NephrologyTier 1Topic

End-stage renal failure - delaying progression of CKD

What changes the slope

Progression is driven by a final common pathway that is independent of the original cause - so the same interventions work in almost every aetiology
Five things change the slope. Everything else is supportive care:
- 1. Blood pressure
- 2. RAS blockade
- 3. SGLT2 inhibition
- 4. Non-steroidal MRA (in diabetic CKD)
- 5. Correcting metabolic acidosis
Albuminuria is both the marker and the mediator - every drug that slows progression lowers it, and the size of the fall predicts the benefit

Rapid progression = eGFR decline >5 mL/min/1.73m2 per year
Untreated diabetic nephropathy declines ~10-12 mL/min/yr; with full therapy ~2-3
~1 in 10 Australian adults have CKD, and most die of cardiovascular disease before reaching ESKD

Nephron loss -> single-nephron hyperfiltration
- -> glomerular capillary hypertension -> podocyte stress and detachment
- -> proteinuria; filtered protein is directly tubulotoxic
- -> interstitial inflammation, fibroblast activation, interstitial fibrosis and tubular atrophy
- -> further nephron loss (self-perpetuating)
How each intervention interrupts the loop
- ACEi/ARB - efferent arteriolar dilatation -> dec intraglomerular pressure; also anti-fibrotic
- SGLT2i - inc distal Na delivery to the macula densa -> restores tubuloglomerular feedback -> afferent constriction -> dec hyperfiltration; plus dec tubular workload and O2 demand
- Non-steroidal MRA - blocks mineralocorticoid receptor-driven inflammation and fibrosis without the steroid-receptor side effects
- Bicarbonate - removes acid-driven ammoniagenesis, complement activation and endothelin-1 signalling in the tubule
*Each of these causes an initial 'dip' in eGFR of 3-5 mL/min - this is haemodynamic, expected, and predicts long-term benefit. Do not stop the drug*

eGFR slope - two or more values over >=3 months; plot it
UACR - the strongest modifiable predictor; confirm on 2 of 3 first-void samples
KFRE (Kidney Failure Risk Equation) - age, sex, eGFR, UACR -> 2- and 5-yr kidney failure risk

Volume depletion, obstruction, nephrotoxins (NSAIDs, contrast), uncontrolled hypertension, uncontrolled diabetes, superimposed AKI, active urinary sepsis
A sudden deviation from a previously linear slope is never 'natural progression'

Target systolic <120 mmHg (standardised office measurement) where tolerated
- Standardised = seated, rested 5 min, correct cuff, average of readings. A casual clinic reading is not the same target
Relax in the frail, orthostatic, or those with limited life expectancy
Sodium restriction <2 g/day (<5 g salt) - without it, RAS blockade and diuretics both underperform

ACEi or ARB at the maximally tolerated dose for CKD with albuminuria, with or without diabetes
Tolerate a creatinine rise up to 30% and a K+ up to ~5.5 - manage the potassium, do not abandon the drug
- Diet, loop diuretic, NaHCO3, potassium binder (sodium zirconium cyclosilicate, patiromer)
*Never combine an ACEi with an ARB* - more hyperkalaemia and AKI, no benefit
Stop and reassess in AKI or intercurrent illness (sick-day rules), then restart

Dapagliflozin or empagliflozin, with or without diabetes (DAPA-CKD, EMPA-KIDNEY)
- Adds further proteinuria reduction and slows progression on top of maximal RAS blockade
- Benefit across aetiologies - diabetic nephropathy, IgAN, FSGS, hypertensive nephrosclerosis
- Not established in ADPKD (excluded from the trials)
Initiate down to eGFR 20 and continue to dialysis or transplant
Australian PBS access for dapagliflozin in CKD widened in 2025 to eGFR 20-<25 regardless of UACR, and to higher eGFR with significant albuminuria
Counsel: genital mycotic infection, euglycaemic DKA (withhold 3 days pre-op and during acute illness or fasting), volume depletion with diuretics

Finerenone - add to RASi + SGLT2i in type 2 diabetes with albuminuria (FIDELIO-DKD, FIGARO-DKD)
- Simultaneous initiation with an SGLT2i is now supported (~52% albuminuria reduction combined)
- Monitor K+; less hyperkalaemia and no gynaecomastia compared with spironolactone
Semaglutide - kidney and cardiovascular benefit in T2DM with CKD (FLOW); benefit preserved alongside an SGLT2i

Treat to serum HCO3- >=22 mmol/L (some guidance uses >21)
Diet high in fruit and vegetables from CKD stage 3 - organic anions metabolised to bicarbonate; no sodium load
Oral sodium bicarbonate (or calcium bicarbonate)
- Benefits: slower progression, better dialysis-free survival, less hyperkalaemia, less muscle wasting
- *Risks: sodium loading -> oedema and hypertension; over-correction to alkalosis*

Glycaemic control - HbA1c ~53 mmol/mol (7%), individualised; metformin to eGFR 30
Weight loss and smoking cessation
Avoid NSAIDs entirely; minimise contrast; relieve obstruction; treat hyperuricaemia only if gout (urate lowering does not slow CKD - CKD-FIX, an Australian trial)
Protein intake ~0.8 g/kg/day; avoid very high protein and creatine supplements
Statin for cardiovascular risk in everyone >=50 not on dialysis
Written sick-day rules: withhold ACEi/ARB, diuretics, metformin, SGLT2i, NSAIDs, MRA in acute illness
Aetiology-specific therapy where it exists - immunosuppression in GN, tolvaptan in ADPKD, treating the systemic disease

Diabetes and hypertension - the two commonest drivers
Obesity - hyperfiltration and obesity-related glomerulopathy; weight loss reduces proteinuria
AKI - each episode leaves a lower baseline; the commonest accelerant
Proteinuria - marker and mediator
Metabolic acidosis, hyperuricaemia, hyperphosphataemia, anaemia
Smoking, obstructive sleep apnoea, NSAID use
Aboriginal and Torres Strait Islander identity - earlier onset, faster progression, higher albuminuria burden
Low birth weight/prematurity - reduced nephron endowment

Decline is approximately linear for a given patient once established - extrapolate the slope to predict when RRT will be needed
Halving the rate of eGFR decline can add a decade before dialysis - the reason to press every lever early
Albuminuria reduction is a validated surrogate: a >=30% fall predicts a lower risk of kidney failure

Most CKD patients die of cardiovascular disease before reaching ESKD - so cardiovascular risk reduction is not a side issue

Initial eGFR dip of 3-5 mL/min with RASi, SGLT2i and finerenone - expected, haemodynamic, reversible, and associated with better long-term outcomes
Recheck creatinine and K+ 1-2 weeks after starting or up-titrating
Failure to progress despite the diagnosis, or accelerated decline, should prompt reassessment of the cause and a search for an accelerant

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