Simon Waller

Eculizumab in atypical haemolytic–uraemic syndrome allows cessation of plasma exchange and dialysis

Disorders in complement regulation are a major cause of atypical haemolytic–uraemic syndrome (aHUS). Eculizumab, a monoclonal antibody targeting complement C5 and blocking the terminal complement cascade, should theoretically be useful in this disease, particularly when associated with specific complement pathway anomalies such as Factor H deficiency. Eculizumab is emerging as an effective treatment for post-transplant aHUS recurrence and may have a role in treating de novo aHUS, halting the haemolytic process. In this case report, we describe the fourth case of aHUS treated with eculizumab. In our patient, with a known complement Factor H mutation, not only has the disease process become quiescent but also this therapy has led to significantly improved renal function so that dialysis is no longer necessary.

Investigating FGF-23 concentrations and its relationship with declining renal function in paediatric patients with pre-dialysis CKD Stages 3–5

BACKGROUND The aims of our study were to investigate (i) the prevalence of elevated fibroblast growth factor-23 (FGF-23), (ii) the relationship between FGF-23 concentrations and level of renal dysfunction and (iii) the main determinants of elevation of FGF-23 concentration in children with pre-dialysis chronic kidney disease (CKD) Stages 3-5. METHODS In this single-centre prospective observational study, 71 children with pre-dialysis CKD Stages 3-5, aged 11.9 ± 3.1 years, had FGF-23 levels measured. Anthropometry and routine laboratory investigations were measured. RESULTS Fourteen (19.7%) patients had normal FGF-23 concentrations defined as < 50 ng/L. FGF-23 [median (interquartile range)] concentrations were 78.7 (55.6-137.6) ng/L and following log transformation normalized data with log FGF-23 [mean (SD)] values of 1.96 ± 0.4 ng/L. Log FGF-23 concentrations had a negative reciprocal relationship with estimated glomerular filtration rate (eGFR) (P < 0.0001) and 1,25 vitamin D3 levels (P = 0.01) and a positive relationship with phosphate (P = 0.03) and percent fractional excretion of phosphate (P = 0.01) but not with log-intact parathyroid hormone (PTH) (P = 0.22). Multiple linear regression demonstrated a strong relationship between log FGF-23 and eGFR only. CONCLUSIONS Elevated FGF-23 concentrations were observed in the majority of a carefully managed cohort of children with non-dialysis CKD with a dominant effect on FGF-23 concentrations with glomerular filtration rate (GFR). These data allow the potential confounding effects of PTH and phosphate elevation with declining GFR to be removed, leaving a clearer picture of the FGF-23-GFR relationship.

The demographic characteristics of children with chronic kidney disease stages 3–5 in South East England over a 5-year period

Objective To analyse the demographics of children with moderate to severe chronic kidney disease (CKD) stages 3–5 over a 5-year period for the population of South East England. Methods Retrospective study of all children <18 years of age with estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 managed at Evelina Childrens Hospital, London from 2005 to 2009. eGFR was estimated using the Schwartz formula, and stages of CKD were defined using Kidney Disease Outcome Quality Initiative criteria. We excluded all patients with a functioning kidney transplant. Results There were 293 children (58% male) with a median (IQR) age of 6.7 (2.3, 12.1) years; 288 were aged <16 years and five 16–18 years at first presentation. The mean incidence and prevalence of children <16 years with CKD stage 3–5 during the 5-year study period was 17.5 and 90.0 per million age-related population (pmarp), respectively. There was a marked increase in incidence and prevalence over the 5 years (incidence 8.4 to 25.2 pmarp; prevalence 79.5 to 104.7 pmarp). There was an initial peak in children presenting under 2 years of age (48/141, 34%) due to congenital renal disease, and a second peak in the 12–15.9-year age group (32/141, 23%) due to glomerulonephritides. Forty-five children (15%) were transplanted, and 22 (8%) transitioned to adult care. There were seven deaths giving a death rate of 0.84 per 100 patient-years. Conclusions We observed a steady increase in the incidence and prevalence of children with CKD stage 3–5. As a result of improved management, the majority of children with CKD will proceed to kidney transplantation, transition to adult nephrology services, and continue to require lifelong medical care.

An institutional experience of pre-emptive liver transplantation for pediatric primary hyperoxaluria type 1

Primary hyperoxaluria type 1 (PH1) is an inherited metabolic disease that culminates in ESRF. Pre‐emptive liver transplantation (pLTx) treats the metabolic defect and avoids the need for kidney transplantation (KTx). An institutional experience of pediatric PH1 LTx is reported and compared to the literature. Between 2004 and 2015, eight children underwent pLTx for PH1. Three underwent pLTx with a median GFR of 40 (30–46) mL/min/1.73 m2 and five underwent sequential combined liver‐kidney transplantation (cLKTx); all were on RRT at the time of cLKTx. In one case of pLTx, KTx was required eight and a half yr later. pLTx was performed in older (median 8 vs. 2 yr) and larger children (median 27 vs. 7.75 kg) that had a milder PH1 phenotype. In pediatric PH1, pLTx, ideally, should be performed before renal and extrarenal systemic oxalosis complications have occurred, and pLTx can be used “early” or “late.” Early is when renal function is preserved with the aim to avoid renal replacement. However, in late (GFR < 30 mL/min/1.73 m2), the aim is to stabilize renal function and delay the need for KTx. Ultimately, transplant strategy depends on PH1 phenotype, disease stage, child size, and organ availability.

Parathyroid hormone and growth in chronic kidney disease

Growth failure is common in children with chronic kidney disease, and successful treatment is a major challenge in the management of these children. The aetiology is multi-factorial with “chronic kidney disease–metabolic bone disorder” being a key component that is particularly difficult to manage. Parathyroid hormone is at the centre of this mineral imbalance, consequent skeletal disease and, ultimately, growth failure. When other aetiologies are treated, good growth can be achieved throughout the course of the disease when parathyroid hormone (PTH) levels are in the normal range or slightly elevated. A direct correlation between PTH levels and growth has not been convincingly established, and the direct effect of PTH on growth has not been adequately described; furthermore, direct actions of PTH on the growth plate are unproven. The effects of PTH on growth stem from the pivotal role that PTH plays in the development of renal osteodystrophy. In severe secondary hyperparathyroidism, the growth plate is altered and growth is affected. At the other end of the spectrum, with an over-suppressed parathyroid gland, the rate of bone turnover and remodelling is markedly diminished, and some data suggest this is associated with poor growth. Most of the data available suggests that avoiding the development of significant bone disease through the strict control of PTH levels permits good growth. Absolute optimal ranges for PTH that maximise growth or minimise growth failure are not yet established.

Collapsing glomerulopathy in a girl with systemic lupus erythematosus

Collapsing glomerulopathy has increasingly been recognised in patients with conditions other than HIV. The non-HIV form of collapsing glomerulopathy generally shows little response to standard therapies. We describe a 12-year-old girl with a pre-existing diagnosis of systemic lupus erythematosus presenting with renal failure. A renal biopsy gave the histological diagnosis of collapsing glomerulopathy with evidence of “full-house” immunostaining. We propose collapsing glomerulopathy in her case, as no other cause was found was secondary to systemic lupus erythematosus. The immunophenotype of her podocytes suggested a partial de-differentiation that might have been important in her partial response to immunosuppression.

A single-centre retrospective study of the safety and efficacy of mycophenolate mofetil in children and adolescents with nephrotic syndrome.

Background The aim of the study was to investigate the efficacy and side effect profile of mycophenolate mofetil (MMF) therapy in children with nephrotic syndrome (NS). Methods A retrospective case note review was performed on all patients with NS who were commenced on MMF between 1 January 2000 and 31 December 2009 and were followed up for a minimum of 1 year. Results The sample size was 73 patients. The duration of follow-up was for a median of 3.2 years, interquartile range (IQR) (1.7–4.7 years). The median age at diagnosis was 3.2 years, IQR (2.3–5.7 years). The median age of MMF commencement was 11 years, IQR (7.9–13.6 years). There were more boys (67%) than girls. The majority were Caucasian (77%), with 18% Asian 4%, Black Africans and 1% other ethnicities. At initial diagnosis, 61 (84%) were steroid sensitive, 9 (12%) steroid resistant, 3 (4%) steroid dependent (SD). Forty-five (74%) of the 61 steroid-sensitive patients became SD, 4 (7%) of them became steroid resistant, 1 (1%) remained steroid-sensitive and 11 (18%) became frequent relapsers. As to the previous use of second-line immunosuppressants, none were used in 5 (7%) patients, one agent in 17 (23%), two in 27 (37%) and three or more agents were used in 23 (32%) patients. MMF was effective in 45 (62%) patients. Of these, 38 (52%) of them were in remission for >2 years; and in 7 (10%) MMF worked for 1 to 2 years (MMF therapy electively stopped/ongoing). MMF therapy allowed 27 (37%) patients to wean steroids completely and 8 (11%) to achieve complete steroid and immunosuppressant withdrawal. A further 8 (11%) had steroids partially weaned. MMF failures were seen in 13 (18%) within the first year and 5 (7%) in the second year. MMF was stopped due to side effects in 4 (6%) and non-compliance in 4 (6%). The majority of patients had no side effects [51 (70%)]. Seven (9%) had gastrointestinal side effects (diarrhoea/abdominal pain); 5 (7%) had immunological side effects (leucopenia/infections); 3 (4%) had both immunological and gastrointestinal side effects; and 2 (3%) suffered arthralgia. Conclusions MMF is well tolerated and effective as a second-line agent in treating steroid-sensitive NS. The drug permitted prolonged remission and steroid weaning or other second-line agent withdrawal in a majority of cases.

The first images of varicella lesions in the bladder

A 3-year-old boy with a recurrent prolapsing vesicostomy presented with multiple lesions over his prolapsed bladder mucosa figure 1. He had recently contracted varicella, and had developed …

Poststreptococcal Acute Glomerulonephritis and Dense Deposit Disease After Pediatric Liver Transplantation

Poststreptococcal acute glomerulonephritis (PSAGN), the most common form of acute glomerulonephritis in children, is usually a mild selflimiting disease (1). Dense deposit disease (DDD) is a rare and progressive disease (2). We describe the first case of PSAGN with associated acute renal failure and DDD in a child who had received a liver transplantation. An 11-year-old boy who received a liver transplantation at the age of 31 months for biliary atresia and unsuccessful Kasai portoenterostomy was admitted to the hospital while receiving low-dose prednisolone (1 mg/ day) and tacrolimus (predose levels between 2 and 3 g/L) because of a 3-day history of fever, macroscopic hematuria, and vomiting. Renal function routinely monitored after transplantation for signs of tacrolimus nephrotoxicity had been always normal. Two weeks before the admission, he had an upper respiratory infection with fever and an erythematous skin rash; the symptoms resolved over 4 days without any treatment. On admission, he was febrile (38.1°C), pale, and dehydrated. There was no periorbital or peripheral edema, and he was normotensive. Laboratory results (Table 1) demonstrate renal dysfunction, moderate proteinuria, and hematuria. Liver graft function was normal, and C reactive protein level was 13.8 mg/L (normal value 5). Tacrolimus serum level was 2.1 g/L. Antistreptolysin-O titer was 600 IU/mL (normal value 100 IU/mL), and anti-DNAse B level was 3000 U/mL (normal value 170 U/mL). Blood, urine, and throat cultures grew no pathogens. Nonorganspecific autoantibodies were negative. The abdominal ultrasound scan demonstrated bilateral bright kidneys. The patient was rehydrated and treated with intravenous antibiotics (piperacillin/tazobactam). Within 24 hr, he became oliguric prompting transfer to the renal unit for consideration of renal replacement therapy. The patient was treated with intravenous pulsed methylprednisolone (300 mg/m for 3 days) followed by high-dose prednisolone (60 mg/m daily). He received two sessions of hemodialysis, and subsequently, his renal function began to improve, although the proteinuria persisted. A renal biopsy specimen showed light microscopy appearances in keeping with PSAGN (Fig. 1A–D). Electron microscopy of the two glomeruli present in the tissue submitted in gluteraldehyde showed features pathognomonic of DDD (Fig. 1E–G). Therefore, the prednisolone tapering regimen was slowed down; at 7 months postpresentation, he remains on 35 mg prednisolone alternate days and 7.5 mg lisinopril daily. His latest results demonstrate a normal renal function and resolution of the proteinuria, although microscopic hematuria persists (Table 1). Investigations of the complement pathway were normal; C3 nephritic factor was absent, complement factor H (CFH) level was normal, and the CFH mutational analysis was negative. On ophthalmologic examination, retinal abnormalities were not found. The pathogenesis of PSAGN is not completely understood. Recent investigations assign a key role to the formation and in situ deposition of circulating immune complexes, triggering a variety of immunologic responses (3). To date, PSAGN and postbacterial glomerulonephritis have not been reported after liver or bone marrow transplantation, whereas only a few cases of patients with renal transplant have been described (4, 5). Long-term immunosuppression with calcineurin inhibitors affects predominantly T-cell function and may affect antibody production (6), but effects on immune complex formation, believed to play a key pathogenic role in PSAGN, are unknown. This case demonstrates that formation of immune complexes is possible in immunosuppressed children, despite relatively low levels of immunosuppression. In our patient, PSAGN had a severe clinical course requiring hemodialysis. Similar clinical courses have been reported in the renal transplant recipients (4, 5), suggesting that the immunosuppression may influence the severity of PSAGN. In patients who develop PSAGN after renal transplant, there is particular concern as the immunologic perturbations of PSAGN, including abnormal production of antibodies, cytokines, and growth factors, could disrupt the previous immunologic balance and induce graft rejection (4). Thus, previous case reports have suggested that the renal transplant patients should receive aggressive therapy with high-dose corticosteroids; whether this therapy modifies the natural history of the PSAGN, prevents renal graft rejection or both, remains speculative (4). Whether in our patient the chronic immunosuppression played a role in TABLE 1. Laboratory tests on admission and 7 mo after the clinical onset