Chronic kidney disease

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

All aetiologies 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.

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 identification of comorbidities such as anaemia 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]

G1: GFR >90 mL/minute/1.73 m², and evidence of kidney damage based on pathological diagnosis, abnormalities of radiographic imaging, or laboratory findings such as haematuria 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

Several classes of agents have been shown to slow CKD progression. Renin-angiotensin system blockade (e.g., with an ACE inhibitor or an angiotensin-II receptor antagonist) and sodium-glucose co-transporter-2 (SGLT2) inhibitors (e.g., empagliflozin, canagliflozin, dapagliflozin) can preserve kidney function by reducing intra-glomerular pressure independently of blood pressure (BP) and glucose control.[62][63][64]

SGLT2 inhibitors are recommended for the treatment of CKD, particularly in adults 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

The major cause of death for patients with CKD is cardiovascular disease. Therefore, treatment of cardiovascular risk factors, such as optimising glycaemic control, optimising BP with an ACE inhibitor or an angiotensin-II receptor antagonist, introducing lipid-lowering agents (e.g., statins, ezetimibe), and reducing proteinuria is recommended.[61][65][66][67]

Diabetes

Glycaemic goals should be individualised. Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend a HbA1c target ranging from <6.5% to <8.0% for patients with diabetes and chronic kidney disease not receiving dialysis. A lower target (e.g., <6.5% or <7.0%) may be appropriate for individuals in whom preventing complications is the key goal, whereas a higher target (e.g., <7.5% or <8.0%) may be preferred in those with multimorbidity or increased burden of hypoglycaemia.[20] In patients with diabetes and CKD, there is a risk for hypoglycaemia 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 anti-hyperglycaemic drugs significantly reduce all-cause or cardiovascular mortality, or major cardiovascular events or renal complications in some patient subgroups, and should be considered independently of HbA1c targets.[68][69][70][71][72]
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.[64][73][74] SGLT2 inhibitors, in addition to reducing hyperglycaemia, have renal benefits through independent effects on renal tubular glucose reabsorption, weight, BP, intra-glomerular pressure, albuminuria, and slowed GFR loss.[75][76]
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).[20] 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.[61] Use of SGLT2 inhibitors is not recommended in patients with end-stage renal disease (ESRD) who are on dialysis.[77]
If additional glycaemic 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) is the preferred option. 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.[20]
As a class of drugs, GLP-1 agonists have beneficial effects on cardiovascular, mortality, and kidney outcomes in patients with type 2 diabetes.[78][79] GLP-1 agonists may be considered for cardiovascular risk reduction.[61] Liraglutide, dulaglutide, and semaglutide are not renally excreted and are the preferred agents in this class.
Studies report that DPP-4 inhibitors are renoprotective but do not have a cardiovascular benefit.[80][81] Some DPP-4 inhibitors require dose adjustment in renal impairment.
Finerenone, a non-steroidal mineralocorticoid receptor antagonist, reduces the progression of kidney disease in patients with type 2 diabetes mellitus and known CKD.[82] Finerenone is approved by the US Food and Drug Administration (FDA) to reduce the risk of kidney function decline, kidney failure, cardiovascular death, non-fatal heart attacks, and hospitalisation for heart failure in adults with CKD associated with type 2 diabetes. Guidelines recommend finerenone for patients with type 2 diabetes and albuminuria, despite maximum tolerated dose of an ACE inhibitor or an angiotensin-II receptor antagonist (if eGFR is ≥25 mL/minute/1.73 m² and serum potassium level is normal).[20][61] Finerenone can be added to an SGLT2 inhibitor and an ACE inhibitor or an angiotensin-II receptor antagonist.

Hypertension

Hypertension is one of the greatest risk factors for the progression of CKD, regardless of aetiology. 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 the 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.[83] 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.[84] 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).[85][86] 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.[62]
A combination of antihypertensive agents should be used to meet the target BP goal. ACE inhibitors and angiotensin-II receptor antagonists should not be combined within the same regimen.[62]
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 non-diabetic CKD.[87][88][89] In one meta-analysis of patients with CKD, blockade of the renin angiotensin system with either ACE inhibitors or angiotensin-II receptor antagonists reduced the risk for kidney failure and cardiovascular events.[90] ACE inhibitors are also more likely to reduce the risk of death in people with CKD.[90]
Other classes of antihypertensive agents (e.g., thiazide or thiazide-like diuretics, beta-blockers, dihydropyridine calcium-channel blockers, aldosterone antagonists, vasodilators, alpha-2 adrenergic agonists) should be added when the target BP is not achieved with the use of an ACE inhibitor or an angiotensin-II receptor antagonist, or if there are other specific clinical indications, such as beta-blockers for angina pectoris.[62]

Dyslipidaemia

Common in patients with CKD.
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 dose regimen based on set targets (i.e., a 'treat and forget' approach).[65] For patients aged ≥50 years with CKD GFR category G3 or G4, ezetimibe can be combined with the statin simvastatin.[66]
Statin therapy has been shown to have cardioprotective effects in patients with CKD.[91][92][93][94] In those individuals not on dialysis, 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).[95]
One meta-analysis found that statin use in patients undergoing dialysis did not improve all-cause mortality or cardiovascular-related deaths.[96]

GFR category G1 to G4 intolerant to first-line therapy

If a patient is unable to tolerate either an ACE inhibitor or angiotensin-II receptor antagonist due to adverse effects, then an alternative is warranted. Non-dihydropyridine calcium-channel blockers have been demonstrated to have more proteinuric-lowering effects than other antihypertensive agents. Clinical trials in both diabetic and non-diabetic CKD have demonstrated greater protein-lowering effects than other classes of antihypertensive agents.[97]

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.[98][99][100] Most CKD-related complications occur during this stage of transition (GFR category G3a/G3b). Identification of comorbidities such as anaemia and secondary hyperparathyroidism is recommended, and treatment commenced if required.

Treatment of anaemia with the use of erythropoietin-stimulating agents is recommended for patients with CKD after other causes of anaemia such as iron, vitamin B12, folate, or blood loss have been excluded.[101] [ ] [ ] [ ] 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 haemoglobin (Hb) falls to <100 g/L (<10 g/dL) and the patient has symptoms and signs of anaemia. The target Hb for patients with CKD on erythropoietin therapy is 10-11 g/dL, as normalisation of Hb has resulted in increased risk for death and cardiovascular disease in this population.[102][103] In the TREAT study of patients with diabetes with CKD and anaemia, treatment with the erythropoietin-stimulating agent darbepoetin failed to show a beneficial effect of active treatment on cardiovascular events, death, or ESRD compared with those receiving placebo (individuals would receive a rescue dose of darbepoetin if the haemoglobin fell to <90g/L [<9 g/dL]).[104] Interestingly, as in other studies of anaemia 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).[105] In their opinion, the risks of treatment may outweigh the benefits, and discussion between the patient and physician should ensue prior to treatment initiation.[101][104][106][107]

All patients should have an assessment of iron stores if erythropoietin therapy is planned. The goal ferritin for those not on haemodialysis is >100 nanograms/mL, while for those on haemodialysis it is <200 nanograms/mL. All patients should have a transferrin saturation >20%. Iron replacement can be given orally or parenterally.[108]

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 drugs. 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 <75 nanomol/L (<30 nanograms/mL), vitamin D supplementation with ergocalciferol should be initiated.[109][110] For those with GFR category G3 to G5 CKD not on dialysis, it is not routinely recommended to use active vitamin D analogues due to the risk of hypercalcaemia and lack of improvement in clinically relevant outcomes.[111] Use of active vitamin D analogue therapy in patients with CKD not requiring dialysis is indicated if hyperparathyroidism is progressive or severe.[111][112] There is evidence that the use of non-calcium-based phosphate binders has a survival advantage over calcium-based phosphate binders in patients with CKD.[111][113][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)?[111]

GFR category G4

Educate patients about renal replacement therapy such as haemodialysis, peritoneal dialysis, and kidney transplantation.[99][114]

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.[99]

Patients should be referred to surgery for dialysis access and/or evaluated for kidney transplantation, based on patient preference for renal replacement modality at GFR category G4.

All patients who are proceeding with haemodialysis should be educated about vein preservation with limiting venipuncture and intravenous access in the access arm.[115]

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 anaemia 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.[111][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?[111] Additionally, for those patients who develop metabolic acidosis, supplementation with oral sodium bicarbonate has been shown to slow progression of CKD.[116] Oral sodium bicarbonate is well tolerated in this group.

GFR category G5 and uraemia

Renal replacement therapy may be initiated once patients have G5 disease or signs of uraemia such as weight loss, lack of appetite, nausea, vomiting, acidosis, hyperkalaemia, or fluid overload.[1] Treatment of anaemia 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 analogues, 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.[111][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?[111] Calcimimetics (e.g., cinacalcet, etelcalcetide) negatively feedback on the parathyroid glands and do not have the consequences of calcium augmentation.[117] 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 hypocalcaemia, and long-term benefits are not known.[118][119] [ ]

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.[120]

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 centre 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.[121][122]

Other measures

Although data are more limited in the CKD population than in the general population, tobacco cessation and weight loss are recommended.

People with CKD (≥ G3) and diabetes who are not on dialysis should target protein intake of 0.8 g/kg body weight per day.[20][61] 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.[123] Severe protein restriction may result in malnourishment and poorer outcomes.[124]

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.

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