Treating CKD

Professor Vlado Perkovic and Dr George Bakris discuss the treatment goals and priorities for optimising treatment of chronic kidney disease (CKD).

The management of CKD relies on a combination of different strategies, including: controlling nephron injury, normalising hyperfiltration, controlling CKD-­related complications, and preparations for kidney replacement therapy.

The core principle of this management is ‘the earlier, the better’, which aims to prevent nephron loss as early as possible and reduce the progression to end-stage renal disease (ESRD)¹.

What are the overall goals when managing CKD?

The management of CKD is based on the clinical diagnosis and disease stage, according to glomerular filtration rate (GFR) and albuminuria. Individualised therapies, that are guided by the cause and pathological processes, are determined by the specific clinical diagnosis². The treatments for CKD aim to^2,3:

• prevent disease development
• slow disease progression
• reduce the complications of decreased GFR
• reduce the risk of cardiovascular disease
• improve survival and quality of life

The disease stage can also be used to guide non-specific therapies that slow the progression of the disease and reduce the risk of complications^2,3. Recommendations based on disease stage are cumulative: early-stage recommendations are included within late-stage recommendations^2,3.

How do you control ongoing nephron injury?

As a variety of triggers can drive nephron injury, disrupting these triggers with treatment can slow the progression of CKD to end-stage renal disease (ESRD)¹.

For genetic causes of kidney disease, treatments are limited to enzyme replacement therapy or substrate supplementation. In cases of immune mediated nephron injury that have a genetic component, CKD progression associated with C3 glomerulonephritis or atypical haemolytic uraemic syndrome can be treated with complement inhibitors⁴.

Immunomodulatory drugs can be used to target immune mediated CKD disorders with the aim of limiting nephron injury⁵

In acute forms of immune mediated nephron injury, presentation is seen as either vasculitis, immune complex glomerulonephritis, or interstitial nephritis (such as allograft rejection).

However, in smouldering immune injuries (such as chronic IgA nephropathy) it is difficult to differentiate immune versus non­immune mechanisms in the progression of CKD and, as a consequence, the efficacy of management through immunosuppression or RAS blockade and blood pressure control is less apparent⁶.

How do you minimise the stress on remnant nephrons in CKD?

It is essential to minimise the stress on remnant nephrons by preventing further acute kidney injury (AKI). It is therefore important to avoid¹:

• nephrotoxins (such as high volumes of radio contrast media, non-steroidal anti-inflammatory drugs, proton pump inhibitors or occupational toxins)
• hypovolaemic states
• urinary outflow obstruction
• smoking-related cardiovascular disease
• specific antibiotic treatment (limited to cases of dysuria, bacteriuria, and leukocyturia)

Specific medications do exist to prevent some of these triggers, such as urinary tract obstruction, infections, and some forms of toxic injury; however, the recovery of the lost nephrons is not possible¹.

How do you normalise single-nephron hyperfiltration?

Angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) can inhibit the renin-angiotensin system (RAS) and consequently significantly reduce single-nephron GFR and glomerular filtration pressure. This leads to decline in proteinuria and total GFR and moderately increased serum creatinine levels⁷.

A moderate increase in serum creatinine levels indicating a decline in single nephron GFR, can be a powerful predictor of a nephroprotective effect⁸

While increased serum creatinine may be disconcerting to patients and some physicians, reducing hyperfiltration in remnant nephrons is essential for reducing the progression of CKD in patients with proteinuria¹. Conversely, ACEi or ARBs do not reduce non­proteinuric forms of CKD progression, such as autosomal dominant polycystic kidney disease⁹.

Various randomised clinical trials have shown that RAS inhibitors can reduce or even prevent CKD progression¹⁰. A further reduction in proteinuria and CKD progression can be achieved with a reduction in dietary salt as well as medications that support the control of blood pressure and hyperlipidaemia^11,12. These interventions can be particularly necessary where kidney replacement therapy is not available or affordable¹.

In diabetic kidney disease (DKD), sodium-glucose cotransporter 2 (SGLT2) inhibition can cause an immediate functional reduction in GFR. The GFR reduction is thought to reduce the tubular transport work and metabolic demand, improving renal cortical oxygenation, which is associated with protection from CKD^13,14. The effect of SGLT2 inhibitors to reduce glomerular hyperfiltration is thought to be a shared mechanism between DKD and CKD¹⁵. In the DAPA-CKD trial, dapagliflozin was evaluated for proteinuric CKD attributed to hypertension or glomerular diseases that did not require immunosuppression. On a background of RAS inhibition, similar risk reductions for the primary and secondary outcomes were observed irrespective of diabetes status or CKD aetiology, with no evidence of statistical interaction by subgroup across primary and secondary outcomes¹⁶.

Why is it important to control the factors associated with CKD progression?

An important part of the management of CKD is addressing the multiple factors that are associated with disease progression. Various general measures have been described in the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines that address cardiovascular health and CKD together, or separately¹⁷.

Cardiovascular disease (CVD) risk factors can indirectly and directly impact CKD progression and so general lifestyle measures are recommended to improve¹⁷:

• cardiovascular health
• blood pressure (BP) control
• Interruption of the renin-angiotensin-aldosterone system (RAAS)

Metabolic parameters, such as blood sugar, uric acid, acidosis, and dyslipidaemia, are also recommended to monitor and control¹⁷.

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How do you manage diabetes and blood pressure in chronic kidney disease patients?

The Kidney Disease: Improving Global Outcomes (KDIGO) guideline for the management of blood pressure in CKD recommends a target systolic blood pressure for adults with high blood pressure and CKD of <120 mm Hg¹⁸. This can be achieved through the use of renin-angiotensin system inhibitors (RASi) for people with high blood pressure, CKD, and moderately-to-severely increased albuminuria with diabetes¹⁸.

The management of patients with type 2 diabetes (T2D) and CKD (Figure 1) should involve¹⁹:

• lifestyle therapy
• first-line treatment with metformin and a sodium-glucose cotransporter-2 (SGLT2) inhibitor
• additional drug therapy as needed for glycaemic control

Figure 1. Treatment algorithm for patients with type 2 diabetes and chronic kidney disease (Adapted¹⁹). Kidney icon indicates eGFR (mL/min/1.73 m²); dialysis machine icon indicates dialysis. CKD, chronic kidney disease; DPP-4, dipeptidyl peptidase-4; eGFR, estimated glomerular filtration rate; GLP-1, glucagon-like peptide-1; SGLT2, sodium-glucose cotransporter-2; TZD, thiazolidinedione.

The higher cardiovascular burden present in these patients also requires comprehensive management through lifestyle interventions that address the underlying comorbidities as well as appropriate pharmacotherapy depending on the severity and stage of the CKD²⁰.

What treatments are available for chronic kidney disease with comorbid blood pressure control, cardiovascular disease, or diabetes?

Professor Hiddo Heerspink points out that the ultimate treatment goal for chronic kidney disease is to slow down the loss of kidney function, a goal that is becoming more achievable with recent approvals for SGLT2 inhibitors and mineralocorticoid receptor antagonists.

Novel treatments for patients with CKD or comorbid CKD have been developed, or approved for clinical use, including²¹:

• Sodium-glucose cotransporter-2 (SGLT2) inhibitors
• Mineralocorticoid receptor antagonists (MRA)
• Glucagon-like peptide-1 receptor agonists (GLP-1 RA)
• Dipeptidyl peptidase-4 inhibitors (DPP4i)

Drugs within these classes have been examined through large clinical trials to evaluate the cardiovascular and kidney outcomes in patients with T2D, CKD, and comorbid CKD¹⁹. The results from these trials were used as the basis for recommendations made within the KDIGO guidelines for patients with T2D and CKD¹⁹.

People with CKD have high cardiovascular risk, with cardiovascular death the leading cause of death²².

Several new treatments to decrease the risk of cardiovascular diseases in CKD are in clinical development or have been already approved, such as SGLT2 inhibitors or mineralocorticoid receptor antagonists, giving hope that cardiovascular risk in patients with CKD may be modifiable²²

Currently, there is limited evidence on the use of specific antihypertensive agents to treat hypertension in CKD. In patients with CKD and high blood pressure, combination therapy with two or more antihypertensive drugs is recommended²³. Antihypertensive treatment algorithms in CKD are based on expert opinion, pathophysiologic or pharmacodynamic considerations, or extrapolated from research findings²³.

Renin-angiotensin system inhibitors (RASi) for diabetic kidney disease

RASi are recommended for patients with diabetes, hypertension, and albuminuria (albumin-creatinine ratio >30 mg/g)¹⁹. RASi slow the progression of CKD in patients with albuminuria and hypertension independent of their blood pressure effects²⁴. KDIGO consider RASi as foundational therapy for diabetic kidney disease (DKD)²⁵.

A network meta-analysis of 119 randomised trials (N = 64,768) of CKD patients, with or without diabetes and albuminuria, examined RASi for kidney and cardiovascular outcomes compared to other treatments and placebo²⁶.

The results showed that angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) both reduce the risk of kidney failure and major cardiovascular events. However, only ACEi reduced the risk of all-cause death compared to active control²⁶.

In CKD patients without diabetes and severely increased albuminuria, three phase 3 trials in the nineties also highlighted the potential cardiovascular benefits of RASi compared to placebo in addition to renal benefits^27–29:

• REIN 1 Phase 3 trial: 2-arm Ramipril Efficacy in Nephropathy Stratum-1
• REIN 2 Phase 3 trial: 3-arm Ramipril Efficacy in Nephropathy Stratum-2
• AIPRI Phase 3 trial: 2-arm Angiotensin-converting enzyme inhibition in progressive renal insufficiency

The early 2000’s also saw two phase 3 studies that demonstrated a beneficial effect of RASi independent of blood pressure control, in CKD compared to placebo^30,31:

• IDNT Phase 3 trial: 3-arm Irbesartan Diabetic Nephropathy Trial
• RENAAL Phase 3 trial: 2-arm Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan Study

Metformin for diabetes

Since its approval in the nineties, metformin has been prescribed for the management of T2D for over 20 years³². While prescribing metformin, the eGFR should be monitored and the dose reduced when the rate is less than 45 mL/min/1.73 m² or withdrawn when eGFR drops to <30 mL/min/1.73 m² or kidney failure develops¹⁹.

Currently, treatment with metformin and a SGLT2 inhibitor is recommended in most patients with an eGFR of ≥30 mL/min/1.73 m², diabetes, and CKD¹⁹

Metformin may increase risk for lactic acidosis and vitamin B12 deficiency; therefore, monitoring of levels is recommended with long-term use³³. When these drugs are not well tolerated or are insufficient to attain glycaemic goals, additional drugs can be considered based on various factors, such as patient preferences, comorbidities, eGFR, and costs (Figure 2)¹⁹.

Figure 2. Patient factors influencing selection of glucose-lowering drugs other than SGLT2 inhibitors and metformin in type 2 diabetes and CKD (Adapted¹⁹). AGI, alpha-glucosidase inhibitor; ASCVD, atherosclerotic cardiovascular disease; DPP4i, dipeptidyl peptidase-4 inhibitor; eGFR, estimated glomerular filtration rate; GLP1RA, glucagon-like peptide-1 receptor agonist; SU, sulfonylurea; TZD, thiazolidinedione.

GLP-1 RAs are notably recommended as additional agents due to their beneficial effects in reducing cardiovascular events as well as their potential to prevent macroalbuminuria or a reduction in eGFR decline¹⁹.

Mineralocorticoid receptor antagonists for diabetic kidney disease

The mineralocorticoid receptor antagonist finerenone is indicated by the US Food and Drugs Administration (USFDA) to reduce the risk of sustained eGFR decline, end-stage kidney disease (ESKD), cardiovascular death, non-fatal myocardial infarction, and hospitalisation for heart failure (HF), in adult patients with CKD associated with type 2 diabetes^34,35.

In the phase II ARTS trial (Arterial Revascularization Therapies Study) with >450 patients with CKD and congestive heart failure (HF), the mineralocorticoid receptor antagonist (MRA) finerenone reduced the urinary albumin-creatinine ratio and NT-proBNP (N-terminal pro-BNP) as much as spironolactone, with significantly lower rates of deteriorating kidney function and hyperkalemia³⁶.

In the phase III trials FIDELIO-DKD (Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease) and FIGARO-DKD (Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease), >13 000 T2D patients with CKD were evaluated to determine whether finerenone can reduce cardiovascular morbidity and mortality or prevent progression of kidney disease^37,38.

In FIDELIO-DKD, during a median follow-up of 2.6 years, a primary outcome event (kidney failure, a sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes) occurred in 504 of 2,833 patients (17.8%) in the finerenone group and 600 of 2,841 patients (21.1%) in the placebo group (HR 0.82; 95% CI, 0.73–0.93; P=0.001). A key secondary outcome event (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalisation for HF) occurred in 367 patients (13.0%) in the finerenone group, and 420 patients (14.8%) in the placebo group (HR 0.86; 95% CI, 0.75–0.99; P=0.03)³⁷.

In FIGARO-DKD, among the patients included in the analysis, during a median follow-up of 3.4 years, a primary outcome event occurred in 458 of 3,686 patients (12.4%) in the finerenone group, and in 519 of 3,666 (14.2%) in the placebo group (HR 0.87; 95% CI, 0.76–0.98; P=0.03), with the benefit driven by a lower incidence of hospitalisation for HF (HR 0.71; 95% CI, 0.56–0.90). The secondary composite outcome (kidney failure, a sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes) occurred in 350 patients (9.5%) in the finerenone group, and in 395 (10.8%) in the placebo group (HR 0.87; 95% CI, 0.76–1.01)³⁸.

As FIDELIO-DKD and FIGARO-DKD show, in patients with CKD and T2D, finerenone therapy can provide cardiorenal protection, compared with placebo^37,38

SGLT2 inhibitors for chronic kidney disease and diabetic kidney disease

In patients with diabetes and CKD, SGLT2 inhibitors have been investigated in various trials for the treatment of diabetes in CKD (Table 1)^39-42. Three SGLT2 inhibitors canagliflozin, dapagliflozin, and empagliflozin, have been approved by the USFDA and EMA, are recommended by the KDIGO guidelines for the treatment of hyperglycaemia in T2D, and as foundational therapy in diabetic kidney disease (DKD)^19,25,43. In an important regulatory shift, some SGLT2 inhibitors are no longer indicated as therapy only for comorbid CKD; they have been approved for treating CKD itself^44–46.

Canagliflozin

Canagliflozin is USFDA and EMA indicated to reduce the risk of ESKD, doubling of serum creatinine, cardiovascular death, and hospitalisation for heart failure in adults with T2D, and diabetic nephropathy with albuminuria^47,48.

The CANVAS programme (Table 1) comprised two double-blind, randomised trials (CANVAS and CANVAS-R) that aimed to evaluate the long-term renal effects of canagliflozin⁴⁰. In the CANVAS study (N = 4,330), patients with T2D were randomised 1:1:1 to receive 300 mg canagliflozin, 100 mg canagliflozin, or placebo⁴⁹. Similarly, CANVAS-R (N = 5,812) patients were randomised 1:1 to receive canagliflozin 100 mg or a matching placebo⁴⁹.

Sustained doubling of serum creatinine, ESKD, and death from renal causes occurred less frequently in the canagliflozin group, compared with the placebo group (HR 0.53; 95% CI, 0.33–0.84; P heterogeneity = 0.21 and >0.50, respectively) in the overall CANVAS programme population^40,50.

In the more recent CREDENCE study (N = 4,401), the first study of an SGLT2 inhibitor with a combined renal end-point as a primary outcome, patients with T2D, CKD, and albuminuria were randomised to receive canagliflozin (100 mg/day) or placebo⁴¹.

The CREDENCE study was prematurely ended after a planned interim analysis due to the clear benefit of canagliflozin compared to placebo⁴¹

The results of the CREDENCE trial showed that the relative risk of the renal-specific composite of ESKD, a doubling of the creatinine level, or death from renal causes was lower by 34% (HR 0.66; 95% CI, 0.53–0.81; P<0.001), and the relative risk of ERSD was lower by 32% (HR 0.68, 95%, CI 0.54–0.86; P = 0.002)⁴¹.

Table 1. Overview of selected large, placebo-controlled clinical outcome trials assessing the benefits and adverse effects of SGLT2i in chronic kidney disease (Adapted^51,25). ACR, albumin-creatinine ratio; DKA, diabetic ketoacidosis; eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate; GMI, genital mycotic infections; MACE, major adverse cardiovascular events; NA, data not published. ↔, no significant difference; ↓, significant reduction in risk [hazard ratio (HR) estimate >0.7 and 95% confidence interval (CI) not overlapping 1]; ↓↓, significant reduction in risk [HR estimate ≤0.7 and 95% CI not overlapping 1].

Dapagliflozin

Dapagliflozin is USFDA indicated to reduce the risk of sustained eGFR decline, ESKD, cardiovascular death, and hospitalisation for HF in adults with CKD at risk of progression⁴⁵. It became the first SGLT2 inhibitor to receive approval by the EMA for the treatment of adults with CKD, with or without diabetes⁴⁴. 

DECLARE-TIMI 58 (Table 1) was a randomised, double-blind, multi-national phase III trial that studied the effects of dapagliflozin on hard renal outcomes⁴².

In T2D patients at risk for atherosclerotic cardiovascular disease, dapagliflozin resulted in a lower rate of cardiovascular death or hospitalization for heart failure⁴²

The results from the trial showed that dapagliflozin met the prespecified criterion for non-inferiority to placebo in terms of major adverse cardiovascular events (P<0.001)⁴².

The two primary efficacy analyses showed that, while dapagliflozin did not produce a lower rate of major adverse cardiovascular events (defined as cardiovascular death, myocardial infarction, or ischemic stroke) compared to placebo (8.8% vs 9.4%; HR 0.93; 95% CI, 0.84–1.03; P=0.17), dapagliflozin resulted in a lower rate of cardiovascular death or hospitalisation for heart failure (4.9% vs 5.8%; HR 0.83; 95% CI, 0.73–0.95; P=0.005)⁴².

In the more recent Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial, the long-term efficacy and safety of dapagliflozin in patients with chronic kidney disease, with or without T2D, was assessed⁵¹.

The primary outcome was a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes⁵¹.

It was found that, over a median of 2.4 years, CKD patients receiving dapagliflozin had a significantly lower risk of experiencing a primary outcome event than patients receiving placebo (9.2% vs 14.5%; HR 0.61; 95% CI, 0.51–0.72; P<0.001)⁵¹. Moreover, death occurred in fewer patients receiving dapagliflozin than patients receiving placebo (4.7% vs 6.8%; HR 0.69; 95% CI, 0.53 to 0.88; P=0.004)⁵¹.

 Empagliflozin

Empagliflozin is USFDA and EMA indicated to reduce the risk of cardiovascular death in adults with T2D, and to reduce the risk of cardiovascular death and hospitalisation for HF and reduced ejection fraction^52,53.

The EMPA-REG OUTCOME study (N = 7,020) randomised patients with T2D to 10 or 25 mg of empagliflozin compared to placebo (Table 1). Of these patients, 5,665 were also receiving treatment with an ACEi or an ARB³⁹. 

In T2D patients at high cardiovascular risk, empagliflozin is associated with slower kidney disease progression and lower rates of renal events than placebo when added to standard care³⁹

The results showed that patients treated with empagliflozin had a reduced incidence in the combined endpoint of progression to macroalbuminuria, renal replacement therapy initiation or death from renal disease (HR [Hazard Ratio] 0.61; 95% CI, 0.53–0.70; P<0.001) compared to placebo³⁹.

Patients in the intervention treatment arm also had lower rates of a post-hoc defined renal composite outcomes: initiation of renal replacement therapy, doubling of serum creatinine, or death from renal disease (HR 0.54; 95% CI, 0.40–0.75; P<0.001)³⁹.

The EMPA-KIDNEY study, a double-blind, randomised, placebo-controlled trial, evaluated the efficacy and safety of empagliflozin in patients with CKD with or without diabetes. The trial, in which more than 6,600 patients were recruited, was stopped early, in March 2022, after an interim analysis of the results showed a clear benefit for patients with CKD⁵⁴. Publication of the full results is pending.

Glucagon-like peptide 1 receptor agonists (GLP-1 RA) for diabetic kidney disease

A number of trials have investigated glucagon-like peptide 1 receptor agonists (GLP-1 RA) for the treatment of diabetes in chronic kidney disease (Table 2)²⁵.

GLP-1 receptor agonists and DPP-4 inhibitors are beneficial for managing patients with T2D across a range of haemoglobin A1C (HbA1c) levels; separately and in addition to glucose lowering therapies⁵⁵. Overall, GLP-1 receptor agonists are preferred over DPP-4 inhibitors due to a greater reduction in HbA1c and clinically significant weight loss⁵⁵.

Liraglutide and semaglutide

In the randomised, placebo-controlled Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial (N = 9,350) and Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) preapproval trial (N = 3,297), the effect of liraglutide and semaglutide on composite renal outcomes was assessed (Table 2)^56,57:

• Overt albuminuria development
• Serum creatinine doubling and eGFR <45 mL/min/1.73 m²
• Renal replacement therapy
• Kidney disease-related death

Composite renal outcomes were decreased in the GLP-1 receptor agonist treatment group compared to placebo (LEADER: HR 0.88; 95% CI, 0.81–0.96; P=0.005 and SUSTAIN-6: HR 0.74; 95% CI, 0.62–0.89; P=0.002)^56,57.

Table 2. Overview of selected large, placebo-controlled clinical outcome trials assessing the benefits and adverse effects of GLP-1 RA in chronic kidney disease (Adapted²⁵). eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate; GI, gastrointestinal symptoms; MACE, major adverse cardiovascular events; NA, data not published. ↔, no significant difference; ↓, significant reduction in risk [hazard ratio (HR) estimate >0.7 and 95% confidence interval (CI) not overlapping 1]; ↓↓, significant reduction in risk [HR estimate ≤0.7 and 95% CI not overlapping 1].

Exenatide and lixisenatide

In the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) study (N = 14,752), there was no significant difference (P=0.39) in eGFR levels between exenatide and placebo (Table 2). New macroalbuminuria was observed in 2.2% and 2.5% of the exenatide and placebo groups, respectively (P=0.19). The renal composite outcome (composite of 40% eGFR decline, renal replacement and renal death) was also not significantly different between the groups (HR 0.88, 95% CI, 0.74­–1.05; P=0.164)⁵⁸.

In the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial (N = 6,068), patients on lixisenatide were approximately 19% less likely to develop new-onset macroalbuminuria (HR 0.808; 95% CI, 0.660­–0.991; P=0.0404). No differences were observed in normoalbuminuria progression to macroalbuminuria or in the proportion of macroalbuminuria showing regression to micro-/normoalbuminuria (Table 2)⁵⁹.

Dipeptidyl peptidase-4 inhibitors (DPP-4i) for diabetes

DPP-4 inhibitors, also known as gliptins, have been shown to have a low hypoglycaemic risk and weight-neutral effects. Moreover, saxagliptin, sitagliptin, alogliptin, and linagliptin have had their cardiovascular safety assessed in a number of randomised clinical trials²⁵.

However, while DPP-4 inhibitors have displayed satisfactory cardiovascular safety, the results of their renal outcomes have been conflicting (Table 3)^25,60.

Saxagliptin

In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial (N = 16,492), patients were randomised to saxagliptin or placebo (Table 3)⁶¹.

Compared to placebo, saxagliptin was more likely to improve the urine albumin-to-creatinine ratio (UACR) (10.7% vs 8.7%, P<0.001), and less likely to have a worsening UACR (13.3% vs 15.9%, P<0.001) at the end of treatment. Moreover, the difference in mean UAC between groups was –3.88 mg/mmol (P<0.004) at 2 years. However, the eGFR change from baseline was similar between groups, and there was no benefit or harm seen in hard renal outcomes⁶¹.

Alogliptin

In the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial (N = 5,380) the primary end-point of a death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke composite was met in 11.3% patients receiving alogliptin (HR 0.96; P<0.001 for non-inferiority). Glycated haemoglobin levels were significantly lower with alogliptin than placebo (−0.36; P<0.001). Incidences of hypoglycaemia, cancer, pancreatitis, and initiation of dialysis were similar between groups (Table 3)⁶².

Table 3. Overview of selected large, placebo-controlled clinical outcome trials assessing the benefits and adverse effects of DPP-4i in chronic kidney disease (Adapted²⁵). eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate; HF, heart failure hospitalisation; MACE, major adverse cardiovascular events; NA, data not published. ↔, no significant difference; ↓, significant reduction in risk [hazard ratio (HR) estimate >0.7 and 95% confidence interval (CI) not overlapping 1]; ↓↓, significant reduction in risk [HR estimate ≤0.7 and 95% CI not overlapping 1].

Sitagliptin

In the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) study (N = 14,671) median UACR levels at 4 years were lower with sitagliptin than placebo, with a mean difference of –0.02 mg/mmol (P=0.031). Mean eGFR was lower with sitagliptin compared to placebo with a difference of –1.34 ml/min/1.73 m² (P<0.001). Incidence rates of microalbuminuria and renal failure were similar between sitagliptin and placebo (Table 3)⁶³.

Linagliptin

The Cardiovascular and Renal Microvascular Outcome (CARMELINA) study (N = 6,991) had a higher proportion of participants (74%) with chronic kidney disease (Table 3)⁶⁴.

The progression of albuminuria was 14% less likely with linagliptin compared to placebo (HR 0.86; 95% CI, 0.78–0.95; P=0.003). The hard renal outcomes were similar in the linagliptin and the placebo arms (9.4% vs 8.8%; HR 1.04; 95% CI, 0.89–1.22; P=0.62)⁶⁴.

When does kidney replacement therapy become necessary?

When ESRD is reached, either renal replacement therapy or conservative treatment will be needed. It is therefore important that early counselling is provided, by a nephrologist and a multidisciplinary team, on the available options:

• Kidney transplant
• Haemodialysis
• Peritoneal dialysis
• No dialysis

Early counselling is essential to prepare patients for kidney failure, while late referral is associated with a⁶⁵:

• worse health status at the initiation of kidney replacement therapy
• higher mortality after starting dialysis
• reduced access to transplant

Timely decision making can however be hampered by the unpredictability of CKD progression^65,66. As CKD may not follow a steady linear decline, early pre­dialysis nephrology care for adults with late-stage CKD may be impacted and lead to compromised outcomes⁶⁷.

The KDIGO guidelines recommend the initiation of dialysis when symptoms or signs of kidney failure are evident². Prior to the initiation of dialysis, pre­emptive renal transplantation should be considered in patients with a GFR of <20 ml/min/1.73 m² as well as evidence of CKD progression in the preceding 6–12 months².

How do you control CKD-related complications?

A number of secondary complications are associated with CKD; in terms of overall mortality, the most notable of these complications is cardiovascular disease (CVD)⁶⁸.

Guidelines, on the basis of diabetic status, aim to achieve target blood pressure through the use of RAS blockers, restricting salt intake, and preventing anaemia^18,69

There have been a range of large randomised controlled trials of patients on haemodialysis that have assessed a range of interventions that specifically aim to reduce cardiovascular events; however, these were mostly unsuccessful^70–72:

• Frequency and length of dialysis sessions and flux
• Erythropoietin stimulating agents
• Statins
• RAS blockade
• Folic acid
• Cinacalcet
• Vitamin D derivatives

How do you prepare patients for haemodialysis for ESRD?

An important step in preparing patients for haemodialysis is the referral for vascular access placement due to the need for pumps, membranes, and dialysates to clear uraemic toxins from the blood¹. Access can be gained through a variety of methods including¹:

• arteriovenous fistulae
• arteriovenous grafts
• central venous catheters (short-term use)

Of these methods, arteriovenous access is the preferred option for haemodialysis as it is, in addition to conversion from central venous catheter to arteriovenous access, associated with better outcomes than central venous catheters^73–75. As a result, it is necessary to avoid venous puncture or intravenous catheter placement proximal to the wrist so that permanent vascular access is not inhibited¹.

What is peritoneal dialysis for ESRD?

Clearing uraemic toxins from the blood can also be carried out by using peritoneal dialysis, a procedure that utilises the peritoneal membrane as an exchange interface. The procedure requires a transcutaneous catheter to be implanted into the peritoneal cavity to allow daily draining and refilling with dialysate fluid. Once equilibrium between uraemic blood and fresh dialysate is established, each dwell can drain excess fluid and metabolic waste products¹.

In the first two years of dialysis, peritoneal dialysis shows improved outcomes and preservation of residual renal function compared to haemodialysis; however, differences in outcomes and preservation normalise after two years⁷⁶.

What are the outcomes of kidney transplantation?

As kidney transplantation can produce superior outcomes to dialysis as a treatment for ESRD, it can be considered an essential component of an integrated treatment and management plan for CKD⁷⁷. Pre-emptive transplantation may also be beneficial in patients with ESRD⁷⁸.

In addition to age, the decision to perform a kidney transplantation is informed by the presence of comorbidities⁷⁹, such as cancer, chronic infections, cardiac or peripheral vascular disease, and the risk of medical noncompliance¹.

The half-life of a transplanted kidney is <20 years; patients will therefore likely continue needing CKD treatments during their life⁸⁰

A number of complications can also occur following transplantation, such as recurrent glomerulonephritis; an unpredictable complication that can impact graft outcome⁸¹.

Rigorous testing is therefore required to improve the short-term and long-term health of the donor¹. Eligibility of potential donors is assessed through a comprehensive health assessment that includes¹:

• blood group and human leukocyte antigen compatibility tests
• GFR measures
• imaging of the kidneys and the urinary tract
• cardiac testing
• specific tests informed by the medical history

When kidney replacement therapy is not an option, such as in cases of older patients with ESRD and comorbidities, dialysis may not increase lifespan or improve quality of life^82–84. In these cases, palliative care aims to control the symptoms of uraemia that may impact quality of life⁸⁵. Moreover, education should be provided to explain comorbidity management that may be needed or to discuss the decision to withdraw from dialysis⁸⁶.

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Incretin-based treatments

While there is controversy with regards to the reduction of the GFR decrease, previous randomised control trials have established that incretin-based drugs can reduce albuminuria of diabetic kidney disease patients⁸⁹.

Notably, albuminuria is associated with the GFR decrease in diabetic kidney disease and as a consequence, incretin-based drugs are likely to be effective. Moreover, incretin-based treatments are used currently as hypoglycaemic agents in diabetic patients⁸⁹.

NF-E2–related factor 2 activators (Nrf2 activators)

Currently recommended treatments, such as RAS inhibitors and SGLT2 inhibitors, only slow GFR decline⁸⁹. This has led to a heightened interest in NF-E2-related factor 2 (Nrf2) activators; a novel drug class that has the potential to improve the GFR of diabetic kidney disease patients⁹⁰.

Notably, the phase III multicentre, placebo-controlled Bardoxolone Methyl in Patients with Diabetic Kidney Disease (AYAME) trial is currently ongoing in Japan (Figure 3). Similar to the previous TSUBAKI study, this study will assess the efficacy of bardoxolone methyl for diabetic kidney disease patients with the aim of elucidating any renoprotective effects⁸⁹.

Figure 3. Clinical trials for incretin-based drugs, Nrf2 activators, AGE inhibitors, HIF-PH inhibitors, and epigenetic regulators (Adapted⁸⁹). AGE, advanced glycation end product; HIF-PH, hypoxia-inducible factor prolyl hydroxylase inhibitor; NrF2, NF-E2–related factor 2; PYR, pyridoxamine.

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PH)

Irreversible kidney damage can occur following a continued progression of CKD past a certain point. It is believed that a vicious cycle of tubular interstitial hypoxia is a common pathway for this progression⁹¹.

A novel treatment class that is currently being investigated are HIF prolyl hydroxylase (HIF-PH) inhibitors that inhibit HIF-α degradation by suppressing HIF-PH (Figure 3). HIF-PH is responsible for the oxygen-dependent degradation, stabilising of expression, and activation of HIF; a key transcription factor in the response to hypoxia⁹².

HIF-PH inhibitors have already been approved for renal anaemia in CKD patients not yet on dialysis. Future clinical trials will be needed to assess the efficacy of HIF-PH inhibitors as a CKD treatment⁸⁹.

Advanced glycation end product inhibitors (AGE inhibitors)

Advanced glycation end product (AGE) is produced through non-enzymatic protein and nucleic acid glycation as a result of high blood sugar and oxidative stress⁹³. As it accumulates it can cause damage to various organs and is associated with diabetic kidney disease progression^94,95.

Clinical trials have previously been carried out to assess AGE inhibitors; however, their efficacy is controversial (Figure 3)⁸⁹. A number of trials failed to show that AGE inhibitors are effective in treating diabetic kidney disease. Despite this, AGE inhibitors are still drawing attention due to the involvement of AGE accumulation in metabolic memory⁸⁹.

Epigenetic regulators

Epigenetics is a DNA sequence-independent regulatory mechanism of gene expression, involving⁸⁹:

• DNA methylation
• histone modification
• non-coding RNA

Epigenetic changes caused by specific factors, such as hyperglycaemia or hypoxia, can be stored as cellular memory and may lead to irreversible renal damage⁹⁶. For this reason, histone modification inhibitors have garnered attention as a novel treatment for these epigenetic changes (Figure 3).

The histone deacetylase inhibitors, such as vorinostat, valproate, sodium butyrate, and trichostatin, have been shown to reduce proteinuria and improve oxidative stress, fibrosis, glomerular damage, and inflammation in murine models^97–101.

If the epigenetic changes in CKD are elucidated, this may increase the therapeutic options that can reverse CKD progression for CKD patients whose disease has progressed irreversibly past a certain point¹⁰².