Diabetic nephropathy
Description
- The single commonest cause of ESKD in Australia (~35-40% of incident dialysis)
- Classically defined by persistent albuminuria + declining eGFR + diabetic retinopathy in someone with long-standing diabetes
- *Diabetic kidney disease' is now preferred - because a large and growing proportion progress with normoalbuminuric eGFR decline*, particularly in type 2 diabetes on RAS blockade
Histology
- Mesangial expansion -> nodular glomerulosclerosis (Kimmelstiel-Wilson nodules)
- GBM thickening (the earliest structural change), hyaline arteriolosclerosis of BOTH afferent and efferent arterioles (the efferent involvement is specific to diabetes)
- Capsular drop and fibrin cap lesions; large kidneys, even when function is poor
Epidemiology
- Develops in ~30-40% of type 1 and ~25-40% of type 2 diabetes
- T1DM: nephropathy is rare before 10 years of disease - the duration clock is reliable
- T2DM: may be present at diagnosis - the onset of hyperglycaemia is unknown
- Aboriginal and Torres Strait Islander peoples: far higher rates, earlier onset, faster progression - the dominant driver of the ESKD disparity
- Risk higher in South Asian, Pacific Islander, Maori and Hispanic populations
Aetiopathogenesis
Metabolic
- Hyperglycaemia -> advanced glycation end-products (AGEs), polyol (aldose reductase) and hexosamine pathway flux, PKC activation
- -> oxidative stress, TGF-beta, VEGF -> mesangial matrix expansion and GBM thickening
Haemodynamic - the reason the drugs work
- SGLT2 upregulation in the proximal tubule -> inc Na and glucose reabsorption
- -> dec distal Na delivery to the macula densa -> tubuloglomerular feedback is deceived into afferent vasodilatation
- -> glomerular hyperfiltration and intraglomerular hypertension
- RAAS activation -> efferent constriction -> further inc intraglomerular pressure
- This is exactly what SGLT2 inhibitors reverse - restoring distal Na delivery and afferent tone
Podocyte and inflammatory
- Podocyte loss and detachment -> albuminuria
- Mineralocorticoid receptor-driven inflammation and fibrosis - the finerenone target
Risk factors
- Glycaemic control (duration and severity), hypertension, dyslipidaemia, smoking, obesity, family history/genetic susceptibility
- Genetic susceptibility is real - not everyone with poor control develops it
Diagnosis
Screening
- Type 1: annual UACR + eGFR from 5 years after diagnosis
- Type 2: annual UACR + eGFR from diagnosis
- Confirm a raised UACR on 2 of 3 samples over 3-6 months (first-void)
- False positives: UTI, exercise in the last 24 h, menstruation, febrile illness, heart failure, marked hyperglycaemia
Staging (Mogensen) - most clearly seen in type 1
| Stage | Feature | eGFR | Timing |
|---|---|---|---|
| 1 | Glomerular hyperfiltration and renal hypertrophy | inc | At diagnosis |
| 2 | Silent - GBM thickening, mesangial expansion | Normal | 2-5 yrs |
| 3 | Moderately increased albuminuria (30-300 mg/day) | Normal or high | 5-15 yrs |
| 4 | Overt proteinuria (>300 mg/day), hypertension | Falling | 15-25 yrs |
| 5 | ESKD | <15 | 25-30 yrs |
- *The earliest stage is hyperfiltration with an INCREASED GFR and renal hypertrophy, before any albuminuria* - so a 'normal' eGFR early is not reassuring
- Normoalbuminuric CKD is common in T2DM - screen with eGFR, not albuminuria alone
When to suspect a non-diabetic cause and biopsy
- Absence of diabetic retinopathy (retinopathy is near-universal with T1DM nephropathy; ~60-70% in T2DM)
- Short duration of diabetes (<5 yrs in T1DM)
- Active urinary sediment - dysmorphic RBCs or RBC casts
- Rapid eGFR decline or abrupt onset of nephrotic syndrome
- Systemic features suggesting another disease; low complement; positive immunology
Baseline and monitoring
- eGFR, UACR, HbA1c, lipids, BP, K+, HCO3-
- Annual retinal screening, foot checks, cardiovascular assessment
Management
The management has been transformed by cardiorenal agents. Glycaemic control alone is no longer the centrepiece.
1. RAS blockade
- ACEi or ARB at the maximally tolerated dose for any albuminuria (with or without hypertension)
- Not both together; not for primary prevention in normoalbuminuric normotensive diabetes
- Tolerate a creatinine rise to 30% and K+ to ~5.5 - manage the potassium
2. SGLT2 inhibitor - now standard
- Empagliflozin or dapagliflozin in essentially every patient with diabetic kidney disease (CREDENCE, DAPA-CKD, EMPA-KIDNEY)
- Initiate down to eGFR 20; continue to dialysis
- Glycaemic effect fades below eGFR 45; the renal and cardiovascular benefit does not
- Counsel on genital mycotic infection and euglycaemic DKA (withhold 3 days pre-op, in acute illness, and when fasting)
3. Non-steroidal MRA
- Finerenone added to RASi + SGLT2i in T2DM with albuminuria (FIDELIO-DKD, FIGARO-DKD)
- Simultaneous initiation with an SGLT2i is supported; combined ~52% albuminuria reduction
- Monitor K+; less hyperkalaemia and no gynaecomastia compared with spironolactone
4. GLP-1 receptor agonist
- Semaglutide - kidney and cardiovascular benefit in T2DM + CKD (FLOW); benefit retained alongside an SGLT2i
- Also weight loss and blood pressure benefit
5. Blood pressure
- <120 mmHg systolic (standardised office measurement) where tolerated
- Sodium restriction <2 g/day
6. Glycaemia
- HbA1c ~53 mmol/mol (7%), individualised - relax to 58-64 in the frail, in advanced CKD, or with hypoglycaemia unawareness
- *Insulin requirements FALL as eGFR falls* (reduced renal insulin clearance) - a common cause of hypoglycaemia
- Metformin down to eGFR 30, dose-reduce below 45; withhold in acute illness
- HbA1c is unreliable in advanced CKD and on dialysis (shortened red cell survival, ESA use) - use glucose monitoring or CGM
7. The rest
- Statin in everyone; smoking cessation, weight, exercise
- Avoid NSAIDs; written sick-day rules
- Treat the other microvascular complications - retinal screening, foot care, autonomic assessment
- Bicarbonate to HCO3- >=22 mmol/L
8. Kidney failure planning
- Prepare at eGFR ~20 or KFRE 2-yr risk >10%
- Consider simultaneous pancreas-kidney transplantation in type 1 diabetes with ESKD - best long-term outcome for suitable candidates
Associations
- Diabetic retinopathy - so closely linked that its absence should prompt a search for another renal diagnosis
- Diabetic peripheral and autonomic neuropathy - gastroparesis, neurogenic bladder (worsens obstruction and infection)
- Cardiovascular disease - the dominant cause of death; the CKD-diabetes combination is a very high risk state
- Peripheral arterial disease, foot ulceration and amputation
- Type 4 RTA (hyporeninaemic hypoaldosteronism) - hyperkalaemia with a mild metabolic acidosis
- Papillary necrosis, emphysematous pyelonephritis, recurrent UTI
- Renal artery stenosis, contrast-associated AKI
- Obesity, metabolic syndrome, obstructive sleep apnoea
- Aboriginal and Torres Strait Islander identity - earlier onset and faster progression
Natural history & complications
The classical sequence
- Hyperfiltration (inc GFR) -> silent structural change -> moderately increased albuminuria -> overt proteinuria + hypertension -> falling eGFR -> ESKD
- Untreated: ~10-12 mL/min/yr eGFR decline once overt proteinuria appears; with full contemporary therapy, ~2-3
- Moderately increased albuminuria regresses in up to a third with good control - it is not an irreversible commitment
Prognosis
- Albuminuria is both the strongest predictor and the therapeutic target - a >=30% fall predicts fewer kidney events
- Cardiovascular mortality exceeds ESKD as an outcome at every stage
- Nephrotic-range proteinuria in diabetic nephropathy carries a poor renal prognosis
Complications and what to monitor
- Progression to ESKD; cardiovascular events - the competing risk
- Hyperkalaemia (type 4 RTA plus RAS blockade plus MRA) - the main barrier to optimal therapy; use a potassium binder rather than stopping the drug
- Hypoglycaemia as eGFR falls
- Monitor eGFR + UACR + K+ 3-6 monthly, HbA1c, lipids, BP, annual retinal and foot review
- Dialysis outcomes in diabetes are worse than in other aetiologies - transplantation, and SPK in type 1, matters more here than anywhere
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