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Accuracy of cystatin C for the detection of abnormal renal function in children undergoing chemotherapy for malignancy: a systematic review using individual patient data

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Abstract

Purpose

We conducted a systematic review and individual patient data (IPD) meta-analysis to examine the utility of cystatin C for evaluation of glomerular function in children with cancer.

Methods

Eligible studies evaluated the accuracy of cystatin C for detecting poor renal function in children undergoing chemotherapy. Study quality was assessed using QUADAS-2. Authors of four studies shared IPD. We calculated the correlation between log cystatin C and GFR stratified by study and measure of cystatin C. We dichotomized the reference standard at GFR 80 ml/min/1.73m2 and stratified cystatin C at 1 mg/l, to calculate sensitivity and specificity in each study and according to age group (0–4, 5–12, and ≥ 13 years). In sensitivity analyses, we investigated different GFR and cystatin C cut points. We used logistic regression to estimate the association of impaired renal function with log cystatin C and quantified diagnostic accuracy using the area under the ROC curve (AUC).

Results

Six studies, which used different test and reference standard thresholds, suggested that cystatin C has the potential to monitor renal function in children undergoing chemotherapy for malignancy. IPD data (504 samples, 209 children) showed that cystatin C has poor sensitivity (63%) and moderate specificity (89%), although use of a GFR cut point of < 60 ml/min/1.73m2 (data only available from two of the studies) estimated sensitivity to be 92% and specificity 81.3%. The AUC for the combined data set was 0.890 (95% CI 0.826, 0.951). Diagnostic accuracy appeared to decrease with age.

Conclusions

Cystatin C has better diagnostic accuracy than creatinine as a test for glomerular dysfunction in young people undergoing treatment for cancer. Diagnostic accuracy is not sufficient for it to replace current reference standards for predicting clinically relevant impairments that may alter dosing of important nephrotoxic agents.

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References

  1. Blufpand HN, Hes N, Bokenkamp A, van de Wetering MD, Kaspers GJ (2014) Diversity in renal function monitoring and dose modifications during treatment for childhood cancer: a call for standardization. Pediatr Blood Cancer 61(2):337–344

    Article  PubMed  Google Scholar 

  2. Skinner R (2011) Nephrotoxicity—what do we know and what don’t we know? J Pediatr Hematol Oncol 33(2):128–134

    Article  PubMed  Google Scholar 

  3. Bardi E, Olah AV, Bartyik K et al (2004) Late effects on renal glomerular and tubular function in childhood cancer survivors. Pediatr Blood Cancer 43(6):668–673

    Article  PubMed  Google Scholar 

  4. Soveri I, Berg UB, Bjork J et al (2014) Measuring GFR: a systematic review. Am J Kidney Dis 64(3):411–424

    Article  PubMed  Google Scholar 

  5. Riley RD, Lambert PC, Abo-Zaid G (2010) Meta-analysis of individual participant data: rationale, conduct, and reporting. BMJ 340:c221

    Article  PubMed  Google Scholar 

  6. Stewart LA, Tierney JF (2002) To IPD or not to IPD? Advantages and disadvantages of systematic reviews using individual patient data. Eval Health Prof 25(1):76–97

    Article  PubMed  Google Scholar 

  7. Broeze KA, Opmeer BC, Bachmann LM et al (2009) Individual patient data meta-analysis of diagnostic and prognostic studies in obstetrics, gynaecology and reproductive medicine. BMC Med Res Methodol 9:22

    Article  PubMed Central  PubMed  Google Scholar 

  8. Whiting PF, Rutjes AW, Westwood ME et al (2011) QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med 155(8):529–536

    Article  PubMed  Google Scholar 

  9. Newson R (2006) Confidence intervals for rank statistics: Somers’ D and extensions. Stata J 6(3):309–334

    Google Scholar 

  10. Gronroos MH, Jahnukainen T, Irjala K et al (2008) Comparison of glomerular function tests in children with cancer. Pediatr Nephrol 23(5):797–803

    Article  PubMed  Google Scholar 

  11. Aydin F, Tezcan G, Gungor O et al (2010) Can serum cystatin C reflect the glomerular filtration rate accurately in pediatric patients under chemotherapeutic treatment? A comparative study with Tc-99m DTPA two-plasma sample method. Nucl Med Commun 31(4):301–306

    Article  CAS  PubMed  Google Scholar 

  12. Barnfield MC, Burniston MT, Reid U, Graham AM, Henderson M, Picton SV (2013) Cystatin C in assessment of glomerular filtration rate in children and young adults suffering from cancer. Nucl Med Commun 34(6):609–614

    Article  CAS  PubMed  Google Scholar 

  13. Blufpand HN, Tromp J, Abbink FC et al (2011) Cystatin C more accurately detects mildly impaired renal function than creatinine in children receiving treatment for malignancy. Pediatr Blood Cancer 57(2):262–267

    Article  PubMed  Google Scholar 

  14. Djemli A, Merouani A, Lambert R et al (2005) Cystatin C: A marker of kidney function in pediatric oncology. Clin Chem 51:A34-A

    Google Scholar 

  15. Lankisch P, Wessalowski R, Maisonneuve P, Haghgu M, Hermsen D, Kramm CM (2006) Serum cystatin C is a suitable marker for routine monitoring of renal function in pediatric cancer patients, especially of very young age. Pediatr Blood Cancer 46(7):767–772

    Article  CAS  PubMed  Google Scholar 

  16. National Institute of Diabetes and Digestive and Kidney Diseases (2015) Creatinine standardization recommendations. https:/www.niddk.nih.gov/health-information/health-communication-programs/nkdep/lab-evaluation/gfr/creatinine-standardization/recommendations/Pages/recommendations.aspx (accessed 15/6/2017)

  17. Smith A, Messenger M, Hall P, Hulme C (2017) The incorporation of data on pre-analytical and analytical factors in model-based Health Technology Assessments (HTAs) of medical tests: a systematic review. PROSPERO International prospective register of systematic reviews. http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42017056778 (accessed)

  18. Harman G, Akbari A, Hiremath S et al (2013) Accuracy of cystatin C-based estimates of glomerular filtration rate in kidney transplant recipients: a systematic review. Nephrol Dial Transplant : Off Publ Eur Dial Transplant Assoc – Eur Renal Assoc 28(3):741–757

    Article  CAS  Google Scholar 

  19. de Souza V, Cochat P, Rabilloud M et al (2015) Accuracy of different equations in estimating GFR in pediatric kidney transplant recipients. Clin J Am Soc Nephrol : CJASN 10(3):463–470

    Article  PubMed Central  PubMed  Google Scholar 

  20. Terpos E, Christoulas D, Kastritis E et al (2013) The Chronic Kidney Disease Epidemiology Collaboration cystatin C (CKD-EPI-CysC) equation has an independent prognostic value for overall survival in newly diagnosed patients with symptomatic multiple myeloma; is it time to change from MDRD to CKD-EPI-CysC equations? Eur J Haematol 91(4):347–355

    CAS  PubMed  Google Scholar 

  21. Hingorani S, Pao E, Schoch G, Gooley T, Schwartz GJ (2015) Estimating GFR in adult patients with hematopoietic cell transplant: comparison of estimating equations with an iohexol reference standard. Clin J Am Soc Nephrol : CJASN 10(4):601–610

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Ito R, Yamakage H, Kotani K et al (2015) Comparison of cystatin C- and creatinine-based estimated glomerular filtration rate to predict coronary heart disease risk in Japanese patients with obesity and diabetes. Endocr J 62(2):201–207

    Article  CAS  PubMed  Google Scholar 

  23. Nejat M, Pickering JW, Walker RJ et al (2010) Urinary cystatin C is diagnostic of acute kidney injury and sepsis, and predicts mortality in the intensive care unit. Crit Care 14(3):R85

    Article  PubMed Central  PubMed  Google Scholar 

  24. Swedish Council on Health Technology Assessment (2012) Methods to estimate and measure renal function (glomerular filtration rate): a systematic review. http://sbu.se/en/Published/Yellow/Methods-to-Estimate-and-Measure-Renal-Function-Glomerular-Filtration-Rate/

  25. Shlipak MG, Matsushita K, Arnlov J et al (2013) Cystatin C versus creatinine in determining risk based on kidney function. N Engl J Med 369(10):932–943

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Bardi E, Bobok I, Olah AV, Olah E, Kappelmayer J, Kiss C (2004) Cystatin C is a suitable marker of glomerular function in children with cancer [see comment]. Pediatr Nephrol 19(10):1145–1147

    Article  PubMed  Google Scholar 

  27. Skinner R, Cole M, Pearson AD et al (1994) Inaccuracy of glomerular filtration rate estimation from height/plasma creatinine ratio. Arch Dis Child 70(5):387–390

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Bernhardt MB, Moffett BS, Johnson M, Tam VH, Thompson P, Garey KW (2015) Agreement among measurements and estimations of glomerular filtration in children with cancer. Pediatr Blood Cancer 62(1):80–84

    Article  PubMed  Google Scholar 

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Acknowledgements

Members of the cystatin C in Childhood Cancer Collaboration Group are as follows: Mark Barnfield (St James’s University Hospital, Leeds, England), Kate Birnie (University of Bristol, England), Hester Blufpand (VU University Medical Center, Amsterdam, The Netherlands), Arend Bokenkamp (VU University Medical Center, Amsterdam, The Netherlands), Marika Grönroos (Turku University Hospital, Finland), Catherine Jameson (University of Bristol, England), Petra Lankisch (University Hospital Düsseldorf, Germany), Bob Philips (University of York, England), Rod Skinner (Great North Children’s Hospital, Newcastle upon Tyne, England), Jonathan Sterne (University of Bristol, England), Penny Whiting (University of Bristol, England). We would like to thank Rebecca Beynon for her help in screening search results and assessing studies for inclusion in the systematic review.

Funding

This project was funded by the Medical Research Council (G0801405/1). JS was supported by National Institute for Health Research (NIHR) Senior Investigator Awards (NF-SI-0611-10168). KB was supported by a Medical Research Council UK fellowship (RD1826). RSP is supported by the National Institute for Health Research (NIHR) Postdoctoral Award (PDF-2014-07-072). PW is funded by a National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care West (NIHR CLAHRC West). The sponsor had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. All authors had full access to all the data in the study.

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Authors and Affiliations

  1. NIHR CLAHRC West, University Hospitals Bristol NHS Foundation Trust, 9th Floor, Whitefriars, Lewins Mead, Bristol, BS1 2NT, UK

    Penny Whiting

  2. Bristol Medical School, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS, UK

    Penny Whiting, Kate Birnie, Jonathan A. C. Sterne & Catherine Jameson

  3. Department of Paediatric and Adolescent Haematology / Oncology and Children’s BMT Unit, Great North Children’s Hospital, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK

    Rod Skinner

  4. Centre for Reviews and Dissemination, University of York, York, YO10 5DD, UK

    Bob Phillips

Authors
  1. Penny Whiting
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  2. Kate Birnie
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  3. Jonathan A. C. Sterne
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  4. Catherine Jameson
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  5. Rod Skinner
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Consortia

the Cystatin C in Childhood Cancer Collaboration Group

  • Mark Barnfield
  • , Kate Birnie
  • , Hester Blufpand
  • , Arend Bokenkamp
  • , Marika Grönroos
  • , Catherine Jameson
  • , Petra Lankisch
  • , Bob Philips
  • , Rod Skinner
  • , Jonathan Sterne
  •  & Penny Whiting

Contributions

PW, JS, and BP conceived the idea for the study and drafted the protocol. PW and CJ identified studies for inclusion, extracted data and performed the risk of bias assessment. PW performed the synthesis of the summary data. KB and JACS performed the analysis of the IPD data. BP and RS provided clinical input. Members of the 5C collaboration shared IPD data from their studies. All authors revised the manuscript for important intellectual content and approved the final version of the manuscript. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Penny Whiting.

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Conflict of interest

The authors declare that they have no conflict of interest.

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Whiting, P., Birnie, K., Sterne, J.A.C. et al. Accuracy of cystatin C for the detection of abnormal renal function in children undergoing chemotherapy for malignancy: a systematic review using individual patient data. Support Care Cancer 26, 1635–1644 (2018). https://doi.org/10.1007/s00520-017-4002-3

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  • DOI: https://doi.org/10.1007/s00520-017-4002-3

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