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Chronic Kidney Disease Learning Zone

Treating CKD

Read time: 130 mins
Last updated:26th Apr 2022
Published:22nd Oct 2021

Find out about the treatments for chronic kidney disease (CKD) and its comorbidities and explore:

  • Goals for the treatment of CKD in our expert videos with Professor Hiddo Heerspink, Professor Vlado Perkovic and Dr George Bakris
  • Strategies for managing comorbid conditions and end-stage kidney disease (ESKD)
  • CKD treatments just over the horizon and links to CKD guideline resources
  • CKD patient case study quizzes to test your understanding

Treatment goals for chronic kidney disease

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 priorities for treatment optimisation in chronic kidney disease?

3

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 to2,3:

  • 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 complications2,3. Recommendations based on disease stage are cumulative: early-stage recommendations are included within late-stage recommendations2,3.

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)
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Managing chronic kidney disease comorbid conditions

Professor Hiddo Heerspink details the key findings from the DAPA-CKD and FIDELIO-DKD clinical trials for non-diabetic chronic kidney disease and diabetic kidney disease.

CKD patients can have multiple comorbid conditions, including diabetes, hypertension, and cardiovascular disease (CVD); high risks of developing hypoglycaemia and adverse drug reactions, multiple life demands, and psychosocial factors that influence behaviours and clinical outcomes. As a result, appropriate treatments are needed to reduce symptoms and minimise the impact on quality of life18,19.

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

T3 CKD_Fig1_T3 CKD_Fig1.png

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?

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

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Managing end-stage kidney disease

Dr George Bakris discusses the main clinical challenges for preventing progression of chronic kidney disease.

End-stage kidney disease (ESKD), also known as end-stage renal disease (ESRD), occurs when chronic kidney disease reaches an advanced state and the kidneys are no longer able to meet the body's needs. As a result, various management strategies exist to manage comorbid conditions and minimise the burden on the patient.

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 progression65,66. 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 anaemia18,69

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 unsuccessful70–72:

  • 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 catheters73–75. 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 life82–84. 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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Chronic kidney disease treatment guidelines


Professor Vlado Perkovic outlines the recommendations for treating chronic kidney disease and drugs most recently approved that can preserve kidney function.

Explore the recommendations and available data for the diagnosis, management, and treatment of chronic kidney disease (CKD). Read the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines on CKD evaluation and management as well as the management of diabetes and blood pressure in patients with CKD. Also find published guidelines from the National Institute for Health care and Excellence (NICE) and the American College of Physicians (ACP).

Kidney Disease: Improving Global Outcomes (KDIGO)

Originally established by the National Kidney Foundation, KDIGO is a global organisation for developing and implementing evidence based clinical practice guidelines in kidney disease.

KDIGO guidelines focus on topics related to kidney disease prevention and management of individuals with kidney diseases

Kidney Disease: Improving Global Outcomes guidelines

The criteria used in the guidelines to prioritise topics include:

  • burden of illness based on prevalence and scope of the condition or clinical problem
  • amenability of a particular condition to prevention or treatment and expected impact
  • existence of a body of evidence of sufficient breadth and depth to enable the development of evidence-based guidelines
  • potential of guidelines to reduce variations in practices, improve health outcomes, or lower treatment costs

KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of CKD

After a decade of innovative research, the KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of CKD updated the 2002 Kidney Disease Outcomes Quality Initiative (KDOQI) clinical practice guidelines for CKD87.

The guideline aims to give up to date guidance on the evaluation, management, and treatment of CKD patients. Specifically providing:

  • an enhanced classification framework for CKD
  • elaboration on the identification and prognosis of CKD
  • guidance on the management of progression and complications of CKD

The updated guideline also further develops the range of CKD care from the timings of specialist referral and dialysis initiation to ongoing management of progressive CKD and implementing a comprehensive treatment programme.

KDIGO guidelines for the Evaluation and Management of CKD

The guideline explores treatment approaches and recommendations based on systematic reviews of relevant clinical trials. It also provides practical comments and statements with important information for healthcare professionals; however, these are ungraded.

The quality of the evidence used in these guidelines, and the strength of recommendations, were appraised though the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Controversies, limitations, and international relevance are provided for discussion as well as suggestions for future research.

KDIGO 2020 Clinical Practice Guideline for Diabetes Management in CKD

The KDIGO 2020 Clinical Practice Guideline for Diabetes Management in CKD is the first KDIGO guideline specifically for diabetes management in CKD and includes topics such as:

  • comprehensive care
  • glycaemic monitoring and targets
  • lifestyle and antihyperglycemic interventions
  • approaches to self-management
  • optimal models of care
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Future chronic kidney disease treatments

What is over the horizon? Dr George Bakris describes the range of current and future treatments and management strategies that may change the future of CKD care.

Key areas in the development of novel CKD treatments are arising due to a growing understanding of causes and consequences of CKD and the development and testing of new therapeutic strategies88. Currently, multiple investigational strategies are under investigation for the management of CKD.

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.

T3 CKD_Fig3.png

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 progression94,95.

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 models97–101.

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.

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