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Papers by David Milford

Trials, 2014

Background: Relapses of childhood steroid-sensitive nephrotic syndrome (SSNS) are treated with a ... more Background: Relapses of childhood steroid-sensitive nephrotic syndrome (SSNS) are treated with a 4-to 8-week course of high-dose oral prednisolone, which may be associated with significant adverse effects. There is a clear association between upper respiratory tract infection (URTI) and relapse development. Previous studies in developing nations have suggested that introducing a 5-to 7-day course of daily prednisolone during an URTI may prevent a relapse developing and the need for a treatment course of high-dose prednisolone. The aim of PREDNOS 2 is to evaluate the effectiveness of a 6-day course of daily prednisolone therapy during an URTI in reducing the development of a subsequent relapse in a developed nation.

Transplant international : official journal of the European Society for Organ Transplantation, 2013

Biomarker-based post-transplant immune monitoring for the prediction of impending graft rejection... more Biomarker-based post-transplant immune monitoring for the prediction of impending graft rejection requires validation in specific patient populations. Serum of 28 pediatric renal transplant recipients within the framework of a well-controlled prospective randomized trial was analyzed pre- and post-transplant for soluble CD30 (sCD30), a biomarker reflecting mainly T-cell reactivity, and anti-human leukocyte antigen (anti-HLA) antibody reactivity, a biomarker for B-cell activation. A sCD30 concentration ≥40.3 U/ml on day 14 was able to discriminate between patients with or without biopsy-proven acute rejection (BPAR) with a sensitivity of 100% and a specificity of 76%. Six of seven patients (86%) with BPAR showed a sCD30 above this cut-off, whereas only 3/21 patients (14%) without BPAR had a sCD30 above this cut-off (P = 0.004). For pre- and post-transplant anti-HLA class II reactivities by enzyme-linked immunosorbent assay, a cut-off value of 140 optical density was able to discrimin...

Health technology assessment (Winchester, England), 2006

To review the clinical and cost-effectiveness of basiliximab, daclizumab, tacrolimus, mycophenola... more 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. Electronic databases were searched up to November 2004. 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. 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,...

Indian journal of pathology & microbiology, 2002

The histological evolution of Focal Segmental Glomerulosclerosis (FSGS) is poorly documented due ... more The histological evolution of Focal Segmental Glomerulosclerosis (FSGS) is poorly documented due to variation in the time at which the biopsy is taken. We looked at patients presenting with steroid resistant nephrotic syndrome (SRNS) in which the first biopsy was performed within 3 months of presentation. FSGS lesion was demonstrable in 68.5% of cases in the first biopsy. Glomerular size was increased in 86% of patients indicating that is an early event in the course of the disease. The group was heterogenous with respect of mesangial cellularity, mesangial matrix, position of FSGS lesion in the glomeruli, glomerular size, lamina densa thickness and immunofluorescence findings. No association of morphological features was seen permitting subclassification of this group on morphological grounds. Thus, both the FSGS lesion and glomerular enlargement occur early in the evolution of idiopathic FSGS presenting with SRNS.

Nature genetics, 2001

Antenatal Bartter syndrome (aBS) comprises a heterogeneous group of autosomal recessive salt-losi... more 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 ...

Clinical nephrology, 1998

Ibuprofen is being widely used as an antipyretic in children. Recent studies indicate that it is ... more Ibuprofen is being widely used as an antipyretic in children. Recent studies indicate that it is as efficacious and with no significant difference in side-effects when compared to paracetamol. We describe three cases that illustrate that renal complications can occur when ibuprofen is prescribed in the presence of intravascular volume depletion and/or pre-existing renal problems. We discuss the mode of action of ibuprofen and recommend that its use as an antiypretic in children should be avoided in actual or potential intravascular volume contraction and in cases with pre-existing renal problems.

BMJ case reports, 2010

Bilateral facial nerve paralysis is an uncommon presentation and even more so in children. There ... more Bilateral facial nerve paralysis is an uncommon presentation and even more so in children. There are reports of different causes of bilateral facial nerve palsy. It is well-established that hypertension and chickenpox causes unilateral facial paralysis and the importance of checking the blood pressure in children with facial nerve paralysis cannot be stressed enough. The authors report a boy with bilateral facial nerve paralysis in association with hypertension and having recently recovered from chickenpox. The authors review aspects of bilateral facial nerve paralysis as well as hypertension and chickenpox causing facial nerve paralysis.

Toxicology Letters, 1997

The aim of this study was to evaluate the ability of verocytotoxin-1 (VT1), VT1 B chain alone, ri... more The aim of this study was to evaluate the ability of verocytotoxin-1 (VT1), VT1 B chain alone, ricin and a hybrid toxin (RASTA2) consisting of ricin A chain linked to VT1 B chain to inhibit protein synthesis and to induce apoptosis. The lethal effects of the toxins were compared using vero cells (originating from green African monkey kidney tissue). As previously described cell death occurred through apoptosis which was quantified using the diphenylamine assay. DNA fragmentation was seen with VT1 at 10 pg/ml but there was no effect with B chain alone. Fragmentation with ricin was seen at 10 ng/ml and with RASTA2 at 1 ng/ml. Protein synthesis inhibition was measured by [(35)S]methionine incorporation. VT1 had an IC50 of 0.0024 ng/ml, B chain alone was ineffective at inhibiting protein synthesis. Ricin had an IC50 of 0.39 ng/ml and RASTA2 of 1.7 ng/ml. In vero cells the B chain of these toxins does not participate in cell killing.

Pediatric Transplantation, 2013

We present three cases of organ transplantation for atypical haemolytic uraemic syndrome secondar... more We present three cases of organ transplantation for atypical haemolytic uraemic syndrome secondary to complement factor H mutation: one isolated renal transplant; one previously reported isolated liver transplant; and one combined liver and kidney transplant. All three patients were treated prior to the licensing of eculizumab for this condition, and all have had favourable outcomes with maintenance of graft function for years following transplantation. We discuss the evolution of transplantation therapy for aHUS over the last two decades. Transplantation decision-making in aHUS has evolved over this time with expanding knowledge of pathophysiology and genetics, alongside refined plasma exchange and anticoagulation protocols and improved centre experience. Our cases demonstrate how individual patient factors within this heterogeneous condition also underlie transplantation decisions and outcomes. Whilst our cases demonstrate that transplantation in aHUS can be a successful long-term treatment providing good quality of life, worldwide experience has proven that most curative treatment for aHUS strategies represents significant risks. Whether new pharmacotherapies such as eculizumab will alter this risk is yet to be determined.

Toxicology Letters, 1999

Infection with verocytotoxin-producing Escherichia coli causes haemolytic uraemic syndrome (HUS).... more Infection with verocytotoxin-producing Escherichia coli causes haemolytic uraemic syndrome (HUS). Verocytotoxin-1 (VT1) is cytopathic to renal microvascular endothelial cells in culture, supporting the hypothesis that the vasculopathy of HUS is caused directly by the toxic action of VT1 on cells. We provide evidence that VT1 inhibits protein synthesis in primary cultures of glomerular epithelial cells (GE), cortical tubular epithelial cells (CTE) and mesangial cells (MC). Using 100 pg/ml of VT1 we saw a decrease in protein synthesis to 14.3+/-1.9% in vero cells (a primate cell line), 1.7+/-0.3% in GE, 0.9+/-0.4% in CTE and 74.8+/-1.3% in MC at 24 h. The human renal epithelial cells are at least as sensitive as vero cells to the protein synthesis inhibitory effects of VT1 if not more so. Cell viability decreased in all cultures as measured by MTT reduction, neutral red incorporation and lactate dehydrogenase release and followed the same pattern of susceptibility as for protein synthesis inhibition. However, unlike vero cells, death occurred without DNA fragmentation. Cell sensitivity was greatest in cells which bound more VT1.

Kidney international, 2015

Acute kidney injury (AKI) is a common syndrome that is independently associated with increased mo... more Acute kidney injury (AKI) is a common syndrome that is independently associated with increased mortality. A standardized definition is important to facilitate clinical care and research. The definition of AKI has evolved rapidly since 2004, with the introduction of the Risk, Injury, Failure, Loss, and End-stage renal disease (RIFLE), AKI Network (AKIN), and Kidney Disease Improving Global Outcomes (KDIGO) classifications. RIFLE was modified for pediatric use (pRIFLE). They were developed using both evidence and consensus. Small rises in serum creatinine are independently associated with increased mortality, and hence are incorporated into the current definition of AKI. The recent definition from the international KDIGO guideline merged RIFLE and AKIN. Systematic review has found that these definitions do not differ significantly in their performance. Health-care staff caring for children or adults should use standard criteria for AKI, such as the pRIFLE or KDIGO definitions, respect...

Child: Care, Health and Development, 2014

Long-term childhood conditions are often managed by hospital-based multidisciplinary teams of pro... more Long-term childhood conditions are often managed by hospital-based multidisciplinary teams 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.

Trials, 2014

Background: Relapses of childhood steroid-sensitive nephrotic syndrome (SSNS) are treated with a ... more Background: Relapses of childhood steroid-sensitive nephrotic syndrome (SSNS) are treated with a 4-to 8-week course of high-dose oral prednisolone, which may be associated with significant adverse effects. There is a clear association between upper respiratory tract infection (URTI) and relapse development. Previous studies in developing nations have suggested that introducing a 5-to 7-day course of daily prednisolone during an URTI may prevent a relapse developing and the need for a treatment course of high-dose prednisolone. The aim of PREDNOS 2 is to evaluate the effectiveness of a 6-day course of daily prednisolone therapy during an URTI in reducing the development of a subsequent relapse in a developed nation.

Transplantation Proceedings, 2002

Transplantation, 2009

Combined liver kidney transplant (CLKT) is a recognized treatment option for end-stage renal dise... more Combined liver kidney transplant (CLKT) is a recognized treatment option for end-stage renal disease due to primary hyperoxaluria (PH-I) and cystic disorders, yet there is only limited data on posttransplant renal function recovery. The objective of this study was to assess postoperative renal function of children with PH-I (group A) undergoing CLKT and to compare this with a cohort of children (group B) who received CLKT for other indications. Twenty-three patients underwent CLKT between 1994 and 2008 (group A: 9 patients; median age 8.6 [1.6-16.7] years; group B: 14 patients; median age 8.5 [1.9-14.6] years). The median follow-up was 88 (14-112) and 22 (4-109) months. Both groups were transplanted with comparable organs. Eight (8/9) and six (6/14) patients received preoperative renal support in each group, respectively, whereas an equal proportion of them required early postoperative renal support (4/8; 50% and 3/6; 50%, respectively). Glomerular function was significantly different between groups until first year posttransplant (median estimated glomerular filtration rate: groups A vs. B; at pretransplant, 3 mo, 6 mo, and 12 mo posttransplant, respectively; 11.06 vs. 12.61 [P=0.4], 40.78 vs. 75.83 [P=0.03], 42.59 vs. 80.56 [P=0.04] and 53.57 vs. 76.75 [P=0.005]). Overall 1-year survival is 89% versus 90% and 5-year survival is 89% versus 62%, respectively. Children with PH-I receiving CLKT seem to have delayed recovery of renal function compared with polycystic disease, possibly due to mobilization of systemic oxalate. Consideration should be given to earlier or preemptive transplantation for children with PH-I.

Transplantation, 2009

Combined liver and kidney transplantation (CLKT) is a surgical challenge in small children becaus... more Combined liver and kidney transplantation (CLKT) is a surgical challenge in small children because of technical aspects, lack of pediatric donors, and restrictions related to the size of the abdominal cavity. We report outcomes after CLKT in this challenging group of smaller children. A review of prospective data on all children undergoing CLKT at the Birmingham Children's Hospital between 1994 and 2008 was performed. An analysis of perioperative data, complications, and survival in children less than 15 kg was carried out, with figures expressed as median (range) and compared with that of children more than 15 kg. A total of 23 children underwent CLKT (14 male [61%] and age 8.6 [1.6-16.7] years), of which 8 (35%) were less than or equal to 15 kg, median age 2.2 (1.6-5.4) years, weight 11.6 (9.1-14.9) kg, and height 76 (66-95) cm, followed up for a median 26 (12-126) months. Donor details included age 13 (3-40) years, weight 60 (15-78) kg, and height 156 (83-168) cm. The median donor-to-recipient weight ratio was 4.8 compared with 1.7 for larger children. The median waiting time was 291 (48-523) compared with 150 (6-455) days for children more than 15 kg. Four of eight (50%) children received preoperative renal support, when compared with 10 of 16 (62%) children more than 15 kg. The intensive care unit and inpatient stay was 2 (2-22) days and 25 (19-93) days, respectively. Mortality was seen in one of eight because of sepsis and multiorgan failure. When compared with children more than 15 kg, survival figures at 1 and 2 years were 87% versus 93% and 78%, respectively. CLKT in small children results in comparable outcomes despite challenges related to donor-recipient size mismatch and longer waiting times. Consequently, body size/stature should not be a limiting factor for multiorgan transplantation.

Nephron Physiology, 2009

Dent disease is an X-linked renal proximal tubulopathy associated with mutations in CLCN5 (Dent 1... more Dent disease is an X-linked renal proximal tubulopathy associated with mutations in CLCN5 (Dent 1) or OCRL1 (Dent 2). OCRL1 mutations also cause the oculocerebrorenal syndrome of Lowe. Dent patients with normal sequence for CLCN5 were sequenced for mutations in OCRL1. By analyzing these and all other OCRL1 mutations reported, a model relating OCRL1 mutations to the resulting disease (Dent 2 or Lowe's) was developed. Six boys with Dent disease had novel OCRL1 mutations: two missense (R301H, G304E) and four mutations predicted to produce premature termination codons (L56DfsX1, S149X, P161PfsX3, and M170IfsX1). These include one of the original patients reported by Dent and Friedman. Slit lamp examinations revealed early cataracts in only one boy with normal vision. None of these Dent 2 patients had metabolic acidosis; 3 had mild mental retardation. Analysis of all known OCRL1 mutations show that Dent 2 mutations fall into two classes that do not overlap with Lowe mutations. Bioinformatics analyses identified expressed OCRL1 splice variants that help explain the variability of those clinical features that distinguish Dent disease from Lowe syndrome. OCRL1 mutations can cause the renal phenotype of Dent disease, without acidosis or the dramatic eye abnormalities typical of Lowe syndrome. We propose a model to explain the phenotypic variability between Dent 2 and Lowe's based on distinctly different classes of mutations in OCRL1 producing splice variants.

QJM, 1994

In the haemolytic uraemic syndrome (HUS), platelet microthrombi and deposition of fibrin in glome... more In the haemolytic uraemic syndrome (HUS), platelet microthrombi and deposition of fibrin in glomeruli may contribute to the development of renal failure. The balance of procoagulant and fibrinolytic activities in the renal vasculature may therefore have an important role. We measured plasminogen-activator inhibitor (PAI) activity in the plasma of 81 children with diarrhoea-associated (D+) HUS, and found elevated PAI activity in many patients. When we categorized patients by need for dialysis, only the dialysed group had significantly higher levels of activity, compared with a group of normal controls. We also compared PAI activity with patient outcome after one year, and found that those with a poor outcome had significantly higher PAI activity than those with a good outcome. We suggest that plasma PAI activity may be an acute marker for dialysis requirement in HUS, and may have prognostic value for long-term outcome. The possible role of PAI in the pathogenesis of HUS requires further investigation.

Postgraduate Medical Journal, 2001

A 6 year old boy who presented with steroid unresponsive nephrotic syndrome is reported. He was f... more 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. (Postgrad Med J 2001;77:523-526)

Trials, 2014

Background: Relapses of childhood steroid-sensitive nephrotic syndrome (SSNS) are treated with a ... more Background: Relapses of childhood steroid-sensitive nephrotic syndrome (SSNS) are treated with a 4-to 8-week course of high-dose oral prednisolone, which may be associated with significant adverse effects. There is a clear association between upper respiratory tract infection (URTI) and relapse development. Previous studies in developing nations have suggested that introducing a 5-to 7-day course of daily prednisolone during an URTI may prevent a relapse developing and the need for a treatment course of high-dose prednisolone. The aim of PREDNOS 2 is to evaluate the effectiveness of a 6-day course of daily prednisolone therapy during an URTI in reducing the development of a subsequent relapse in a developed nation.

Transplant international : official journal of the European Society for Organ Transplantation, 2013

Biomarker-based post-transplant immune monitoring for the prediction of impending graft rejection... more Biomarker-based post-transplant immune monitoring for the prediction of impending graft rejection requires validation in specific patient populations. Serum of 28 pediatric renal transplant recipients within the framework of a well-controlled prospective randomized trial was analyzed pre- and post-transplant for soluble CD30 (sCD30), a biomarker reflecting mainly T-cell reactivity, and anti-human leukocyte antigen (anti-HLA) antibody reactivity, a biomarker for B-cell activation. A sCD30 concentration ≥40.3 U/ml on day 14 was able to discriminate between patients with or without biopsy-proven acute rejection (BPAR) with a sensitivity of 100% and a specificity of 76%. Six of seven patients (86%) with BPAR showed a sCD30 above this cut-off, whereas only 3/21 patients (14%) without BPAR had a sCD30 above this cut-off (P = 0.004). For pre- and post-transplant anti-HLA class II reactivities by enzyme-linked immunosorbent assay, a cut-off value of 140 optical density was able to discrimin...

Health technology assessment (Winchester, England), 2006

To review the clinical and cost-effectiveness of basiliximab, daclizumab, tacrolimus, mycophenola... more 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. Electronic databases were searched up to November 2004. 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. 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,...

Indian journal of pathology & microbiology, 2002

The histological evolution of Focal Segmental Glomerulosclerosis (FSGS) is poorly documented due ... more The histological evolution of Focal Segmental Glomerulosclerosis (FSGS) is poorly documented due to variation in the time at which the biopsy is taken. We looked at patients presenting with steroid resistant nephrotic syndrome (SRNS) in which the first biopsy was performed within 3 months of presentation. FSGS lesion was demonstrable in 68.5% of cases in the first biopsy. Glomerular size was increased in 86% of patients indicating that is an early event in the course of the disease. The group was heterogenous with respect of mesangial cellularity, mesangial matrix, position of FSGS lesion in the glomeruli, glomerular size, lamina densa thickness and immunofluorescence findings. No association of morphological features was seen permitting subclassification of this group on morphological grounds. Thus, both the FSGS lesion and glomerular enlargement occur early in the evolution of idiopathic FSGS presenting with SRNS.

Nature genetics, 2001

Antenatal Bartter syndrome (aBS) comprises a heterogeneous group of autosomal recessive salt-losi... more 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 ...

Clinical nephrology, 1998

Ibuprofen is being widely used as an antipyretic in children. Recent studies indicate that it is ... more Ibuprofen is being widely used as an antipyretic in children. Recent studies indicate that it is as efficacious and with no significant difference in side-effects when compared to paracetamol. We describe three cases that illustrate that renal complications can occur when ibuprofen is prescribed in the presence of intravascular volume depletion and/or pre-existing renal problems. We discuss the mode of action of ibuprofen and recommend that its use as an antiypretic in children should be avoided in actual or potential intravascular volume contraction and in cases with pre-existing renal problems.

BMJ case reports, 2010

Bilateral facial nerve paralysis is an uncommon presentation and even more so in children. There ... more Bilateral facial nerve paralysis is an uncommon presentation and even more so in children. There are reports of different causes of bilateral facial nerve palsy. It is well-established that hypertension and chickenpox causes unilateral facial paralysis and the importance of checking the blood pressure in children with facial nerve paralysis cannot be stressed enough. The authors report a boy with bilateral facial nerve paralysis in association with hypertension and having recently recovered from chickenpox. The authors review aspects of bilateral facial nerve paralysis as well as hypertension and chickenpox causing facial nerve paralysis.

Toxicology Letters, 1997

The aim of this study was to evaluate the ability of verocytotoxin-1 (VT1), VT1 B chain alone, ri... more The aim of this study was to evaluate the ability of verocytotoxin-1 (VT1), VT1 B chain alone, ricin and a hybrid toxin (RASTA2) consisting of ricin A chain linked to VT1 B chain to inhibit protein synthesis and to induce apoptosis. The lethal effects of the toxins were compared using vero cells (originating from green African monkey kidney tissue). As previously described cell death occurred through apoptosis which was quantified using the diphenylamine assay. DNA fragmentation was seen with VT1 at 10 pg/ml but there was no effect with B chain alone. Fragmentation with ricin was seen at 10 ng/ml and with RASTA2 at 1 ng/ml. Protein synthesis inhibition was measured by [(35)S]methionine incorporation. VT1 had an IC50 of 0.0024 ng/ml, B chain alone was ineffective at inhibiting protein synthesis. Ricin had an IC50 of 0.39 ng/ml and RASTA2 of 1.7 ng/ml. In vero cells the B chain of these toxins does not participate in cell killing.

Pediatric Transplantation, 2013

We present three cases of organ transplantation for atypical haemolytic uraemic syndrome secondar... more We present three cases of organ transplantation for atypical haemolytic uraemic syndrome secondary to complement factor H mutation: one isolated renal transplant; one previously reported isolated liver transplant; and one combined liver and kidney transplant. All three patients were treated prior to the licensing of eculizumab for this condition, and all have had favourable outcomes with maintenance of graft function for years following transplantation. We discuss the evolution of transplantation therapy for aHUS over the last two decades. Transplantation decision-making in aHUS has evolved over this time with expanding knowledge of pathophysiology and genetics, alongside refined plasma exchange and anticoagulation protocols and improved centre experience. Our cases demonstrate how individual patient factors within this heterogeneous condition also underlie transplantation decisions and outcomes. Whilst our cases demonstrate that transplantation in aHUS can be a successful long-term treatment providing good quality of life, worldwide experience has proven that most curative treatment for aHUS strategies represents significant risks. Whether new pharmacotherapies such as eculizumab will alter this risk is yet to be determined.

Toxicology Letters, 1999

Infection with verocytotoxin-producing Escherichia coli causes haemolytic uraemic syndrome (HUS).... more Infection with verocytotoxin-producing Escherichia coli causes haemolytic uraemic syndrome (HUS). Verocytotoxin-1 (VT1) is cytopathic to renal microvascular endothelial cells in culture, supporting the hypothesis that the vasculopathy of HUS is caused directly by the toxic action of VT1 on cells. We provide evidence that VT1 inhibits protein synthesis in primary cultures of glomerular epithelial cells (GE), cortical tubular epithelial cells (CTE) and mesangial cells (MC). Using 100 pg/ml of VT1 we saw a decrease in protein synthesis to 14.3+/-1.9% in vero cells (a primate cell line), 1.7+/-0.3% in GE, 0.9+/-0.4% in CTE and 74.8+/-1.3% in MC at 24 h. The human renal epithelial cells are at least as sensitive as vero cells to the protein synthesis inhibitory effects of VT1 if not more so. Cell viability decreased in all cultures as measured by MTT reduction, neutral red incorporation and lactate dehydrogenase release and followed the same pattern of susceptibility as for protein synthesis inhibition. However, unlike vero cells, death occurred without DNA fragmentation. Cell sensitivity was greatest in cells which bound more VT1.

Kidney international, 2015

Acute kidney injury (AKI) is a common syndrome that is independently associated with increased mo... more Acute kidney injury (AKI) is a common syndrome that is independently associated with increased mortality. A standardized definition is important to facilitate clinical care and research. The definition of AKI has evolved rapidly since 2004, with the introduction of the Risk, Injury, Failure, Loss, and End-stage renal disease (RIFLE), AKI Network (AKIN), and Kidney Disease Improving Global Outcomes (KDIGO) classifications. RIFLE was modified for pediatric use (pRIFLE). They were developed using both evidence and consensus. Small rises in serum creatinine are independently associated with increased mortality, and hence are incorporated into the current definition of AKI. The recent definition from the international KDIGO guideline merged RIFLE and AKIN. Systematic review has found that these definitions do not differ significantly in their performance. Health-care staff caring for children or adults should use standard criteria for AKI, such as the pRIFLE or KDIGO definitions, respect...

Child: Care, Health and Development, 2014

Long-term childhood conditions are often managed by hospital-based multidisciplinary teams of pro... more Long-term childhood conditions are often managed by hospital-based multidisciplinary teams 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.

Trials, 2014

Background: Relapses of childhood steroid-sensitive nephrotic syndrome (SSNS) are treated with a ... more Background: Relapses of childhood steroid-sensitive nephrotic syndrome (SSNS) are treated with a 4-to 8-week course of high-dose oral prednisolone, which may be associated with significant adverse effects. There is a clear association between upper respiratory tract infection (URTI) and relapse development. Previous studies in developing nations have suggested that introducing a 5-to 7-day course of daily prednisolone during an URTI may prevent a relapse developing and the need for a treatment course of high-dose prednisolone. The aim of PREDNOS 2 is to evaluate the effectiveness of a 6-day course of daily prednisolone therapy during an URTI in reducing the development of a subsequent relapse in a developed nation.

Transplantation Proceedings, 2002

Transplantation, 2009

Combined liver kidney transplant (CLKT) is a recognized treatment option for end-stage renal dise... more Combined liver kidney transplant (CLKT) is a recognized treatment option for end-stage renal disease due to primary hyperoxaluria (PH-I) and cystic disorders, yet there is only limited data on posttransplant renal function recovery. The objective of this study was to assess postoperative renal function of children with PH-I (group A) undergoing CLKT and to compare this with a cohort of children (group B) who received CLKT for other indications. Twenty-three patients underwent CLKT between 1994 and 2008 (group A: 9 patients; median age 8.6 [1.6-16.7] years; group B: 14 patients; median age 8.5 [1.9-14.6] years). The median follow-up was 88 (14-112) and 22 (4-109) months. Both groups were transplanted with comparable organs. Eight (8/9) and six (6/14) patients received preoperative renal support in each group, respectively, whereas an equal proportion of them required early postoperative renal support (4/8; 50% and 3/6; 50%, respectively). Glomerular function was significantly different between groups until first year posttransplant (median estimated glomerular filtration rate: groups A vs. B; at pretransplant, 3 mo, 6 mo, and 12 mo posttransplant, respectively; 11.06 vs. 12.61 [P=0.4], 40.78 vs. 75.83 [P=0.03], 42.59 vs. 80.56 [P=0.04] and 53.57 vs. 76.75 [P=0.005]). Overall 1-year survival is 89% versus 90% and 5-year survival is 89% versus 62%, respectively. Children with PH-I receiving CLKT seem to have delayed recovery of renal function compared with polycystic disease, possibly due to mobilization of systemic oxalate. Consideration should be given to earlier or preemptive transplantation for children with PH-I.

Transplantation, 2009

Combined liver and kidney transplantation (CLKT) is a surgical challenge in small children becaus... more Combined liver and kidney transplantation (CLKT) is a surgical challenge in small children because of technical aspects, lack of pediatric donors, and restrictions related to the size of the abdominal cavity. We report outcomes after CLKT in this challenging group of smaller children. A review of prospective data on all children undergoing CLKT at the Birmingham Children's Hospital between 1994 and 2008 was performed. An analysis of perioperative data, complications, and survival in children less than 15 kg was carried out, with figures expressed as median (range) and compared with that of children more than 15 kg. A total of 23 children underwent CLKT (14 male [61%] and age 8.6 [1.6-16.7] years), of which 8 (35%) were less than or equal to 15 kg, median age 2.2 (1.6-5.4) years, weight 11.6 (9.1-14.9) kg, and height 76 (66-95) cm, followed up for a median 26 (12-126) months. Donor details included age 13 (3-40) years, weight 60 (15-78) kg, and height 156 (83-168) cm. The median donor-to-recipient weight ratio was 4.8 compared with 1.7 for larger children. The median waiting time was 291 (48-523) compared with 150 (6-455) days for children more than 15 kg. Four of eight (50%) children received preoperative renal support, when compared with 10 of 16 (62%) children more than 15 kg. The intensive care unit and inpatient stay was 2 (2-22) days and 25 (19-93) days, respectively. Mortality was seen in one of eight because of sepsis and multiorgan failure. When compared with children more than 15 kg, survival figures at 1 and 2 years were 87% versus 93% and 78%, respectively. CLKT in small children results in comparable outcomes despite challenges related to donor-recipient size mismatch and longer waiting times. Consequently, body size/stature should not be a limiting factor for multiorgan transplantation.

Nephron Physiology, 2009

Dent disease is an X-linked renal proximal tubulopathy associated with mutations in CLCN5 (Dent 1... more Dent disease is an X-linked renal proximal tubulopathy associated with mutations in CLCN5 (Dent 1) or OCRL1 (Dent 2). OCRL1 mutations also cause the oculocerebrorenal syndrome of Lowe. Dent patients with normal sequence for CLCN5 were sequenced for mutations in OCRL1. By analyzing these and all other OCRL1 mutations reported, a model relating OCRL1 mutations to the resulting disease (Dent 2 or Lowe's) was developed. Six boys with Dent disease had novel OCRL1 mutations: two missense (R301H, G304E) and four mutations predicted to produce premature termination codons (L56DfsX1, S149X, P161PfsX3, and M170IfsX1). These include one of the original patients reported by Dent and Friedman. Slit lamp examinations revealed early cataracts in only one boy with normal vision. None of these Dent 2 patients had metabolic acidosis; 3 had mild mental retardation. Analysis of all known OCRL1 mutations show that Dent 2 mutations fall into two classes that do not overlap with Lowe mutations. Bioinformatics analyses identified expressed OCRL1 splice variants that help explain the variability of those clinical features that distinguish Dent disease from Lowe syndrome. OCRL1 mutations can cause the renal phenotype of Dent disease, without acidosis or the dramatic eye abnormalities typical of Lowe syndrome. We propose a model to explain the phenotypic variability between Dent 2 and Lowe's based on distinctly different classes of mutations in OCRL1 producing splice variants.

QJM, 1994

In the haemolytic uraemic syndrome (HUS), platelet microthrombi and deposition of fibrin in glome... more In the haemolytic uraemic syndrome (HUS), platelet microthrombi and deposition of fibrin in glomeruli may contribute to the development of renal failure. The balance of procoagulant and fibrinolytic activities in the renal vasculature may therefore have an important role. We measured plasminogen-activator inhibitor (PAI) activity in the plasma of 81 children with diarrhoea-associated (D+) HUS, and found elevated PAI activity in many patients. When we categorized patients by need for dialysis, only the dialysed group had significantly higher levels of activity, compared with a group of normal controls. We also compared PAI activity with patient outcome after one year, and found that those with a poor outcome had significantly higher PAI activity than those with a good outcome. We suggest that plasma PAI activity may be an acute marker for dialysis requirement in HUS, and may have prognostic value for long-term outcome. The possible role of PAI in the pathogenesis of HUS requires further investigation.

Postgraduate Medical Journal, 2001

A 6 year old boy who presented with steroid unresponsive nephrotic syndrome is reported. He was f... more 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. (Postgrad Med J 2001;77:523-526)