Pediatr Blood Cancer 2004;43:668–673

Late Effects on Renal Glomerular and Tubular Functionin Childhood Cancer Survivors

Edit Bardi, MD,1* Anna V. Olah, PhD,2 Katalin Bartyik, MD,3 Emoke Endreffy, PhD,3 Csaba Jenei, MD,4

Janos Kappelmayer, MD, PhD,2 and Csongor Kiss, MD, PhD, DSc1

INTRODUCTION

As the outcome of childhood cancer improved sub-stantially during the last three decades, the attitude ofpediatric oncology has changed from ‘‘cure at any cost’’ to‘‘cure at least cost’’ [1]. Acute renal side effects ofchemotherapy are well characterized. However, there is apaucity of data concerning late nephrotoxicity that mayinterfere with the child’s development and cause perma-nent morbidity. Impairment of renal function may be dueto the malignant process or may be secondary to a varietyof treatment modalities, such as cytostatic, irradiation,surgical, or even supportive therapy [2].

Few cytostatic agents have been associated with cli-nically relevant chronic nephrotoxicity. Among them,cisplatin (CPL) was reported to induce both long-lastingreduction in glomerular filtration rate (GFR) and renalmagnesium wasting, in some instances associated withhypocalcemia [3,4]. The decrease in GFR and tubulardysfunction depend on the administration schedule of thedrug [5]. Carboplatin (CARBO), a structural analogue ofCPL has been proposed as less nephrotoxic, since CARBOis associated with a less intensive lipid peroxidation thanCPL, and a decreased accumulation in renal tubular cellsas well [6].

Ifosfamide (IFO) has been shown to induce tubulardysfunction including proteinuria, Fanconi sydrome, andhypophosphatemic rickets [7,8]. Additional CPL therapymay increase the level of IFO-induced impairment oftubular function [9].

Late renal side effects of methotexate (MTX) arepoorly documented. Koch Nogueira et al. [10] investigatedrenal function of osteosarcoma survivors, who receivedhigh dose MTX in addition to CPL and IFO. Glomerularfunction was not significantly altered, only mild tubulardysfunction was observed.

The aim of this study was to evaluate renal functionand to assess late glomerular and tubular damages in 115children and young adults at least 48 months after com-pleting complex antineoplastic treatment.

Background. Late nephrotoxicity amongchildhood cancer survivors is poorly documen-ted. Methods.We investigated 115 patients and86 controls assessing serum cystatin C concen-tration (CysC), urinary N-acetyl-b-D-glucosami-nidase activity (NAG), and microalbuminuria.Protenuria was quantified and electrophoresisperformed. Polymorphism of the angiotensinconvertase enzyme (ACE) gene was determinedby genomic PCR. Results. CysC was elevated inWilms tumor (WT) patients. Gross proteinuriawas observed in 30 patients including threepatients with progressive proteinuria whoimproved on ACE-inhibitor treatment. Neither

patients with proteinuria nor the entire studypopulation differed from controls with respect toACE polymorphism. Pathologically elevatedurinary NAG was noted in 38% of leukemia/lymphoma, 54% of solid tumor, 20% of WTsurvivors. A similar distribution of pathologi-cal microalbuminuria was found. Conclusions.Mild-to-moderate subclinical glomerular andtubular damage can be identified in manychildhood cancer survivors. However, mostpatients experience some spontaneous recoveryfrom acute nephrotoxicity. Pediatr Blood Cancer2004;43:668–673. � 2004 Wiley-Liss, Inc.

Key words: ACE gene polymorphism; ACE-inhibitor treatment; cystatin C; latenephrotoxicity; N-acetyl-b-D-glucosaminidase; proteinuria

——————1Department of Pediatrics, Medical and Health Science Center,

University of Debrecen, Debrecen, Hungary

2Department of Clinical Biochemistry and Molecular Pathology,

Medical and Health Science Center, University of Debrecen,

Debrecen, Hungary

3Department of Pediatrics, Faculty of Medicine, Albert Szent-Gyorgyi

Medical and Pharmaceutical Center, University Szeged, Szeged,

Hungary

4H-Med Diagnostic and Research Laboratory, Budapest, Hungary

Grant sponsor: Health Science Council of the Ministry of Education

Republic of Hungary (ETT); Grant number: 225; Grant sponsor: ‘‘For

the leukemic children’’ foundations; Grant sponsor: ‘‘Hope for the

leukemic children’’ foundations.

*Correspondence to: Dr. Edit Bardi, Department of Pediatrics, Medical

and Health Science Center, University of Debrecen, H-4012 Debrecen,

P.O. Box 32, Hungary. E-mail: editbardi@hotmail.com

Received 9 September 2003; Accepted 11 June 2004

� 2004 Wiley-Liss, Inc.DOI 10.1002/pbc.20143

PATIENTS AND METHODS

Patients

This study evaluated renal function in children andyoung adults with cancer (65 males and 50 females, allCaucasian) treated at the Hematology-Oncology Unit ofthe Department of Pediatrics of the Medical and HealthScience Center of the University of Debrecen (MHSCUD)between 1984 and 2001. The median age at diagnosis was5 years (range: 0.3–20 years, mean: 6 years) and themedian time of follow-up at the time of investigation was7 years (range: 2–23 years, mean: 7 years). The medianage at the time of testing was 13 years (range: 3–24 years,mean 13 years). All patients were treated according tostandard protocols applied by the Hungarian PediatricOncology Group (HPOG). During the 17 years between1984 and 2001 different protocols were used; therefore,for further analysis, we divided the 115 patients into threegroups: leukemia-lymphoma (60 cases), Wilms tumor(WT) (22 cases), and (other) solid tumors (33 cases).Patients with leukemia and lymphoma were treatedaccording to BFM protocols [11–13] consisting of highdose (HD) MTX, cyclophosphamide (CYC), and IFO forhigh risk (HR), and Burkitt leukemia/lymphoma patients.Twenty-one WT patients underwent heminephrectomy,polar resection was performed in one case. Standardand medium risk patients (18 cases) were treated withvincristine and D-actinomycine, HR patients (4 cases)received IFO, and CARBO in addition. Eleven WTpatients received local (flank) irradiation. Twenty-oneadditional WT patients, treated in the Hematology-Oncology Unit of the Department of Pediatrics of theUniversity of Szeged, were included for determining theangiotensin I-converting enzyme (ACE) gene polymorph-ism. Patients with solid tumors (15 neuroblastoma, 6Ewing sarcoma/PNET, 4 germ cell tumor, 3 osteosarcoma,2 brain tumor, 2 retinoblastoma, and 1 soft tissue sarcoma)received either IFO or platinum derivates or HD MTXor combinations of these agents with or without addi-tional cytostatic drugs that have been considered lessnephrotoxic.

Eighty six children (46 males and 40 females) with amedian age of 10 years (range: 2–20 years, mean 12 years)without any renal or urinary tract disease were studied ascontrols. Informed consent was obtained from the parentsand/or guardians. The study protocol was accepted by theEthical Committee of MHSCUD.

Methods

Physical examination, blood pressure (RR) measure-ment, complete blood count, measurement of serum elec-trolytes, and standard urinalysis of a freshly void earlymorning midstream sample was performed according tostandard methods at every checkup. In case of persistent

(>12 months) gross proteinuria, as checked with dipsticktest, the amount of excreted protein was quantitated from a24 hr urine collection and electrophoresis was performed.Abdominal ultrasound (AUS) was obtained to check thesize, structure, and echogenicity of the kidney(s).

Serum cystatin C (cysC) concentration, expressed inmg/L was determined by particle enhanced immuno-turbidimetric assay (PETIA; Dako, Glostrup, Denmark)to characterize GFR [14–16]. The assay was performedon a Hitachi 717 analyzer (Boehringer, Mannheim,Germany), using the manufacturer’s recommendedprotocol.

Serum and urinary creatinine concentration was deter-mined using the kinetic Jaffes method on Hitachi 717analyser (Boehringer). GFR was calculated according tothe Counahan formula: 38�L (cm)/SCr (mmol/L) andgives an estimate in ml/min/1.73 m2 (L, body length; SCr,serum creatinine).

Urinary N-acetyl-b-D-glucosaminidase (NAG) enzymeactivity was determined by the modification of the methodof Horak et al., as described earlier together with age-specific reference values. NAG activities were normalizedfor urinary creatinine concentration was given as NAGindices (NAGi) and expressed in mmol/min/mmol creati-nine units [16]. To compare NAGi in patients with differentage, normalized age-specific NAGi (relative NAGi) wasexpressed in % as related to upper limit of the age matchedreference range. Microalbuminuria was determined in a24 hr collection sample by immunturbidimetric method(Cobas Integra 400, Roche, Basel, Switzerland) [17].

We performed genomic PCR to determine the insertion/deletion (I/D) polymorphism of the angiotensin con-vertase enzyme (ACE) gene. For screening the 273 bp Alurepeat I/D polymorphism in intron 16 of the ACE genewe used the following sense and antisense primers, takenfrom the literature: 5-CTGGAGACCACTCCCATCCTT-TCT-3 and 5-GATGTGGCCATCACATTCGTCAGAT-3,respectively. In 21 cases, an additional primer: 5-TCGA-GACCATCCCGGCTAAAAC-3, specific for the I allelewas included. The PCR reaction contained 50 ng oftemplate DNA, 1� reaction buffer, 2.5 mmol MgCl2,200 mmol of each of the dNTP, 0.6 mmol of each primerand 1U AmpliTaq DNA polymerase, in a final volume of25 ml. The PCR program consisted of an initial step of4 min at 958C, followed by 36 cycles of 30 sec at 948C,45 sec at 588C, and 45 sec at 728C. The PCR products of454 bp for I allele and 167 bp for the D allele wereseparated by agarose gel electrophoresis [18,19].

Statistical Analysis

Descriptive statistics test of Statistica for Windows wasused to determine normal distribution within groups. Theresults are reported as mean� standard deviation. CysC,relative NAGi, and microalbumin concentrations were

Late Nephrotoxicity in Childhood Cancer 669

compared by one-way ANOVA. Critical differencesbetween groups were assessed by Newman–Keuls post-hoc test. Correlation analysis was calculated by ‘‘Statisticafor Windows.’’ P values below 0.05 were reported asstatistically significant.

RESULTS

Each patient, except for one with chronic renal failure,was in a good general health at the time of testing(s).Baseline blood and urine laboratory values were withinthe normal range except for 30 patients exhibiting grossproteinuria, i.e., exhibiting a positive dipstick test. In WTpatients AUS revealed a 10% increase in the longestdiameter of the remaining kidney versus the size ofkidneys of the leukemia-lymphoma, solid tumor survivorsand age- and sex-matched controls. The kidneys of pa-tients with proteinuria showed an increased echogenicity.

CysC concentrations, used to characterize glomerularfunction of patients were not significantly different fromthat of the controls. In parallel with cysC, serum creatinineconcentrations and GFR values were within the normalrange (Table I). Assessing the three subgroups of patients,CysC, serum creatinine concentrations, and GFR values ofleukemia-lymphoma and solid tumor survivors did notdiffer from the control group and fell within the normalrange. We found however, a significantly elevated cysC inWT patients, in particular in HR patients (Fig. 1). In thissubgroup of patients, serum creatinine concentrationswere also mildly elevated (71� 21 mmol/L), whereas theGFR values (71� 27 ml/min/1.73 m2) were significantlylower (P< 0.05) than within the control group (132�79 ml/min/1.73 m2). One patient with WT-aniridia hasbeen put on chronic hemodialysis 7 years after hemine-phrectomy when he presented because of frequent vomit-ing at the Department of Internal Medicine of the CountyHospital, Szolnok. Biopsy was not performed because ofthe end-stage nature of renal failure. History revealedfrequent episodes of viral and bacterial respiratory tractinflammatory diseases since having lost to follow-up fromour institute 3 years after diagnosis.

We identified 30 patients with gross proteinuria. Pro-teinuria disappeared completely in 20 cases spotaneouslywithin 12 months after discovery. Persisting proteinuriawas further analyzed with quantitation of the excreted

protein in a 24 hr collection sample and by electrophoresis.Out of ten patients, five glomerular and five mixed(glomerular and tubular) proteinuria were noted. Of thesepatients four had leukemia-lymphoma, two had solidtumors, and four had WT. Each WT survivor had advanceddisease, requiring treatment with IFO and CARBOcontaining protocols with additional irradiation. The glo-merular proteinuria was selective in one case and non-selective in nine cases, its extent was from 214 to 907 mg/24 hr (mean: 455 mg/24 hr). In addition to gross glomer-ular proteinuria, these patients exhibited impaired tubularfunction, i.e., microalbuminuria (mean: 33 mg/L) andelevated NAGi (mean: 1.13 mmol/min/mmol creatinine).As expected, the degree of proteinuria correlated signi-ficantly with the amount of microalbuminuria (P< 0.05).We did not find significant correlations between otherparameters of glomerular and tubular functions amongpatients with persisting proteinuria, i.e., between thedegree of proteinuria, cysC, and NAGi (data not shown).During an average follow-up of 36 months from itsdiscovery, persisting proteinuria improved spontaneouslyin seven cases and progressed in three cases. Thesepatients, similar to all the other patients, had normal bloodpressure values at the time of testing. However, patientswith persisting proteinuria were put on ACE inhibitortherapy: two patients received enalapril (Renitec1, MSD,Whitehouse Station, NJ, USA, 2� 2.5 mg/day) andone patient received captopril (Tensiomin1, EGIS Co.,Budapest, Hungary, 2� 12.5 mg/day) because of her age(2½ years at the time of testing). After 12 months, pro-teinuria disappeared almost completely in the two patientson enalapril therapy and the third patient on captoprilexperienced a moderate improval.

Fig. 1. Distribution of cystatin C concentration of controls, leukemia-

lymphoma, solid tumor, and Wilms tumor (WT) survivors representing

GFR glomerular function parameters. Closed circles represent actual

patient and control values. Shaded areas indicate the reference range.

Lines represent mean values �1 SD. Open square indicates cystatin C

concentrations of HR WT patients. There was a statistically significant

difference (P< 0.05) in cystatin C concentrations of WT patients and

controls.

TABLE I. Cystatin C and Serum Creatinine Concentrations andGlomerular Filtration Rate (GFR) Values of Patients and Controls

Patients Controls

Cystatin C (mg/L)

Serum creatinine (mmol/L) 66� 17

GFR (ml/min/1.73 m2) 102� 35

Mean� SD values are given.

670 Bardi et al.

We investigated the ACE gene polymorphism ofpatients with proteinuria. The prevalence of the D allele,representing a risk factor in other forms of proteinuria, didnot differ significantly from that of the control group(Fig. 2). The distribution of genotypes, i.e., DD, ID and IIwere also similar to controls (not shown). Moreover,patients, including WT survivors did not differ signi-ficantly from the controls with respect to D and I allelefrequencies and ACE genotypes and were similar to that ofreported in other groups of healthy Caucasian individuals(Fig. 2).

Proximal tubular function was assessed by urinaryNAG and microalbuminuria. Pathologically elevated rela-tive NAGi exceeding age-related reference values werenoted in 24 (38%) among leukemia-lymphoma, in 13(54%)among solid tumor, in 4 (20%) among WT survivors. Asimilar distribution of pathological microalbuminuria(>20 mg/L) was found within these groups: in 12 (16%)among leukemia-lymphoma, in 7 (25%) among solidtumor, and in 1 (5%) among WT survivors (Table II).Relative NAGi and microalbuminuria was significantlyelevated only in solid tumor survivors. Former WT pa-tients exhibiting either pathologic relative NAGi or urinarymicroalbumin levels received CARBO and IFO because

of unfavorable disease. The mean� SD relative NAGi

and urinary microalbumin levels were 178.2� 10.5% and29.2� 4.1 mg/L in HR WT patients, whereas 92.7� 8.1%and 11.0� 5.8 mg/L in standard and intermediate riskgroups of WT patients.

DISCUSSION

We investigated late nephrotoxicity in former child-hood cancer patients. The spectrum of the patient popu-lation was broad both with respect of the underlyingmalignancy and of the time interval of admittance forprimary treatment. The design of the study allowed us tocharacterize both glomerular and tubular aspects of latenephrotoxicity. The advantage of such a study is to obtaina cross sectional view on potential hazards that mighthamper quality of life of pediatric patients cured fromcancer. Similar results have rarely been reported in theliterature [20,23,24]. On the other hand, patients weretreated with different drugs and combinations because ofthe differences in their former diseases and even changesin therapeutic protocols to be applied for the same diseaseover time. Therefore, our study is less powerful in iden-tifying single agents, dosages or combinations that mayresult in late kidney damage in particular in specific partsof the nephron. To overcome this disadvantage of thestudy, leukemia/lymphoma, WT, and (other) solid tumorsurvivors were analyzed separately since the treatmentmodalities with respect of potential kidney damage, suchas heminephrectomy, the use of known nephrotoxic agentswere different in these subpopulations, and similar withineach group.

We found less frequent and less severe late nephrotoxicside effects, involving both glomerular and tubular func-tion, among our patients than did most other investigators.However, the mean follow-up time (1–48 months) inthose studies was shorter than in our study (86 months)[21–24]. Recovery from CPL- and IFO-induced nephro-toxic damage may require up to 7 years as indicated byserial investigations [25,26].

Similar to our earlier observations, cysC proved moresensitive than serum creatinine and creatinine clearance tocharacterize glomerular function in children with cancer[15]. WT survivors exhibited a mean of 22%, a significantincrease in cysC concentration, as compared to the controlgroup. Overt chronic renal failure developed only in onepatient with the WT-aniridia complex. Persistent grossproteinuria, another indicator of glomerular functiondamage, was found in 10/115 patients, four leukemia/lymphoma, two solid tumor, and four WT survivors.Glomerular proteinuria improved spontaneously within24 months in seven patients and responded to ACEinhibitor therapy in three patients. Our results did notsupport an influence of ACE polymorphism on cyto-static therapy-induced late glomerular proteinuria, since

Fig. 2. Insertion/deletion polymorphism of angiotensin converting

enzyme (ACE) gene among controls and patients There are no statis-

tically significant differences between controls and investigated sub-

groups of patients.

TABLE II. Relative Urinary NAGi and Microalbuminuria inDifferent Groups of Patients and Controls

Patients Relative NAGi (%) Microalbuminuria (mg/L)

Leukemia-lymphoma 107.6� 67.0 16.4� 2.1

Wilms tumor 129.4� 12.7 16.6� 2.4

Solid tumor 247.4� 20.8* 24.9� 2.7**

Controls 95.3� 28.9* 15.78� 1.2**

Mean� SD values are given. NAGi was expressed in % as related to

mean age-specific reference value (100%).

*,**Represents statistically significant differences (P< 0.05) between

the corresponding values.

Late Nephrotoxicity in Childhood Cancer 671

patients with proteinuria did not differ significantly fromthe control group with respect of the prevalence of thedeletional (D) allele of the ACE gene. However, thenumber of patients with persistent gross proteinuria in thiscohort was too small to draw a final conclusion.

The elevated excretion of the lysosomal enzyme,NAG identified the most patients with impaired proximaltubular function (38% among leukemia/lymphoma, 54%among solid tumor and 20% among WT survivors). Finket al. found dramatical increases in the extent of enzymuriain patients one month after bone marrow transplantation(BMT). There were three autologous BMT survivors,among our patients. Two of these patients exhibited highNAGi (0.37 and 0.95 mmol/min/mmol creatinine) andelevated cysC (1.83 and 1.09 mg/L) at the same time.These two patients were cured from a hepatorenal syn-drome (HRS), a disorder associated with striking enzy-muria according to the observations of Fink et al. [24].Recent observations indicate that endothelial injury, asin HRS, results in an elevated serum level of NAG,which may contribute to the elevated degree of enzy-muria, in particular in patients with impaired glomerularfunction [27].

Similar to other studies, our results suggest an etiologicrole of platinum derivatives, CYC and IFO and HDMTX, particularly applied in combinations, in elicitinglate nephrotoxicity in children with cancer [9,10,28–30].First, cysC concentrations were exceedingly high in HRWT survivors, having received IFO and CARBO, sug-gesting that treatment with nephrotoxic agents may furthercompromise glomerular function in addition to hemine-phrectomy. Second, HR, but not low risk (SR) andintermediate risk (IR) WT survivors exhibited pathologicNAGi and microalbumin excretion. Third, proximaltubular dysfunction was not only most frequent but alsomost severe among solid tumor survivors. All of thesepatients received either IFO, CYC, platinum derivatives,or HD MTX or combinations of these cytostatics duringtheir treatment. Leukemia/lymphoma patients did notreceive platinum compounds, were exposed to lessercumulative doses of CYC than the majority of solid tumorpatients, only HR and Burkitt leukemia/lymphomapatients were treated with IFO. The cumulative dose ofMTX was the highest in osteosarcoma patients.

CONCLUSION

Due to routinely applied preventive measures duringchemotherapy, development of clinically significant renalabnormalities is an exception rather than a rule. Mostpatients experience some spontaneous recovery fromacute nephrotoxicity after completing antineoplastic ther-apy. However, mild-to-moderate subclinical glomerularand tubular damage can be identified in a notable pro-portion of childhood cancer survivors. Glomerular and

tubular compensatory mechanisms may moreover have anas yet unpredictable impact on long-term outcome of renalfunction. Therefore, patients at risk should be identifiedand subjected to life-long checkup programs to detectand manage kidney-associated late morbidity and thus,preserve quality of life. The paucity of data concerningchronic tubular toxicity of children cured from leukemia/lymphoma and WT warrant further studies aimed at thesetwo particular patient population. A further search fornovel nephroprotective drugs and measures is alsorequired. The role of ACE polymorphism, the indicationsof ACE inhibitor therapy and the selection of the optimalACE inhibitor(s) in improving chemotherapy-inducedproteinuria remains to be established in multi-centerclinical trials.

ACKNOWLEDGMENT

The help of Zsolt Karanyi in performing statisticalanalysis is acknowledged. We thank Giulio J. D’Angio,MD and Ildiko Bobok, MD for consultation and advice.Preliminary results of this study were published as anabstract on the 7th International Conference on Long TermComplications of Children and Adolescents with Cancer,in Niagara-on-the-Lake, 2002.

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