editorials

INDIAN PEDIATRICS 259 VOLUME 51__APRIL 15, 2014

E D I T O R I A LE D I T O R I A LE D I T O R I A LE D I T O R I A LE D I T O R I A L SSSSS

How Should We Manage Vitamin D Deficiency Rickets?JOHN M PETTIFOR

MRC/University Developmental Pathways for Health Research Unit, Faculty of Health Sciences, University of the Witwatersrand,Johannesburg, South Africa. [email protected]

Despite considerable concern being expressedby health professionals about the almostglobal distribution and high prevalence ofvitamin D deficiency among communities

[1,2], there are few trials that have evaluated the efficacyof various treatment regimens against one another for theprevention or management of vitamin D deficiencyrickets in children. In this issue, Gupta and his colleagues[3] have assessed the efficacy of two different levels ofStoss therapy, to not only treat vitamin D rickets but alsoto correct the vitamin D status, of young children. Theyconcluded that both 300,000 IU and 600,000 IU vitaminD3 as single day doses were equally effective in treatingchildren between 6 months and 5 years of age withvitamin D deficiency rickets, but that neither dose wasable to normalize the vitamin D status of the children – 3months after the administered dose. Although no adverseclinical events were detected during the course of thestudy, a small number of children had asymptomatichypercalcemia at 4 weeks or 3 months.

Although the management, both of vitamin Ddeficiency rickets, and of maintaining an adequatevitamin D status, is theoretically straight forward, as allthat is required is a daily dose of vitamin D – which willvary in size depending on whether one is correctingvitamin D deficiency or maintaining vitamin D status –the realities are very different. A number of studies in bothdeveloped and developing countries have highlighteddifficulties in ensuring patient treatment adherence,which is likely to be particularly problematic in theprevention strategies [4,5]. Thus in discussing possibleoptions for management, it is appropriate to discuss thetreatment of vitamin D deficiency separately from thatused for the prevention of vitamin D deficiency.

Single dose treatment (Stoss therapy) for vitamin Ddeficiency rickets makes considerable sense as it ensurespatient compliance and reduces the risk of incorrectdosage being administered by the caregiver; however,there is no consensus among health providers as to what isthe most appropriate dose. A single day dose between

300,000 IU and 600,000 IU vitamin D2 or D3 given orallyor intramuscularly has been recommended [6], butasymptomatic hypercalcemia and hypercalciuria havebeen reported by a number of researchers [3,7,8]. Lowerdoses of between 150,000 IU and 200,000 IU have alsoresulted in rapid healing of the biochemical andradiological abnormalities of rickets without the adverseeffects [7,9,10]. Although further studies may be requiredto confirm the efficacy of 150,000 IU as a treatment dose,health professionals should in the meantime be cautiousabout using higher doses of vitamin D (such as 600,000IU), especially in young children, in light of the reportedadverse effects.

The prevention of vitamin D deficiency at apopulation level requires a concerted effort from publichealth specialists. Although the use of daily supplementsis effective for individual subjects, who are at risk ofvitamin D deficiency, it is unlikely to address the problemin communities or segments of communities at-risk (suchas infants and young children, teenagers, and pregnantwomen). Intermittent vitamin D supplementation [11,12]or appropriate food fortification [13] should beconsidered. The possibility of combining intermittentvitamin D supplements with the immunization schedulewould allow for targeting of young children, whileproviding supplements (100,000 IU) every three to fourmonths at high school would target adolescents [14].Although the use of intermittent therapy makesconsiderable practical sense at a public health level,Hollis and Wagner provide a cautionary note that theactual circulating concentrations of the parent compounditself (vitamin D) might play an important role in thevitamin D endocrine/autocrine system [15], and thus theysuggest that daily treatment regimens may have differenteffects in comparison to those using intermittentregimens. As yet, empirical information is limited, but weshould be aware of the possibility of different outcomesdepending on the frequency of vitamin Dsupplementation.

With all the highly sophisticated technologies and


EDITORIALS

advances that are available and have been made in clinicalmedicine, the failure to eradicate vitamin D deficiency andparticularly rickets is an indictment on the healthprofessionals’ and national governments’ commitment toaddress the problem. Perhaps now that research issuggesting that a poor vitamin D status might haveconsequences on the health of adults, our legislators mightpay more attention to eradicating vitamin D deficiency.

Funding: None; Competing interests: None stated.

REFERENCES

1. Hossein-nezhad A, Holick MF. Vitamin D for health: aglobal perspective. Mayo Clin Proc. 2013;88:720-55.

2. Harinarayan CV, Joshi SR. Vitamin D status in India – itsimplications and remedial measures. J Assoc PhysiciansIndia. 2009;57:40-48.

3. Mittal H, Rai S, Shah D, Madhu SV, Mehrotra G, MalhotraRK, et al. 300,000 IU or 600,000 IU of oral vitamin D3 fortreatment of nutritional rickets: A randomized controlledtrial. Indian Pediatr. 2014;51:265-72

4. Grant CC, Stewart AW, Scragg R, Milne T, Rowden J,Ekeroma A, et al. Vitamin D during pregnancy and infancyand infant serum 25-hydroxyvitamin D concentration.Pediatrics. 2014;133:e143-53.

5. Rodd C, Jean-Philippe S, Vanstone C, Weiler H.Comparison of 2 vitamin D supplementation modalities innewborns: adherence and preference. Appl Physiol NutrMetab. 2011;36:414-8.

6. Shah BR, Finberg L. Single-day therapy for nutritionalvitamin D-deficiency rickets: a preferred method. J Pediatr.1994;125:487-90.

7. Cesur Y, Caksen H, Gundem A, Kirimi E, Odabas D.Comparison of low and high dose of vitamin D treatment in

nutritional vitamin D deficiency rickets. J PediatrEndocrinol Metab. 2003;16:1105-9.

8. Markestad T, Hesse V, Siebenhuner M, Jahreis G, AksnesL, Plenert W, et al. Intermittent high-dose vitamin Dprophylaxis during infancy: effect on vitamin Dmetabolites, calcium, and phosphorus. Am J Clin Nutr.1987;46:652-8.

9. Billoo AG, Murtaza G, Memon MA, Khaskheli SA, IqbalK, Rao MH. Comparison of oral versus injectable vitamin-D for the treatment of nutritional vitamin-D deficiencyrickets. J Coll Physicians Surg Pak. 2009;19:428-31.

10. Emel T, Doðan DA, Erdem G, Faruk O. Therapy strategiesin vitamin D deficiency with or without rickets: efficiencyof low-dose stoss therapy. J Pediatr Endocrinol Metab.2012;25:107-10.

11. Shaw NJ, Pal BR. Vitamin D deficiency in UK Asianfamilies: activating a new concern. Arch Dis Child.2002;86:147-9.

12. Oliveri B, Cassinelli H, Mautalen C, Ayala M. Vitamin Dprophylaxis in children with a single dose of 150000 IU ofvitamin D. Eur J Clin Nutr. 1996;50:807-10.

13. Ekbote VH, Khadilkar AV, Chiplonkar SA, HanumanteNM, Khadilkar VV, Mughal MZ. A pilot randomizedcontrolled trial of oral calcium and vitamin Dsupplementation using fortified laddoos in underprivilegedIndian toddlers. Eur J Clin Nutr. 2011;65:440-6.

14. Duhamel JF, Zeghoud F, Sempe M, Boudailliez B, OdievreM, Laurans M, et al. Prevention of vitamin D deficiency inadolescents and pre-adolescents. An interventionalmulticenter study on the biological effect of repeated dosesof 100,000 IU of vitamin D3. Arch Pediatr. 2000;7:148-53.

15. Hollis BW, Wagner CL. The role of the parent compoundvitamin D with respect to metabolism and function: whyclinical dose intervals can affect clinical outcomes. J ClinEndocrinol Metab. 2013;98:4619-28.

regimen, and shows that the lower dose of 300,000 unitsis not inferior to double this dose. It is also important tostress that the dose is effective orally. Many children aretreated with the same dose by intra-muscular injectionwhich is painful and unnecessary. This study shows goodclinical outcomes, and is in line with other clinical andpharmacokinetic studies showing effectiveness of oralVitamin D therapy [4,5]. The practice of injectingchildren should stop, except for rare instances – such as

Is Single Oral Dose of 300,000 IU Vitamin D3 Adequate forTreatment of Nutritional Rickets?

BENJAMIN JACOBSConsultant Pediatrician and Director of Children’s Service Royal National Orthopaedic Hospital, Stanmore, UK. [email protected]

Nutritional Rickets has recently re-emerged asa problem in many countries where it wasthought to have been eradicated [1]. Recentanalysis shows that hospitalization rates for

rickets in England are now the highest in five decades [2].Still, many modern clinicians in developed countries

have little experience or training in the management ofthis condition. The study published in this issue [3] ishelpful in highlighting the efficacy of a simple single dose


EDITORIALS

rickets associated with severe malabsorption – whereeven high oral doses are ineffective.

The authors comment on the risk of hypercalcaemia,but this study was not designed or powered to assess thispotential side-effect of vitamin D therapy. Hypercalcemiamay be due to other causes and should not preventclinicians treating rickets with adequate doses of vitaminD and/or calcium. Also it is important to remember thatafter effective treatments, such as those used in this study,a satisfactory blood level of vitamin D at follow-upshould not encourage clinicians or families to stop theregular low-dose prevention of doses of vitamin D whichare required long-term to prevent relapse of rickets. It ismy practice to recommend children diagnosed withrickets to take 1000 units of vitamin D daily to until theyhave finished growing, which would be more than 10years for most of the children in this study. Appropriatevitamin D and calcium intake should be also encouragedfor their siblings. That way many cases of rickets can beprevented. The financial savings in terms of blood tests,

X-rays and clinical follow-up should more than balancethe cost of the vitamin D.


REFERENCES

1. Lowdon J. Rickets: concerns over the worldwide increase.J Fam Health Care. 2011;21:25-9.

2. Goldacre M, Hall N, Yeates DG. Hospitalisation forchildren with rickets in England: a historical perspective.Lancet. 2014;383:597-8.

3. Mittal H, Rai S, Shah D, Madhu SV, Mehrotra G,Malhotra RK, et al. 300,000 IU or 600,000 IU of oralvitamin D3 for treatment of nutritional rickets: Arandomized controlled trial. Indian Pediatr. 2014;51:265-72.

4. Balasubramanian S, Dhanalakshmi K, Amperayani S.Vitamin D deficiency in childhood – a review of currentguidelines on diagnosis and management. Indian Pediatr.2013;50:669-75.

5. Shah BR, Finberg L. Single-day therapy for nutritionalvitamin D-deficiency rickets: a preferred method. JPediatr. 1994;125:487-90.


EDITORIALS

Accurate assessment of glomerular filtrationrate (GFR) is critical to estimate degree ofrenal impairment, intervening early toprevent end-stage renal failure, and dose

adjustment of drugs in renal impairment. An ideal renalfunction marker is one which is produced at a constantrate, is filtered freely in the glomeruli without any tubularsecretion, and is completely catabolized in the tubules.Conventionally, renal inulin clearance is the goldstandard for GFR estimation, but the method is flawed bydifficulty in collecting timed urine samples, especially inchildren with vesico-ureteral reflux or bladderdysfunction and lack of availability outside a researchsetting [1].

Creatinine clearance-based estimates of GFR arewidely used in children but are inaccurate because ofinfluence of various factors such as age, gender, musclemass and its catabolism and hydration status. Schwartzformula that takes into account height compensates forincrease muscle mass with age but leads tooverestimation of moderate to severely reduced GFR(<50 mL/min/1.73 m2) [2]. Though it obviates the need oftedious urine sampling, plasma creatinine values maychange with dietary intake of protein, nutritional status,hepatic disease and increased tubular creatinine secretion[3]. Moreover, creatinine is actively secreted by proximaltubules and tubular secretion increases at lower GFR.

Besides this, radio-isotopes like 51Cr-EDTA, 99Tc-DTPA, 125I-iothalamate and Iohexol are exclusivelyexcreted by glomerular filtration, and are precise andaccurate in measurement of GFR [4]. In patients withsignificant edema or ascites, tracer disappears into theexpanded extra-cellular volume leading to GFRoverestimation. Although accurate and precise, themethods are relatively cumbersome, invasive, andexpensive.

In search of an ideal marker of renal function,researchers have found serum cystatin C (s-cysC) anendogenous low molecular weight protein of cysteineproteinase family which is freely filtered in the glomeruli,completely reabsorbed by proximal tubule and isproduced at a constant rate [5]. S-CysC has beenproposed as a more sensitive marker of renal function

than plasma creatinine as subtle changes in GFR arereadily detected due to shorter half life of cystatin C andits level is not affected by age, gender, race and musclemass. By analyzing data from 536 children with variousrenal disorders, Filler and Lepage proposed a novel cysC-based GFR estimate [6]. Studies comparing cystatin-based formulas to Schwartz formula have showncontradictory results. While some have shown superiorityin terms of precision and accuracy [6,7] others did notprove any advantage [8]. For cysC, Knight, et al. [9]showed in a multivariate analysis adjusted for the level ofrenal function in a general population (8058 subjects) thats-cysC levels may be influenced by multiple factorsindependent of the renal function, especially high Creactive protein levels. Serum cystatin levels are alsoinfluenced by corticosteroid therapy, thyroid dysfunctionand ketonuria in diabetic children [4]. Hence, combinedserum cystatin C and creatinine based formulas mightincrease accuracy and precision to estimate GFR toovercome the disadvantages of individual marker.

Bouvet, et al. [10] prospectively studied 100 childrenand compared 51Cr-ethylenediaminetetraacetate (actualGFR) with estimated GFR by combined creatinine andserum cystatin C based equation. The estimation of GFRusing the final equation based on the four covariates(cysC, SCr, BW, and age) was less biased and moreprecise than the Schwartz formula. However for patientswith GFR <50 mL/min/1.73 m2, there was anoverestimation of GFR.

Hari, et al. [11] have studied 100 children with earlyCKD (GFR between 60-90 ml/min/1.73 m2) with 99mTc-diethylenetriamine penta acetic acid estimated GFR(dGFR) and by applying regression analysis derivedequation with creatinine, height and serum cystatin C ascovariates. The derived new equation for cystatin alonewhen compared with actual GFR was found tooverestimate, while combined creatinine and cystatinequation underestimated GFR. Cystatin C-basedequation [GFR=96.9 -30.4 x cystatin C] had significantlyless median bias (1.9 vs -12.4 mL/min/1.73 m2) (Signrank test, P=0.05), higher precision (13.1 vs 25.6 ml/min/1.73 m2) and accuracy (92.1% vs 75.7%) as compared tocreatinine-based equation. The authors concluded that

Is Combined Cystatin C and Creatinine Based EquationBetter in Predicting GFR?

ABHIJEET SAHADivision of Pediatric Nephrology, Department of Pediatrics, PGIMER, Dr RML Hospital, New Delhi, India.

[email protected]


EDITORIALS

Areliable and accurate assessment ofglomerular filtration rate (GFR) is critical fordiagnosing acute and chronic kidneyimpairment, intervening early to prevent end-

stage renal failure, prescribing nephrotoxic drugs anddrugs cleared by a failing kidney, and monitoring for sideeffects of medications. Estimation of GFR usingexogenously administered substances is well establishedand precise, but these methods are cumbersome and timeconsuming [1].

Plasma creatinine is the most commonly used indexfor estimating renal function in the clinical practice. Dueto its small size and lack of protein binding, it is freely

Estimating Accurate Glomerular Filtration Rate in ChildrenSIDHARTH KUMAR SETHI

Pediatric Nephrology, Kidney and Urology Institute, Medanta, The Medicity, Gurgaon, India. [email protected]

filtered through the glomerulus. However, it is alsoactively secreted by the proximal tubules at unpredictablerates. Moreover, with decreasing GFR, the fraction oftubular secretion increases, leading to an over-estimationof 10-40% when compared to that of inulin clearance [2].Especially in children, estimation of creatinine isdifficult, as there is a muscle mass related increase inplasma creatinine in children after 2 years of life.Moreover, plasma creatinine may change in cases ofexcessive dietary intake of meat, malnourished childrenand anorectic adolescents [3]. On the other hand, cystatinC is produced endogeneously at a constant rate, is freelyfiltered by the glomerulus, and is completely reabsorbedand catabolised by the renal tubule cells. Blood levels of

cystatin C-based equation was significantly better thancreatinine-based equation in terms of bias, precision andaccuracy in children with early CKD. Authors also foundthat adding creatinine to the cystatin C-based formula didnot improve the accuracy of predicted GFR. The majorstrength of this study is its methodologic rigor. Theauthors have rightly used Bland-Altman plots in the dataanalysis which strengthened the study conclusions andprovided a more precise evaluation of agreement. Furtherresearch is required – on a large, well-defined pediatricpopulation with carefully matched controls – to confirmthe usefulness of cystatin based estimation of GFR inpatients with early CKD.

Funding: None; Competing interest: None stated.

REFERENCES

1. Schwartz DJ, Work DF. Measurement and estimation ofGFR in Children and Adolescents. Clin J Am Soc Nephrol.2009;4:1832-43.

2. Seikaly MG, Browne R, Bajaj G, Arant BS Jr. Limitationsto body length/serum creatinine ratio as an estimate ofglomerular filtration in children. Pediatr Nephrol.1996;10:709-71.

3. Schwartz GJ, Brion LP, Spitzer A. The use of plasmacreatinine concentration for estimating glomerularfiltration rate in infants, children, and adolescents. PediatrClin North Am. 1987;34:571-90.

4. Andersen TP, Eskild-Jensen A, Frøkiær J, Brøchner-

Mortensen J. Measuring glomerular filtration rate inchildren; can cystatin C replace established methods? Areview. Pediatr Nephrol. 2009;24:929-41.

5. Filler G, Bökenkamp A, Hofmann W, Le Bricon T,Martinez-Bru C, Grubb A. Cystatin C as a marker of GFR-history, indications, and future research. Clin Biochem.2005;38:1-8.

6. Filler G, Lepage N. Should the Schwartz formula forestismation of GFR be replaced by cystatin C formula?Pediatr Nephrol. 2003;18:981-5.

7. Dharnidharka VR, Kwon C, Stevens G .Serum cystatin C issuperior to serum creatinine as a marker of kidney function:a meta-analysis. Am J Kidney Dis. 2002;40:221-6.

8. Willems HL, Hilbrands LB, van de Calseyde JF, MonnensLA, Swinkels DW. Is serum cystatin C the marker of choiceto predict glomerular filtration rate in pediatric patients?Ann Clin Biochem. 2003;40:60-4.

9. Knight EL, Verhave JC, Spiegelman D, Hillege HL, deZeeuw D, Curhan GC, et al. Factors influencingserum cystatin C levels other than renal function and theimpact on renal function measurement. Kidney Int.2004;65:1416-21.

10. Bouvet Y, Bouissou F, Coulais Y ,Vivien SS , Tafani M,Decramer S, Chatelut E. GFR is better estimated byconsidering both serum cystatin C and creatinine levels.Pediatr Nephrol. 2006;21:1299-1306.

11. Hari P, Ramakrishnan L, Gupta R, Kumar R, Bagga A.Cystatin C-based glomerular filtration rate estimatingequations in early chronic kidney disease. Indian Pediatr.2014:51:273-77.


EDITORIALS

cystatin C have been found to be a reliable indicator ofrenal function. The levels of cystatin C are independent ofage, height, obesity and malnutrition [3,4]. Recent studiesalso suggest that serum cystatin-C is better than serumcreatinine in detecting acute kidney injury in critically illchildren [2]. Due to high cost, difficult assaymethodologies and standardization, and non-availabilityof definite cut-off values, cystatin C has still not replacedcreatinine in the clinical practice.

To compensate for the increasing muscle mass duringchildhood, creatinine based formulae which includeheight and muscle mass have been developed. The mostcommonly used formula is the Schwartz formula. Thelow muscle mass in malnourished children, may influencethe value of k, and may affect the GFR estimation, andthus may lead to over-estimation of GFR in this subset[3]. Moreover, the value of k should be different based onthe method of estimation of serum creatinine. Schwartz,et al. [5], using the enzymatic method of creatinineestimation, recently proposed a new k value of 0.413. Toimprove the bias and accuracy of the GFR estimation, it isimportant for all the pediatricians to understand that thevalue of k should be locally derived based on the methodof creatinine estimation, reference GFR estimation andthe local population characteristics. Hari, et al. [6], basedon the regression analysis, found the value of k to be 0.42in Indian children where the creatinine was estimated bykinetic Jaffe method and 99mTc-DTPA GFR was thereference GFR.

Cystatin-C based equations have been found to havebetter accuracy of predicting GFR, as compared to thecreatinine based equations. The combined equations havegenerally been found to have better accuracy in theestimation, than individual equations [2]. In the currentissue of Indian Pediatrics, Hari, et al. [7] prove thatcystatin-C equations have better accuracy [7]. They alsofound that the combined cystatin-C and creatinine-basedequation was not better than only cystatin-C or creatininebased equation. The strengths of the study are testing theequation in the GFR 60-90 mL/min/1.73m2. Earlydetection of chronic kidney disease and monitoring ofrenal function deterioration requires an equation whichworks well in early stages of chronic kidney disease.Another strength of this study is its relevance for thepediatricians in India which can help in the currentclinical practice. There is a need to have more studies in

children and adolescents with an early chronic kidneydisease, to enhance the use of these equations.

It is important for pediatricians to understand thatchildren and adolescents with early chronic kidneydisease and a well-maintained fluid and electrolytebalance, the urinalysis may be entirely normal. Therefore,a reduced GFR may serve as the only clinical sign ofkidney damage. Early intervention in the course of renalimpairment offers the best chance of preventing end stagerenal disease in children. There currently exists noequation for monitoring acute changes in GFR [8].However, the equations developed till now, may be ableto determine longitudinal changes in GFR over time. Theparameters used in the equation may be used on thelocally available marker, which has been standardizedaccording to the local laboratory.


REFERENCES

1. Schwartz GJ, Brion LP, Spitzer A. The use of plasmacreatinine concentration for estimating glomerularfiltration rate in infants, children, and adolescents. PediatrClin North Am. 1987;34:571-90.

2. Andersen TB, Eskild-Jensen A, Frøkiaer J, Brøchner-Mortensen J. Measuring glomerular filtration rate inchildren; can cystatin C replace established methods? Areview. Pediatr Nephrol. 2009;24:929-41.

3. Hari P, Bagga A, Mahajan P, Lakshmy R. Effect ofmalnutrition on serum creatinine and cystatin C levels.Pediatr Nephrol. 2007;22:1757-61.

4. Bökenkamp A, Domanetzki M, Zinck R, Schumann G,Byrd D, Brodehl J. Cystatin C — a new marker ofglomerular filtration rate in children independent of ageand height. Pediatrics. 1998;101:875-81.

5. Schwartz GJ, Muñoz A, Schneider MF, Mak RH, Kaskel F,Warady BA, et al. New equations to estimate GFR inchildren with CKD. J Am Soc Nephrol. 2009;20:629-37.

6. Hari P, Biswas B, Pandey R, Kalaivani M, Kumar R, BaggaA. Updated height- and creatinine-based equation and itsvalidation for estimation of glomerular filtration rate inchildren from developing countries. Clin Exp Nephrol.2012;16:697-705.

7. Hari P, Ramakrishnan L, Gupta R, Kumar R, Bagga A.Cystatin-C based glomerular filtration rate estimatingequations in early chronic kidney disease. Indian Pediatr2014;51:273-77.

8. Schwartz GJ, Work DF. Measurement and estimation ofGFR in children and adolescents. Clin J Am Soc Nephrol.2009;4:1832-43.

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