Congress highlights

Congress highlights with Professor Navdeep Tangri

Watch our expert Professor Navdeep Tangri discuss research highlights from the 2022 ERA Congress. Professor Tangri focuses on the latest updates to ongoing CKD clinical trials (such as DAPA-CKD and REVEAL-CKD), the status of SGLT2 inhibitors and MRAs, as well as new research on the overlap between cardiovascular disease and type 2 diabetes in patients with CKD.

Congress Highlights with Professor Hiddo Heerspink

Watch Professor Hiddo Heerspink discuss research highlights from the 2022 ERA Congress.

Day One Highlights – CKD diagnosis and treatment from the mini-oral sessions

By Ben Gallarda

Key chronic kidney disease developments from the mini-oral sessions

The European Renal Association (ERA) 2022 Congress began with a good number of virtual mini-oral sessions and abstracts, discussing a wide range of topics in brief online presentations. In this article, we bring you some of the key developments in chronic kidney disease (CKD) from these mini-oral sessions.

Diagnosing CKD

In a mini-oral session on lab methods, glomerular filtration rate (GFR) measurement and urine proteomics, a good part of the discussion focused on detecting CKD earlier, particularly with albuminuria testing (Figure 1). Antonio Garreta Rufas presented the results of a systematic review examining barriers that may prevent adherence to Kidney Disease Improving Global Outcomes (KDIGO) guidelines for albuminuria testing¹. One of the main identified barriers was physicians’ perception that test results would not materially impact patient care. Dr Garreta Rufas concluded his presentation noting that “testing of albuminuria rates are low, and we need to improve,” along with suggestions for several ways to achieve this. These results were supported by a separate modelling study, which showed that regular urine albumin-to-creatinine ratio (UACR) testing is both cost-effective and likely to prevent more severe outcomes of CKD, including late stage disease, dialysis, and cardiovascular disease (CVD)-related deaths (Figure 1)².

Simple and cost-effective methods exist for early detection of CKD, but are often under-utilised

Another study presented by Emilio Rodrigo asked whether routine urine analysis is appropriate for people with monoclonal gammopathy of undetermined significance (MGUS), a condition that increases in prevalence with age that may correlate with monoclonal gammopathy of renal significance (MGRS), a sign of renal damage³. Retrospective analysis of 360 patients showed that only 32% of patients with MGUS received proteinuria analysis, but that those with albuminuria or haemoglobinuria showed worse GFR. The authors conclude by recommending regular urine analysis of patient with MGUS in order to assess the potential presence of kidney damage.

Figure 1. Key highlights from the mini-oral sessions (Adapted^1,2,10). CrCl, creatinine clearance; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; KDIGO, Kidney Disease Improving Global Outcomes; QALY, quality-adjusted life-year; SGLT2, sodium-glucose cotransporter-2; UACR, urine albumin-to-creatinine ratio.

Treating CKD

In keeping with major developments in CKD treatment in previous years, data on several sodium-glucose cotransporter 2 (SGLT2) inhibitors and a mineralocorticoid receptor antagonist were highlighted in various mini oral sessions:

• Addition of 10 mg empagliflozin daily in 30 non-diabetic patients with proteinuria significantly reduced proteinuria and blood pressure, but did not change serum creatinine levels or GFR⁴
• Subgroup analysis from phase 3 trials of finerenone in patients with CKD and type 2 diabetes (T2D) showed that overall positive results related to changes in UACR, estimated GFR (eGFR), and composite kidney and CV outcomes was as prominent in stage 4 CKD as in stages 1–3, with no difference in adverse events between the subgroups⁵
• A small, real-world study of dapagliflozin in 9 diabetic patients and 1 non-diabetic patient also receiving angiotensin-receptor blockers or angiotensin-converting enzyme inhibitors showed a preservation of kidney function and reduction in proteinuria with no documented major kidney side effects⁶

Promising treatments for CKD, in patients both with and without diabetes, are showing benefits in clinical trials

While SGLT2 inhibitors are showing benefits in preserving kidney function in patients withT2D, it has been documented that some patients receiving an SGTL2 inhibitor may initially see an acute decline in eGFR^7-9. While this effect is typically reversible, it has the potential to affect adherence to treatment and resulting outcomes. Constanza Gaudio discussed a study examining this effect of SGLT2 inhibitor treatment in relation to high sodium and high protein intake, and measured creatinine clearance as a method to assess the extent of this eGFR dip (Figure 1)¹⁰. This study found significant correlations between high sodium and protein intake and a 6% reduction in eGFR with treatment, which were also associated with a 19% reduction in mean creatinine clearance (n = 27). Dr Gaudio concluded by noting, “A higher dietary sodium and protein intake may amplify the extent of early dip in glomerular filtration rate in diabetic patients undergoing SGLT2 inhibitor treatment,” and “measured creatinine clearance is a very sensitive method to detect this.”

One final study presented by Maria Marques Vidas looked at the safety profile of SGLT2 inhibitors in patients 75 years of age or older (75+, n = 33) and found no increase in the rate of side effects when compared to younger patients (<75, n = 120). The most common side effect in both groups was genitourinary tracts infections in 10.3% of all patients, which were more common in the first year of treatment¹¹.

Day Two Highlights – From late-breaking trials to CKD classification

By Anita Reid

Late-breaking clinical trials

Several late-breaking clinical summaries were revealed on the second day of the European Renal Association (ERA) 2022 Congress.

Patrick Rossignol reported that “all endpoints were statistically and convincingly” met in the DIAMOND Trial¹² investigating patiromer, a novel K+ binder, in patients with comorbid heart failure (HF) with reduced ejection fraction and chronic kidney disease (CKD), and in whom hyperkalaemia leads to compromised treatment with renin-angiotensin-aldosterone system inhibitors (RAASi)¹³. Patiromer maintained lower serum K+ levels vs placebo across all CKD subgroups and resulted in a lower incidence of hyperkalaemic events, as well as a greater proportion of patients being maintained on a mineralocorticoid receptor antagonist (MRA) at target doses vs placebo across all CKD groups.

K+ binder, patiromer, reduces incidence of hyperkalaemic events in CKD with HF

The tubular stress biomarker, urinary dickkopf-3 (uDKK3), is a predictor of acute kidney injury (AKI) risk and chronic kidney disease (CKD) progression in adults^14-16. According to Franz Schaefer and colleagues’ post-hoc analysis of the 4CS¹⁷ and ESCAPE trials¹⁸, higher levels of uDKK3 were associated with faster loss of estimated glomerular filtration rate (eGFR) in paediatric CKD. This was independent of underlying disease, age, baseline eGFR, proteinuria, hypertension and obesity. It was only in patients with high uDKK3 levels that RAAS inhibition and intensified blood pressure control were associated with reduced eGFR loss. “UDKK3 is a promising new biomarker that may be useful in predicting responsiveness to nephroprotective therapies and designing risk-adapted personalised medicine,” said Dr Schaefer.

Classification of CKD

The classification of CKD continues to be challenged; however a study by the UK Biobank cautions against age-related thresholds for CKD diagnosis in older people¹⁹.

Do age-related thresholds overlook the risk of CV disease associated with CKD?

Age-related thresholds have been proposed for CKD diagnosis²⁰ to reflect the normal age-related decline in renal function over the age of 40 years, by raising the existing threshold for CKD under 40 years and reducing it over 65 years¹⁹. However, as Jennifer Lees pointed out: “The primary risk associated with CKD is cardiovascular (CV) disease; lowering the threshold may miss this risk in this [elderly] group”. Dr Lees was reporting a UK Biobank study that showed cystatin C testing for eGFR (eGFRcys) detected a substantial number of high-risk individuals not identified as having CKD by creatinine testing (eGFRcr). Lower, age-adapted thresholds for CKD diagnosis, may therefore be inadequate at detecting broader risks associated with CKD in older people.

Progression in diabetic kidney disease

A symposium on diabetic kidney disease (DKD) included progress in the early detection of DKD and new emerging treatments.

In the first presentation, Gove Spasovski reviewed progress in earlier (molecular) detection of DKD with proteonomics, including the prediction of microalbuminuria and eGFR decline in the clinical trial, PRIORITY^{21, 22}. Disappointingly, subsequent early intervention with aldosterone blocker, spirolactone, did not delay progression of early diabetic nephropathy vs placebo²³. Dr Spasovski also reviewed guidance on treatment recommendations in DKD:

• Use SGLT2 inhibitors whenever possible in type 2 diabetes (T2D) (eGFR > 30 ml/min/1.73 m²) to reduce the risk of CKD and cardiorenal outcomes, as shown in CREDENCE and other studies, including a meta-analysis^24-26. In addition, SLGT-2 inhibitors have protective effects beyond glycaemic control for the kidneys, heart and other organs27, including antioxidative effects²⁸
• Use GLP-1 receptor agonists in advanced CKD (eGFR <30 ml/min/1.73m²) and HF, as shown by a systematic review and meta-analysis of CV outcome trials²⁹
• Add a MRA (finerenone) to standard care in CKD with HF: in the FIDELIO-DKD study, finerenone vs placebo protected against CV events and kidney disease progression in patients with T2D and early- or late-stage CKD, irrespective of baseline HF³⁰.

SGLT2 inhibitors should be used whenever possible in T2D to reduce the risk of CKD and negative cardiorenal outcomes

Is AKI preventable in CKD? Arici Mustafa explored this question by first highlighting that CKD is the leading cause of AKI, and that AKI directly exacerbates CKD progression³¹. Interrupting this cycle is therefore of clinical significance. While the use of the nephrology rapid response team (NRRT) has proven to be effective in preventing AKI³², novel strategies are still under investigation. One such strategy is the use of automated e-alerts based on static patient data, however, in numerous, large cohort, multi-centre studies, no significant improvements in AKI prevention were observed³³. Another strategy that is currently in development is the use of artificial intelligence (AI) to create individual prediction models using baseline and evolving clinical data collected during hospital admission. Studies investigating AKI risk prediction using AI have demonstrated improved patient outcomes, however the technology still needs to be optimised and developed in a way that can be easily implemented in clinic³⁴. Dr Arici concluded by noting that until AI risk-prediction becomes clinically reliable, the most effective method of AKI prevention is the NRRT.

Day Three Highlights – Patient experience of COVID and treatment studies in CKD

By Anita Reid

Day Four Highlights – The pillars of therapy to reduce cardio renal risk

By Anita Reid

During the last day of the ERA 2022 conference, there was a thorough discussion of the FIDELITY study in patients with CKD and type 2 diabetes, which called for a holistic approach to treatment.

Clinicians now have the benefit of add-on treatment with a new class of non-steroidal mineralocorticoid receptor antagonists

Individuals with type 2 diabetes (T2D) have a strong residual risk of chronic kidney disease (CKD) progression, despite being treated with current therapies, i.e., angiotensin-converting enzyme inhibitors (ACEi), angiotensin-receptor blockers (ARBs) and the sodium-glucose cotransporter 2 inhibitors (SGLT2i)⁵².

However, clinicians now have the benefit of add-on treatment with a new class of non-steroidal mineralocorticoid receptor antagonists (MRA), specifically finerenone, which has been the most extensively studied agent within the class to date, with pending results from glucagon-like peptide 1 receptor agonists (GLP1-RA) also showing promising results as add-on treatment.

Katherine Tuttle emphasised the importance of precise phenotyping, even based on the patient’s clinical picture, to improve the selection of therapies and how to apply them for therapeutic safety and efficacy.

George Bakris reviewed the results of FIDELITY, a large, pooled analysis of individual patient data (N=13171) taken from FIDELIO-DKD and FIGARO-DKD^53,54. Both trials investigated the effect of finerenone on kidney and cardiovascular (CV) outcomes in patients with CKD and T2D.

FIDELITY showed that, on top of standard care (ACEIs/ARBs), finerenone reduced the risk of clinically meaningful CV and kidney outcomes in patients with T2D over a broad spectrum of CKD:

• endpoint CV composite: 14% (HR 0.86; 95% CI, 0.78–0.95; P=0.0018)
• hospitalisation for heart failure (HHF): 22% (HR 0.78; 95% CI, 0.66–0.92; P=0.0030)
• kidney composite: 23% (HR 0.77; 95% CI, 0.77–0.88; P=0.0002)
• dialysis: 20% (HR 0.80; 0.64–0.99; P=0.040) In addition to standard care, finerenone demonstrated CV benefits and preservation of kidney function in patients with T2D, regardless of the baseline estimated glomerular filtration rate (eGFR) or urinary albumin:creatinine ratio (UACR) and the use of SGLT2s or GLP-1RAs, with benefit primarily driven by reduction in HHF. Finerenone showed modest effects on systolic blood pressure and no sexual side-effects. Although hyperkalaemia increased with finerenone, the clinical impact was low; interestingly, for yet unknown reasons, hyperkalaemia risk is decreased in the presence of SGLT2is⁵³

Dr Bakris asked nephrologists to think like cardiologists about treatment, inviting them to think of ‘pillars of therapy’ rather than drug A vs drug B, or fixing sugar or fixing blood pressure. He described the pillars of therapy to reduce cardio renal risk: firstly, maximally tolerated doses of ACE inhibitors and ARBs, secondly, SGLT2i, and now finerenone, a non-steroidal MRA.

The pooling of data in FIDELITY, from the FIDELIO-DKD and FIGARO-DKD trials, has provided a large group of more than 13000 patients⁵³. Subgroup analyses enables the use of finerenone to be refined in subgroups of patients with CKD and T2D. Peter Rossing concluded that in all the subgroups studied, whether in albuminuria, eGFR, presence of CV disease defined in different ways, different levels of blood pressure, different levels of glycaemic control, whether on GLP-1RA or SGLT2i therapy, very consistent kidney and cardio benefits of finerenone compared with placebo were observed. Dr Rossing summarised the key subgroup analyses performed so far from FIDELITY; further analysis is still being completed.

• Based on kidney outcomes (albuminuria), finerenone helps protect against CV events and kidney disease progression; the CV outcome is consistent for micro- or macroalbuminuria
• Using a different renal endpoint, i.e., slope in eGFR, finerenone shows a benefit in all patients
• In different subgroups of CV disease (myocardial infarction [MI] and/or ischaemic stroke, coronary artery disease, peripheral artery disease), finerenone consistently reduced the risk of CV events in all these subgroups; in addition, the risk of CV events was reduced, with or without a history of a CV event
• Modest reduction in blood pressure vs placebo occurred across baseline blood pressure⁵⁶

Diabetes is responsible for approximately 50% of all cases of CKD and kidney failure or end-stage kidney disease (ESKD) worldwide⁵⁷; indeed in Katherine Tuttle’s experience, nephrologists take care of more diabetic patients than endocrinologists, while most diabetes-associated cardiovascular disease occurs in those with CKD. The latest KDIGO guideline recommends a holistic approach for these patients using a portfolio of therapies to personalise treatment⁵⁸. Dr Tuttle reviewed the safety data for finerenone and how to individualise it for individuals with diabetes and CKD. As an add-on to first-line therapy, Dr Tuttle stated that finerenone is for patients who have persistently low albuminuria and normal potassium to protect both the heart and the kidney in these individuals.

Finerenone is not a fire and forget medicine. For safe administration it requires monitoring and careful attention to both GFR and K+

Dr Tuttle addressed the risk of hyperkalaemia, which has been the main limitation to finerenone and other MRA inhibitors. Several predictive factors for hyperkalaemia were identified by the FIDELIO-DKD study⁵³, especially baseline K+ >4.5 mEq/L or a low eGFR <45 mg/ml/1.73m² and the use of betablockers, but mitigating factors, SGLT2i or diuretic, were also identified.

Dr Tuttle reviewed a prescribing protocol to safely individualise finerenone prescribing by adjusting for both eGFR and serum K+ levels. She emphasised the importance of follow-up eGFR and K+ monitoring and adjustment of dosage.

Chronic kidney disease affects approximately 11% of the global population, yet remains under-diagnosed, especially in the early stages⁵⁹

This statistic formed the basis of Dr De Nicolas’ presentation of the REVEAL-CKD study investigating the prevalence of undiagnosed stage 3 CKD in the global population. Dr De Nicolas’ presentation focused on preliminary data of undiagnosed stage 3 CKD in an Italian population which recruited 65,676 patients, 15,129 of which had an existing CKD diagnosis and 50,547 without⁶⁰, Of the undiagnosed group, 15% were found to have CKD, with median diagnosis time taking 1.1 years. Further analysis revealed that among this group, 77% had undiagnosed stage 3 CKD, with the chances of misdiagnosis increasing if the patients were female, >65 and had comorbidities. Dr De Nicola concluded his presentation by noting that undiagnosed CKD is a critical problem. He emphasised that timely diagnosis is vitally important for reducing progression and complications and should be a central focus for all treating physicians⁶¹.

References

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