Life after a pediatric kidney transplant.

INTRODUCTION AND OBJECTIVES: There is currently no doubt that a kidney transplant with good function is the best treatment we can offer a child with severe kidney failure, improving their growth, development and life in general. But there are few works that follow these patients over the years to find out what their life is like as adults, their achievements and if there are any difficulties that may have arisen from their illness. That has been the objective of this work. MATERIAL AND METHODS: We have collected the evolution of 287 patients who received at least one kidney transplant in pediatric age, analyzing not only the survival of grafts and recipients but, fundamentally, their current quality of life. RESULTS: Over a 40-year period (1979-2019), 345 kidney transplants were performed in 287 pediatric recipients, with a rate of retransplantation before reaching the age of majority of 16.7%. Survival, both of patients and grafts, has improved remarkably in the last 20 years. The survival of transplanted patients in the period from 1979 to 1996 at 10, 20 and 25 years after the intervention was 83%, 76% and 65% respectively, and 94% and 82% at 10 and 20 years respectively in those transplanted in the period from 1997 to 2019. Graft survival in the period from 1979 to 1996 at 10 and 20 years was 39% and 18%, increasing in the second period to 68% and 34% respectively. Survival of the first living donor graft (LD) at 5 and 10 years was 94% and 89%. Currently 150 of these patients are adults. Of these, 32% have a stable partner and 6.6% have children. The level of training is lower than that of the general population and many of them have other comorbidities. CONCLUSIONS: The life expectancy of pediatric patients with kidney failure transplanted during childhood has improved markedly in recent decades, as has graft survival, being better with a living donor. In general, they consider themselves satisfied with their lives, with great acceptance of their illness and limitations, but -analyzing their testimonies- we conclude that they lack social support, both for themselves and their families, to achieve a higher level of education and better quality of life.

Vida tras un trasplante renal pediátrico / Life after a pediatric kidney transplant

Introducción y objetivos: Actualmente no hay duda de que un trasplante renal con buena función es el mejor tratamiento que podemos ofrecer a un niño con insuficiencia renal severa, mejorando su crecimiento, su desarrollo y su actividad en general. Pero hay pocos trabajos que sigan a estos pacientes a lo largo de los años para conocer cómo es su vida de adultos, sus logros y si hay dificultades que han podido derivarse de su enfermedad. Este ha sido el objetivo del presente trabajo. Material y métodos: Hemos recogido la evolución de 287 pacientes que recibieron al menos un trasplante renal en edad pediátrica en nuestra unidad, analizando no solo la supervivencia de los injertos y receptores sino, fundamentalmente, su calidad de vida actual. Resultados: En un periodo de 40años (1979-2019) se realizaron 345 trasplantes renales en 287 receptores pediátricos, con una tasa de retrasplantes antes de cumplir la mayoría de edad del 16,7%. La supervivencia, tanto de los pacientes como de los injertos, ha mejorado notablemente en los últimos 20años. La supervivencia de los pacientes trasplantados en el periodo de 1979 a 1996 a los 10, 20 y 25años de la intervención fue del 83, del 76 y del 65%, respectivamente, y del 94 y del 82% a los 10 y 20años, respectivamente, en los trasplantados en el periodo de 1997 a 2019. La supervivencia del injerto en el periodo de 1979 a 1996 a los 10 y 20años fue del 39 y del 18%, aumentando en el segundo periodo al 68 y al 34%, respectivamente. La supervivencia del primer injerto con donante vivo a los 5 y 10años fue del 94 y del 89%. Actualmente son adultos 150 de estos pacientes. De ellos, el 32% tienen pareja estable y el 6,6% tienen hijos. El nivel de formación es menor que el de la población general, y muchos de ellos tienen otras comorbilidades. (AU)

Introduction and objectives: There is currently no doubt that a kidney transplant with good function is the best treatment we can offer a child with severe kidney failure, improving their growth, development and life in general. But there are few works that follow these patients over the years to find out what their life is like as adults, their achievements and if there are any difficulties that may have arisen from their illness. That has been the objective of this work. Material and methods: We have collected the evolution of 287 patients who received at least one kidney transplant in pediatric age, analyzing not only the survival of grafts and recipients but, fundamentally, their current quality of life. Results: Over a 40-year period (1979-2019), 345 kidney transplants were performed in 287 pediatric recipients, with a rate of retransplantation before reaching the age of majority of 16.7%. Survival, both of patients and grafts, has improved remarkably in the last 20years. The survival of transplanted patients in the period from 1979 to 1996 at 10, 20 and 25years after the intervention was 83%, 76% and 65% respectively, and 94% and 82% at 10 and 20years respectively in those transplanted in the period from 1997 to 2019. Graft survival in the period from 1979 to 1996 at 10 and 20years was 39% and 18%, increasing in the second period to 68% and 34% respectively. Survival of the first living donor graft at 5 and 10years was 94% and 89%.Currently 150 of these patients are adults. Of these, 32% have a stable partner and 6.6% have children. The level of training is lower than that of the general population and many of them have other comorbidities.(AU)

Is the atypical hemolytic uremic syndrome risk polymorphism in Membrane Cofactor Protein MCPggaac relevant in kidney transplantation? A case report.

aHUS is a rare disease characterized by episodes of TMA that frequently progresses to CKD and often recurs after KT. The most frequent cause of aHUS is defective regulation of complement activation because of genetic anomalies. Eculizumab interrupts the process of TMA and improves renal function. We describe one female patient with aHUS who debuted in 2005 at 3-mo-old with extrarenal manifestations and progressed to end-stage kidney disease (ESKD) within a year. Her family history included several affected members with similar bad outcomes. Our patient carries a strong aHUS genetic predisposition consisting in a pathogenic gain-of-function mutation in complement factor B concurrent with the MCP aHUS risk haplotype MCPggaac. She received a kidney transplant in 2011 without eculizumab prophylaxis. The graft, which was negative for the MCPggaac risk haplotype, had an unexpected excellent evolution without aHUS recurrence. Different retrospective studies have shown that the risk of aHUS recurrence after KT correlates well with the genetic load of aHUS risk factors. Knowing important contribution of the MCPggaac risk haplotype to the risk of developing aHUS in Factor B mutations carriers, we speculate whether the absence of this polymorphism in the graft that our patient received may have decreased the risk of aHUS recurrence after KT.

Poor phenotype-genotype association in a large series of patients with Type III Bartter syndrome.

INTRODUCTION: Type III Bartter syndrome (BS) is an autosomal recessive renal tubule disorder caused by loss-of-function mutations in the CLCNKB gene, which encodes the chloride channel protein ClC-Kb. In this study, we carried out a complete clinical and genetic characterization in a cohort of 30 patients, one of the largest series described. By comparing with other published populations, and considering that 80% of our patients presented the p.Ala204Thr Spanish founder mutation presumably associated with a common phenotype, we aimed to test the hypothesis that allelic differences could explain the wide phenotypic variability observed in patients with type III BS. METHODS: Clinical data were retrieved from the referral centers. The exon regions and flanking intronic sequences of the CLCNKB gene were screened for mutations by polymerase chain reaction (PCR) followed by direct Sanger sequencing. Presence of gross deletions or duplications in the region was checked for by MLPA and QMPSF analyses. RESULTS: Polyuria, polydipsia and dehydration were the main common symptoms. Metabolic alkalosis and hypokalemia of renal origin were detected in all patients at diagnosis. Calciuria levels were variable: hypercalciuria was detected in 31% of patients, while 23% had hypocalciuria. Nephrocalcinosis was diagnosed in 20% of the cohort. Two novel CLCNKB mutations were identified: a small homozygous deletion (c.753delG) in one patient and a small deletion (c.1026delC) in another. The latter was present in compound heterozygosis with the already previously described p.Glu442Gly mutation. No phenotypic association was obtained regarding the genotype. CONCLUSION: A poor correlation was found between a specific type of mutation in the CLCNKB gene and type III BS phenotype. Importantly, two CLCNKB mutations not previously described were found in our cohort.

Outcomes of pediatric living donor kidney transplantation: A single-center experience.

Renal transplantation is the treatment of choice for children with ESRD offering advantages of improved survival, growth potential, cognitive development, and quality of life. The aim of our study was to compare the outcomes of LDKT vs DDKT performed in children at a single center. Retrospective chart review of pediatric patients who underwent kidney transplantation from 2005 to 2014 was performed. Ninety-one renal transplants were accomplished, and 31 cases (38.27%) were LDKT, and in 96.7% of the cases, the graft was obtained through laparoscopy. Thirty-four receptors weighted <25 kg. LDKT group had statistically significant lower cold ischemia times than DDKT one. Complication rate was 9.67% for LDKT and 18.33% for DDKT. eGFR was better in LDKT. Patient survival rate was 100% for LDKT and 98.3% for DDKT, and graft survival rate was 96.7% for LDKT and 88.33%-80% for DDKT at a year and 5 years. Our program of pediatric kidney transplantation has achieved optimal patient and graft survival rates with low rate of complications. Living donor pediatric kidney transplants have higher patient and better graft survival rates than deceased donor kidney transplants.

Eculizumab in dense-deposit disease after renal transplantation.

BACKGROUND: Dense-deposit disease (DDD) is a rare glomerulopathy characterized by electron-dense deposits in the glomerular basement membrane. About 50 % of patients with DDD progress to end-stage kidney disease and require dialysis within 10 years of diagnosis, and the disease often recurs after renal transplantation. CASE-DIAGNOSIS/TREATMENT: We describe a 14-year-old girl with recurrent DDD in her transplanted kidney. Clinical onset was at 8 years of age, when steroid-resistant nephrotic syndrome was diagnosed with microhematuria, severe hypocomplementemia and normal kidney function. Although remission was initially observed after several plasma exchanges, nephrotic proteinuria returned and kidney function further declined 1 year later. The patient received a living-related kidney transplant. Initial allograft function was good, but proteinuria reappeared 3 months after transplantation, accompanied by a slight deterioration in kidney function. After histological confirmation of DDD recurrence and subsequent management with plasmapheresis, the patient was treated for 30 months with eculizumab, a humanized monoclonal antibody that binds to C5 complement protein. This intervention proved effective and resulted in complement inhibition, sustained remission of proteinuria and preservation of renal function. A graft biopsy 6 months later showed no progression of the renal lesions. CONCLUSIONS: Early clinical and histological recurrence of DDD in the transplanted kidney in this 14-year-old patient was treated for 30 months with eculizumab. The patient remains asymptomatic, has no proteinuria and her kidney function is intact.

Genetics of type III Bartter syndrome in Spain, proposed diagnostic algorithm.

The p.Ala204Thr mutation (exon 7) of the CLCNKB gene is a "founder" mutation that causes most of type III Bartter syndrome cases in Spain. We performed genetic analysis of the CLCNKB gene, which encodes for the chloride channel protein ClC-Kb, in a cohort of 26 affected patients from 23 families. The diagnostic algorithm was: first, detection of the p.Ala204Thr mutation; second, detecting large deletions or duplications by Multiplex Ligation-dependent Probe Amplification and Quantitative Multiplex PCR of Short Fluorescent Fragments; and third, sequencing of the coding and flanking regions of the whole CLCNKB gene. In our genetic diagnosis, 20 families presented with the p.Ala204Thr mutation. Of those, 15 patients (15 families) were homozygous (57.7% of overall patients). Another 8 patients (5 families) were compound heterozygous for the founder mutation together with a second one. Thus, 3 patients (2 siblings) presented with the c. -19-?_2053+? del deletion (comprising the entire gene); one patient carried the p.Val170Met mutation (exon 6); and 4 patients (3 siblings) presented with the novel p.Glu442Gly mutation (exon 14). On the other hand, another two patients carried two novel mutations in compound heterozygosis: one presented the p.Ile398_Thr401del mutation (exon 12) associated with the c. -19-?_2053+? del deletion, and the other one carried the c.1756+1G>A splice-site mutation (exon 16) as well as the already described p.Ala210Val change (exon 7). One case turned out to be negative in our genetic screening. In addition, 51 relatives were found to be heterozygous carriers of the described CLCNKB mutations. In conclusion, different mutations cause type III Bartter syndrome in Spain. The high prevalence of the p.Ala204Thr in Spanish families thus justifies an initial screen for this mutation. However, should it not be detected further investigation of the CLCNKB gene is warranted in clinically diagnosed families.

Prospective study of infectious complications in a cohort of pediatric renal transplant recipients.

UNLABELLED: Infections are frequent and serious in pediatric RT recipients; however, the information available is scarce. The aim of this study was to determine the incidence, etiology, and risk factors for infection in these patients. This was a prospective, observational study of a consecutive pediatric RT recipient cohort. Risk factors for infection and descriptive analyses during the first two post-transplantation years were performed. Twenty-one patients (58.3%) had at least one infection (incidence 1.5 episodes/patient/first year of transplantation). There were 33 bacterial infections (73.3%), 11 viral infections (24.4%), and one protozoal infection. UTI was the most common syndrome (48.3%), followed by CMV infection (15.5%). The main microorganisms isolated were Escherichia coli (28.9%), 46.1% of which were ESBL producers, and CMV (20%). Patient and graft survival at the end of follow-up were 97.2% and 83.3%, respectively. The only risk factor for infection was cold ischemia time >800 min (OR 5.7, CI 95% 1.7-19.3). CONCLUSIONS: In pediatric RT recipients, UTI is the most frequent syndrome. Bacterial infections are the most common, with a high rate of ESBL producer strains. Despite their good prognosis, infections are a cause of morbidity that could potentially be reduced by decreasing cold ischemia times.

Anti-glutathione S-transferase T1 antibody-mediated rejection in C4d-positive renal allograft recipients.

BACKGROUND: Chronic humoral rejection is a progressive form of graft injury, with defined diagnostic criteria, the crucial one being the evidence of circulating anti-donor antibodies. These antibodies are mainly directed against human leucocyte antigens (HLA), but other targets have also been described. We previously reported that antibodies against the Glutathione S-transferase T1 (GSTT1) enzyme appear in recipients without the GSTT1 gene who receive a graft from a GSTT1-positive donor. The primary aim of this study was to analyse the role of GSTT1 in cases of antibody-mediated rejection (AMR) in the absence of anti-HLA antibodies. A second objective was to describe the distribution of the GSTT1 enzyme in the human kidney. METHODS: Four renal biopsies from four renal transplanted patients with declined renal function and circulating anti-donor GSTT1 antibodies were studied for C4d deposits in sections of paraffin-embedded tissue samples. Anti-donor-specific HLA and MICA antibody detection was done with the Luminex platform and anti-GSTT1 antibodies were tested by indirect immunofluorescence on rat tissues and ELISA assay. DNA of the patients was extracted for GSTT1 genotyping. RESULTS: Four patients with the GSTT1 donor/recipient mismatch developed anti-GSTT1 antibodies 32, 42, 48 and 60 months after the transplant. One patient also had donor-specific anti-HLA antibodies. Their biopsies showed pathologic lesions compatible with chronic antibody-mediated rejection (CAMR), along with positive C4d deposition in peritubular capillaries in three of them, being no valuable in the other case. CONCLUSION: This is the first study reporting an association between the appearance of chronic antibody-mediated renal allograft rejection and the occurrence of de novo production of anti-GSTT1 antibodies, in the absence of anti-HLA donor-specific antibodies. This fact suggests a potential role of the GSTT1 system in anti-graft immune response.

Vesicoureteral reflux after kidney transplantation in children.

We analyzed the frequency of vesicoureteral reflux and the factors that favor its appearance after kidney transplantation in pediatric patients. This retrospective analysis examined the prevalence of post-transplant vesicoureteral reflux in a total of 181 kidney transplants performed in children at our center between 1978 and 2004. In patients who required corrective surgery for this problem, we analyzed pretransplant residual diuresis, pretransplant pathology and post-transplant problems related to vesicoureteral reflux. We also analyzed form of presentation, whether reflux was to the graft or to the native kidney, degree of reflux, and surgical technique used to correct reflux. Ten patients (5.5%) needed surgery to correct reflux to the graft (nine children) or to the native kidney (one child). Reflux was manifested as urinary tract infection in six children and progressive graft failure in one. Urethrovesical disorders that favored vesicoureteral reflux were present in eight patients (non-compliance bladder, detrusor overactivity, posterior urethral valves, urethral stenosis). Lengthening the submucosal tunnel stopped urinary tract infections in all 10 patients, whereas six-month voiding cystourethrograms showed resolution in 8 patients and (only) reduction in the degree of reflux in two. The high percentage of post-transplant vesicoureteral reflux in pediatric patients were related with higher frequencies of ureterovesical pathology in children who received the transplant. Lengthening the submucosal ureteral tunnel vesicoureteral reflux was corrected in 80%. We recommend during implantation in children with pretransplant urethrovesical abnormality an initial technique, which utilizes a longer submucosal tunnel such as the Lich-Gregoir.