Trigenic COL4A3/COL4A4/COL4A5 pathogenic variants in Alport syndrome: a case report.

Alport syndrome (AS) is a hereditary kidney disorder of type IV collagen caused by pathogenic variants in the COL4A3, COL4A4 and COL4A5 genes. Previously several cases of digenic AS, caused by two pathogenic variants in two of the three COL4A genes, have been reported. Patients with digenic AS may present with a more severe phenotype compared to patients with single variants, depending on the percentage affected type IV trimeric collagen chain. We report a newly discovered case of trigenic AS. A 52-year-old female presented with hematuria at the age of 24 years and developed hypertension by the age of 30. Over the years she developed chronic kidney disease; the most recent eGFR was 44ml/min/1.73m2. She has symmetric high-tone sensorineural hearing loss. Full genetic analysis revealed a heterozygous pathogenic variant c.2691del in COL4A3, a heterozygous pathogenic variant c.1663dup in COL4A4, and a complete heterozygous deletion of COL4A5. We describe the first patient with AS caused by pathogenic variants in all three COL4A genes, designated trigenic AS. This case report emphasizes the importance of examining all three COL4A genes, even in patients with a mild Alport phenotype, for optimal follow-up of the patient and adequate genetic counseling of family members.

Anesthesia and intensive care unit care in pediatric kidney transplantation: An international survey.

BACKGROUND: Despite the high perioperative risk profile, international guidelines for anesthesia and intensive care unit (ICU) care in pediatric kidney transplantation do not exist. Optimizing hemodynamics can be challenging in these patients, while scientific data to guide decisions in hemodynamic monitoring, hemodynamic targets, and perioperative fluid management are lacking. The limited annual number of pediatric kidney transplantations, even in reference centers, necessitates the urge for international collaboration to share knowledge and develop research and guidelines. The aim of this study was to collect data on current perioperative anesthesia and ICU care practices in pediatric kidney transplantation. METHODS: An international survey with an anonymized link was sent from a validated electronic data capture system (Castor). Inclusion criteria were: medical doctor in anesthesia, (ICU), or pediatric nephrology working in a pediatric kidney transplantation specialized center; and signed informed consent. Data were analyzed using descriptive statistics. RESULTS: Thirty-three records were analyzed. Responders were anesthesiologists (58%), pediatric nephrologists (30%), and pediatric intensivists (12%), representing 13 countries worldwide. About half of the centers (48%) performed more than 10 pediatric kidney transplantations a year. Perioperative hemodynamic support was guided by intra-arterial blood pressure (88%), central venous pressure (CVP; 88%), and cardiac output (CO; 39%). The most variation was seen in the hemodynamic targets CVP and CO, fluid administration, and inotrope/vasopressor use. The protocolized use of furosemide (46%) and mannitol (61%) also varied between centers. Postoperative care for the youngest recipients occurred in the pediatric intensive care unit at all centers. CONCLUSION: The results of this survey reveal a large variation in anesthesia and ICU care in pediatric kidney transplantation centers worldwide, particularly in CVP and CO targets, hemodynamic therapy, and the use of furosemide and mannitol. These data identify areas for further research and can be a starting point for international research collaboration and guideline development.

Cardiac output-guided hemodynamic therapy for adult living donor kidney transplantation in children under 20 kg: A pilot study.

BACKGROUND: A living-donor (adult) kidney transplantation in young children requires an increased cardiac output to maintain adequate perfusion of the relatively large kidney. To achieve this, protocols commonly advise liberal fluid administration guided by high target central venous pressure. Such therapy may lead to good renal outcomes, but the risk of tissue edema is substantial. AIMS: We aimed to evaluate the safety and feasibility of the transpulmonary thermodilution technique to measure cardiac output in pediatric recipients. The second aim was to evaluate whether a cardiac output-guided hemodynamic therapy algorithm could induce less liberal fluid administration, while preserving good renal results and achieving increased target cardiac output and blood pressure. METHODS: In twelve consecutive recipients, cardiac output was measured with transpulmonary thermodilution (PiCCO device, Pulsion). The algorithm steered administration of fluids, norepinephrine and dobutamine. Hemodynamic values were obtained before, during and after transplantation. Results are given as mean (SD) [minimum-maximum]. RESULTS: Age and weight of recipients was 3.2 (0.97) [1.6-4.9] yr and 14.1 (2.4) [10.4-18] kg, respectively. No complications related to cardiac output monitoring occurred. After transplantation, cardiac index increased with 31% (95% CI = 15%-48%). Extravascular lung water and central venous pressure did not change. Fluids given decreased from 158 [124-191] mL kg-1 in the first 2 patients to 80 (18) [44-106] mL kg-1 in the last 10 patients. The latter amount was 23 mL kg-1 less (95% CI = 6-40 mL kg-1 ) than in one recent study, but similar to that in another. After reperfusion, all patients received norepinephrine (maximum dose 0.45 (0.3) [0.1-0.9] mcg kg-1  min-1 ). Patient and graft survivals were 100% with excellent kidney function at 6 months post-transplantation. CONCLUSION: Transpulmonary thermodilution-cardiac output monitoring appeared to be safe and feasible. Using the cardiac output-guided algorithm led to excellent renal results with a trend toward less fluids in favor of norepinephrine.

Epidemiology and management of hypertension in paediatric and young adult kidney transplant recipients in The Netherlands.

INTRODUCTION: Hypertension in kidney transplant recipients (KTRs) is a risk factor for cardiovascular mortality and graft loss. Data on the prevalence of hypertension and uncontrolled hypertension (uHT) in paediatric and young adult KTRs are scarce. Also, it is unknown whether 'transition' (the transfer from paediatric to adult care) influences control of hypertension. We assessed the prevalence of hypertension and uHT among Dutch paediatric and young adult KTRs and analysed the effects of transition. Additionally, we made an inventory of variations in treatment policies in Dutch transplant centres. METHODS: Cross-sectional and longitudinal national data from living KTRs ≤30 years of age (≥1-year post-transplant, eGFR >20 mL/min) were extracted from the 'RICH Q' database, which comprises information about all Dutch KTRs <19 years of age, and the Netherlands Organ Transplant Registry database for adult KTRs (≥18-30 years of age). We used both upper-limit blood pressure (BP) thresholds for treatment according to Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. uHT was defined as a BP above the threshold. A questionnaire on treatment policies was sent to paediatric and adult nephrologists at eight Dutch transplant centres. RESULTS: Hypertension and uHT were more prevalent in young adult KTRs (86.4 and 75.8%) than in paediatric KTRs (62.7 and 38.3%) according to the KDIGO definition. Time after transplantation was comparable between these groups. Longitudinal analysis showed no evidence of effect of transition on systolic BP or prevalence of uHT. Policies vary considerably between and within centres on the definition of hypertension, BP measurement and antihypertensive treatment. CONCLUSION: Average BP in KTRs increases continuously with age between 6 and 30 years. Young adult KTRs have significantly more uHT than paediatric KTRs according to KDIGO guidelines. Transition does not influence the prevalence of uHT.

Breakthrough VZV infection after immunization, presenting as herpes zoster.

An immunocompromized, VZV-vaccinated child had a breakthrough infection with VZV, acquired at a day-care centre during a chickenpox outbreak. Interestingly, the infection manifested as herpes zoster of 1 dermatome. Typing showed wild-type virus, which suggests that exogenous reinfection with a new strain may present as herpes zoster.

Intrathecal rituximab treatment for pediatric post-transplant lymphoproliferative disorder of the central nervous system.

Post-transplant lymphoproliferative disorder (PTLD) in the central nervous system (CNS) has a poor prognosis. New therapeutic approaches should be explored. We report our experience with intrathecal administration of rituximab in a 10-year-old kidney allograft recipient with PTLD in the CNS. After standard treatment had failed, we tried to treat the patient by administering rituximab directly into the cerebral ventricle through an Omaya reservoir, in addition to conventional intrathecal and systemic chemotherapy. This strategy resulted in a disappearance of clinical symptoms and a negative positron emission tomogram. Intrathecal administration of rituximab may be a feasible approach in children with PTLD in the CNS. However, its specific role in our patient remains uncertain.

Maintenance immunosuppression with mycophenolate mofetil and corticosteroids in pediatric kidney transplantation: temporary benefit but not without risk.

BACKGROUND: Aiming at reducing cyclosporine toxicity, we investigated safety and efficacy of mycophenolate mofetil (MMF) as an immunosuppressive drug in pediatric kidney transplantation compared with cyclosporine (CsA), both in combination with corticosteroids. METHODS: One year after kidney transplantation, children on triple immunosuppression, having experienced no more than one, steroid-sensitive, acute rejection episode, were randomized to withdrawal of either CsA or MMF and were followed for 2 yr. RESULTS: In each group, two patients had an acute rejection episode during withdrawal. Treatment failure occurred in 3 of 21 MMF and 5 of 23 CsA patients. Final analysis was for 18 patients in either group. A larger than 10 mL/min 1.73 m decrease in glomerular filtration rate was observed in more patients on CsA than on MMF (73% vs. 29%, P=0.019). No differences in blood pressure or nightly decrease of blood pressure were noted. Hypercholesterolism improved in the MMF (-16%), but not the CsA group (+5%, P<0.05), over the first, but not over both study years. Differences in triglycerid levels between groups were not shown. At study end, MMF patients tended to have lower hemoglobin levels than patients on CsA. Two MMF patients experienced a first acute rejection episode during the second study year, resulting in chronic transplant glomerulopathy with graft loss in one and deterioration of kidney function in the other. CONCLUSION: In pediatric kidney transplantation, maintenance immunosuppression with MMF together with corticosteroids has short-term benefits for kidney function and lipid pattern compared with CsA but is not without risk of complications.

Etiology and epidemiology of end-stage renal disease in Dutch children 1987-2001.

In this retrospective study 351 children (<16.0 years) with end-stage renal disease (ESRD) accepted for renal replacement therapy (RRT) in the four Dutch pediatric centers were analyzed for the period 1987-2001. The data were compared with a previous study performed in 1979-1986. Eighty patients were of non-Dutch origin. An annual ESRD incidence of 5.8 patients per million of the child population (p.m.c.p.) was calculated, without significant changes with time. The final prevalence in Dutch children under 15 years of ESRD was 38.7 p.m.c.p. The most frequent primary renal disease leading to ESRD was urethral valves, with a significant increase vs. the previous observation period (14% vs. 6%). The distribution of primary renal diseases was similar in patients of non-Dutch origin and in Dutch patients. Peritoneal dialysis was the most frequent dialysis procedure initially applied (62% vs. 26% in the earlier observation period). Thirteen percent of all first transplantations (n=278) were pre-emptive and 19% from living donors. Five-year graft survival after a living-donor and a cadaver graft was 80% and 73%, respectively. Overall patient survival after 10 years on RRT was 94%.