Malcolm G. Coulthard

Nephrotoxicity after ifosfamide.

Eleven children and adolescents with previously normal renal function who received ifosfamide for the treatment of extrarenal solid tumours underwent detailed investigation of glomerular and renal tubular function to assess the incidence and extent of renal damage. None had received cisplatin. Glomerular filtration rate (measured by plasma clearance of 51Cr labelled edetic acid) was reduced in six children. All 11 patients had evidence of proximal, and six of distal, tubular damage. Proximal tubular toxicity was indicated by phosphaturia and hypophosphataemia (n = 4), glycosuria (n = 5), increased urine beta 2 microglobulin excretion (n = 11), and generalised aminoaciduria (n = 10); distal tubular damage caused a reduction of the osmolality of the urine in an early morning sample. Two children developed clinical hypophosphataemic rickets, and one of these also had severe nephrogenic diabetes insipidus. Glomerular and tubular nephrotoxicity are common and potentially serious complications of ifosfamide treatment in children.

Risk factors for ifosfamide nephrotoxicity in children

BACKGROUNDnRisk factors for long-term nephrotoxicity after ifosfamide for childhood cancers are not fully known. We have studied patient-related and treatment-related risk factors for chronic ifosfamide nephrotoxicity.nnnMETHODSnA group of 23 children who had received ifosfamide at age 2.1-16.2 years (median 6.9) for various cancers were assessed for nephrotoxicity, at 1-28 (2) months after the end of treatment, by renal function testing, laboratory values, and a grading score (none, mild, moderate, severe). No patient had received cisplatin or undergone nephrectomy. 13 children were reassessed at 10-26 (23) months; eight had died and two were not evaluable. The median total ifosfamide dose was 100.8 (9.0-160.4) g/m2 over a median of 15 courses every 3 weeks as a 48-72 h continuous intravenous infusion (in 22 cases), with mesna and hydration.nnnFINDINGSnGlomerular filtration rate was below normal in ten (45%) of 22 evaluable children; their rate was 61-85 mL/min per 1.73 m2. Proximal tubular toxicity led to hypophosphataemic rickets and/or renal tubular acidosis in six children, and distal tubular toxicity caused nephrogenic diabetes insipidus in one. Of the risk factors analysed by multiple regression, only total ifosfamide dose was associated with proximal tubular toxicity. Only two of ten evaluable patients who received under 100 g/m2 developed moderate nephrotoxicity, whereas six of ten who received over this dose had moderate or severe nephrotoxicity.nnnINTERPRETATIONnHigh total ifosfamide dose was the only risk factor we identified. Although inter-patient variability was high, cumulative doses of 100 g/m2 or higher should be avoided in children with cancer.

Cisplatin dose rate as a risk factor for nephrotoxicity in children.

The purpose of the study was to evaluate the incidence, risk factors and changes in severity with time of cisplatin nephrotoxicity in children. A total of 35 children underwent measurement of glomerular filtration rate (GFR) and tubular function after completion of cisplatin chemotherapy. No child received ifosfamide. A clinically relevant nephrotoxicity score was derived from GFR and serum magnesium. Follow-up studies were performed in 16 children at 1 year and in 15 at 2 years after cisplatin. Considerable interpatient variability in nephrotoxicity was observed. Treatment was modified in three patients because of nephrotoxicity. GFR was low in 18 out of 31 patients. Proximal nephron toxicity caused hypomagnesaemia in ten patients and hypocalcaemia in five patients. Elevated urinary N-acetylglucosaminidase excretion was seen in 22 out of 30 children, indicating subclinical tubular toxicity. Nephrotoxicity was less severe in children who received cisplatin courses at a dose rate of 40 mg m(-2) day(-1) than in those who received higher dose rates (P < 0.005), but there was no correlation with total dose received. Follow-up studies revealed partial recovery of GFR (P < 0.05). Glomerular and proximal nephron toxicity are common in children treated with cisplatin, and more severe at higher dose rates. Despite partial recovery of GFR, the long-term outcome of nephrotoxicity remains unknown and careful monitoring of chronic toxicity is necessary.

Assessment of chemotherapy-associated nephrotoxicity in children with cancer

SummaryAssessment of the toxicity caused by chemotherapy in children with cancer has become more important as the number of long-term survivors has continued to increase. It is vital to monitor both acute life-threatening adverse effects and long-term toxicity that may impair the childs development and cause permanent morbidity. Renal damage may follow treatment with cytotoxic drugs, especially cisplatin or ifosfamide, and lead to glomerular, proximal tubular or distal tubular impairment or to any combination of these. Greater understanding of nephrotoxicity and of its prevention may enable the use of more intensive schedules or of higher doses of potentially nephrotoxic chemotherapy. However, the evaluation of cytotoxic drug-induced nephrotoxicity has frequently depended mainly on measurement of the plasma creatinine concentration, which may remain normal despite substantial glomerular impairment or severe tubular dysfunction. Detailed assessment of nephrotoxicity depends on an understanding of normal renal physiology and requires evaluation of all aspects of function. A comprehensive but simple investigatory protocol that enables assessment of the nature and severity of nephrotoxicity in children is described, which can be performed without admission to hospital.Glomerular function is assessed by measurement of the glomerular filtration rate from the plasma clearance of [51Cr]-ethylenediaminetetraacetic acid ([51Cr]-EDTA).Proximal nephron function is evaluated in three ways: by measurement of the concentration of calcium, magnesium, phosphate, glucose and urate in blood and urine along with calculations of their fractional excretion and of the renal threshold for phosphate; by determination of the excretion in urine of low-molecular-weight proteins (e.g. retinol-binding protein); and by investigation of urinary bicarbonate excretion in patients who are acidotic.Distal nephron function is initially investigated by examination of the concentration (osmolality) and acidification (pH) of an early morning sample of urine. Finally, a group of general investigations is performed, including quantitation of urinary excretion of renal tubular enzymes (e.g.N-acetylglucosaminidase) and measurement of blood pressure.

Maturation of glomerular filtration in preterm and mature babies

Glomerular filtration rate (GFR) was measured in 39 healthy infants (gestation 27-40 weeks, birthweight 0.68-3.71 kg) by prolonged inulin infusion between 2 and 63 days of age. Absolute GFR showed a logarithmic rise with conceptional age (gestational plus postnatal age) which was independent of postnatal age. GFR per kilogram showed a slow rise with gestational age, and a rapid rise with increasing postnatal age which was shown to be due to a temporary cessation of growth rather than a true acceleration in renal maturation. GFR per unit surface area showed similar, but steeper rises. Formulae were constructed to predict GFR in the first month of life from postnatal age (PA), weight and birthweight (BW); (GFR = (0.24 BW + 0.18 PA + 0.45) X weight), or from conceptional age (CA); (GFR = 100.0618 CA-1.859). 95% of the predictions fell within 66 and 151%, and 58 and 172% of the measured values, respectively. Data from 14 studies were expressed in the same format where possible. The agreement between the reported data and this study was close. Apparent contradictions between these studies had been largely due to their different forms of presentation.

Neonatal Fanconi syndrome due to deficiency of complex III of the respiratory chain

Fanconi syndrome is an important presentation of respiratory chain disease. We report three patients who presented in the neonatal period with Fanconi syndrome, lactic acidosis and intrauterine growth retardation. In all three patients the major biochemical defect was in complex III of the mitochondrial respiratory chain, a relatively uncommon defect. The diagnosis could only be made by muscle biopsy as the defect was not expressed in cultured skin fibroblasts. Treatment with vitamins C and K3 and ubiquinone did not alter the course of the disease and all patients died before the age of 4 months.

Comparison of methods of measuring renal function in preterm babies using inulin

Glomerular filtration rate and urine flow were measured in 40 babies of 26 to 40 weeks gestationwithout the need for accurately timed collections of urine by infusing inulin continuously for ≥24 hours. Estimates of GFR and urine flow were similar to those obtained when timed specimens of urine were also collected, the coefficient of variation being only 6.1% (22 studies). Although the plasma inulin concentration 80 minutes after a bolus and continuous infusion changed only slowly, it still closely reflected the size of the bolus dose (eight studies, P 0.1). The agreement was closer (P

Creatinine and urea clearances compared to inulin clearance in preterm and mature babies

Simultaneous clearances of inulin, urea and creatinine were compared in 41 babies of 26-40 weeks gestation on 122 occasions during the first month of life. In each case creatinine was measured by a reaction rate method, and in thirty specimens it was also measured after adsorption onto resin. Urea clearance averaged only 62% of inulin clearance (P less than 0.001), and was a poor marker of glomerular filtration. Creatinine clearance measured by resin adsorption equalled inulin clearance, but the assay is manual and not suitable for routine clinical use. Creatinine clearance measured by reaction rate analysis underestimated inulin clearance by a quarter (P less than 0.01) because this automated method overestimated plasma creatinine by an average of 22 mumol/l. Urinary creatinine excretion was 72 +/- 17 nmol/kg per min (mean +/- S.D.) during the first week of life, and 66 +/- 13 nmol/kg per min in weeks two to four, and was not influenced by gestation or body size. Using these values, glomerular filtration rate, urine flow, and the urinary excretion rates of substances may be estimated from measurements made on plasma and untimed urines. Although these estimates are imprecise, with 9% confidence limits of 62-161%, they are useful in clinical practice because they avoid the need to make accurately timed collections of urine.

Specificity of pH and osmolality of early morning urine sample in assessing distal renal tubular function in children: results in healthy children

A simple method of evaluating distal tubular function in children would be useful because water deprivation tests are potentially dangerous and acid loading tests are unpleasant. Osmolality of an early morning urine sample is often taken as a measure of urinary concentration in children with a history of polydipsia and polyuria, and the pH of an early morning sample is used to evaluate urinary acidification in several renal and metabolic disorders. A pH of 5.4 or less is usually taken as adequate acidification1 and an osmolality of 600 mmol/kg or more as excluding clinically significant impairment of urinary concentration.2 We determined the likelihood of achieving these values in a single early morning urine sample from healthy children.nnWe collected an early morning urine sample from 322 healthy children and adolescents (age range 3 years 11 months to 18 …

Urinary creatinine excretion in the newborn.

We write to congratulate Dr Jonathon Shaw on his comprehensive and balanced review of copper deficiency in infancy and its relation to fractures diagnosed as nonaccidental injury. We trust that it will put an end to poorly supported attempts on the part of some expert witnesses to ascribe fractures to copper deficiency in circumstances when it is manifestly not present. These attempts have been the subject of adverse comment in the Appeal Court2 and Family Division of the High Court3 in both criminal and wardship proceedings. The waste of time, money, and emotional damage which results from the protracted and complicated legal proceedings is incalculable. Dr Shaw together with Dr Carty,4 in the same issue of your journal have established clearly the criteria which should apply before the diagnosis of copper deficiency is considered possible and have shown that proper analysis of clinical, radiological, and laboratory criteria even in the absence of serum copper concentrations are quite adequate in most cases. It is our view, borne out by the data and arguments presented by Drs Shaw and Carty, that infants who sustain fractures but do not have recognised risk factors for copper deficiency, have normal bone structure, and no haematological abnormalities do not need to have copper and caeruloplasmin concentrations measured on clinical grounds. It is questionable whether it would be ethical to do them for purely forensic reasons in the absence of reasonable evidence suggesting that they might be abnormal. We are concerned at the prospect of multiple requests for serum copper determination. It would be unfair both to the infants and the laboratories. While we accept that premature infants may represent a special risk group because of diminished hepatic copper reserves, many of the references cited by Shaw involve infants given outmoded parenteral feeding formulae or receiving partial enteral feeds. With the use of modern crystalline amino acid parenteral feeding solutions together with a trace element solution (supplying 0-3 tmol/kg/day of copper) we have found copper deficiency rare.