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NDT Advance Access originally published online on September 6, 2008
Nephrology Dialysis Transplantation 2008 23(12):4079-4080; doi:10.1093/ndt/gfn508
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


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Nephrol Dial Transplant 2008; doi:10.1093/ndt/gfn507

E-mail: vm.kimmel{at}t-online.de

Sir,

We thank Gambaro et al. for the discussion of some aspects of our paper [1] focussing on the value of cystatin C as a biomarker in contrast-induced nephropathy (CIN).

There is an international consensus for the need of new biomarkers in acute kidney injury (AKI), and CIN is one of the most frequent reasons of AKI. Up to now, all biomarkers in AKI have limitations, but a whole panel of markers will be tested in ongoing studies. The definition of AKI is revised by the RIFLE criteria, with the intention to include changes in the glomerular filtration rate (GFR) and urine output [2].

In AKI and CIN, renal function is commonly monitored by following the variations in serum creatinine, but this variable has limitations as a marker of GFR in these patients. The serum creatinine concentration depends not only on the urinary clearance of creatinine but also on the rate of production and the volume of distribution [2]. Furthermore, acetylcysteine seems to affect the tubular handling of creatinine directly, so a decrease in serum creatinine concentration with this drug does not necessarily lead to a protective effect on the GFR [3].

Small molecular weight proteins, like cystatin C, have long been proposed as markers of GFR as they are normally freely filtered through the glomerular membrane. Cystatin C is produced at a constant rate by all nucleated cells and is catabolized by the tubulus [4]. Dharnidharka et al. reported in a meta-analysis that cystatin C is a superior marker of GFR [5]. One of the major problems in AKI and CIN trials is a lot of different definitions and a missing gold standard for GFR changes in AKI.

Finally, we will briefly address the comments in detail:

  1. The value of the two discussed biomarkers of GFR can be summarized: cystatin C is promising, but has to be better validated in special clinical situations and creatinine has its well-known limitations, especially in CIN. Our study does not prove the superiority of cystatin C over creatinine in CIN, but we detected changes in cystatin C not observed by creatinine. Today we indeed do not yet know the clinical benefit of a cystatin C-based CIN definition and we need larger trials (with hopefully a whole panel of biomarkers) with long-term prognostic outcome parameters.
  2. There should be no influence by release of cystatin C from atherosclerotic lesions in our study, because the groups were well matched and there was no significant difference in the CAD frequency between the groups.
  3. Gambaro et al. tried to explain our observed increments in cystatin C after contrast application by a cystatin C variability reported by Keevil et al. 10 years ago. Keevil et al. studied a whole different population: just 12 healthy volunteers with normal renal function using a turbidimetric assay [6]—we were studying a population with chronic kidney disease using a nephelometric assay. The accuracy, reference values, etc. of the available assays are different, as discussed 7 years later in the same journal [7]. Therefore, these old data cannot be an argument against an expected, significant increase in cystatin C after contrast application. Furthermore, the time course of our data is supported by Rickli et al., studying cystatin C in CIN without any pharmacological intervention [8].
  4. The data in Figure 1 are presented as mean + SD, and the observed variability in cystatin C from d-1 to d0 is not significant.
  5. Our observed creatinine drop during hydration with a stable cystatin C cannot be fully explained. There are several possible speculations; the one reported in the paper was based on different kinetic parameters: half-time of creatinine in blood is 2–3 min [9] and half-time of cystatin C is described to be 20 min [4]. An extensive literature research revealed a more complicated picture, which is contradictory to the speculation in our paper. Taking the volume distribution into account, the production rate and the nonrenal clearance of cystatin C, the time to attain a new steady-state of cystatin C will be about a third of that for creatinine [10].

In summary, our data are preliminary and we cannot prove the superiority of cystatin C—there are indeed larger trials needed. Based on our data, in future prevention trials of CIN we prefer cystatin C, but recommend to use a pattern of several biomarkers of AKI, for example, cystatin C, creatinine and neutrophil gelatinase-associated lipocalin.

Conflict of interest statement. None declared.

Martin Kimmel and Dominik Mark Alscher

Robert-Bosch-Hospital, Auerbachstr. 110, D-70376 Stuttgart, Germany

References

  1. Kimmel M, Butscheid M, Brenner S, et al. Improved estimation of glomerular filtration rate by serum cystatin C in preventing contrast induced nephropathy by N-acetylcysteine or zinc—preliminary results. Nephrol Dial Transplant (2008) 23:1241–1245.[Abstract/Free Full Text]
  2. Lameire N, Van Biesen W, Vanholder R. Acute renal failure. Lancet (2005) 365:417–430.[Web of Science][Medline]
  3. Hoffmann U, Fischereder M, Kruger B, et al. The value of N-acetylcysteine in the prevention of radiocontrast agent-induced nephropathy seems questionable. J Am Soc Nephrol (2004) 15:407–410.[Abstract/Free Full Text]
  4. Filler G, Bokenkamp A, Hofmann W, et al. Cystatin C as a marker of GFR—history, indications, and future research. Clin Biochem (2005) 38:1–8.[CrossRef][Web of Science][Medline]
  5. Dharnidharka VR, Kwon C, Stevens G. Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis. Am J Kidney Dis (2002) 40:221–226.[CrossRef][Web of Science][Medline]
  6. Keevil BG, Kilpatrick ES, Nichols SP, et al. Biological variation of cystatin C: implications for the assessment of glomerular filtration rate. Clin Chem (1998) 44:1535–1539.[Abstract/Free Full Text]
  7. Laterza OF, Price CP, Scott MG. Cystatin C: an improved estimator of glomerular filtration rate? Clin Chem (2002) 48:699–707.[Abstract/Free Full Text]
  8. Rickli H, Benou K, Ammann P, et al. Time course of serial cystatin C levels in comparison with serum creatinine after application of radiocontrast media. Clin Nephrol (2004) 61:98–102.[Web of Science][Medline]
  9. Gressner A, Arndt T. Lexikon der medizinischen Laboratoriumsdiagnostik. Springer Heidelberg (2007) 735.
  10. Sjöström P, Tidman M, Jones I. Determination of the production rate and non-renal clearance of cystatin C and estimation of the glomerular filtration rate from the serum concentration of cystatin C in humans. Scand J Clin Lab Invest (2005) 65:111–124.[Web of Science][Medline]

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Related articles in NDT:

Cystatin C and contrast-induced nephropathy
Giovanni Gambaro, Maria Stella Graziani, and Flavio Ribichini
NDT 2008 23: 4079. [Extract] [FREE Full Text]  




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