- Email: [email protected]
Response to ‘Cystatin C: a promising misunderstood biomarker for the diagnosis of acute kidney injury’
letter to the editor
http://www.kidney-international.org & 2008 International Society of Nephrology
Cystatin C: a promising misunderstood biomarker for the diagnosis of acute kidney injury Kidney International (2008) 74, 1623; doi:10.1038/ki.2008.431
To the Editor: Recently, we read with interest and pleasure Coca et al.’s1 systematic review of the accuracy and reliability of serum and urinary biomarkers for the diagnosis and risk stratification of acute kidney injury (AKI). One of Coca et al.’s findings is that serum cystatin C (CysC) performed best for early as well as differential diagnosis of established AKI. Timing for the detection of early-stage renal impairment is extremely important, especially in the therapeutic management of complex illness. In an acute condition, the absence of a reliable biomarker and the reliance on serum Cr (sCr) markedly delays the diagnosis and, consequently, the institution of therapy. Recently, research interest on the role of serum CysC in an intensive care unit (ICU) population has been stopped after the presumed association of CysC with inflammatory biomarkers in non-critically ill patients.2 We retrospectively reviewed all laboratory data referral to 1000 patients (611 mean, mean age 64.3 years) admitted in the ICU or the post-cardiac surgery intensive care unit (PCSICU). PCSICU population was submitted to extracorporeal circulation during cardiac surgical intervention. A total of 3993 samples tested contemporaneously for sCr, CysC and C-reactive protein (CRP) were selected (Table 1). Renal replacement therapy and known thyreopathy were exclusion criteria. No correlations between CysC vs CRP and sCr vs CRP were found either in ICU or in PCSICU. Moreover, we observed a well-known correlation between sCr and CysC in our entire population (r ¼ 0.739, Po0.01). Our results are encouraging for the resumption of the use of CysC
Table 1 | Mean and standard deviation (s.d.) of age, sCr, CysC and C-reactive protein (CRP) in our ICU population Age (years)
Cystatin C (0.55–0.95 mg/l)
CRP (o5 mg/ 100 ml)
Creatinine (0.7–1.2 mg/100 ml)
Women N 1662 Mean 65.4 s.d. 16.1
1662 1.94 1.14
1662 102.8 95.5
1661 0.97 0.75
Men N 2331 Mean 58.9 s.d. 18.1
2331 1.786 1.08
2331 105.7 97.7
2328 1.16 1.10
Total N 3993 Mean 61.6 s.d. 17.6
3993 1.85 1.10
3993 104.5 96.8
3989 1.08 0.97
CysC, cystatin C; ICU, intensive care unit; sCr, serum Cr.
Kidney International (2008) 74, 1623–1627
for monitoring renal function in critically ill patients. Large multicenter studies in ICU populations are needed for definitive approval or not of serum CysC in early AKI diagnosis. 1.
2.
Coca SG, Yalavarthy R, Concato J et al. Biomarkers for the diagnosis and risk stratification of acute kidney injury: a systematic review. Kidney Int 2008; 73: 1008–1016. Knight EL, Verhave JC, Spiegelman D et al. Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement. Kidney Int 2004; 65: 1416–1421.
Michele Ferrannini1, Gisella Vischini1 and Nicola Di Daniele1 1
Department of Internal Medicine, Nephrology and Dialysis Unit, ‘Tor Vergata’ University, Rome, Italy Correspondence: Michele Ferrannini, Nephrology and Dialysis Unit, ‘Tor Vergata’ Hospital, Viale Oxford 81-00133, Rome, Italy. E-mail: [email protected]
Response to ‘Cystatin C: a promising misunderstood biomarker for the diagnosis of acute kidney injury’ Kidney International (2008) 74, 1623–1624; doi:10.1038/ki.2008.435
We read with interest the letter in response to our systematic review and the new data from Ferrannini et al.,1 which demonstrates that serum cystatin C is not correlated with C-reactive protein and is strongly correlated with serum creatinine. We agree that more studies investigating the utility of serum cystatin C in acute kidney injury (AKI) for critically ill patients should be conducted. It is important, however, to not just correlate cystatin C concentration with serum creatinine concentration, as was presented in the study. The objective of the novel biomarker studies should be to replace serum creatinine or strengthen the current diagnostic and prognostic assessment along with serum creatinine. Thus, it is important to design studies and perform analyses, that would delineate other attributes of the new diagnostic tool rather than mimicking the diagnostic abilities of serum creatinine. For example, a study by Herget-Rosenthal et al.,2 demonstrated that the rise in serum cystatin C preceded the rise in serum creatinine by 1.5±0.6 days. This study also compared the performance of cystatin C against clinically meaningful end points, including the RIFLE definitions for AKI and dialysis-requiring AKI. 1623
letter to the editor
Thus, the three major goals of future biomarker studies, as discussed in our review, should be the following: (1) to differentiate types of AKI at the time of diagnosis (acute tubular necrosis vs. prerenal vs. other); (2) to predict or diagnose AKI earlier than the ‘delayed’ clinical diagnosis via creatinine; (3) to predict hard outcomes (need for dialysis, length of stay, death) at the time of injury.3 In the absence of associations between biomarkers and these hard end points, the availability of another biomarker that ‘mimics’ creatinine will not be beneficial in advancing the field of AKI. We would encourage Ferrannini et al. to perform the analyses we have mentioned in order to determine how cystatin C performs for predicting these types of end points. 1. Ferrannini M, Vischini G, De Daniele N. Cystatin C: a promising misunderstood biomarker for the diagnosis of acute kidney injury. Kidney Int 2008, in press. 2. Herget-Rosenthal S, Marggraf G, Husing J et al. Early detection of acute renal failure by serum cystatin C. Kidney Int 2004; 66: 1115–1122. 3. Coca SG, Yalavarthy R, Concato J et al. Biomarkers for the diagnosis and risk stratification of acute kidney injury: a systematic review. Kidney Int 2008; 73: 1008–1016.
Chirag R. Parikh1,2 and Steven G. Coca3
times are utilized whenever possible with the modal dialysis time being 4.5 h. Our center utilizes postdilution hemodiafiltration as standard. There is increasing evidence that the use of hemodiafiltration is associated with improvements in blood pressure control, incidence of intradialytic hypotension and a reduction in mortality.2–4 Predialysis hypertension does not obviate hypotension episodes5 and not having targets for blood pressure control will not necessarily reduce the frequency of hypotension episodes. When improved control of blood pressure is desired, modifications to the dialysis treatment itself should be considered as part of the management strategy. ACKNOWLEDGMENTS
The authors acknowledge that all aspects of dialysis treatment at the John Stevenson Lynch Unit, Crosshouse Hospital are jointly decided with Dr Mackay I., Dr Innes A., Dr MacGregor M., and Dr Velasco N. in equal share. We thank the Chief Dialysis Technician Mr John Wright for facilitating this audit and the Dialysis Nurses and patients at Crosshouse Hospital. 1.
2.
1
Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut, USA; 2Clinical Epidemiology Research Center, Veterans Affairs Medical Center, West Haven, Connecticut, USA and 3Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA Correspondence: Chirag R. Parikh, Section of Nephrology, Yale University School of Medicine and VAMC, 950 Campbell Ave, Mail Code 151B, Building 35A, Room 219, West Haven, Connecticut 6516, USA. E-mail: [email protected]
Dialysis hypotension: don’t blame the targets Kidney International (2008) 74, 1624; doi:10.1038/ki.2008.433
To the Editor: The article by Davenport et al.1 suggests that improved blood pressure control increases intradialytic hypotension. It is unlikely that the reported higher incidence of hypotension is caused by trying to achieve the Renal Association targets alone. In a study of 991 dialysis treatments in 111 patients over a 3-week period, we documented predialysis blood pressures of 136.9±23.4/67.8±14.0 mm Hg and postdialysis blood pressures of 133.0±24.0/65.8±12.5 mm Hg. The Renal Association targets were achieved by 56.8% of patients predialysis, 44.1% postdialysis, and 37.8% achieved both targets. Intradialytic hypotension occurred in 2.4% of all treatments. No significant differences were demonstrated in the blood pressure, interdialytic weight gains or prescribed medication of those who experienced hypotension and those who did not. Two critical factors implemented in our unit may contribute to these findings. We recognize that short dialysis times make ultrafiltration more difficult to tolerate and increase the potential for hypotension. Longer treatment 1624
3.
4.
5.
Davenport A, Cox C, Thuraisingham R. Achieving blood pressure targets during dialysis improves control but increases intradialytic hypotension. Kidney Int 2008; 73: 759–764. Canaud B. Effect of online hemodiafiltration on morbidity and mortality of chronic kidney disease patients. Contrib Nephrol 2007; 158: 216–224. Velasco N. Convection with conviction-online hemodiafiltration for all: single center clinical observations. Hemodial Int 2006; 10(Suppl 1): S67–S71. Ansell D, Roderick P, Hodsman A et al. Chapter 6: Survival of Incident and Prevalent Patients. 93–120. 2007. Bristol. UK Renal Registry Report 2007. Kilmarnock 110. Takeda A, Toda T, Fujii T et al. Can predialysis hypertension prevent intradialytic hypotension in hemodialysis patients? Nephron Clin Pract 2006; 103: c137–c143.
Elaine M. Spalding1 and Nestor Velasco1 1 Renal Unit, Crosshouse Hospital, Kilmarnock, UK Correspondence: Nestor Velasco, Renal Unit, Crosshouse Hospital, Kilmarnock KA2 0BE, Scotland, UK. E-mail: [email protected]
Response to ‘Dialysis hypotension: don’t blame the targets’ Kidney International (2008) 74, 1624–1625; doi:10.1038/ki.2008.437
High blood pressure is a major health issue in all regions of the world,1 and myocardial infarction and stroke are the commonest causes of death and disability worldwide.2 However, although there is a strong relationship between blood pressure and the risk of cardio- and cerebrovascular disease in the general population,1,2 this relationship is less clear for hemodialysis patients, despite the increased incidence of hypertension in this patient group. Assuming a normal distribution, then the 95% confidence limits for pre-dialysis blood pressure recordings were 183/95–91/ 39 mm Hg, and 181/91–85/41 mm Hg post-dialysis recordings for the patients dialysing in Kilmarnock, and as such only just over one-third of patients achieved the current KDOQI blood pressure targets. Thus even in a single unit, Kidney International (2008) 74, 1623–1627
http://www.kidney-international.org & 2008 International Society of Nephrology
Cystatin C: a promising misunderstood biomarker for the diagnosis of acute kidney injury Kidney International (2008) 74, 1623; doi:10.1038/ki.2008.431
To the Editor: Recently, we read with interest and pleasure Coca et al.’s1 systematic review of the accuracy and reliability of serum and urinary biomarkers for the diagnosis and risk stratification of acute kidney injury (AKI). One of Coca et al.’s findings is that serum cystatin C (CysC) performed best for early as well as differential diagnosis of established AKI. Timing for the detection of early-stage renal impairment is extremely important, especially in the therapeutic management of complex illness. In an acute condition, the absence of a reliable biomarker and the reliance on serum Cr (sCr) markedly delays the diagnosis and, consequently, the institution of therapy. Recently, research interest on the role of serum CysC in an intensive care unit (ICU) population has been stopped after the presumed association of CysC with inflammatory biomarkers in non-critically ill patients.2 We retrospectively reviewed all laboratory data referral to 1000 patients (611 mean, mean age 64.3 years) admitted in the ICU or the post-cardiac surgery intensive care unit (PCSICU). PCSICU population was submitted to extracorporeal circulation during cardiac surgical intervention. A total of 3993 samples tested contemporaneously for sCr, CysC and C-reactive protein (CRP) were selected (Table 1). Renal replacement therapy and known thyreopathy were exclusion criteria. No correlations between CysC vs CRP and sCr vs CRP were found either in ICU or in PCSICU. Moreover, we observed a well-known correlation between sCr and CysC in our entire population (r ¼ 0.739, Po0.01). Our results are encouraging for the resumption of the use of CysC
Table 1 | Mean and standard deviation (s.d.) of age, sCr, CysC and C-reactive protein (CRP) in our ICU population Age (years)
Cystatin C (0.55–0.95 mg/l)
CRP (o5 mg/ 100 ml)
Creatinine (0.7–1.2 mg/100 ml)
Women N 1662 Mean 65.4 s.d. 16.1
1662 1.94 1.14
1662 102.8 95.5
1661 0.97 0.75
Men N 2331 Mean 58.9 s.d. 18.1
2331 1.786 1.08
2331 105.7 97.7
2328 1.16 1.10
Total N 3993 Mean 61.6 s.d. 17.6
3993 1.85 1.10
3993 104.5 96.8
3989 1.08 0.97
CysC, cystatin C; ICU, intensive care unit; sCr, serum Cr.
Kidney International (2008) 74, 1623–1627
for monitoring renal function in critically ill patients. Large multicenter studies in ICU populations are needed for definitive approval or not of serum CysC in early AKI diagnosis. 1.
2.
Coca SG, Yalavarthy R, Concato J et al. Biomarkers for the diagnosis and risk stratification of acute kidney injury: a systematic review. Kidney Int 2008; 73: 1008–1016. Knight EL, Verhave JC, Spiegelman D et al. Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement. Kidney Int 2004; 65: 1416–1421.
Michele Ferrannini1, Gisella Vischini1 and Nicola Di Daniele1 1
Department of Internal Medicine, Nephrology and Dialysis Unit, ‘Tor Vergata’ University, Rome, Italy Correspondence: Michele Ferrannini, Nephrology and Dialysis Unit, ‘Tor Vergata’ Hospital, Viale Oxford 81-00133, Rome, Italy. E-mail: [email protected]
Response to ‘Cystatin C: a promising misunderstood biomarker for the diagnosis of acute kidney injury’ Kidney International (2008) 74, 1623–1624; doi:10.1038/ki.2008.435
We read with interest the letter in response to our systematic review and the new data from Ferrannini et al.,1 which demonstrates that serum cystatin C is not correlated with C-reactive protein and is strongly correlated with serum creatinine. We agree that more studies investigating the utility of serum cystatin C in acute kidney injury (AKI) for critically ill patients should be conducted. It is important, however, to not just correlate cystatin C concentration with serum creatinine concentration, as was presented in the study. The objective of the novel biomarker studies should be to replace serum creatinine or strengthen the current diagnostic and prognostic assessment along with serum creatinine. Thus, it is important to design studies and perform analyses, that would delineate other attributes of the new diagnostic tool rather than mimicking the diagnostic abilities of serum creatinine. For example, a study by Herget-Rosenthal et al.,2 demonstrated that the rise in serum cystatin C preceded the rise in serum creatinine by 1.5±0.6 days. This study also compared the performance of cystatin C against clinically meaningful end points, including the RIFLE definitions for AKI and dialysis-requiring AKI. 1623
letter to the editor
Thus, the three major goals of future biomarker studies, as discussed in our review, should be the following: (1) to differentiate types of AKI at the time of diagnosis (acute tubular necrosis vs. prerenal vs. other); (2) to predict or diagnose AKI earlier than the ‘delayed’ clinical diagnosis via creatinine; (3) to predict hard outcomes (need for dialysis, length of stay, death) at the time of injury.3 In the absence of associations between biomarkers and these hard end points, the availability of another biomarker that ‘mimics’ creatinine will not be beneficial in advancing the field of AKI. We would encourage Ferrannini et al. to perform the analyses we have mentioned in order to determine how cystatin C performs for predicting these types of end points. 1. Ferrannini M, Vischini G, De Daniele N. Cystatin C: a promising misunderstood biomarker for the diagnosis of acute kidney injury. Kidney Int 2008, in press. 2. Herget-Rosenthal S, Marggraf G, Husing J et al. Early detection of acute renal failure by serum cystatin C. Kidney Int 2004; 66: 1115–1122. 3. Coca SG, Yalavarthy R, Concato J et al. Biomarkers for the diagnosis and risk stratification of acute kidney injury: a systematic review. Kidney Int 2008; 73: 1008–1016.
Chirag R. Parikh1,2 and Steven G. Coca3
times are utilized whenever possible with the modal dialysis time being 4.5 h. Our center utilizes postdilution hemodiafiltration as standard. There is increasing evidence that the use of hemodiafiltration is associated with improvements in blood pressure control, incidence of intradialytic hypotension and a reduction in mortality.2–4 Predialysis hypertension does not obviate hypotension episodes5 and not having targets for blood pressure control will not necessarily reduce the frequency of hypotension episodes. When improved control of blood pressure is desired, modifications to the dialysis treatment itself should be considered as part of the management strategy. ACKNOWLEDGMENTS
The authors acknowledge that all aspects of dialysis treatment at the John Stevenson Lynch Unit, Crosshouse Hospital are jointly decided with Dr Mackay I., Dr Innes A., Dr MacGregor M., and Dr Velasco N. in equal share. We thank the Chief Dialysis Technician Mr John Wright for facilitating this audit and the Dialysis Nurses and patients at Crosshouse Hospital. 1.
2.
1
Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut, USA; 2Clinical Epidemiology Research Center, Veterans Affairs Medical Center, West Haven, Connecticut, USA and 3Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA Correspondence: Chirag R. Parikh, Section of Nephrology, Yale University School of Medicine and VAMC, 950 Campbell Ave, Mail Code 151B, Building 35A, Room 219, West Haven, Connecticut 6516, USA. E-mail: [email protected]
Dialysis hypotension: don’t blame the targets Kidney International (2008) 74, 1624; doi:10.1038/ki.2008.433
To the Editor: The article by Davenport et al.1 suggests that improved blood pressure control increases intradialytic hypotension. It is unlikely that the reported higher incidence of hypotension is caused by trying to achieve the Renal Association targets alone. In a study of 991 dialysis treatments in 111 patients over a 3-week period, we documented predialysis blood pressures of 136.9±23.4/67.8±14.0 mm Hg and postdialysis blood pressures of 133.0±24.0/65.8±12.5 mm Hg. The Renal Association targets were achieved by 56.8% of patients predialysis, 44.1% postdialysis, and 37.8% achieved both targets. Intradialytic hypotension occurred in 2.4% of all treatments. No significant differences were demonstrated in the blood pressure, interdialytic weight gains or prescribed medication of those who experienced hypotension and those who did not. Two critical factors implemented in our unit may contribute to these findings. We recognize that short dialysis times make ultrafiltration more difficult to tolerate and increase the potential for hypotension. Longer treatment 1624
3.
4.
5.
Davenport A, Cox C, Thuraisingham R. Achieving blood pressure targets during dialysis improves control but increases intradialytic hypotension. Kidney Int 2008; 73: 759–764. Canaud B. Effect of online hemodiafiltration on morbidity and mortality of chronic kidney disease patients. Contrib Nephrol 2007; 158: 216–224. Velasco N. Convection with conviction-online hemodiafiltration for all: single center clinical observations. Hemodial Int 2006; 10(Suppl 1): S67–S71. Ansell D, Roderick P, Hodsman A et al. Chapter 6: Survival of Incident and Prevalent Patients. 93–120. 2007. Bristol. UK Renal Registry Report 2007. Kilmarnock 110. Takeda A, Toda T, Fujii T et al. Can predialysis hypertension prevent intradialytic hypotension in hemodialysis patients? Nephron Clin Pract 2006; 103: c137–c143.
Elaine M. Spalding1 and Nestor Velasco1 1 Renal Unit, Crosshouse Hospital, Kilmarnock, UK Correspondence: Nestor Velasco, Renal Unit, Crosshouse Hospital, Kilmarnock KA2 0BE, Scotland, UK. E-mail: [email protected]
Response to ‘Dialysis hypotension: don’t blame the targets’ Kidney International (2008) 74, 1624–1625; doi:10.1038/ki.2008.437
High blood pressure is a major health issue in all regions of the world,1 and myocardial infarction and stroke are the commonest causes of death and disability worldwide.2 However, although there is a strong relationship between blood pressure and the risk of cardio- and cerebrovascular disease in the general population,1,2 this relationship is less clear for hemodialysis patients, despite the increased incidence of hypertension in this patient group. Assuming a normal distribution, then the 95% confidence limits for pre-dialysis blood pressure recordings were 183/95–91/ 39 mm Hg, and 181/91–85/41 mm Hg post-dialysis recordings for the patients dialysing in Kilmarnock, and as such only just over one-third of patients achieved the current KDOQI blood pressure targets. Thus even in a single unit, Kidney International (2008) 74, 1623–1627