NEWS & VIEWS with post-transplant FSGS are available. Another podocyte-targeted therapy is ciclosporin; in vitro data suggest that blocking calcineurin-mediated dephosphorylation of synaptopodin, an adapter protein for regulated Rho GTPase signalling in podocytes, preserves the phosphorylation-dependent synaptopodin‑14‑3-3 β interaction, protecting synaptopodin from cathepsin L‑mediated degradation. 10 In addition, deletion of mTORC1 and mTORC2 from mouse podocytes aggravated glomerular lesions, and increased mTOR activity accompanied diabetic nephropathy in patients, characterized by early glomerular hypertrophy and hyperfiltration.10 These findings indicate a requirement for tightly balanced mTOR activity in podocyte homeostasis and suggest that mTOR inhib ition can protect podocytes from injury under some conditions. The study by Yu et al.2 is yet another testament to the importance of targeting the podocyte for therapy. Although the podocyte CD80 pathway seems to have an important role in some proteinuric glomerular diseases, clinical results suggest that targeting this mechanism needs further molecular and cellular studies including evaluation of drug-target engagement as well as biomarker analysis of CD80 in urine. The gold standard will be a prospective clinical investigation with proper controls. Such a study would have to be successful before the clinical use of CD80 blockade in podocyte disorders could be generally recommended. Department of Medicine, Rush University Medical Center, 1735 West Harrison Street, Cohn Building, Suite 724, Chicago, IL 60612, USA (J. Reiser). Department of Medicine, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, 600 Wolfe Street, Brady 502, Baltimore, MD 21287, USA (N. Alachkar). Correspondence to: J. Reiser [email protected] Competing interests J. Reiser has pending or issued patents on novel kidney-protective therapies. He stands to gain royalties from their commercialization. N. Alachkar declares no competing interests. 1.
2.
3.
Maxwell, L. J. & Singh, J. A. Abatacept for rheumatoid arthritis: a Cochrane systematic review. J. Rheumatol. 37, 234–245 (2010). Yu, C.‑C. et al. Abatacept in B7‑1‑positive proteinuric kidney disease. N. Engl. J. Med. http://dx.doi.org/10.1056/NEJMoa1304572. Vincenti, F. et al. A phase III study of belataceptbased immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am. J. Transplant. 10, 535–546 (2010).
130 | MARCH 2014 | VOLUME 10
4.
5.
6.
7.
Pestana, J. O. M. et al. Three-year outcomes from BENEFIT-EXT: a phase III study of belatacept versus cyclosporine in recipients of extended criteria donor kidneys. Am. J. Transplant. 12, 630–639 (2012). Wei, C. et al. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat. Med. 17, 952–960 (2011). Clement, L. C. et al. Podocyte-secreted angiopoietin‑like‑4 mediates proteinuria in glucocorticoid-sensitive nephrotic syndrome. Nat. Med. 17, 117–122 (2011). Reiser, J. et al. Induction of B7–1 in podocytes is associated with nephrotic syndrome. J. Clin. Invest. 113, 1390–1397 (2004).
8.
Ishimoto, T. et al. Toll-like receptor 3 ligand, polyIC, induces proteinuria and glomerular CD80, and increases urinary CD80 in mice. Nephrol. Dial. Transplant. 28, 1439–1446 (2013). 9. Furie, R. et al. Efficacy and safety of abatacept over 12 months in patients with lupus nephritis: results from a multicenter, randomized, doubleblind, placebo controlled phase II/III study [abstract]. Arthritis Rheum. 63 (Suppl. 10), a2469 (2011). 10. Cravedi, P., Kopp, J. B. & Remuzzi, G. Recent progress in the pathophysiology and treatment of FSGS recurrence. Am. J. Transplant. 13, 266–274 (2013).
TRANSPLANTATION
Increased ESRD and mortality risk for kidney donors? Arthur J. Matas
For most patients with end-stage renal disease (ESRD), a kidney transplant is the best treatment option. Compared with dialysis, a successful kidney transplant is associated with increased life expectancy and improved quality of life; a living donor transplant is associated with better long-term results than a deceased donor transplant. Matas, A. J. Nat. Rev. Nephrol. 10, 130–131 (2014); published online 21 January 2014; doi:10.1038/nrneph.2014.2
The major disadvantage of living donor transplantation is the risk to the donor, who undergoes surgery, with all its associ ated risks, but gets no physical benefit from donating a kidney. The donor oper ation has been, in part, justified because long-term donor risks have been thought to be minimal. However, a new study by Mjøen and c olleagues provides a different perspective.1 Short-term donor risks are well-defined. Over the past four decades in the USA, kidney donor mortality has averaged 0.03% and major morbidity 30 years is small, and the control group has been the general population. The latter is particularly important for long-term living donor follow-up studies, as donors are a healthy subset of the general population. Mjøen and colleagues have now compared long-term living donor outcomes www.nature.com/nrneph
© 2014 Macmillan Publishers Limited. All rights reserved
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
2.
3.
Maxwell, L. J. & Singh, J. A. Abatacept for rheumatoid arthritis: a Cochrane systematic review. J. Rheumatol. 37, 234–245 (2010). Yu, C.‑C. et al. Abatacept in B7‑1‑positive proteinuric kidney disease. N. Engl. J. Med. http://dx.doi.org/10.1056/NEJMoa1304572. Vincenti, F. et al. A phase III study of belataceptbased immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am. J. Transplant. 10, 535–546 (2010).
130 | MARCH 2014 | VOLUME 10
4.
5.
6.
7.
Pestana, J. O. M. et al. Three-year outcomes from BENEFIT-EXT: a phase III study of belatacept versus cyclosporine in recipients of extended criteria donor kidneys. Am. J. Transplant. 12, 630–639 (2012). Wei, C. et al. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat. Med. 17, 952–960 (2011). Clement, L. C. et al. Podocyte-secreted angiopoietin‑like‑4 mediates proteinuria in glucocorticoid-sensitive nephrotic syndrome. Nat. Med. 17, 117–122 (2011). Reiser, J. et al. Induction of B7–1 in podocytes is associated with nephrotic syndrome. J. Clin. Invest. 113, 1390–1397 (2004).
8.
Ishimoto, T. et al. Toll-like receptor 3 ligand, polyIC, induces proteinuria and glomerular CD80, and increases urinary CD80 in mice. Nephrol. Dial. Transplant. 28, 1439–1446 (2013). 9. Furie, R. et al. Efficacy and safety of abatacept over 12 months in patients with lupus nephritis: results from a multicenter, randomized, doubleblind, placebo controlled phase II/III study [abstract]. Arthritis Rheum. 63 (Suppl. 10), a2469 (2011). 10. Cravedi, P., Kopp, J. B. & Remuzzi, G. Recent progress in the pathophysiology and treatment of FSGS recurrence. Am. J. Transplant. 13, 266–274 (2013).
TRANSPLANTATION
Increased ESRD and mortality risk for kidney donors? Arthur J. Matas
For most patients with end-stage renal disease (ESRD), a kidney transplant is the best treatment option. Compared with dialysis, a successful kidney transplant is associated with increased life expectancy and improved quality of life; a living donor transplant is associated with better long-term results than a deceased donor transplant. Matas, A. J. Nat. Rev. Nephrol. 10, 130–131 (2014); published online 21 January 2014; doi:10.1038/nrneph.2014.2
The major disadvantage of living donor transplantation is the risk to the donor, who undergoes surgery, with all its associ ated risks, but gets no physical benefit from donating a kidney. The donor oper ation has been, in part, justified because long-term donor risks have been thought to be minimal. However, a new study by Mjøen and c olleagues provides a different perspective.1 Short-term donor risks are well-defined. Over the past four decades in the USA, kidney donor mortality has averaged 0.03% and major morbidity 30 years is small, and the control group has been the general population. The latter is particularly important for long-term living donor follow-up studies, as donors are a healthy subset of the general population. Mjøen and colleagues have now compared long-term living donor outcomes www.nature.com/nrneph
© 2014 Macmillan Publishers Limited. All rights reserved
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
