Risk Factor Analysis for Long-Term Graft Survival Following Pediatric Kidney Transplantation: The Importance of Pretransplantation Time on Dialysis and Donor/Recipient Age Difference.

Recognizing risk factors that may negatively affect long-term graft survival following pediatric kidney transplantation is a key element in the decision-making process during organ allocation. We retrospectively reassessed all cases of pediatric kidney transplantation performed in our center in the last 20 years with the aim of determining baseline characteristics that could be identified as prognostic risk factors for long-term graft survival. Between 2001 and 2020, a total of 91 kidney transplantations in children under the age of 18 years were undertaken in our center. Early graft failure was observed in six of the 91 patients (7%). The median follow-up of the remaining 85 children was 100 months, and the overall kidney graft survival rates at 5, 10, 15 and 20 years were 85.2%, 71.4%, 46.0% and 30.6%, respectively. Small children with a body surface area of <1 m2 were significantly associated with better long-term graft survival outcomes, while adolescents aged more than twelve years showed poorer graft survival rates than younger children. Body surface area of the recipient of ≥1 m2, pretransplantation duration of the recipient on dialysis ≥18 months, hemodialysis prior to transplantation and donor/recipient age difference of ≥25 years were significantly associated with poorer long-term graft survival.

Clean Intermittent Catheterization in Children under 12 Years Does Not Have a Negative Impact on Long-Term Graft Survival following Pediatric Kidney Transplantation.

BACKGROUND: Congenital anomalies of the kidneys and urinary tract (CAKUTs) are one of the most prevalent primary causes of end-stage renal disease (ESRD) in young children, and approximately one-third of these children present with lower urinary tract dysfunction (LUTD). Many children with LUTD require therapy with clean intermittent catheterization (CIC). CIC commonly leads to bacteriuria, and considerations have arisen regarding whether CIC in immunosuppressed children is safe or whether repeated febrile urinary tract infections (UTIs) may lead to the deterioration of kidney graft function. MATERIAL AND METHODS: We retrospectively reviewed all cases of primary kidney transplantation performed in our center between 2001 and 2020 in recipients aged less than twelve years. The number of episodes of febrile UTIs as well as the long-term kidney graft survival of children undergoing CIC were compared to those of children with urological causes of ESRD not undergoing CIC, as well as to those of children with nonurological causes of ESRD. RESULTS: Following successful kidney transplantation in 41 children, CIC was needed in 8 of these patients. These 8 children undergoing CIC had significantly more episodes of febrile UTIs than did the 18 children with a nonurological cause of ESRD (p = 0.04) but not the 15 children with a urological cause of ESRD who did not need to undergo CIC (p = 0.19). Despite being associated with a higher rate of febrile UTIs, CIC was not identified as a risk factor for long-term kidney graft survival, and long-term graft survival did not significantly differ between the three groups at a median follow-up of 124 months. CONCLUSIONS: Our study demonstrates that, under regular medical care, CIC following pediatric transplantation is safe and is not associated with a higher rate of long-term graft loss.

Homozygous familial hypercholesterolemia with severe involvement of the aortic valve-A sibling-controlled case study on the efficacy of lipoprotein apheresis.

BACKGROUND: Homozygous familial hypercholesterolemia (hoFH) can cause severe atherosclerotic cardiovascular disease (ASCVD) in early infancy. Diagnosis and initiation of effective lipid-lowering therapy (LLT) are recommended as early as possible to prevent ASCVD-related morbidity and mortality. METHODS: The clinical courses of a pair of siblings with an identical hoFH genotype, who exhibited major similarities of their clinical phenotype were analyzed in a case-control fashion including the family. RESULTS: The older sibling was diagnosed with hoFH at the age of 4. Untreated LDL-cholesterol (LDL-C) was 17 mmol/L (660 mg/dL). LLT including lipoprotein apheresis (LA) was initiated and has been successful for 8 years now. A reduction of estimated cholesterol burden by 74% was achieved by LA and combined drug therapy including statins and ezetimibe. The efficacy of escalation of drug therapy was limited because the underlying LDL receptor (LDLR) mutation in the family resulted in substantially reduced receptor function. Treatment with proprotein convertase subtilisin-kexin type 9 (PCSK9)-antibodies failed. His younger brother died at the age of 2 years shortly after the hoFH diagnosis of the elder sibling. Postmortem examination revealed advanced aortic root atheroma and aortic valve stenosis. In the older sibling, aortic valve stenosis and insufficiency were treated at the age of 9 years with mechanical aortic valve replacement. CONCLUSIONS: LLT including LA should be initiated as early as possible following the diagnosis of hoFH with very high LDL-C levels. With the same genotype, the phenotype of hoFH can exhibit similar patterns but outcome is substantially related to treatment.

Clinical courses and complications of young adults with Autosomal Recessive Polycystic Kidney Disease (ARPKD).

Autosomal recessive polycystic kidney disease (ARPKD) is a severe pediatric hepatorenal disorder with pronounced phenotypic variability. A substantial number of patients with early diagnosis reaches adulthood and some patients are not diagnosed until adulthood. Yet, clinical knowledge about adult ARPKD patients is scarce. Here, we describe forty-nine patients with longitudinal follow-up into young adulthood that were identified in the international ARPKD cohort study ARegPKD. Forty-five patients were evaluated in a cross-sectional analysis at a mean age of 21.4 (±3.3) years describing hepatorenal findings. Renal function of native kidneys was within CKD stages 1 to 3 in more than 50% of the patients. Symptoms of hepatic involvement were frequently detected. Fourteen (31%) patients had undergone kidney transplantation and six patients (13%) had undergone liver transplantation or combined liver and kidney transplantation prior to the visit revealing a wide variability of clinical courses. Hepatorenal involvement and preceding complications in other organs were also evaluated in a time-to-event analysis. In summary, we characterize the broad clinical spectrum of young adult ARPKD patients. Importantly, many patients have a stable renal and hepatic situation in young adulthood. ARPKD should also be considered as a differential diagnosis in young adults with fibrocystic hepatorenal disease.

Low-Frequency Stimulation of Silent Nociceptors Induces Secondary Mechanical Hyperalgesia in Human Skin.

Secondary mechanical hyperalgesia to punctate mechanical stimuli and light touch (allodynia) are prominent symptoms in neuropathic pain states. In a combined microneurographic and psychophysical study, we investigated the role of mechano-insensitive (silent) nociceptors regarding induction. Electrical thresholds of mechano-sensitive and silent nociceptors were assessed by microneurography with two closely spaced intracutaneous electrodes (i.c.) and a transcutaneous configuration (t.c.) in the foot dorsum. For t.c. stimulation there was a marked difference between silent (median, quartiles; 60, 50-70 mA, n = 63) and mechano-sensitive fibers (3, 2-5 mA, n = 107). In silent fibers, thresholds were lower for i.c. stimulation (16, 14-19 mA, n = 8), but higher in mechano-sensitive units (6, 5-6 mA, n = 13). Corresponding psychophysical tests showed no difference between the stimulation configuration for pain thresholds, but lower thresholds for the i.c. stimulation in axon reflex erythema (12 vs. 21 mA), punctate hyperalgesia (9 vs. 15 mA) and allodynia (15 vs. 18 mA). Punctate hyperalgesia was evoked at very low stimulation frequencies of 1/20 Hz (7/7 subjects), whereas the induction of an axon reflex flare required stimulation at 1/5 Hz. Electrical stimulation which is sufficient to excite mechano-insensitive C nociceptors can induce secondary mechanical hyperalgesia even at low frequencies supporting a role of such low-level input to clinical pain states. Thus, differential nociceptor class-specific input to the spinal cord adds to the complexity of modulatory mechanisms that determine nociceptive processing in the spinal cord.

Transition structures and timing of transfer from paediatric to adult-based care after kidney transplantation in Germany: a qualitative study.

OBJECTIVES: It is known that transition, as a shift of care, marks a vulnerable phase in the adolescents' lives with an increased risk for non-adherence and allograft failure. Still, the transition process of adolescents and young adults living with a kidney transplant in Germany is not well defined. The present research aims to assess transition-relevant structures for this group of young people. Special attention is paid to the timing of the process. SETTING: In an observational study, we visited 21 departments of paediatric nephrology in Germany. Participants were doctors (n=19), nurses (n=14) and psychosocial staff (n=16) who were responsible for transition in the relevant centres. Structural elements were surveyed using a short questionnaire. The experiential viewpoint was collected by interviews which were transcribedverbatim before thematic analysis was performed. RESULTS: This study highlights that professionals working within paediatric nephrology in Germany are well aware of the importance of successful transition. Key elements of transitional care are well understood and mutually agreed on. Nonetheless, implementation within daily routine seems challenging, and the absence of written, structured procedures may hamper successful transition. CONCLUSIONS: While professionals aim for an individual timing of transfer based on medical, social, emotional and structural aspects, rigid regulations on transfer age as given by the relevant health authorities add on to the challenge. TRIAL REGISTRATION NUMBER: ISRCTN Registry no 22988897; results (phase I) and pre-results (phase II).

Unexpected recovery from longterm renal failure in severe diffuse proliferative lupus nephritis.

BACKGROUND: Severe renal manifestation of systemic lupus erythematosus (SLE) is not uncommon and is associated with an indeterminate prognosis. Complete remission can be obtained, however, at least in the young when chronic lesions are absent and adequate anti-inflammatory therapy is immediately initiated. CASE PRESENTATION: We report the unusual case of a 12-year-old girl who presented with severe oliguric renal failure, macrohematuria and skin rash. Renal biopsy revealed the diagnosis of severe diffuse proliferative glomerulonephritis (GN) with cellular crescents in 15 out of 18 glomeruli and full-house pattern in immunofluorescence indicating lupus nephritis IVB according to WHO, IV-G(A) according to ISN/RPS classification. The serological parameters confirmed the diagnosis of SLE and the patient was immediately treated with methylprednisolone, cyclophosphamide and immunoadsorption. Initially, despite rapid amelioration of her general condition, no substantial improvement of renal function could be achieved and the patient needed hemodialysis treatment for 12 weeks. Unexpectedly, in the further follow-up at first diuresis increased and thereafter also creatinine levels substantially declined so that hemodialysis could be discontinued. Today, 6 years after the initial presentation, the patient has normal renal function and a SLEDAI score of 0 under a continuous immunosuppressive therapy with Mycophenolate mofetil (MMF) and low dose steroid. CONCLUSION: Despite the severity of the initial renal injury and the unfavourable renal prognosis the kidney apparently has a tremendous capacity to recover in young patients when the damage is acute and adequate anti-inflammatory therapy is initiated without delay.

Experimental thermal lesions induce beta-thromboglobulin release from activated platelets.

Time courses of beta-thromboglobulin release, and protein extravasation after thermal inflammation of human skin was compared to neurogenic inflammation induced by histamine iontophoresis. Beta-TG and protein levels were sampled by intradermal microdialysis. Three microdialysis membranes were inserted at each stimulation site. The collected samples were measured photometrically for protein by the Coomassie blue method and for beta-TG by ELISA. Heat stimuli of 40°C and 47°C, and histamine iontophoresis were inflicted directly above the membranes. In vitro recovery rates of beta-TG and bovine albumin were measured using a latex chamber. Recovery rates at a continuous flow rate of 3 µl/min for bovine albumin ranged between 20% and 35%; those for beta-TG ranged between 14% and 17%. Heat stimulation at 40°C showed a slight but insignificant increase of beta-TG during the stimulation period. Temperatures of 47°C produced a significant, long-lasting increase of beta-TG, whereas histamine iontophoresis did not. Protein extravasation corresponded with beta-TG release; a long-lasting significant increase during and after the burn lesion, and only an initial increase of protein extravasation during the 40°C heat stimulus. Long lasting heat stimuli to the skin induced beta-TG release from platelets, whereas histamine iontophoresis although provoking protein extravasation and neurogenic flare, did not. Using microdialysis techniques we detected beta-TG release during an inflammatory response. We conclude that local platelet activation is induced by the heating stimulus. Platelet mediators, such as beta-TG might contribute to the subsequent inflammatory process which is also characterized by mechanical and heat hyperalgesia.

Stable graft function after reduction of calcineurin inhibitor dosage in paediatric kidney transplant patients.

BACKGROUND: Chronic calcineurin inhibitor (CNI) toxicity contributes to the development and progression of chronic allograft nephropathy (CAN), which is still the major cause of transplant dysfunction and graft loss. Reduction in dosage of CNI may delay the development of CAN, leading to longer graft survival. METHODS: Therefore, 19 paediatric kidney transplant patients under immunosuppressive therapy with CNI (12/19 ciclosporin A, CSA, 7/19 tacrolimus, Tac), mycophenolat mofetil and some patients on steroids were included in a prospective study. Over a period of 9 months CNI dosage was stepwise reduced from CSA trough levels of 100-150 ng/ml to 50-70 ng/ml and Tac trough levels of 5-8 ng/ml to 2-3 ng/ml, respectively. RESULTS: Glomerular filtration rate was stabilized in patients after CSA and Tac reduction. One borderline rejection occurred in a patient prior to reduction of Tac. In patients on CSA, one interstitial cellular rejection (BANFF IA) was noted. Reduction of CNI had no significant effects on blood pressure, lipid status and the infection frequency. CONCLUSIONS: In paediatric kidney transplant patients, reduction of CNI down to low trough levels stabilizes renal function. However, the risk of acute rejection episodes may be increased. Therefore, further studies based on protocol biopsies within a randomized trial are warranted.