Case Report: Combined Liver-Kidney Transplantation to Correct a Mutation in Complement Factor B in an Atypical Hemolytic Uremic Syndrome Patient.

Pathogenic gain-of-function variants in complement Factor B were identified as causative of atypical Hemolytic Uremic syndrome (aHUS) in 2007. These mutations generate a reduction on the plasma levels of complement C3. A four-month-old boy was diagnosed with hypocomplementemic aHUS in May 2000, and he suffered seven recurrences during the following three years. He developed a severe hypertension which required 6 anti-hypertensive drugs and presented acrocyanosis and several confusional episodes. Plasma infusion or exchange, and immunosuppressive treatments did not improve the clinical evolution, and the patient developed end-stage renal disease at the age of 3 years. Hypertension and vascular symptoms persisted while he was on peritoneal dialysis or hemodialysis, as well as after bilateral nephrectomy. C3 levels remained low, while C4 levels were normal. In 2005, a heterozygous gain-of-function mutation in Factor B (K323E) was found. A combined liver and kidney transplantation (CLKT) was performed in March 2009, since there was not any therapy for complement inhibition in these patients. Kidney and liver functions normalized in the first two weeks, and the C3/C4 ratio immediately after transplantation, indicating that the C3 activation has been corrected. After remaining stable for 4 years, the patient suffered a B-cell non-Hodgkin lymphoma that was cured by chemotherapy and reduction of immunosuppressive drugs. Signs of liver rejection with cholangitis were observed a few months later, and a second liver graft was done 11 years after the CLKT. One year later, the patient maintains normal kidney and liver functions, also C3 and C4 levels are within the normal range. The 12-year follow-up of the patient reveals that, in spite of severe complications, CLKT was an acceptable therapeutic option for this aHUS patient.

Acidosis tubular renal distal (ATRd): aspectos epidemiológicos, diagnósticos, de seguimiento clínico y terapéuticos. Resultados de una encuesta a un colectivo de nefrólogos / Distar Renal Tubular Acidosis (dRTA): Epidemiological, diagnostics, clinical follow-up and therapeutical issues. Nephrologists cohort survey outcome

ANTECEDENTES Y OBJETIVOS: La acidosis tubular renal distal (ATRd) es una enfermedad minoritaria, de origen genético o adquirido, caracterizada por una incapacidad de excreción urinaria de hidrogeniones (H+), hipobicarbonatemia, hipercloremia, hipocitraturia y habitualmente hipokaliemia e hipercalciuria. Las formas genéticas suelen diagnosticarse en los primeros meses de vida y su tratamiento consiste en suplementos de álcali encaminados a evitar las consecuencias clínicas a largo plazo, sobre todo la enfermedad renal crónica (presente en algunas series hasta en el 82% de los pacientes) y la enfermedad ósea asociada. Se desarrolló una encuesta multirrespuesta cerrada de 10 preguntas encaminada a conocer aspectos epidemiológicos, diagnósticos, del manejo clínico y terapéutico, dentro del colectivo de nefrólogos españoles. MATERIALES Y MÉTODOS: Encuesta distribuida a los asistentes a un foro científico sobre ATRd durante el congreso de 2019 de la Sociedad Española de Nefrología (SEN); las respuestas se recogieron a la salida del mismo. Los resultados se analizaron con un test estadístico paramétrico estableciéndose el porcentaje de cada respuesta a las 10 preguntas. RESULTADOS: De entre los que respondieron a la encuesta, el 44,4 y el 37,7% no atendieron a ningún paciente con ATRd en el último año ni en los tres anteriores, respectivamente. Cuando se sospecha la patología, el diagnóstico genético confirmatorio se realiza solo en el 13,3% de los casos y el estudio familiar solo en el 11,1%. Solo el 26,6% afirman que el control metabólico es excelente, bueno o muy bueno, y el 69% piensan que el cumplimiento terapéutico es regular, malo o muy malo. CONCLUSIONES: La encuesta ha puesto de manifiesto el relativo desconocimiento de esta patología, así como la baja satisfacción con el control metabólico y el pobre cumplimiento terapéutico, lo cual puede conllevar una mayor severidad en la enfermedad renal y ósea asociadas a la ATRd

BACKGROUND AND OBJECTIVES: dRTA is a genetic or acquired rare disease, characterized by an unability to excrete hydrogens (H+) into urine, hypobicarbonatemia, hyperchloremia, and frequently hypercalciuria and hypokalaemia. Genetic forms are usually diagnosed during the first months of life and its treatment is based on providing alkali supplements in order to prevent long term clinical consequences, particularly chronic kidney disease (described in some cohorts up to 82% of dRTA patients) and the associated bone disease. A 10 queries multi choice closed response survey was designed to know more about epidemiological, diagnostics, clinical management and therapeutical issues of this disease among Spanish nephrologists. MATERIALS AND METHODS: This survey was delivered to the attendees to a scientific meeting on dRTA at the Spanish Nephrology Society congress in 2019. Surveys were collected at the end of this dRTA event. Results were analyzed by using a parametric statistical test, obtaining the percentage of each response for the 10 questions. RESULTS: Among the survey responders, 44.4% and 37.7% did not visit any dRTA patient during the 1st and 3rd last year respectively. When having a suspicious diagnose, confirming genetic diagnostic test is only performed on the 13.3% of cases and pedigree studies only on 11.1%. Only a 26.6% confirms that metabolic control is excellent, good or very good, and 69% of the responders believe that treatment compliance is not bad, bad or very bad. CONCLUSIONS: This survey enhances the fact that dRTA is not a well known entity, satisfaction with metabolic control is poor and compliance is low. All these factors can lead to a higher severity of renal and bone diseases associated to dRTA

Distar Renal Tubular Acidosis (dRTA): Epidemiological, diagnostics, clinical follow-up and therapeutical issues. Nephrologists cohort survey outcome. / Acidosis tubular renal distal (ATRd): aspectos epidemiológicos, diagnósticos, de seguimiento clínico y terapéuticos. Resultados de una encuesta a un colectivo de nefrólogos.

BACKGROUND AND OBJECTIVES: dRTA is a genetic or acquired rare disease, characterized by an unability to excrete hydrogens (H+) into urine, hypobicarbonatemia, hyperchloremia, and frequently hypercalciuria and hypokalaemia. Genetic forms are usually diagnosed during the first months of life and its treatment is based on providing alkali supplements in order to prevent long term clinical consequences, particularly chronic kidney disease (described in some cohorts up to 82% of dRTA patients) and the associated bone disease. A 10 queries multi choice closed response survey was designed to know more about epidemiological, diagnostics, clinical management and therapeutical issues of this disease among Spanish nephrologists. MATERIALS AND METHODS: This survey was delivered to the attendees to a scientific meeting on dRTA at the Spanish Nephrology Society congress in 2019. Surveys were collected at the end of this dRTA event. Results were analyzed by using a parametric statistical test, obtaining the percentage of each response for the 10 questions. RESULTS: Among the survey responders, 44.4% and 37.7% did not visit any dRTA patient during the 1st and 3rd last year respectively. When having a suspicious diagnose, confirming genetic diagnostic test is only performed on the 13.3% of cases and pedigree studies only on 11.1%. Only a 26.6% confirms that metabolic control is excellent, good or very good, and 69% of the responders believe that treatment compliance is not bad, bad or very bad. CONCLUSIONS: This survey enhances the fact that dRTA is not a well known entity, satisfaction with metabolic control is poor and compliance is low. All these factors can lead to a higher severity of renal and bone diseases associated to dRTA.

Limited sampling strategies for tacrolimus exposure (AUC0-24) prediction after Prograf(®) and Advagraf(®) administration in children and adolescents with liver or kidney transplants.

To develop limited sampling strategies (LSSs) to predict total tacrolimus exposure (AUC0-24 ) after the administration of Advagraf(®) and Prograf(®) (Astellas Pharma S.A, Madrid, Spain) to pediatric patients with stable liver or kidney transplants. Forty-one pharmacokinetic profiles were obtained after Prograf(®) and Advagraf(®) administration. LSSs predicting AUC0-24 were developed by linear regression using three extraction time points. Selection of the most accurate LSS was made based on the r(2) , mean error, and mean absolute error. All selected LSSs had higher correlation with AUC0-24 than the correlation found between C0 and AUC0-24 . Best LSS for Prograf(®) in liver transplants was C0_1.5_4 (r(2)  = 0.939) and for kidney transplants C0_1_3 (r(2)  = 0.925). For Advagraf(®) , the best LSS in liver transplants was C0_1_2.5 (r(2)  = 0.938) and for kidney transplants was C0_0.5_4 (r(2)  = 0.931). Excluding transplant type variable, the best LSS for Prograf(®) is C0-1-3 (r(2)  = 0.920) and the best LSS for Advagraf(®) was C0_0.5_4 (r(2)  = 0.926). Considering transplant type irrespective of the formulation used, the best LSS for liver transplants was C0_2_3 (r(2)  = 0.913) and for kidney transplants was C0_0.5_4 (r(2)  = 0.898). Best LSS, considering all data together, was C0_1_4 (r(2)  = 0.898). We developed several LSSs to predict AUC0-24 for tacrolimus in children and adolescents with kidney or liver transplants after Prograf(®) and/or Advagraf(®) treatment.

Conversion from Prograf to Advagraf in stable paediatric renal transplant patients and 1-year follow-up.

BACKGROUND: The conversion from Prograf to Advagraf on a 1:1 (mg:mg) basis has been questioned in light of the publication of studies showing a decrease in tacrolimus blood concentrations after the administration of Advagraf. METHODS: The bioavailability of Prograf and Advagraf was evaluated in an open-label conversion study in 21 stable renal transplant paediatric patients. Serial blood samples for determining tacrolimus levels were collected during a 24-h period before (on Prograf) and after (on Advagraf) conversion. Tacrolimus pharmacokinetic parameters were calculated using a non-compartmental approach and the relative bioavailability calculated. Clinical and analytical data were obtained at 30, 90, 180 and 360 days after study enrolment. RESULTS: The mean ratio and 90 % confidence interval (CI) for peak plasma drug concentration (C(max)) and the area under the time-concentration curve during the first 24 h (AUC(0-24)) were 81.54 (95 % CI 71.6-92.87) and 87.19 (95 % CI 79.91-95.13), respectively. Renal glomerular filtration rate remained stable over the course of the follow-up. Two patients presented clinical events unrelated to tacrolimus. Tacrolimus levels decreased in the first month, the dose/level ratio increased between months 1 and 6 and slight dose adjustments were required during the follow-up period. CONCLUSIONS: Our results show that Advagraf bioequivalence cannot be ensured in this population. Significant changes in tacrolimus levels and dose were observed on long-term follow-up.

Cytomegalovirus and paediatric renal transplants: is this a current issue?

OBJECTIVE: An observational retrospective multicentre study of kidney transplants in paediatric patients was performed to evaluate the current situation of cytomegalovirus (CMV) in this population, before our participation in an international clinical trial of prophylaxis for 6 months. MATERIAL AND METHOD: Our study included 239 patients aged <19 years, from 5 Spanish centres between 2005-2009, with 1 year of follow-up. RESULTS: Pretransplant CMV serology was negative in 54% of recipients and 34.7% of donors. Sixty patients (25.1%) were considered at high risk (D+/R-) for CMV infection. Prophylaxis was used in 80.8% of recipients, including all high-risk patients, for an average time of 65.5 days. CMV viraemia occurred in 24.26% (58 cases among 239 patients), and disease in 6.7%. CMV infection was associated with serological status (D/R) (P<.001), positive serology of the donor (P<.001) and duration of prophylaxis <20 days (P<.05). There were no cases of patient or graft loss secondary to infection, nor resistance to treatment. CONCLUSIONS: The main preventative strategy against CMV in paediatric renal transplantation in our country is chemical prophylaxis (81%), with an incidence of infection and disease of 24% and 6.7%, respectively. There were no serious direct or indirect effects in the first year post-transplant. The incidence is mainly linked with serological D/R and positive donor status.

Citomegalovirus y trasplante renal pediátrico: ¿es un problema actualmente? / Cytomegalovirus and paediatric renal transplants: is this a current issue?

Objetivo: Estudio retrospectivo observacional multicéntrico de los pacientes trasplantados renales pediátricos, para conocer la situación actual frente al citomegalovirus (CMV), antes de participar en un ensayo clínico internacional de profilaxis durante 6 meses. Material y métodos: Se incluyen 239 pacientes menores de 19 años, procedentes de 5 centros entre 2005-2009, con seguimiento de 1 año. Resultados: La serología frente al CMV era negativa en 54 % de los receptores y 34,7 % de los donantes. Sesenta pacientes (25,1 %) fueron considerados de alto riesgo [Donante (D)+/Receptor (R)-] para infección por CMV. El 80,8 % realizó algún tipo de profilaxis, incluyendo todos los pacientes de alto riesgo, un tiempo medio de 65,5 días. La incidencia de positivización de CMV fue del 24,26 % (58 pacientes de los 239 trasplantados), con una incidencia de enfermedad del 6,7 %. La infección por CMV se asociaba con el estatus serológico (D/R) (p < 0,001), con la seropositividad del donante (p < 0,001) y con un tiempo de profilaxis < 20 días (p < 0,05). No hubo ningún caso de éxitus o pérdida del injerto secundaria a la infección, ni de resistencia al tratamiento. Conclusiones: La principal estrategia preventiva frente al CMV en el trasplante renal pediátrico en nuestro país es la quimioprofilaxis (81 %), con una incidencia de CMV del 24 % y de enfermedad del 6,7%, sin graves efectos directos ni indirectos en el primer año postrasplante. Su incidencia está relacionada, fundamentalmente, con el estatus serológico D/R y con la seropositividad del donante (AU)

Objective: An observational retrospective multicentre study of kidney transplants in paediatric patients was performed to evaluate the current situation of cytomegalovirus (CMV) in this population, before our participation in an international clinical trial of prophylaxis for 6 months. Material and method: Our study included 239 patients aged <19 years, from 5 Spanish centres between 2005-2009, with 1 year of follow-up. Results: Pretransplant CMV serology was negative in 54% of recipients and 34.7% of donors. Sixty patients (25.1%) were considered at high risk (D+/R-) for CMV infection. Prophylaxis was used in 80.8% of recipients, including all high-risk patients, for an average time of 65.5 days. CMV viraemia occurred in 24.26% (58 cases among 239 patients), and disease in 6.7%. CMV infection was associated with serological status (D/R) (P<.001), positive serology of the donor (P<.001) and duration of prophylaxis <20 days (P<.05). There were no cases of patient or graft loss secondary to infection, nor resistance to treatment. Conclusions: The main preventative strategy against CMV in paediatric renal transplantation in our country is chemical prophylaxis (81%), with an incidence of infection and disease of 24% and 6.7%, respectively. There were no serious direct or indirect effects in the first year post-transplant. The incidence is mainly linked with serological D/R and positive donor status (AU)

[Children as receptors of living donors]. / El receptor infantil de donante vivo.

The most important factor in life expectancy for children on renal replacement therapy (RRT) is to have a functioning graft when they reach adulthood (63 years  on transplantation vs 37 years on dialysis). The pediatric recipient is very suitable for a living donor transplantation (LDT), with few contraindications. There are several reasons that make LDT the most recommended RRT in children: pre-emptive transplant avoiding dialysis, good renal mass, minimal cold ischemia time, better HLA-matching and the possibility to program the time of surgery. Long term graft survival in LDT is significantly better than in cadaveric donor transplantation (CDT) (81.3%  LDT vs 60.8 % CDT at 10 years follow-up). Calculated half-life graft survival for recipients aged 2-5 years reaches 27.5 years in some series, making LDT the ideal option for these children. Adolescent recipients (12-17 years) have an excellent early graft survival, but the worst long term outcome compared with the rest of pediatric population. However, preemptive LDT has a 70% of graft survival at 10 years. Late rejections episodes associated with non-adherence factors are found in all series. Unrelated LDT in pediatric recipients outcome remain unclear.

Acute renal failure due to bilateral pieloureteral stone impaction in a 10-month-old boy.

Urolithiasis (UL) can present with its classic signs and symptoms, such as flank or abdominal pain and gross hematuria. However, atypical complaints can be more common in younger children. We report here a case of bilateral ureteropelvic junction (UPJ) stones in a 10-month-old boy who only showed nonspecific symptoms at the time of presentation. The initial blood test revealed renal failure (serum creatinine 3.4 mg/dl), hyperkalemia (6.4 mEq/l), hyperphosphoremia (9.4 mEq/l) and mild metabolic acidosis. Medical treatment for electrolyte disorders was started. The ultrasonography revealed impacted stones in both ureteropelvic junctions. A pigtail catheter was placed in each ureter. High urine flow was promptly achieved after the pigtail procedure, and the serum creatinine level dropped quickly from 4.5 to 0.32 mg/dl. Quantitative determination of urinary amino acids by ion exchange chromatography showed high cystine levels of 8.43 mmol/g creatinine. Outpatient follow-up was scheduled every 3 months to monitor patient compliance with potassium citrate. In the first 6 months, the patient underwent three febrile urinary tract infections (UTIs). Since both pigtail catheters were removed, he has been free of UTIs and stones. Our case emphasizes the need for considering UL in infants who complain with unclear signs, because UL can only show nonspecific symptoms in children younger than 1 year old. Since cystinuria can cause loss of renal function due to urinary system obstruction and UTI, an early diagnosis and a close follow-up are the key to achieving the best long-term outcome.

El receptor infantil de donante vivo / Children as receptors of living donors

La esperanza de vida del niño con enfermedad renal terminal (ERT) depende de un trasplante funcionante (trasplante 63 años frente a diálisis 37 años). El receptor pediátrico es muy adecuado para un injerto de donante vivo, y las contraindicaciones son muy escasas. La posibilidad de evitar la diálisis, elegir el momento del trasplante, proporcionar una buena masa renal, con mínimo tiempo de isquemia fría y mejores identidades en muchos casos hacen del trasplante de donante cadáver una elección idónea. La supervivencia del injerto de donante vivo a largo plazo es significativamente mejor que la de donante cadá- ver (donante vivo 81,3% frente a donante cadáver 60,8% a 10 años). La vida media calculada de donante vivo en receptores de edades comprendidas entre 2 y 5 años es de 27 años, por lo que es el donant e idóneo en menores de 5 años. Los adolescentes (12-17 años) tienen una excelente supervivencia del injerto precoz, pero la peor de todas las edades a largo plazo. Episodios tardíos de rechazo tardío asociados a incumplimiento terapéutico son los factores encontrados en t odas las series publicadas. Sin embargo, el trasplante con donante vivo prediálisis tiene una supervivencia del injerto a 10 años del 70% . Los resultados con donante vivo no emparentado en receptores pediátricos son de difícil interpretación (AU)

The most import nt fact or in lif e expectancy for children on renal replacement therapy (RRT) is to have a unctioning graft when they reach adult hood (63 years on transplantation vs 37 years on dialysis). The pediat ric recipient is very suitable for a living donor transplantation (LDT), with few contraindications. There are several reasons that make LDT the most recommended RRT in children: pre-emptive transplant avoiding dialysis, good renal mass, minimal cold ischaemia time, better HLA-matching and the possibility to programt he time of surgery. Long term graft survival in LDT is significantly better than in cadaveric donor transplant at ion (CDT) (81.3% LDT vs 60.8 % CDT at 10 years follow -up). Calculat ed half -lif e graft survival for recipient s aged 2-5 years reaches 27.5 years in some series, making LDT t he ideal opt ion for these children. Adolescent recipient s (12-17 years) have an excellent early graft survival, but the worst long term out come compared with the rest of pediatric population. However, preempt ive LDT has a 70% of graft survival at 10 years. Late rejections episodes associated w it h non-adherence factors are f ound in all series (AU)