Françoise Janssen

CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency.

Antibody deficiencies constitute the largest group of symptomatic primary immunodeficiency diseases. In several patients, mutations in CD19 have been found to underlie disease, demonstrating the critical role for the protein encoded by this gene in antibody responses; CD19 functions in a complex with CD21, CD81, and CD225 to signal with the B cell receptor upon antigen recognition. We report here a patient with severe nephropathy and profound hypogammaglobulinemia. The immunodeficiency was characterized by decreased memory B cell numbers, impaired specific antibody responses, and an absence of CD19 expression on B cells. The patient had normal CD19 alleles but carried a homozygous CD81 mutation resulting in a complete lack of CD81 expression on blood leukocytes. Retroviral transduction and glycosylation experiments on EBV-transformed B cells from the patient revealed that CD19 membrane expression critically depended on CD81. Similar to CD19-deficient patients, CD81-deficient patients had B cells that showed impaired activation upon stimulation via the B cell antigen receptor but no overt T cell subset or function defects. In this study, we present what we believe to be the first antibody deficiency syndrome caused by a mutation in the CD81 gene and consequent disruption of the CD19 complex on B cells. These findings may contribute to unraveling the genetic basis of antibody deficiency syndromes and the nonredundant functions of CD81 in humans.

Mutations in the Human Laminin β2 (LAMB2) Gene and the Associated Phenotypic Spectrum

Mutations of LAMB2 typically cause autosomal recessive Pierson syndrome, a disorder characterized by congenital nephrotic syndrome, ocular and neurologic abnormalities, but may occasionally be associated with milder or oligosymptomatic disease variants. LAMB2 encodes the basement membrane protein laminin β2, which is incorporated in specific heterotrimeric laminin isoforms and has an expression pattern corresponding to the pattern of organ manifestations in Pierson syndrome. Herein we review all previously reported and several novel LAMB2 mutations in relation to the associated phenotype in patients from 39 unrelated families. The majority of disease‐causing LAMB2 mutations are truncating, consistent with the hypothesis that loss of laminin β2 function is the molecular basis of Pierson syndrome. Although truncating mutations are distributed across the entire gene, missense mutations are clearly clustered in the N‐terminal LN domain, which is important for intermolecular interactions. There is an association of missense mutations and small in frame deletions with a higher mean age at onset of renal disease and with absence of neurologic abnormalities, thus suggesting that at least some of these may represent hypomorphic alleles. Nevertheless, genotype alone does not appear to explain the full range of clinical variability, and therefore hitherto unidentified modifiers are likely to exist. Hum Mutat 31:992–1002, 2010.

Ureteral Stenosis After Kidney Transplantation: True Incidence and Long-Term Followup After Surgical Correction

Between March 1965 and December 31, 1982, 421 kidney transplantations were performed in our department. The over-all incidence of ureteral stenosis was 5.5 per cent. However, when the number of patients at risk at various times after transplantation was considered the probability for ureteral stenosis to develop was 4.6 per cent at 1 year, 7.7 per cent at 2 years and 9.7 per cent at 5 years. Preoperative and postoperative complications were frequent. The wound infection rate was 21.9 per cent and 2 of the 24 patients died of septic shock. Graft survival rate after definitive surgical correction of ureteral stenosis was 71 per cent at 1 and 2 years, and 65 per cent at 3 years. Late results justify the efforts to re-establish correct urinary drainage of the graft.

Genotype-phenotype correlation in primary hyperoxaluria type 1: the p.Gly170Arg AGXT mutation is associated with a better outcome

We sought to ascertain the long-term outcome and genotype-phenotype correlations available for primary hyperoxaluria type 1 in a large retrospective cohort study. We examined the clinical history of 155 patients (129 families primarily from Western Europe, North Africa, or the Middle East) as well as the enzymatic or genetic diagnosis. The median age at first symptom was 4 years, and at diagnosis 7.7 years, at which time 43% had reached end-stage renal disease. Presentations included: (1) early nephrocalcinosis and infantile renal failure, (2) recurrent urolithiasis and progressive renal failure diagnosed during childhood, (3) late onset with occasional stone passage diagnosed in adulthood, (4) diagnosis occurring on post-transplantation recurrence, and (5) family screening. The cumulative patient survival was 95, 86, and 74% at ages 10, 30, and 50 years, respectively, with the cumulative renal survival of 81, 59, 41, and 10% at ages 10, 20, 30, and 50 years, respectively; 72 patients had undergone a total of 97 transplantations. Among the 136 patients with DNA analysis, the most common mutation was p.Gly170Arg (allelic frequency 21.5%), with a median age at end-stage renal disease of 47 years for homozygotes, 35 years for heterozygotes, and 21 years for other mutations. Our results underscore the severe prognosis of primary hyperoxaluria type 1 and the necessity for early diagnosis and treatment, as well as confirm a better prognosis of the p.Gly170Arg mutation.

A prospective, randomized, multicenter trial of tacrolimus-based therapy with or without basiliximab in pediatric renal transplantation.

In a 6‐month, multicenter, randomized, controlled, open‐label, parallel‐group trial, we investigated the efficacy and safety of adding basiliximab to a standard tacrolimus‐based regimen in pediatric renal transplant recipients. Patients <18 years received tacrolimus/azathioprine/steroids (TAS, n = 93) or tacrolimus/azathioprine/steroids/basiliximab (TAS + B, n = 99). Target tacrolimus levels were 10–20 ng/mL between days 0–21 and 5–15 ng/mL thereafter. Steroid dosing was identical in both groups. Basiliximab was administered at 10 mg (patients <40 kg) or 20 mg (patients ≥40 kg) within 4 h of reperfusion; the same dose was repeated on day 4. Biopsy‐proven acute rejection rates were 20.4% (TAS) and 19.2% (TAS + B); steroid‐resistant acute rejection rates were 3.2% and 3.0%, respectively. Patient survival was 100%; graft survival rates were 95% in both arms. The nature and incidence of adverse events were similar in both arms except toxic nephropathy and abdominal pain, which were significantly higher in the TAS + B arm (14.1% vs. 4.3%; p = 0.03 and 11.1% vs. 2.2%; p = 0.02; respectively). Median serum creatinine concentrations at 6 months were 86 μmol/L in the TAS and 91 μmol/L in the TAS + B arm; glomerular filtration rate was 79.4 and 77.6 (mL/min/1.73 m2), respectively. Adding basiliximab to a tacrolimus‐based regimen is safe in pediatric patients, but does not improve clinical efficacy.

Neonatal disease in neutral endopeptidase alloimmunization: lessons for immunological monitoring

Neutral endopeptidase (NEP) alloimmunization has recently been determined to cause severe forms of neonatal disease as a result of the transplacental passage of anti-NEP antibodies. However there is a wide spectrum of neonatal disease variability. We present the medical histories of a large family, specifically of two alloimmunized sisters in their second pregnancy in whom we established the basis of immunological surveillance and therapeutic intervention during pregnancy and after delivery. One mother developed dramatically high titers of IgG1 and IgG4, and was treated with IvIg and one plasma exchange, both of which substantially reduced the anti-NEP Ab titer. However, the neonatal syndrome observed in her infant was severe, partly due to treatment delay. Anti-NEP Ab were also found in the mother’s milk and the infant’s urine. In contrast, the other mother had a normal second pregnancy and delivered a healthy neonate, which was related to the fact that she only produced the non-complement activating IgG4 subclass of anti-NEP antibodies. Thus, anti-NEP Ab (titer and subclass) seem to be highly sensitive biomarkers of neonatal risk. Interventional strategy aimed at reducing anti-NEP titer, should be started early during pregnancy and, possibly, even before pregnancy in those mothers producing anti-NEP IgG1. Careful monitoring of anti-NEP Ab titer and subclass is mandatory in NEP-deficient mothers during their pregnancies.

Effect of conservative treatment on the renal outcome of children with primary hyperoxaluria type 1

Primary hyperoxaluria type 1 results from alanine:glyoxylate aminotransferase deficiency. Due to genotype/phenotype heterogeneity in this autosomal recessive disorder, the renal outcome is difficult to predict in these patients and the long-term impact of conservative management in children is unknown. We report here a multicenter retrospective study on the renal outcome in 27 affected children whose biological diagnosis was based on either decreased enzyme activity or identification of mutations in the patient or his siblings. The median age at first symptoms was 2.4 years while that at initiation of conservative treatment was 4.1 years; 6 children were diagnosed upon family screening. The median follow-up was 8.7 years. At diagnosis, 15 patients had an estimated glomerular filtration rate (eGFR) below 90, and 7 children already had stage 2-3 chronic kidney disease. The median baseline eGFR was 74, which rose to 114 with management in the 22 patients who did not require renal replacement therapy. Overall, 20 patients had a stable eGFR, however, 7 exhibited a decline in eGFR of over 20 during the study period. In a Cox regression model, the only variable significantly associated with deterioration of renal function was therapeutic delay with a relative risk of 1.7 per year. Our study strongly suggests that early and aggressive conservative management may preserve renal function of compliant children with this disorder, thereby avoiding dialysis and postponing transplantation.

Vesicoureteral reflux in children : endoscopic treatment

Endoscopic correction of vesicoureteral reflux in children has been increasingly used in the last years with encouraging results. During a 4-year period 152 children were treated by endoscopic injection of Teflon. A follow-up, ranging from 3 months to 5 years, was available for 173 refluxing ureters. For primary reflux, correction was observed after a single injection in 87% of the cases and in 93% after a second injection in some failures. In duplication, the technique is somewhat more difficult but the results quite satisfactory with 58% success after one injection, increasing to 74% after a second injection. The limitations of these techniques are underlined, the major concern being the safety of the injectable Teflon particles, eliciting a foreign-body granulomatous reaction with the potential hazard of distant migration. So far no long-term morbidity and complications have been observed with the use of Teflon to correct reflux. Extensive pathological study in 7 children submitted to ureteral reimplantation for failure of endoscopic correction showed a typical encapsulated granulomatous reaction below the intramural ureter, but particles of Teflon were noted in only one hypogastric ganglion when the Teflon was injected outside of the bladder. There is a need for finding an ideal substance for endoscopic injection, preferably prepared from the patients own tissue allowing simple and safe correction of vesicoureteral reflux in children.

Early prognostic factors of infants with chronic renal failure caused by renal dysplasia

Abstract Renal dysplasia (RD) is a common cause of chronic renal failure (CRF) in children. The evolution towards end-stage renal failure is unpredictable due to the paucity of early prognostic factors. In order to identify early prognostic clinical criteria, we have retrospectively analyzed renal function and growth in 11 infants with RD and CRF from birth up to 4 years of age. Children with obstructive RD were not included. Glomerular filtration rate (GFR) was estimated from Schwartz formula. In infants with a GFR below 15 ml/min per 1.73 m2 at 6 months of age (group A, n=5), kidney function did not further improve; 4 reached end-stage renal failure between 8 months and 6 years of age. In contrast, infants with a GFR above 15 ml/min per 1.73 m2 at 6 months of age (group B, n=6) experienced a significant improvement in renal function during follow-up, and none required renal replacement therapy. During the first 3 months of life all infants with RD and CRF developed severe growth retardation. Between 6 months and 4 years of age, children from group B grew significantly better than those from group A. In conclusion, our experience suggests that GFR, estimated from Schwartz formula at 6 months of age, is a useful prognostic factor in infants with RD and CRF. Infants with a GFR below 15 ml/min per 1.73 m2 are at risk of severe growth delay and the need for early renal replacement therapy, whereas those with a GFR above 15 ml/min per 1.73 m2 have a relatively favorable long-term prognosis.

Combined liver-kidney transplantation in primary hyperoxaluria type 1 : bone histopathology and oxalate body content

In three patients with end-stage renal failure due to primary hyperoxaluria type 1, successful combined liver-kidney transplantation enabled us to assess the insoluble oxalate pool, which was compared with the histopathological changes observed in iliac crest biopsy specimens. Good correlation was observed between the histopathological grade of bone oxalosis and the estimated oxalate content of the body. In the end-stage of oxalate bone disease, hyperparathyroidism does not play a significant role in bone resorption, which appears to be the consequence of the granulomatous reaction induced by oxalate deposition. Combined liver-kidney transplantation should be performed long before this stage. Early hepatorenal grafting in uremia secondary to primary hyperoxaluria type 1 would avoid the deleterious clinical consequences of systemic oxalosis and shorten the duration of postransplant hyperoxaluria, which may compromise the course of kidney graft.