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Acute Kidney Injury and CKD: No Respite for a Weary Kidney
Editorial Acute Kidney Injury and CKD: No Respite for a Weary Kidney Related Articles, p. 591 and p. 602
I
n the Department of Veterans Affairs system, the largest health care organization in the United States, acute kidney injury (AKI) was the seventh most frequent cause for medical hospitalization from 2001 through 2003. Current data suggest that up to 20% of patients who have AKI will develop late-stage chronic kidney disease (CKD), and notable risk factors for kidney failure subsequent to AKI include preexisting CKD, older age, and diabetes mellitus.1 When these and other traditional AKI risk indicators are considered, especially in a larger, more demographically mixed population, which risk factors emerge as critically important? In this issue of AJKD, 2 meta-analyses2,3 that together include almost 1.3 million patients, provide important insights into this question. These metaanalyses examined the incidence and risk factors for developing AKI in relation to pre-existing decreased estimated glomerular filtration rate (eGFR); the presence of albuminuria; age, race, and sex; and diabetes and hypertension. Among the risk factors examined, albuminuria and decreased eGFR emerged as the strongest predictors of AKI. Over a mean follow-up period of 4 years, a urinary albumin-creatinine ratio (ACR) of 300 mg/g was associated with a hazard ratio (HR) for AKI of 2.73 (95% confidence interval [CI], 2.18-3.43) as compared with an ACR of 5 mg/g. With respect to level of kidney function, patients with an eGFR of 45 mL/min/1.73 m2 had an adjusted HR for AKI of 3.35 (95% CI, 2.75-4.07) compared with patients having an eGFR of 80 mL/min/1.73 m2. Other risk factors were weaker in comparison to albuminuria and decreased eGFR. The remainder of this editorial considers these findings from a physiological vantage point, their significance to clinicians dealing with everyday clinical care decision making, and finally their implications regarding public health. Nephrologists recognize that regardless of the underlying cause of kidney disease, proteinuria is a significant risk factor for its progression. However, the link between proteinuria and AKI risk requires further study and an understanding of putative mechanisms. Multiple lines of experimental evidence show that Address correspondence to Lakhmir S. Chawla, MD, 50 Irving St, Department of Medicine, Veterans Affairs Medical Center, Washington, DC 20422. E-mail: [email protected] Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2015.08.014 552
proteinuria itself is nephrotoxic due to its adverse effects on regulation of GFR and tubular function as well as its proinflammatory properties. In the MunichWistar rat model system of puromycin-induced nephrotic syndrome, micropuncture studies from 3 decades ago showed that there are marked changes in glomerular hemodynamics. More specifically, in this experimental system proteinuria is associated with a significant decrease in measured and single-nephron GFR as well as reductions in the ultrafiltration coefficient (Kuf), absolute reabsorption by the proximal tubule, and urinary sodium excretion (this last observation was attributed to increased reabsorption of sodium by nephron segments beyond the distal convoluted tubule). Interestingly, some of these effects are reversed or attenuated by administering the angiotensin blocker saralasin. Published in 1983,4 these findings were an early suggestion that proteinuria and the reninangiotensin system (RAS) are functionally interrelated, and that, in proteinuric patients, activation of the RAS may increase susceptibility to ischemic insults. Consistent with this early work, more recent studies in cultured proximal tubular cells exposed to high concentrations of albumin have found upregulated expression of angiotensinogen, angiotensin-converting enzyme (ACE), and the angiotensin II type 1 receptor.5 Further studies have revealed that albuminuria is associated with activation of a vast array of proinflammatory mediators, including endothelin 1, monocyte chemoattractant protein 1 (encoded by CCL2), RANTES (encoded by CCL5), NF-kB, and complement (reviewed in6). Some effects of albumin on renal tubular cells are mediated by megalin, a member of the low-density lipoprotein receptor family responsible for tubular reabsorption of luminal proteins. As opposed to megalin-deficient proximal tubular cells, megalin-rich cells take up more albumin, immunoglobulin (Ig) light chains, IgA, and IgG; express greater amounts of tubular injury markers; and have increased evidence of cellular apoptosis.7 These lines of evidence may explain why renal tubules exposed to serum proteins are primed to suffer earlier and more severe damage in the setting of ischemia, nephrotoxins, or sepsis. The strength of the association between albuminuria and AKI in these meta-analyses, in conjunction with data supporting proteinuria’s toxicity, provides a rationale for pharmacological approaches to decrease proteinuria in patients. The current armamentarium includes RAS blockers, which, although they reduce proteinuria, also affect autoregulation, which is a critical defense for the kidney against ischemia. Unfortunately, many patients are intolerant of the most Am J Kidney Dis. 2015;66(4):552-554
Editorial
commonly used drugs for this indication: ACE inhibitors and angiotensin receptor blockers (ARBs). This state of affairs should stimulate the pharmaceutical industry community to seek new drugs that reduce protein excretion but do not block renal autoregulation or cause significant hyperkalemia. In the cohorts they meta-analyzed, Grams et al2 and James et al3 also found pre-existing decreased eGFR to be a strong predictor of AKI. The interconnection between CKD (defined by decreased GFR and presence of proteinuria) and AKI has been recently reviewed.8 In the current meta-analyses, patient were identified as having AKI based on ICD-9/10 (International Classification of Diseases, Ninth or Tenth Revision) codes recorded during hospital admissions. Although highly specific, this approach, as correctly pointed out by the authors, lacks sensitivity.9 This obvious limitation leads to underestimation of the true incidence of AKI, for example by ignoring AKI in the outpatient setting. Consensus classifications, such as those recommended by KDIGO (Kidney Disease: Improving Global Outcomes), greatly assist epidemiologists in assessing clinical and epidemiological features of de novo AKI, but the classification of AKI in the setting of pre-existing CKD is more problematic. Making sense of clinical data that are generated by health care systems requires differentiating between underlying clinical entities and data points originating from health care system processes. The fact is that AKI is not equivalent to having a hospital admission for AKI. This has several important implications regarding the meaning of the interactions reported by Grams et al and James et al among AKI, eGFR, age, diabetes, and hypertension. Many patients who have an admission that includes an AKI billing code are initially admitted for another reason and develop AKI during that admission. Older age, diabetes, and hypertension increase the risk for all-cause hospitalization, so patients who are younger and less ill are less likely to be admitted to the hospital. However, in the current studies, patients who are not admitted cannot—by definition—have AKI. Therefore, the current meta-analyses are to some extent designed to show an association of age, diabetes, and hypertension with AKI. Whether these covariates are also associated with the underlying clinical entity of AKI (which may occur even more often in outpatients than inpatients) is not specifically addressed. Any hypotheses about causation in the AKI-CKD relationship will need to be tested in prospective studies with longitudinal follow-up. If AKI is prevented or mitigated, we need to learn whether downstream CKD progression is slowed. Electronic health records that document longitudinal serum creatinine trajectories strongly suggest that, in certain subsets of patients with CKD, serum creatinine Am J Kidney Dis. 2015;66(4):552-554
values are highly variable, and, in the absence of precipitating factors or severity that warrants hospitalizations, many of these perhaps milder cases of AKI may not be captured by ICD-9/10 billing codes. Thus, the incidence of AKI is very likely underestimated and so too is its role in CKD progression. Notwithstanding the valuable contribution of the authors to our understanding of effect size of the AKI-CKD connection (and the conditions under which this effect size varies), we still need to examine this complex relationship further, beyond what may be extracted from hospital records. If, in interventional trials to reduce AKI, we find that the treated patients also have slower CKD progression, this may help us better understand to what extent AKI has a causal impact on CKD. An interesting finding in the meta-analyses is that the association between age and AKI is stronger for those without reduced eGFR. Similarly, the association between pre-existing decreased eGFR and AKI is stronger for those without diabetes. Why would this be? One possible explanation for both findings is based on 2 assumptions, both of which require further study: first, many inpatient AKI events are iatrogenic, and second, health care providers are more careful to avoid certain medications or imaging tests in frail patients, who are defined by older age, diabetes, and/ or decreased eGFR. If both of these assumptions are true, then older patients with decreased eGFR and those with diabetes might have a lower incidence of iatrogenic events that result in AKI. In other words, one might speculate that these findings may provide more insight about health care practice than about the relationships between age and the underlying clinical entities of AKI, CKD, and diabetes per se. An important challenge confronting clinical providers is the diagnosis and management of unexpected increments in serum creatinine in patients with CKD in the absence of clear causes of AKI. Adjustments in diuretic and anti-hypertensive medication doses, withdrawal of other nephrotoxins, and other more subtle interventions may lead to improvement and total or partial return to baseline kidney function. However, it is likely that these episodes are not inconsequential, but rather, in the long run, accelerate progression to late-stage CKD. Management guidelines for AKI and sensitive urinary biomarkers to facilitate early diagnosis of AKI must be made available to clinicians treating patients with CKD so that clinicians may be able to better differentiate among the various causes of unexpected changes in serum creatinine levels in order to reduce the risk of kidney failure. AKI biomarkers that perform well in patients with pre-existing CKD would be particularly welcome given that the risk of AKI appears to be highest amongst those with pre-existing kidney disease in the form of either decreased eGFR or the presence of proteinuria. 553
Palant, Amdur, and Chawla
In summary, AKI is a significant public health hazard. This pair of meta-analyses further demonstrates that the burden of AKI is borne by those who can least tolerate it: patients with pre-existing kidney disease. Advanced CKD is a significant risk factor for major adverse cardiovascular events, and the arsenal of therapies available for AKI remains at zero. Therapies for the treatment of AKI, particularly in patients with CKD, are required. Accordingly, public health leaders should reappraise the current meager commitment to AKI research. Carlos Palant, MD Richard Amdur, PhD Lakhmir S. Chawla, MD Veterans Affairs Medical Center Washington, DC
ACKNOWLEDGEMENTS Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests.
REFERENCES 1. Amdur RL, Chawla LS, Amodeo S, Kimmel PL, Palant CE. Outcomes following diagnosis of acute renal failure in U.S.
554
veterans: focus on acute tubular necrosis. Kidney Int. 2009;76(10): 1089-1097. 2. Grams ME, Sang Y, Ballew SH, et al. A meta-analysis of the association of estimated GFR, albuminuria, age, race, and sex with acute kidney injury. Am J Kidney Dis. 2015;66(4):591-601. 3. James MT, Grams ME, Woodward M, et al. A meta-analysis of the association of estimated GFR, albuminuria, diabetes mellitus, and hypertension with acute kidney injury. Am J Kidney Dis. 2015;66(4):602-612. 4. Ichikawa I, Rennke HG, Hoyer JR, Badr KF, Schor N, Troy JL. Role for intrarenal mechanisms in the impaired salt excretion of experimental nephrotic syndrome. J Clin Invest. 1983;71(1):91-103. 5. Wei C, Zhou QG, Jing N, et al. Albumin overload activates intrarenal angiotensin system through protein kinase C and NADPH oxidase-dependent pathway. J Hypertens. 2011;29(7): 1411-1421. 6. Remuzzi G, Bertani T. Pathophysiology of progressive nephropathies. N Engl J Med; 1998. 33(20)9:1448-1456. 7. Motoyoshi Y, Matsusaka T, Saito A, et al. Megalin contributes to the early injury of proximal tubule cells during nonselective proteinuria. Kidney Int. 2008;74(10):1262-1269. 8. Chawla LS, Eggers PW, Star RA, Kimmel PL. Acute kidney injury and chronic kidney disease as interconnected syndromes. N Engl J Med. 2014;371(1):58-66. 9. Waikar SS, Wald R, Chertow GM, et al. Validity of international classification of diseases, ninth revision, clinical modification codes for acute renal failure. J Am Soc Nephrol. 2006;17(6): 1688-1694.
Am J Kidney Dis. 2015;66(4):552-554
I
n the Department of Veterans Affairs system, the largest health care organization in the United States, acute kidney injury (AKI) was the seventh most frequent cause for medical hospitalization from 2001 through 2003. Current data suggest that up to 20% of patients who have AKI will develop late-stage chronic kidney disease (CKD), and notable risk factors for kidney failure subsequent to AKI include preexisting CKD, older age, and diabetes mellitus.1 When these and other traditional AKI risk indicators are considered, especially in a larger, more demographically mixed population, which risk factors emerge as critically important? In this issue of AJKD, 2 meta-analyses2,3 that together include almost 1.3 million patients, provide important insights into this question. These metaanalyses examined the incidence and risk factors for developing AKI in relation to pre-existing decreased estimated glomerular filtration rate (eGFR); the presence of albuminuria; age, race, and sex; and diabetes and hypertension. Among the risk factors examined, albuminuria and decreased eGFR emerged as the strongest predictors of AKI. Over a mean follow-up period of 4 years, a urinary albumin-creatinine ratio (ACR) of 300 mg/g was associated with a hazard ratio (HR) for AKI of 2.73 (95% confidence interval [CI], 2.18-3.43) as compared with an ACR of 5 mg/g. With respect to level of kidney function, patients with an eGFR of 45 mL/min/1.73 m2 had an adjusted HR for AKI of 3.35 (95% CI, 2.75-4.07) compared with patients having an eGFR of 80 mL/min/1.73 m2. Other risk factors were weaker in comparison to albuminuria and decreased eGFR. The remainder of this editorial considers these findings from a physiological vantage point, their significance to clinicians dealing with everyday clinical care decision making, and finally their implications regarding public health. Nephrologists recognize that regardless of the underlying cause of kidney disease, proteinuria is a significant risk factor for its progression. However, the link between proteinuria and AKI risk requires further study and an understanding of putative mechanisms. Multiple lines of experimental evidence show that Address correspondence to Lakhmir S. Chawla, MD, 50 Irving St, Department of Medicine, Veterans Affairs Medical Center, Washington, DC 20422. E-mail: [email protected] Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2015.08.014 552
proteinuria itself is nephrotoxic due to its adverse effects on regulation of GFR and tubular function as well as its proinflammatory properties. In the MunichWistar rat model system of puromycin-induced nephrotic syndrome, micropuncture studies from 3 decades ago showed that there are marked changes in glomerular hemodynamics. More specifically, in this experimental system proteinuria is associated with a significant decrease in measured and single-nephron GFR as well as reductions in the ultrafiltration coefficient (Kuf), absolute reabsorption by the proximal tubule, and urinary sodium excretion (this last observation was attributed to increased reabsorption of sodium by nephron segments beyond the distal convoluted tubule). Interestingly, some of these effects are reversed or attenuated by administering the angiotensin blocker saralasin. Published in 1983,4 these findings were an early suggestion that proteinuria and the reninangiotensin system (RAS) are functionally interrelated, and that, in proteinuric patients, activation of the RAS may increase susceptibility to ischemic insults. Consistent with this early work, more recent studies in cultured proximal tubular cells exposed to high concentrations of albumin have found upregulated expression of angiotensinogen, angiotensin-converting enzyme (ACE), and the angiotensin II type 1 receptor.5 Further studies have revealed that albuminuria is associated with activation of a vast array of proinflammatory mediators, including endothelin 1, monocyte chemoattractant protein 1 (encoded by CCL2), RANTES (encoded by CCL5), NF-kB, and complement (reviewed in6). Some effects of albumin on renal tubular cells are mediated by megalin, a member of the low-density lipoprotein receptor family responsible for tubular reabsorption of luminal proteins. As opposed to megalin-deficient proximal tubular cells, megalin-rich cells take up more albumin, immunoglobulin (Ig) light chains, IgA, and IgG; express greater amounts of tubular injury markers; and have increased evidence of cellular apoptosis.7 These lines of evidence may explain why renal tubules exposed to serum proteins are primed to suffer earlier and more severe damage in the setting of ischemia, nephrotoxins, or sepsis. The strength of the association between albuminuria and AKI in these meta-analyses, in conjunction with data supporting proteinuria’s toxicity, provides a rationale for pharmacological approaches to decrease proteinuria in patients. The current armamentarium includes RAS blockers, which, although they reduce proteinuria, also affect autoregulation, which is a critical defense for the kidney against ischemia. Unfortunately, many patients are intolerant of the most Am J Kidney Dis. 2015;66(4):552-554
Editorial
commonly used drugs for this indication: ACE inhibitors and angiotensin receptor blockers (ARBs). This state of affairs should stimulate the pharmaceutical industry community to seek new drugs that reduce protein excretion but do not block renal autoregulation or cause significant hyperkalemia. In the cohorts they meta-analyzed, Grams et al2 and James et al3 also found pre-existing decreased eGFR to be a strong predictor of AKI. The interconnection between CKD (defined by decreased GFR and presence of proteinuria) and AKI has been recently reviewed.8 In the current meta-analyses, patient were identified as having AKI based on ICD-9/10 (International Classification of Diseases, Ninth or Tenth Revision) codes recorded during hospital admissions. Although highly specific, this approach, as correctly pointed out by the authors, lacks sensitivity.9 This obvious limitation leads to underestimation of the true incidence of AKI, for example by ignoring AKI in the outpatient setting. Consensus classifications, such as those recommended by KDIGO (Kidney Disease: Improving Global Outcomes), greatly assist epidemiologists in assessing clinical and epidemiological features of de novo AKI, but the classification of AKI in the setting of pre-existing CKD is more problematic. Making sense of clinical data that are generated by health care systems requires differentiating between underlying clinical entities and data points originating from health care system processes. The fact is that AKI is not equivalent to having a hospital admission for AKI. This has several important implications regarding the meaning of the interactions reported by Grams et al and James et al among AKI, eGFR, age, diabetes, and hypertension. Many patients who have an admission that includes an AKI billing code are initially admitted for another reason and develop AKI during that admission. Older age, diabetes, and hypertension increase the risk for all-cause hospitalization, so patients who are younger and less ill are less likely to be admitted to the hospital. However, in the current studies, patients who are not admitted cannot—by definition—have AKI. Therefore, the current meta-analyses are to some extent designed to show an association of age, diabetes, and hypertension with AKI. Whether these covariates are also associated with the underlying clinical entity of AKI (which may occur even more often in outpatients than inpatients) is not specifically addressed. Any hypotheses about causation in the AKI-CKD relationship will need to be tested in prospective studies with longitudinal follow-up. If AKI is prevented or mitigated, we need to learn whether downstream CKD progression is slowed. Electronic health records that document longitudinal serum creatinine trajectories strongly suggest that, in certain subsets of patients with CKD, serum creatinine Am J Kidney Dis. 2015;66(4):552-554
values are highly variable, and, in the absence of precipitating factors or severity that warrants hospitalizations, many of these perhaps milder cases of AKI may not be captured by ICD-9/10 billing codes. Thus, the incidence of AKI is very likely underestimated and so too is its role in CKD progression. Notwithstanding the valuable contribution of the authors to our understanding of effect size of the AKI-CKD connection (and the conditions under which this effect size varies), we still need to examine this complex relationship further, beyond what may be extracted from hospital records. If, in interventional trials to reduce AKI, we find that the treated patients also have slower CKD progression, this may help us better understand to what extent AKI has a causal impact on CKD. An interesting finding in the meta-analyses is that the association between age and AKI is stronger for those without reduced eGFR. Similarly, the association between pre-existing decreased eGFR and AKI is stronger for those without diabetes. Why would this be? One possible explanation for both findings is based on 2 assumptions, both of which require further study: first, many inpatient AKI events are iatrogenic, and second, health care providers are more careful to avoid certain medications or imaging tests in frail patients, who are defined by older age, diabetes, and/ or decreased eGFR. If both of these assumptions are true, then older patients with decreased eGFR and those with diabetes might have a lower incidence of iatrogenic events that result in AKI. In other words, one might speculate that these findings may provide more insight about health care practice than about the relationships between age and the underlying clinical entities of AKI, CKD, and diabetes per se. An important challenge confronting clinical providers is the diagnosis and management of unexpected increments in serum creatinine in patients with CKD in the absence of clear causes of AKI. Adjustments in diuretic and anti-hypertensive medication doses, withdrawal of other nephrotoxins, and other more subtle interventions may lead to improvement and total or partial return to baseline kidney function. However, it is likely that these episodes are not inconsequential, but rather, in the long run, accelerate progression to late-stage CKD. Management guidelines for AKI and sensitive urinary biomarkers to facilitate early diagnosis of AKI must be made available to clinicians treating patients with CKD so that clinicians may be able to better differentiate among the various causes of unexpected changes in serum creatinine levels in order to reduce the risk of kidney failure. AKI biomarkers that perform well in patients with pre-existing CKD would be particularly welcome given that the risk of AKI appears to be highest amongst those with pre-existing kidney disease in the form of either decreased eGFR or the presence of proteinuria. 553
Palant, Amdur, and Chawla
In summary, AKI is a significant public health hazard. This pair of meta-analyses further demonstrates that the burden of AKI is borne by those who can least tolerate it: patients with pre-existing kidney disease. Advanced CKD is a significant risk factor for major adverse cardiovascular events, and the arsenal of therapies available for AKI remains at zero. Therapies for the treatment of AKI, particularly in patients with CKD, are required. Accordingly, public health leaders should reappraise the current meager commitment to AKI research. Carlos Palant, MD Richard Amdur, PhD Lakhmir S. Chawla, MD Veterans Affairs Medical Center Washington, DC
ACKNOWLEDGEMENTS Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests.
REFERENCES 1. Amdur RL, Chawla LS, Amodeo S, Kimmel PL, Palant CE. Outcomes following diagnosis of acute renal failure in U.S.
554
veterans: focus on acute tubular necrosis. Kidney Int. 2009;76(10): 1089-1097. 2. Grams ME, Sang Y, Ballew SH, et al. A meta-analysis of the association of estimated GFR, albuminuria, age, race, and sex with acute kidney injury. Am J Kidney Dis. 2015;66(4):591-601. 3. James MT, Grams ME, Woodward M, et al. A meta-analysis of the association of estimated GFR, albuminuria, diabetes mellitus, and hypertension with acute kidney injury. Am J Kidney Dis. 2015;66(4):602-612. 4. Ichikawa I, Rennke HG, Hoyer JR, Badr KF, Schor N, Troy JL. Role for intrarenal mechanisms in the impaired salt excretion of experimental nephrotic syndrome. J Clin Invest. 1983;71(1):91-103. 5. Wei C, Zhou QG, Jing N, et al. Albumin overload activates intrarenal angiotensin system through protein kinase C and NADPH oxidase-dependent pathway. J Hypertens. 2011;29(7): 1411-1421. 6. Remuzzi G, Bertani T. Pathophysiology of progressive nephropathies. N Engl J Med; 1998. 33(20)9:1448-1456. 7. Motoyoshi Y, Matsusaka T, Saito A, et al. Megalin contributes to the early injury of proximal tubule cells during nonselective proteinuria. Kidney Int. 2008;74(10):1262-1269. 8. Chawla LS, Eggers PW, Star RA, Kimmel PL. Acute kidney injury and chronic kidney disease as interconnected syndromes. N Engl J Med. 2014;371(1):58-66. 9. Waikar SS, Wald R, Chertow GM, et al. Validity of international classification of diseases, ninth revision, clinical modification codes for acute renal failure. J Am Soc Nephrol. 2006;17(6): 1688-1694.
Am J Kidney Dis. 2015;66(4):552-554