For decades, RAAS blockade stood almost alone as a disease-modifying therapy in CKD. That era is over. A handful of trials in the last few years have given nephrology a set of additional pillars — SGLT2 inhibitors above all, then finerenone, and now the GLP-1 agonists — each proven to slow progression, each acting on a different point of the final common pathway, and each adding to the others. Modern CKD care is the deliberate stacking of these pillars, and this chapter is the centre of the volume because it is where the mechanism of Chapter 2 meets the most powerful therapeutics nephrology has.
The pillars, and why they stack
The organising idea is the pillar. Just as heart-failure care layers four drug classes that each improve outcomes by a different mechanism, CKD care now layers several: renin-angiotensin blockade as the foundation, SGLT2 inhibition, the non-steroidal mineralocorticoid antagonist finerenone, and — increasingly — GLP-1 receptor agonists, all on a base of blood-pressure control, proteinuria reduction, and lifestyle. They stack because they are not redundant: each interrupts the progression pathway at a distinct point, so their benefits add rather than overlap. The practical consequence is a shift in expectation — for most patients with progressive CKD, RAAS blockade alone is no longer enough, and the question has become which pillars this patient needs and in what order.
SGLT2 inhibitors: restoring tubuloglomerular feedback
The SGLT2 inhibitor is the transformative pillar, and its renal mechanism is elegant. It blocks the sodium-glucose cotransporter in the proximal tubule, so less sodium is reabsorbed there and more is delivered downstream to the macula densa. The macula densa reads that increased sodium as a signal that the glomerulus is over-filtering, and through tubuloglomerular feedback it constricts the afferent arteriole — lowering the intraglomerular pressure that, since Chapter 2, we have known to be the engine of progression. In other words, the drug works by restoring a feedback loop that hyperfiltration had switched off, dilating nothing and constricting the afferent rather than the efferent, which complements RAAS blockade's efferent dilation. On top of this haemodynamic core sit further benefits: a natriuresis and mild diuresis, a reduced tubular workload and oxygen demand, and metabolic and anti-inflammatory effects. The result is protection that begins at the glomerulus and extends through the tubulointerstitium.
Glucose-independent, and proven across CKD
Because that mechanism is haemodynamic and not glycaemic, the kidney protection is glucose-independent — it does not depend on lowering blood sugar and is undiminished in patients without diabetes. This was the conceptual leap the trials confirmed. CREDENCE established the benefit in albuminuric diabetic CKD; DAPA-CKD extended it to CKD with or without diabetes, including non-diabetic causes; and EMPA-KIDNEY broadened it further across a wide range of eGFR and to patients without albuminuria. Together they show large, consistent reductions in CKD progression to dialysis, in cardiovascular death, and in heart-failure hospitalisation, in populations that span most of the CKD clinic. An SGLT2 inhibitor is now indicated in CKD down to an eGFR of around 20, started there and continued until dialysis or transplant, with the glycaemic effect fading at low eGFR while the kidney and cardiovascular benefit persists.
The dip that is not damage
As with RAAS blockade, starting an SGLT2 inhibitor produces a small, reversible fall in eGFR — a dip of a few millilitres per minute over the first weeks — and as with RAAS blockade, this alarms the unwary into stopping the drug. The dip is the mechanism, not toxicity: the restored tubuloglomerular feedback has constricted the afferent arteriole and lowered glomerular pressure, exactly as intended, and the trials show that patients who dip go on to have slower long-term decline. The eGFR stabilises and the long-term slope is gentler than without the drug. The discipline is identical to the RAAS lesson of the previous chapter — expect the dip, continue through it, and do not mistake the sign of the drug working for a sign of harm.
Using SGLT2 inhibitors safely
The safety profile is favourable but has specific pitfalls. Genital mycotic infections are the commonest adverse effect, a consequence of the glucosuria the drug induces. The natriuresis can cause volume depletion, so doses of concurrent diuretics may need adjusting. Rare but serious is euglycaemic diabetic ketoacidosis — ketoacidosis without the expected high glucose — which is why these drugs are held during acute dehydrating illness, around surgery, and in any state of starvation or volume stress, the sick-day rules of the poisoning chapter. Fournier's gangrene is a rare association. They are not used for kidney protection in type 1 diabetes. None of this offsets the benefit for the great majority, but each item is a thing to anticipate, counsel on, and build into the prescription.
Finerenone: blocking the profibrotic aldosterone signal
The third pillar addresses a mechanism the first two leave standing: aldosterone's direct profibrotic and pro-inflammatory action on the kidney, noted in Chapter 2. Finerenone is a selective, non-steroidal mineralocorticoid-receptor antagonist, distinct from the steroidal spironolactone in being more selective and causing less hyperkalaemia and fewer hormonal effects. In diabetic CKD with albuminuria, in patients already on optimised RAAS blockade, the FIDELIO and FIGARO trials — pooled in FIDELITY — showed it further reduces kidney and cardiovascular events. Its place is therefore as an add-on in diabetic CKD with residual albuminuria despite maximal RAAS blockade. Its main caution is hyperkalaemia, less than with spironolactone but real, so potassium is monitored — which leads to the synergy that makes the modern stack workable.
Stacking the pillars, and the potassium synergy
Layering these drugs raises an obvious worry: RAAS blockade and finerenone both raise potassium, so stacking them might seem to court hyperkalaemia. Here the SGLT2 inhibitor helps in an unexpected way — it tends to lower potassium, partly through its diuretic and other effects, offsetting the rise from the other two and making the combination more tolerable than its parts suggest. So the stack is not merely additive in benefit but partly self-balancing in its commonest side effect. The emerging fourth pillar, the GLP-1 receptor agonists, adds another mechanism: in diabetic CKD the FLOW trial showed semaglutide reduces kidney and cardiovascular outcomes, alongside its weight and glycaemic benefits, making it an increasingly attractive addition in diabetic and obese CKD. The modern prescription, then, is a considered stack — RAAS blockade plus an SGLT2 inhibitor for almost all progressive CKD, finerenone added in albuminuric diabetic CKD, and a GLP-1 agonist where diabetes and obesity argue for it — with potassium watched across the whole.
Where the evidence is firm, and where it is still moving
Little in nephrology is as firm as the SGLT2-inhibitor evidence: multiple large trials, consistent across diabetic and non-diabetic CKD and across the eGFR range, with kidney and cardiovascular benefit — this is grade-A, practice-defining data. Finerenone's benefit in albuminuric diabetic CKD is well established, and the GLP-1 kidney data are now strong and growing. What is still moving is the optimal sequence and combination — which pillar first, how fast to stack, how to individualise in the non-albuminuric or the very advanced — and the long-term data on the full four-pillar combination are still maturing. The honest summary is that the individual pillars are proven and the architecture of combining them is being built in real time, so practice should deploy each proven pillar confidently while remaining open as the stacking evidence matures.
