of a first immunosuppressive line the outcome was better with a very low mortality. An hystological resolution of acute rejection is reported in 89% of cardiac transplant patients. The rate of response is similar even in the other transplanted patients treated with ECP. A better control of alloreactivity has been also reported in both cardiac and renal transplant patients with recurrent rejection. In renal allograft the treatment induces a reduction of both lymphocytes and monocytes infiltrate and downregulates the expression of HLA-DR and integrins ICAM-1 and VCAM-1 on tubular cells. Markers of fibrogenesis such as TGFbeta1 and ASMA are only moderately reduced with a more focal pattern of distribution in the post-ECP specimens. The optimal schedule and the length of treatment are still unclear and probably a patient-tailored treatment is needed at least in responder patients. ECP is effective for patients resistant to conventional treatments, particularly when it is started early. This beneficial effect is obtained without the complications typically encountered with immunosuppressive regimens used to control rejection.

Animals↗

PubMed2002

Expression of nuclear transcription factor PAX2 in renal biopsies of juvenile nephronophthisis.

PAX2, a homeotic gene of 'paired box family', is a nuclear transcription factor expressed in mesenchymal/epithelial conversion during the early stages of nephrogenesis; however, its repression is necessary for terminal differentiation of mature tubular cells. Transgenic overexpression in animal model causes epithelial hyperproliferation and microcyst formation. In humans, PAX2 expression has been observed in cystic and dysplasic tubular epithelia in kidney malformation and in kidney disease. We have investigated PAX2 expression and its colocalization with cytokeratin and/or vimentin in 17 biopsies of juvenile nephronophthisis (NPH), an autosomal-recessive renal disease characterized by diffuse renal fibrosis and occasional cysts. Fourteen cases were analyzed for deletion and mutation in the NPH1 gene locus and 33% resulted to be deleted or mutated; for the remaining cases the diagnosis was based on clinical and pathological criteria. The control group included 4 congenital dysplastic kidneys, and 10 biopsies of nephropathies with secondary chronic tubulointerstitial damage. In all cases of renal dysplasia a strong nuclear positivity was observed in immature tubules surrounded by alphaSMA-positive mesenchymal cells. In NI biopsies the tubular epithelia were almost PAX2 negative, although tubulointerstitial damage was severe. In 14/17 NPH1 moderate-to-strong nuclear PAX2 positivity of tubular cells was observed, particularly in cystic distal tubules located at the corticomedullary junction, but also in proximal tubular sections. The PAX2 signal co-localized more with cytokeratin staining than with vimentin. Our results confirm the observation of PAX2 expression in immature dysplastic tubules and its repression in mature renal tubular cells, also in the presence of severe secondary interstitial fibrosis. PAX2 seems to be overexpressed in NPH. The genetic defect of NPH, a disease probably due to a primary defect along the cascade of mesenchymal epithelial differentiation, could generate a functionally abnormal protein involved in focal adhesion signaling and cell/matrix interaction. The failure of PAX2 repression or its reactivation in NPH could be a marker of hyperproliferation and incomplete maturation of epithelial tubular cells, probably due to a defect cell/matrix cross-talk, and involved in interstitial fibrosis and cysts formation.

Biopsy↗

PubMed2000

Thrombotic microangiopathy associated with parvovirus B 19 infection after renal transplantation.

Human parvovirus B19 is considered an etiologic agent of aplastic anemia in immunosuppressed patients. Microscopic vasculitis, with or without renal involvement, has recently been attributed to this viral infection in immunocompetent patients. This study describes four cases of thrombotic renal graft microangiopathy presumably secondary to B19 infection. Twelve to 50 days after transplantation, four patients presented a renal graft dysfunction with creatinine rising to 360 to 1088 micromol/L and requiring hemodialysis in three cases. Renal involvement appeared after a systemic illness characterized by fever, fatigue and arthralgia, aplastic anemia (hemoglobin ranged from 5.3 to 7.8 g/dl), and thrombocytopenia. A thrombotic microangiopathy was observed in the renal biopsies, and the parvovirus B19 genome was isolated by PCR from the specimens. All four patients also became IgM-positive for parvovirus. Three of the four renal biopsies taken at the time of transplantation (T0) from the same patients were found positive for the B19 genome. Graft function recovered, with resolution of the aplastic anemia, within 22 to 110 d. Twenty biopsies performed as routine controls or for suspected acute rejection and nine T0 biopsies of patients with no signs of B19 infection were used. The B19 genome was found in two of 20 posttransplant biopsies and in one of nine T0 biopsies. The temporal association between aplastic anemia and the onset of thrombotic graft microangiopathy, isolation of the viral genome in renal specimens, seroconversion, and endothelial tropism of the virus suggests that B19 could be the etiologic agent of thrombotic microangiopathy in these cases. The development of the disease after infection could depend on other detrimental cofactors, which make the patient more susceptible to microthrombi formation in the renal microvasculature. The renal graft could represent the route of B19 transmission.

Adolescent↗

PubMedDate not supplied

CMV and BKV ureteritis: which prognosis for the renal graft?

This report describes two cases of ureteral stricture in renal graft recipients related to cytomegalovirus (CMV) and human polyoma BK virus (BKV) ureteritis with the same onset characterized by acute graft failure with no clinical signs of systemic viral infections. The histological analysis did not show other causes of graft impairment (i.e. drug toxicity and acute rejection). Ultrasound scan (US) revealed absent or mild hydronephrosis. The diuretic-MAG3 renal scan showed a urinary flow obstruction. The viral genomes were isolated from urine, peripheral blood and graft or ureteral tissues samples. A percutaneous nephrostomy confirmed the stricture, but it restored urine flow only in the graft affected by CMV ureteritis, the association with a specific antiviral therapy probably produced a stable restoration of graft function. In BKV ureteritis,the graft prognosis was poor; graft loss could be due to the progress of BKV nephropathy. A correct differential diagnosis of the etiologic agent responsible for the ureteritis is mandatory, because treatment and outcome of the infection are different.

Adolescent↗