1.2.1 CKD is common and associated with risk of progression to kidney replacement therapy.
The age-standardized prevalence of CKD in adults in the UK is estimated to be about 6-11% (1). In the absence of effective new interventions, this proportion is predicted to rise as the population ages, premature mortality from cardiovascular and other causes declines further, and type 2 diabetes mellitus (DM) becomes more prevalent(2).
Worldwide, diabetic kidney disease accounts for 30-50% of advanced CKD (i.e. stages 4-5) (3, 4). In the UK, currently about 30% of those starting maintenance kidney replacement therapy have diabetic nephropathy as their primary kidney disease, peaking at 38% among those starting at the ages of 55-64 years (5).
CKD can be a progressive condition, with albuminuria representing a significant risk factor for more rapid kidney function decline both in people with and without diabetes (6). The avoidance of progressive CKD is important as end-stage kidney disease (ESKD) has adverse effects on morbidity and quality of life, dialysis or transplantation incur substantial societal costs (7, 8), and low levels of kidney function increase cardiovascular risk (9).
Albuminuria is a marker of intraglomerular hypertension and has been used as a means to select participants at high risk of kidney disease progression into CKD trials. Such trials have often studied diabetic nephropathy separately from other causes of CKD. For example, pharmacological inhibition of the renin-angiotensin system (RAS) reduces efferent arteriolar tone and hence intraglomerular pressure, and large trials have shown this reduces albuminuria and the risk of overt diabetic nephropathy progressing to ESKD (10, 11).
However, intraglomerular hypertension is also considered to be a common pathway for kidney disease progression shared by some non-diabetic forms of CKD (12). The concept centres on the idea that reduced nephron numbers induces hyperfiltration in the remaining glomeruli. Support for this concept includes the observations that: (i) for a given level of urinary albumin excretion, the risk of ESKD is relatively independent of the primary kidney diagnosis (13); and (ii) trial meta-analyses show that RAS-inhibition slows progression of a range of proteinuric non-diabetic kidney diseases (14, 15). Single agent RAS-inhibition is therefore the standard of care for proteinuric CKD. Nevertheless, despite use of appropriate RAS-inhibition alongside suitably intensive glycaemic (16-18) and blood pressure (19-22) control, substantial residual risk of ESKD remains in people with proteinuric CKD (10, 11).
1.2.2 People with CKD are at high risk of structural heart disease and heart failure
In cohorts with appropriate cardiac imaging, structural heart disease is identified in about one-half of people with CKD stage 4-5 (23). CKD often co-exists with heart failure, due to a combination of shared risk factors and integrated pathophysiology (24). This may more commonly present as heart failure with preserved ejection fraction (HFpEF). Many people with CKD consequently die from cardiovascular disease before progression to ESKD. Management of CKD therefore includes modification of risk of both kidney disease progression and associated cardiovascular risk (24, 25). SGLT-2 inhibitors have emerged as a potential therapy to address both the cardiac complications of CKD and risk of kidney disease progression (26-36).