Amir Qaseem, MD, PhD, MHA; Robert H. Hopkins Jr., MD; Donna E. Sweet, MD; Melissa Starkey, PhD; Paul Shekelle, MD, PhD; for the Clinical Guidelines Committee of the American College of Physicians *
Note: Clinical practice guidelines are “guides” only and may not apply to all patients and all clinical situations. Thus, they are not intended to override clinicians’ judgment. All ACP clinical practice guidelines are considered automatically withdrawn or invalid 5 years after publication, or once an update has been issued.
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Potential Conflicts of Interest: Dr. Shekelle: Personal fees: ECRI Institute, Veterans Affairs, UptoDate; Grants: Agency for Healthcare Research and Quality, Veterans Affairs, Centers for Medicare & Medicaid Services, Office of the National Coordinator for Health Information Technology. All other authors have no disclosures. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-3186. A record of conflicts of interest is kept for each Clinical Guidelines Committee meeting and conference call and can be viewed at www.acponline.org/clinical_information/guidelines/guidelines/conflicts_cgc.htm.
Requests for Single Reprints: Amir Qaseem, MD, PhD, MHA, American College of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106: e-mail, email@example.com.
Current Author Addresses: Drs. Qaseem and Starkey: American College of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106.
Dr. Hopkins: University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AK 72205.
Dr. Sweet: The University of Kansas School of Medicine–Wichita, 1010 North Kansas, Wichita, KS 67214.
Dr. Shekelle: West Los Angeles Veterans Affairs Medical Center, 11301 Wilshire Boulevard, Los Angeles, CA 90073.
Author Contributions: Conception and design: A. Qaseem, R.H. Hopkins, D.E. Sweet, P. Shekelle.
Analysis and interpretation of the data: A. Qaseem, R.H. Hopkins, M. Starkey.
Drafting of the article: A. Qaseem, R.H. Hopkins, D.E. Sweet, M. Starkey.
Critical revision for important intellectual content: A. Qaseem, R.H. Hopkins, M. Starkey, P. Shekelle.
Final approval of the article: A. Qaseem, R.H. Hopkins, D.E. Sweet, P. Shekelle.
Statistical expertise: A. Qaseem.
Administrative, technical, or logistic support: A. Qaseem, M. Starkey.
Collection and assembly of data: A. Qaseem, R.H. Hopkins.
The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations on the screening, monitoring, and treatment of adults with stage 1 to 3 chronic kidney disease.
This guideline is based on a systematic evidence review evaluating the published literature on this topic from 1985 through November 2011 that was identified by using MEDLINE and the Cochrane Database of Systematic Reviews. Searches were limited to English-language publications. The clinical outcomes evaluated for this guideline included all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, chronic heart failure, composite vascular outcomes, composite renal outcomes, end-stage renal disease, quality of life, physical function, and activities of daily living. This guideline grades the evidence and recommendations by using ACP's clinical practice guidelines grading system.
ACP recommends against screening for chronic kidney disease in asymptomatic adults without risk factors for chronic kidney disease. (Grade: weak recommendation, low-quality evidence)
ACP recommends against testing for proteinuria in adults with or without diabetes who are currently taking an angiotensin-converting enzyme inhibitor or an angiotensin II–receptor blocker. (Grade: weak recommendation, low-quality evidence)
ACP recommends that clinicians select pharmacologic therapy that includes either an angiotensin-converting enzyme inhibitor (moderate-quality evidence) or an angiotensin II–receptor blocker (high-quality evidence) in patients with hypertension and stage 1 to 3 chronic kidney disease. (Grade: strong recommendation)
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)
Table 1. Definition of CKD Stages Based on GFR
Table 2. The American College of Physicians’ Guideline Grading System
Table 3. Summary of Evidence for CKD Treatment
Summary of the American College of Physicians guideline on screening, monitoring, and treatment of stage 1 to 3 CKD.
ACE = angiotensin-converting enzyme; ARB = angiotensin II–receptor blocker; CKD = chronic kidney disease; ESRD = end-stage renal disease; GFR = glomerular filtration rate.
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Dr. Gauranga C. Dhar
Bangladesh Institute of Family Medicine and Research
October 25, 2013
Earlieast detection of earlier stages of CKD is vital
I do not agree with the recent ACP guideline regarding not to screen asymptomatic individuals for CKD.
Type 2 diabetes and hypertension are the two most common conditions causing chronic kidney disease (CKD). Patients up to third and most cases of fourth stage of CKD are usually asymptomatic and can be named as “silent killer”. Earliest detection of CKD in asymptomatic individuals can be done by simple tests (preferably by testing twice in different dates); eGFR and UACR. These are very simple and inexpensive tests may cause no harm to the patients. I think only the harm may be financial.
Earliest detection of earlier stages of CKD is vital because the disease is progressive in nature which can go to ESRD without any prior signals. Once detected, we, the physicians can take necessary steps to reduce progression to ESRD.
In case of type 2 diabetes patients, guideline says that the patients should be screened for micro-vascular complications including nephropathy at the time of diagnosis because micro-vascular complication may develop at the stage of pre-diabetes and even a decade before diagnosis of overt type 2 diabetes.
I have number of type 2 diabetes patients who are already at G3aA1 to G3bA2 at diagnosis. Non-adherence to treatment leads some of them progression to G4A2 even G4A3 within 2 years of time.
Decline in eGFR can be found in patients with type 2 diabetes patients even in the state of normo-albuminuria which was first described by Lane et al. in 1992. NHANES III in 2002 showed that normoalbuminuric decline in eGFR is common.
Decline in eGFR (even at 50-59ml/min/1.73M2) leads to increase in FGF-23, PTH, reduced conversion of 25-(OH)-D to 1,25-(OH)2-D and hyperphosphatemia. All these factors lead to increased risk of cardiovascular events. NHANES III showed that CV event risk is four fold in type 2 diabetes patients having eGFR <60ml/min/M2 in comparison to patients having eGFR >90ml/min/1.73M2. With existing CVD, such risk goes beyond 10 folds.
My strong opinion is that all asymptomatic patients having cardiometabolic syndrome specifically type 2 diabetes and hypertension should be screened periodically for CKD by eGFR and UACR.
Vanderbilt University, Nephrology and Hypertension Division
November 11, 2013
A more nuanced approach
I appreciate the rigor and efforts of the authors in producing the ACP’s Chronic Kidney Disease (CKD) Clinical Practice Guidelines. However, a more nuanced view may benefit patients.
While the authors recommend that clinicians use an angiotensin converting enzyme (ACE) inhibitor or angiotensin II-receptor blocker (ARB) in hypertensive patients with CKD stage 1 to 3,(1) they also recognize that “monotherapy with ACE inhibitors or ARBs statistically significantly reduced the risk for ESRD in patients with CKD, but benefits were limited to patients with macroalbuminuria...”(1)
This clarification deserves greater attention and emphasis. CKD is predominantly a disease of older adults who have relatively low rates of macroalbuminuria in the CKD stage 1-3 range.(2, 3) On the other hand, older adults (including those with CKD) are commonly taking multiple medications including diuretics and non-steroidal anti-inflammatory drugs.(4) The concurrent use of these medications can lead to serious adverse effects,(5, 6) which are likely to be more common in the setting of CKD.
I believe clinicians would be better served by individualizing therapy in non-proteinuric CKD patients and considering ACE inhibitors and ARBs as first line therapy in patients with demonstrable macroalbuminuria/proteinuria or documented cardiovascular indications.
Similarly, while the committee recommends against testing for proteinuria in individuals taking an ACE inhibitor or ARB, they do not comment on the dose of the prescribed medication. Proteinuric patients receiving 2.5mg of ramipril or 5mg of benazepril would likely benefit from dose titration to levels that were rigorously studied and shown to improve clinically important outcomes.
1. Qaseem, A, Hopkins, RH, Sweet, DE, 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. Annals of Internal Medicine, N/A: N/A-N/A, 2013.
2. Garg, AX, Kiberd, BA, Clark, WF, Haynes, RB, Clase, CM: Albuminuria and renal insufficiency prevalence guides population screening: results from the NHANES III. Kidney Int, 61: 2165-2175, 2002.
3. O'Hare, AM, Kaufman, JS, Covinsky, KE, Landefeld, CS, McFarland, LV, Larson, EB: Current guidelines for using angiotensin-converting enzyme inhibitors and angiotensin II-receptor antagonists in chronic kidney disease: is the evidence base relevant to older adults? Ann Intern Med, 150: 717-724, 2009.
4. Patel, K, Diamantidis, C, Zhan, M, Hsu, VD, Walker, LD, Gardner, J, Weir, MR, Fink, JC: Influence of creatinine versus glomerular filtration rate on non-steroidal anti-inflammatory drug prescriptions in chronic kidney disease. Am J Nephrol, 36: 19-26, 2012.
5. Lapi, F, Azoulay, L, Yin, H, Nessim, SJ, Suissa, S: Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study. BMJ, 346: e8525, 2013.
6. Loboz, KK, Shenfield, GM: Drug combinations and impaired renal function -- the 'triple whammy'. British journal of clinical pharmacology, 59: 239-243, 2005.
Hiddo J. Lambers Heerspink, Carlo JAM Gaillard, Ron T Gansevoort
Department of Clinical Pharmacology and Internal Medicine; University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
November 28, 2013
Measuring proteinuria to optimize renoprotective effects of RAAS-blockade
Dear editor, A recently issued clinical practice guideline from the American College of Physicians (ACP) recommends against testing for proteinuria in adults with or without diabetes who are currently taking an ACE-inhibitor or Angiotensin Receptor Blocker (ARB). In our opinion this is an erroneous recommendation not supported by literature and if implemented in clinical practice a step backwards with respect to achieving optimal patient care. Several trials in populations with different etiologies of kidney disease have shown that ACE-inhibitors and ARBs dose-dependently decrease proteinuria.(1) Furthermore, randomized controlled clinical trials (RCTs) indicate that these agents confer renoprotection. In these RCTs the magnitude of the ACE-inhibitor or ARB induced reduction in albuminuria is the most important determinant of the long-term renoprotective benefit.(2) This effect was independent of changes in blood pressure. In addition, residual albuminuria during therapy with ACE-inhibitors or ARBs is associated with long-term outcome.(2) The importance of this finding is highlighted by a study in patients with proteinuric non-diabetic CKD receiving a conventional dosage of the ACE-inhibitor benazepril (10 mg/d) or the ARB losartan (50 mg/d), or individual up-titration of benazepril or losartan to optimal anti-albuminuric and tolerated dosages.(3) This trial showed that optimal anti-albuminuric dosages of these agents, at comparable blood pressure control, led to a greater reduction in albuminuria and a marked reduction in the incidence of end-stage renal disease (ESRD) compared with their conventional dosages. Taken together, there is ample evidence that measurement of albuminuria during treatment with ACE-inhibitors or ARBs is essential to titrate the dosage of these drugs to achieve optimal renoprotection.The guideline states that the variability in albuminuria causes concern about the ability to monitor this variable over time. We agree that albuminuria shows intra-individual variability.(4) The variability in albuminuria is acknowledged in international CKD guidelines by the advice to measure albuminuria several times to reliably evaluate the risk of an individual. In 2011 the incidence of ESRD in the United States was 357 per million of the population (pmp) overall and for diabetes 157 pmp (5). These rates are higher than in nearly all other countries in the world. In the Netherlands for instance, incidence of ESRD was 117 pmp and 18.6 pmp, respectively. Given the high incidence of ESRD in the USA we call upon the ACP to develop an action plan to combat the epidemic of ESRD especially in the diabetic subpopulation. Based on available evidence one recommendation should be to monitor albuminuria also after initiation of ACE-inhibitors or ARBs in order to titrate and monitor effectiveness of instituted therapy like Dutch guidelines recommend.(6)References1. Gansevoort RT, de Zeeuw D, de Jong PE. Is the antiproteinuric effect of ACE inhibition mediated by interference in the renin-angiotensin system? Kidney Int 1994;45(3):861-7.2. Heerspink HJ. Therapeutic approaches in lowering albuminuria: travels along the renin-angiotensin-aldosterone-system pathway. Adv Chronic Kidney Dis 2011;18(4):290-9.3. Hou FF, Xie D, Zhang X, Chen PY, Zhang WR, Liang M, Guo ZJ, Jiang JP. Renoprotection of Optimal Antiproteinuric Doses (ROAD) Study: a randomized controlled study of benazepril and losartan in chronic renal insufficiency. J Am Soc Nephrol 2007;18(6):1889-98.4. Witte EC, Lambers Heerspink HJ, de Zeeuw D, Bakker SJ, de Jong PE, Gansevoort R. First morning voids are more reliable than spot urine samples to assess microalbuminuria. J Am Soc Nephrol 2009;20(2):436-43.5.USRDS Atlas of ESRD: Incidence, prevalence, patient characteristics and treatment modalities. http://www.usrds.org/atlas.aspx [last accessed: 25 November 2013]6. Dutch Guideline Chronic Renal Failure: http://www.kwaliteitskoepel.nl/assets/structured-files/NIV/Betrokkenbij/Chronische-nierschade-2009.pdf [last accessed: 25 November 2013]
Andeera Levin, MD, Paul E. Stevens, MD, Joseph Coresh, MD, Andrew Levey, MD
University of British Columbia
December 10, 2013
We believe the recently published ACP guideline on Screening Monitoring and Treatment of Stage 1 to 3 Chronic Kidney Disease lacks context and clarity and is not reconciled with recently published KDIGO guidelines (1,2). Consequently, the recommendations may be confusing to readers and may negatively impact physician practice and patient care.
Recommendation 1 forswears screening for CKD in asymptomatic adults without risk factors: all published guidelines are in agreement with this, and neither the KDIGO guideline, nor the KDOQI guidelines that preceded them have ever advocated general population screening (2,). It is unclear to us why the recommendation is written as a negative. It would be more useful to describe who should be screened (i.e. adults with risk factors for CKD, including diabetes, hypertension, family history of CKD). If the intention is to highlight that general population screening is not recommended, then that should be stated.
Recommendation 2 is against testing for proteinuria in adults who are taking an ACEI or ARB. ACEI or ARB are indicated for treatment of hypertension in patients with proteinuria, so the motivation for this statement is presumably based on the premise that those on ACEI or ARB are already ‘treated’ and that the test result is not of value. However, the level of proteinuria is a key measure in assessing the presence and severity of kidney disease and monitoring progression. Thus, the KDIGO guideline specifically recommended assessment of proteinuria (as albuminuria) for diagnosis and classification for all patients with CKD because of its prognostic importance, not only as a guide to ACEI or ARB treatment.
Recommendation 3 advocates use of ACEI or ARB in patients with hypertension and CKD. Although concordant with some other guidelines, it fails to incorporate the importance of albuminuria as an effect modifier, as in the recommendations in the KDIGO CKD and Blood pressure guidelines (2,3). Published studies do not support additional benefit for ACEI or ARB in people with CKD without albuminuria and may possibly be harmful in certain patient groups ().
Recommendation 4 recommends statins to manage elevated LDL in those with CKD stages 1-3. The recommendation from the KDIGO Lipid guideline workgroup (5), which recommends statins for patients with CKD older than 50 years of age or with 10-year risk for coronary death or non-fatal myocardial infarction >10%, irrespective of LDL levels.
These subtle differences in the messages in different guidelines for CKD , deserve further clarification.
1. Qaseem, A, Hopkins R, Sweet, D, 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. Annals of Internal Medicine, 2013:159
2. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney inter., Suppl. 2013; 3: 1–150
3. Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney inter.,Suppl. 2012; 2: 337–414.
4. Tomlinson LA, Abel GA, Chaudhry AN, Tomson CR, Wilkinson IB, Roland MO, Payne RA. ACE Inhibitor and Angiotensin Receptor-II Antagonist Prescribing and Hospital Admissions with Acute Kidney Injury: A Longitudinal Ecological Study. PLoS One. 2013 Nov 6;8(11):e78465. doi: 10.1371/journal.pone.0078465
5. Kidney Disease: Improving Global Outcomes (KDIGO) Lipid Work Group. KDIGO Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease. Kidney inter., Suppl. 2013; 3: 259–305
Amir Qaseem, MD, PhD, MHA, Timothy J. Wilt, MD, Thomas D. Denberg, MD
Americal College of Physicians, VAMC, Carilion Clinic
April 21, 2014
IN RESPONSE: We thank Drs. Dhar, Abdel-Kader, Levin, Stevens, Coresh, Levey, Heerspink, Gaillard, and Gansevoort for their comments regarding the American College of Physicians' recent clinical guideline on screening for stage 1-3 CKD in adults. Dr. Dhar points out that the only harm of screening tests for CKD is financial. We disagree. Screening is a process, not just a simple test, that results in a cascade of additional diagnostic and treatment events. In addition to the financial costs of the screening test (which may be low cost) there are additional costs associated with follow up evaluation of abnormal results, unnecessary treatment and complications, and adverse effects of treatment. The overuse of screening tests is an important component of unnecessary health care costs in the United States (1). Recommending against CKD screening for asymptomatic patients without risk factors provides clinicians with guidance in that more judicious use of such tests will improve care quality and reduce costs. Levin et al. compare the ACP guideline to the recent KDIGO guidelines and identify areas where the 2 are not aligned. Although we acknowledge that having different recommendations for the same topic can be confusing, we developed this guideline based on a systematic review of the evidence regarding the benefits and harms of interventions in individuals with and without CKD. Thus we based all of our recommendations strictly on evidence, regardless of what other guidelines recommend. Our guideline recommendation specifically points out not to screen in the general asymptomatic population without CKD risk factors. We noted that randomized trials did demonstrate a benefit in patients with CKD and dyslipidemia and treatment is recommended in these individuals. However, no RCTs have assessed the effectiveness of statins in general risk asymptomatic patients with screen-detected CKD, especially those with microalbuminuria and normal serum creatinine levels. It is not certain that these individuals have a 10 year CHD risk that exceeds 10 percent, and the balance of benefits and harms in these individuals is not known. For patients with CKD risk factors, ACP found that “although there are known risk factors for CKD (diabetes, hypertension, and cardiovascular disease), the current evidence is insufficient to evaluate the benefits and harms of screening for CKD in asymptomatic adults with CKD risk factors”. Thus we made no recommendation in these individuals. ACP suggests that we should not adopt screening programs until the evidence of potential benefits or harms has been shown in the scientific literature (2). The current evidence is not convincing, particularly in light of no evidence that knowing early CKD status will impact treatment decisions or alter health outcomes in high-risk populations who are already taking medications. Also, it is important to differentiate between screening and case-finding and disease management strategies such as assessment of serum creatinine levels, especially in patients who are receiving medications that might have adverse effects on serum creatinine (3). Heerspink, Gaillard, and Gansevoort advocate for measuring albuminuria in patients taking ACEI and ARBs to titrate dosage and monitor effectiveness. We did not find any evidence that titrating doses of ACEI and ARBs affects clinical outcomes. Although they may modulate proteinuria levels, proteinuria itself is an intermediate marker and its impact on patient symptoms or clinical outcomes is yet to be determined. We agree that albuminuria or GFR are adverse prognostic markers. However, current evidence does not show that treatments targeting to improve these markers reduce mortality. Mortality in patients with hypertension or diabetes may not be directly related to CKD, and these patients will likely die of a fatal cardiovascular event before ESRD. No studies specifically tested the effectiveness of CKD monitoring or modifying interventions based on CKD monitoring. Evidence does not show incremental benefit of monitoring patients, altering type or dose of therapy or aiming for different intermediate targets based on CKD status among individuals already taking ACEI or ARBs. While proteinuria levels may provide prognostic value, there is no evidence that knowing proteinuria levels positively impacts treatment decisions or improves patient outcomes. Additionally, low-quality evidence shows that interventions to reduce proteinuria levels do not improve clinical outcomes.Abdel-Kader suggests using ACE and ARBs only in patients with macroalbuminuria/proteinuria or cardiovascular indications, cautioning of adverse effects from concurrent medication use. As far as “CKD is predominantly a disease of older adults”, we believe that age-associated decrement in GFR is not a disease, rather it is an expected age-related change. This is the population where there is overdiagnosis of CKD. When it comes to drug-related adverse events, clinicians need to take variables into account such as age or multidrug regimens. Amir Qaseem, MD, PhD, MHA, FACPAmerican College of PhysiciansTimothy J. Wilt MD, MPHMinneapolis VA Center for Epidemiological and Clinical ResearchThomas D. Denberg, MD, PhDCarilion ClinicCurrent Author Addresses:A. Qaseem190 N. Independence Mall West, Philadelphia, PA 19106T. J. WiltVA Medical Center (111-0), Minneapolis, MN 55417T. D. DenbergP.O. Box 13727, Roanoke, VA 24036 References1. Owens DK, Qaseem A, Chou R, Shekelle P. High-value, cost-conscious health care: concepts for clinicians to evaluate the benefits, harms, and costs of medical interventions. Ann Intern Med. 2011;154(3):174-80.2. Harris R. Overview of Screening: Where We Are and Where We May Be Headed. Epidemiologic Reviews. 2011;33(1):1-6.3. Wilson JMG, Jungner G. Principles and practice of screening for disease. Geneva: WHO; 1968.
Qaseem A, Hopkins RH, Sweet DE, Starkey M, Shekelle P, for the Clinical Guidelines Committee of the American College of Physicians. Screening, Monitoring, and Treatment of Stage 1 to 3 Chronic Kidney Disease: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2013;159:835–847. doi: 10.7326/0003-4819-159-12-201312170-00726
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Published: Ann Intern Med. 2013;159(12):835-847.
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