- Email: [email protected]
Response to ‘Hemoglobin level in dialysis patients: Revisiting the normal hematocrit study’
letter to the editor
http://www.kidney-international.org & 2007 International Society of Nephrology
Hemoglobin level in dialysis patients: Revisiting the normal hematocrit study Kidney International (2007) 72, 1161; doi:10.1038/sj.ki.5002498
To the Editor: Vanbelleghem et al.1 (21 March 2007) imply that the Normal Hematocrit study2 (NHS) should not be used as a rationale for proposing conservative hemoglobin targets (a minimum hemoglobin of 10 g/dl used in the UK guidelines). Implicit in their discussion is that the NHS is not generalizable to the dialysis population, echoing a similar refrain made by Macdougall and Ritz3 several years ago. On the contrary, I would submit that the NHS is quite representative of the dialysis population. Most importantly, as has been noted elsewhere,4 the 24% mortality observed in NHS was very similar to the 20.4% mortality per 1000 patients reported by the United States Renal Data System. Indeed, cardiovascular disease is highly prevalent among the dialysis population,5 as it was in the NHS. It is also important to note that while the NHS was stopped by the Data and Safety Monitoring Board, discontinuation was because of safety concerns with regards to mortality.2 The authors of the NHS state ‘(The) Study was halted when differences in mortality between the groups were recognized as sufficient to make it very unlikely that continuation of the study would reveal a benefit for the normal-hematocrit group and the results were nearing the statistical boundary of a higher mortality rate in the normal hematocrit group.’ Indeed, the NHS represents the largest randomized controlled study conducted in dialysis patients examining hemoglobin targets. Quite curiously, despite the mortality signal from NHS, this question has not subsequently been examined in any similarly sized study in dialysis patients. In the wake of recent data in the non-dialysis chronic kidney disease patients6,7 that reinforce the safety signal that emerged from the NHS, the FDA black box advisory,8 and the less than compelling quality of life benefits4 for a higher hemoglobin target, surely a prudent strategy is to aim for the lowest possible hemoglobin level needed to avoid blood transfusions and optimize quality of life. 1. Vanbelleghem H, Vanholder R, Levin NW et al. The Kidney Disease: Improving Global Outcomes website: comparison of guidelines as a tool for harmonization. Kidney Int 2007; 71: 1054–1061; 21 March 2007. 2. Besarab A, Bolton WK, Browne JK et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. New Engl J Med 1998; 339: 584–590. 3. Macdougall IC, Ritz E. The Normal Haematocrit Trial in dialysis patients with cardiac disease: are we any the less confused about target haemoglobin? Nephrol Dial Transplant 1998; 13: 3030–3033. 4. Strippoli GF, Craig JC, Manno C, Schena FP. Hemoglobin targets for the anemia of chronic kidney disease: a meta-analysis o randomized, controlled trials. J Am Soc Nephrol 2004; 15: 3154–3165. 5. Cheung AK, Sarnak MJ, Yan G, et al., Levey AS HEMO Study Group. Cardiac diseases in maintenance hemodialysis patients: results of the HEMO Study. Kidney Int 2004; 65: 2380–2389. Kidney International (2007) 72, 1161–1165
6.
7.
8.
Singh AK, Szczech L, Tang KL, et al., Reddan D CHOIR Investigators. Correction of anemia with epoetin alfa in chronic kidney disease. New Engl J Med 2006; 355: 2085–2098. Drueke TB, Locatelli F, Clyne N, et al., CREATE Investigators. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. New Engl J Med 2006; 355: 2071–2084. http://www.fda.gov/cder/drug/advisory/RHE2007.htm.
AK Singh1 1 Department of Medicine, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA Correspondence: AK Singh, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA. E-mail: [email protected]
Response to ‘Hemoglobin level in dialysis patients: Revisiting the normal hematocrit study’ Kidney International (2007) 72, 1161–1162; doi:10.1038/sj.ki.5002538
We thank Dr Singh1 for his comments on our recent publication comparing current major guidelines on the Kidney Disease: Improving Global Outcomes (KDIGO) website.2 His expressed concern about the generalizability of the Normal Hematocrit Study (NHS)3 is quite appropriate. The guidelines are currently under re-examination by guideline development groups in light of recent data from the CREATE and CHOIR studies on the correction of anemia in chronic kidney disease with erythropoiesisstimulating agents.4,5 This is well beyond the actual message of our article, which was that nephrology guidelines worldwide come to different recommendations and evidence grading, in spite of being based on the same literature.2 As such, the paper mentioned the UK anemia guideline to be discordant from other major guidelines, but never suggested that the UK guidelines or any other guidelines were wrong or should be discarded because of this discordance. Importantly, as the averages in the lowhemoglobin groups in the CREATE and CHOIR studies were higher than 11 g/dl, there are still no data to comment unequivocally on any target hemoglobin below 11 g/dl, as do the UK guidelines. The CREATE and CHOIR studies were not referenced in our article because neither had appeared in print when the paper was submitted for publication. Additionally, their results had not been included in the evidence tables of any published guidelines. This analysis is currently under way 1161
letter to the editor
and will be included on the KDIGO website when published. 1. Singh. Hemoglobin level in dialysis patients: Revisiting the normal hematocrit study. Kidney Int 2007 (in press). 2. Vanbelleghem H, Vanholder R, Levin NW et al. The kidney disease: improving global outcomes website: comparison of guidelines as a tool for harmonization. Kidney Int 2007; 71: 1054–1061. 3. Besarab A, Bolton WK, Browne JK et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998; 339: 584–590. 4. Drueke TB, Locatelli F, Clyne N et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Eng J Med 2006; 355: 2071–2084. 5. Singh AK, Szczech L, Tang KL et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006; 355: 2085–2098.
R Vanholder1, H Vanbelleghem1, N Lameire1 and G Eknoyan1 1 Department of Nephrology, University of Ghent, Waregem, Belgium Correspondence: H Vanbelleghem, Department of Nephrology, University of Ghent, Walstraat 178, 9870 Zulte, Belgium. E-mail: [email protected]
Advisory about gadolinium calls for caution in the treatment of uremic patients with lanthanum carbonate
Gadolinium is the 64th element of the periodic table at the center of the lanthanide series (14 elements) (Figure 1). It is known that all the members of the series display very close physical-chemical characteristics yielding trivalent ions whose (very small) differences in their chemical behavior are essentially determined by the changes in the mass to charge ratio.3 The use of lanthanum-carbonate salts as chelating agents might have some analogies with what we are learning from the gadodiamide story. Lanthanum-carbonate has been selected for its insolubility. However, it has been reported that lanthanum concentration is increased 10-fold in blood and fivefold in bone after short-term supplementation.4,5 What’s about long-term treatments? Equilibrium shifts and transmetallation reactions may lead to unexpected interferences with basic physiological processes and the upsurge of diseased states as shown with gadodiamide. Clearly, more work appears necessary to assess potential toxic effects associated to the use of lanthanide-based drugs. By now, as many uremic patients are taking lanthanumcarbonate as phosphate-binder, nephrologists are strongly recommended to look at any symptoms evoking NSF/NSD in post-marketing drug-safety surveillance system. 1.
2.
Kidney International (2007) 72, 1162–1163; doi:10.1038/sj.ki.5002503
To the Editor: The FDA issued advisories concerning the risk for patients with renal failure who receive gadolinium-chelates for developing a sometimes fatal disorder called NephrogenicFibrosis-Dermopathy (NFD)/Nephrogenic-Systemic-Fibrosis (NSF).1 Although the disease mechanism has yet to be elucidated, there is consensus that NFD/NFS could be associated to the release of free gadolinium in the tissues. The cells may act as sponges for the free-gadolinium ions by exploiting (and thus interfering) the calcium regulatory machinery.2
3. 4.
5.
FDA. Public Health Advisory – Gadolinium-containing Contrast Agents for Magnetic Resonance Imaging (MRI): Omniscan, OptiMARK, Magnevist, ProHance, and MultiHance. Available at: http://www.fda.gov/ cder/drug/advisory/gadolinium_agents.htm Accessed May, 2007. Cabella C, Crich SG, Corpillo D et al. Cellular labeling with Gd(III) chelates: only high thermodynamic stabilities prevent the cells acting as ‘sponges’ of Gd3+ions. Contrast Media Mol Imaging 2006; 1: 23–29. Evans CH. Biochemistry of the Lanthanides. Plenum Press: New York and London, 1990. Canavese C, Mereu C, Nordio M et al. Blast from the past: the aluminum’s ghost on the lanthanum salts. Curr Med Chem 2005; 12: 1631–1636. Slatopolsky E, Liapis H, Finch J. Progressive accumulation of lanthanum in the liver of normal and uremic rats. Kidney Int 2006; 68: 2809–2813.
S Aime1, C Canavese2 and P Stratta2 1 Department of Chemistry IF.M and Molecular Imaging Center of the University of Torino, Maggiore Hospital, Novara, Italy and 2Clinical
Periodic table of the elements H
He
LI
Be
B
C
N
O
F
Ne
Na
Mg
Al
Si
P
S
Cl
Ar
K
Ca
Ga
Ge
As
Se
Br
Kr
Sc
Ti
V
Cr
Mn
Fe
Co
Ni
Cu
Zn
Rb
Sr
Y
Zr
Nb
Mo
Tc
Ru
Rh
Pd
Ag
Cd
In
Sn
Sb
Te
I
Xe
Cs
Ba
La
Hf
Ta
W
Re
Os
Ir
Pt
Au
Hg
TI
Pb
Bi
Po
At
Rn
Fr
Ra
Ac
Rf
Db
Sg
Bh
Hs
Mt
Uun
Uuu
Uub
Lanthanide series Ce
Pr
Nd
Pm
Sm
Eu
Gd
Tb
Dy
Ho
Er
Tm
Yb
Lu
Th
Pa
U
Np
Pu
Am
Cm
Bk
Cf
Es
Fm
Md
No
Lr
Actinide series
Figure 1 | Periodic table of the elements: gadolinium (Gd) belongs to the lanthanide series. 1162
Kidney International (2007) 72, 1161–1165
http://www.kidney-international.org & 2007 International Society of Nephrology
Hemoglobin level in dialysis patients: Revisiting the normal hematocrit study Kidney International (2007) 72, 1161; doi:10.1038/sj.ki.5002498
To the Editor: Vanbelleghem et al.1 (21 March 2007) imply that the Normal Hematocrit study2 (NHS) should not be used as a rationale for proposing conservative hemoglobin targets (a minimum hemoglobin of 10 g/dl used in the UK guidelines). Implicit in their discussion is that the NHS is not generalizable to the dialysis population, echoing a similar refrain made by Macdougall and Ritz3 several years ago. On the contrary, I would submit that the NHS is quite representative of the dialysis population. Most importantly, as has been noted elsewhere,4 the 24% mortality observed in NHS was very similar to the 20.4% mortality per 1000 patients reported by the United States Renal Data System. Indeed, cardiovascular disease is highly prevalent among the dialysis population,5 as it was in the NHS. It is also important to note that while the NHS was stopped by the Data and Safety Monitoring Board, discontinuation was because of safety concerns with regards to mortality.2 The authors of the NHS state ‘(The) Study was halted when differences in mortality between the groups were recognized as sufficient to make it very unlikely that continuation of the study would reveal a benefit for the normal-hematocrit group and the results were nearing the statistical boundary of a higher mortality rate in the normal hematocrit group.’ Indeed, the NHS represents the largest randomized controlled study conducted in dialysis patients examining hemoglobin targets. Quite curiously, despite the mortality signal from NHS, this question has not subsequently been examined in any similarly sized study in dialysis patients. In the wake of recent data in the non-dialysis chronic kidney disease patients6,7 that reinforce the safety signal that emerged from the NHS, the FDA black box advisory,8 and the less than compelling quality of life benefits4 for a higher hemoglobin target, surely a prudent strategy is to aim for the lowest possible hemoglobin level needed to avoid blood transfusions and optimize quality of life. 1. Vanbelleghem H, Vanholder R, Levin NW et al. The Kidney Disease: Improving Global Outcomes website: comparison of guidelines as a tool for harmonization. Kidney Int 2007; 71: 1054–1061; 21 March 2007. 2. Besarab A, Bolton WK, Browne JK et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. New Engl J Med 1998; 339: 584–590. 3. Macdougall IC, Ritz E. The Normal Haematocrit Trial in dialysis patients with cardiac disease: are we any the less confused about target haemoglobin? Nephrol Dial Transplant 1998; 13: 3030–3033. 4. Strippoli GF, Craig JC, Manno C, Schena FP. Hemoglobin targets for the anemia of chronic kidney disease: a meta-analysis o randomized, controlled trials. J Am Soc Nephrol 2004; 15: 3154–3165. 5. Cheung AK, Sarnak MJ, Yan G, et al., Levey AS HEMO Study Group. Cardiac diseases in maintenance hemodialysis patients: results of the HEMO Study. Kidney Int 2004; 65: 2380–2389. Kidney International (2007) 72, 1161–1165
6.
7.
8.
Singh AK, Szczech L, Tang KL, et al., Reddan D CHOIR Investigators. Correction of anemia with epoetin alfa in chronic kidney disease. New Engl J Med 2006; 355: 2085–2098. Drueke TB, Locatelli F, Clyne N, et al., CREATE Investigators. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. New Engl J Med 2006; 355: 2071–2084. http://www.fda.gov/cder/drug/advisory/RHE2007.htm.
AK Singh1 1 Department of Medicine, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA Correspondence: AK Singh, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA. E-mail: [email protected]
Response to ‘Hemoglobin level in dialysis patients: Revisiting the normal hematocrit study’ Kidney International (2007) 72, 1161–1162; doi:10.1038/sj.ki.5002538
We thank Dr Singh1 for his comments on our recent publication comparing current major guidelines on the Kidney Disease: Improving Global Outcomes (KDIGO) website.2 His expressed concern about the generalizability of the Normal Hematocrit Study (NHS)3 is quite appropriate. The guidelines are currently under re-examination by guideline development groups in light of recent data from the CREATE and CHOIR studies on the correction of anemia in chronic kidney disease with erythropoiesisstimulating agents.4,5 This is well beyond the actual message of our article, which was that nephrology guidelines worldwide come to different recommendations and evidence grading, in spite of being based on the same literature.2 As such, the paper mentioned the UK anemia guideline to be discordant from other major guidelines, but never suggested that the UK guidelines or any other guidelines were wrong or should be discarded because of this discordance. Importantly, as the averages in the lowhemoglobin groups in the CREATE and CHOIR studies were higher than 11 g/dl, there are still no data to comment unequivocally on any target hemoglobin below 11 g/dl, as do the UK guidelines. The CREATE and CHOIR studies were not referenced in our article because neither had appeared in print when the paper was submitted for publication. Additionally, their results had not been included in the evidence tables of any published guidelines. This analysis is currently under way 1161
letter to the editor
and will be included on the KDIGO website when published. 1. Singh. Hemoglobin level in dialysis patients: Revisiting the normal hematocrit study. Kidney Int 2007 (in press). 2. Vanbelleghem H, Vanholder R, Levin NW et al. The kidney disease: improving global outcomes website: comparison of guidelines as a tool for harmonization. Kidney Int 2007; 71: 1054–1061. 3. Besarab A, Bolton WK, Browne JK et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998; 339: 584–590. 4. Drueke TB, Locatelli F, Clyne N et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Eng J Med 2006; 355: 2071–2084. 5. Singh AK, Szczech L, Tang KL et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006; 355: 2085–2098.
R Vanholder1, H Vanbelleghem1, N Lameire1 and G Eknoyan1 1 Department of Nephrology, University of Ghent, Waregem, Belgium Correspondence: H Vanbelleghem, Department of Nephrology, University of Ghent, Walstraat 178, 9870 Zulte, Belgium. E-mail: [email protected]
Advisory about gadolinium calls for caution in the treatment of uremic patients with lanthanum carbonate
Gadolinium is the 64th element of the periodic table at the center of the lanthanide series (14 elements) (Figure 1). It is known that all the members of the series display very close physical-chemical characteristics yielding trivalent ions whose (very small) differences in their chemical behavior are essentially determined by the changes in the mass to charge ratio.3 The use of lanthanum-carbonate salts as chelating agents might have some analogies with what we are learning from the gadodiamide story. Lanthanum-carbonate has been selected for its insolubility. However, it has been reported that lanthanum concentration is increased 10-fold in blood and fivefold in bone after short-term supplementation.4,5 What’s about long-term treatments? Equilibrium shifts and transmetallation reactions may lead to unexpected interferences with basic physiological processes and the upsurge of diseased states as shown with gadodiamide. Clearly, more work appears necessary to assess potential toxic effects associated to the use of lanthanide-based drugs. By now, as many uremic patients are taking lanthanumcarbonate as phosphate-binder, nephrologists are strongly recommended to look at any symptoms evoking NSF/NSD in post-marketing drug-safety surveillance system. 1.
2.
Kidney International (2007) 72, 1162–1163; doi:10.1038/sj.ki.5002503
To the Editor: The FDA issued advisories concerning the risk for patients with renal failure who receive gadolinium-chelates for developing a sometimes fatal disorder called NephrogenicFibrosis-Dermopathy (NFD)/Nephrogenic-Systemic-Fibrosis (NSF).1 Although the disease mechanism has yet to be elucidated, there is consensus that NFD/NFS could be associated to the release of free gadolinium in the tissues. The cells may act as sponges for the free-gadolinium ions by exploiting (and thus interfering) the calcium regulatory machinery.2
3. 4.
5.
FDA. Public Health Advisory – Gadolinium-containing Contrast Agents for Magnetic Resonance Imaging (MRI): Omniscan, OptiMARK, Magnevist, ProHance, and MultiHance. Available at: http://www.fda.gov/ cder/drug/advisory/gadolinium_agents.htm Accessed May, 2007. Cabella C, Crich SG, Corpillo D et al. Cellular labeling with Gd(III) chelates: only high thermodynamic stabilities prevent the cells acting as ‘sponges’ of Gd3+ions. Contrast Media Mol Imaging 2006; 1: 23–29. Evans CH. Biochemistry of the Lanthanides. Plenum Press: New York and London, 1990. Canavese C, Mereu C, Nordio M et al. Blast from the past: the aluminum’s ghost on the lanthanum salts. Curr Med Chem 2005; 12: 1631–1636. Slatopolsky E, Liapis H, Finch J. Progressive accumulation of lanthanum in the liver of normal and uremic rats. Kidney Int 2006; 68: 2809–2813.
S Aime1, C Canavese2 and P Stratta2 1 Department of Chemistry IF.M and Molecular Imaging Center of the University of Torino, Maggiore Hospital, Novara, Italy and 2Clinical
Periodic table of the elements H
He
LI
Be
B
C
N
O
F
Ne
Na
Mg
Al
Si
P
S
Cl
Ar
K
Ca
Ga
Ge
As
Se
Br
Kr
Sc
Ti
V
Cr
Mn
Fe
Co
Ni
Cu
Zn
Rb
Sr
Y
Zr
Nb
Mo
Tc
Ru
Rh
Pd
Ag
Cd
In
Sn
Sb
Te
I
Xe
Cs
Ba
La
Hf
Ta
W
Re
Os
Ir
Pt
Au
Hg
TI
Pb
Bi
Po
At
Rn
Fr
Ra
Ac
Rf
Db
Sg
Bh
Hs
Mt
Uun
Uuu
Uub
Lanthanide series Ce
Pr
Nd
Pm
Sm
Eu
Gd
Tb
Dy
Ho
Er
Tm
Yb
Lu
Th
Pa
U
Np
Pu
Am
Cm
Bk
Cf
Es
Fm
Md
No
Lr
Actinide series
Figure 1 | Periodic table of the elements: gadolinium (Gd) belongs to the lanthanide series. 1162
Kidney International (2007) 72, 1161–1165