NEWS & VIEWS proximal tubular cells.9 Consistent with this hypothesis, PECs have a life-long proliferative ability, they express a gradient of marker proteins that are also expressed by stem cells or progenitor cells (suggesting progressive differentiation), and they are located within the same compartment and on the same side of the basement membrane as podocytes and proximal tubule cells.9 However, whether PECs serve as renal progenitor cells in adult mammals is an issue of ongoing controversy. One study from our group showed that in juvenile mice, fully differentiated podocytes are recruited from cells in the Bowman capsule after birth.10 Subsequently, we showed that these cells are committed podocytes and no PEC-to-podocyte differentiation could be detected in adult mice.2 It might, therefore, be premature to designate PECs as renal progenitor cells and further studies are required to address this issue. In summary, a consensus has emerged that PECs are the major constituents of hyperplastic lesions. PECs are activated in these lesions and two novel signalling pathways that seem to be specifically induced in activated PECs have now been identified: the CXCR4–SDF‑1 axis and the RAAS. 1 These signalling pathways are potential pharmacological targets for the treatment of proliferative glomerulonephritis. Department of Nephrology and Clinical Immunology, RWTH University Hospital, Aachen University, Pauwelsstrasse 30, D‑52074 Aachen, Germany (M. J. Moeller, C. Kuppe). Correspondence to: M. J. Moeller [email protected] Acknowledgements The authors’ work is supported by the German Research Foundation SFB/TRR57 TP17 (M. J. Moeller) and the Else Kroener Fresenius Foundation (C. Kuppe). Competing interests The authors declare no competing interests. 1.
2.
3.
4.
5.
6.
Rizzo, P. et al. Nature and mediators of parietal epithelial cell activation in glomerulonephritides of human and rat. Am. J. Pathol. http:// dx.doi.org/10.1016/j.ajpath.2013.08.008. Berger, K. et al. The regenerative potential of parietal epithelial cells in adult mice. J. Am. Soc. Nephrol. (in press). Ding, M. et al. Loss of the tumor suppressor Vhlh leads to upregulation of Cxcr4 and rapidly progressive glomerulonephritis in mice. Nat. Med. 12, 1081–1087 (2006). Fatima, H. et al. Parietal epithelial cell activation marker in early recurrence of FSGS in the transplant. Clin. J. Am. Soc. Nephrol. 7, 1852–1858 (2012). Le Hir, M. & Besse-Eschmann, V. A novel mechanism of nephron loss in a murine model of crescentic glomerulonephritis. Kidney Int. 63, 591–599 (2003). Smeets, B. et al. Tracing the origin of glomerular extracapillary lesions from parietal
6 | JANUARY 2014 | VOLUME 10
7.
8.
epithelial cells. J. Am. Soc. Nephrol. 20, 2604–2615 (2009). Smeets, B. & Moeller, M. J. Parietal epithelial cells and podocytes in glomerular diseases. Semin. Nephrol. 32, 357–367 (2012). Smeets, B. et al. Angiotensin converting enzyme inhibition prevents development of collapsing focal segmental glomerulosclerosis in Thy‑1.1
transgenic mice. Nephrol. Dial. Transplant. 21, 3087–3097 (2006). 9. Ronconi, E. et al. Regeneration of glomerular podocytes by human renal progenitors. J. Am. Soc. Nephrol. 20, 322–332 (2009). 10. Appel, D. et al. Recruitment of podocytes from glomerular parietal epithelial cells. J. Am. Soc. Nephrol. 20, 333–343 (2009).
SCREENING
Screening for kidney disease —a lost opportunity Bruce A. Molitoris
The ACP has published ‘weak’ guidelines for screening patients for kidney disease based on limited or no data, which could harm patients with undiagnosed or progressive kidney disease. As kidney experts weren’t involved in the development of these guidelines, what should all health professionals know about screening for kidney disease? Molitoris, B. A. Nat. Rev. Nephrol. 10, 6–8 (2014); published online 3 December 2013; doi:10.1038/nrneph.2013.258
The American College of Physicians (ACP)—an organization with a longstanding interest in the development of clinical guidelines to help inform practice and policy—has published guidelines recommending that adults without symptoms or risk factors should not be screened for kidney disease. 1 The ACP’s guidelines include four recommendations (Box 1), and in response the American Society of Nephrology (ASN) has raised concerns regarding the potential for harm resulting from two of these recommendations.2 Recommendations three and four of the new guidelines are based on sound data, reflect current clinical nephrology practice, are widely accepted, and were rated as ‘strong’ by the ACP. ASN has registered a strong objection, however, to recommendations one and two: if broadly applied, these recommendations will delay care and reduce quality of life for many patients with kidney disease, particularly those who have not yet been diagnosed.2 Concluding that the clinical evidence for recommendations one and two was ‘low quality’, the ACP shares the ASN’s concerns and rates these recommendations as ‘weak’. Although the ACP recognizes that diabetes mellitus, hypertension, and cardiovascular disease are major risk factors for the development of chronic kidney disease (CKD), it is indecisive regarding which risk factors for CKD should be included in the decision supporting recommendation one.
“Although there are known risk factors for CKD (diabetes, hypertension, and cardiovascular disease), ACP found the current evidence insufficient to evaluate the benefits and harms of screening for CKD in asympto matic adults with CKD risk factors.” 1 I believe the ACP should have evaluated the benefits and harms of not screening patients at high risk of developing progressive kidney disease leading to the known comorbidities, such as a 10-fold increase in cardiovascular disease progression and end-stage renal disease (ESRD) leading to dialysis or transplantation. Furthermore, ACP did not delineate if ‘other’ risk factors should be included to identify those patients to be screened, and there was no quantification as to the extent or severity of risk factors prior to inclusion in the risk analysis for quantitative phenotypic traits. For instance, obesity and age are mentioned as known risk factors, yet ACP failed to explain at what BMI or age screening for kidney disease should occur. Many risk factors for developing CKD were not mentioned in the guidelines: a positive family history, recurrent urinary tract infections, recurrent exposure to potential nephrotoxins such as non-steroidal antiinflammatory drugs, radiocontrast dye, some antibiotics, some herbal treatments, or occupational exposures. Nephrologists recognize that these factors are particularly important in patients with any form of kidney disease leading to CKD stage 1–3, because CKD increases an individual’s www.nature.com/nrneph
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS Box 1 | ACP recommendations1 Recommendation 1: ACP recommends against screening for chronic kidney disease in asymptomatic adults without risk factors for chronic kidney disease. (Grade: weak recommendation, low-quality evidence) Recommendation 2: ACP recommends against testing for proteinuria in adults with or without diabetes who are currently taking an ACE inhibitor or an ARB. (Grade: weak recommendation, low-quality evidence) Recommendation 3: ACP recommends that clinicians select pharmacologic therapy that includes either an ACE inhibitor (moderate-quality evidence) or ARB (high-quality evidence) in patients with hypertension and stage 1 to 3 chronic kidney disease. (Grade: strong recommendation) Recommendation 4: ACP recommends that clinicians choose statin therapy to manage elevated low-density lipoprotein in patients with stage 1 to 3 chronic kidney disease. (Grade: strong recommendation, moderate-quality evidence) Abbreviations: ACE, angiotensin-converting enzyme; ACP, American College of Physicians; ARB, angiotensin II– receptor blocker. Reproduced with permission from the American College of Physicians © Qaseem, A. et al. Ann. Intern. Med. http://dx.doi.org/10.7326/0003‑4819‑159‑12‑201312170‑00726.
risk of acute kidney injury (AKI), which occurs in 23% of all hospitalized patients3 and accelerates the progression of CKD to ESRD. To minimize this risk, specific guidelines have been developed to help prevent AKI in patients with CKD, but such preventive efforts require that the patient has been formally diagnosed with CKD. The Centers for Disease Control and Prevention (CDC) estimates that more than 20% of Americans aged >20 years who have hypertension also have CKD.4 Indeed, the interaction between the heart and the kidney in congestive heart failure results in the newly-named cardiorenal syndrome. In addition, diabetes mellitus is the leading cause of patients with ESRD requiring dialysis or transplantation as lifesaving therapies. These therapies are extremely expensive and result in an annual expenditure for CKD and ESRD of US$77 billion.5 Early detection, limiting the increased risk of AKI, and dietary and therapeutic approaches to slow progression of kidney disease would reduce overall costs. Furthermore, the patient suffering, comorbidities, and disability-adjusted life-years (DALYs) often associated with CKD or ESRD are all too often attributed to diabetes mellitus and cardiovascular disease.6 Kidney disease is not recognized as a major cause of death by the WHO and yet this ailment contributes to markedly reduced life expectancies, accelerated vascular disease (including cerebral vascular disease), myocardial infarctions, and peripheral vascular disease in patients with cardiovascular disease or diabetes. Screening is, therefore, of the utmost importance. In recommendation two, the ACP dismisses the fact that many patients with CKD, or an associated disease such as diabetes mellitus, might have a secondary cause
of proteinuria. This is concerning given the incidence of diabetes in the general population, which could mask other causes of proteinuria. By following this recommendation and failing to screen adults with or without diabetes who are currently taking an angiotensin-converting enzyme (ACE) inhibitor or an angiot ensin II–receptor blocker (ARB) for the presence of protein uria, health professionals will miss secondary causes of kidney disease and associated proteinuria will go undetected, and untreated. ACP also implies that use of an ACE inhibitor or an ARB, independent of dose, proteinuria reduction or blood pressure control, is sufficient for general monitoring. A lack of response to these agents should drive dose increases, questioning of patient compliance and consideration of another disorder. ACP notes that recommendation two is also ‘weak’ and is based on ‘low-quality data’. Kidney care organizations believe that patients with proteinuria represent a highrisk group. Therefore, the ACP’s recommendation to not screen patients on ACE inhibitors or ARBs for proteinuria might result in inadequate follow-up, undertreated progression of kidney disease, and more patients receiving dialysis. By failing to highlight these risk factors in their guidelines, the ACP missed an important opportunity to educate at-risk Americans, their health-care providers, and insurers about the necessity of screening for kidney disease. In contrast to the ACP, the American Academy of Family Physicians and the US Preventive Services Task Force (USPSTF) concluded that the evidence was insufficient to assess the balance of benefits and harms of routine screening in asympto matic adults. 7,8 In its final assessment,
NATURE REVIEWS | NEPHROLOGY
USPSTF concluded “that the evidence on routine screening for CKD in asymptomatic adults is lacking, and that the balance of benefits and harms cannot be determined.”8 Thus, the ACP-generated recommendations one and two are in contrast by defining that opinion-based ‘risks’ warrant a specific recommendation not to screen. As ASN has previously stated, “a lack of evidence is not the same as evidence that screening, or subsequent interventions, is ineffective.”9 According to ACP, the guidelines it issues are “‘evidence-based clinical practice guidelines,’ which means our guidelines follow a rigorous development process and are based on the highest quality scientific evidence.”10 Why the two recommendations rated by ACP as ‘weak’ and based on ‘low quality evidence’ were included in this publication is, therefore, unclear. There is widespread concern that the four recommendations will be adopted as a unit and that many patients who might otherwise be given tools to halt progression of their kidney disease will not be identified in a timely manner. Early detection and early intervention can slow the progression of kidney disease and reduce the likelihood of kidney failure. We should be committed to supporting all approaches that will change kidney disease from a silent disease too often discovered in its late stages to one that is identified when modifications can affect the progression of the disease. By the time patients have stage 3 CKD, they have lost more than 50% of their total kidney function and at stage 3b they are at a point where progression to ESRD is all-too likely. The entire medical community must act sooner and enlist patients’ help in minimizing the comorbidities and progression that too often remain undetected until very late in the disease process. When ACP agrees with the experts and recognizes that recommendations one and two must be revisited, I am hopeful that they will enlist ASN and other nephrology organizations to help develop appropriate guidelines and, ultimately, improve kidney care throughout the world. Division of Nephrology, Department of Medicine, Indiana University School of Medicine, 950 West Walnut Street, R‑2 202‑C, Indianapolis, IN 46202, USA. Correspondence to: [email protected] Acknowledgements This article reflects the opinions of Bruce A. Molitoris, past president of the American Society of Nephrology (ASN). The ASN is currently drafting a morecomprehensive response to the American College of Physicians’ guidelines on screening, monitoring, and treatment of stage 1 to 3 chronic kidney disease.
VOLUME 10 | JANUARY 2014 | 7 © 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS Competing interests The author declares associations with the following company: FAST BioMedical. See the article online for full details of the relationships. 1.
Qaseem, A., Hopkins, R., Sweet, D. E., Starkey, M. & Shekelle, P. Screening, monitoring, and treatment of stage 1 to 3 chronic kidney disease: a clinical practice guideline from the Clinical Guidelines Committee of the American College of Physicians. Ann. Intern. Med. http://dx.doi.org/ 10.7326/0003-4819-159-12-20131217000726. 2. American Society of Nephrology. ASN emphasizes need for early detection of kidney disease, a silent killer [online], http:// www.newswise.com/articles/asn-emphasizesneed-for-early-detection-of-kidney-disease-asilent-killer-in-the-u-s (2013). 3. Susantitaphong, P. et al. World incidence of AKI: a meta-analysis. Clin. J. Am. Soc. Nephrol. 8, 1482–1493 (2013). 4. Centers for Disease Control and Prevention. Prevalence of chronic kidney disease and associated risk factors—United States,
1999–2004. MMWR Morb. Mortal. Wkly Rep. 56, 161–165 (2007). 5. United States Renal Data System. 2012 USRDS Annual Data Report: atlas of chronic kidney disease and end-stage renal disease in the United States [online], http://www.usrds.org/ atlas.aspx (2012). 6. Murray, C. J. & Lopez, A. D. Measuring the global burden of disease. N. Engl. J. Med. 369, 448–457 (2013). 7. American Academy of Family Clinicians. Screening chronic kidney disease [online], http://www.aafp.org/patient-care/clinicalrecommendations/all/kidney-disease.html (2012). 8. Moyer, V. A. et al. Screening for chronic kidney disease: U.S. Preventive Services Task Force recommendation statement. Ann. Intern. Med. 157, 567–570 (2012). 9. De Boer, I. H. et al. Screening for chronic kidney disease. Ann. Intern. Med. 158, 362–363 (2013). 10. Qaseem, A. et al. The development of clinical practice guidelines and guidance statements of the American College of Physicians: summary of methods. Ann. Intern. Med. 153, 194–199 (2010).
ACUTE KIDNEY INJURY
Short-term statin therapy for prevention of contrast-induced AKI Dimitri P. Mikhailidis and Vasilios G. Athyros
Two recent studies suggest that periprocedural statin administration can prevent contrast-induced acute kidney injury in cardiac patients undergoing percutaneous coronary intervention and in renal patients undergoing angiography, with or without intervention. These studies support the routine administration of potent statins before contrast media infusion in these vulnerable patients. Mikhailidis, D. P. & Athyros, V. G. Nat. Rev. Nephrol. 10, 8–9 (2014); published online 12 November 2013; doi:10.1038/nrneph.2013.249
Contrast-induced nephropathy (CIN), defined as an increase in serum creatin ine of 44 μmol/l or 25% over baseline, is a common complication after invasive diagnostic and/or therapeutic procedures.1 CIN is a significant cause of hospital-acquired renal failure, accounting for ~11% of all cases.1 CIN is linked to increased resource use, prolonged hospital stay and increased long-term mortality.2 Although no definitive measures to prevent CIN are currently available, hydration with isotonic saline administration, both before and for 24 h after contrast media infusion, might help.2 Oral N-acetylcysteine (600 mg twice daily starting on the day before the procedure) in addition to parenteral hydration has also been suggested for patients at high risk of CIN.2 8 | JANUARY 2014 | VOLUME 10
Results from two recently published randomized trials3,4 suggest that statin administration reduces the incidence of CIN. The first study was carried out in China and tested the efficacy of rosuvastatin in preventing CIN in patients with type 2 diab etes mellitus and mild-to-moderate (mainly stage 2) chronic kidney disease (CKD).3 All of the patients (n = 2,998) were undergoing coronary or peripheral arterial angiography, with or without intervention. The patients were randomly assigned to receive either rosuvastatin 10 mg per day (n = 1,498) for 5 days (2 days before, 3 days post-procedure) or to standard care (n = 1,500) in the control group.3 Hydration therapy was standard and at the physician’s discretion. Metformin or aminophylline was withdrawn for at least 2 days before
contrast media administration. Patients receiving rosuvastatin had a significantly lower incidence of CIN when compared with those receiving standard care (2.3% versus 3.9%, respectively; P = 0.01, odds ratio [OR] 0.58, 95% CI 0.38–0.89). During the 30 days following angiography, the rate of worsening heart failure was significantly lower in patients treated with rosuvastatin than in the control group (2.6% versus 4.3%, P = 0.02). Any useful effect of statins on heart failure might be related, in part, to a beneficial effect on kidney function, as suggested for atorvastatin by the findings of the large TNT Study 5 and the smaller GREACE study.6 An earlier study from Italy, the NAPLES II trial, investigated the rates of CIN in 202 patients after administration of a single dose (80 mg) of atorvastatin within 24 h before contrast media exposure, compared with 208 patients not given statins.7 CIN rate was lower in the atorvastatin group (4.5%) in patients both with and without type 2 diabetes and in patients with moderate CKD (stage 3, estimated glomerular filtration rate [eGFR] 31–60 ml/min/1.73 m2) than in control (no statin) patients (17.8%, P = 0.005, OR 0.22, 95% CI 0.07–0.69).7 The second recently published ran domized study 4 evaluated whether highdose rosuvastatin exerts a protective effect against CIN in patients with acute coronary syndrome (ACS). These patients are known to be at high risk of developing CIN. Consecutive statin-naive non-ST elevation patients with ACS scheduled for early percutaneous coronary intervention (PCI) were randomly assigned to receive rosuva statin (40 mg on admission, then 20 mg per day, n = 252) or no statin treatment (control group, n = 252).4 All patients received intravenous hydration with isotonic saline for 12 h both before and after the procedure and oral N-acetylcysteine twice daily from the day before to the day after angiography. Any nephrotoxic medications (metformin or non-steroidal anti-inflammatory drugs) were discontinued on admission. The rate of CIN was significantly lower in the statin group than in the control group (6.7% versus 15.1%, P = 0.003, OR 0.38, 95% CI 0.20‑0.71). The 30-day rate of adverse cardiovascular and renal events (including death, dialysis, myocardial infarction, stroke or persistent renal damage) was also significantly reduced in the statin group (3.6% versus 7.9%, P = 0.036).4 Moreover, early administration of statin was associated with a reduced rate of death or non-fatal www.nature.com/nrneph
© 2014 Macmillan Publishers Limited. All rights reserved
2.
3.
4.
5.
6.
Rizzo, P. et al. Nature and mediators of parietal epithelial cell activation in glomerulonephritides of human and rat. Am. J. Pathol. http:// dx.doi.org/10.1016/j.ajpath.2013.08.008. Berger, K. et al. The regenerative potential of parietal epithelial cells in adult mice. J. Am. Soc. Nephrol. (in press). Ding, M. et al. Loss of the tumor suppressor Vhlh leads to upregulation of Cxcr4 and rapidly progressive glomerulonephritis in mice. Nat. Med. 12, 1081–1087 (2006). Fatima, H. et al. Parietal epithelial cell activation marker in early recurrence of FSGS in the transplant. Clin. J. Am. Soc. Nephrol. 7, 1852–1858 (2012). Le Hir, M. & Besse-Eschmann, V. A novel mechanism of nephron loss in a murine model of crescentic glomerulonephritis. Kidney Int. 63, 591–599 (2003). Smeets, B. et al. Tracing the origin of glomerular extracapillary lesions from parietal
6 | JANUARY 2014 | VOLUME 10
7.
8.
epithelial cells. J. Am. Soc. Nephrol. 20, 2604–2615 (2009). Smeets, B. & Moeller, M. J. Parietal epithelial cells and podocytes in glomerular diseases. Semin. Nephrol. 32, 357–367 (2012). Smeets, B. et al. Angiotensin converting enzyme inhibition prevents development of collapsing focal segmental glomerulosclerosis in Thy‑1.1
transgenic mice. Nephrol. Dial. Transplant. 21, 3087–3097 (2006). 9. Ronconi, E. et al. Regeneration of glomerular podocytes by human renal progenitors. J. Am. Soc. Nephrol. 20, 322–332 (2009). 10. Appel, D. et al. Recruitment of podocytes from glomerular parietal epithelial cells. J. Am. Soc. Nephrol. 20, 333–343 (2009).
SCREENING
Screening for kidney disease —a lost opportunity Bruce A. Molitoris
The ACP has published ‘weak’ guidelines for screening patients for kidney disease based on limited or no data, which could harm patients with undiagnosed or progressive kidney disease. As kidney experts weren’t involved in the development of these guidelines, what should all health professionals know about screening for kidney disease? Molitoris, B. A. Nat. Rev. Nephrol. 10, 6–8 (2014); published online 3 December 2013; doi:10.1038/nrneph.2013.258
The American College of Physicians (ACP)—an organization with a longstanding interest in the development of clinical guidelines to help inform practice and policy—has published guidelines recommending that adults without symptoms or risk factors should not be screened for kidney disease. 1 The ACP’s guidelines include four recommendations (Box 1), and in response the American Society of Nephrology (ASN) has raised concerns regarding the potential for harm resulting from two of these recommendations.2 Recommendations three and four of the new guidelines are based on sound data, reflect current clinical nephrology practice, are widely accepted, and were rated as ‘strong’ by the ACP. ASN has registered a strong objection, however, to recommendations one and two: if broadly applied, these recommendations will delay care and reduce quality of life for many patients with kidney disease, particularly those who have not yet been diagnosed.2 Concluding that the clinical evidence for recommendations one and two was ‘low quality’, the ACP shares the ASN’s concerns and rates these recommendations as ‘weak’. Although the ACP recognizes that diabetes mellitus, hypertension, and cardiovascular disease are major risk factors for the development of chronic kidney disease (CKD), it is indecisive regarding which risk factors for CKD should be included in the decision supporting recommendation one.
“Although there are known risk factors for CKD (diabetes, hypertension, and cardiovascular disease), ACP found the current evidence insufficient to evaluate the benefits and harms of screening for CKD in asympto matic adults with CKD risk factors.” 1 I believe the ACP should have evaluated the benefits and harms of not screening patients at high risk of developing progressive kidney disease leading to the known comorbidities, such as a 10-fold increase in cardiovascular disease progression and end-stage renal disease (ESRD) leading to dialysis or transplantation. Furthermore, ACP did not delineate if ‘other’ risk factors should be included to identify those patients to be screened, and there was no quantification as to the extent or severity of risk factors prior to inclusion in the risk analysis for quantitative phenotypic traits. For instance, obesity and age are mentioned as known risk factors, yet ACP failed to explain at what BMI or age screening for kidney disease should occur. Many risk factors for developing CKD were not mentioned in the guidelines: a positive family history, recurrent urinary tract infections, recurrent exposure to potential nephrotoxins such as non-steroidal antiinflammatory drugs, radiocontrast dye, some antibiotics, some herbal treatments, or occupational exposures. Nephrologists recognize that these factors are particularly important in patients with any form of kidney disease leading to CKD stage 1–3, because CKD increases an individual’s www.nature.com/nrneph
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS Box 1 | ACP recommendations1 Recommendation 1: ACP recommends against screening for chronic kidney disease in asymptomatic adults without risk factors for chronic kidney disease. (Grade: weak recommendation, low-quality evidence) Recommendation 2: ACP recommends against testing for proteinuria in adults with or without diabetes who are currently taking an ACE inhibitor or an ARB. (Grade: weak recommendation, low-quality evidence) Recommendation 3: ACP recommends that clinicians select pharmacologic therapy that includes either an ACE inhibitor (moderate-quality evidence) or ARB (high-quality evidence) in patients with hypertension and stage 1 to 3 chronic kidney disease. (Grade: strong recommendation) Recommendation 4: ACP recommends that clinicians choose statin therapy to manage elevated low-density lipoprotein in patients with stage 1 to 3 chronic kidney disease. (Grade: strong recommendation, moderate-quality evidence) Abbreviations: ACE, angiotensin-converting enzyme; ACP, American College of Physicians; ARB, angiotensin II– receptor blocker. Reproduced with permission from the American College of Physicians © Qaseem, A. et al. Ann. Intern. Med. http://dx.doi.org/10.7326/0003‑4819‑159‑12‑201312170‑00726.
risk of acute kidney injury (AKI), which occurs in 23% of all hospitalized patients3 and accelerates the progression of CKD to ESRD. To minimize this risk, specific guidelines have been developed to help prevent AKI in patients with CKD, but such preventive efforts require that the patient has been formally diagnosed with CKD. The Centers for Disease Control and Prevention (CDC) estimates that more than 20% of Americans aged >20 years who have hypertension also have CKD.4 Indeed, the interaction between the heart and the kidney in congestive heart failure results in the newly-named cardiorenal syndrome. In addition, diabetes mellitus is the leading cause of patients with ESRD requiring dialysis or transplantation as lifesaving therapies. These therapies are extremely expensive and result in an annual expenditure for CKD and ESRD of US$77 billion.5 Early detection, limiting the increased risk of AKI, and dietary and therapeutic approaches to slow progression of kidney disease would reduce overall costs. Furthermore, the patient suffering, comorbidities, and disability-adjusted life-years (DALYs) often associated with CKD or ESRD are all too often attributed to diabetes mellitus and cardiovascular disease.6 Kidney disease is not recognized as a major cause of death by the WHO and yet this ailment contributes to markedly reduced life expectancies, accelerated vascular disease (including cerebral vascular disease), myocardial infarctions, and peripheral vascular disease in patients with cardiovascular disease or diabetes. Screening is, therefore, of the utmost importance. In recommendation two, the ACP dismisses the fact that many patients with CKD, or an associated disease such as diabetes mellitus, might have a secondary cause
of proteinuria. This is concerning given the incidence of diabetes in the general population, which could mask other causes of proteinuria. By following this recommendation and failing to screen adults with or without diabetes who are currently taking an angiotensin-converting enzyme (ACE) inhibitor or an angiot ensin II–receptor blocker (ARB) for the presence of protein uria, health professionals will miss secondary causes of kidney disease and associated proteinuria will go undetected, and untreated. ACP also implies that use of an ACE inhibitor or an ARB, independent of dose, proteinuria reduction or blood pressure control, is sufficient for general monitoring. A lack of response to these agents should drive dose increases, questioning of patient compliance and consideration of another disorder. ACP notes that recommendation two is also ‘weak’ and is based on ‘low-quality data’. Kidney care organizations believe that patients with proteinuria represent a highrisk group. Therefore, the ACP’s recommendation to not screen patients on ACE inhibitors or ARBs for proteinuria might result in inadequate follow-up, undertreated progression of kidney disease, and more patients receiving dialysis. By failing to highlight these risk factors in their guidelines, the ACP missed an important opportunity to educate at-risk Americans, their health-care providers, and insurers about the necessity of screening for kidney disease. In contrast to the ACP, the American Academy of Family Physicians and the US Preventive Services Task Force (USPSTF) concluded that the evidence was insufficient to assess the balance of benefits and harms of routine screening in asympto matic adults. 7,8 In its final assessment,
NATURE REVIEWS | NEPHROLOGY
USPSTF concluded “that the evidence on routine screening for CKD in asymptomatic adults is lacking, and that the balance of benefits and harms cannot be determined.”8 Thus, the ACP-generated recommendations one and two are in contrast by defining that opinion-based ‘risks’ warrant a specific recommendation not to screen. As ASN has previously stated, “a lack of evidence is not the same as evidence that screening, or subsequent interventions, is ineffective.”9 According to ACP, the guidelines it issues are “‘evidence-based clinical practice guidelines,’ which means our guidelines follow a rigorous development process and are based on the highest quality scientific evidence.”10 Why the two recommendations rated by ACP as ‘weak’ and based on ‘low quality evidence’ were included in this publication is, therefore, unclear. There is widespread concern that the four recommendations will be adopted as a unit and that many patients who might otherwise be given tools to halt progression of their kidney disease will not be identified in a timely manner. Early detection and early intervention can slow the progression of kidney disease and reduce the likelihood of kidney failure. We should be committed to supporting all approaches that will change kidney disease from a silent disease too often discovered in its late stages to one that is identified when modifications can affect the progression of the disease. By the time patients have stage 3 CKD, they have lost more than 50% of their total kidney function and at stage 3b they are at a point where progression to ESRD is all-too likely. The entire medical community must act sooner and enlist patients’ help in minimizing the comorbidities and progression that too often remain undetected until very late in the disease process. When ACP agrees with the experts and recognizes that recommendations one and two must be revisited, I am hopeful that they will enlist ASN and other nephrology organizations to help develop appropriate guidelines and, ultimately, improve kidney care throughout the world. Division of Nephrology, Department of Medicine, Indiana University School of Medicine, 950 West Walnut Street, R‑2 202‑C, Indianapolis, IN 46202, USA. Correspondence to: [email protected] Acknowledgements This article reflects the opinions of Bruce A. Molitoris, past president of the American Society of Nephrology (ASN). The ASN is currently drafting a morecomprehensive response to the American College of Physicians’ guidelines on screening, monitoring, and treatment of stage 1 to 3 chronic kidney disease.
VOLUME 10 | JANUARY 2014 | 7 © 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS Competing interests The author declares associations with the following company: FAST BioMedical. See the article online for full details of the relationships. 1.
Qaseem, A., Hopkins, R., Sweet, D. E., Starkey, M. & Shekelle, P. Screening, monitoring, and treatment of stage 1 to 3 chronic kidney disease: a clinical practice guideline from the Clinical Guidelines Committee of the American College of Physicians. Ann. Intern. Med. http://dx.doi.org/ 10.7326/0003-4819-159-12-20131217000726. 2. American Society of Nephrology. ASN emphasizes need for early detection of kidney disease, a silent killer [online], http:// www.newswise.com/articles/asn-emphasizesneed-for-early-detection-of-kidney-disease-asilent-killer-in-the-u-s (2013). 3. Susantitaphong, P. et al. World incidence of AKI: a meta-analysis. Clin. J. Am. Soc. Nephrol. 8, 1482–1493 (2013). 4. Centers for Disease Control and Prevention. Prevalence of chronic kidney disease and associated risk factors—United States,
1999–2004. MMWR Morb. Mortal. Wkly Rep. 56, 161–165 (2007). 5. United States Renal Data System. 2012 USRDS Annual Data Report: atlas of chronic kidney disease and end-stage renal disease in the United States [online], http://www.usrds.org/ atlas.aspx (2012). 6. Murray, C. J. & Lopez, A. D. Measuring the global burden of disease. N. Engl. J. Med. 369, 448–457 (2013). 7. American Academy of Family Clinicians. Screening chronic kidney disease [online], http://www.aafp.org/patient-care/clinicalrecommendations/all/kidney-disease.html (2012). 8. Moyer, V. A. et al. Screening for chronic kidney disease: U.S. Preventive Services Task Force recommendation statement. Ann. Intern. Med. 157, 567–570 (2012). 9. De Boer, I. H. et al. Screening for chronic kidney disease. Ann. Intern. Med. 158, 362–363 (2013). 10. Qaseem, A. et al. The development of clinical practice guidelines and guidance statements of the American College of Physicians: summary of methods. Ann. Intern. Med. 153, 194–199 (2010).
ACUTE KIDNEY INJURY
Short-term statin therapy for prevention of contrast-induced AKI Dimitri P. Mikhailidis and Vasilios G. Athyros
Two recent studies suggest that periprocedural statin administration can prevent contrast-induced acute kidney injury in cardiac patients undergoing percutaneous coronary intervention and in renal patients undergoing angiography, with or without intervention. These studies support the routine administration of potent statins before contrast media infusion in these vulnerable patients. Mikhailidis, D. P. & Athyros, V. G. Nat. Rev. Nephrol. 10, 8–9 (2014); published online 12 November 2013; doi:10.1038/nrneph.2013.249
Contrast-induced nephropathy (CIN), defined as an increase in serum creatin ine of 44 μmol/l or 25% over baseline, is a common complication after invasive diagnostic and/or therapeutic procedures.1 CIN is a significant cause of hospital-acquired renal failure, accounting for ~11% of all cases.1 CIN is linked to increased resource use, prolonged hospital stay and increased long-term mortality.2 Although no definitive measures to prevent CIN are currently available, hydration with isotonic saline administration, both before and for 24 h after contrast media infusion, might help.2 Oral N-acetylcysteine (600 mg twice daily starting on the day before the procedure) in addition to parenteral hydration has also been suggested for patients at high risk of CIN.2 8 | JANUARY 2014 | VOLUME 10
Results from two recently published randomized trials3,4 suggest that statin administration reduces the incidence of CIN. The first study was carried out in China and tested the efficacy of rosuvastatin in preventing CIN in patients with type 2 diab etes mellitus and mild-to-moderate (mainly stage 2) chronic kidney disease (CKD).3 All of the patients (n = 2,998) were undergoing coronary or peripheral arterial angiography, with or without intervention. The patients were randomly assigned to receive either rosuvastatin 10 mg per day (n = 1,498) for 5 days (2 days before, 3 days post-procedure) or to standard care (n = 1,500) in the control group.3 Hydration therapy was standard and at the physician’s discretion. Metformin or aminophylline was withdrawn for at least 2 days before
contrast media administration. Patients receiving rosuvastatin had a significantly lower incidence of CIN when compared with those receiving standard care (2.3% versus 3.9%, respectively; P = 0.01, odds ratio [OR] 0.58, 95% CI 0.38–0.89). During the 30 days following angiography, the rate of worsening heart failure was significantly lower in patients treated with rosuvastatin than in the control group (2.6% versus 4.3%, P = 0.02). Any useful effect of statins on heart failure might be related, in part, to a beneficial effect on kidney function, as suggested for atorvastatin by the findings of the large TNT Study 5 and the smaller GREACE study.6 An earlier study from Italy, the NAPLES II trial, investigated the rates of CIN in 202 patients after administration of a single dose (80 mg) of atorvastatin within 24 h before contrast media exposure, compared with 208 patients not given statins.7 CIN rate was lower in the atorvastatin group (4.5%) in patients both with and without type 2 diabetes and in patients with moderate CKD (stage 3, estimated glomerular filtration rate [eGFR] 31–60 ml/min/1.73 m2) than in control (no statin) patients (17.8%, P = 0.005, OR 0.22, 95% CI 0.07–0.69).7 The second recently published ran domized study 4 evaluated whether highdose rosuvastatin exerts a protective effect against CIN in patients with acute coronary syndrome (ACS). These patients are known to be at high risk of developing CIN. Consecutive statin-naive non-ST elevation patients with ACS scheduled for early percutaneous coronary intervention (PCI) were randomly assigned to receive rosuva statin (40 mg on admission, then 20 mg per day, n = 252) or no statin treatment (control group, n = 252).4 All patients received intravenous hydration with isotonic saline for 12 h both before and after the procedure and oral N-acetylcysteine twice daily from the day before to the day after angiography. Any nephrotoxic medications (metformin or non-steroidal anti-inflammatory drugs) were discontinued on admission. The rate of CIN was significantly lower in the statin group than in the control group (6.7% versus 15.1%, P = 0.003, OR 0.38, 95% CI 0.20‑0.71). The 30-day rate of adverse cardiovascular and renal events (including death, dialysis, myocardial infarction, stroke or persistent renal damage) was also significantly reduced in the statin group (3.6% versus 7.9%, P = 0.036).4 Moreover, early administration of statin was associated with a reduced rate of death or non-fatal www.nature.com/nrneph
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