Georges Deschenes - Academia.edu (original) (raw)

Papers by Georges Deschenes

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 2015

Data on anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis are scarce in children.... more Data on anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis are scarce in children. The current study is aimed at describing the clinical features and outcomes of childhood-onset ANCA-associated vasculitis (AAV). We conducted a retrospective French multicentre study involving patients in whom AAV was diagnosed before the age of 18 years. Inclusion criteria were (i) granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) according to classification criteria of the European League Against Rheumatism/Paediatric Rheumatology European Society, and (ii) ANCA positivity. Patient and renal survival were analysed. Among 66 children included, 80% were female, 42% had GPA and 58% MPA including renal-limited vasculitis, 67% were pANCA+ and 33% cANCA+. The mean incidence of reported cases increased to 0.45 per million children/year in the period 2006-10. Median age at diagnosis was 11.5 years, and median time to diagnosis was 1 month. Initial symptoms included feve...

Case reports in nephrology, 2014

A patient aged 17 with dense deposit disease associated with complement activation, circulating C... more A patient aged 17 with dense deposit disease associated with complement activation, circulating C3 Nef, and Factor H mutation presented with nephrotic syndrome and hypertension. Steroid therapy, plasma exchange, and rituximab failed to improve proteinuria and hypertension despite a normalization of the circulating sC5b9 complex. Eculizumab, a monoclonal antibody directed against C5, was used to block the terminal product of the complement cascade. The dose was adapted to achieve a CH50 below 10%, but proteinuria and blood pressure were not improved after 3 months of treatment.

Orphanet journal of rare diseases, 2011

Nephropathic cystinosis is an autosomal recessive disorder resulting in an impaired transport of ... more Nephropathic cystinosis is an autosomal recessive disorder resulting in an impaired transport of cystine trough the lysosomal membrane causing an accumulation of free cystine in lysosomes. The only specific treatment for nephropathic cystinosis is cysteamine bitartrate. This study was aimed to describe the relationship between cysteamine plasma concentrations and white blood cell cystine levels, and to simulate an optimized administration scheme to improve the management of patients with cystinosis. Cysteamine and cystine concentrations were measured in 69 nephropathic cystinosis patients. A total of 250 cysteamine plasma concentrations and 243 intracellular cystine concentrations were used to perform a population pharmacokinetic and pharmacodynamic analysis. An optimized administration scheme was simulated in order to maintain cystine levels below 1 nmol half-cystine/mg of protein and to investigate the possibility of administrating the treatment less than 4 times a day (QID, recom...

Pediatric nephrology (Berlin, Germany), 2001

A patient with homozygous factor H deficiency presented with hemolytic uremic syndrome (HUS) at t... more A patient with homozygous factor H deficiency presented with hemolytic uremic syndrome (HUS) at the age of 7 months. After a 2-year period of stability, renal failure and erythrocyte fragmentation recurred between the age of 3 and 4 years. Fresh frozen plasma infusions allowed renal function to be improved and erythrocyte fragmentation to be stopped. Withdrawal of plasma therapy led to a relapse of the biological signs of HUS.

Liver Transplantation, 2014

Primary hyperoxaluria type 1 (PH1) is a hepatic metabolic defect leading to end-stage renal failu... more Primary hyperoxaluria type 1 (PH1) is a hepatic metabolic defect leading to end-stage renal failure. The posttransplant recurrence of kidney disease can suggest a need for combined liver-kidney transplantation (LKT). However, the risk of LKT is theoretically far higher than the risk of kidney-alone transplantation (KAT). An unselected consecutive series of 54 patients with PH1 was analyzed according to the type of transplantation initially performed between May 1979 and June 2010 at 10 French centers. The duration of dialysis, extrarenal lesions, age, and follow-up were similar between the groups. Postoperative morbidity and mortality did not differ between the groups, and 10-year patient survival rates were similar for the LKT (n = 33) and KAT groups (n = 21; 78% versus 70%). Kidney graft survival at 10 years was better after LKT (87% versus 13%, P < .001) . Four patients (12.1%) lost their first kidney graft in the LKT group, whereas 19 (90%) did in the KAT group (P < .001). The recurrence of oxalosis occurred in 11 renal grafts (52%) in the KAT group but in none in the LKT group (P < .001). End-stage renal failure resulting from rejection was also higher in the KAT group (19% versus 9%, P < 0.0001). A second kidney transplant was performed for 15 patients (71%) in the KAT group versus 4 patients (12%) in the LKT group (P < 0.001). In conclusion, LKT for PH1 provides better kidney graft survival, less rejection, and similar long-term patient survival and is not associated with an increased short-term mortality risk. LKT must be the first-line treatment for PH1 patients with end-stage renal disease.

Although steroid-free remission can usually be achieved with cyclosporin A (CsA) in patients with... more Although steroid-free remission can usually be achieved with cyclosporin A (CsA) in patients with steroiddependent nephrotic syndrome (SDNS), some CsA-treated patients require long-term steroid therapy. Data on growth in these patients are scarce. Sixty-four boys with SDNS receiving long-term CsA and steroid therapy were retrospectively analyzed. During the 10-year follow-up period, height standard deviation score (HSDS) remained in the normal range in 47 patients but was below −2 SD in 17 patients. The occurrence of growth retardation was influenced by height at diagnosis and the number of relapses. Thirty patients were followed for at least 3 years before and after age 12. The decrease in HSDS per year of disease in patients older than 12 years was twice that observed in children younger than 12. However, adult height was ≤ −2 SD in only two of the 14 patients reaching adult height, reflecting potential catchup growth during late puberty. Careful monitoring of growth is recommended, given than up to 25% of patients experienced severe growth retardation during the course of their disease.

Therapeutic drug monitoring, 2012

Valganciclovir is used for the prophylaxis of cytomegalovirus infection in pediatric solid transp... more Valganciclovir is used for the prophylaxis of cytomegalovirus infection in pediatric solid transplant patients. The current pediatric dose regimen resulted in large variability in drug exposure. A posterior dosage adaptation was required in children to achieve the daily target area under the curve (AUC) of 40-50 μg·h·mL(-1). However, a clinically feasible tool for valganciclovir dosage adjustment based on individual AUC is not available. The objective of this study was to develop and validate a reliable and clinically applicable limited sampling strategy using Bayesian estimation for individualizing valganciclovir dose in pediatric kidney transplant patients. The Bayesian estimator to calculate ganciclovir AUC was developed using the original pharmacokinetic dataset consisting of 28 full profiles from 22 pediatric kidney transplant patients. External validation was prospectively performed in an independent validation group consisting of 14 full pharmacokinetic profiles from 14 pedia...

Idiopathic nephrotic syndrome is characterized by glomerular proteinuria in the absence of infilt... more Idiopathic nephrotic syndrome is characterized by glomerular proteinuria in the absence of infiltrating cells or immunoglobulin deposits. Although it is suspected that T cells secrete a circulating factor that leads to proteinuria by altering the permeability of the glomerular filtration barrier, the precise etiology of this syndrome is unknown. Because an animal model that mimics human idiopathic nephrotic syn- drome

Molecular Cytogenetics, 2015

Background: Here we report the clinical and molecular characterization of two Xp11.22 deletions i... more Background: Here we report the clinical and molecular characterization of two Xp11.22 deletions including SHROOM4 and CLCN5 genes. These deletions appeared in the same X chromosome of the same patient. Results: The patient is a six-year-old boy who presented hydrocephalus, severe psychomotor and growth retardation, facial dysmorphism and renal proximal tubulopathy associated with low-molecular-weight proteinuria, hypercalciuria, hyperaminoaciduria, hypophosphatemia and hyperuricemia. Standard and high resolution karyotypes showed a 46,XY formula. Array-CGH revealed two consecutive cryptic deletions in the region Xp11.22, measuring respectively 148 Kb and 2.6 Mb. The two deletions were inherited from the asymptomatic mother. Conclusions: Array-CGH allowed us to determine candidate genes in the deleted region. The disruption and partial loss of CLCN5 confirmed the diagnostic of Dent disease for this patient. Moreover, the previously described involvement of SHROOM4 in neuronal development is discussed.

Journal of Pediatrics, 2006

Objective To describe the safety and efficacy of rituximab in the treatment of childhood-onset sy... more Objective To describe the safety and efficacy of rituximab in the treatment of childhood-onset systemic lupus erythematosus (SLE).

Micropuncture studies of the distal nephron and measurements of Na,K-ATPase activity in microdiss... more Micropuncture studies of the distal nephron and measurements of Na,K-ATPase activity in microdissected col- lecting tubules have suggested that renal retention of sodium in puromycin aminonucleoside (PAN) nephrotic rats originates in the collecting duct. The present study demonstrated this hy- pothesis by in vitro microperfusion and showed that amiloride was able to restore sodium balance. Indeed, isolated perfused cortical collecting

Factor H (FH) is the major regulatory protein of the complement alternative pathway, with a struc... more Factor H (FH) is the major regulatory protein of the complement alternative pathway, with a structure consisting of a tandem array of 20 homologous units, called short consensus repeats (SCR). Reported are 16 FH-deficient patients. Among six patients with homozygous deficiency, four presented with membranoproliferative glomerulonephritis, and two with atyp- ical hemolytic uremic syndrome (HUS). The ten other patients had

Orphanet Journal of Rare Diseases, 2012

Arteriosclerosis and emphysema develop in individuals with Schimke immuno-osseous dysplasia (SIOD... more Arteriosclerosis and emphysema develop in individuals with Schimke immuno-osseous dysplasia (SIOD), a multisystem disorder caused by biallelic mutations in SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily alike 1). However, the mechanism by which the vascular and pulmonary disease arises in SIOD remains unknown.

Journal of Clinical Investigation, 1994

The type IV collagen a5 chain (COL4A5) gene of 88 unrelated male patients with X-linked Alport sy... more The type IV collagen a5 chain (COL4A5) gene of 88 unrelated male patients with X-linked Alport syndrome was tested for major gene rearrangements by Southern blot analysis, using COL4A5 cDNA probes. 14 different deletions were detected, providing a 16% deletion rate in the COL4A5 gene in the patient population. The deletions are dispersed all over the gene with different sizes, ranging from 1 kb to the complete absence of the gene (> 250 kb) in one patient. In four patients with intragenic deletions, absence of the a3(IV) chain in the glomerular basement membrane was demonstrated by immunohistochemical studies. This finding supports the hypothesis that abnormalities in the a5 (IV) chain may prevent normal incorporation of the a3(IV) chain into the glomerular basement membrane. Direct sequencing of cDNA amplified from lymphoblast mRNA of four patients with internal gene deletions, using appropriate combinations of primers amplifying across the predicted boundaries of the deletions, allowed us to determine the effect of the genomic rearrangements on the transcripts and, by inference, on the a5(IV) chain. Regardless of the extent of deletion and of the putative protein product, the 14 deletions occur in patients with juvenile-type Alport syndrome. (J. Clin.

The Journal of Pediatrics, 2014

Objectives To determine the long-term effects of delayed-release cysteamine bitartrate (DR-CYS) b... more Objectives To determine the long-term effects of delayed-release cysteamine bitartrate (DR-CYS) based on our previous work that established the short-term noninferiority of DR-CYS every 12 hours compared with immediaterelease cysteamine bitartrate every 6 hours.

Annales de biologie clinique, 2014

Pediatric Nephrology, 1996

A cluster of four patients (1 girl, 3 boys) from a French village (2,000 inhabitants) had acute h... more A cluster of four patients (1 girl, 3 boys) from a French village (2,000 inhabitants) had acute haemolytic uraemic syndrome (HUS) between March 1992 and May 1993. All had prodromes with fever and diarrhoea, then acute renal failure, anaemia, schistocytosis and thrombocytopenia. Peritoneal dialysis was carried out in three children (duration 3–12 days). The verotoxin VT2 gene was identified by

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 2015

Data on anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis are scarce in children.... more Data on anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis are scarce in children. The current study is aimed at describing the clinical features and outcomes of childhood-onset ANCA-associated vasculitis (AAV). We conducted a retrospective French multicentre study involving patients in whom AAV was diagnosed before the age of 18 years. Inclusion criteria were (i) granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) according to classification criteria of the European League Against Rheumatism/Paediatric Rheumatology European Society, and (ii) ANCA positivity. Patient and renal survival were analysed. Among 66 children included, 80% were female, 42% had GPA and 58% MPA including renal-limited vasculitis, 67% were pANCA+ and 33% cANCA+. The mean incidence of reported cases increased to 0.45 per million children/year in the period 2006-10. Median age at diagnosis was 11.5 years, and median time to diagnosis was 1 month. Initial symptoms included feve...

Case reports in nephrology, 2014

A patient aged 17 with dense deposit disease associated with complement activation, circulating C... more A patient aged 17 with dense deposit disease associated with complement activation, circulating C3 Nef, and Factor H mutation presented with nephrotic syndrome and hypertension. Steroid therapy, plasma exchange, and rituximab failed to improve proteinuria and hypertension despite a normalization of the circulating sC5b9 complex. Eculizumab, a monoclonal antibody directed against C5, was used to block the terminal product of the complement cascade. The dose was adapted to achieve a CH50 below 10%, but proteinuria and blood pressure were not improved after 3 months of treatment.

Orphanet journal of rare diseases, 2011

Nephropathic cystinosis is an autosomal recessive disorder resulting in an impaired transport of ... more Nephropathic cystinosis is an autosomal recessive disorder resulting in an impaired transport of cystine trough the lysosomal membrane causing an accumulation of free cystine in lysosomes. The only specific treatment for nephropathic cystinosis is cysteamine bitartrate. This study was aimed to describe the relationship between cysteamine plasma concentrations and white blood cell cystine levels, and to simulate an optimized administration scheme to improve the management of patients with cystinosis. Cysteamine and cystine concentrations were measured in 69 nephropathic cystinosis patients. A total of 250 cysteamine plasma concentrations and 243 intracellular cystine concentrations were used to perform a population pharmacokinetic and pharmacodynamic analysis. An optimized administration scheme was simulated in order to maintain cystine levels below 1 nmol half-cystine/mg of protein and to investigate the possibility of administrating the treatment less than 4 times a day (QID, recom...

Pediatric nephrology (Berlin, Germany), 2001

A patient with homozygous factor H deficiency presented with hemolytic uremic syndrome (HUS) at t... more A patient with homozygous factor H deficiency presented with hemolytic uremic syndrome (HUS) at the age of 7 months. After a 2-year period of stability, renal failure and erythrocyte fragmentation recurred between the age of 3 and 4 years. Fresh frozen plasma infusions allowed renal function to be improved and erythrocyte fragmentation to be stopped. Withdrawal of plasma therapy led to a relapse of the biological signs of HUS.

Liver Transplantation, 2014

Primary hyperoxaluria type 1 (PH1) is a hepatic metabolic defect leading to end-stage renal failu... more Primary hyperoxaluria type 1 (PH1) is a hepatic metabolic defect leading to end-stage renal failure. The posttransplant recurrence of kidney disease can suggest a need for combined liver-kidney transplantation (LKT). However, the risk of LKT is theoretically far higher than the risk of kidney-alone transplantation (KAT). An unselected consecutive series of 54 patients with PH1 was analyzed according to the type of transplantation initially performed between May 1979 and June 2010 at 10 French centers. The duration of dialysis, extrarenal lesions, age, and follow-up were similar between the groups. Postoperative morbidity and mortality did not differ between the groups, and 10-year patient survival rates were similar for the LKT (n = 33) and KAT groups (n = 21; 78% versus 70%). Kidney graft survival at 10 years was better after LKT (87% versus 13%, P < .001) . Four patients (12.1%) lost their first kidney graft in the LKT group, whereas 19 (90%) did in the KAT group (P < .001). The recurrence of oxalosis occurred in 11 renal grafts (52%) in the KAT group but in none in the LKT group (P < .001). End-stage renal failure resulting from rejection was also higher in the KAT group (19% versus 9%, P < 0.0001). A second kidney transplant was performed for 15 patients (71%) in the KAT group versus 4 patients (12%) in the LKT group (P < 0.001). In conclusion, LKT for PH1 provides better kidney graft survival, less rejection, and similar long-term patient survival and is not associated with an increased short-term mortality risk. LKT must be the first-line treatment for PH1 patients with end-stage renal disease.

Although steroid-free remission can usually be achieved with cyclosporin A (CsA) in patients with... more Although steroid-free remission can usually be achieved with cyclosporin A (CsA) in patients with steroiddependent nephrotic syndrome (SDNS), some CsA-treated patients require long-term steroid therapy. Data on growth in these patients are scarce. Sixty-four boys with SDNS receiving long-term CsA and steroid therapy were retrospectively analyzed. During the 10-year follow-up period, height standard deviation score (HSDS) remained in the normal range in 47 patients but was below −2 SD in 17 patients. The occurrence of growth retardation was influenced by height at diagnosis and the number of relapses. Thirty patients were followed for at least 3 years before and after age 12. The decrease in HSDS per year of disease in patients older than 12 years was twice that observed in children younger than 12. However, adult height was ≤ −2 SD in only two of the 14 patients reaching adult height, reflecting potential catchup growth during late puberty. Careful monitoring of growth is recommended, given than up to 25% of patients experienced severe growth retardation during the course of their disease.

Therapeutic drug monitoring, 2012

Valganciclovir is used for the prophylaxis of cytomegalovirus infection in pediatric solid transp... more Valganciclovir is used for the prophylaxis of cytomegalovirus infection in pediatric solid transplant patients. The current pediatric dose regimen resulted in large variability in drug exposure. A posterior dosage adaptation was required in children to achieve the daily target area under the curve (AUC) of 40-50 μg·h·mL(-1). However, a clinically feasible tool for valganciclovir dosage adjustment based on individual AUC is not available. The objective of this study was to develop and validate a reliable and clinically applicable limited sampling strategy using Bayesian estimation for individualizing valganciclovir dose in pediatric kidney transplant patients. The Bayesian estimator to calculate ganciclovir AUC was developed using the original pharmacokinetic dataset consisting of 28 full profiles from 22 pediatric kidney transplant patients. External validation was prospectively performed in an independent validation group consisting of 14 full pharmacokinetic profiles from 14 pedia...

Idiopathic nephrotic syndrome is characterized by glomerular proteinuria in the absence of infilt... more Idiopathic nephrotic syndrome is characterized by glomerular proteinuria in the absence of infiltrating cells or immunoglobulin deposits. Although it is suspected that T cells secrete a circulating factor that leads to proteinuria by altering the permeability of the glomerular filtration barrier, the precise etiology of this syndrome is unknown. Because an animal model that mimics human idiopathic nephrotic syn- drome

Molecular Cytogenetics, 2015

Background: Here we report the clinical and molecular characterization of two Xp11.22 deletions i... more Background: Here we report the clinical and molecular characterization of two Xp11.22 deletions including SHROOM4 and CLCN5 genes. These deletions appeared in the same X chromosome of the same patient. Results: The patient is a six-year-old boy who presented hydrocephalus, severe psychomotor and growth retardation, facial dysmorphism and renal proximal tubulopathy associated with low-molecular-weight proteinuria, hypercalciuria, hyperaminoaciduria, hypophosphatemia and hyperuricemia. Standard and high resolution karyotypes showed a 46,XY formula. Array-CGH revealed two consecutive cryptic deletions in the region Xp11.22, measuring respectively 148 Kb and 2.6 Mb. The two deletions were inherited from the asymptomatic mother. Conclusions: Array-CGH allowed us to determine candidate genes in the deleted region. The disruption and partial loss of CLCN5 confirmed the diagnostic of Dent disease for this patient. Moreover, the previously described involvement of SHROOM4 in neuronal development is discussed.

Journal of Pediatrics, 2006

Objective To describe the safety and efficacy of rituximab in the treatment of childhood-onset sy... more Objective To describe the safety and efficacy of rituximab in the treatment of childhood-onset systemic lupus erythematosus (SLE).

Micropuncture studies of the distal nephron and measurements of Na,K-ATPase activity in microdiss... more Micropuncture studies of the distal nephron and measurements of Na,K-ATPase activity in microdissected col- lecting tubules have suggested that renal retention of sodium in puromycin aminonucleoside (PAN) nephrotic rats originates in the collecting duct. The present study demonstrated this hy- pothesis by in vitro microperfusion and showed that amiloride was able to restore sodium balance. Indeed, isolated perfused cortical collecting

Factor H (FH) is the major regulatory protein of the complement alternative pathway, with a struc... more Factor H (FH) is the major regulatory protein of the complement alternative pathway, with a structure consisting of a tandem array of 20 homologous units, called short consensus repeats (SCR). Reported are 16 FH-deficient patients. Among six patients with homozygous deficiency, four presented with membranoproliferative glomerulonephritis, and two with atyp- ical hemolytic uremic syndrome (HUS). The ten other patients had

Orphanet Journal of Rare Diseases, 2012

Arteriosclerosis and emphysema develop in individuals with Schimke immuno-osseous dysplasia (SIOD... more Arteriosclerosis and emphysema develop in individuals with Schimke immuno-osseous dysplasia (SIOD), a multisystem disorder caused by biallelic mutations in SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily alike 1). However, the mechanism by which the vascular and pulmonary disease arises in SIOD remains unknown.

Journal of Clinical Investigation, 1994

The type IV collagen a5 chain (COL4A5) gene of 88 unrelated male patients with X-linked Alport sy... more The type IV collagen a5 chain (COL4A5) gene of 88 unrelated male patients with X-linked Alport syndrome was tested for major gene rearrangements by Southern blot analysis, using COL4A5 cDNA probes. 14 different deletions were detected, providing a 16% deletion rate in the COL4A5 gene in the patient population. The deletions are dispersed all over the gene with different sizes, ranging from 1 kb to the complete absence of the gene (> 250 kb) in one patient. In four patients with intragenic deletions, absence of the a3(IV) chain in the glomerular basement membrane was demonstrated by immunohistochemical studies. This finding supports the hypothesis that abnormalities in the a5 (IV) chain may prevent normal incorporation of the a3(IV) chain into the glomerular basement membrane. Direct sequencing of cDNA amplified from lymphoblast mRNA of four patients with internal gene deletions, using appropriate combinations of primers amplifying across the predicted boundaries of the deletions, allowed us to determine the effect of the genomic rearrangements on the transcripts and, by inference, on the a5(IV) chain. Regardless of the extent of deletion and of the putative protein product, the 14 deletions occur in patients with juvenile-type Alport syndrome. (J. Clin.

The Journal of Pediatrics, 2014

Objectives To determine the long-term effects of delayed-release cysteamine bitartrate (DR-CYS) b... more Objectives To determine the long-term effects of delayed-release cysteamine bitartrate (DR-CYS) based on our previous work that established the short-term noninferiority of DR-CYS every 12 hours compared with immediaterelease cysteamine bitartrate every 6 hours.

Annales de biologie clinique, 2014

Pediatric Nephrology, 1996

A cluster of four patients (1 girl, 3 boys) from a French village (2,000 inhabitants) had acute h... more A cluster of four patients (1 girl, 3 boys) from a French village (2,000 inhabitants) had acute haemolytic uraemic syndrome (HUS) between March 1992 and May 1993. All had prodromes with fever and diarrhoea, then acute renal failure, anaemia, schistocytosis and thrombocytopenia. Peritoneal dialysis was carried out in three children (duration 3–12 days). The verotoxin VT2 gene was identified by