NEWS & VIEWS with outcomes of a highly selected healthy control group from the general population.1 The authors of this study report that with a mean follow-up duration of 15.1 years, living kidney donors have an increased risk of all-cause mortality (hazard ratio [HR] 1.3, 95% CI 1.1–1.5), cardiovascular mortality (HR 1.4, 95% CI 1.0–1.9), and ESRD (HR 11.4, 95% CI 4.4–29.6).1 Two other studies with highly selected control populations, but with shorter follow-up times, did not find any increase in risk to donors.5,6
‘‘
...every healthy young donor has some risk of developing ESRD
’’
The findings reported by Mjøen et al.1 raise three important questions. Firstly, was there something unique about the particular donor population studied, compared with those in previous studies, that might explain the difference in results? Indeed, of the 1,901 donors, 1,519 (80%) were first-degree relatives of the transplant recipient. 1 This population, therefore, differs from previous studies that included non-first-degree relatives and of whom up to 30% were unrelated donors.2,3,5,6 Numerous studies have shown that ESRD (often immunological) is markedly increased in first-degree relatives of a patient with ESRD,7–9 and this factor alone might explain the findings reported by Mjøen and colleagues.1 In fact, the main cause of ESRD in the donors studied was immunological disease.4 Secondly, what is the absolute magnitude of the reported effect? For all-cause mortality, no difference was observed between donors and controls up to 15 years after donation and, after 25 years, a ~5% increase in mortality risk for donors was evident.1 Given the low mortality rate in the highly selected general population controls, the absolute increase in the number of deaths was small. For cardiovascular mortality, after adjustment, no substantial difference between the groups was observed. 1 For ESRD, only nine donors out of the 1,901 studied (0.47%) developed ESRD, and all were family members. 1 This very small number of living kidney donors developing ESRD was associated with correspondingly wide confidence intervals. Of the nine donors developing ESRD, renal failure in five (56%) was caused by immunological diseases, compared with only six of the 22 controls (27%).4
Finally, how does the increased long-term risk of mortality and ESRD in living kidney donors affect future discussions with donor candidates? The findings reported by Mjøen and colleagues1 are consistent with those reported for the general population and cannot be ignored. Importantly, however, these observations might only apply to first-degree relatives of kidney transplant recipients, and, even further, might only apply to first-degree relatives of recipients with immunological or potentially inherited diseases. Donor evaluations only determine the health of the donor at that specific time and, given that most ESRD develops late in life (only 13% by age 44 years), every healthy young donor has some risk of developing ESRD.10 Donor candidates need to be fully informed to make their decision about whether or not to proceed with donation and, going forward, the slight increase in long-term risk should be discussed. I agree with the conclusion of Mjøen and colleagues, “Our findings will not change our opinion in promoting live-kidney donation. However, potential donors should be informed of the increased risks, although small, associated with donation in [the] short-term and long-term perspective.” At the same time, additional long-term donor follow-up studies are necessary to validate their observations and to determine if the increased risks reported1 are true for all donors or only apply to firstdegree relatives of those i ndividuals with immunological diseases.
Department of Surgery, University of Minnesota, 420 Delaware Street S.E., MMC 195, Minneapolis, MN 55455, USA. [email protected] Competing interests The author declares no competing interests. 1.
Mjøen, G. et al. Long-term risks for kidney donors. Kidney Int. http://dx.doi.org/10.1038/ ki.2013.460. 2. Ibrahim, H. N. et al. Long-term consequences of kidney donation. N. Engl. J. Med. 360, 459–469 (2009). 3. Childress, J. F. & Beauchamp, T. L. in Principles of Biomedical Ethics, 6th edn (Oxford University Press, 2008). 4. Matas, A. J. & Ibrahim, H. N. The unjustified classification of kidney donors as patients with CKD: critique and recommendations. Clin. J. Am. Soc. Nephrol. 8, 1406–1413 (2013). 5. Segev, D. L. et al. Perioperative mortality and long-term survival following live kidney donation. JAMA 303, 959–966 (2010). 6. Garg, A. X. et al. Cardiovascular disease in kidney donors: matched cohort study. BMJ 344, e1203 (2012). 7. Lei, H. H., Perneger, T. V., Klag, M. J., Whelton, P. K. & Coresh, J. Familial aggregation of renal disease in a population-based casecontrol study. J. Am. Soc. Nephrol. 9, 1270–1276 (1998). 8. O’Dea, D. F., Murphy, S. W., Hefferton, D. & Parfrey, P. S. Higher risk for renal failure in firstdegree relatives of white patients with endstage renal disease: a population-based study. Am. J. Kidney Dis. 32, 794–801 (1998). 9. McClellan, W. M. et al. Individuals with a family history of ESRD are a high-risk population for CKD: implications for targeted surveillance and intervention activities. Am. J. Kidney Dis. 53 (Suppl. 3), S100–S106 (2009). 10. Steiner, R. W. ‘Normal for now’ or ‘at future risk’: a double standard for selecting young and older living kidney donors. Am. J. Transplant. 10, 737–741 (2010).
CHRONIC KIDNEY DISEASE
Haemodialysis catheter care in practice Sunil V. Badve and David W. Johnson
A new haemodialysis catheter-care procedure has been reported, including exit-site disinfection with chlorhexidine gluconate that results in a sustained reduction in bacteraemia rates, new intravenous antibiotic starts and sepsis-associated and access-associated hospitalization rates compared with standard care. These findings have potential implications for the prevention of haemodialysis catheter-associated infections. Badve, S. V. & Johnson, D. W. Nat. Rev. Nephrol. 10, 131–133 (2014); published online 21 January 2014; doi:10.1038/nrneph.2014.3
Haemodialysis catheter use is associated with an increased risk of both all-cause and infectious mortality rates compared with either arteriovenous fistulas or grafts;1
NATURE REVIEWS | NEPHROLOGY
however, nearly 80% of patients with incident end-stage kidney disease in the USA commenced haemodialysis with a catheter in 2010.2 After 4 months, 53% of these patients VOLUME 10 | MARCH 2014 | 131
© 2014 Macmillan Publishers Limited. All rights reserved
The Irish Image Collection/Design Pics/Valueline/Thinkstock
NEWS & VIEWS
were still receiving haemodialysis via a catheter.2 Techniques to reduce haemodialysis catheter-associated bloodstream infections range from extraluminal methods, such as exit-site cleaning, wound dressing and the use of topical antimicrobial prophylaxis, to intraluminal methods that include catheter antimicrobial lock solutions.3 Catheteraccess practices at the facility level, such as chlorhexidine antisepsis, hand hygiene and aseptic technique, have been associated with clinical outcomes,4 but failure to implement infection prevention guidelines is common, at least in peritoneal dialysis.5 Thus, facilitylevel systematic implementation of infectionprevention strategies, such as those recently reported by Rosenblum et al.,6 could substantially reduce haemodialysis catheterassociated bacteraemia rates, morbidity, mortality and health-care costs. Rosenblum and colleagues conducted a cluster-randomized controlled trial of a new haemodialysis catheter-care protocol, including exit-site disinfection with 2% chlorhexidine gluconate and catheter cap and hub disinfection with a 70% alcohol pad, versus usual care of exit-site disinfection, catheter cap soaking and hub soaking with either povidone-iodine or sodium hypochlorite. The study involved all patients receiving haemodialysis via a catheter at 211 Fresenius Medical Care North America (FMCNA) facility pairs matched by region, facility size and positive blood culture rate.6 The primary end point was catheterassociated bacteraemia rate (defined as the number of positive blood culture episodes) during a 3-month period. Compared with control facilities, there was a 22% reduction in catheter-a ssociated bacteraemia rates (0.81 versus 1.04 episodes per 1,000 catheter days, P = 0.02) and a 20% reduction 132 | MARCH 2014 | VOLUME 10
in new intravenous antibiotic starts (2.53 starts versus 3.15 starts per 1,000 catheter days, P 7 days to develop, timed from admission or lowest creatinine measurement after admission. Although s-AKI is unlikely to be a distinct syndrome from AKI, the association with increased mortality highlights the need to monitor patient creatinine levels. Endre, Z. H. & Pickering, J. W. Nat. Rev. Nephrol. 10, 133–134 (2014); published online 28 January 2014; doi:10.1038/nrneph.2014.9
Consensus definitions of acute kidney injury (AKI) have evolved over the past 12 years. Initially, AKI was characterized by a rapid decline in glomerular filtration rate (GFR), identified by increased levels of creatinine within 7 days or olig uria, but GFR was later removed as a criterion. Now, AKI criteria state that it must develop within 48 h of a precipitating event and includes an absolute increase in creatinine levels (26.5 μmol/l) to deal with equivalent injury at different baseline creatinine values, as even small increases in creatinine are associated with increased mortality.1 The KDIGO (Kidney Disease Improving Global Outcomes) definition of AKI brought the RIFLE (Risk, Injury, Failure, Loss and ESRD [end-stage renal disease]) and AKIN (Acute Kidney Injury Network) definitions together as the two identify different patients in the mildest category of AKI who have increased mortality risk. 2 The ADQI (Acute Dialysis Quality Initiative) group has now recommended the inclusion of biomarkers of kidney damage into the definition,3 as it is clear from retrospective4 and prospective5 studies that patients with increased levels of biomarkers of kidney damage, such as urinary neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury mol ecule 1 (KIM‑1), but without increased levels of creatinine (termed as biomarkerpositive, creatinine-negative), are also at increased risk of mortality and dialysis. Thus, AKI is best viewed as a continuum of injury of variable duration and severity.6 Fujii and colleagues7 describe the epi demiology of a cohort of patients, designated as having ‘subacute’ kidney injury (s-AKI), who developed AKI after admission to hospital or after an arbitrary baseline value over 8–90 days. In a retrospective study of 56,567 patients admitted to a single
NATURE REVIEWS | NEPHROLOGY
teaching hospital in Japan, 1.1% of admissions had s-AKI, compared with 11.0% who developed AKI within 7 days (defined by the RIFLE criteria). Patients with s-AKI had less severe kidney injury than those diagnosed with AKI, as evidenced by levels of serum creatini ne, but demonstrated increased rates of in-hospital m ortality compared with patients without AKI (shown by multivariable regression analysis). Patients with AKI were at even greater risk of inhospital mortality when compared with patients with s-AKI. When s-AKI was categorized according to severity, (R, I, or F of the RIFLE criteria), a linear correlation with mortality was observed. No data were provided on the duration of s-AKI, which is probably a more critical link with mortality than incidence.8 What does expansion of the detection window for AKI beyond 7 days do? Limiting increases in creatinine levels to within 48 h favours identification of AKI following severe injury, such as after cardiopulmonary bypass or renal transplantation. Expanding the window to 7 days enables the identification of AKI that develops after the accumulation of less serious injuries, which incrementally or together decrease GFR, for example after repeated nephrotoxic drug exposure or the cytokine storm of sepsis. As such, removing the restriction of AKI to within 48 h after a potential initiating event is logical. However, the
ronstik/iStock/Thinkstock
VOLUME 10 | MARCH 2014 | 133 © 2014 Macmillan Publishers Limited. All rights reserved
‘‘
...every healthy young donor has some risk of developing ESRD
’’
The findings reported by Mjøen et al.1 raise three important questions. Firstly, was there something unique about the particular donor population studied, compared with those in previous studies, that might explain the difference in results? Indeed, of the 1,901 donors, 1,519 (80%) were first-degree relatives of the transplant recipient. 1 This population, therefore, differs from previous studies that included non-first-degree relatives and of whom up to 30% were unrelated donors.2,3,5,6 Numerous studies have shown that ESRD (often immunological) is markedly increased in first-degree relatives of a patient with ESRD,7–9 and this factor alone might explain the findings reported by Mjøen and colleagues.1 In fact, the main cause of ESRD in the donors studied was immunological disease.4 Secondly, what is the absolute magnitude of the reported effect? For all-cause mortality, no difference was observed between donors and controls up to 15 years after donation and, after 25 years, a ~5% increase in mortality risk for donors was evident.1 Given the low mortality rate in the highly selected general population controls, the absolute increase in the number of deaths was small. For cardiovascular mortality, after adjustment, no substantial difference between the groups was observed. 1 For ESRD, only nine donors out of the 1,901 studied (0.47%) developed ESRD, and all were family members. 1 This very small number of living kidney donors developing ESRD was associated with correspondingly wide confidence intervals. Of the nine donors developing ESRD, renal failure in five (56%) was caused by immunological diseases, compared with only six of the 22 controls (27%).4
Finally, how does the increased long-term risk of mortality and ESRD in living kidney donors affect future discussions with donor candidates? The findings reported by Mjøen and colleagues1 are consistent with those reported for the general population and cannot be ignored. Importantly, however, these observations might only apply to first-degree relatives of kidney transplant recipients, and, even further, might only apply to first-degree relatives of recipients with immunological or potentially inherited diseases. Donor evaluations only determine the health of the donor at that specific time and, given that most ESRD develops late in life (only 13% by age 44 years), every healthy young donor has some risk of developing ESRD.10 Donor candidates need to be fully informed to make their decision about whether or not to proceed with donation and, going forward, the slight increase in long-term risk should be discussed. I agree with the conclusion of Mjøen and colleagues, “Our findings will not change our opinion in promoting live-kidney donation. However, potential donors should be informed of the increased risks, although small, associated with donation in [the] short-term and long-term perspective.” At the same time, additional long-term donor follow-up studies are necessary to validate their observations and to determine if the increased risks reported1 are true for all donors or only apply to firstdegree relatives of those i ndividuals with immunological diseases.
Department of Surgery, University of Minnesota, 420 Delaware Street S.E., MMC 195, Minneapolis, MN 55455, USA. [email protected] Competing interests The author declares no competing interests. 1.
Mjøen, G. et al. Long-term risks for kidney donors. Kidney Int. http://dx.doi.org/10.1038/ ki.2013.460. 2. Ibrahim, H. N. et al. Long-term consequences of kidney donation. N. Engl. J. Med. 360, 459–469 (2009). 3. Childress, J. F. & Beauchamp, T. L. in Principles of Biomedical Ethics, 6th edn (Oxford University Press, 2008). 4. Matas, A. J. & Ibrahim, H. N. The unjustified classification of kidney donors as patients with CKD: critique and recommendations. Clin. J. Am. Soc. Nephrol. 8, 1406–1413 (2013). 5. Segev, D. L. et al. Perioperative mortality and long-term survival following live kidney donation. JAMA 303, 959–966 (2010). 6. Garg, A. X. et al. Cardiovascular disease in kidney donors: matched cohort study. BMJ 344, e1203 (2012). 7. Lei, H. H., Perneger, T. V., Klag, M. J., Whelton, P. K. & Coresh, J. Familial aggregation of renal disease in a population-based casecontrol study. J. Am. Soc. Nephrol. 9, 1270–1276 (1998). 8. O’Dea, D. F., Murphy, S. W., Hefferton, D. & Parfrey, P. S. Higher risk for renal failure in firstdegree relatives of white patients with endstage renal disease: a population-based study. Am. J. Kidney Dis. 32, 794–801 (1998). 9. McClellan, W. M. et al. Individuals with a family history of ESRD are a high-risk population for CKD: implications for targeted surveillance and intervention activities. Am. J. Kidney Dis. 53 (Suppl. 3), S100–S106 (2009). 10. Steiner, R. W. ‘Normal for now’ or ‘at future risk’: a double standard for selecting young and older living kidney donors. Am. J. Transplant. 10, 737–741 (2010).
CHRONIC KIDNEY DISEASE
Haemodialysis catheter care in practice Sunil V. Badve and David W. Johnson
A new haemodialysis catheter-care procedure has been reported, including exit-site disinfection with chlorhexidine gluconate that results in a sustained reduction in bacteraemia rates, new intravenous antibiotic starts and sepsis-associated and access-associated hospitalization rates compared with standard care. These findings have potential implications for the prevention of haemodialysis catheter-associated infections. Badve, S. V. & Johnson, D. W. Nat. Rev. Nephrol. 10, 131–133 (2014); published online 21 January 2014; doi:10.1038/nrneph.2014.3
Haemodialysis catheter use is associated with an increased risk of both all-cause and infectious mortality rates compared with either arteriovenous fistulas or grafts;1
NATURE REVIEWS | NEPHROLOGY
however, nearly 80% of patients with incident end-stage kidney disease in the USA commenced haemodialysis with a catheter in 2010.2 After 4 months, 53% of these patients VOLUME 10 | MARCH 2014 | 131
© 2014 Macmillan Publishers Limited. All rights reserved
The Irish Image Collection/Design Pics/Valueline/Thinkstock
NEWS & VIEWS
were still receiving haemodialysis via a catheter.2 Techniques to reduce haemodialysis catheter-associated bloodstream infections range from extraluminal methods, such as exit-site cleaning, wound dressing and the use of topical antimicrobial prophylaxis, to intraluminal methods that include catheter antimicrobial lock solutions.3 Catheteraccess practices at the facility level, such as chlorhexidine antisepsis, hand hygiene and aseptic technique, have been associated with clinical outcomes,4 but failure to implement infection prevention guidelines is common, at least in peritoneal dialysis.5 Thus, facilitylevel systematic implementation of infectionprevention strategies, such as those recently reported by Rosenblum et al.,6 could substantially reduce haemodialysis catheterassociated bacteraemia rates, morbidity, mortality and health-care costs. Rosenblum and colleagues conducted a cluster-randomized controlled trial of a new haemodialysis catheter-care protocol, including exit-site disinfection with 2% chlorhexidine gluconate and catheter cap and hub disinfection with a 70% alcohol pad, versus usual care of exit-site disinfection, catheter cap soaking and hub soaking with either povidone-iodine or sodium hypochlorite. The study involved all patients receiving haemodialysis via a catheter at 211 Fresenius Medical Care North America (FMCNA) facility pairs matched by region, facility size and positive blood culture rate.6 The primary end point was catheterassociated bacteraemia rate (defined as the number of positive blood culture episodes) during a 3-month period. Compared with control facilities, there was a 22% reduction in catheter-a ssociated bacteraemia rates (0.81 versus 1.04 episodes per 1,000 catheter days, P = 0.02) and a 20% reduction 132 | MARCH 2014 | VOLUME 10
in new intravenous antibiotic starts (2.53 starts versus 3.15 starts per 1,000 catheter days, P 7 days to develop, timed from admission or lowest creatinine measurement after admission. Although s-AKI is unlikely to be a distinct syndrome from AKI, the association with increased mortality highlights the need to monitor patient creatinine levels. Endre, Z. H. & Pickering, J. W. Nat. Rev. Nephrol. 10, 133–134 (2014); published online 28 January 2014; doi:10.1038/nrneph.2014.9
Consensus definitions of acute kidney injury (AKI) have evolved over the past 12 years. Initially, AKI was characterized by a rapid decline in glomerular filtration rate (GFR), identified by increased levels of creatinine within 7 days or olig uria, but GFR was later removed as a criterion. Now, AKI criteria state that it must develop within 48 h of a precipitating event and includes an absolute increase in creatinine levels (26.5 μmol/l) to deal with equivalent injury at different baseline creatinine values, as even small increases in creatinine are associated with increased mortality.1 The KDIGO (Kidney Disease Improving Global Outcomes) definition of AKI brought the RIFLE (Risk, Injury, Failure, Loss and ESRD [end-stage renal disease]) and AKIN (Acute Kidney Injury Network) definitions together as the two identify different patients in the mildest category of AKI who have increased mortality risk. 2 The ADQI (Acute Dialysis Quality Initiative) group has now recommended the inclusion of biomarkers of kidney damage into the definition,3 as it is clear from retrospective4 and prospective5 studies that patients with increased levels of biomarkers of kidney damage, such as urinary neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury mol ecule 1 (KIM‑1), but without increased levels of creatinine (termed as biomarkerpositive, creatinine-negative), are also at increased risk of mortality and dialysis. Thus, AKI is best viewed as a continuum of injury of variable duration and severity.6 Fujii and colleagues7 describe the epi demiology of a cohort of patients, designated as having ‘subacute’ kidney injury (s-AKI), who developed AKI after admission to hospital or after an arbitrary baseline value over 8–90 days. In a retrospective study of 56,567 patients admitted to a single
NATURE REVIEWS | NEPHROLOGY
teaching hospital in Japan, 1.1% of admissions had s-AKI, compared with 11.0% who developed AKI within 7 days (defined by the RIFLE criteria). Patients with s-AKI had less severe kidney injury than those diagnosed with AKI, as evidenced by levels of serum creatini ne, but demonstrated increased rates of in-hospital m ortality compared with patients without AKI (shown by multivariable regression analysis). Patients with AKI were at even greater risk of inhospital mortality when compared with patients with s-AKI. When s-AKI was categorized according to severity, (R, I, or F of the RIFLE criteria), a linear correlation with mortality was observed. No data were provided on the duration of s-AKI, which is probably a more critical link with mortality than incidence.8 What does expansion of the detection window for AKI beyond 7 days do? Limiting increases in creatinine levels to within 48 h favours identification of AKI following severe injury, such as after cardiopulmonary bypass or renal transplantation. Expanding the window to 7 days enables the identification of AKI that develops after the accumulation of less serious injuries, which incrementally or together decrease GFR, for example after repeated nephrotoxic drug exposure or the cytokine storm of sepsis. As such, removing the restriction of AKI to within 48 h after a potential initiating event is logical. However, the
ronstik/iStock/Thinkstock
VOLUME 10 | MARCH 2014 | 133 © 2014 Macmillan Publishers Limited. All rights reserved
