For updates on diagnosis and management of coexisting conditions during the pandemic, see our topic "Management of coexisting conditions in the context of COVID-19".
All etiologies of CKD are progressive. The main goal of treatment is to slow the progressive loss of kidney function and prevent the need for renal replacement therapy or kidney transplantation. The most important factor in treatment is to identify patients early in the course of their disease and classify the stage of CKD (GFR category G1-G5) so that risk factor modification can ensue and identification of comorbidities such as anemia and secondary hyperparathyroidism may be treated.
CKD is divided into 6 distinct categories based on glomerular filtration rate (GFR). The GFR category (G1-G5) has the same GFR thresholds as the CKD stages 1 to 5 recommended previously:[1]Kidney Disease: Improving Global Outcomes (KDIGO). KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013 Jan;3(1):1-150.
https://kdigo.org/wp-content/uploads/2017/02/KDIGO_2012_CKD_GL.pdf
G1: GFR >90 mL/minute/1.73 m², and evidence of kidney damage based on pathologic diagnosis, abnormalities of radiographic imaging, or laboratory findings such as hematuria and/or proteinuria
G2: GFR of 60 to 89 mL/minute/1.73 m²
G3a: GFR of 45 to 59 mL/minute/1.73 m²
G3b: GFR of 30 to 44 mL/minute/1.73 m²
G4: GFR of 15 to 29 mL/minute/1.73 m²
G5: GFR <15 mL/minute/1.73 m².
GFR category G1 to G4 first-line therapy
The major cause of death for patients with CKD is cardiovascular disease. Therefore, treatment of cardiovascular risk factors, such as optimizing glycemic control, optimizing blood pressure (BP) with an ACE inhibitor or an angiotensin-II receptor antagonist, introducing lipid-lowering agents (e.g., statins, ezetimibe), and reducing proteinuria is recommended.[56]Kidney Disease: Improving Global Outcomes (KDIGO). KDIGO clinical practice guideline for lipid management in chronic kidney disease. Kidney Int Suppl. 2013 Nov;3(3):259-303.
https://kdigo.org/wp-content/uploads/2017/02/KDIGO-2013-Lipids-Guideline-English.pdf
[57]Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011 Jun 25;377(9784):2181-92.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60739-3/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/21663949?tool=bestpractice.com
[58]Fox CS, Matsushita K, Woodward M, et al. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis. Lancet. 2012 Nov 10;380(9854):1662-73.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3771350/
http://www.ncbi.nlm.nih.gov/pubmed/23013602?tool=bestpractice.com
Diabetes
Glycemic goals should be individualized. For many patients, the goal of HbA1c <7% is appropriate. However, HbA1c 7.0% to 7.9% may be more appropriate in some patients, such as those with advanced age, limited life expectancy, known cardiovascular disease, high risk of severe hypoglycemia, or difficulty achieving lower HbA1c goals despite the use of multiple antihyperglycemic medications and insulin.[59]American Diabetes Association. Standards of medical care in diabetes - 2021. Diabetes Care. 2021 Jan;44(Supplement 1):S1-232.
https://care.diabetesjournals.org/content/44/Supplement_1
In patients with diabetes and CKD, there is a risk for hypoglycemia because of impaired kidney clearance of medications, such as insulin (two-thirds of insulin is degraded by the kidney) or sulfonylureas, and because of impaired kidney gluconeogenesis.
Patients with type 1 diabetes require treatment with insulin, regardless of whether they are on dialysis or not.
In patients with type 2 diabetes, some specific antihyperglycemic medications significantly reduce all-cause or cardiovascular mortality, or major cardiovascular events or renal complications in some patient subgroups, and may be considered independently of HbA1c targets.[60]Rangaswami J, Bhalla V, de Boer IH, et al. Cardiorenal protection with the newer antidiabetic agents in patients with diabetes and chronic kidney disease: a scientific statement from the American Heart Association. Circulation. 2020 Oct 27;142(17):e265-86.
https://www.ahajournals.org/doi/10.1161/CIR.0000000000000920
http://www.ncbi.nlm.nih.gov/pubmed/32981345?tool=bestpractice.com
[61]Buse JB, Wexler DJ, Tsapas A, et al. 2019 update to: management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2020 Feb;43(2):487-93. [Erratum in: Diabetes Care. 2020 Jul;43(7):1670.]
https://care.diabetesjournals.org/content/43/2/487.long
http://www.ncbi.nlm.nih.gov/pubmed/31857443?tool=bestpractice.com
[62]Zelniker TA, Wiviott SD, Raz I, et al. Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in Type 2 diabetes mellitus. Circulation. 2019 Apr 23;139(17):2022-31.
https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.118.038868
http://www.ncbi.nlm.nih.gov/pubmed/30786725?tool=bestpractice.com
[63]Kaul S. Mitigating cardiovascular risk in type 2 diabetes with antidiabetes drugs: a review of principal cardiovascular outcome results of EMPA-REG OUTCOME, LEADER, and SUSTAIN-6 trials. Diabetes Care. 2017 Jul;40(7):821-31. [Erratum in: Diabetes Care. 2018 Mar;41(3):640.]
https://care.diabetesjournals.org/content/40/7/821.long
http://www.ncbi.nlm.nih.gov/pubmed/28637887?tool=bestpractice.com
Among the antihyperglycemic medications that reduce cardiovascular mortality in some patient subgroups are metformin (if estimated glomerular filtration rate [eGFR] is >30 mL/minute/1.73 m²), sodium-glucose co-transporter 2 (SGLT2) inhibitors (empagliflozin, canagliflozin), and glucagon-like peptide-1 (GLP-1) agonists (liraglutide).[62]Zelniker TA, Wiviott SD, Raz I, et al. Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in Type 2 diabetes mellitus. Circulation. 2019 Apr 23;139(17):2022-31.
https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.118.038868
http://www.ncbi.nlm.nih.gov/pubmed/30786725?tool=bestpractice.com
[64]Kwon S, Kim YC, Park JY, et al. The long-term effects of metformin on patients with type 2 diabetic kidney disease. Diabetes Care. 2020 May;43(5):948-55.
http://www.ncbi.nlm.nih.gov/pubmed/32132005?tool=bestpractice.com
[65]Griffin SJ, Leaver JK, Irving GJ. Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes. Diabetologia. 2017 Sep;60(9):1620-29.
https://link.springer.com/article/10.1007%2Fs00125-017-4337-9
http://www.ncbi.nlm.nih.gov/pubmed/28770324?tool=bestpractice.com
[66]Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019 Jan 5;393(10166):31-9.
http://www.ncbi.nlm.nih.gov/pubmed/30424892?tool=bestpractice.com
There is evidence that the use of SGLT2 inhibitors prevents major kidney outcomes (e.g., dialysis, transplantation, or death due to kidney disease) in people with type 2 diabetes.[67]Neuen BL, Young T, Heerspink HJL, et al. SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2019 Nov;7(11):845-54.
http://www.ncbi.nlm.nih.gov/pubmed/31495651?tool=bestpractice.com
SGLT2 inhibitors, in addition to reducing hyperglycemia, have renal benefits through independent effects on renal tubular glucose reabsorption, weight, BP, intraglomerular pressure, albuminuria, and slowed GFR loss.[68]Alicic RZ, Neumiller JJ, Johnson EJ, et al. Sodium-glucose cotransporter 2 inhibition and diabetic kidney disease. Diabetes. 2019 Feb;68(2):248-57. [Erratum in: Diabetes. 2019 May;68(5):1094.]
https://diabetes.diabetesjournals.org/content/68/2/248.long
http://www.ncbi.nlm.nih.gov/pubmed/30665953?tool=bestpractice.com
[69]Heerspink HJL, Kosiborod M, Inzucchi SE, et al. Renoprotective effects of sodium-glucose cotransporter-2 inhibitors. Kidney Int. 2018 Jul;94(1):26-39.
http://www.ncbi.nlm.nih.gov/pubmed/29735306?tool=bestpractice.com
The use of SGLT2 inhibitors is not generally recommended in patients with an eGFR of <45 mL/minute/1.73 m² (<60 mL/minute/1.73 m² for ertugliflozin); however, the CREDENCE trial included patients with an eGFR 30 to 90 mL/minute/1.73m² and demonstrated a decreased risk of kidney failure and cardiovascular events.[70]Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019 Jun 13;380(24):2295-306.
http://www.ncbi.nlm.nih.gov/pubmed/30990260?tool=bestpractice.com
Use of SGLT2 inhibitors is contraindicated in patients with an eGFR of <30 mL/minute/1.73 m², including patients with end-stage renal disease (ESRD) who are on dialysis. As a class of drugs, GLP-1 agonists have beneficial effects on cardiovascular, mortality, and kidney outcomes in patients with type 2 diabetes.[71]Kristensen SL, Rørth R, Jhund PS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol. 2019 Oct;7(10):776-85.
http://www.ncbi.nlm.nih.gov/pubmed/31422062?tool=bestpractice.com
Experience with GLP-1 agonists in patients with renal dysfunction is limited; therefore, these agents should be used with caution.[72]Lo C, Toyama T, Wang Y, et al. Insulin and glucose-lowering agents for treating people with diabetes and chronic kidney disease. Cochrane Database Syst Rev. 2018 Sep 24;(9):CD011798.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD011798.pub2/full
http://www.ncbi.nlm.nih.gov/pubmed/30246878?tool=bestpractice.com
Liraglutide, albiglutide, dulaglutide, and semaglutide are not renally excreted and are the preferred agents in this class.
Studies report that dipeptidyl peptidase-4 (DPP-4) inhibitors are renoprotective but did not have a cardiovascular benefit.[73]Mega C, Teixeira-de-Lemos E, Fernandes R, et al. Renoprotective effects of the dipeptidyl peptidase-4 inhibitor sitagliptin: a review in type 2 diabetes. J Diabetes Res. 2017;2017:5164292.
https://www.hindawi.com/journals/jdr/2017/5164292/
http://www.ncbi.nlm.nih.gov/pubmed/29098166?tool=bestpractice.com
[74]Bailey CJ, Marx N. Cardiovascular protection in type 2 diabetes: insights from recent outcome trials. Diabetes Obes Metab. 2019 Jan;21(1):3-14.
http://www.ncbi.nlm.nih.gov/pubmed/30091169?tool=bestpractice.com
Some DPP-4 inhibitors require dose adjustment in renal impairment.
Hypertension
Hypertension is one of the greatest risk factors for the progression of CKD, regardless of etiology. Most patients with CKD will require at least two or three different types of antihypertensive agent to achieve the optimal BP control.
There is ongoing debate on optimal BP target for patients with CKD. The 2014 Joint National Committee 8 redefined the target BP goal for patients with CKD as <140/90 mmHg.[75]James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014 Feb 5;311(5):507-20.
https://jamanetwork.com/journals/jama/fullarticle/1791497
http://www.ncbi.nlm.nih.gov/pubmed/24352797?tool=bestpractice.com
However, the 2017 American College of Cardiology/American Heart Association guideline recommends adults with hypertension and CKD should be treated to a BP goal of less than 130/80 mmHg.[76]Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018 May 15;71(19):e127-248.
https://www.jacc.org/doi/10.1016/j.jacc.2017.11.006
http://www.ncbi.nlm.nih.gov/pubmed/29146535?tool=bestpractice.com
There may be benefit in strict BP control to reduce the relative risk of death, and delay the onset of ESRD in some subgroups of patients with CKD (age ≥40 years, BMI ≥30 kg/m²).[77]Chang AR, Lóser M, Malhotra R, et al. Blood pressure goals in patients with CKD: a review of evidence and guidelines. Clin J Am Soc Nephrol. 2019 Jan 7;14(1):161-9.
https://cjasn.asnjournals.org/content/14/1/161
http://www.ncbi.nlm.nih.gov/pubmed/30455322?tool=bestpractice.com
[78]Ku E, Sarnak MJ, Toto R, et al. Effect of blood pressure control on long-term risk of end-stage renal disease and death among subgroups of patients with chronic kidney disease. J Am Heart Assoc. 2019 Aug 20;8(16):e012749.
https://www.ahajournals.org/doi/10.1161/JAHA.119.012749
http://www.ncbi.nlm.nih.gov/pubmed/31411082?tool=bestpractice.com
The 2021 Kidney Disease: Improving Global Outcomes (KDIGO) guideline recommends a target systolic BP of less than 120 mmHg, if tolerated, in patients with CKD, with and without diabetes, and not receiving dialysis.[79]Cheung AK, Chang TI, Cushman WC, et al. Executive summary of the KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease. Kidney Int. 2021 Mar;99(3):559-569.
https://www.doi.org/10.1016/j.kint.2020.10.026
http://www.ncbi.nlm.nih.gov/pubmed/33637203?tool=bestpractice.com
A combination of antihypertensive agents should be used to meet the target BP goal (except that ACE inhibitors and angiotensin-II receptor antagonists should not be combined within the same regimen).
ACE inhibitors and angiotensin-II receptor antagonists have been shown in numerous clinical trials to slow the progression of CKD and delay the need for renal replacement therapy in both diabetic and nondiabetic CKD.[80]Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001 Sep 20;345(12):851-60.
https://www.nejm.org/doi/10.1056/NEJMoa011303
http://www.ncbi.nlm.nih.gov/pubmed/11565517?tool=bestpractice.com
[81]Brenner BM, Cooper ME, de Zeeuw D, et al; RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001 Sep 20;345(12):861-9.
https://www.nejm.org/doi/full/10.1056/NEJMoa011161
http://www.ncbi.nlm.nih.gov/pubmed/11565518?tool=bestpractice.com
[82]Wright JT Jr, Bakris G, Greene T, et al; African American Study of Kidney Disease and Hypertension Study Group. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA. 2002 Nov 20;288(19):2421-31.
https://jamanetwork.com/journals/jama/fullarticle/195530
http://www.ncbi.nlm.nih.gov/pubmed/12435255?tool=bestpractice.com
In a meta-analysis of patients with CKD, blockade of the renin angiotensin system with either ACE inhibitors or angiotensin-II receptor antagonists was associated with a reduction in the risk of myocardial infarction, congestive heart failure, and total cardiovascular outcomes when compared with treatment with either placebo or controlled arms with other antihypertensive agents.[83]Balamuthusamy S, Srinivasam L, Verma M, et al. Renin angiotensin system blockade and cardiovascular outcomes in patients with chronic kidney disease and proteinuria: a meta-analysis. Am Heart J. 2008 May;155(5):791-805.
http://www.ncbi.nlm.nih.gov/pubmed/18440325?tool=bestpractice.com
This emphasizes the importance of these agents as the first-line therapy in the treatment of CKD.
Although previously thought that a complete blockade of the renin angiotensin system with combination therapy of ACE inhibitors and angiotensin-II receptor antagonists or direct renin inhibitors would delay progression in CKD, clinical trial results have failed to confirm any such benefit. In the ONTARGET trial, individuals were assigned to telmisartan, ramipril, or combination therapy, evaluating the effectiveness of dual therapy on cardiac and renal outcomes.[84]Yusuf S, Teo KK, Pogue J, et al; ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008 Apr 10;358(15):1547-59.
https://www.nejm.org/doi/full/10.1056/NEJMoa0801317
http://www.ncbi.nlm.nih.gov/pubmed/18378520?tool=bestpractice.com
The study concluded that there was no difference in deaths from cardiovascular causes, in myocardial infarctions, cerebrovascular accidents, or hospitalizations for congestive heart failure, in the treatment groups. Also, the rates of renal outcomes defined as the first time for dialysis, death, or doubling of the serum creatinine were greater in the combination arm as compared with the single-based therapy arms. Thus, there is currently no clinical evidence that supports the use of this combination in the CKD population, and such therapy should not be recommended due to the increased risk of hyperkalemia and acute kidney injury. Although not recommended for CKD, combination therapy with ACE inhibitors and angiotensin-II receptor antagonists is sometimes used in patients with nephrotic syndromes and glomerulonephritis to reduce proteinuria.
Other classes of antihypertensive agents (e.g., thiazide or thiazide-like diuretics, beta-blockers, etc.) can be combined with ACE inhibitors or angiotensin-II receptor antagonists if target BP is not achieved with these first-line agents.
Aliskiren was previously recommended for use in combination with ACE inhibitors or angiotensin-II receptor antagonists; however, in December 2011, the manufacturer recommended that physicians should no longer prescribe aliskiren-containing products with these two classes of drugs based on the results, and subsequent early termination, of the ALTITUDE trial.[85]Parving HH, Brenner BM, McMurray JJ, et al; ALTITUDE Investigators. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012 Dec 6;367(23):2204-13.
https://www.nejm.org/doi/full/10.1056/NEJMoa1208799
http://www.ncbi.nlm.nih.gov/pubmed/23121378?tool=bestpractice.com
The trial assessed the effects of aliskiren in combination with ACE inhibitors or angiotensin-II receptor antagonists in people with type 2 diabetes at high risk for cardiovascular and renal events, and found an increased risk for nonfatal stroke, renal complications, hyperkalemia, and hypotension in patients taking the drug for 18-24 months. The Food and Drug Administration (FDA) now recommends that the combination of aliskiren with ACE inhibitors or angiotensin-II receptor antagonists is contraindicated in patients with diabetes because of the risk of renal impairment, hypotension, and hyperkalemia. The FDA also recommends that this combination of drugs be avoided in patients with moderate to severe renal impairment (i.e., GFR <60 mL/minute/1.73 m²).
Dyslipidemia
Dyslipidemia is common in patients with CKD. Although specific treatment targets for cholesterol and low-density lipoprotein have been recommended for CKD patients, this "treat to target" approach has not been well established in clinical trials.
As such, the KDIGO guidelines recommend that CKD patients not on dialysis should start treatment with a statin without the need for routine follow-up to check lipid values, or to change treatment regimen based on set targets (i.e., a "treat and forget" approach).[56]Kidney Disease: Improving Global Outcomes (KDIGO). KDIGO clinical practice guideline for lipid management in chronic kidney disease. Kidney Int Suppl. 2013 Nov;3(3):259-303.
https://kdigo.org/wp-content/uploads/2017/02/KDIGO-2013-Lipids-Guideline-English.pdf
For patients ages ≥50 years with CKD GFR category G3 or G4, ezetimibe can be combined with the statin simvastatin.[57]Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011 Jun 25;377(9784):2181-92.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60739-3/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/21663949?tool=bestpractice.com
Statin therapy has been shown to have cardioprotective effects in patients with CKD.[86]Navaneethan SD, Hegbrant J, Strippoli GF. Role of statins in preventing adverse cardiovascular outcomes in patients with chronic kidney disease. Curr Opin Nephrol Hypertens. 2011 Mar;20(2):146-52.
http://www.ncbi.nlm.nih.gov/pubmed/21245764?tool=bestpractice.com
[87]Jablonski KL, Chonchol M. Cardiovascular disease: should statin therapy be expanded in patients with CKD? Nat Rev Nephrol. 2012 Jul 3;8(8):440-1.
http://www.ncbi.nlm.nih.gov/pubmed/22751508?tool=bestpractice.com
[88]Palmer SC, Craig JC, Navaneethan SD, et al. Benefits and harms of statin therapy for persons with chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med. 2012 Aug 21;157(4):263-75.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955032/
http://www.ncbi.nlm.nih.gov/pubmed/22910937?tool=bestpractice.com
[89]Upadhyay A, Earley A, Lamont JL, et al. Lipid-lowering therapy in persons with chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med. 2012 Aug 21;157(4):251-62.
http://www.ncbi.nlm.nih.gov/pubmed/22910936?tool=bestpractice.com
In those individuals not on dialysis therapy, the use of statins in a large meta-analysis resulted in the reduction of all-cause mortality by 21% (relative risk [RR] 0.79, 95% CI 0.69 to 0.91) and cardiovascular mortality by 23% (RR 0.77, 95% CI 0.69 to 0.87).[90]Palmer SC, Navaneethan SD, Craig JC, et al. HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis. Cochrane Database Syst Rev. 2014 May 31;(5):CD007784.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD007784.pub2/full
http://www.ncbi.nlm.nih.gov/pubmed/24880031?tool=bestpractice.com
It was noted that there was no difference in adverse effects for statin users as compared with those in the placebo arms. Despite previous evidence that statins may be renoprotective via anti-inflammatory effects in the kidney, the use of statins in these trials did reduce proteinuria but overall did not improve kidney function.
Unfortunately, the beneficial effect of statin use in CKD has not been shown in the dialysis population. In both single investigations and one meta-analysis, statin use in patients undergoing dialysis did not improve all-cause mortality or cardiovascular-related deaths.[91]Palmer SC, Navaneethan SD, Craig JC, et al. HMG CoA reductase inhibitors (statins) for dialysis patients. Cochrane Database Syst Rev. 2013 Sep 11;(9):CD004289.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD004289.pub5/full
http://www.ncbi.nlm.nih.gov/pubmed/24022428?tool=bestpractice.com
GFR category G1 to G4 intolerant to first-line therapy
If a patient is unable to tolerate either an ACE inhibitor or an angiotensin-II receptor antagonist due to adverse effects, then an alternative is warranted. Nondihydropyridine calcium-channel blockers have been demonstrated to have more proteinuric-lowering effects than other antihypertensive agents. Clinical trials in both diabetic and nondiabetic CKD have demonstrated greater protein-lowering effects than other classes of antihypertensive agents.[92]Bakris GL, Weir MR, Secic M, et al. Differential effects of calcium antagonist subclasses on markers of nephropathy progression. Kidney Int. 2004 Jun;65(6):1991-2002.
http://www.ncbi.nlm.nih.gov/pubmed/15149313?tool=bestpractice.com
GFR category G2
The directed therapy is to continue to modify cardiovascular risk factors, but also estimate the rate of loss of kidney function to determine the eventual need for renal replacement therapy (i.e., dialysis, transplant).
GFR category G3a/G3b
Education can play a significant role in delaying progression of CKD, as well as helping the patient understand his/her options if CKD progresses.[93]Johns TS, Yee J, Smith-Jules T, et al. Interdisciplinary care clinics in chronic kidney disease. BMC Nephrol. 2015 Oct 12;16:161.
https://bmcnephrol.biomedcentral.com/articles/10.1186/s12882-015-0158-6
http://www.ncbi.nlm.nih.gov/pubmed/26458811?tool=bestpractice.com
[94]Shukla AM, Hinkamp C, Segal E, et al. What do the US advanced kidney disease patients want? Comprehensive pre-ESRD patient education (CPE) and choice of dialysis modality. PLoS One. 2019 Apr 9;14(4):e0215091.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215091
http://www.ncbi.nlm.nih.gov/pubmed/30964936?tool=bestpractice.com
[95]Easom AM, Shukla AM, Rotaru D, et al. Home run - results of a chronic kidney disease Telemedicine Patient Education Study. Clin Kidney J. 2019 Aug 22;13(5):867-72.
https://academic.oup.com/ckj/article/13/5/867/5553047
http://www.ncbi.nlm.nih.gov/pubmed/33123362?tool=bestpractice.com
Most CKD-related complications occur during this stage of transition (GFR category G3a/G3b). Identification of comorbidities such as anemia and secondary hyperparathyroidism is recommended, and treatment commenced if required.
Treatment of anemia with the use of erythropoietin-stimulating agents is recommended for patients with CKD after other causes of anemia such as iron, vitamin B12, folate, or blood loss have been excluded.[96]KDIGO Anemia Work Group. KDIGO clinical practice guideline for anemia in chronic kidney disease. Kidney Int Suppl. 2012 Aug;2(4):279-335.
https://kdigo.org/wp-content/uploads/2016/10/KDIGO-2012-Anemia-Guideline-English.pdf
[
]
How does two-weekly administration of erythropoiesis-stimulating agents compare with weekly and monthly administration for people with anemia due to chronic kidney disease who are not on dialysis?/cca.html?targetUrl=https://cochranelibrary.com/cca/doi/10.1002/cca.1679/fullShow me the answer
[
]
How does recombinant human erythropoietin compare with placebo/no treatment in people with anemia of chronic kidney disease who do not require dialysis?/cca.html?targetUrl=https://cochranelibrary.com/cca/doi/10.1002/cca.1224/fullShow me the answer
[
]
How do newer continuous erythropoiesis receptor activators compare with older erythropoiesis-stimulating agents in people with anemia of chronic kidney disease?/cca.html?targetUrl=https://cochranelibrary.com/cca/doi/10.1002/cca.1866/fullShow me the answer Patients with CKD frequently have iron deficiency, and iron replacement should be considered as a goal of treatment.
Erythropoietin stimulating therapy may be initiated if the hemoglobin (Hb) falls to <10 g/dL and the patient has signs and symptoms of anemia. The target Hb for patients with CKD on erythropoietin therapy has changed in the last several years but clinical expert opinion suggests that a target of 10-11 g/dL is appropriate, as normalization of Hb has resulted in increased risk for death and cardiovascular disease in this population.[97]Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006 Nov 16;355(20):2085-98.
http://www.ncbi.nlm.nih.gov/pubmed/17108343?tool=bestpractice.com
[98]Drüeke TB, Locatelli F, Clyne N, et al; CREATE Investigators. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006 Nov 16;355(20):2071-84.
http://www.ncbi.nlm.nih.gov/pubmed/17108342?tool=bestpractice.com
In the TREAT study of patients with diabetes with CKD and anemia, treatment with the erythropoietin-stimulating agent darbepoetin failed to show a beneficial effect of active treatment on cardiovascular events, death, or ESRD as compared with those receiving placebo (individuals would receive a rescue dose of medication if the hemoglobin fell below 9 g/dL).[99]Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009 Nov 19;361(21):2019-32.
http://www.ncbi.nlm.nih.gov/pubmed/19880844?tool=bestpractice.com
Interestingly, as in other studies of anemia treatment in CKD, the TREAT investigators demonstrated that individuals in the active treatment arm had an increased risk of stroke (RR 1.92, 95% CI 1.38 to 2.68).[100]Skali H, Parving HH, Parfrey PS, et al; TREAT Investigators. Stroke in patients with type 2 diabetes mellitus, chronic kidney disease, and anemia treated with darbepoetin alfa: the Trial to Reduce cardiovascular Events with Aranesp Therapy (TREAT) experience. Circulation. 2011 Dec 20;124(25):2903-8.
https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.111.030411
http://www.ncbi.nlm.nih.gov/pubmed/22104547?tool=bestpractice.com
[
]
What are the effects of erythropoiesis-stimulating agents for anemia in adults with chronic kidney disease?/cca.html?targetUrl=https://cochranelibrary.com/cca/doi/10.1002/cca.1294/fullShow me the answer In their opinion, the risks of treatment may outweigh the benefits, and discussion between the patient and physician should ensue prior to treatment initiation.[96]KDIGO Anemia Work Group. KDIGO clinical practice guideline for anemia in chronic kidney disease. Kidney Int Suppl. 2012 Aug;2(4):279-335.
https://kdigo.org/wp-content/uploads/2016/10/KDIGO-2012-Anemia-Guideline-English.pdf
[99]Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009 Nov 19;361(21):2019-32.
http://www.ncbi.nlm.nih.gov/pubmed/19880844?tool=bestpractice.com
[101]Koulouridis I, Alfayez M, Trikalinos TA, et al. Dose of erythropoiesis-stimulating agents and adverse outcomes in CKD: a metaregression analysis. Am J Kidney Dis. 2013 Jan;61(1):44-56.
http://www.ncbi.nlm.nih.gov/pubmed/22921639?tool=bestpractice.com
[102]Wilhelm-Leen ER, Winkelmayer WC. Mortality risk of darbepoetin alfa versus epoetin alfa in patients with CKD: systematic review and meta-analysis. Am J Kidney Dis. 2015 Jul;66(1):69-74.
http://www.ncbi.nlm.nih.gov/pubmed/25636816?tool=bestpractice.com
All patients should have an evaluation of iron stores if erythropoietin therapy is planned. The goal ferritin for those not on hemodialysis is >100 nanograms/mL, while for those on hemodialysis it is <200 nanograms/mL. All patients should have a transferrin saturation >20%. Iron replacement can be given orally or parenterally.[103]O'Lone EL, Hodson EM, Nistor I, et al. Parenteral versus oral iron therapy for adults and children with chronic kidney disease. Cochrane Database Syst Rev. 2019 Feb 21;(2):CD007857.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD007857.pub3/full
http://www.ncbi.nlm.nih.gov/pubmed/30790278?tool=bestpractice.com
For secondary hyperparathyroidism, calcium, phosphorus, and intact parathyroid hormone (PTH) levels should be measured every 6 to 12 months. The calcium and phosphorus levels should be maintained in the normal range with dietary restriction and/or phosphate-binding medications. The optimal PTH level is currently not known. It is recommended to exclude concomitant 25-OH vitamin D deficiency and prescribe 25, dihydroxyvitamin D if <30 nanograms/dL. For those with GFR category G3 to G5 CKD not on dialysis, it is not routinely recommended to use active vitamin D analogs due to the risk of hypercalcemia and lack of improvement in clinically relevant outcomes.[104]Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl. 2017 Jul;7(1):1-59.
https://kdigo.org/wp-content/uploads/2017/02/2017-KDIGO-CKD-MBD-GL-Update.pdf
Use of active vitamin D analog therapy in patients with CKD not requiring dialysis is indicated if hyperparathyroidism is progressive or severe.[104]Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl. 2017 Jul;7(1):1-59.
https://kdigo.org/wp-content/uploads/2017/02/2017-KDIGO-CKD-MBD-GL-Update.pdf
[105]Coyne DW, Goldberg S, Faber M, et al. A randomized multicenter trial of paricalcitol versus calcitriol for secondary hyperparathyroidism in stages 3-4 CKD. Clin J Am Soc Nephrol. 2014 Sep 5;9(9):1620-6.
https://cjasn.asnjournals.org/content/9/9/1620.long
http://www.ncbi.nlm.nih.gov/pubmed/24970869?tool=bestpractice.com
There is emerging evidence that the use of noncalcium-based phosphate binders has a survival advantage over calcium-based phosphate binders in patients with CKD.[104]Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl. 2017 Jul;7(1):1-59.
https://kdigo.org/wp-content/uploads/2017/02/2017-KDIGO-CKD-MBD-GL-Update.pdf
[106]Jamal SA, Vandermeer B, Raggi P, et al. Effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease: an updated systematic review and meta-analysis. Lancet. 2013 Oct 12;382(9900):1268-77.
http://www.ncbi.nlm.nih.gov/pubmed/23870817?tool=bestpractice.com
[Evidence B]3f301fbb-346f-4be5-8285-2c05fee4f5fcguidelineBWhat are the effects of calcium-containing phosphate binders versus calcium-free phosphate binders in people with chronic kidney disease-mineral and bone disorder (CKD-MBD)?[107]Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl. 2017 Jul;7(1):1-59.
https://kdigo.org/wp-content/uploads/2017/02/2017-KDIGO-CKD-MBD-GL-Update.pdf
GFR category G4
Patients need to be educated about renal replacement therapy such as hemodialysis, peritoneal dialysis, and kidney transplantation.[94]Shukla AM, Hinkamp C, Segal E, et al. What do the US advanced kidney disease patients want? Comprehensive pre-ESRD patient education (CPE) and choice of dialysis modality. PLoS One. 2019 Apr 9;14(4):e0215091.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215091
http://www.ncbi.nlm.nih.gov/pubmed/30964936?tool=bestpractice.com
[108]Shukla AM, Easom A, Singh M, et al. Effects of a comprehensive predialysis education program on the home dialysis therapies: a retrospective cohort study. Perit Dial Int. 2017 Sep-Oct;37(5):542-7.
http://www.ncbi.nlm.nih.gov/pubmed/28546368?tool=bestpractice.com
Patients should be referred to surgery for dialysis access and/or evaluated for kidney transplantation, based on patient preference for renal replacement modality at this stage. All patients should undergo CKD education for modality choice.[94]Shukla AM, Hinkamp C, Segal E, et al. What do the US advanced kidney disease patients want? Comprehensive pre-ESRD patient education (CPE) and choice of dialysis modality. PLoS One. 2019 Apr 9;14(4):e0215091.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215091
http://www.ncbi.nlm.nih.gov/pubmed/30964936?tool=bestpractice.com
Patient preference, family support, underlying comorbid conditions, and proximity to a dialysis facility should be addressed when choosing a modality or consideration for palliative care.[109]Cassidy BP, Harwood L, Getchell LE, et al. Educational support around dialysis modality decision making in patients with chronic kidney disease: qualitative study. Can J Kidney Health Dis. 2018 Oct 8;5:2054358118803323.
https://journals.sagepub.com/doi/10.1177/2054358118803323
http://www.ncbi.nlm.nih.gov/pubmed/30327720?tool=bestpractice.com
All patients who are proceeding with hemodialysis should be educated on vein preservation with limiting venipuncture and intravenous access to the access arm.[110]Association for Vascular Access, American Society of Diagnostic and Interventional Nephrology. Preservation of peripheral veins in patients with chronic kidney disease. Mar 2011 [internet publication].
https://cdn.ymaws.com/www.avainfo.org/resource/resmgr/Files/Position_Statements/Preservation_of_Peripheral_V.pdf
Kidney transplantation is indicated once the eGFR is <20 mL/minute and the patient has been evaluated and undergone the required testing process by a transplant team.
Treatment of anemia and secondary hyperparathyroidism should be continued. It is recommended to check serum calcium and phosphate every 3 to 6 months, and intact PTH every 6 to 12 months.[104]Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl. 2017 Jul;7(1):1-59.
https://kdigo.org/wp-content/uploads/2017/02/2017-KDIGO-CKD-MBD-GL-Update.pdf
[Evidence C]a39ca5ed-e51b-4a6f-b292-af5505178759guidelineCWhat are the effects of lower versus higher levels of serum phosphate or calcium in people with chronic kidney disease (CKD) G3a-G5 or G5D?[107]Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl. 2017 Jul;7(1):1-59.
https://kdigo.org/wp-content/uploads/2017/02/2017-KDIGO-CKD-MBD-GL-Update.pdf
Additionally, for those patients who develop metabolic acidosis, supplementation with oral sodium bicarbonate to a target serum bicarbonate level of >20 mEq/L has been shown to slow progression of CKD and improve nutritional parameters. Oral sodium bicarbonate is well tolerated in this group.[111]Susantitaphong P, Sewaralthahab K, Balk EM, et al. Short- and long-term effects of alkali therapy in chronic kidney disease: a systematic review. Am J Nephrol. 2012;35(6):540-7.
http://www.ncbi.nlm.nih.gov/pubmed/22653322?tool=bestpractice.com
GFR category G5 and uremia
Renal replacement therapy may be initiated once patients have G5 disease and/or signs of uremia such as weight loss, lack of appetite, nausea, vomiting, acidosis, hyperkalemia, or fluid overload.[1]Kidney Disease: Improving Global Outcomes (KDIGO). KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013 Jan;3(1):1-150.
https://kdigo.org/wp-content/uploads/2017/02/KDIGO_2012_CKD_GL.pdf
Treatment of anemia and secondary hyperparathyroidism should be continued. Those with G5 CKD on dialysis, calcium, phosphorus, and intact PTH should be managed with phosphate binding agents, calcimimetics, active vitamin D analogs, or a combination of these therapies, based on serial laboratory assessments of calcium and phosphate every 1 to 3 months, and PTH every 3 to 6 months.[104]Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl. 2017 Jul;7(1):1-59.
https://kdigo.org/wp-content/uploads/2017/02/2017-KDIGO-CKD-MBD-GL-Update.pdf
[Evidence C]a39ca5ed-e51b-4a6f-b292-af5505178759guidelineCWhat are the effects of lower versus higher levels of serum phosphate or calcium in people with chronic kidney disease (CKD) G3a-G5 or G5D?[107]Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl. 2017 Jul;7(1):1-59.
https://kdigo.org/wp-content/uploads/2017/02/2017-KDIGO-CKD-MBD-GL-Update.pdf
Calcimimetics (e.g., cinacalcet, etelcalcetide) negatively feedback on the parathyroid glands and do not have the consequences of calcium augmentation.[112]National Institute for Health and Care Excellence. Cinacalcet for the treatment of secondary hyperparathyroidism in patients with end-stage renal disease on maintenance dialysis therapy. Jan 2007 [internet publication].
https://www.nice.org.uk/guidance/TA117
Cinacalcet lowers PTH levels in patients with CKD and secondary hyperparathyroidism both prior to and after the initiation of dialysis, but it is associated with hypocalcemia, and long-term benefits are not known.[113]Chonchol M, Locatelli F, Abboud HE, et al. A randomized, double-blind, placebo-controlled study to assess the efficacy and safety of cinacalcet HCl in participants with CKD not receiving dialysis. Am J Kidney Dis. 2009 Feb;53(2):197-207.
http://www.ncbi.nlm.nih.gov/pubmed/19110359?tool=bestpractice.com
[114]Garside R, Pitt M, Anderson R, et al. The effectiveness and cost-effectiveness of cinacalcet for secondary hyperparathyroidism in end-stage renal disease patients on dialysis: a systematic review and economic evaluation. Health Technol Assess. 2007 May;11(18):iii, xi-xiii, 1-167.
http://www.ncbi.nlm.nih.gov/pubmed/17462168?tool=bestpractice.com
[
]
In adults with chronic kidney disease and secondary hyperparathyroidism, what are the benefits and harms of cinacalcet?/cca.html?targetUrl=https://cochranelibrary.com/cca/doi/10.1002/cca.1024/fullShow me the answer
There is no other medical therapy to keep patients alive once they have reached the need for dialysis, other than kidney transplantation. Of note, patients aged over 80 years and those with significant comorbidities, such as advanced congestive heart failure, may do poorly with dialysis and frequently are not considered transplant candidates. For these patients, and for all patients approaching ESRD for that matter, the treating nephrologist should have a discussion with the patient regarding end of life care and palliative care as an additional option.[115]O'Connor NR, Kumar P. Conservative management of end-stage renal disease without dialysis: a systematic review. J Palliat Med. 2012 Feb;15(2):228-35.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3318255/
http://www.ncbi.nlm.nih.gov/pubmed/22313460?tool=bestpractice.com
For those who are considered transplant candidates, transplant confers a significant survival advantage over maintenance dialysis therapy, predominantly due to a decrease in the risk of cardiovascular death. All patients who are on dialysis therapy are potentially eligible for kidney transplantation. A transplant center including a nephrologist and transplant surgeon will determine the final eligibility and status of the patient for kidney transplantation, after a complete medical history and evaluation.[116]Blake PG, Bargman JM, Brimble KS, et al; Canadian Society of Nephrology Work Group on Adequacy of Peritoneal Dialysis. Clinical practice guidelines and recommendations on peritoneal dialysis adequacy 2011. Perit Dial Int. 2011 Mar-Apr;31(2):218-39.
http://www.ncbi.nlm.nih.gov/pubmed/21427259?tool=bestpractice.com
[117]Berdud I, Arenas MD, Bernat A, et al; Grupo de Trabajo de Hemodiálisis Extrahospitalaria (Outpatient Haemodialysis Group). Appendix to dialysis centre guidelines: recommendations for the relationship between outpatient haemodialysis centres and reference hospitals. Opinions from the Outpatient Dialysis Group. Grupo de Trabajo de Hemodiálisis Extrahospitalaria. Nefrologia. 2011;31(6):664-9.
https://www.revistanefrologia.com/en-appendix-dialysis-centre-guidelines-recommendations-articulo-X2013251411000251
http://www.ncbi.nlm.nih.gov/pubmed/22130281?tool=bestpractice.com
Other measures
Although data are more limited in the CKD population than in the general population, tobacco cessation and weight loss are recommended. Severe protein restriction should not be recommended until late GFR category G4 or G5 disease as a management strategy to delay the initiation of dialysis.[118]Hahn D, Hodson EM, Fouque D. Low protein diets for non-diabetic adults with chronic kidney disease. Cochrane Database Syst Rev. 2020 Oct 29;(10):CD001892.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD001892.pub5/full
http://www.ncbi.nlm.nih.gov/pubmed/33118160?tool=bestpractice.com
Severe protein restriction may result in malnourishment and poorer outcomes.[119]Clase CM, Smyth A. Chronic kidney disease: diet. BMJ Clin Evid. 2015 Jun 29;2015:2004.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4484327/
http://www.ncbi.nlm.nih.gov/pubmed/26121377?tool=bestpractice.com
Aspirin use has also been beneficial for cardioprotection in those with CKD, although there is a higher risk for minor bleeding than in the general population.