morphine is frequently used to relieve pain and achieve sedation in many age groups . in preterm infants , morphine is largely used for pain control in neonatal intensive care units and for the management of the neonatal abstinence syndrome ( nas ) . despite its recognized benefits , the use of morphine is associated with adverse effects on the cardiovascular , gastrointestinal and nervous systems such as hypotension , bradycardia , seizures , decreased gastrointestinal motility , intestinal obstruction and respiratory depression [ 1 , 2 ] . renal side effects of morphine ( urethral spasm , spasm of bladder sphincters , urinary retention or hesitancy , antidiuretic effect and rhabdomyolysis ) have been previously reported in adult patients [ 3 , 4 ] . little is however known about the adverse kidney effects of morphine on paediatric patients and , in particular , in preterm infants [ 1 , 2 , 5 , 6 ] . studies in adults indicate that peripheral mechanisms may play a role in opioid - induced bladder dysfunction and urinary retention [ 7 , 8 ] . however , the exact mechanism by which morphine causes urinary retention and renal impairment in premature infants is unknown . age - related difference in morphine clearance may contribute to the observed different response to opioid therapy from infancy to adulthood [ 911 ] . preliminary data suggest that variation in genes coding the drug - metabolizing enzyme ( ugt2b7 ) , mu - opioid receptors ( oprm1 ) , the enzyme degrading catecholamines ( comt ) and intracellular drug accumulation by p - glycoprotein ( abcb1 ) can significantly influence the clinical outcome of patients given morphine therapy [ 1316 ] . despite this , the pharmacogenetics of morphine have not been previously considered in the paediatric population as an explanation for poor drug response and/or for drug side effects . we report a case of acute kidney injury and bilateral hydronephrosis in a premature infant homozygous for the c3435 t polymorphism in the abcb1 gene treated with oral morphine . we believe that this is the first published report demonstrating a relationship between renal morphine toxicity and genetic background in paediatric patients . a 2240 g caucasian male neonate was born at 34 weeks of gestation by emergency caesarean section performed for premature rupture of membrane . the mother was hiv - positive and had a history of cocaine and heroin abuse throughout her pregnancy . apgar scores at 1 and 5 min after birth were 6 and 8 , respectively . one hour after birth , the infant developed an nas characterized by central nervous system irritability , tremors , poor feeding , exaggerated moro reflex , increased muscle tone and uncoordinated sucking . his finnegan score ( which comprehensively scores all relevant clinical signs of nas in newborn infants during the first days of life assessing central nervous system hyperirritability , gastrointestinal dysfunction , respiratory distress and vague autonomic signs in a semi - quantitative way ) yielded a result of > 12 ( a finnegan score of 8 or higher is considered severe and requires medical therapy ) . a urine test performed soon after birth was positive for cocaine and heroin . treatment with oral morphine was immediately started ( 0.5 mg / kg/24 h in four divided doses given every 6 h and then decreased to 0.4 mg / kg/24 h in three divided doses given every 8 h ) . to reduce the risk of vertical hiv transmission , oral zidovudine was started at 6 h of life . on day 5 , urine output decreased gradually and the serum creatinine level increased from 77.8 to 93.7 mol / l ( from 0.88 to 1.06 mg / dl ) on day 7 ( table 1 ) . the potassium level rose concomitantly from 4.1 to 6.2 mmol / l ( from 4.1 to 6.2 meq / l ) , whereas sodium remained normal without the development of metabolic acidosis . physical examination revealed hypotonia , lethargy , distended abdomen and a vesical globe . a renal ultrasound showed bladder distension with bilateral hydronephrotic kidneys [ bipolar length 4.5 cm ( normal for age 34 cm ) ] . urinary catheterization drained 73 ml of straw - coloured urine with resolution of the bladder distension . morphine was discontinued without rebound or adverse effects and over the subsequent 3 days , renal function returned to normal ( table 1 ) . table 1.time course of the main biochemical and clinical parameters observed in our patientparametersday 1day 2day 3day 4day 5day 6day 7day 8day 9day 10at dischargenormal valuess . creatinine ( mol / l)77.885.782.293.779.671.646.950100urine output ( ml / kg / h)wet diaperwet diaperwet diaper32.03.02.73.02.54.0>12s . potassium ( mmol / l)3.94.03.53.94.15.36.24.64.24.64.13.55.0morphine dose ( mg / kg/24 h)0.50.70.60.40.40.3interruptedfinnegan 's score1211466548442<8the patient was not catheterized and no quantitative assessment was performed.urinary catheterization performed , residual volume 73 ml . time course of the main biochemical and clinical parameters observed in our patient the patient was not catheterized and no quantitative assessment was performed . an additional blood sample was collected for pharmacogenetic analyses ( after informed consent was obtained from the mother ) . according to pyrosequencing analysis , the patient was wild type for the most common allelic variants of ugt2b7 , oprm1 and comt genes . however , he was homozygous for the c3435 t ( rs1045642 ) polymorphism of the abcb1 gene that has been previously associated with absent / impaired p - glycoprotein activity . the infant was discharged on day 33 : no further urinary retention was observed during hospitalization . the infant was followed during the first 18 months of life to monitor growth and renal development : no sign of renal impairment was reported and the transmission of hiv infection was excluded . a few cases of acute kidney injury and hydronephrosis have been reported in the literature after opioid administration in preterm infants [ 5 , 6 ] . to our knowledge , this is the first case in which a possible pharmacogenetic cause has been identified . other important causes of acute kidney injury bladder distension and hydronephrosis , such as urological malformations , neoplasia , vesicoureteral reflux and neurogenic bladder , were excluded in this case . the clinical evidence thus suggests a pathophysiological mechanism related to morphine . nevertheless , the possibility that other as yet unknown factors may be involved can not be excluded . our patient was homozygous for a polymorphic variant in position 3435 of the abcb1 gene . this gene encodes for p - glycoprotein , a protein that belongs to the abc transporter family and is expressed in leucocytes , hepatocytes , blood  brain barrier and mainly on the brush border of enterocytes and renal tubular cells . importantly , p - glycoprotein is also expressed in urothelial cells [ 1922 ] , playing a key role in the disposition of chemotherapy in urothelial cancers [ 19 , 21 ] . our patient experienced acute kidney injury and bilateral hydronephrosis while receiving oral morphine for the control of nas . this resolved after urinary catheterization , suggesting that the site of the obstruction was the bladder neck . we hypothesize that acute renal toxicity was related to accumulation of morphine and its metabolite within urothelial cells due to genetically determined , impaired p - glycoprotein activity . a potential limitation is that we did not measure the plasma concentrations of morphine and its main glucuronide metabolite . however , studies showing the impact of c3435 t polymorphism in the abcb1 gene on clinical outcomes have consistently failed to demonstrate an association with blood drug concentrations , suggesting a local ( rather than systemic ) effect on drug disposition [ 15 , 23 ] . p - glycoprotein is an efflux transporter that actively transports lipophilic drugs from the intracellular to the extracellular domain . consequently , reduced expression and/or altered activity of p - glycoprotein can increase the intracellular and tissue drug concentrations , ultimately resulting in local drug toxicity . studies aimed at investigating the role of abcb1 polymorphisms on morphine efficacy and/or safety have provided conflicting results . some studies have reported significant associations between allelic t variants of abcb1 with morphine - induced adverse gastrointestinal and central drug reactions in adults patients with cancer [ 14 , 15 ] , whereas other investigators have failed to document a role of genetic factors with morphine response [ 2426 ] . no clinical studies have previously addressed the role of abcb1 polymorphisms on morphine - related kidney injury and our single case report does not provide a definitive conclusion on this topic . nevertheless , we believe that it provides an intriguing mechanistic hypothesis that needs further investigation . morphine is one of the most important and widely used opioids in neonatology ; but , large variability in its efficacy and/or safety represents a major clinical challenge . clinical pharmacology studies in adults have demonstrated the importance of pharmacogenetics in determining the response to drug therapy [ 2729 ] . our observation is in line with these data and suggests that pharmacogenetics can aid our understanding of morphine - induced adverse effects in neonates as in other age groups .
a 34-week infant born from a mother with a history of drug abuse developed neonatal abstinence syndrome ( nas ) in the first hours of life . 
 urine drug screening was positive for cocaine and heroin . 
 the infant developed acute kidney injury and bilateral hydronephrosis while receiving oral morphine for control of nas . 
 cessation of morphine therapy and urinary catheterization resulted in a rapid and complete resolution of the symptoms . 
 our patient was homozygous for the c3435 t polymorphism in the abcb1 gene , a polymorphism previously associated with impaired p - glycoprotein activity . 
 we hypothesize that acute renal toxicity was related to accumulation of morphine within urothelial cells due to genetically determined impaired p - glycoprotein activity .