Santiago Mendizábal

An update for atypical haemolytic uraemic syndrome: diagnosis and treatment: A consensus document

Haemolytic uraemic syndrome (HUS) is a clinical entity defined as the triad of nonimmune haemolytic anaemia, thrombocytopenia, and acute renal failure, in which the underlying lesions are mediated by systemic thrombotic microangiopathy (TMA). Atypical HUS (aHUS) is a sub-type of HUS in which the TMA phenomena are the consequence of decreased regulation of the alternative complement pathway on cell surfaces due to a genetic cause. aHUS is an extremely rare disease that, despite the administration of standard treatment with plasma therapy, often progresses to terminal chronic renal failure with a high associated rate of mortality. In recent years, research has established the key role that the complement system plays in the induction of endothelial damage in patients with aHUS, through the characterisation of multiple mutations and polymorphisms in the genes that code for certain complement factors. Eculizumab is a monoclonal antibody that inhibits the terminal fraction of the complement protein, blocking the formation of a cell membrane attack complex. In prospective studies in patients with aHUS, administering eculizumab produces a rapid and sustained interruption in the TMA process, with significant improvements in long-term renal function and an important decrease in the need for dialysis or plasma therapy. In this document, we review and bring up to date the important aspects of this disease, with special emphasis on how recent advancements in diagnostic and therapeutic processes can modify the treatment of patients with aHUS.

TRPC6 mutational analysis in a large cohort of patients with focal segmental glomerulosclerosis

BACKGROUND Mutations in the TRPC6 gene have been reported in six families with adult-onset (17-57 years) autosomal dominant focal segmental glomerulosclerosis (FSGS). Electrophysiology studies confirmed augmented calcium influx only in three of these six TRPC6 mutations. To date, the role of TRPC6 in childhood and adulthood non-familial forms is unknown. METHODS TRPC6 mutation analysis was performed by direct sequencing in 130 Spanish patients from 115 unrelated families with FSGS. An in silico scoring matrix was developed to evaluate the pathogenicity of amino acid substitutions, by using the bio-physical and bio-chemical differences between wild-type and mutant amino acid, the evolutionary conservation of the amino acid residue in orthologues, homologues and defined domains, with the addition of contextual information. RESULTS Three new missense substitutions were identified in two clinically non-familial cases and in one familial case. The analysis by means of this scoring system allowed us to classify these variants as likely pathogenic mutations. One of them was detected in a female patient with unusual clinical features: mesangial proliferative FSGS in childhood (7 years) and partial response to immunosupressive therapy (CsA + MMF). Asymptomatic carriers of this likely mutation were found within her family. CONCLUSIONS We describe for the first time TRPC6 mutations in children and adults with non-familial FSGS. It seems that TRPC6 is a gene with a very variable penetrance that may contribute to glomerular diseases in a multi-hit setting.

Targeted next-generation sequencing in steroid-resistant nephrotic syndrome: mutations in multiple glomerular genes may influence disease severity

Genetic diagnosis of steroid-resistant nephrotic syndrome (SRNS) using Sanger sequencing is complicated by the high genetic heterogeneity and phenotypic variability of this disease. We aimed to improve the genetic diagnosis of SRNS by simultaneously sequencing 26 glomerular genes using massive parallel sequencing and to study whether mutations in multiple genes increase disease severity. High-throughput mutation analysis was performed in 50 SRNS and/or focal segmental glomerulosclerosis (FSGS) patients, a validation cohort of 25 patients with known pathogenic mutations, and a discovery cohort of 25 uncharacterized patients with probable genetic etiology. In the validation cohort, we identified the 42 previously known pathogenic mutations across NPHS1, NPHS2, WT1, TRPC6, and INF2 genes. In the discovery cohort, disease-causing mutations in SRNS/FSGS genes were found in nine patients. We detected three patients with mutations in an SRNS/FSGS gene and COL4A3. Two of them were familial cases and presented a more severe phenotype than family members with mutation in only one gene. In conclusion, our results show that massive parallel sequencing is feasible and robust for genetic diagnosis of SRNS/FSGS. Our results indicate that patients carrying mutations in an SRNS/FSGS gene and also in COL4A3 gene have increased disease severity.

Effectiveness of mycophenolate mofetil in C3 glomerulonephritis

C3 glomerulonephritis is a clinicopathologic entity defined by the presence of isolated or dominant deposits of C3 on immunofluorescence. To explore the effect of immunosuppression on C3 glomerulonephritis, we studied a series of 60 patients in whom a complete registry of treatments was available over a median follow-up of 47 months. Twenty patients had not received immunosuppressive treatments. In the remaining 40 patients, 22 had been treated with corticosteroids plus mycophenolate mofetil while 18 were treated with other immunosuppressive regimens (corticosteroids alone or corticosteroids plus cyclophosphamide). The number of patients developing end-stage renal disease was significantly lower among treated compared with untreated patients (3 vs. 7 patients, respectively). No patient in the corticosteroids plus mycophenolate mofetil group doubled serum creatinine nor developed end-stage renal disease, as compared with 7 (significant) and 3 (not significant), respectively, in patients treated with other immunosuppressive regimens. Renal survival (100, 80, and 72% at 5 years) and the number of patients achieving clinical remission (86, 50, and 25%) were significantly higher in patients treated with corticosteroids plus mycophenolate mofetil as compared with patients treated with other immunosuppressive regimens and untreated patients, respectively. Thus, immunosuppressive treatments, particularly corticosteroids plus mycophenolate mofetil, can be beneficial in C3 glomerulonephritis.

Eculizumab in secondary atypical haemolytic uraemic syndrome

Background. Complement dysregulation occurs in thrombotic microangiopathies (TMAs) other than primary atypical haemolytic uraemic syndrome (aHUS). A few of these patients have been reported previously to be successfully treated with eculizumab. Methods. We identified 29 patients with so‐called secondary aHUS who had received eculizumab at 11 Spanish nephrology centres. Primary outcome was TMA resolution, defined by a normalization of platelet count (>150 × 109/L) and haemoglobin, disappearance of all the markers of microangiopathic haemolytic anaemia (MAHA), and improvement of renal function, with a ≥25% reduction of serum creatinine from the onset of eculizumab administration. Results. Twenty‐nine patients with secondary aHUS (15 drug‐induced, 8 associated with systemic diseases, 2 with postpartum, 2 with cancer‐related, 1 associated with acute humoral rejection and 1 with intestinal lymphangiectasia) were included in this study. The reason to initiate eculizumab treatment was worsening of renal function and persistence of TMA despite treatment of the TMA cause and plasmapheresis. All patients showed severe MAHA and renal function impairment (14 requiring dialysis) prior to eculizumab treatment and 11 presented severe extrarenal manifestations. A rapid resolution of the TMA was observed in 20 patients (68%), 15 of them showing a ≥50% serum creatinine reduction at the last follow‐up. Comprehensive genetic and molecular studies in 22 patients identified complement pathogenic variants in only 2 patients. With these two exceptions, eculizumab was discontinued, after a median of 8 weeks of treatment, without the occurrence of aHUS relapses. Conclusion. Short treatment with eculizumab can result in a rapid improvement of patients with secondary aHUS in whom TMA has persisted and renal function worsened despite treatment of the TMA‐inducing condition.

31 Recidiva de la esclerosis segmentaria y focal postrasplante

La esclerosis segmentaria y focal (ESF) en su forma primaria es causa de sindrome nefrotico corticorresistente, con potencial evolucion a la insuficiencia renal y recidiva postrasplante. El objetivo de esta comunicacion es presentar la experiencia en nuestro servicio sobre la evolucion postrasplante de los ninos trasplantados con ESF como enfermedad de base. Material y metodos Se han realizado 27 trasplantes en 22 ninos (59 % varones). Son 21 primeros trasplantes, 5 segundos y 1 tercero. Todos recibieron terapia de induccion y la inmunosupresion de mantenimiento fue: AZA + prednisona en 7 casos, CsA + AZA + prednisona en 15, CsA + MMF + prednisona en 4 y FK + MMF + prednisona en uno. El numero de identidades oscilo entre 0 y 6 con una media de 2. Analizamos la frecuencia de recidiva y la evolucion postrasplante, junto con la edad de comienzo de enfermedad, tiempo de evolucion a IRT, histologia, nefrectomia previa e inmunosupresion administrada. Resultados Presentaron recidiva 15 casos (55 %), inmediata en 13, en los otros dos al 3.° mes y 2.° ano, respectivamente. De los factores estudiados solo la proliferacion mesangial en la biopsia diagnostica actuo como protector. Ni la edad de comienzo, ni el tiempo de evolucion a la IRT, ni la inmunosupresion o el numero de identidades HLA fueron factores pronosticos. La probabilidad de supervivencia no fue estadisticamente diferente entre los que recidivaron o no, ni entre el grupo total y los pacientes trasplantados con otra histologia. Conclusiones 1 . No encontramos en nuestra serie los factores pronosticos evidenciados en la literatura. 2 . Los resultados del trasplante no fueron diferentes entre recidiva o no recidiva. 3 . Nuestros resultados apoyan el hecho de que la ESF no es una unica enfermedad.

Estudio radiológico del síndrome de hipertensión venosa renal izquierda en la edad pediátrica

Objetivos Valorar la aportacion al diagnostico y actitud terapeutica de los metodos de imagen utilizados en nuestros casos con sindrome de hipertension venosa renal izquierda (SHVRI). Material y metodos Se revisaron las exploraciones —ecografia modo B, Doppler-color, tomografia computarizada (TC) helicoidal y venografia renal— de nueve pacientes con SHVRI. Se observo la vena renal izquierda (VRI), su situacion anatomica, los posibles trayectos anomalos, el paso en la pinza aortomesenterica, su diametro y la velocidad de flujo en diferentes porciones. Se midio la distancia entre aorta y arteria mesenterica y su angulo en el paso de la VRI. Mediante venografia renal selectiva se cuantifico el gradiente de presion entre VRI y vena cava inferior. Se visualizo la circulacion colateral varicosa compensadora. Resultados Tres pacientes muestran trayectos anomalos de la VRI, dos en posicion retroaortica y uno con vena renal accesoria varicosa por drenaje anomalo, y seis con compresion de VRI en la pinza aortomesenterica. La relacion velocidad de flujo porcion aortomesenterica/hiliar de VRI fue de 3,35 (1,5-5,4); el diametro en hilio renal de 7,18 mm (5-9); la relacion diametros entre ambas porciones de 2,84 (2,5-3,6); la distancia aortomesenterica de 3 mm (2,1-4,3), y el angulo aortomesenterico de 23° (15-26). Dos pacientes presentaron gradiente de presion VRI respecto a vena cava Conclusiones Las anomalias anatomicas de la VRI observadas en TC helicoidal y la hipertension venosa medida por diferencia de gradiente entre VRI y vena cava con circulacion colateral varicosa, son demostrativas del sindrome; sin embargo, la velocidad de flujo, el diametro de la VRI y las medidas anatomicas de la pinza aortomesenterica no fueron concluyentes.