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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. 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 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:
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
The major cause of death for patients with CKD is cardiovascular disease. Therefore, treatment of cardiovascular risk factors, such as optimising glycaemic control, optimising 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.
Glycaemic goals should be individualised. 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 hypoglycaemia, or difficulty achieving lower HbA1c goals despite the use of multiple anti-hyperglycaemic medications and insulin. In patients with diabetes and CKD, there is a risk for hypoglycaemia 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 anti-hyperglycaemic 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. Among the anti-hyperglycaemic 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).
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. 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. 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. 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.
Experience with GLP-1 agonists in patients with renal dysfunction is limited; therefore, these agents should be used with caution. Liraglutide, albiglutide, dulaglutide, and semaglutide are not renally excreted and are the preferred agents in this class.
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 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. 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. 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). 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.
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 non-diabetic CKD. 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. This emphasises 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. The study concluded that there was no difference in deaths from cardiovascular causes, in myocardial infarctions, cerebrovascular accidents, or hospitalisations for congestive heart failure, in the treatment groups. In addition, the rate 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 hyperkalaemia 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. 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 non-fatal stroke, renal complications, hyperkalaemia, and hypotension in patients taking the drug for 18 to 24 months. In the US, 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 hyperkalaemia. 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).
Dyslipidaemia 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). For patients aged ≥50 years with CKD GFR category G3 or G4, ezetimibe can be combined with the statin simvastatin.
Statin therapy has been shown to have cardioprotective effects in patients with CKD. 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). 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.
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.
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. 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. [ ] [ ] [ ] 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 has changed in the last several years but clinical expert opinion suggests that a target of 100-110 g/L (10-11 g/dL) is appropriate, as normalisation of Hb has resulted in increased risk for death and cardiovascular disease in this population. 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 as compared with those receiving placebo (individuals would receive a rescue dose of medication if the haemoglobin fell to <90g/L [<9 g/dL]). 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). [ ] In their opinion, the risks of treatment may outweigh the benefits, and discussion between the patient and physician should ensue prior to treatment initiation. 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.
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 <75 nanomol/L (<30 nanograms/mL). 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. Use of active vitamin D analogue therapy in patients with CKD not requiring dialysis is indicated if hyperparathyroidism is progressive or severe. There is emerging evidence that the use of non-calcium-based phosphate binders has a survival advantage over calcium-based phosphate binders in patients with CKD.[Evidence B]
GFR category G4
Patients need to be educated about renal replacement therapy such as haemodialysis, peritoneal dialysis, and kidney transplantation. 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. 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 who are proceeding with haemodialysis should be educated about vein preservation with limiting venipuncture and intravenous access in the access arm. 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.[Evidence C] 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.
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. 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.[Evidence C] Calcimimetics (e.g., cinacalcet, etelcalcetide) negatively feedback on the parathyroid glands and do not have the consequences of calcium augmentation. 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. [ ]
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.
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.
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. Severe protein restriction may result in malnourishment and poorer outcomes. 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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