Chronic kidney disease

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Chronisch nierlijden (multidisciplinaire aanpak)Published by: WORELLast published: 2017GPC pluridisciplinaire sur la néphropathie chronique (IRC)Published by: Groupe de travail Développement de recommandations de première ligneLast published: 2017

All etiologies of chronic kidney disease (CKD) are progressive. The main goal of treatment is to slow the progressive loss of kidney function and prevent the need for kidney replacement therapy or kidney transplantation.

It is important 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 comorbidities such as anemia and secondary hyperparathyroidism may be identified and 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]

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 60-89 mL/minute/1.73 m²
G3a: GFR of 45-59 mL/minute/1.73 m²
G3b: GFR of 30-44 mL/minute/1.73 m²
G4: GFR of 15-29 mL/minute/1.73 m²
G5: GFR <15 mL/minute/1.73 m²

GFR category G1 to G4

Several classes of agents have been shown to slow CKD progression. Renin-angiotensin system (RAS) blockade (e.g., with an ACE inhibitor or an angiotensin-II receptor antagonist) and sodium-glucose cotransporter-2 (SGLT2) inhibitors (e.g., empagliflozin, canagliflozin, dapagliflozin) can preserve kidney function by reducing intraglomerular pressure, independently of blood pressure (BP) and glucose control.[60][81][82][83]

Management of cardiovascular risk factors is recommended. Measures include optimizing glycemic control, optimizing BP with an ACE inhibitor or an angiotensin-II receptor antagonist, introducing lipid-lowering agents (e.g., statins, ezetimibe), and reducing proteinuria.[80][84][85][86]

ACE inhibitor or angiotensin-II receptor antagonist

Recommended for patients with CKD (with or without diabetes) who have severely increased albuminuria (albumin to creatinine ratio [ACR] ≥300 mg/g), even in the absence of high BP.[1] If albuminuria is moderately increased (ACR ≥30 mg/g), an ACE inhibitor or angiotensin-II receptor antagonist is recommended in patients with diabetes, and should be considered for those without diabetes.[1]

Patients with CKD and high BP or heart failure may receive an ACE inhibitor or angiotensin-II receptor antagonist regardless of albuminuria.[1] ACE inhibitors or angiotensin-II receptor antagonists should be used at the highest tolerated dose to maximize benefits.[1] Monitor BP, serum creatinine, and potassium within 2-4 weeks. Hyperkalemia should be managed without reducing the dose or discontinuation of the ACE inhibitor or angiotensin-II receptor antagonist, if possible. Continue treatment even if the estimated GFR (eGFR) decreases to <30 mL/minute/1.73 m².[1][87]

SGLT2 inhibitors

Recommended for the treatment of CKD, particularly in patients at risk of progression, in combination with an ACE inhibitor or an angiotensin-II receptor antagonist. BMJ Rapid Recommendation: SGLT2-inhibitors for adults with CKD Opens in new window

Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend SGLT2 inhibitors for patients with CKD (if eGFR level ≥20 mL/minute/1.73 m²) and increased albuminuria (ACR ≥200 mg/g), or type 2 diabetes, or heart failure. SGLT2 treatment should be considered for patients with ACR <200 mg/g and eGFR level 20-45 mL/minute/1.73 m².[1]

Statins

Recommended for patients with CKD (not on kidney replacement therapy) age ≥50 years, and those age <50 years with additional cardiovascular risk factors.[1] Statin therapy has been shown to have cardioprotective effects in patients with CKD.[88][89][90][91]

GFR category G1 to G4: patients with comorbid diabetes

Glycemic goals should be individualized. KDIGO guidelines recommend an HbA1c target ranging from <6.5% to <8.0% (<48 mmol/mol to <64 mmol/mol) for patients with diabetes and CKD not receiving dialysis. A lower target (e.g., <6.5% or <7.0% [<48 mmol/mol to <53 mmol/mol]) may be appropriate for individuals in whom preventing complications is the key goal; a higher target (e.g., <7.5% or <8.0% [<58 mmol/mol to <64 mmol/mol]) may be preferred in those with multimorbidity or increased burden of hypoglycemia.[92][93] In patients with diabetes and CKD, there is a risk for hypoglycemia because of impaired kidney clearance of drugs (such as insulin or sulfonylureas) and 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 drugs significantly reduce all-cause or cardiovascular mortality, major cardiovascular events, or kidney complications in some patient subgroups, and should be considered independently of HbA1c targets.[94][95][96][97][98]

An SGLT2 inhibitor is recommended for glycemic control in type 2 diabetes to reduce kidney disease progression. SGLT2 inhibitors prevent major kidney outcomes (e.g., dialysis, transplantation, or death due to kidney disease) and cardiovascular events in people with type 2 diabetes.[82][99][100][101][102] Renoprotection attributable to SGLT2 inhibition involves glucose-dependent and independent effects.[103][104]

KDIGO guidelines advise that most patients with type 2 diabetes and CKD would benefit from treatment with metformin (if eGFR ≥30 mL/minute/1.73 m²) and an SGLT2 inhibitor (if eGFR ≥20 mL/minute/1.73 m²).[92] The American Diabetes Association recommends the use of SGLT2 inhibitors in patients with CKD and type 2 diabetes (if eGFR ≥20 mL/minute/1.73 m²), regardless of urinary albuminuria.[80]

Use of SGLT2 inhibitors is not generally recommended in patients with an eGFR of <20 mL/minute/1.73 m².[1][80] However, renal and cardiovascular benefits with SGLT2 therapy are seen at eGFR levels as low as 20 mL/minute/1.73 m²; if tolerated, SGLT2 therapy may be continued at eGFR levels below 20 mL/minute/1.73 m² unless kidney replacement therapy is started.[1][92] Use of SGLT2 inhibitors is not recommended in patients with end-stage kidney disease who are on dialysis.[105]

If additional glycemic control is required for patients receiving metformin and an SGLT2 inhibitor, a drug from a different class should be selected. A glucagon-like peptide-1 (GLP-1) receptor agonist is the preferred option.[1][92] If required, other agents (e.g., a dipeptidyl peptidase-4 [DPP-4] inhibitor, a sulfonylurea, insulin, a thiazolidinedione, or an alpha-glucosidase inhibitor) may be considered based on eGFR, comorbidities, and patient preference.[92] GLP-1 receptor agonists and DPP-4 inhibitors should not be used in combination.[92]

GLP-1 receptor agonists have beneficial effects on cardiovascular, mortality, and kidney outcomes in patients with type 2 diabetes.[106][107][108] GLP-1 receptor agonists may be considered for cardiovascular risk reduction.[80] Liraglutide, dulaglutide, and semaglutide are not renally excreted and are the preferred agents in this class.

DPP-4 inhibitors are renoprotective but do not have a cardiovascular benefit.[109][110][111] Some DPP-4 inhibitors require dose adjustment in renal impairment.

Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, reduces the progression of kidney disease in patients with type 2 diabetes mellitus and known CKD.[112] Finerenone is approved by the Food and Drug Administration (FDA) to reduce the risk of kidney function decline, kidney failure, cardiovascular death, nonfatal heart attacks, and hospitalization for heart failure in adults with CKD associated with type 2 diabetes. Guidelines recommend finerenone for patients with type 2 diabetes and albuminuria (ACR ≥30 mg/g), despite maximum tolerated dose of RAS inhibitor (if eGFR is ≥25 mL/minute/1.73 m² and serum potassium level is normal).[80][92] Finerenone can be added to an SGLT2 inhibitor and an ACE inhibitor or an angiotensin-II receptor antagonist.

See Diabetic kidney disease.

GFR category G1 to G4: patients with comorbid hypertension

Hypertension is one of the most important 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 optimal BP control.

An individualized approach should be used for BP targets, taking into account age, comorbidities, risk of progression of CKD, and tolerance to treatments.[1] KDIGO guidelines suggest a target systolic BP of less than 120 mmHg, if tolerated, in patients with CKD, with and without diabetes, and not receiving dialysis.[1][81][113][114] Office BP measurement must be standardized when using this target. Less intensive BP-lowering therapy may be considered for specific patients, such as those with frailty, high risk of fracture and falls, postural hypotension, or limited life expectancy.[1] Certain guidelines advocate less intensive BP targets, which might be more achievable.[54][115]

There may be benefit in strict BP control to reduce the relative risk of death, and delay the onset of end-stage kidney disease, particularly in some subgroups of patients with CKD.[116][117] However, one Cochrane systematic review suggests little to no difference in outcomes between standard (≤140 to 160/90 to 100 mmHg) and low (≤130/80 mmHg) BP targets in people with CKD.[118]

ACE inhibitors and angiotensin-II receptor antagonists slow the progression of CKD and delay the need for kidney replacement therapy in both diabetic and nondiabetic CKD.[119][120][121] RAS blockade with either ACE inhibitors or angiotensin-II receptor antagonists reduced the risk for kidney failure and cardiovascular events in one meta-analysis of patients with CKD.[122] ACE inhibitors are more likely to reduce the risk of death in people with CKD.[122]

A combination of antihypertensive agents is often needed to meet the target BP goal, but ACE inhibitors and angiotensin-II receptor antagonists should not be combined within the same regimen.[81][98] Other classes of antihypertensive agents should be added when the target BP is not achieved with the use of an ACE inhibitor or an angiotensin-II receptor antagonist.[81]

Evidence supporting the choice of additional antihypertensive agents in patients with CKD is lacking. KDIGO guidelines suggest adding a calcium-channel blocker and/or a thiazide-like diuretic, based on evidence of improved cardiovascular outcomes in primary hypertension. Nondihydropyridine calcium-channel blockers may have the additional benefit of reducing proteinuria.[81][123] If BP cannot be controlled with a combination of three drugs (ACE inhibitor or angiotensin-II receptor antagonist, calcium-channel blocker, and diuretic), then additional agents may be considered, including aldosterone antagonists, alpha-blockers, beta-blockers, hydralazine, minoxidil, or centrally acting agents.[81] Note that some agents may be recommended for specific indications (e.g., beta-blockers for angina pectoris).[81]

GFR category G1 to G4: patients with comorbid dyslipidemia

Common in patients with CKD. Dietary changes may be recommended (e.g., considering a plant-based Mediterranean diet), along with lipid-lowering therapy.[1]

KDIGO guidelines recommend that CKD patients not on dialysis should start treatment without the need for routine follow-up to check lipid values, or to change dose regimen based on set targets (i.e., a "treat and forget" approach).[84]

For patients ages ≥50 years with CKD GFR category G1 or G2, a statin is recommended.[1] For patients ages ≥50 years with CKD GFR category G3 or G4, ezetimibe can be combined with a statin.[1][124] The addition of ezetimibe to statin therapy may improve tolerability and reduce the risk of adverse effects in patients with advanced CKD who are less able to tolerate higher doses of statins.[84][85] For patients ages 18-49 years with CKD, statin treatment is recommended in the presence of known coronary disease, diabetes mellitus, prior ischemic stroke, or estimated 10-year incidence of coronary death or nonfatal myocardial infarction >10%.[1]

Statin therapy has cardioprotective effects in patients with CKD.[88][89][90][91] One large meta-analysis reported that statins reduce death and major cardiovascular events by about 20% in patients with CKD not requiring dialysis, including patients without existing cardiovascular disease.[125] There was no difference in adverse effects for statin users compared with those in the placebo arms. The use of statins did not reduce the risk of stroke or kidney failure.[125]

One meta-analysis found that statin use in patients undergoing dialysis did not improve all-cause mortality or cardiovascular-related deaths.[126]

GFR category G1 to G4: patients with comorbid ischemic heart disease

Use of low-dose aspirin is recommended for secondary prevention (of cardiovascular disease events) in patients with CKD and ischemic cardiovascular disease.[1] There is a higher risk for minor bleeding than in the general population. Other antiplatelet agents (e.g., clopidogrel) may be considered for patients with intolerance to aspirin.

When assessing 10-year cardiovascular risk, a validated tool that incorporates CKD should be used to guide treatment for prevention of cardiovascular disease. In patients with CKD and stable stress-test confirmed ischemic heart disease, KDIGO guidelines recommend a conservative approach with intensive medical therapy, rather than initial invasive interventions, which may increase risk of dialysis initiation, stroke, and death.[1][127] In those with acute or unstable coronary disease, unacceptable levels of angina (e.g., patient dissatisfaction), left ventricular systolic dysfunction attributable to ischemia, or left main disease, revascularization should be considered.[1]

GFR category G1 to G4: patients with comorbid obesity

Advise patients with obesity and CKD to lose weight.[1] Options for weight loss in patients with CKD include lifestyle interventions, pharmacotherapy, and metabolic surgery.[128]

The GLP-1 receptor agonist semaglutide may have a role in preventing CKD progression in patients with CKD and obesity (independent of diabetes). Improved kidney outcomes have been reported in patients with overweight/obesity and nondiabetic CKD receiving semaglutide.[129][130] Patients with obesity, type 2 diabetes, and CKD may benefit from a GLP-1 receptor agonist for weight loss (in addition to improved cardiovascular and kidney outcomes).[92]

GFR category G2

Continue to modify cardiovascular risk factors and consider therapy to reduce progression of kidney disease, if not previously indicated. Estimate the rate of loss of kidney function to determine the eventual need for kidney replacement therapy (i.e., dialysis, transplant).

Validated risk prediction equations can predict kidney failure or ≥40% decline in eGFR in patients with CKD GFR category G2.[1][131][132][133] CKD Prognosis Consortium: risk models Opens in new window

GFR category G3a/G3b

Education can play a significant role in delaying progression of CKD, as well as helping patients understand their options if CKD progresses.[134][135][136]

Patients should be offered an assessment using a validated risk equation to estimate the absolute risk of kidney failure. This can be used to personalize education, determine the need for referral, and inform plans for future care.[1][137][138][139] The Kidney Failure Risk Equation Opens in new window

[ Kidney Failure Risk (KFRE) (8 variable) Opens in new window ]

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.

GFR category G3a/G3b: patients with comorbid anemia

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, or folate deficiency, or blood loss, have been excluded.[61] [ ] [ ] [ ] Patients with CKD frequently have iron deficiency, and iron replacement should be considered as a goal of treatment.

Erythropoietin-stimulating agents may be initiated if the hemoglobin (Hb) level falls to <10 g/dL and the patient has signs and symptoms of anemia. A target Hb of 10.0 to 11.5 g/dL is appropriate, as normalization of Hb (>13 g/dL) has resulted in increased risk for death and cardiovascular disease in this population.[140][141][142] For most patients, Hb concentration should be maintained at <11.5 g/dL with erythropoietin-stimulating agents to manage anemia.[61][143][144]

The results from one Cochrane review and network meta-analysis suggest that erythropoietin-stimulating agents are superior to placebo for preventing blood transfusion, but increase the risk of hypertension.[145] The impact of erythropoietin-stimulating agents on mortality, major cardiovascular events, and kidney failure is uncertain, and evidence is lacking to compare the efficacy and safety of different formulations.[145] The potential risks and benefits of therapy with an erythropoietin-stimulating agent should be discussed with the patient prior to treatment initiation.[61][146][147][148]

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.[149][150]

See Anemia of chronic disease.

GFR category G3a/G3b: patients with comorbid secondary hyperparathyroidism

Monitoring for secondary hyperparathyroidism should be carried out in patients with GFR category G3a to G3b CKD. Serum calcium and phosphorus levels should be measured every 6-12 months; frequency of intact parathyroid hormone (PTH) testing should be determined by baseline level and CKD progression.[62]

The initial approach to managing secondary hyperparathyroidism is to maintain serum calcium and phosphorus levels in the normal range with dietary restriction and/or phosphate-binding drugs.[62] Phosphate binders should be initiated to normalize phosphorus levels if patients are unable to sufficiently restrict phosphorus in the diet.[62] The optimal PTH level is currently not known.

25-OH vitamin D deficiency should be excluded. If the serum level of 25-OH vitamin D is <30 nanograms/mL, vitamin D supplementation with ergocalciferol should be initiated.[151][152] For those with GFR category G3 to G5 CKD not on dialysis, use of active vitamin D analogs is not routinely recommended due to the risk of hypercalcemia and lack of improvement in clinically relevant outcomes.[62] Use of active vitamin D analog therapy in patients with CKD not requiring dialysis is indicated if hyperparathyroidism is progressive or severe.[62][153]

There is evidence that the use of noncalcium-based phosphate binders has a survival advantage over calcium-based phosphate binders in patients with CKD.[62][154][155][Evidence B]What 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)?[62]

See Secondary hyperparathyroidism.

GFR category G3a/G3b: patients with comorbid hyperuricemia

KDIGO guidelines recommend that people with CKD with symptomatic hyperuricemia should be offered uric acid-lowering therapy.[1] This can be considered after the first episode of gout, particularly where there is no avoidable precipitant or serum uric acid concentration is >9 mg/dL [>535 micromol/L]).

Xanthine oxidase inhibitors are preferred to uricosuric agents for patients with CKD and symptomatic hyperuricemia. Low-dose colchicine or intra-articular/oral glucocorticoids are preferred for symptomatic treatment of acute gout in patients with CKD.

Uric acid-lowering therapy is not recommended in people with CKD and asymptomatic hyperuricemia to delay CKD progression.

See Gout.

GFR category G4

Educate patients about kidney replacement therapy such as hemodialysis, peritoneal dialysis, and kidney transplantation.[135][156]

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. All patients should undergo CKD education for modality choice.[135]

Guidelines suggest planning for dialysis or kidney transplantation when GFR is <15-20 mL/minute/1.73 m² or risk of kidney failure is >40% over 2 years.[1] Patients should be referred to surgery for dialysis access and/or evaluated for kidney transplantation, based on patient preference for kidney replacement modality.

All patients who are proceeding with hemodialysis should be educated on vein preservation with limiting venipuncture and intravenous access to the access arm.[157]

GFR category G4: patients with comorbid anemia, secondary hyperparathyroidism, metabolic acidosis, or hyperuricemia

Treatment of anemia and secondary hyperparathyroidism should be continued. Serum calcium and phosphorus levels should be checked every 3-6 months, and intact PTH every 6-12 months.[62][Evidence C]What are the effects of lower versus higher levels of serum phosphate or calcium in people with chronic kidney disease (CKD) G3a-G5 or G5D?[62] Additionally, for those patients who develop metabolic acidosis, supplementation with oral sodium bicarbonate has been shown to slow progression of CKD.[158] Oral sodium bicarbonate is well tolerated in this group.

Patients in this group with symptomatic hyperuricemia should be offered uric acid-lowering therapy.[1]

GFR category G5

Kidney replacement therapy should be initiated based on assessment of signs and symptoms, GFR, quality of life, and patient preferences. It is usually indicated once patients have G5 disease (often when GFR is between 5 and 10 mL/minute/1.73 m²) and if any of the following are present:[1]

symptoms or signs of kidney failure, including neurologic symptoms and signs due to uremia, pericarditis, anorexia, acid-base or electrolyte abnormalities, intractable pruritus, serositis
loss of BP control or control of volume status (fluid overload)
progressive deterioration in nutritional status refractory to intervention
cognitive impairment

For those who are considered 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.[159][160]

GFR category G5: patients with comorbidity (anemia, secondary hyperparathyroidism)

For patients with GFR category G5 CKD on dialysis therapy, calcium, phosphorus, and intact PTH should be managed with dietary restriction and phosphate-binding agents, calcimimetics, active vitamin D analogs, or a combination of these therapies, based on serial laboratory assessments of calcium and phosphate every 1-3 months, and PTH every 3-6 months.[62][Evidence C]What are the effects of lower versus higher levels of serum phosphate or calcium in people with chronic kidney disease (CKD) G3a-G5 or G5D?[62]

Calcimimetics (e.g., cinacalcet, etelcalcetide) negatively feedback on the parathyroid glands and do not have the consequences of calcium augmentation.[161] 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.[162][163] [ ]

GFR category G5: older patients and those with other significant comorbidity (considerations for kidney replacement therapy)

Patients ages 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. The survival benefits of dialysis compared with conservative management are uncertain for older, frail patients.[164][165][166] For these patients, and for all patients approaching end-stage kidney disease, the treating nephrologist should discuss conservative management with the patient, including palliative care and end-of-life care.[164][166][167]

Conservative management focuses on maintaining quality of life, managing symptoms, and preserving kidney function for as long as possible (but does not include kidney replacement therapy).[164][168] Decisions about conservative management should be made using an informed shared decision-making process.

Lifestyle and dietary measures

Tobacco cessation and maintaining a healthy weight are recommended. Physical activity (e.g., moderate-intensity physical activity for at least 150 minutes per week), adopting a healthy diet, and achieving a healthy weight should be encouraged.[1][54][169] Evidence for cardiovascular or mortality benefit from weight loss interventions, including lifestyle changes, appetite-suppressing drugs, and weight-loss surgery, is lacking. However, general health benefits and improvement in body weight are likely.[170]

Individualized dietary education (including advice on sodium, phosphorus, potassium, and protein intake) should be considered for patients with CKD.[1] Guidelines suggest that patients at risk of progression should avoid high protein intake, and that those with G3 or higher category disease with diabetes (not on dialysis) should aim for a target protein intake of 0.8 g/kg body weight per day.[80][92]

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.[171] Severe protein restriction may result in malnourishment and poorer outcomes.[172]

For patients with CKD and high BP, reducing sodium intake to <2 g per day (equivalent to <5 g of sodium chloride per day) is suggested.[81]

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