Management of Diabetic Kidney Disease

Abstract

The global prevalence of chronic kidney disease (CKD) from all causes is increasing with parallel increases in the number of people undergoing renal replacement therapy and increases in costs of care. The pathophysiology of diabetic kidney disease (DKD) is complex and heterogeneous. Clinical trials have shown benefits in renal outcomes with drugs acting on the renin-angiotensin-aldosterone system (RAAS) axis, as well as sodium-glucose cotransporter 2 (SGLT2) inhibitors, and GLP1RA. In this manuscript we review the management of diabetic kidney disease.

Introduction

Chronic kidney disease (CKD) is defined by the presence of reduced glomerular filtration rate (GFR) and/or increased urinary albumin excretion for at least three months.^1,2

The global prevalence of CKD from all causes was >840 million in 2019, with a projected increase in prevalence by 16%, and an approximate 24% increase in the number of people undergoing renal replacement therapy by 2026, with parallel increases in costs of care. The mortality from CKD, and years of life lost increased by 34% and 21% respectively in the decade from 2007–2017. Diabetic kidney disease (DKD) is the most common cause of CKD and presents a six-fold greater risk of cardiovascular (CV) events and mortality. Therefore, early recognition and proactive management of CKD have the potential to improve outcomes.^1,2

Pathophysiology of DKD

It is worth reviewing the complex and heterogeneous pathophysiology of DKD to remind ourselves of potential future targets for DKD management. Despite varying relative contributions, alterations in glomerular haemodynamics, inflammation, and interstitial fibrosis and tubular atrophy (IFTA) are the primary drivers of DKD. Hyperglycaemia and the consequent products of advanced glycation end-products (AGE) and reactive oxygen species play an important role, but the variations in aetiology, pathophysiology and histopathology between type 1 (T1DM) and type 2 diabetes (T2DM) may, in part, be explained by disparate contributions of hyperinsulinemia and insulin resistance.

Activation of the renin-angiotensin-aldosterone system (RAAS) and downstream pathways leads to enhanced renal plasma flow (RPF) with a consequent elevations in filtration fraction (FF) and glomerular filtration rate (GFR) due to renal hypertrophy and a disproportionate impact on afferent versus efferent arteriolar resistance by differentially increased circulating vasodilators (atrial natriuretic peptide, nitric oxide and prostanoids) and vasoconstrictors (angiotensin II, thromboxane and endothelin 1).

The early upregulation of the sodium-glucose cotransporters (both SGLT1 and SGLT2) in DM, with decreased sodium delivery to the macula densa via tubuloglomerular feedback further decreases afferent arteriolar tone with increases in RPF, FF and GFR.

Impaired autoregulatory responses of the afferent arterioles to fluctuations in blood pressure in DM further exacerbate glomerular hyperfiltration. The sum total of these pathophysiological changes triggers intra-glomerular changes in capillary walls, podocytes and mesangium, ultimately starting a cascade of profibrotic response, sclerosis and DKD.

Glomerular hyperfiltration is associated with worsening albuminuria and GFR decline. The comparative increased prevalence of hyperfiltration in type 1 diabetes may be explained partially by the older age of individuals and frequent co-existence of hypertension leading to glomerulosclerosis and senescence of the kidney in type 2 diabetes.

Hyperglycaemia activates protein kinase C (PKC), leading to reduced nitric oxide synthase (eNOS) and increased levels of the endothelin 1 and vascular endothelial growth factor (VEGF), which promotes endothelial instability and nuclear factor-kappa B (NF-κB) production. AGE, upon binding to receptors in various cells, and stimulation of toll-like receptors by hyperglycaemia trigger production of numerous cytokines (tumour necrosis factor [TNF], interleukin 6 [IL-6], IL-1beta) via activation of NF-κB and other nuclear transcription factors. This creates a vicious cycle of oxidative stress and inflammation.

Macrophage infiltration, mesangial cell hypertrophy and matrix accumulation, vascular proliferation and endothelial permeability all augment oxidative stress through similar pathways (VEGF, transforming growth factor [TGF]-beta, platelet-derived growth factor, and TNF-alpha), leading to renal hypertrophy and podocyte and tubular epithelial cell injury, further enhancing the cascade of cytokine recruitment and inflammation.^3–5

Management of DKD

All the above pathways suggest future target pathways for drug development and intervention to modulate the course of DKD. However, at present, management of DKD is focused on modulating the RAAS pathway, with recent evidence adding SGLT2 inhibitors and potentially GLP1 receptor agonists to the therapeutic armamentarium. ⁶

Multi-factorial risk reduction of optimising blood glucose, blood pressure and lipid control, along with lifestyle modification including weight loss and smoking cessation are fundamental to DKD management.^6,7

ACE Inhibitors (ACEi) and Angiotensin Receptor Blockers (ARB)

Since activation of the RAAS system is a key component in the pathophysiology of DKD, drugs aimed at blocking either angiotensin converting enzyme (ACE), ACEi, or blocking the angiotensin receptor (AR), ARB are frequently the first line of therapy management of DKD. Both groups of agents are similarly efficacious; however, combination therapy, whilst not improving progression of renal disease or death, increases the rate of serious adverse events and is therefore not recommended.^8,9

Early studies using captopril, and subsequently other ACEi, showed a slowing of the annual rate of decline of creatinine clearance and progression in diabetic nephropathy in both hypertensive and normotensive patients with T1DM. In T2DM with hypertension, using irbesartan reduced the likelihood of a doubling of serum creatinine and non-significantly reduced the incidence of ESKD. Similar results were seen with losartan. RAAS inhibition with ARB reduces the risk of progression at every stage of albuminuria, from normal to mild, to moderate, to severe. However, to date, no major clinical trial has shown prevention of ESKD in non-albuminuric DKD with these classes of drugs when compared to other antihypertensive agents.^8,9

SGLT2 Inhibitors

SGLT2 inhibitors address the dual defects of upregulation of the sodium-glucose cotransporters in T2DM and decreased sodium delivery to the macula densa. The primary mediator of glucose uptake in the kidney is the SGLT2. Blocking the activity of this pump reduces glucose reabsorption along with sodium. Apart from reducing the glycaemic load, this reflects in an increased delivery of sodium to the macula densa, resulting in

a natriuresis driven reduction in intravascular volume and blood pressure,

normalisation of tubule-glomerular feedback, which leads

constriction of the aberrantly dilated afferent arteriole,

reduction in the intraglomerular pressure and finally,

reduction in glomerular hyperfiltration.

Three seminal clinical trials, CREDENCE, DAPA-CKD and EMPA-KIDNEY enrolled individuals on standard of care (ACEi or ARB) with eGFR between 25 and 90 with varying degrees of albuminuria. The aetiology of CKD varied from diabetes, hypertension, IGA nephropathy and others. Irrespective of the cause of CKD, treatment with SGLT2 inhibitors reduced the incidence of end-stage kidney disease (ESKD) and decline in eGFR. The greater the degree of albuminuria, the greater the reduction, suggesting that the benefits of SGLT2 inhibitor therapy may be greater among those with higher levels of albuminuria.^10–12

Non-steroidal Mineralocorticoid Receptor antagonists

Aldosterone represents a downstream target of the RAAS system. Two trials, FIDELIO and FIGARO assessed the safety and efficacy of finerenone, a non-steroidal MR antagonist, in improving CV and renal outcomes.

The FIDELIO-DKD trial assessed the safety and efficacy of finerenone in reducing CV and renal events among patients with T2DM and CKD who were already on a background of maximal RAS blockade therapy. The primary composite outcome of kidney failure, sustained decrease of 40% in the eGFR from baseline, or death from renal causes for finerenone vs. placebo was 17.8% vs. 21.1% (hazard ratio 0.82, 95% confidence interval 0.73-0.93, P = .0014) with reduction of kidney failure 7.3% vs. 8.3% and end-stage kidney disease 4.2% vs. 4.9% for the control arm.^13,14

The FIGARO-DKD trial was the first phase 3 study showing that selective, non-steroidal MR antagonism reduces the progression of kidney disease in CKD in individuals with T2DM who are already treated with the maximally tolerated dose of ACE or ARB. This trial assessed composite of kidney failure, a sustained decrease from baseline of at least 40% in the eGFR, or death from renal causes as the first secondary outcome which occurred in 350 patients (9.5%) in the finerenone group and in 395 (10.8%) in the placebo group (hazard ratio, 0.87; 95% CI, 0.76 to 1.01).^13,15

GLP1 Receptor Agonists

FLOW is a randomised, double-blind, parallel-group, multinational, phase 3b trial investigating the effects of once-weekly semaglutide on renal outcomes for prevention of progression of renal impairment and risk of renal and cardiovascular mortality in individuals with CKD and T2D. This trial was originally due to report in 2024 but was closed in October 2023 as the interim analysis met the pre-specified criteria for stopping the trial early for efficacy. Final results are awaited.^16,17

Summary

It is only recently that clinical trials have shown benefits in renal outcomes with drugs acting on the RAAS axis, as well as SGLT2 inhibitors, and GLP1RA. However, whether there is any additional benefit with combinations of any or multiple agents remains to be explored. Agents modulating metabolic memory, tubulointerstitial hypoxia, AGE inhibitors, and histone modification inhibitors are expected to increase our options for renoprotection. ¹⁸