- Email: [email protected]
Unraveling the mechanisms of progressive peritoneal membrane fibrosis
commentary
transplantation. Biomarkers Med. 2014;8: 1247–1262. 8. Suthanthiran M, Schwartz JE, Ding R, et al, for the CTOT-04 Study Investigators. Urinarycell mRNA profile and acute cellular rejection in kidney allografts. N Engl J Med. 2013;369: 20–31.
9. Mischak H, Delles C, Vlahou A, Vanholder R. Proteomic biomarkers in kidney disease: issues in development and implementation. Nat Rev Nephrol. 2015;11:221–232. 10. Sidgel TK, Gao Y, He J, et al. Mining the human urine proteome for monitoring renal transplant injury. Kidney Int. 2016;89:1244–1252.
Unraveling the mechanisms of progressive peritoneal membrane fibrosis Simon J. Davies1,2 Continuous glucose exposure contributes to severe ultrafiltration failure in peritoneal dialysis. In their study, Wang et al. describe a mechanistic pathway involving direct activation by glucose of mesothelial cell protein kinase C a that, when blocked, or absent in a mouse knockout model, prevents fibrosis and the associated reduction in ultrafiltration. Interestingly, this pathway involves the 3 main mechanisms of membrane injury (inflammation, neoangiogenesis, and fibrogenesis), offering a potential target for therapeutic intervention. Kidney International (2016) 89, 1185–1187; http://dx.doi.org/10.1016/j.kint.2016.02.029 Copyright ª 2016, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
see basic research on page 1253
P
rogressive changes in the functional characteristics of the peritoneal membrane continue to limit the longer-term use of peritoneal dialysis (PD). These changes are now well described and are broadly of 2 types:1 an increase in the rate of transport of small solutes that is indicative of increased blood flow and vascularity of the membrane and a progressive reduction in the osmotic conductance that is best explained by progressive membrane fibrosis (Figure 1). Both reduce the fluid transport capacity of the membrane, leading to poor ultrafiltration. Rapid 1 Institute for Applied Clinical Sciences, Keele University, Newcastle-under-Lyme, UK; and 2 University Hospitals of North Midlands, Stoke-onTrent, UK
Correspondence: Simon J. Davies, Kidney Unit, University Hospitals of North Midlands, Newcastle Road, Stoke-on-Trent, Staffordshire ST46QG, UK. E-mail: [email protected] Kidney International (2016) 89, 1180–1191
solute transport causes an early loss in the glucose osmotic gradient that limits the effectiveness of fluid removal and encourages fluid reabsorption once the gradient has dissipated,2 whereas reduced conductance means that for a given osmotic gradient the ultrafiltration is less efficient due to the restrictive effects of tissue fibrosis on the flow of fluid.3 Whereas the former is open to amelioration by dialysis prescription—for instance, use of automated dialysis to achieve shorter exchanges or glucose polymers to obtain sustained ultrafiltration in long dwells—the latter leads to treatment failure and an increased risk of encapsulating peritoneal sclerosis.4 Epidemiologic studies implicate both peritoneal infections and the poor biocompatibility of commercial dialysis solutions as the main drivers of these changes over time. There is also evidence that local inflammation within the
peritoneal cavity, as opposed to systemic inflammation, varies between individuals and is the main determinant of peritoneal solute transport as well as contributing to the progression of membrane fibrosis.5 For example, interleukin-6, which is produced locally, can, via STAT1, induce T cells to produce interferon gamma that mediates membrane fibrosis in a repeated animal model of peritonitis.6 Glucose degradation products, present in standard PD solutions due to heat sterilization at high pH, appear to play a role in the early increase in solute transport rate, as this was abolished by the use of ultralow glucose degradation product solutions in the balANZ study, although this benefit seems to have been independent of effects on local inflammation.7 Evidence that glucose degradation products are the sole mechanism of dialysis solution–related injury is lacking at this time, but this seems unlikely as cases of encapsulating peritoneal sclerosis have been seen in patients using biocompatible solutions. There is strong evidence that glucose itself is also a driver of membrane injury, but the mechanism by which it initiates membrane injury, be it inflammation, neovascularization, or fibrosis, is less clear. The study reported in this issue of Kidney International by Wang et al.8 (2016) provides evidence for a pathway that links glucose exposure to these injurious processes. In an animal model of “long-term” PD exposure, which in the case of mice is considered to be 5 weeks, they examined the hypothesis that glucose is able to induce damage via activation of protein kinase C a (PKCa) located in peritoneal mesothelial cells. PKCa is known to play a significant role in the progression of diabetic kidney disease–associated fibrosis, so to test this theory they did parallel experiments in PKCa knockout mice and a wild mouse strain by administering the PKCa inhibitor Go6976. They were able to show that PKCa is expressed constitutively as the predominant isoform in immortalized mouse peritoneal mesothelial cells and that it can be stimulated by glucose in concentrations simulating PD treatment. Inhibition of PKCa prevented the fibrotic membrane injury that they observed in 1185
commentary
Figure 1 | Potential pathways of peritoneal membrane injury. Causes of progressive ultrafiltration failure can be broken down into 3 phases: drivers, mechanisms, and functional consequences, with potential effector pathways shown. Protein kinase C a (PKCa) is a potential target for preventing glucose-mediated injury, although potentially many pathways are involved. EMT, epithelial-to-mesenchymal transition; GDPs, glucose degradation products; IFN, interferon; IL, interleukin; MC, mesothelial cell; MCP, monocyte chemoattractant protein; TGF, transforming growth factor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.
the PD-treated controls, and this was associated with a reduction in the effluent concentrations of the fibrosis mediator transforming growth factor-b. Notably, blockade of PKCa reduced mediators and evidence of all 3 mechanisms of membrane injury: inflammation, neovascularization, and fibrosis. Demonstration of the latter was via prevention of epithelial-to-mesenchymal transition, whereas the neovascularization was mediated by vascular endothelial growth factor. Evidence of inflammation came from the increase in a number of dialysate effluent cytokines, interleukin-6, tumor necrosis factor-a, interleukin-17, and an inflammatory cell infiltrate, all abrogated by Go6976. Similar effects were observed in the knockout mice, although it was noted that this strain was much less susceptible to PD-induced membrane injury. The histologic evidence of fibrosis was accompanied by a 1186
reduction in peritoneal ultrafiltration. Finally, the authors repeated their cell experiments in human omentumderived mesothelial tissue cell culture and found similar effects. The attractive aspects of this study are the demonstration of a potentially important common pathway that brings together all 3 of the known mechanisms of membrane injury and the demonstration that they are linked to morphologic and functional change that characterizes the problem faced in long-term PD (Figure 1), providing a logical target for drug intervention that could be delivered locally. As ever, however, it is necessary to sound a note of caution. Translating these observations, observed over a relatively short time period (5 weeks compared to several years in humans), to the human situation may be problematic, especially when, as the authors note, experiments in animal models are often highly strain
specific. It is also likely that there are multiple pathways involved in progressive membrane injury, as for example the repeated infection model referred to above or the extensive tissue injury thought to be associated with massive deposition of advanced glycation end products seen after prolonged dialysis treatment. Furthermore, the model as presented is highly dependent on a central role for mesothelial cells as a source for transforming growth factor-b and the process of epithelial-tomesenchymal transition. Mesothelial cell denudation is a common observation in long-term PD, especially when severe membrane fibrosis is developing, and it is generally agreed that this cell population is more protective than being the driver of injury. Recent lineage experiments have also indicated that epithelial-tomesenchymal transition may not be the main mechanism of fibrosis progression in PD, suggesting a greater role for submesothelial fibroblasts.9 This does not preclude a role for PKCa, but further experiments should focus on this cell population. Taking the broader view, this study, by providing a credible mechanistic pathway by which glucose can injure the peritoneal membrane, draws attention to the need to continue to find alternatives to glucose-based dialysate solutions rather than relying on the useful but only partial answers to the biocompatibility problem developed so far. Clinical practices that avoid excessive use of glucose prescription, such as preservation of residual kidney function, remain the key tools available to the clinician for the time being. DISCLOSURE
SJD has received research funding and honoraria for lecturing and advisory board participation from Baxter Healthcare and Fresenius Medical Care. REFERENCES 1. Mushahar L, Lambie M, Tan K, et al. Long-term changes in solute and water transport. Contrib Nephrol. 2009;163:15–21. 2. Asghar RB, Davies SJ. Pathways of fluid transport and reabsorption across the peritoneal membrane. Kidney Int. 2008;73:1048–1053. 3. Rippe B, Venturoli D. Simulations of osmotic ultrafiltration failure in CAPD using a serial three-pore membrane/fiber matrix model. Am J Physiol Renal Physiol. 2007;292:F1035–F1043. 4. Morelle J, Sow A, Hautem N, et al. Interstitial fibrosis restricts osmotic water transport in Kidney International (2016) 89, 1180–1191
commentary
encapsulating peritoneal sclerosis. J Am Soc Nephrol. 2015;26:2521–2533. 5. Lambie M, Chess J, Donovan KL, et al. Independent effects of systemic and peritoneal inflammation on peritoneal dialysis survival. J Am Soc Nephrol. 2013;24:2071–2080. 6. Fielding CA, Jones GW, McLoughlin RM, et al. Interleukin-6 signaling drives fibrosis in unresolved inflammation. Immunity. 2014;40: 40–50. 7. Cho Y, Johnson DW, Vesey DA, et al. Dialysate interleukin-6 predicts increasing peritoneal
solute transport rate in incident peritoneal dialysis patients. BMC Nephrol. 2014;15:8. 8. Wang L, Balzer MS, Rong S, et al. Protein kinase C a inhibition prevents peritoneal damage in a mouse model of chronic peritoneal exposure to high-glucose dialysate. Kidney Int. 2016;89:1253–1267. 9. Chen Y-T, Chang Y-T, Pan S-Y, et al. Lineage tracing reveals distinctive fates for mesothelial cells and submesothelial fibroblasts during peritoneal injury. J Am Soc Nephrol. 2014;25: 2847–2858.
Sleepless in CKD: a novel risk factor for CKD progression? Mark J. Sarnak1 and Mark Unruh2,3 Disorders of sleep have been associated with adverse outcomes in both the general population and in patients with chronic kidney disease. McMullan et al. add to this literature by demonstrating an association between short sleep duration and more rapid decline in glomerular filtration rate. We discuss the potential implications of these results but also offer some caution in over-interpretation of the data, given limitations in both the assessment of sleep as well as the kidney outcomes. Kidney International (2016) 89, 1187–1188; http://dx.doi.org/10.1016/j.kint.2016.02.028 KEYWORDS: cardiovascular disease; chronic kidney disease Copyright ª 2016, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
see clinical investigation on page 1324
S
leep is a basic human function necessary for survival. It plays a key role in human growth and development, memory, metabolic regulation, immune function, and attention. Abnormalities in sleep are associated with several adverse outcomes in the general population including development of hypertension, diabetes, depression,
1 Division of Nephrology, Tufts University School of Medicine, Boston, Massachusetts, USA; 2Renal Division, Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico, USA; and 3Renal Section, Medicine Service, Department of Medicine, Raymond G. Murphy VA Medical Center, School of Medicine, University of New Mexico, Albuquerque, New Mexico, USA
Correspondence: Mark J. Sarnak, Box 391, Division of Nephrology, Tufts Medical Center, 800 Washington Street, Boston, Massachusetts 02111, USA. E-mail: [email protected] Kidney International (2016) 89, 1180–1191
anxiety, and cardiovascular disease.1 Sleep abnormalities increase in prevalence as kidney function declines and may be associated with adverse outcomes in the chronic kidney disease (CKD) population.2,3 The current study in this issue of Kidney International adds to the literature by evaluating the relationship between sleep and rate of decline in kidney function in a prospective cohort study.4 The authors assessed the relationship between sleep duration and kidney function decline over an 11-year period in 4238 participants of the Nurses Health Study. Sleep quality was ascertained through a self-reported questionnaire that asked the participant the number of hours slept per 24 hours. The primary kidney outcome was a 30% decline in estimated glomerular filtration rate (eGFR), whereas development of
incident CKD (eGFR less than 60 ml/ min/1.73 m2) and annualized rate of decline in eGFR were secondary outcomes. The primary outcome was reached in 12% of participants, with those reaching this outcome having a final eGFR of 59 ml/min/1.73 m2. Thirteen percent of participants reached incident CKD. For both analyses, those participants having fewer than or equal to 5 hours of sleep were at higher odds of developing the kidney outcome. Results were consistent in multivariable analyses as well as in sensitivity analyses including additional measures of kidney function, which were not incorporated into the primary analyses, as well as in analyses adjusted for development of incident hypertension, diabetes, and cardiovascular disease. Because long sleep has been associated with albuminuria, hypertension, diabetes, and poor health outcomes including mortality in the Nurses Health Study as well as other cohorts, there was a notable lack of an association of long sleep with decline in eGFR.5–7 The strengths of the study include the large study sample, a wellcharacterized population with accurate ascertainment of comorbid conditions, as well as the various sensitivity analyses. The authors were also cautious in not over-interpreting the data. There are, however, several limitations to the strength of inferences that can be drawn. First, sleep was ascertained through a self-reported questionnaire, which may lead to misclassification of the exposure variable. It is well recognized that there are differences between subjective and objective measures of sleep,8 and, furthermore, as acknowledged by the authors the intra-class correlation for repeated measures of sleep duration is only moderate. Use of a self-reported questionnaire that only provides data on duration of sleep also does not distinguish different forms of sleep abnormalities, such as early awakening versus difficulty falling asleep, disrupted sleep, and short sleep because of environmental factors, each of which may imply different pathophysiology, prognosis, and treatment. Second, the kidney outcomes only include very early 1187
transplantation. Biomarkers Med. 2014;8: 1247–1262. 8. Suthanthiran M, Schwartz JE, Ding R, et al, for the CTOT-04 Study Investigators. Urinarycell mRNA profile and acute cellular rejection in kidney allografts. N Engl J Med. 2013;369: 20–31.
9. Mischak H, Delles C, Vlahou A, Vanholder R. Proteomic biomarkers in kidney disease: issues in development and implementation. Nat Rev Nephrol. 2015;11:221–232. 10. Sidgel TK, Gao Y, He J, et al. Mining the human urine proteome for monitoring renal transplant injury. Kidney Int. 2016;89:1244–1252.
Unraveling the mechanisms of progressive peritoneal membrane fibrosis Simon J. Davies1,2 Continuous glucose exposure contributes to severe ultrafiltration failure in peritoneal dialysis. In their study, Wang et al. describe a mechanistic pathway involving direct activation by glucose of mesothelial cell protein kinase C a that, when blocked, or absent in a mouse knockout model, prevents fibrosis and the associated reduction in ultrafiltration. Interestingly, this pathway involves the 3 main mechanisms of membrane injury (inflammation, neoangiogenesis, and fibrogenesis), offering a potential target for therapeutic intervention. Kidney International (2016) 89, 1185–1187; http://dx.doi.org/10.1016/j.kint.2016.02.029 Copyright ª 2016, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
see basic research on page 1253
P
rogressive changes in the functional characteristics of the peritoneal membrane continue to limit the longer-term use of peritoneal dialysis (PD). These changes are now well described and are broadly of 2 types:1 an increase in the rate of transport of small solutes that is indicative of increased blood flow and vascularity of the membrane and a progressive reduction in the osmotic conductance that is best explained by progressive membrane fibrosis (Figure 1). Both reduce the fluid transport capacity of the membrane, leading to poor ultrafiltration. Rapid 1 Institute for Applied Clinical Sciences, Keele University, Newcastle-under-Lyme, UK; and 2 University Hospitals of North Midlands, Stoke-onTrent, UK
Correspondence: Simon J. Davies, Kidney Unit, University Hospitals of North Midlands, Newcastle Road, Stoke-on-Trent, Staffordshire ST46QG, UK. E-mail: [email protected] Kidney International (2016) 89, 1180–1191
solute transport causes an early loss in the glucose osmotic gradient that limits the effectiveness of fluid removal and encourages fluid reabsorption once the gradient has dissipated,2 whereas reduced conductance means that for a given osmotic gradient the ultrafiltration is less efficient due to the restrictive effects of tissue fibrosis on the flow of fluid.3 Whereas the former is open to amelioration by dialysis prescription—for instance, use of automated dialysis to achieve shorter exchanges or glucose polymers to obtain sustained ultrafiltration in long dwells—the latter leads to treatment failure and an increased risk of encapsulating peritoneal sclerosis.4 Epidemiologic studies implicate both peritoneal infections and the poor biocompatibility of commercial dialysis solutions as the main drivers of these changes over time. There is also evidence that local inflammation within the
peritoneal cavity, as opposed to systemic inflammation, varies between individuals and is the main determinant of peritoneal solute transport as well as contributing to the progression of membrane fibrosis.5 For example, interleukin-6, which is produced locally, can, via STAT1, induce T cells to produce interferon gamma that mediates membrane fibrosis in a repeated animal model of peritonitis.6 Glucose degradation products, present in standard PD solutions due to heat sterilization at high pH, appear to play a role in the early increase in solute transport rate, as this was abolished by the use of ultralow glucose degradation product solutions in the balANZ study, although this benefit seems to have been independent of effects on local inflammation.7 Evidence that glucose degradation products are the sole mechanism of dialysis solution–related injury is lacking at this time, but this seems unlikely as cases of encapsulating peritoneal sclerosis have been seen in patients using biocompatible solutions. There is strong evidence that glucose itself is also a driver of membrane injury, but the mechanism by which it initiates membrane injury, be it inflammation, neovascularization, or fibrosis, is less clear. The study reported in this issue of Kidney International by Wang et al.8 (2016) provides evidence for a pathway that links glucose exposure to these injurious processes. In an animal model of “long-term” PD exposure, which in the case of mice is considered to be 5 weeks, they examined the hypothesis that glucose is able to induce damage via activation of protein kinase C a (PKCa) located in peritoneal mesothelial cells. PKCa is known to play a significant role in the progression of diabetic kidney disease–associated fibrosis, so to test this theory they did parallel experiments in PKCa knockout mice and a wild mouse strain by administering the PKCa inhibitor Go6976. They were able to show that PKCa is expressed constitutively as the predominant isoform in immortalized mouse peritoneal mesothelial cells and that it can be stimulated by glucose in concentrations simulating PD treatment. Inhibition of PKCa prevented the fibrotic membrane injury that they observed in 1185
commentary
Figure 1 | Potential pathways of peritoneal membrane injury. Causes of progressive ultrafiltration failure can be broken down into 3 phases: drivers, mechanisms, and functional consequences, with potential effector pathways shown. Protein kinase C a (PKCa) is a potential target for preventing glucose-mediated injury, although potentially many pathways are involved. EMT, epithelial-to-mesenchymal transition; GDPs, glucose degradation products; IFN, interferon; IL, interleukin; MC, mesothelial cell; MCP, monocyte chemoattractant protein; TGF, transforming growth factor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.
the PD-treated controls, and this was associated with a reduction in the effluent concentrations of the fibrosis mediator transforming growth factor-b. Notably, blockade of PKCa reduced mediators and evidence of all 3 mechanisms of membrane injury: inflammation, neovascularization, and fibrosis. Demonstration of the latter was via prevention of epithelial-to-mesenchymal transition, whereas the neovascularization was mediated by vascular endothelial growth factor. Evidence of inflammation came from the increase in a number of dialysate effluent cytokines, interleukin-6, tumor necrosis factor-a, interleukin-17, and an inflammatory cell infiltrate, all abrogated by Go6976. Similar effects were observed in the knockout mice, although it was noted that this strain was much less susceptible to PD-induced membrane injury. The histologic evidence of fibrosis was accompanied by a 1186
reduction in peritoneal ultrafiltration. Finally, the authors repeated their cell experiments in human omentumderived mesothelial tissue cell culture and found similar effects. The attractive aspects of this study are the demonstration of a potentially important common pathway that brings together all 3 of the known mechanisms of membrane injury and the demonstration that they are linked to morphologic and functional change that characterizes the problem faced in long-term PD (Figure 1), providing a logical target for drug intervention that could be delivered locally. As ever, however, it is necessary to sound a note of caution. Translating these observations, observed over a relatively short time period (5 weeks compared to several years in humans), to the human situation may be problematic, especially when, as the authors note, experiments in animal models are often highly strain
specific. It is also likely that there are multiple pathways involved in progressive membrane injury, as for example the repeated infection model referred to above or the extensive tissue injury thought to be associated with massive deposition of advanced glycation end products seen after prolonged dialysis treatment. Furthermore, the model as presented is highly dependent on a central role for mesothelial cells as a source for transforming growth factor-b and the process of epithelial-tomesenchymal transition. Mesothelial cell denudation is a common observation in long-term PD, especially when severe membrane fibrosis is developing, and it is generally agreed that this cell population is more protective than being the driver of injury. Recent lineage experiments have also indicated that epithelial-tomesenchymal transition may not be the main mechanism of fibrosis progression in PD, suggesting a greater role for submesothelial fibroblasts.9 This does not preclude a role for PKCa, but further experiments should focus on this cell population. Taking the broader view, this study, by providing a credible mechanistic pathway by which glucose can injure the peritoneal membrane, draws attention to the need to continue to find alternatives to glucose-based dialysate solutions rather than relying on the useful but only partial answers to the biocompatibility problem developed so far. Clinical practices that avoid excessive use of glucose prescription, such as preservation of residual kidney function, remain the key tools available to the clinician for the time being. DISCLOSURE
SJD has received research funding and honoraria for lecturing and advisory board participation from Baxter Healthcare and Fresenius Medical Care. REFERENCES 1. Mushahar L, Lambie M, Tan K, et al. Long-term changes in solute and water transport. Contrib Nephrol. 2009;163:15–21. 2. Asghar RB, Davies SJ. Pathways of fluid transport and reabsorption across the peritoneal membrane. Kidney Int. 2008;73:1048–1053. 3. Rippe B, Venturoli D. Simulations of osmotic ultrafiltration failure in CAPD using a serial three-pore membrane/fiber matrix model. Am J Physiol Renal Physiol. 2007;292:F1035–F1043. 4. Morelle J, Sow A, Hautem N, et al. Interstitial fibrosis restricts osmotic water transport in Kidney International (2016) 89, 1180–1191
commentary
encapsulating peritoneal sclerosis. J Am Soc Nephrol. 2015;26:2521–2533. 5. Lambie M, Chess J, Donovan KL, et al. Independent effects of systemic and peritoneal inflammation on peritoneal dialysis survival. J Am Soc Nephrol. 2013;24:2071–2080. 6. Fielding CA, Jones GW, McLoughlin RM, et al. Interleukin-6 signaling drives fibrosis in unresolved inflammation. Immunity. 2014;40: 40–50. 7. Cho Y, Johnson DW, Vesey DA, et al. Dialysate interleukin-6 predicts increasing peritoneal
solute transport rate in incident peritoneal dialysis patients. BMC Nephrol. 2014;15:8. 8. Wang L, Balzer MS, Rong S, et al. Protein kinase C a inhibition prevents peritoneal damage in a mouse model of chronic peritoneal exposure to high-glucose dialysate. Kidney Int. 2016;89:1253–1267. 9. Chen Y-T, Chang Y-T, Pan S-Y, et al. Lineage tracing reveals distinctive fates for mesothelial cells and submesothelial fibroblasts during peritoneal injury. J Am Soc Nephrol. 2014;25: 2847–2858.
Sleepless in CKD: a novel risk factor for CKD progression? Mark J. Sarnak1 and Mark Unruh2,3 Disorders of sleep have been associated with adverse outcomes in both the general population and in patients with chronic kidney disease. McMullan et al. add to this literature by demonstrating an association between short sleep duration and more rapid decline in glomerular filtration rate. We discuss the potential implications of these results but also offer some caution in over-interpretation of the data, given limitations in both the assessment of sleep as well as the kidney outcomes. Kidney International (2016) 89, 1187–1188; http://dx.doi.org/10.1016/j.kint.2016.02.028 KEYWORDS: cardiovascular disease; chronic kidney disease Copyright ª 2016, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
see clinical investigation on page 1324
S
leep is a basic human function necessary for survival. It plays a key role in human growth and development, memory, metabolic regulation, immune function, and attention. Abnormalities in sleep are associated with several adverse outcomes in the general population including development of hypertension, diabetes, depression,
1 Division of Nephrology, Tufts University School of Medicine, Boston, Massachusetts, USA; 2Renal Division, Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico, USA; and 3Renal Section, Medicine Service, Department of Medicine, Raymond G. Murphy VA Medical Center, School of Medicine, University of New Mexico, Albuquerque, New Mexico, USA
Correspondence: Mark J. Sarnak, Box 391, Division of Nephrology, Tufts Medical Center, 800 Washington Street, Boston, Massachusetts 02111, USA. E-mail: [email protected] Kidney International (2016) 89, 1180–1191
anxiety, and cardiovascular disease.1 Sleep abnormalities increase in prevalence as kidney function declines and may be associated with adverse outcomes in the chronic kidney disease (CKD) population.2,3 The current study in this issue of Kidney International adds to the literature by evaluating the relationship between sleep and rate of decline in kidney function in a prospective cohort study.4 The authors assessed the relationship between sleep duration and kidney function decline over an 11-year period in 4238 participants of the Nurses Health Study. Sleep quality was ascertained through a self-reported questionnaire that asked the participant the number of hours slept per 24 hours. The primary kidney outcome was a 30% decline in estimated glomerular filtration rate (eGFR), whereas development of
incident CKD (eGFR less than 60 ml/ min/1.73 m2) and annualized rate of decline in eGFR were secondary outcomes. The primary outcome was reached in 12% of participants, with those reaching this outcome having a final eGFR of 59 ml/min/1.73 m2. Thirteen percent of participants reached incident CKD. For both analyses, those participants having fewer than or equal to 5 hours of sleep were at higher odds of developing the kidney outcome. Results were consistent in multivariable analyses as well as in sensitivity analyses including additional measures of kidney function, which were not incorporated into the primary analyses, as well as in analyses adjusted for development of incident hypertension, diabetes, and cardiovascular disease. Because long sleep has been associated with albuminuria, hypertension, diabetes, and poor health outcomes including mortality in the Nurses Health Study as well as other cohorts, there was a notable lack of an association of long sleep with decline in eGFR.5–7 The strengths of the study include the large study sample, a wellcharacterized population with accurate ascertainment of comorbid conditions, as well as the various sensitivity analyses. The authors were also cautious in not over-interpreting the data. There are, however, several limitations to the strength of inferences that can be drawn. First, sleep was ascertained through a self-reported questionnaire, which may lead to misclassification of the exposure variable. It is well recognized that there are differences between subjective and objective measures of sleep,8 and, furthermore, as acknowledged by the authors the intra-class correlation for repeated measures of sleep duration is only moderate. Use of a self-reported questionnaire that only provides data on duration of sleep also does not distinguish different forms of sleep abnormalities, such as early awakening versus difficulty falling asleep, disrupted sleep, and short sleep because of environmental factors, each of which may imply different pathophysiology, prognosis, and treatment. Second, the kidney outcomes only include very early 1187