commentary
3.
4.
Schlieper G, Brandenburg V, Djuric Z et al. Risk factors for cardiovascular calcifications in nondiabetic Caucasian haemodialysis patients. Kidney Blood Press Res 2009; 32: 161–168. Leroux-Berger M, Queguiner I, Maciel TT et al. Pathologic calcification of adult vascular smooth muscle cells differs on their crest or mesodermal embryonic origin. J Bone Miner Res 2011; 26: 1543–1553.
5.
6.
Cheung C, Bernardo AS, Trotter MW et al. Generation of human vascular smooth muscle subtypes provides insight into embryological origin-dependent disease susceptibility. Nat Biotechnol 2012; 30: 165–173. Bostrom KI, Rajamannan NM, Towler DA. The regulation of valvular and vascular sclerosis by osteogenic morphogens. Circ Res 2011; 109: 564–577.
see clinical investigation on page 677
Structure, not just function W. Charles O’Neill1 Although kidney size can be important in the evaluation of renal disease, it has not been carefully studied and true volume is rarely measured, and good normative data are lacking. Wang et al. measured both cortical and medullary volumes in potential transplant donors and correlate these with physiologic, morphometric, and metabolic parameters. The results reveal interesting and potentially important correlations and differential responses between the two compartments, providing a framework for future investigation. Kidney International (2014) 85, 503–505. doi:10.1038/ki.2013.426
Nephrologists usually take a dysfunctional approach to kidney disease. Not that there is anything wrong with us, but our detection of kidney disease and stratification of its severity are based almost entirely on altered function rather than structure. On top of that, we take a glomerulocentric view of kidney dysfunction, focusing only on albuminuria and reduced glomerular filtration rate (GFR) as if the kidney consists exclusively of cortex composed entirely of glomeruli. Kidney disease is presumed absent when glomerular function is normal, and thus many cases of early disease are missed, while chronic kidney disease (CKD) or acute kidney injury is diagnosed when GFR is decreased, even though the dysfunction may be entirely hemodynamic and the kidneys structurally normal. Additional problems with this approach are the impracticality of measuring GFR and 1 Renal Division, Emory University School of Medicine, Atlanta, Georgia, USA Correspondence: W. Charles O’Neill, Emory University, Renal Division, WMB 338, 1639 Pierce Drive, Atlanta, Georgia 30322, USA. E-mail: [email protected]
Kidney International (2014) 85
the poor correlation between estimated GFR and true GFR when serum creatinine is in the normal range.1 Therefore, if we are to improve our diagnostic and prognostic approach to kidney disease, we must move beyond measurements of function and focus on structural changes as well. The study by Wang et al.2 (this issue) is an important step in this direction. Recent studies have demonstrated the potential utility of simple structural changes, recognizable by standard noninvasive imaging, in identifying and managing CKD. A good example is autosomal dominant polycystic kidney disease, in which decreased GFR occurs too late in the disease to be a useful parameter for prognosis or evaluating therapies. However, renal enlargement occurs much earlier and can accurately predict disease progression.3 Sporadic cysts, long thought to be of little clinical significance, are associated with reduced kidney size and altered function4–6 and are probably an early indicator of underlying damage.7 Renal enlargement occurs early in diabetes and is a risk factor for nephropathy.8,9 These examples demonstrate the
clinical significance of basic structural changes. The simplest structural parameter is kidney size, a decrease in which is frequent in advanced CKD and is often used to confirm this diagnosis. It is reasonable to assume that this loss begins at earlier stages of CKD, but, amazingly, there has been little attention to this as a clinical or research tool. Even though it is well known that kidney size varies with body size, there are no published nomograms based on data from subjects without renal disease that can be used to analyze kidney size in adults. Therefore, most renal sonograms are interpreted without correction for or even consideration of body size, clearly limiting the ability to recognize CKD at earlier stages. Other potential determinants of kidney size, such as sex and age, are also not considered. Although these corrections would enhance the ability of ultrasound to recognize kidney disease at an earlier stage, this is limited by the imprecision of ultrasound. Sonographic measurement of kidney volume entails measuring three orthogonal dimensions and modeling the kidney as an ellipsoid. However, there are errors in these measurements, particularly in the two transverse dimensions, that become very large when multiplied in the formula. Furthermore, the kidney rarely approximates an ellipsoid and varies considerably in shape. Thus renal length is the only useful sonographic indication of kidney size, but its correlation with actual volume is poor.10 Accurate measurements of kidney volume require either computed tomography or magnetic resonance imaging with summation of cross-sectional areas from multiple sequential images. Their relative utility is dictated by availability, cost, and radiation exposure. The kidney is also composed of nonparenchymal tissues (sinus fat, calyces, blood vessels, nerves, and lymphatics), and recent studies have used computed tomography to exclude them in order to measure true parenchymal volume. A prior study of 224 potential kidney transplant donors11 found a strong correlation between renal parenchymal volume and body surface area (r ¼ 0.68), a larger volume in males independent of 503
commentary
Volume
Total
Medulla
Cortex
Age 20
40
60
Figure 1 | Effect of age on kidney size. Cortical volume appears to decrease throughout adulthood, but whether this is due to nephron loss or decreased nephron size is unclear. Because of an increase in medullary volume, which could be compensatory, total parenchymal volume remains unchanged. When the increase in medullary volume ceases after age 60, total volume decreases.
body size, and no decrease with age (though there were few subjects older than 60 years). Wang et al. used the same approach in 1344 subjects and, remarkably, found the identical correlation between parenchymal volume and body surface area, again with greater volume in males and little effect of age up to 60.2 However, they went a step further and also examined the cortical and medullary compartments, which can be distinguished on different phases of a contrastenhanced scan. Importantly, they found that cortical volume decreases throughout adulthood and is masked by an increase in medullary volume (Figure 1). This relationship differed slightly in females, and, interestingly, certain metabolic parameters also correlated differently with cortical and medullary volume, the meaning of which remains to be determined. Of the many questions about kidney size that remain to be answered, two important ones are the identity of other determinants of size and the relationship with function. Body size, age, and sex account for only about half the variability in renal parenchymal volume,11 and even after correction for these variables, kidney volume varies as much as twofold between subjects. Is this due to differences in nephron number, which is fixed in the neonatal period and can vary as much as eightfold,12,13 or is it due to differe504
nces in nephron size? The latter could be the result of diet or of other metabolic parameters, as explored by Wang et al.2 Although glycemia correlated with parenchymal volume or cortical volume, this is probably explained by overweight, as the correlation was lost when volume was corrected for body size. A direct effect of obesity on parenchymal volume was shown in patients before and after weight loss in the previously cited study.11 GFR correlates strongly with parenchymal volume11— as Wang et al. confirm2—and parenchymal volume accounts entirely for the effects of body surface area, age, sex, and ethnicity on GFR.11 Although Wang et al. showed that cortical volume also correlates strongly with GFR, this could not fully account for the age-related decline in GFR. The fact that GFR varies almost twofold in subjects with similar volumes indicates additional variability in single-nephron GFR or tubular mass per nephron. Whether kidney size drives GFR or vice versa and whether size is a risk factor for CKD are additional important questions that cannot be answered by cross-sectional studies. The positive correlation between cortical volume and albuminuria found by Wang et al.2 is intriguing and suggests that volume measurements may have prognostic value. Interestingly, this was not explained by GFR in a multivariate model, suggesting that it may not be simply due to
hyperfiltration. Other cardiovascular risk factors such as smoking, uric acid, and high-density lipoprotein cholesterol also correlated with cortical or medullary volume, again supporting the potential of parenchymal volume as a risk factor. Future longitudinal studies will be needed to explore these tantalizing findings. Even the best of studies have limitations that always need to be considered. Although the study population was apparently normal and healthy, there is a potential selection bias that could have influenced this. Specifically, it is reasonable to assume that a large proportion of the subjects were family members of patients with advanced CKD and could have shared genetic or familial traits that predispose to CKD. Also, the differentiation between cortex and medulla is a functional rather than an anatomic distinction based on the delivery of the contrast agent. The timing of the cortical phase (and thus calculation of cortical and medullary volumes) can vary between individuals and is influenced by hemodynamics, contrast dose, and rate of injection. Repeat studies by Wang et al. on some of the subjects suggest that this variability is not large. While the study of Wang et al.2 does not yield specific insights into CKD, it raises important questions, demonstrates the methodology to answer them, and provides important reference data. It is clear that there is a potentially very informative yet largely unexplored role of simple structural parameters in the evaluation of kidney disease and that our approach to kidney disease needs to become less dysfunctional and more dysmorphic. Unfortunately, few nephrologists have much knowledge or understanding of renal imaging, even fewer actually image kidneys, and just a handful have an academic focus in this area. Whereas the anatomy of the nephron is well understood by nephrologists, most are lost when zooming out to the whole kidney. Nephrologists will need to take a greater interest in renal imaging and pay more attention to structure, not just function. DISCLOSURE
The author declared no competing interests. Kidney International (2014) 85
commentary
REFERENCES 1.
2.
3.
4.
5.
6.
7.
Bostom AG, Kronenberg F, Ritz E. Predictive performance of renal function equations for patients with chronic kidney disease and normal serum creatinine levels. J Am Soc Nephrol 2002; 13: 2140–2144. Wang X, Vrtiska TJ, Avula RT et al. Age, kidney function, and risk factors associate differently with cortical and medullary volumes of the kidney. Kidney Int 2014; 85: 677–685. Chapman AB, Bost JE, Torres VE et al. Kidney volume and functional outcomes in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 2012; 7: 479–486. Al-Said JM, O’Neill WC. Reduced kidney size in patients with simple renal cysts. Kidney Int 2003; 64: 1059–1064. Al-Said J, Moghazi S, Brumback M et al. Reduced renal function in patients with simple renal cysts. Kidney Int 2004; 65: 2303–2308. Rule AD, Sasiwimonphan K, Lieske JC et al. Characteristics of renal cystic and solid lesions based on contrast-enhanced computed tomography of potential kidney donors. Am J Kidney Dis 2012; 59: 611–618. Grantham JJ. Solitary renal cysts: worth a second look? Am J Kidney Dis 2012; 59: 593–594.
8.
9.
10.
11.
12.
13.
Feldt-Rasmussen B, Hegedus L, Mathiesen ER. Kidney volume in type I (insulin-dependent) diabetic patients with normal or increased urinary albumin excretion: effect of long-term improved metabolic control. Scand J Clin Lab Invest 1991; 51: 31–36. Baumgartl HJ, Sigl G, Banholzer P et al. On the prognosis of IDDM patients with large kidneys. Nephrol Dial Transplant 1998; 13: 630–634. Bakker J, Olree M, Kaatee R et al. Renal volume measurements: accuracy and repeatability of US compared with that of MR imaging. Radiology 1999; 211: 623–628. Johnson S, Rishi R, Andone A et al. Determinants and functional significance of renal parenchymal volume in adults. Clin J Am Soc Nephrol 2011; 6: 70–76. Nyengaard JR, Bendtsen TF. Glomerular number and size in relation to age, kidney weight, and body surface in normal men. Anat Rec 1992; 232: 194–201. Hoy W, Douglas-Denton R, Hughson M et al. A stereologic study of glomerular number and volume: preliminary findings in a multiracial study of kidneys at autopsy. Kidney Int 2003; 63: 31–37.
see clinical investigation on page 693
Cognitive impairment in chronic kidney disease: keep vascular disease in mind David A. Drew1 and Daniel E. Weiner1 Cognitive impairment is a major cause of morbidity in people with chronic kidney disease (CKD) and is associated with worse survival. Prior data suggest a relationship between vascular disease and cognitive impairment in individuals with CKD. Clinicians should be aware of the high rates of cognitive impairment that occur in all stages of CKD, which, although sometimes subtle, may impact comprehension and decision making and may herald future, more debilitating impairment. Kidney International (2014) 85, 505–507. doi:10.1038/ki.2013.437
Cognitive impairment is a major cause of morbidity in chronic kidney disease (CKD). Individuals with cognitive impairment often have lower quality of life, have more difficulty adhering to medications, and have worse survival.1 Importantly, cognitive deficits become both more 1 Division of Nephrology, Department of Medicine, Tufts Medical Center, Boston, Massachusetts, USA Correspondence: Daniel E. Weiner, Tufts Medical Center, 800 Washington Street, Box #391, Boston, Massachusetts 02111, USA. E-mail: [email protected]
Kidney International (2014) 85
prevalent and more severe at lower levels of kidney function.2 For patients with kidney failure treated with dialysis, this translates to a prevalence of cognitive impairment anywhere from 30 to 70%.3,4 Reflecting the complex medical issues present in people with CKD, the cause of cognitive impairment is probably multifactorial in this population. As in the general population, aging patients with kidney disease can be at risk for developing Alzheimer’s disease, which initially affects memory most
prominently; however, rates of Alzheimer’s in CKD patients appear similar to those in age- and sex-matched controls, therefore not explaining an observed excess of cognitive impairment.5 In contrast, cerebrovascular disease is common in all stages of CKD, with the highest rates occurring in those treated with dialysis. Brain magnetic resonance imaging in dialysis patients confirms a high burden of white matter disease, atrophy, and cerebral infarcts, even in those without a known history of stroke.6 Supporting the hypothesis that cerebrovascular disease is most responsible for cognitive impairment in people with CKD are several factors: (1) Neurocognitive manifestations of cerebrovascular disease predominantly affect executive function domains rather than memory, and most prior studies of individuals with CKD reveal that executive function is more severely affected than other cognitive domains.3,4,7,8 (2) Systemic cardiovascular disease (CVD) and CVD risk factors are associated with significantly worse executive function.7 (3) In earlier stages of CKD, higher levels of albuminuria, probably representing systemic vascular burden, are associated with both worse executive functioning and brain magnetic resonance image findings.5,9,10 (4) More intensive dialysis with more effective clearance of uremic solutes does not improve cognitive function.11 In addition to a high burden of traditional CVD risk factors among individuals with CKD, nontraditional risk factors such as inflammation may be more prominent in individuals with CKD and may also predispose to cardiovascular and cerebrovascular disease (Figure 1). Few data exist on how inflammation in individuals with CKD may contribute to abnormal brain function. Attempting to address these questions, Seidel et al.12 (this issue) performed a cross-sectional study evaluating cognitive performance in 119 patients with CKD stages 3–5D as well as 54 control subjects, all of whom had an estimated glomerular 505
3.
4.
Schlieper G, Brandenburg V, Djuric Z et al. Risk factors for cardiovascular calcifications in nondiabetic Caucasian haemodialysis patients. Kidney Blood Press Res 2009; 32: 161–168. Leroux-Berger M, Queguiner I, Maciel TT et al. Pathologic calcification of adult vascular smooth muscle cells differs on their crest or mesodermal embryonic origin. J Bone Miner Res 2011; 26: 1543–1553.
5.
6.
Cheung C, Bernardo AS, Trotter MW et al. Generation of human vascular smooth muscle subtypes provides insight into embryological origin-dependent disease susceptibility. Nat Biotechnol 2012; 30: 165–173. Bostrom KI, Rajamannan NM, Towler DA. The regulation of valvular and vascular sclerosis by osteogenic morphogens. Circ Res 2011; 109: 564–577.
see clinical investigation on page 677
Structure, not just function W. Charles O’Neill1 Although kidney size can be important in the evaluation of renal disease, it has not been carefully studied and true volume is rarely measured, and good normative data are lacking. Wang et al. measured both cortical and medullary volumes in potential transplant donors and correlate these with physiologic, morphometric, and metabolic parameters. The results reveal interesting and potentially important correlations and differential responses between the two compartments, providing a framework for future investigation. Kidney International (2014) 85, 503–505. doi:10.1038/ki.2013.426
Nephrologists usually take a dysfunctional approach to kidney disease. Not that there is anything wrong with us, but our detection of kidney disease and stratification of its severity are based almost entirely on altered function rather than structure. On top of that, we take a glomerulocentric view of kidney dysfunction, focusing only on albuminuria and reduced glomerular filtration rate (GFR) as if the kidney consists exclusively of cortex composed entirely of glomeruli. Kidney disease is presumed absent when glomerular function is normal, and thus many cases of early disease are missed, while chronic kidney disease (CKD) or acute kidney injury is diagnosed when GFR is decreased, even though the dysfunction may be entirely hemodynamic and the kidneys structurally normal. Additional problems with this approach are the impracticality of measuring GFR and 1 Renal Division, Emory University School of Medicine, Atlanta, Georgia, USA Correspondence: W. Charles O’Neill, Emory University, Renal Division, WMB 338, 1639 Pierce Drive, Atlanta, Georgia 30322, USA. E-mail: [email protected]
Kidney International (2014) 85
the poor correlation between estimated GFR and true GFR when serum creatinine is in the normal range.1 Therefore, if we are to improve our diagnostic and prognostic approach to kidney disease, we must move beyond measurements of function and focus on structural changes as well. The study by Wang et al.2 (this issue) is an important step in this direction. Recent studies have demonstrated the potential utility of simple structural changes, recognizable by standard noninvasive imaging, in identifying and managing CKD. A good example is autosomal dominant polycystic kidney disease, in which decreased GFR occurs too late in the disease to be a useful parameter for prognosis or evaluating therapies. However, renal enlargement occurs much earlier and can accurately predict disease progression.3 Sporadic cysts, long thought to be of little clinical significance, are associated with reduced kidney size and altered function4–6 and are probably an early indicator of underlying damage.7 Renal enlargement occurs early in diabetes and is a risk factor for nephropathy.8,9 These examples demonstrate the
clinical significance of basic structural changes. The simplest structural parameter is kidney size, a decrease in which is frequent in advanced CKD and is often used to confirm this diagnosis. It is reasonable to assume that this loss begins at earlier stages of CKD, but, amazingly, there has been little attention to this as a clinical or research tool. Even though it is well known that kidney size varies with body size, there are no published nomograms based on data from subjects without renal disease that can be used to analyze kidney size in adults. Therefore, most renal sonograms are interpreted without correction for or even consideration of body size, clearly limiting the ability to recognize CKD at earlier stages. Other potential determinants of kidney size, such as sex and age, are also not considered. Although these corrections would enhance the ability of ultrasound to recognize kidney disease at an earlier stage, this is limited by the imprecision of ultrasound. Sonographic measurement of kidney volume entails measuring three orthogonal dimensions and modeling the kidney as an ellipsoid. However, there are errors in these measurements, particularly in the two transverse dimensions, that become very large when multiplied in the formula. Furthermore, the kidney rarely approximates an ellipsoid and varies considerably in shape. Thus renal length is the only useful sonographic indication of kidney size, but its correlation with actual volume is poor.10 Accurate measurements of kidney volume require either computed tomography or magnetic resonance imaging with summation of cross-sectional areas from multiple sequential images. Their relative utility is dictated by availability, cost, and radiation exposure. The kidney is also composed of nonparenchymal tissues (sinus fat, calyces, blood vessels, nerves, and lymphatics), and recent studies have used computed tomography to exclude them in order to measure true parenchymal volume. A prior study of 224 potential kidney transplant donors11 found a strong correlation between renal parenchymal volume and body surface area (r ¼ 0.68), a larger volume in males independent of 503
commentary
Volume
Total
Medulla
Cortex
Age 20
40
60
Figure 1 | Effect of age on kidney size. Cortical volume appears to decrease throughout adulthood, but whether this is due to nephron loss or decreased nephron size is unclear. Because of an increase in medullary volume, which could be compensatory, total parenchymal volume remains unchanged. When the increase in medullary volume ceases after age 60, total volume decreases.
body size, and no decrease with age (though there were few subjects older than 60 years). Wang et al. used the same approach in 1344 subjects and, remarkably, found the identical correlation between parenchymal volume and body surface area, again with greater volume in males and little effect of age up to 60.2 However, they went a step further and also examined the cortical and medullary compartments, which can be distinguished on different phases of a contrastenhanced scan. Importantly, they found that cortical volume decreases throughout adulthood and is masked by an increase in medullary volume (Figure 1). This relationship differed slightly in females, and, interestingly, certain metabolic parameters also correlated differently with cortical and medullary volume, the meaning of which remains to be determined. Of the many questions about kidney size that remain to be answered, two important ones are the identity of other determinants of size and the relationship with function. Body size, age, and sex account for only about half the variability in renal parenchymal volume,11 and even after correction for these variables, kidney volume varies as much as twofold between subjects. Is this due to differences in nephron number, which is fixed in the neonatal period and can vary as much as eightfold,12,13 or is it due to differe504
nces in nephron size? The latter could be the result of diet or of other metabolic parameters, as explored by Wang et al.2 Although glycemia correlated with parenchymal volume or cortical volume, this is probably explained by overweight, as the correlation was lost when volume was corrected for body size. A direct effect of obesity on parenchymal volume was shown in patients before and after weight loss in the previously cited study.11 GFR correlates strongly with parenchymal volume11— as Wang et al. confirm2—and parenchymal volume accounts entirely for the effects of body surface area, age, sex, and ethnicity on GFR.11 Although Wang et al. showed that cortical volume also correlates strongly with GFR, this could not fully account for the age-related decline in GFR. The fact that GFR varies almost twofold in subjects with similar volumes indicates additional variability in single-nephron GFR or tubular mass per nephron. Whether kidney size drives GFR or vice versa and whether size is a risk factor for CKD are additional important questions that cannot be answered by cross-sectional studies. The positive correlation between cortical volume and albuminuria found by Wang et al.2 is intriguing and suggests that volume measurements may have prognostic value. Interestingly, this was not explained by GFR in a multivariate model, suggesting that it may not be simply due to
hyperfiltration. Other cardiovascular risk factors such as smoking, uric acid, and high-density lipoprotein cholesterol also correlated with cortical or medullary volume, again supporting the potential of parenchymal volume as a risk factor. Future longitudinal studies will be needed to explore these tantalizing findings. Even the best of studies have limitations that always need to be considered. Although the study population was apparently normal and healthy, there is a potential selection bias that could have influenced this. Specifically, it is reasonable to assume that a large proportion of the subjects were family members of patients with advanced CKD and could have shared genetic or familial traits that predispose to CKD. Also, the differentiation between cortex and medulla is a functional rather than an anatomic distinction based on the delivery of the contrast agent. The timing of the cortical phase (and thus calculation of cortical and medullary volumes) can vary between individuals and is influenced by hemodynamics, contrast dose, and rate of injection. Repeat studies by Wang et al. on some of the subjects suggest that this variability is not large. While the study of Wang et al.2 does not yield specific insights into CKD, it raises important questions, demonstrates the methodology to answer them, and provides important reference data. It is clear that there is a potentially very informative yet largely unexplored role of simple structural parameters in the evaluation of kidney disease and that our approach to kidney disease needs to become less dysfunctional and more dysmorphic. Unfortunately, few nephrologists have much knowledge or understanding of renal imaging, even fewer actually image kidneys, and just a handful have an academic focus in this area. Whereas the anatomy of the nephron is well understood by nephrologists, most are lost when zooming out to the whole kidney. Nephrologists will need to take a greater interest in renal imaging and pay more attention to structure, not just function. DISCLOSURE
The author declared no competing interests. Kidney International (2014) 85
commentary
REFERENCES 1.
2.
3.
4.
5.
6.
7.
Bostom AG, Kronenberg F, Ritz E. Predictive performance of renal function equations for patients with chronic kidney disease and normal serum creatinine levels. J Am Soc Nephrol 2002; 13: 2140–2144. Wang X, Vrtiska TJ, Avula RT et al. Age, kidney function, and risk factors associate differently with cortical and medullary volumes of the kidney. Kidney Int 2014; 85: 677–685. Chapman AB, Bost JE, Torres VE et al. Kidney volume and functional outcomes in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 2012; 7: 479–486. Al-Said JM, O’Neill WC. Reduced kidney size in patients with simple renal cysts. Kidney Int 2003; 64: 1059–1064. Al-Said J, Moghazi S, Brumback M et al. Reduced renal function in patients with simple renal cysts. Kidney Int 2004; 65: 2303–2308. Rule AD, Sasiwimonphan K, Lieske JC et al. Characteristics of renal cystic and solid lesions based on contrast-enhanced computed tomography of potential kidney donors. Am J Kidney Dis 2012; 59: 611–618. Grantham JJ. Solitary renal cysts: worth a second look? Am J Kidney Dis 2012; 59: 593–594.
8.
9.
10.
11.
12.
13.
Feldt-Rasmussen B, Hegedus L, Mathiesen ER. Kidney volume in type I (insulin-dependent) diabetic patients with normal or increased urinary albumin excretion: effect of long-term improved metabolic control. Scand J Clin Lab Invest 1991; 51: 31–36. Baumgartl HJ, Sigl G, Banholzer P et al. On the prognosis of IDDM patients with large kidneys. Nephrol Dial Transplant 1998; 13: 630–634. Bakker J, Olree M, Kaatee R et al. Renal volume measurements: accuracy and repeatability of US compared with that of MR imaging. Radiology 1999; 211: 623–628. Johnson S, Rishi R, Andone A et al. Determinants and functional significance of renal parenchymal volume in adults. Clin J Am Soc Nephrol 2011; 6: 70–76. Nyengaard JR, Bendtsen TF. Glomerular number and size in relation to age, kidney weight, and body surface in normal men. Anat Rec 1992; 232: 194–201. Hoy W, Douglas-Denton R, Hughson M et al. A stereologic study of glomerular number and volume: preliminary findings in a multiracial study of kidneys at autopsy. Kidney Int 2003; 63: 31–37.
see clinical investigation on page 693
Cognitive impairment in chronic kidney disease: keep vascular disease in mind David A. Drew1 and Daniel E. Weiner1 Cognitive impairment is a major cause of morbidity in people with chronic kidney disease (CKD) and is associated with worse survival. Prior data suggest a relationship between vascular disease and cognitive impairment in individuals with CKD. Clinicians should be aware of the high rates of cognitive impairment that occur in all stages of CKD, which, although sometimes subtle, may impact comprehension and decision making and may herald future, more debilitating impairment. Kidney International (2014) 85, 505–507. doi:10.1038/ki.2013.437
Cognitive impairment is a major cause of morbidity in chronic kidney disease (CKD). Individuals with cognitive impairment often have lower quality of life, have more difficulty adhering to medications, and have worse survival.1 Importantly, cognitive deficits become both more 1 Division of Nephrology, Department of Medicine, Tufts Medical Center, Boston, Massachusetts, USA Correspondence: Daniel E. Weiner, Tufts Medical Center, 800 Washington Street, Box #391, Boston, Massachusetts 02111, USA. E-mail: [email protected]
Kidney International (2014) 85
prevalent and more severe at lower levels of kidney function.2 For patients with kidney failure treated with dialysis, this translates to a prevalence of cognitive impairment anywhere from 30 to 70%.3,4 Reflecting the complex medical issues present in people with CKD, the cause of cognitive impairment is probably multifactorial in this population. As in the general population, aging patients with kidney disease can be at risk for developing Alzheimer’s disease, which initially affects memory most
prominently; however, rates of Alzheimer’s in CKD patients appear similar to those in age- and sex-matched controls, therefore not explaining an observed excess of cognitive impairment.5 In contrast, cerebrovascular disease is common in all stages of CKD, with the highest rates occurring in those treated with dialysis. Brain magnetic resonance imaging in dialysis patients confirms a high burden of white matter disease, atrophy, and cerebral infarcts, even in those without a known history of stroke.6 Supporting the hypothesis that cerebrovascular disease is most responsible for cognitive impairment in people with CKD are several factors: (1) Neurocognitive manifestations of cerebrovascular disease predominantly affect executive function domains rather than memory, and most prior studies of individuals with CKD reveal that executive function is more severely affected than other cognitive domains.3,4,7,8 (2) Systemic cardiovascular disease (CVD) and CVD risk factors are associated with significantly worse executive function.7 (3) In earlier stages of CKD, higher levels of albuminuria, probably representing systemic vascular burden, are associated with both worse executive functioning and brain magnetic resonance image findings.5,9,10 (4) More intensive dialysis with more effective clearance of uremic solutes does not improve cognitive function.11 In addition to a high burden of traditional CVD risk factors among individuals with CKD, nontraditional risk factors such as inflammation may be more prominent in individuals with CKD and may also predispose to cardiovascular and cerebrovascular disease (Figure 1). Few data exist on how inflammation in individuals with CKD may contribute to abnormal brain function. Attempting to address these questions, Seidel et al.12 (this issue) performed a cross-sectional study evaluating cognitive performance in 119 patients with CKD stages 3–5D as well as 54 control subjects, all of whom had an estimated glomerular 505
