Assessing bone mineralisation in children with chronic kidney disease: what clinical and research tools are available?

Mineral and bone disorder in chronic kidney disease (CKD-MBD) is a triad of biochemical imbalances of calcium, phosphate, parathyroid hormone and vitamin D, bone abnormalities and soft tissue calcification. Maintaining optimal bone health in children with CKD is important to prevent long-term complications, such as fractures, to optimise growth and possibly also to prevent extra-osseous calcification, especially vascular calcification. In this review, we discuss normal bone mineralisation, the pathophysiology of dysregulated homeostasis leading to mineralisation defects in CKD and its clinical consequences. Bone mineralisation is best assessed on bone histology and histomorphometry, but given the rarity with which this is performed, we present an overview of the tools available to clinicians to assess bone mineral density, including serum biomarkers and imaging such as dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. We discuss key studies that have used these techniques, their advantages and disadvantages in childhood CKD and their relationship to biomarkers and bone histomorphometry. Finally, we present recommendations from relevant guidelines-Kidney Disease Improving Global Outcomes and the International Society of Clinical Densitometry-on the use of imaging, biomarkers and bone biopsy in assessing bone mineral density. Given low-level evidence from most paediatric studies, bone imaging and histology remain largely research tools, and current clinical management is guided by serum calcium, phosphate, PTH, vitamin D and alkaline phosphatase levels only.

A 10-year longitudinal follow-up study of a U.K. paediatric transplant population to assess for skin cancer.

BACKGROUND: Our earlier study, published in 2004,found no skin cancer in a cohort of paediatric organ transplant recipients (POTRs) 5-16 years post-transplantation. We re-evaluated the same cohort 10 years later. OBJECTIVES: To determine the prevalence of premalignant and malignant skin lesions and identify known risk factors associated with melanocytic naevi in a U.K. paediatric transplant population. METHODS: Ninety-eight POTRs from the original 2004 study were invited to participate in this longitudinal follow-up study. History of sun exposure, demographics and transplantation details were collected using face-to-face interviews, questionnaires and case note reviews. Skin examination was performed for regional count of malignant lesions, benign and atypical naevi. RESULTS: Of the 98 patients involved in the initial study, 45 POTRs (eight kidney, 37 liver), with a median follow-up of 19 years (range 15-26 years), agreed to participate. Neither skin cancer nor premalignant lesions were detected in these patients. When compared with the 2004 cohort, 41 patients in our current cohort had increased numbers of benign naevi (P < 0·001) with 11 patients having ≥ 50 benign naevi. Seventy-one per cent of benign naevi in our 2014 cohort occurred on sun-exposed sites (13% head/neck, 35% arms and 23% legs). Patients who regularly used sunscreen had more benign naevi on their arms (P = 0·008). CONCLUSIONS: Although skin cancer was not observed in our cohort, we identified a significant increase in the number of benign naevi, particularly in those reporting frequent sunburn and sunscreen use.

Nodular glomerulosclerosis in a patient with cystic fibrosis, but not diabetes mellitus: A paediatric case.

BACKGROUND: Nodular glomerulosclerosis is seen in insulin dependent diabetic patients with nephropathy. Kimmelstiel-Wilson nodules on biopsy are considered pathognomonic. Diabetic nephropathy is a spectrum of glomerular and tubular disease which correlates with the duration of the diabetes and the extent of glycaemic control. CASE REPORT: An eleven year old girl with cystic fibrosis was referred with persistent heavy proteinuria. She underwent a renal biopsy which revealed nodular glomerulosclerosis with Kimmelstiel-Wilson-like nodules. Her investigations for diabetes were negative and she was treated with enalapril. CONCLUSION: Nodular glomerulosclerosis in the absence of diabetes and poor glycaemic control have not previously been reported in a paediatric patient. In adult patients without diabetes, smoking, hypertension, hypercholestrolaemia and extrarenal vascular disease have been implicated. The proteinuria decreased after commencement of treatment with enalapril. A recurrence of proteinuria responded to a dose increase.

Distributed expertise: qualitative study of a British network of multidisciplinary teams supporting parents of children with chronic kidney disease.

BACKGROUND: Long-term childhood conditions are often managed by hospital-based multidisciplinary teams (MDTs) of professionals with discipline specific expertise of a condition, in partnership with parents. However, little evidence exists on professional-parent interactions in this context. An exploration of professionals' accounts of the way they individually and collectively teach parents to manage their child's clinical care at home is, therefore, important for meeting parents' needs, informing policy and educating novice professionals. Using chronic kidney disease as an exemplar this paper reports on one aspect of a study of interactions between professionals and parents in a network of 12 children's kidney units in Britain. METHODS: We conducted semi-structured, qualitative interviews with a convenience sample of 112 professionals (clinical-psychologists, dietitians, doctors, nurses, pharmacists, play-workers, therapists and social workers), exploring accounts of their parent-educative activity. We analysed data using framework and the concept of distributed expertise. RESULTS: Four themes emerged that related to the way expertise was distributed within and across teams: (i) recognizing each other's' expertise, (ii) sharing expertise within the MDT, (iii) language interpretation, and (iv) acting as brokers. Two different professional identifications were also seen to co-exist within MDTs, with participants using the term 'we' both as the intra-professional 'we' (relating to the professional identity) when describing expertise within a disciplinary group (for example: 'As dietitians we aim to give tailored advice to optimize children's growth'), and the inter-professional 'we' (a 'team-identification'), when discussing expertise within the team (for example: 'We work as a team and make sure we're all happy with every aspect of their training before they go home'). CONCLUSIONS: This study highlights the dual identifications implicit in 'being professional' in this context (to the team and to one's profession) as well as the unique role that each member of a team contributes to children's care. Our methodology and results have the potential to be transferred to teams managing other conditions.

Dental abnormalities in Schimke immuno-osseous dysplasia.

Described for the first time in 1971, Schimke immuno-osseous dysplasia (SIOD) is an autosomal-recessive multisystem disorder that is caused by bi-allelic mutations of SMARCAL1, which encodes a DNA annealing helicase. To define better the dental anomalies of SIOD, we reviewed the records from SIOD patients with identified bi-allelic SMARCAL1 mutations, and we found that 66.0% had microdontia, hypodontia, or malformed deciduous and permanent molars. Immunohistochemical analyses showed expression of SMARCAL1 in all developing teeth, raising the possibility that the malformations are cell-autonomous consequences of SMARCAL1 deficiency. We also found that stimulation of cultured skin fibroblasts from SIOD patients with the tooth morphogens WNT3A, BMP4, and TGFß1 identified altered transcriptional responses, raising the hypothesis that the dental malformations arise in part from altered responses to developmental morphogens. To the best of our knowledge, this is the first systematic study of the dental anomalies associated with SIOD.

Successful isolated liver transplantation in a child with atypical hemolytic uremic syndrome and a mutation in complement factor H.

A male infant was diagnosed with atypical hemolytic uremic syndrome (aHUS) at the age of 5.5 months. Sequencing of the gene (CFH) encoding complement factor H revealed a heterozygous mutation (c.3644G>A, p.Arg1215Gln). Despite maintenance plasmapheresis he developed recurrent episodes of aHUS and vascular access complications while maintaining stable renal function. At the age of 5 years he received an isolated split liver graft following a previously established protocol using pretransplant plasma exchange (PE) and intratransplant plasma infusion. Graft function, renal function and disease remission are preserved 2 years after transplantation. Preemptive liver transplantation prior to the development of end stage renal disease is a valuable option in the management of aHUS associated with CFH mutations.

A randomized trial to assess the impact of early steroid withdrawal on growth in pediatric renal transplantation: the TWIST study.

Minimizing steroid exposure in pediatric renal transplant recipients can improve linear growth and reduce metabolic disorders. This randomized multicenter study investigated the impact of early steroid withdrawal on mean change in height standard deviation score (SDS) and the safety and efficacy of two immunosuppressive regimens during the first 6 months after transplantation. Children received tacrolimus, MMF, two doses of daclizumab and steroids until day 4 (TAC/MMF/DAC, n=98) or tacrolimus, MMF and standard-dose steroids (TAC/MMF/STR, n=98). Mean change in height SDS was 0.16 +/- 0.32 with TAC/MMF/DAC and 0.03 +/- 0.32 with TAC/MMF/STR. The mean treatment group difference was 0.13 (p < 0.005 [95% CI 0.04-0.22]), 0.21 in prepubertal (p = 0.009 [95% CI 0.05-0.36]) and 0.05 in pubertal children (p = ns). Frequency of biopsy-proven acute rejection was 10.2%, TAC/MMF/DAC, and 7.1%, TAC/MMF/STR. Patient and graft survival and renal function were similar. Significantly greater reductions in total cholesterol and triglycerides but significantly higher incidences of infection and anemia were found with TAC/MMF/DAC (p < 0.05 all comparisons). Early steroid withdrawal significantly aided growth at 6 months more so in prepubertal than pubertal children. This was accompanied by significantly better lipid and glucose metabolism profiles without increases in graft rejection or loss.

Skin surveillance of a U.K. paediatric transplant population.

BACKGROUND: Solid organ transplant recipients are at increased risk of skin cancer. Melanoma is less common than nonmelanoma skin cancer (NMSC) although the relative proportion of melanoma among skin cancers has been shown to be higher in paediatric than adult recipients. Multiple melanocytic naevi and/or atypical naevi may be a risk factor for the development of melanoma. The relationship between naevus counts and phenotypic characteristics, disease-related variables and sun exposure has not been explored in paediatric transplant patients. OBJECTIVES: To determine the prevalence of premalignant and malignant skin lesions and to identify known risk factors associated with benign and atypical melanocytic naevi in a U.K. paediatric transplant population. METHODS: Paediatric (< or = 19 years) renal and liver transplant patients, who were 5 or more years post-transplantation, were reviewed over 12 months. Lifetime history of sun exposure, episodes of sunburn, sunny holidays, sunscreen use, sun bed use, demographic and transplantation details were collected using interview, questionnaire and case note review. A skin examination was performed for regional counts of malignant lesions, benign and atypical naevi. RESULTS: Ninety-eight patients (82 liver, 13 renal, three multiorgan) with a median follow up of 9 years (range 5-16) were reviewed. Neither skin cancer nor premalignant lesions for NMSC were detected in this group. Eighty-five patients had benign naevi (median 6, range 1-57). Clinical risk factors for increased counts of benign naevi included increasing age (P = 0.03), more episodes of sunburn (P = 0.003) and prolonged treatment with cyclosporin (P = 0.009). The presence of atypical naevi in six patients was significantly associated with more episodes of sunburn (P = 0.006) and more transplants (P = 0.04). Other variables including phenotype, skin type, sun exposure, holidays abroad, residence abroad and total duration of immunosuppression did not correlate with benign or atypical naevus counts. CONCLUSIONS: Skin cancer was not observed in paediatric solid organ transplant recipients who were 5-16 years post-transplantation. Both benign and atypical naevus counts were higher in children with frequent episodes of sunburn. As both naevi and sunburn are risk factors for melanoma, we should target fair-skinned transplant recipients with naevi for intensive sun avoidance education. A prospective, longitudinal follow-up study should determine the onset of skin cancer post-transplantation and the significance of benign and atypical naevus counts in this cohort.

A systematic review and economic model of the clinical and cost-effectiveness of immunosuppressive therapy for renal transplantation in children.

OBJECTIVES: To review the clinical and cost-effectiveness of basiliximab, daclizumab, tacrolimus, mycophenolate mofetil (MMF), mycophenolate sodium (MPS) and sirolimus as possible immunosuppressive therapies for renal transplantation in children. DATA SOURCES: Electronic databases were searched up to November 2004. REVIEW METHODS: Data from selected studies were extracted and quality assessed. An economic model [Birmingham Sensitivity Analysis paediatrics (BSAp)] was produced based on an adaptation of a model previously developed for the assessment of the cost-effectiveness of immunosuppressants in adults following renal transplant. RESULTS: For the addition of basiliximab, one unpublished paediatric randomised control trial (RCT), reported that the addition of basiliximab to tacrolimus-based triple therapy (BTAS) failed to significantly improve 6-month biopsy-proven acute rejection (BPAR), graft function, graft loss and all-cause mortality. No significant difference between groups was seen in 6-month or 1-year or longer graft loss, all-cause mortality and side-effects. In a meta-analysis of adult RCTs, the addition of basiliximab to a ciclosporin, azathioprine and steroid regimen (CAS) significantly reduced short-term BPAR. There was no significant difference in short- or long-term graft loss, all-cause mortality or side-effects. One adult RCT was included for the addition of daclizumab to CAS, which reported reduced 1-year BPAR, although no difference between groups was seen in either 1- or 3-year graft loss, all-cause mortality and side-effects. For tacrolimus versus ciclosporin, one unpublished paediatric RCT found that a regimen of tacrolimus, azathioprine and a steroid (TAS) reduced 6-month BPAR and improved graft function [glomerular filtration rate (GFR)] compared with CAS. This improvement in BPAR with tacrolimus was as shown in the meta-analysis of adult RCTs. There was evidence, particularly in children, that in comparison with ciclosporin, tacrolimus may reduce long-term graft loss, although there is no benefit on total mortality. The total level of withdrawal in children was reduced in children receiving tacrolimus. Adult RCTs showed an increase in post-transplant diabetes mellitus with tacrolimus. For MMF versus azathioprine, a meta-analysis of adult RCTs showed MMF [regimen of ciclosporin, MMF and a steroid (CMS)] to reduce 1-year BPAR compared with azathioprine (CAS). There was evidence, particularly in children, that in comparison with azathioprine, tacrolimus may reduce long-term graft loss, although there is no benefit on total mortality. There was an increase in the level of cytomegalovirus infection with MMF, although the overall level of withdrawal due to adverse events was not different to that of azathioprine-treated adults. No study comparing MPS with azathioprine (CAS) was identified. In an adult RCT comparing MMF with MPS, there was no significant difference between groups in 1-year efficacy or side-effects. One unpublished paediatric RCT assessed the addition of sirolimus to CAS. BPAR, graft loss and all-cause mortality were not reported. In two adult RCTs, compared with azathioprine, sirolimus reduced 1-year BPAR, reduced graft function (as assessed by an increased serum creatinine) and increased the level of hyperlipidaemia. No significant differences were seen in other efficacy and side-effect outcomes. On an adult RCT comparing sirolimus with ciclosporin, there were no significant differences between groups in 1-year efficacy or side-effects with the exception of an increased level of hyperlipidaemia with sirolimus substitution. Both the assessment group and drug companies assessed the cost-effectiveness of the newer renal immunosuppressants currently licensed in children using an adaptation (BSAp) of the Birmingham Sensitivity Analysis (BSA) model. This model is based on a 10-year extrapolation of 1-year BPAR results sourced from paediatric RCTs or adult RCTs (where paediatric RCTs were not available). The addition of basiliximab and that of daclizumab to CAS was found to increase quality-adjusted life-years (QALYs) and decreased overall costs, a finding that was robust to sensitivity analyses. The incremental cost-effectiveness ratio (ICER) of replacing ciclosporin with tacrolimus was highly sensitive to the selection of the hazard ratio for graft loss from acute rejection, dialysis costs and the incorporation (or not) of side-effects. The ICERs for tacrolimus versus ciclosporin ranged from about 46,000 pounds/QALY to about 146,000 pounds/QALY. Although sensitive to varying the hazard ratio for graft loss with acute rejection, the ICER for replacing azathioprine with MMF remained in excess of 55,000 pounds/QALY. CONCLUSIONS: In general, compared with a regimen of ciclosporin, azathioprine and steroid, the newer immunosuppressive agents consistently reduced the incidence of short-term biopsy-proven acute rejection. However, evidence of the impact on side-effects, long-term graft loss, compliance and overall health-related quality of life is limited. Cost-effectiveness was estimated based on the relationship between short-term acute rejection levels from RCTs and long-term graft loss. Both the addition of daclizumab and that of basiliximab were found to be dominant strategies, that is, regarding cost savings and increased QALYs. The incremental cost-effectiveness of tacrolimus relative to ciclosporin was highly sensitive to key model parameter values and therefore may well be a cost-effective strategy. The incremental cost-effectiveness of MMF compared with azathioprine, although also sensitive to model parameter, was unattractive. There is a particular need for RCTs to assess the use of MMF, MPS and daclizumab for renal transplantation in children where no such evidence currently exists. Future comparative studies need to report not only on the impact of the newer immunosuppressants on short- and long-term clinical outcomes but also on side-effects, compliance, healthcare resource, costs and health-related quality of life.

A prospective, randomized, multicenter trial of tacrolimus-based therapy with or without basiliximab in pediatric renal transplantation.

In a 6-month, multicenter, randomized, controlled, open-label, parallel-group trial, we investigated the efficacy and safety of adding basiliximab to a standard tacrolimus-based regimen in pediatric renal transplant recipients. Patients < 18 years received tacrolimus/azathioprine/steroids (TAS, n = 93) or tacrolimus/azathioprine/steroids/basiliximab (TAS + B, n = 99). Target tacrolimus levels were 10-20 ng/mL between days 0-21 and 5-15 ng/mL thereafter. Steroid dosing was identical in both groups. Basiliximab was administered at 10 mg (patients < 40 kg) or 20 mg (patients > or = 40 kg) within 4 h of reperfusion; the same dose was repeated on day 4. Biopsy-proven acute rejection rates were 20.4% (TAS) and 19.2% (TAS + B); steroid-resistant acute rejection rates were 3.2% and 3.0%, respectively. Patient survival was 100%; graft survival rates were 95% in both arms. The nature and incidence of adverse events were similar in both arms except toxic nephropathy and abdominal pain, which were significantly higher in the TAS + B arm (14.1% vs. 4.3%; p = 0.03 and 11.1% vs. 2.2%; p = 0.02; respectively). Median serum creatinine concentrations at 6 months were 86 micromol/L in the TAS and 91 micromol/L in the TAS + B arm; glomerular filtration rate was 79.4 and 77.6 (mL/min/1.73 m2), respectively. Adding basiliximab to a tacrolimus-based regimen is safe in pediatric patients, but does not improve clinical efficacy.

Renal function following liver transplantation for unresectable hepatoblastoma.

Combination of cyclosporine (CsA) and tacrolimus immunosuppression post-liver transplantation (LT) and the chemotherapeutic drugs used to treat hepatoblastoma (HB), are nephrotoxic. We aimed to determine the severity and duration of nephrotoxicity in children following LT for unresectable HB. We reviewed all children undergoing LT for unresectable HB at the Liver Unit, Birmingham Children's Hospital, UK, from 1991 to July 2000. Thirty-six children undergoing LT for biliary atresia, matched for age and sex, were selected as controls to compare pre- and post-LT renal function. Renal function was determined by estimation of glomerular filtration rate (eGFR) derived from plasma creatinine using Schwartz's formula. Twelve children with HB (mean age of diagnosis 33 months) who underwent LT (mean age 47 months) and 36 controls (mean age of LT 34 months) were studied. CsA was the main immunosuppressive drug used in each group. The median eGFR before, and at 3, 6, 12, 24 and 36 months after LT in HB group was significantly lower than controls (93 vs. 152, 66 vs. 79, 62 vs. 86, 66 vs. 87, 64 vs. 94, 53 vs. 90 mL/min/1.73 m2, respectively; 0.01 < p < 0.03). The reductions in the median eGFR of both the HB group and controls before and at 36 months after LT were 49 and 41%, respectively. At 36 months after LT, there was a trend for partial recovery of the eGFR in the controls but not in the HB group. Children who underwent LT for unresectable HB had renal dysfunction before transplantation that persisted for 36 months after LT.

Hypertension: a cause of growth impairment.

The effects of high blood pressure on growth are not fully understood and while hypertension may be associated with failure to thrive, hypertension causing failure to thrive in children is poorly documented. We describe four children presenting with failure to thrive due to hypertension consequent to various aetiologies. Control of hypertension with appropriate therapy resulted in improved growth. The exact pathogenesis of failure to thrive in hypertensive children is not known. These cases demonstrate the importance of careful measurement of blood pressure in children with failure to thrive.

Mutation of BSND causes Bartter syndrome with sensorineural deafness and kidney failure.

Antenatal Bartter syndrome (aBS) comprises a heterogeneous group of autosomal recessive salt-losing nephropathies. Identification of three genes that code for renal transporters and channels as responsible for aBS has resulted in new insights into renal salt handling, diuretic action and blood-pressure regulation. A gene locus of a fourth variant of aBS called BSND, which in contrast to the other forms is associated with sensorineural deafness (SND) and renal failure, has been mapped to chromosome 1p. We report here the identification by positional cloning, in a region not covered by the human genome sequencing projects, of a new gene, BSND, as the cause of BSND. We examined ten families with BSND and detected seven different mutations in BSND that probably result in loss of function. In accordance with the phenotype, BSND is expressed in the thin limb and the thick ascending limb of the loop of Henle in the kidney and in the dark cells of the inner ear. The gene encodes a hitherto unknown protein with two putative transmembrane alpha-helices and thus might function as a regulator for ion-transport proteins involved in aBS, or else as a new transporter or channel itself.

ARC syndrome: an expanding range of phenotypes.

AIM: To describe the clinical phenotype in infants with ARC syndrome, the association of arthrogryposis, renal tubular acidosis, and cholestasis. METHODS: The medical records for six patients with ARC syndrome were reviewed, presenting over 10 years to three paediatric referral centres. RESULTS: All patients had the typical pattern of arthrogryposis. Renal Fanconi syndrome was present in all but one patient, who presented with nephrogenic diabetes insipidus. Although all patients had severe cholestasis, serum gamma glutamyltransferase values were normal. Many of our patients showed dysmorphic features or ichthyosis. All had recurrent febrile illnesses, diarrhoea, and failed to thrive. Blood films revealed abnormally large platelets. CONCLUSIONS: ARC syndrome exhibits notable clinical variability and may not be as rare as previously thought. The association of Fanconi syndrome, ichthyosis, dysmorphism, jaundice, and diarrhoea has previously been reported as a separate syndrome: our observations indicate that it is part of the ARC spectrum.

Human hypertension caused by mutations in WNK kinases.

Hypertension is a major public health problem of largely unknown cause. Here, we identify two genes causing pseudohypoaldosteronism type II, a Mendelian trait featuring hypertension, increased renal salt reabsorption, and impaired K+ and H+ excretion. Both genes encode members of the WNK family of serine-threonine kinases. Disease-causing mutations in WNK1 are large intronic deletions that increase WNK1 expression. The mutations in WNK4 are missense, which cluster in a short, highly conserved segment of the encoded protein. Both proteins localize to the distal nephron, a kidney segment involved in salt, K+, and pH homeostasis. WNK1 is cytoplasmic, whereas WNK4 localizes to tight junctions. The WNK kinases and their associated signaling pathway(s) may offer new targets for the development of antihypertensive drugs.

Mitochondrial cytopathy presenting with focal segmental glomerulosclerosis, hypoparathyroidism, sensorineural deafness, and progressive neurological disease.

A 6 year old boy who presented with steroid unresponsive nephrotic syndrome is reported. He was found to have focal segmental glomerulosclerosis and associated hypoparathyroidism and sensorineural deafness. The child progressed to end stage renal failure and was successfully managed by dialysis and cadaveric renal transplantation. He later developed progressive neurological deterioration and mitochondrial myopathy and neuropathy was diagnosed.