Management of bone disease in cystinosis: Statement from an international conference.

Cystinosis is an autosomal recessive storage disease due to impaired transport of cystine out of lysosomes. Since the accumulation of intracellular cystine affects all organs and tissues, the management of cystinosis requires a specialized multidisciplinary team consisting of pediatricians, nephrologists, nutritionists, ophthalmologists, endocrinologists, neurologists' geneticists, and orthopedic surgeons. Treatment with cysteamine can delay or prevent most clinical manifestations of cystinosis, except the renal Fanconi syndrome. Virtually all individuals with classical, nephropathic cystinosis suffer from cystinosis metabolic bone disease (CMBD), related to the renal Fanconi syndrome in infancy and progressive chronic kidney disease (CKD) later in life. Manifestations of CMBD include hypophosphatemic rickets in infancy, and renal osteodystrophy associated with CKD resulting in bone deformities, osteomalacia, osteoporosis, fractures, and short stature. Assessment of CMBD involves monitoring growth, leg deformities, blood levels of phosphate, electrolytes, bicarbonate, calcium, and alkaline phosphatase, periodically obtaining bone radiographs, determining levels of critical hormones and vitamins, such as thyroid hormone, parathyroid hormone, 25(OH) vitamin D, and testosterone in males, and surveillance for nonrenal complications of cystinosis such as myopathy. Treatment includes replacement of urinary losses, cystine depletion with oral cysteamine, vitamin D, hormone replacement, physical therapy, and corrective orthopedic surgery. The recommendations in this article came from an expert meeting on CMBD that took place in Salzburg, Austria, in December 2016.

Urinary tract effects of HPSE2 mutations.

Urofacial syndrome (UFS) is an autosomal recessive congenital disease featuring grimacing and incomplete bladder emptying. Mutations of HPSE2, encoding heparanase 2, a heparanase 1 inhibitor, occur in UFS, but knowledge about the HPSE2 mutation spectrum is limited. Here, seven UFS kindreds with HPSE2 mutations are presented, including one with deleted asparagine 254, suggesting a role for this amino acid, which is conserved in vertebrate orthologs. HPSE2 mutations were absent in 23 non-neurogenic neurogenic bladder probands and, of 439 families with nonsyndromic vesicoureteric reflux, only one carried a putative pathogenic HPSE2 variant. Homozygous Hpse2 mutant mouse bladders contained urine more often than did wild-type organs, phenocopying human UFS. Pelvic ganglia neural cell bodies contained heparanase 1, heparanase 2, and leucine-rich repeats and immunoglobulin-like domains-2 (LRIG2), which is mutated in certain UFS families. In conclusion, heparanase 2 is an autonomic neural protein implicated in bladder emptying, but HPSE2 variants are uncommon in urinary diseases resembling UFS.

LRIG2 mutations cause urofacial syndrome.

Urofacial syndrome (UFS) (or Ochoa syndrome) is an autosomal-recessive disease characterized by congenital urinary bladder dysfunction, associated with a significant risk of kidney failure, and an abnormal facial expression upon smiling, laughing, and crying. We report that a subset of UFS-affected individuals have biallelic mutations in LRIG2, encoding leucine-rich repeats and immunoglobulin-like domains 2, a protein implicated in neural cell signaling and tumorigenesis. Importantly, we have demonstrated that rare variants in LRIG2 might be relevant to nonsyndromic bladder disease. We have previously shown that UFS is also caused by mutations in HPSE2, encoding heparanase-2. LRIG2 and heparanase-2 were immunodetected in nerve fascicles growing between muscle bundles within the human fetal bladder, directly implicating both molecules in neural development in the lower urinary tract.

Demographics of blood pressure and hypertension in children on renal replacement therapy in Europe.

Hypertension is a well-known complication in children on renal replacement therapy and an important risk factor for cardiovascular disease in later life. In order to define the prevalence of and risk factors for hypertension among children, we enrolled 3337 pediatric patients from 15 countries in the ESPN/ERA-EDTA Registry of whom 464 were on hemodialysis, 851 on peritoneal dialysis, and 2023 had received a renal allograft. Hypertension was defined as either systolic or diastolic blood pressures in the 95th percentile or greater for age, height, and gender or use of antihypertensive medication. Analyses were adjusted for age, gender, duration, and modality of renal replacement therapy. In 10 countries in which information on the use of antihypertensive medication was available, hypertension was present in over two-thirds of hemodialysis, peritoneal dialysis, or transplant patients. Blood pressure values above the 95th percentile were significantly more prevalent in very young patients (under 3 years) compared to 13- to 17-year olds (odds ratio 2.47), during the first year compared to over 5 years of renal replacement therapy (odds ratio 1.80), and in patients on hemodialysis compared to transplant recipients or those on peritoneal dialysis (odds ratios of 2.48 and 1.59, respectively). Over time, mean blood pressures decreased in both hemodialysis and transplant patients, but not in peritoneal dialysis patients. Hence, our findings highlight the extent of the problem of hypertension in children with end-stage renal disease in Europe.

Improvement in the renal prognosis in nephropathic cystinosis.

BACKGROUND AND OBJECTIVES: Nephropathic cystinosis (NC) is an autosomal recessive disorder occurring in one to two per 100,000 newborns. Because of the rarity of NC, long-term outcome data are scarce. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: 245 NC patients from 18 countries provided data to the ESPN/ERA-EDTA registry. We matched NC patients on renal replacement therapy (RRT) to non-NC children on RRT. RESULTS: Between 1979 and 2008, mean age at the start of RRT among NC children increased by 0.15 year per calendar year (95% confidence interval, 0.10 to 0.21) from 8.8 to 12.7 years, whereas we did not observe this in non-NC children. Five-year survival after the start of RRT improved in NC patients from 86.1% (before 1990) to 100% (since 2000) as compared with the control population (89.6% and 94.0%). NC patients received a renal allograft more often (relative risk, 1.09; 95% confidence interval, 1.00 to 1.17) as compared with matched RRT children, and 5-year graft survival was better (94.0% versus 84.0%). NC dialysis patients were less often hypertensive than non-NC children matched for age, country, and dialysis modality (42.7% versus 51.7%) and had lower parathyroid hormone levels (median, 56 versus 140 pg/ml). Although height at start of RRT slightly improved during the past decade, children with NC remained significantly shorter than non-NC children at the start of RRT. CONCLUSIONS: We demonstrated improved survival of the renal function as well as better patient and graft survival after the start of RRT in a large European cohort of NC patients over the last two decades.

Antithymocyte treatment of steroid-resistant acute rejection in renal transplantation.

To evaluate the outcome of early (ER <3 months) and late (LR >3 months) episodes of corticosteroid resistant acute allograft rejection (CRR) treated with anti-thymocyte globulin (ATG) in pediatric renal allograft recipients. Retrospective study of 15 children, mean age 13.2 y, who received ATG for the treatment of biopsy proven CRR over a 15 year period. Seven children received ATG for ER (median 26 days post transplantation) and 8 for LR (median 763 days). There was a significant improvement in the 3 month eGFR (70.3 ml/min/1.73m(2), SD 22.3, p = 0.018) when compared with the value prior to ATG treatment (23.3 ml/min/1.73m(2), SD 10.2) in the ER group. In the LR group (4 DSA positive) there was no improvement in the eGFR at 3 months (42 ml/min/1.73m(2), SD 10.5, p = 0.32) when compared with the value prior to ATG (38 ml/min/1.73 m(2), SD 9.7). At final review, eGFR in the ER group was 72.3 ml/min/1.73m(2) (SD 33) vs. 37.7 ml/min/1.73m(2) (SD 17.9) in the LR group after a mean follow up of 10.4 y and 1.2 y, respectively. ATG therapy in CRR is associated with reversal of rejection and excellent graft outcome in children with ER. The benefits remain uncertain in LR, the etiology of which is multifactorial.

Transition to adult services for children with renal failure: age or ability to cope?

Established renal failure is a manageable but incurable problem. Safely transitioning young people from paediatric to adult services remains a major challenge.

UK Renal Registry 12th Annual Report (December 2009): chapter 14: demography of the UK paediatric renal replacement therapy population in 2008.

AIMS: To describe the demographics of the paediatric RRT population in the UK and analyse changes in demographics with time. METHODS: Extraction and analysis of data from the UK Paediatric Renal Registry and the UK Renal Registry (UKRR). RESULTS: The UK paediatric established renal failure (ERF) population in December 2008 was 905 patients. The prevalence under the age of 16 years was 56 per million age related population (pmarp) and the incidence 7.4 pmarp. The incidence and prevalence for South Asian patients was much higher than that of the White and Black populations. Renal dysplasia was the most common cause of ERF accounting for 33% of prevalent cases. Diseases with autosomal recessive inheritance were a common cause of ERF in all ethnic groups, 23.5% of prevalent and 18% of incident cases. Whilst the incidence and prevalence of diseases with autosomal recessive inheritance in the South Asian population was 3 times that of the white population, this was not the sole reason for the increased proportion of South Asian patients with ERF, as diseases with no defined inheritance were twice as common in this ethnic group than in White patients. Prevalent mortality stood at 9.4%. Most deaths were in patients presenting with ERF early in life and mortality varied markedly according to the aetiology of ERF. The proportion with new grafts from living donors has steadily risen to 54%. Children from ethnic minority groups were less likely to have an allograft and living donation was less frequent in this population. For those on dialysis, 56% were receiving peritoneal dialysis. This was the main treatment modality for patients under 4 years of age. CONCLUSIONS: The paediatric ERF population continued to expand slowly. Incidence and prevalence rates were stable and similar to other developed nations. The high incidence in patients from ethnic minority groups will lead to a greater proportion of the population being from these groups in time. To maintain the high proportion of engrafted patients it will be necessary to encourage living donation in the ethnic minority population. Case note analysis of the factors involved in mortality would be valuable.

Intravenous methylprednisolone in idiopathic childhood nephrotic syndrome.

The aim of our study was to determine the clinical course of children with idiopathic childhood nephrotic syndrome (ICNS) who received intravenous methylprednisolone (ivMP) following failure to achieve remission with standard oral prednisolone therapy. This study was designed as a retrospective case record review from 1993 to 2007. Sixteen children received ivMP over the 15-year study period, of whom ten responded, achieving clinical remission. The remaining six children with steroid resistant nephrotic syndrome (SRNS) underwent biopsy [four focal segmental glomerulosclerosis (FSGS), two minimal change disease (MCD)]. Three responders developed late secondary steroid resistance (two FSGS, one MCD). At the latest follow-up (mean 6.7 years), three of the ten ivMP responders and none (0/6) of the children with SRNS had heavy proteinuria and chronic kidney disease (CKD) stage 3-5. The remaining 13 children demonstrated significant steroid dependency but had achieved stable remission following cyclophosphamide and/or ciclosporin therapy. The majority of children with ICNS who do not respond to 4 weeks of daily prednisolone therapy will enter remission following three to five doses of ivMP, thus avoiding a renal biopsy at initial presentation. These children are likely to develop steroid dependency, and the majority will require treatment with alkylating agents and/or ciclosporin to maintain remission. The requirement for ivMP in this setting appears to be associated with a risk of developing CKD in the longer term.

UK Renal Registry 11th Annual Report (December 2008): Chapter 13 Demography of the UK paediatric renal replacement therapy population.

AIMS: To describe the demographics of the paediatric RRT population in the UK and analyse changes in demographics with time. METHODS: Extraction and analysis of data from the UK paediatric Renal Registry. RESULTS: The UK paediatric established renal failure (ERF) population in April 2008 was 875 patients. The prevalence under the age of 16 years was 55 per million age related population (pmp) and the incidence 7.92 pmp. The incidence and prevalence for South Asian and Other ethnic groups were 3 times that of the White and Black populations. Renal dysplasia was the most common cause of ERF accounting for 33% of prevalent cases. Diseases with autosomal recessive inheritance were more common in patients from ethnic minority groups. The spectrum of diseases seen has changed over a generation. Overall 5 year survival for children with ERF was 91.8%. Five year survival of infants starting dialysis was just 62%. Transplanted patients accounted for 74% of the current population. The proportion with grafts from living donors has steadily risen to 34%. Children from ethnic minority groups were less likely to have an allograft and living donation was less frequent in this population. For those on dialysis, 57% were receiving peritoneal dialysis. This was the main treatment modality for patients under 4 years of age. CONCLUSIONS: The paediatric ERF population continued to expand slowly. Incidence and prevalence rates were stable and similar to other developed nations. The high incidence in patients from ethnic minority groups will lead to a greater proportion of the population being from these groups in time. To maintain the high proportion of engrafted patients it will be necessary to encourage living donation in the ethnic minority population. The spectrum of diseases seen has already changed over a generation with the treatment of young children with diseases such as congenital nephrosis. The incidence of cystinosis causing ERF was reduced, probably reflecting better early treatment.

Demography of renal disease in childhood.

The demography of renal failure in childhood is examined through an analysis of the UK Renal Registry data on patients in established renal failure (ERF) and studies of chronic kidney disease populations. The predominant cause is renal dysplasia and related conditions. Congenital obstructive uropathy is the third largest group overall and the second in early childhood. Males predominate in both these groups. Antenatal diagnoses are frequently not made despite routine scanning. Those children, who present to nephrology after the age of 3 months without an antenatal diagnosis, progress to ERF later than those diagnosed antenatally. Discrepancies exist between the demography of antenatal diagnoses and those seen postnatally. This is likely to represent the limitations of antenatal ultrasound as a diagnostic screening tool.

Successful renal transplantation in children in the presence of thrombosis of the inferior vena cava.

Thrombosis of the inferior vena cava (IVC) has previously been considered to be a contraindication to renal transplantation in children because of the technical difficulties associated with surgery and the increased risk of graft thrombosis. We report three children with previous IVC thrombosis who underwent renal transplantation at our institution over the last 5 years. The pretransplant imaging of these patients included direct venography or magnetic resonance venography to evaluate venous outflow. Two children (19 kg and 36 kg) received deceased donor renal allografts with no surgical complications or delayed graft function. At the latest follow-up 3.0 and 4.6 years posttransplantation, respectively, they were well, with estimated glomerular filtration rates of 52 and 64 ml/min per 1.73 m(2), respectively. The third child underwent a live-related-donor renal transplant at the age of 4.9 years (weight 13.5 kg). There was primary graft nonfunction. Renal vein thrombosis was noted on postoperative day 12, with subsequent graft loss. Children with previous IVC thrombosis can be successfully transplanted with adult-sized kidneys provided detailed evaluation of the venous drainage has been performed. There is substantial risk of graft thrombosis, and detailed counselling regarding the specific risks of the procedure is essential.

Outcome of Henoch-Schönlein purpura nephritis treated with long-term immunosuppression.

This retrospective study investigated the outcome of 27 children (19 male) with Henoch-Schönlein purpura nephritis (HSN) of International Study of Kidney Disease in Children (ISKDC) grade 3b or higher treated with long-term immunosuppressive therapy in a single centre over a 10-year period. The mean age at presentation was 9.7 years. The median estimated glomerular filtration rate (eGFR) was 91.3 ml/min per 1.73 m(2), with the median urine protein creatinine ratio (UP:UC) 556 mg/mmol. The treatment protocol comprised daily steroids and cyclophosphamide for 8-12 weeks followed by azathioprine and a reducing regimen of alternate-day steroids for 8-12 months. After a mean follow-up period of 7 years following presentation, 37% made a complete recovery, 40.7% had persistent proteinuria, 7.4% had persistent proteinuria and were on antihypertensive therapy and 14.8% had progressed to end-stage kidney failure (ESKF). Children with poor outcome were older at presentation (p 0.005), had more crescents (p 0.015) and had heavier proteinuria 6 months post initial biopsy (p 0.023). All of the four children with ESKF had nephrotic range proteinuria and greater than 50% crescents on initial biopsy. Despite long-term immunosuppression, the majority of children with HSN grade 3b or higher will have persistent renal abnormalities on long-term follow-up.

Accuracy of ultrasonic detection of renal scarring in different centres using DMSA as the gold standard.

BACKGROUND: There is an ongoing debate over the radiological investigations of children with urinary tract infections (UTIs) with some authorities suggesting that ultrasound scan (USS) alone is an accurate tool to diagnose renal parenchymal scarring post-pyelonephritis. All studies on this subject have been performed at paediatric teaching centres whereas most children with UTIs are managed by General Paediatricians in District General Hospitals (DGHs) in the United Kingdom. We wished to identify whether results of scans in DGHs differed from those in teaching centres. METHODS: We looked at all children with a clinical history of UTIs having a DMSA and USS over a one year period in two DGHs and one teaching centre. A total of 476 children's results were reviewed, 297 from the DGHs and 179 from the teaching centre. RESULTS: The cohort had a total of 949 renal units. There were 79 scarred renal units (kidneys) on DMSA (8%) in 72 patients (15%). Just 18 renal units were detected as being scarred on USS (22.8%). Nine of 32 scarred renal units in the teaching centre were detected compared with nine of 47 in the DGHs (P = 0.40). Thirty-nine (49%) of the scarred renal units were in patients >5-years old. Of these 12 (30.7%) were detected on USS, nine of 17 within the teaching centre compared with just three of 22 at the DGHs (P = 0.01). CONCLUSION: Overall only a small percentage of scars are detected on USS. In the over 5-year old group, where USS alone might be preferred, DGHs were significantly worse at detecting scarred kidneys. We conclude that if the detection of renal scars is a prime reason for imaging in children with UTIs, ultrasonography alone is inappropriate at any age and DMSA ought to be the primary investigation.

Percutaneous real-time ultrasound-guided renal biopsy by automated biopsy gun in children: safety and complications.

BACKGROUND: Percutaneous renal biopsy under real time ultrasound guidance is a routine procedure in pediatric nephrology and allows a histological diagnosis to be made in children with evidence of renal disease. METHODS: Retrospective case note review. RESULTS: Over four years 191 renal biopsies were attempted in 116 patients; 186 biopsies were performed successfully: 102 native and 84 renal allografts. 151 renal biopsies were performed under sedation and 34 biopsies were performed under general anesthetic, one biopsy without sedation. Problems during sedation were recorded in 5/151 (3.3%) cases. All patients remained in hospital overnight for observation following the biopsy. Complications were reported in 23/185 (12%) of biopsies. Macroscopic hematuria was recorded in 13/185 (7%), presenting within 6-hours of biopsy, on first void, in 11 patients. Two patients developed macroscopic hematuria four and six days after the procedure. One patient with macroscopic hematuria required a single blood transfusion. Three patients developed urinary retention requiring catheterization for up to 48 hours post-procedure, two of whom also had macroscopic hematuria. Pain post procedure was reported in 7.6% episodes and was reported significantly more often with elective native biopsies. CONCLUSIONS: Renal biopsy can safely be performed as a day care procedure, if patients are observed for six hours instead of 24-hours post biopsy.

Nurse bullying: organizational considerations in the maintenance and perpetration of health care bullying cultures.

AIM: To examine bullying within nursing from a micro-sociological perspective and elucidate interactive mechanisms contributing to its causes and continuation within the nursing profession. BACKGROUND: The paper is part of a doctoral research study into bullying within nursing. It considers issues pertinent to management, and in the role of negotiated interactions within the National Health Service when dealing with bullying problems. The complex dynamics involved can be problematic for management when dealing with bullying, while often managers have been targets of bullying themselves and not infrequently accused of it. Features of bullying activity are explored, along with issues of target and bully awareness, a central feature in bullying negotiations. Issues of awareness and emergence of bullying behaviour have been identified through vignettes and unstructured interviews, and the research has identified complex interactive events in the creation and maintenance of nurse bullying activity. It is hoped that with a clearer understanding of such mechanisms and manifestations that bullying in the workplace can be reduced or eliminated. The paper is of practical use to nurse managers in illuminating such mechanisms and bringing bullying awareness to the fore. Such activity is ultimately damaging to the organization in both cost and time; and significant for professional practice by its impact upon the nurse and their work in supportive and safe environments. It will also to allow managers to consider their own practice and reactions to bullying activity within the profession. CONCLUSIONS: The overall findings from the research point strongly to bullying activity being essentially 'learned behaviour' within the workplace rather than any predominantly psychological deficit within individual perpetrators and targets.

Long-term outcome of meningococcal sepsis-associated acute renal failure.

SETTING: Twenty-one of 209 children admitted to the intensive care unit with meningococcal septicemia developed oliguric acute renal failure necessitating renal replacement therapy. PATIENTS: Twelve survivors underwent renal assessment at a median of 4.2 yrs postpresentation. RESULT: Two had abnormal glomerular filtration rate, proteinuria, and hypertension; one had isolated proteinuria; and one had an isolated renal parenchymal defect on DMSA scan. CONCLUSION: Long-term follow-up of this population is recommended.

Complete necrosis of allograft ureter after cadaveric renal transplantation.

Complete necrosis of a transplant ureter is a rare complication that needs to be considered early in cases of severe graft dysfunction if successful surgical intervention and restoration of graft function is to be achieved. We report on two cases of this complication occurring in children and discuss the surgical management. Surgical exploration of grafts where there is an early sudden decline in function is imperative as routine imaging will not exclude this potentially treatable problem.

Serum leptin and IGF-I during growth hormone treatment in chronic renal failure.

Serum leptin decreases during growth hormone (hGH) treatment and pre-treatment values have been suggested as a predictor of the response to hGH in GH deficiency (GHD) but not in non-GHD syndromes. To investigate whether this holds true in children with chronic renal failure (CRF), we evaluated changes in serum leptin, insulin-like growth factor-I (IGF-I) and height before(b) and during the 1st year (3 months, 6 months, 9 months, 12 months) of hGH treatment (1 IU/kg per week) in 11 children (median age(b) 10.1 years, mean height(b) -2.9 SDS) with CRF. Serum leptin and IGF-I were compared with values from healthy children. Each patient also served as his/her own control, with values during treatment compared with those before treatment. Growth improved in all patients during treatment (mean change(12 m) +7.2 cm, change in height SDS(12 m) +0.5, P=0.001). Weight decreased (median decrease(12 m) 0.3 SDS, P=0.02) but body mass index (BMI) and serum leptin did not change during treatment. Serum IGF-I levels were low before (mean -1.1 SDS) but increased during hGH treatment, the increment being greatest at 10 days (mean increment +1.9 SDS, P<0.0001). Serum leptin(b) did not correlate with change in serum IGF-I(10d), height(12 m) or weight(12 m). Serum IGF-I SDS(b) correlated with height SDS at 12 months ( r=0.80, P=0.006) of hGH treatment. Serum leptin(b) correlated with BMI ( r(s)=0.75, P=0.01). Levels adjusted for BMI did not differ from values in healthy children and did not change during treatment. Despite an IGF-I and growth response during hGH treatment, serum leptin did not change and pre-treatment values did not predict the growth response in these children with CRF.