1462 Archives ofdisese in Childhood 1992; 67: 1462-1466 Birminghm Children's Hospitl, Birminghm C Mpofu J R Mnn rrespondence to: Dr C Mpofu, Twm Hospitl, PO Box 15258, Al Ain, Abu Dhbi, United Arb Emirtes. Accepted 2 August 1992 Urinry protein/cretinine index in follow up of ptients with Wilms' tumour fter nephrectomy C Mpofu, J R Mnn Abstrct The protein/cretinine index (p/c) ws determined in erly morning urine (EMU) smples from vilble ptients with Wilms' tumour who hd hd nephrectomy nd whose dignosis hd been mde between Jnury 197 nd December 1989. Clinicl detils were obtined by cse note review. Results were obtined from 36 boys nd 4 girls. The men intervl between nephrectomy nd mesurement of the EMUp/c ws 9- yers (2-23). Eleven ptients hd EMUp/c greter thn 2 mg/mmol (norml rnge less thn 2). Of the 11 ptients with proteinuri, there were in ddition to nephrectomy other dverse fetures including bilterl tumours, tretment with nephrotoxic drugs, nd dysplstic kidneys. Renl dysfunction seems most likely to occur where there re dverse fctors in ddition to unilterl nephrectomy. There ws significnt correltion between the glomerulr filtrtion rte nd the EMUp/c, nd it is thought tht this is simple tool which cn be used for the regulr monitoring of renl function in these ptients. (Arch Dis Child 1992;67:1462-6) The high survivl rte for children with Wilms' tumour hs rised concern bout the bility of the remining kidney to sustin dequte renl function nd llow norml life spn. The min source of concern is the growing number of reports of glomerulr hyperfiltrtion.' 2 Children with Wilms' tumour invribly lose t lest hlf of their renl mss nd therefore need systemtic investigtion to define the extent of the problem nd to identify specil risk fctors. The need for regulr monitoring of these children's renl funtion lso rises the issue of how extensively tests should be crried out during follow up. Ptients nd methods Assessment of renl function ws crried out between Jnury 1989 nd December 199 for ptients receiving long term follow up for Wilms' tumour t The Children's Hospitl in Birminghm. Only children whose dignoses were mde between Jnury 197 nd December 1989 were included. Instructions were given to prents bout the collection of erly morning urine (EMU) smples on the morning tht they were due to visit the clinic for review. Prticulr emphsis ws plced on the need for the smples to be collected before the ptient ws mbulnt. Urinry protein/ cretinine indices (EMUp/c) were then mesured on these smples using the omssie blue dye-binding method.3 The upper limit of norml vlues for the EMUp/c hs been estblished s 2 mg/mmol.4 Blood pressure ws mesured, the distolic pressure being tken s the point of disppernce of ll sounds. Urine ws lso collected for culture. Estimtes of the glomerulr filtrtion rte were mde, where cretinine mesurements were vilble, from the formul heightx k/plsm cretinine, where k is constnt whose vlue depends on ge nd sex.5 Clernce of chromium-s1 lbelled EDTA ws determined in other ptients. The subjects were divided into two groups ccording to the ssocited EMUp/c vlues. Renl biopsy smples were tken from two ptients in view of the severity of their disese. A retrospective review of the dignoses nd mngement detils of the ptients ws crried out using their cse notes. The ptients were ll receiving unrestricted diets, with the exception of two for whom dietry protein intke hd been reduced in n ttempt to slow down the rte of renl deteriortion. There were no documented urinry trct infections t the time of ssessment. Results Ninety seven urine smples were obtined from 76 ptients (36 boys nd 4 girls). The men intervl from nephrectomy ws 9- yers (2-23 yers). The men ge t nephrectomy ws 3-41 yers. There ws no significnt difference in ge t nephrectomy between the ptients with proteinuri nd those without. In 11 ptients the EMUp/c ws greter thn 2 mg/mmol, wheres in 65 ptients it ws below the upper limit of norml. Sixty four (99%) of the ltter hd unilterl tumours, nd one (2%) hd bilterl tumours. Of those with EMUp/c greter thn 2 mg/mmol, seven (64%) hd unilterl tumours nd four (36%) hd bilterl tumours. All ptients with EMUp/c greter thn 2 mg/mmol lso hd positive lbustix tests. No hemturi ws detected in ny of the ptients. RADIOTHERAPY A totl of 42 (55%) ptients hd received rdiotherpy. Thirty one (74%) hd received rdition to the renl bed only, seven (17%) hd received rdition to the whole bdomen, two (5%) hd received rdition to the renl bed nd lungs, one (2%) hd received rdition to the whole bdomen nd lungs, nd one (2%) hd received rdition to the lungs only. Arch Dis Child: first published s 1.1136/dc.67.12.1462 on 1 December 1992. Downloded from http://dc.bmj.com/ on 15 August 218 by guest. Protected by copyright.
Mpofu, Mnn 14 r 12 = N 1. E 'Lo cr* 8 ~f. L C co 6 E 4 CD 2 - U. : m 5 The medin rdition dose for those children with EMUp/c greter thn 2 mg/mmol ws 282 cgy, nd tht for children with EMUp/c less thn 2 mg/mmol ws 2 cgy. However these dose differences were not sttisticlly significnt (p> 5 by Wilcoxon rnk sum test). Those ptients receiving whole bdominl rdition were eqully distrubuted between those with proteinuri nd those without (three in ech group). Only one ptient with bilterl disese received rdiotherpy to one renl bed fter nephrectomy, but this ws stopped fter only one frction (totl dose 15 cgy). BLOOD PRESSURE Two ptients were receiving tretment for hypertension (distolic blood pressure persistently bove the 97th centile for ge nd sex). These two ptients hd bnorml renl function nd their blood pressures hd been norml before the deteriortion in renl function. They hd hd bilterl tumours, one of them lso 25 r- (A 2 ) lp cbq 15 z 5 n 22 11 * v33 1.2 3 5-4-5;-3-38 -2-25 -1-13 - 1-13 2-25 3-38 4-5 SD score Figure I pressurie. u2 ) @. 15 c 25 r.1-. Frequency histogrm: SD scores for systolic blood -4- -3- -2--1- - 1-2- 3* 4- SD score Figure 2 Frequency histogrm: SD scores for distolic blood pressure. U U 1 EMUp/c (mg/mmol) Figure 3 rreltion between glomerulr filtrtion rte nd the EMUplc. m. 15 2 hving underlying multicystic kidney disese. The blood pressure results were expressed s SD scores. These were derived from the Report of the Second Tsk Force on Blood Pressure ntrol in Children.6 For systolic pressure the men (SD) ws -72 (1-29) (medin -77). For distolic pressure the men (SD) ws -48 (1-14) (medin 54) (figs 1 nd 2). URINARY TRACT INFECTIONS Nine ptients hd recorded urinry trct infections. Five hd EMUp/c less thn 2 mg/mmol nd four hd EMUp/c greter thn 2 mg/mmol. Only one of these ptients hd recurrent infections; ll the others were single episodes tht were successfully treted. GLOMERULAR FILTRATION RATE Results of glomerulr filtrtion rte estimtions were vilble from 55 ptients. Only four of these were obtined from chromium-51 lbelled EDTA clernce mesurements; the rest were estimted from serum cretinine concentrtions. Forty six ptients hd EMUp/c less thn 2 mg/mmol nd nine greter thn 2. No ptient hd glomerulr filtrtion rte less thn 8 ml min/i73 m2 in the group with EMUp/c less thn 2 mg/mmol, nd their men glomerulr filtrtion rte ws 14-51 ml/min/1-73 m2 (96-1-132-35). In those ptients with EMUp/c greter thn 2 mg/mmol, three (33%) hd glomerulr filtrtion rte less thn 8 ml/min/ 1-73 m2) (men 88-66 (39-121-6)). The men (rnge) intervls between nephrectomy nd glomerulr filtrtion rte results were 3-36 (-1-112) yers nd 9 52 (1-6-22-2) yers for those with EMUp/c less thn nd greter thn 2 mg/mmol respectively. There ws significnt correltion between the EMUp/c nd glomerulr filtrtion rte (Person's correltion coefficient --61) (fig 3). The glomerulr filtrtion rte of the five ptients with bilterl tumours re shown in tble 1. CHARACTERISTICS OF PATIENTS WITH A EMUP/C >2 MG/MMOL Tble 2 summrises the min fetures of those 11 ptients with bnorml renl function. Their men ge t nephrectomy ws 2-42 yers. mpred with 3-59 yers for the 64 ptients with EMUp/c less thn 2 mg/mmol. This difference ws not significnt. Four of the ptients were severely ffected (EMUp/c >8 mg/mmol) nd three of these hd bilterl tumours. Of the seven ptients with less severe proteinuri (EMUp/c 23-28-9 mg/mmol), only one hd bilterl tumours. This ptient's vlues Tble I Glomerulr filtrtion rte for children with bilterl Wilms' tumour Ptient No Glomerulr EM Up/c filtrtion (mglmmol) rte (mllmin/1 73 i2) 1 39 >2 2 61-7 >2 3 97-2 >2 4 116-5 >2 5 115-5 <2 1463 Arch Dis Child: first published s 1.1136/dc.67.12.1462 on 1 December 1992. Downloded from http://dc.bmj.com/ on 15 August 218 by guest. Protected by copyright.
1464 Urinry proteinlcretinine index infollow up of Wilms' tumour Tble 2 Chrcteristics of children with EM Up/c greter thn 2 mglmmol Ptient Site of Opertion Chemotherpyf Rdiotherpy Other Age t No of Intervl EMUp/c No tumour performed* chrcteristics nephrectomy urinry between (mglmmol) (yers) trct nephrectomy nd infections mesurement (yers) I Bilterl CU VAC Renl bed Polycystic 1.1 22 198 2 Bilterl BPN AVA - - 2-1 5 42 3 Bilterl BPN AVA - Polycystic 1-7 Recurrent 12 17 niridi; Wilms' pyelonephritis 4 Bilterl UN AVA Whole lung - 2-4 1 3 43 VICA 5 Unilterl UN AVA Renl bed, - 19-13 4 VIC pelvis 6 Unilterl UN VCR Whole bdomen - 3-4 - 14 27 7 Unilterl UN AVA Whole bdomen, - 7- - 5 93 VI pelvis 8 Unilterl UN AV - Dysmorphic 2-7 - 5 29 syndrome 9 Unilterl UN AVA - 1-7 - 16 56 1 Unilterl UN AVA - Toxic gentmicin 1 5-15 22 concentrtions 11 Unilterl UN AV Whole bdomen - -8-16 23 'UN=unilterl nephrectomy; BPN=bilterl prtil nephrectomy; CU=complete nephrectomy nd contrlterl prtil nephrectomy. tvac=vincristine, ctinomycin, nd cyclophosphmide; AVA=ctinomycin, vincristine, nd Adrimycin; VICA=vincristine, ifosfmide, nd crbopltin; VIC=vincristine, ifosfmide, nd cispltin; VI=vincristine nd ifosfmide; AV=ctinomycin nd vincristine; VCR=vincristine. for the EMUp/c hve stedily decresed from 52 to 2-3 mg/mmol. There were four ptients with bilterl tumours necessitting extensive surgery. One of these ptients hd unilterl multicystic renl dysplsi nd the other hd bilterl multicystic renl dysplsi nd the niridi-wilms' tumour syndrome, recurrent urinry trct infections, nd histologicl evidence of chronic pyelonephritis. The other ptient's renl biopsy smple showed widespred interstitil fibrosis, tubulr trophy, mrked glomerulr enlrgement, nd hilr rteriolr thickening with intrmurl hyline deposits. Two of 11 glomeruli were globlly sclerosed, with no focl segmentl sclerosis being identified. These findings probbly represented the results of previous irrdition with chnges of glomerulr hyperfiltrtion superimposed. The biopsy smples hd been tken in view of the severity of these ptient's renl disese. Another of these four ptients lso received ifosfmide (1-8 g/m2), crbopltin (733-3 mg/m2), nd whole lung irrdition for pulmonry relpses. Only one ptient in this group received renl rdition (15 cgy). Of the remining seven ptients (unilterl tumours), two hd Beckwith's syndrome. They received whole bdominl rdition (225 nd 3 cgy), one of them lso receiving ifosfmide (6 g/m2) for recurrence of the tumour. Another ptient with recurrence of the tumour received tretment tht included ifosfmide (6 g/m2) nd cispltin (3 mg/m2). One ptient received whole bdominl rdition, nother received cyclovir for chickenpox prophlyxis nd toxic concentrtions of gentmicin during tretment of fever nd neutropeni. One ptient hd fmilil syndrome of mentl retrdtion nd hypotoni. In the remining ptient no dditionl fetures were identified. A totl of three ptients hs received nephrotoxic drugs, mking it impossible to determine the correltion between drug dose nd degree of proteinuri. None of the ptients with norml protein excretion hd received nephrotoxic drugs. Discussion One of the erliest studies of renl function in survivors of Wilms' tumour ws crried out by Mitus et l.7 It focused on the role of rdiotherpy to the remining kidney nd clculted the dose of rdition using the known sctter of rdition from the old orthovoltge mchines. They concluded tht t doses greter thn 12 cgy there ws significnt kidney dmge. Brrer et l found tht only two of 16 children hd mild proteinuri.8 They hd norml glomerulr filtrtion rtes, were normotensive, nd rdiotherpy ws not found to be importnt in the etiology of the proteinuri. Two studies hve been published suggesting tht renl function is norml for most survivors of unilterl Wilms' tumour. In the study by Bhisitkul et l,9 renl functionl reserve ws found to be norml in 12 survivors of unilterl Wilms' tumour (follow up 9-23 yers) nd their mtched controls. This ws determined by mesurement of cretinine clernce before nd fter n cute protein lod by mouth. They concluded tht for up to 15 yers fter nephrectomy for unilterl Wilms' tumour there ws no evidence of hyperfiltrtion injury. In the study by Mkipern et l four of 3 subjects hd subnorml kidney length nd five hd hypertension.' Tubulr function ws norml, nd lbumin excretion ws greter thn 2 mg/24 hours in three subjects. No correltion ws estblished between lbuminuri nd tretment modlities. The follow up time for this study ws 11-28 yers. There hve, however, been cse reports of children with congenitl single kidneys who hve subsequently developed serious renl impirment. Thorner et l reported three children with single kidneys who developed persistent proteinuri nd deteriortion in the glomerulr filtrtion rte. "l All hd renl biopsy smples showing focl segmentl glomerulosclerosis. In nother report two children treted for Wilms' tumour t 3 5 nd 18 months of ge developed persistent proteinuri nd glomerulosclerosis,'2 one of them requiring kidney trnsplnt t 21 yers of ge. Arch Dis Child: first published s 1.1136/dc.67.12.1462 on 1 December 1992. Downloded from http://dc.bmj.com/ on 15 August 218 by guest. Protected by copyright.
Mpofu, Mnn 1465 In our study we used the protein/cretinine index in erly morning urine smples s n indictor of renl function, nd only crried out more detiled ssessment in those ptients with bnorml results. Support for this pproch cn be found in niml nd humn studies. Provoost et l crried out work on rts in which they ssessed the effect of vrious levels of dietry protein on renl function in nephrectomised nd non-nephrectomised rts. 3 Exmintion of their curves for glomerulr filtrtion rte nd urinry protein excretion shows tht proteinuri preceded the decrese in glomerulr filtrtion rte. A similr pproch ws tken by Milford et l.'4 In their study of children with dirrhoe ssocited hemolytic uremic syndrome, they found strong correltion between the level of protein excretion nd renl function. Brrtt et l lso observed tht significnt glomerulr disese could be present in the bsence of ny chnges in glomerulr filtrtion rte mesurements.'5 The mesurement of proteinuri therefore provides method of detecting glomerulr disese t n erly stge nd wy of monitoring its course nd response to tretment. Assessment of proteinuri cn be crried out simply nd relibly by mesurement of the protein:cretinine rtio in single urine smples,'6 17 the effect of exercise nd the upright posture being eliminted by using erly morning urine.4 The results of our study show tht 1 of 11 of the ptients with n bnorml EMUp/c hd dverse fctors in ddition to nephrectomy contributing to -impired renl function. This finding is supported by nother study of ptients undergoing nephrectomy in childhood.'8 The significnce of the syndrome of mentl retrdtion, dysmorphism, nd hypotoni in reltion to renl function remins uncler, however. The presence of bilterl tumours ws clerly ssocited with the subsequent development of proteinuri (four of five such ptients), the common feture being loss of lrge proportions of kidney tissue. The most severely ffected ptients were those with bilterl tumours (three of four), the less severely ffected hving unilterl tumours (six of seven). In ddition to this two of the severely ffected ptients hd underlying renl bnormlities tht could themselves hve led to endstge renl filure (multicystic dysplstic kidneys), nd one subsequently received ifosfmide nd crbopltin (nephrotoxic drugs). Although we hve no biopsy mteril, it is well known tht Beckwith's syndrome is ssocited with renl disese. 9 The two ptients with this syndrome hd received whole bdominl rdition nd one hd lso received ifosfmide, so they hd multiple resons for the development of impired renl function. The one ptient with no obvious fctors in ddition to nephrectomy could hve impired renl function due to glomerulr hyperfiltrtion. This hs been described in severl studies on unilterlly nephrectomised rts' 2 2 nd the underlying pthology is identified s focl segmentl glomerulosclerosis. Other studies hve shown glomerulr hyperfiltrtion in children nd young dults with dibetes mellitus.2'23 Morit et l,24 in their study of renl biopsy smples from children nd dults with reflux nephropthy, found strong positive correltion between the percentge of glomeruli showing focl segmentl glomerulosclerosis nd the severity of proteinuri (r= 89; p< 1). The two renl biopsy smples showed chronic pyelonephritis in one nd erly chnges of glomerulr hyperfiltrtion in the other. Our study found tht most (86%) of the children surviving Wilms' tumour hd norml renl function. Impired renl function ws found in 1% of ptients with unilterl Wilms' tumour (seven of 71), nd 8% with bilterl tumours (four of five). Bilterl tumours clerly pose high risk of developing impired renl function. Pre-existing renl bnormlity, whole bdominl rdition, nd the use of nephrotoxic drugs provided extr risk fctors for those ptients with unilterl nd those with bilterl tumours. The ge t nephrectomy ws lower for ptients with reduced renl function compred with those whose renl function ws norml, though this difference ws not sttisticlly significnt. Other studies hve lso found similr results.25 26 We consider tht the use of the protein/ cretinine index in erly morning urine smples, with mesurement of blood pressure, is simple wy of monitoring these ptients. Our current prctice is to perform bseline determintion of the EMUp/c on completion of tretment nd nnully therefter s long s results re norml. When bnorml results re obtined the ptients re referred to the nephrology deprtment for further evlution nd mngement. To understnd more clerly the nturl course of renl function fter nephrectomy for Wilms' tumour longitudinl studies over prolonged periods of time re needed. It is plnned to crry out such studies in our centre, nd these will include mesurements of blood pressure, renl mss, nd function, nd storge of urine smples should llow future mesurement of proteins not currently mesurble. This study ws supported by the Leukemi Reserch Fund. We lso thnk Dr F Rft (Deprtment of pthology, Birminghm Children's Hospitl) nd Professor R H R White (Deprtment of nephrology, Birminghm Children's Hospitl) for llowing us to quote their opinions on the renl biopsy smples, nd Dr C M Tylor (deprtment of nephrology) for his dvice on the preprtion of this pper. 1 Brenner BM, Meyer TW, Hostetter TH. Dietry protein intke nd the progressive nture of kidney disese: the role of hemodynmiclly medited glomerulr injury in the pthogenesis of progressive glomerulr sclerosis in ging, renl bltion, nd intrinsic renl disese. N Engi Jf Med 1982;37:652-9. 2 Hostetter TH, Olson JL, Rennke HG, Venktchlm MA, Brenner BM. Hyperfiltrtion in remnnt nephrons: potentilly dverse response to renl bltion. AmJ3 Physiol 1981;241:F85-93. 3 Brdford MM. A rpid nd sensitive method for the quntittion of microgrm quntities of protein utilizing the principle of protein-dye binding. Ann Biochem 1976;72:248-54. 4 Elises JS, Griffiths PD, Hocking MD, Tylor CM, White RHR. Simplified quntittion of urinry protein excretion in children. C'ln Nephrol 1988,3:225-9. 5 Schwrtz GJ, Brion LP, Spitzer A. The use of plsm cretinine concentrtion for estimting glomerulr filtrtion rte in infnts, children, nd dolescents. Pedir Clin North Am 1987,34:571-9. 6 Report of the Second Tsk Force on Blood Pressure ntrol in Children. Peditrics 1987;79:1-25. 7 Mitus A, Tefft M, Fellers FX. Long term follow-up of renl Arch Dis Child: first published s 1.1136/dc.67.12.1462 on 1 December 1992. Downloded from http://dc.bmj.com/ on 15 August 218 by guest. Protected by copyright.
1466 Urinry proteinlcretinine index infouow up ofwilms' tumour functions of 18 children who underwent nephrectomy tor mlignnt disese. Peditrics 1%9;44:912-21. 8 Brrer M, Roy LP, Stevens M. Long-term follow-up fter unilterl nephrectomy nd rdiotherpy for Wilms' tumour. Peditr Nephrol 1989;3:43-2. 9 Bhisitkul DM, Morgn ER, Vozer MA, Lngmn CB. Renl functionl reserve in long-term survivors of Wilms' tumour. J Peditr 1991;118:698-72. 1 Mkipern A, Koskimies, Jskelinen J, Teppo AM, Siimes MA. Renl growth nd function 11-28 yers fter tretment of Wilms' tumour. Eur J Peditr 199;15: 444-7. 11 Thorner PS, Arbus GS, Celermjer DS, Buml R. Focl segmentl glomerulosclerosis nd progressive renl filure ssocited with unilterl kidney. Peditrics 1984;73: 86-1. 12 Welch TR, McAdms AJ. Focl glomerulosclerosis s lte sequel of Wilms' tumour. J Peditr 1986;18:15-9. 13 Provoost AP, De Keijzer MH, Molenr JC. Effect of protein intke on life long chnges in renl function of rts unilterlly nephrectomized t young ge. J Lb Clin Med 1989;114:19-26. 14 Milford DV, White RHR, Tylor CM. Prognostic significnce of proteinuri one yer fter onset of dirrhessocited hemolytic-uremic syndrome. I Peditr 199;118: 191-4. 15 Brrtt TM, McLine PN, Soothill JF. Albumin excretion s mesure of glomerulr dysfunction in children. Arch Dis Child 197;45:496-51. 16 Ginsberg JM, Chng BS, Mtrese RA, Grell S. Use of single voided urine smples to estimte quntittive proteinuri. N EnglJMed 1983;39:1543-6. 17 Houser M. Assessment of proteinuri using rndom urine smples.j7 Peditr 1984;14:845-8. 18 Robitille P, Lortie L, Mongeu J, Sinnssmy P. Long-term follow-up of ptients who underwent unilterl nephrectomy in childhood. Lncet 1985;i:1297-9. 19 Mulvihill DM, Mercdo M, Boineu FG. Beckwith- Wiedemnn syndrome nd its ssocition with type III polycystic kidney disese. Peditr-Nephrol 1989;3:286-9. 2 Shimmur T, Morrison AB. A progressive glomerulosclerosis occurring in prtil five-sixths nephrectomized rts. Am J Pthol 1975;79:95-11. 21 Schwrtz M, Ditzel J. Abnormlity incresed glomerulr filtrtion rte in short-term insulin treted dibetic subjects. Dibetes 1967;16:264-7. 22 Mogensen CE. Renl function chnges in dibetes. Dibetes 1976;25:872-9. 23 Christinsen JS, Frndsen M, Prving H-H. The effect of intrvenous insulin infusion on kidney function in insulindependent dibetes. Dibetologi 1981;2:199-24. 24 Morit M, Yoshir S, White RHR, Rft F. The glomerulr chnges in children with reflux nephropthy. J Pthwl 199;162:245-53. 25 Aperi A, Broberger, Wikstd I, Wilton P. Renl growth nd function in ptients nephrectomized in childhood. Act PeditrScnd 1977;66:185-92. 26 Boner G, Shelp WD, Newton M, Rieselbch RE. Fctors influencing the glomerulr filtrtion rte in the remining kidney of trnsplnt donors. AmJ Med 1973;55:169. Arch Dis Child: first published s 1.1136/dc.67.12.1462 on 1 December 1992. Downloded from http://dc.bmj.com/ on 15 August 218 by guest. Protected by copyright.