Renal Medicine

Key Facts

CKD is a major public health burden with significant cardiovascular implications. Cardiovascular disease is the leading cause of death in CKD patients, not progression to end-stage renal disease. Early detection and management of risk factors are essential.

Epidemiology

• Affects ~7% of UK adults; prevalence increases with age (30-40% in over 75s)
• ~3 million people in the UK; majority undiagnosed
• Approximately 65,000 patients on renal replacement therapy (dialysis or transplant) in the UK
• CKD disproportionately affects South Asian and African-Caribbean populations
• Costs the NHS an estimated £1.45 billion per year

Aetiology

• Diabetes mellitus: 30% (most common cause of ESRD in the UK)
• Hypertension: 25%
• Glomerulonephritis: 15%
• Polycystic kidney disease (ADPKD): 5-10%
• Renovascular disease: 5%
• Chronic pyelonephritis/reflux nephropathy: 5%
• Drugs: NSAIDs, lithium, calcineurin inhibitors
• Unknown/idiopathic: 10-20%

Pathophysiology

• Progressive nephron loss → compensatory hyperfiltration in remaining nephrons
• Hyperfiltration causes glomerular hypertension and further injury (vicious cycle)
• Proteinuria is both a marker and mediator of progressive renal damage
• RAAS activation drives fibrosis and progressive scarring
• Complications develop progressively: anaemia (reduced EPO), mineral bone disease (reduced 1α-hydroxylation, phosphate retention), acidosis, hyperkalaemia
• Cardiovascular risk driven by hypertension, dyslipidaemia, chronic inflammation, vascular calcification

Early CKD (Stages G1-G3a)

• Usually asymptomatic – detected on screening bloods
• Nocturia (loss of concentrating ability)
• Foamy urine (proteinuria)

Advanced CKD (Stages G3b-G4)

• Fatigue and lethargy (anaemia)
• Peripheral oedema and fluid retention
• Hypertension
• Pruritus
• Anorexia and weight loss
• Restless legs

End-Stage Renal Disease (Stage G5)

• Uraemic symptoms: nausea, vomiting, metallic taste, hiccoughs
• Uraemic encephalopathy: confusion, drowsiness, asterixis, seizures
• Pericarditis: chest pain, friction rub
• Peripheral neuropathy: glove-and-stocking sensory loss
• Skin changes: sallow complexion, uraemic frost, pruritus

Red Flags

• Rapid decline in eGFR (>5 mL/min/year) → accelerated investigation
• Haematuria with proteinuria → consider glomerulonephritis
• Uncontrolled hyperkalaemia → urgent intervention
• Uraemic pericarditis or encephalopathy → urgent dialysis

Bedside

• Urinalysis: dipstick for blood/protein
• Blood pressure: ideally ambulatory/home monitoring
• BMI and cardiovascular risk assessment

Bloods

• eGFR (CKD-EPI equation): defines stage; repeat at 3 months to confirm chronicity
• Urine albumin:creatinine ratio (ACR): early morning sample; A1 (<3), A2 (3-30), A3 (>30 mg/mmol)
• Calcium, phosphate, PTH: CKD-mineral bone disease assessment from stage G3b
• FBC: normocytic normochromic anaemia (reduced EPO)
• Iron studies: ferritin and transferrin saturation (iron deficiency common)
• Bicarbonate: metabolic acidosis
• Lipid profile: cardiovascular risk
• HbA1c: diabetic control

Imaging

• Renal ultrasound: assess kidney size (small = chronic, large = ADPKD/amyloid/diabetic nephropathy), cortical thickness, obstruction
• MR angiography: if renovascular disease suspected

Special Tests

• Renal biopsy: if unexplained CKD with active sediment, nephrotic-range proteinuria, or rapidly declining eGFR
• Immunology screen: ANA, ANCA, complement, immunoglobulins if GN suspected
• Serum and urine electrophoresis: if myeloma suspected
• Genetic testing: ADPKD, Alport syndrome

Non-pharmacological

• Lifestyle modification: smoking cessation, weight management, regular exercise
• Dietary advice: reduce sodium intake (<6g/day), potassium restriction in advanced CKD, phosphate restriction, adequate protein intake (0.8-1.0 g/kg/day in G4-G5)
• Fluid management: generally unrestricted unless oliguric/fluid overloaded
• Education: sick day rules – stop ACEi/ARB/NSAIDs/metformin/diuretics during acute illness

Pharmacological

Blood pressure control:

• ACE inhibitor (ramipril 1.25-10mg OD) or ARB (losartan 25-100mg OD): first-line, especially with proteinuria
• Target: <140/90 mmHg (or <130/80 if ACR ≥70 or diabetic with ACR ≥3)
• Monitor creatinine and K+ 1-2 weeks after starting/dose change (accept up to 25% rise in creatinine)

SGLT2 inhibitors:

• Dapagliflozin 10mg OD: recommended if ACR ≥22.6 mg/mmol (DAPA-CKD trial – 39% reduction in composite renal endpoint)
• Can be initiated down to eGFR 15 mL/min

Anaemia:

• IV iron first (ferric carboxymaltose 500-1000mg) if ferritin <200 or TSAT <20%
• ESAs (epoetin alfa, darbepoetin alfa): if Hb <100 g/L despite iron repletion; target Hb 100-120 g/L

CKD-Mineral Bone Disease:

• Phosphate binders: calcium acetate, sevelamer, lanthanum if phosphate elevated
• Alfacalcidol 0.25-1mcg OD or calcitriol: if PTH elevated despite phosphate control
• Cinacalcet: for secondary/tertiary hyperparathyroidism not controlled with above

Other:

• Sodium bicarbonate 500mg-1g TDS: if serum bicarbonate <22 mmol/L
• Statin therapy: atorvastatin 20mg for cardiovascular risk reduction
• Erythropoietin: as above for anaemia management

Referral Criteria (NICE NG203)

• eGFR <30 mL/min (G4-G5)
• ACR ≥70 mg/mmol (unless known diabetic already optimised)
• eGFR decline >5 mL/min/year or >10 mL/min within 5 years
• Uncontrolled hypertension despite 4+ agents
• Suspected renal artery stenosis
• Haematuria with proteinuria after urological causes excluded
• Plan for renal replacement therapy (eGFR <20)

• CKD G3a: minimal progression risk with good management; 10-year ESRD risk <5%
• CKD G4: 20-30% progress to ESRD within 5 years
• CKD G5: requires renal replacement therapy (median life expectancy on dialysis ~5-10 years)
• Cardiovascular mortality: 5-10× higher than age-matched general population
• Death from cardiovascular disease is more common than progression to ESRD in most CKD stages
• Transplant recipients have a 10-year graft survival of approximately 60-70%
• SGLT2 inhibitors reduce progression to ESRD by ~40% (DAPA-CKD, EMPA-KIDNEY trials)

CKD Staging (NICE NG203)

Albuminuria Staging

Landmark Trials in CKD

Key Facts

Diabetic nephropathy (diabetic kidney disease) is a clinical diagnosis based on persistent albuminuria and/or declining eGFR in a patient with diabetes, in the absence of alternative causes.

Epidemiology

• Most common cause of ESRD globally and in the UK
• Affects 30-40% of T1DM and 20-30% of T2DM patients
• Incidence increasing due to rising T2DM prevalence
• More common in South Asian and Afro-Caribbean populations
• Peak incidence: 15-25 years after diabetes diagnosis

Aetiology

• Chronic hyperglycaemia is the primary driver
• Risk factors: poor glycaemic control, hypertension, genetic susceptibility, smoking, obesity, dyslipidaemia
• Family history of diabetic nephropathy confers 3-4 fold increased risk

Pathophysiology

• Hyperglycaemia → advanced glycation end-products (AGEs), activation of protein kinase C, polyol pathway
• Early: glomerular hyperfiltration (increased GFR) and glomerular hypertension
• Mesangial matrix expansion and glomerular basement membrane thickening
• Kimmelstiel-Wilson nodules (nodular glomerulosclerosis): pathognomonic histological finding

• Tubulointerstitial fibrosis contributes to progressive disease

Early Disease

• Asymptomatic – detected on screening
• Microalbuminuria (ACR 3-30 mg/mmol)
• Normal or elevated GFR (hyperfiltration phase)

Established Disease

• Macroalbuminuria (ACR >30 mg/mmol) with proteinuria
• Declining eGFR (typically 5-10 mL/min/year without treatment)
• Hypertension (present in >80%)
• Peripheral oedema and nephrotic syndrome
• Often co-exists with diabetic retinopathy (>90% of T1DM with nephropathy have retinopathy)

Advanced Disease

• Uraemic symptoms: fatigue, nausea, pruritus
• Fluid overload: pulmonary oedema, anasarca
• Accelerated cardiovascular disease

Red Flags

• Absence of diabetic retinopathy → consider alternative diagnosis
• Rapid decline in eGFR (>5 mL/min/year) → consider superimposed pathology
• Active urine sediment (red cell casts) → consider glomerulonephritis
• Short duration of diabetes (<5 years T1DM) with nephropathy → consider other causes

Bedside

• Urinalysis: dipstick for protein, blood
• Blood pressure: target <130/80
• Fundoscopy: assess for diabetic retinopathy (absent retinopathy questions diagnosis)
• Foot examination: peripheral neuropathy, peripheral vascular disease

Bloods

• eGFR: to stage CKD
• Urine ACR: early morning sample preferred; repeat × 2 if elevated to confirm
• HbA1c: glycaemic control
• Lipid profile: cardiovascular risk
• Calcium, phosphate, PTH: if eGFR <30
• FBC: anaemia (may occur earlier in diabetic nephropathy than other CKD causes)

Imaging

• Renal ultrasound: kidneys may be normal or large in early disease (unlike other CKD causes)
• MR angiography: if renovascular disease suspected

Special Tests

• Renal biopsy: NOT routine; indicated if atypical features (haematuria, rapid decline, short diabetes duration, no retinopathy)
• Retinal screening: essential (presence of retinopathy supports diagnosis)

Non-pharmacological

• Glycaemic control: dietary modification, structured education (DAFNE for T1DM, DESMOND for T2DM)
• Smoking cessation: critical for slowing progression
• Sodium restriction: <6g/day
• Weight management: aim for BMI 18.5-25
• Exercise: 150 minutes/week moderate intensity

Pharmacological

Blood pressure and renoprotection:

• ACE inhibitor (ramipril up to 10mg OD) or ARB (losartan up to 100mg OD): first-line for all patients with ACR ≥3 mg/mmol
• Target BP: <130/80 mmHg (NICE NG28/NG136)
• Add CCB (amlodipine) or thiazide as second-line

SGLT2 inhibitors:

• Dapagliflozin 10mg OD or empagliflozin 10mg OD: add to ACEi/ARB if ACR ≥22.6 mg/mmol
• CREDENCE trial: canagliflozin reduced composite renal endpoint by 30%
• DAPA-CKD trial: dapagliflozin reduced composite renal endpoint by 39%

Finerenone (non-steroidal MRA):

• Finerenone 10-20mg OD: for T2DM with CKD despite ACEi/ARB (FIDELIO-DKD trial – 18% reduction in kidney failure)
• Monitor potassium closely

Glycaemic control:

• HbA1c target: 48-58 mmol/mol (adjust based on CKD stage)
• Metformin: reduce dose if eGFR 30-45; stop if <30
• SGLT2 inhibitors: continue for renoprotection down to eGFR 15 even if glycaemic effect diminishes
• GLP-1 receptor agonists (semaglutide, liraglutide): cardiovascular and renal benefits
• Insulin: may be required as renal function declines (reduced clearance → hypoglycaemia risk)

Referral Criteria

• eGFR <30 or rapidly declining eGFR → nephrology
• Nephrotic-range proteinuria (ACR >220 mg/mmol)
• Atypical features suggesting non-diabetic kidney disease → renal biopsy consideration
• Planning for renal replacement therapy (eGFR <20)

• Without treatment: ~50% progress to ESRD within 10 years of macroalbuminuria
• ACEi/ARBs reduce progression to ESRD by 30-40%
• SGLT2 inhibitors provide additional 30-40% risk reduction on top of RAAS blockade
• 5-year survival on dialysis for diabetic patients: approximately 30-40% (vs 50-60% for non-diabetic)
• Cardiovascular mortality is the leading cause of death, not ESRD progression
• Early detection and treatment of microalbuminuria can reverse to normoalbuminuria in 30-50% of patients

Stages of Diabetic Nephropathy (Mogensen Classification – T1DM)

Landmark Trials

Key Facts

Hypertensive nephropathy is a clinical diagnosis made in patients with long-standing hypertension, CKD, and no other identifiable cause of renal disease. It is often a diagnosis of exclusion.

Epidemiology

• Second most common cause of ESRD in the UK (~25%)
• More prevalent in Afro-Caribbean populations (APOL1 gene variants)
• Increasing incidence due to ageing population and obesity
• Most common in patients with >10 years of poorly controlled hypertension

Aetiology

• Essential hypertension is the primary cause
• Risk factors: age, Afro-Caribbean ethnicity, obesity, smoking, diabetes, dyslipidaemia, salt intake
• APOL1 gene variants (G1 and G2 alleles) confer significantly increased risk in African populations

Pathophysiology

Benign nephrosclerosis:

• Reduced renal blood flow → ischaemic glomerulosclerosis and tubular atrophy
• Slow progressive fibrosis

Malignant nephrosclerosis:

• Severe hypertension → fibrinoid necrosis of arterioles (onion-skin hyperplastic arteriolitis)
• Thrombotic microangiopathy → rapid GFR decline
• Medical emergency requiring urgent BP reduction

Benign Nephrosclerosis

• Usually asymptomatic until advanced stages
• Long history of poorly controlled hypertension
• Gradually rising creatinine over years
• Mild proteinuria (usually <1 g/day)
• Small kidneys bilaterally on USS
• Evidence of other hypertensive target organ damage (LVH, retinopathy)

Malignant Hypertension

• BP >180/120 mmHg with target organ damage
• Headache, visual disturbance, seizures
• Papilloedema (grade IV retinopathy)
• Rapidly declining renal function
• Microangiopathic haemolytic anaemia (MAHA)
• Heart failure, encephalopathy

Red Flags

• Rapid decline in GFR → consider renal artery stenosis, malignant hypertension, or superimposed GN
• Significant haematuria or proteinuria >1g/day → consider alternative diagnosis
• Young patient with severe hypertension → consider secondary causes
• Flash pulmonary oedema → consider bilateral renal artery stenosis

Bedside

• Blood pressure: sitting and standing; ambulatory BP monitoring
• Urinalysis: bland sediment (absence of active sediment supports diagnosis)
• Fundoscopy: hypertensive retinopathy grading
• ECG: LVH (Sokolow-Lyon criteria)

Bloods

• U&Es: creatinine, eGFR, potassium
• Urine ACR: usually <30 mg/mmol (if >70, consider alternative)
• FBC: blood film for MAHA in malignant hypertension
• Lipid profile: cardiovascular risk
• HbA1c: exclude diabetes
• Renin and aldosterone: if secondary hypertension suspected

Imaging

• Renal ultrasound: bilateral small kidneys (<10 cm), smooth contour, no obstruction
• MR angiography: if renal artery stenosis suspected
• Echocardiogram: assess for LVH, cardiac function

Special Tests

• Renal biopsy: rarely needed; considered if atypical features
• 24-hour urinary metanephrines: if phaeochromocytoma suspected
• Blood film: fragments in malignant hypertension (MAHA)

Non-pharmacological

• Lifestyle modification: sodium restriction <6g/day, DASH diet, weight loss, exercise, smoking cessation, alcohol moderation
• Cardiovascular risk reduction: statin therapy, aspirin if indicated

Pharmacological

Chronic management (per NICE NG136):

• ACE inhibitor (ramipril) or ARB (losartan): first-line, particularly with proteinuria
• Calcium channel blocker (amlodipine 5-10mg): add if needed, first-line in Afro-Caribbean patients without proteinuria
• Thiazide-like diuretic (indapamide 1.5-2.5mg): third-line
• Spironolactone 25-50mg: fourth-line for resistant hypertension (PATHWAY-2 trial)
• Target BP: <130/80 mmHg if proteinuria; <140/90 otherwise

Malignant hypertension:

• Admit to high-dependency/ICU
• IV labetalol 50mg bolus then 1-2mg/min infusion
• IV GTN or sodium nitroprusside for severe cases
• Aim to reduce BP by no more than 25% in first 24 hours (risk of watershed infarction)
• Transition to oral agents when stable

Referral Criteria

• eGFR <30 or rapidly declining → nephrology
• Resistant hypertension (uncontrolled on 4+ agents)
• Suspected secondary hypertension
• Malignant hypertension → urgent medical admission

• Benign nephrosclerosis: slow progression; many patients die of cardiovascular causes before reaching ESRD
• Rate of eGFR decline: typically 2-5 mL/min/year (faster in Afro-Caribbean patients)
• Malignant hypertension: without treatment, >90% mortality at 1 year; with treatment, 5-year survival ~75%
• Adequate BP control can reduce rate of GFR decline by 40-60%
• Overall 5-year survival on dialysis for hypertensive nephropathy: approximately 45-55%

Keith-Wagener-Barker Retinopathy Grading

PATHWAY-2 Trial

• Spironolactone superior to bisoprolol and doxazosin as add-on therapy for resistant hypertension
• Supports the role of aldosterone excess in resistant hypertension

Key Facts

IgA nephropathy is a mesangioproliferative glomerulonephritis characterised by IgA deposition in the glomerular mesangium. It has a highly variable course, from benign microscopic haematuria to rapidly progressive glomerulonephritis.

Epidemiology

• Most common primary GN worldwide; accounts for 25-30% of biopsied GN cases
• Peak age: 20-30 years; M:F ratio 2-3:1
• Higher incidence in East Asian and Caucasian populations
• Lower incidence in Afro-Caribbean populations
• UK incidence: approximately 2-3 per 100,000/year

Aetiology

• Genetic predisposition (GWAS studies identify HLA and complement loci)

• Environmental triggers: mucosal infections (URTI, GI)

Pathophysiology

• Defective O-glycosylation of IgA1 in the hinge region (galactose-deficient IgA1)
• Anti-glycan IgG antibodies form immune complexes with galactose-deficient IgA1

• Progressive inflammation → glomerulosclerosis and tubulointerstitial fibrosis
• Crescent formation indicates severe disease with potential for RPGN

Classic Presentation

• Synpharyngitic macroscopic haematuria: painless, dark/cola-coloured urine occurring within 1-2 days of URTI or GI infection
• Episodes last 2-5 days then resolve spontaneously
• Between episodes: persistent microscopic haematuria (most common finding)

Other Presentations

• Asymptomatic microscopic haematuria with or without proteinuria (most common overall)
• Nephrotic syndrome (5-10% of cases)
• RPGN with crescents (rare but serious)
• Chronic renal impairment detected incidentally

Prognostic Indicators

• Proteinuria >1g/day: strongest modifiable risk factor for progression
• eGFR at presentation: lower = worse prognosis
• Hypertension: associated with progression
• Histological findings: crescents, tubular atrophy, interstitial fibrosis

Red Flags

• Nephrotic-range proteinuria → more aggressive disease
• Associated purpura, arthralgia, abdominal pain → IgA vasculitis (HSP)

Bedside

• Urinalysis: haematuria (dipstick positive for blood), proteinuria; urine microscopy for red cell casts
• Blood pressure: hypertension assessment

Bloods

• U&Es: creatinine, eGFR – assess renal function
• Urine PCR: quantify proteinuria
• Serum IgA: elevated in ~50% (but neither sensitive nor specific)
• C3/C4: normal (unlike post-infectious GN)
• FBC, CRP: exclude systemic disease
• Immunology: ANA, ANCA, anti-GBM if indicated

Imaging

• Renal ultrasound: usually normal; assess kidney size

Special Tests

• Renal biopsy: definitive diagnosis
  • Light microscopy: mesangial hypercellularity, +/- crescents
  • Immunofluorescence: granular mesangial IgA deposition (diagnostic; often with C3 co-deposition)
  • Electron microscopy: mesangial electron-dense deposits
• Oxford MEST-C classification applied to biopsy for prognosis

Non-pharmacological

• Supportive care: dietary sodium restriction, weight management
• Fish oil supplementation (omega-3): limited evidence; some studies suggest modest benefit

Pharmacological

First-line (all patients with proteinuria):

• ACE inhibitor (ramipril 2.5-10mg) or ARB (losartan 50-100mg): target proteinuria <0.5g/day and BP <130/80
• Maximise dose and ensure adequate compliance for 3-6 months before considering immunosuppression

SGLT2 inhibitors:

• Dapagliflozin 10mg OD: renoprotection based on DAPA-CKD subgroup data

Immunosuppression (if proteinuria >1g/day despite 3-6 months optimised RAAS blockade):

• Corticosteroids: TESTING trial protocol – methylprednisolone 0.4mg/kg/day (max 32mg) tapering over 6-9 months; STOP-IgAN showed benefit for steroid pulse therapy
• Mycophenolate mofetil: used in some centres, particularly in Asian populations
• Cyclophosphamide + steroids: reserved for crescentic IgAN (treat as RPGN)

Emerging therapies:

• Sparsentan (dual endothelin/angiotensin receptor antagonist): PROTECT trial showed superior proteinuria reduction
• Budesonide (Nefecon/Tarpeyo): targeted-release budesonide to Peyer's patches (NefIgArd trial – 34% reduction in proteinuria)

Referral Criteria

• All suspected IgA nephropathy → nephrology for biopsy consideration
• Persistent proteinuria >0.5g/day despite RAAS blockade
• Declining eGFR
• Crescentic disease or RPGN

• 20-40% progress to ESRD over 20 years
• ~30% have spontaneous remission, particularly those presenting with isolated haematuria
• Proteinuria <0.5g/day after treatment: excellent prognosis (<5% progress to ESRD)
• Proteinuria >1g/day: poor prognosis; 50% progress to ESRD within 10-20 years
• Recurrence rate in transplant: 30-50%, but graft loss from recurrence is only ~5-10%
• Children generally have better prognosis than adults

Oxford MEST-C Classification

IgA Nephropathy vs Post-Streptococcal GN

Key Facts

MCD is a podocytopathy where T-cell-derived circulating factors damage podocytes, causing proteinuria. It is defined by the absence of significant changes on light microscopy with characteristic foot process effacement on EM.

Epidemiology

• Commonest cause of nephrotic syndrome in children (80%) – peak age 2-6 years
• 10-15% of adult nephrotic syndrome
• Annual incidence in children: 2-4 per 100,000
• M:F ratio in children: 2:1; adults: equal

Aetiology

• Primary/idiopathic: majority of cases
• Secondary causes: NSAIDs, lithium, interferon, lymphoma (Hodgkin), atopy, infections
• T-cell dysfunction with production of circulating permeability factors is hypothesised

Pathophysiology

• Circulating factors (likely T-cell derived) damage podocytes and disrupt the glomerular filtration barrier

• No immune complex deposition, no complement activation
• Normal GBM on EM
• Associated with atopy and lymphoma suggests immune dysregulation

Classic Presentation

• Sudden-onset generalised oedema: periorbital (especially morning), peripheral, scrotal/labial, ascites
• Frothy urine (heavy proteinuria)
• Often preceded by URTI or atopic flare

Nephrotic Syndrome Features

• Proteinuria >3.5g/day (often >10g/day)
• Hypoalbuminaemia (<25 g/L)
• Hyperlipidaemia (raised cholesterol and triglycerides)
• Lipiduria: oval fat bodies, maltese cross under polarised light

Complications

• Infection: peritonitis (particularly pneumococcal), cellulitis – due to immunoglobulin loss
• Thromboembolism: DVT, PE, renal vein thrombosis – due to loss of antithrombin III
• Acute kidney injury: hypovolaemia, sepsis

Red Flags

• AKI at presentation → consider MCD with ATN or consider alternative diagnosis
• Adult-onset MCD → screen for secondary causes (lymphoma, drugs)
• Steroid resistance → reconsider diagnosis (may be FSGS on repeat/deeper biopsy)

Bedside

• Urinalysis: heavy proteinuria (3-4+ on dipstick), no haematuria
• Blood pressure: usually normal or low in children
• Weight: daily (fluid status monitoring)

Bloods

• Serum albumin: low (<25 g/L, often <15 g/L)
• Urine PCR: very high (often >300 mg/mmol)
• U&Es: usually normal renal function (AKI in 5%)
• Lipid profile: raised cholesterol and triglycerides
• FBC: haemoconcentration
• Immunoglobulins: low (particularly IgG)
• Complement (C3/C4): normal

Imaging

• Renal ultrasound: normal-sized kidneys; exclude other pathology
• Chest X-ray: pleural effusions in severe nephrotic syndrome

Special Tests

• Renal biopsy: NOT required in typical childhood MCD (children <12 with classic features treated empirically with steroids)
• Biopsy indicated: adults with nephrotic syndrome, steroid-resistant children, atypical features
  • LM: normal
  • IF: negative
  • EM: diffuse podocyte foot process effacement (diagnostic)
• Selectivity index: highly selective proteinuria (mainly albumin); less used now

Non-pharmacological

• Fluid and sodium restriction during oedema
• Dietary advice: adequate protein intake, avoid excessive salt
• Pneumococcal vaccination: if not previously immunised
• Thromboprophylaxis: consider if albumin <20 g/L and additional risk factors

Pharmacological

Children (first episode):

• Prednisolone 60mg/m²/day (max 80mg) for 4 weeks, then 40mg/m² on alternate days for 4 weeks, then taper over 2-4 weeks
• PREDNOS trial: longer initial course (16 weeks) reduces relapse rate vs 8 weeks

Adults:

• Prednisolone 1mg/kg/day (max 80mg) for a minimum of 4 weeks (up to 16 weeks if needed)
• Slower response than children: 70-80% achieve remission
• Taper over 6 months

Relapsing/steroid-dependent:

• Cyclophosphamide 2mg/kg/day for 8-12 weeks (induces prolonged remission in 70-80%)
• Ciclosporin 3-5mg/kg/day or tacrolimus 0.05-0.1mg/kg/day: steroid-sparing; high relapse on discontinuation
• Mycophenolate mofetil 500mg-1g BD: alternative steroid-sparing agent
• Rituximab 375mg/m² × 1-2 doses: increasingly used for frequently relapsing/steroid-dependent MCD; sustained remission in 60-80%

Symptomatic:

• Diuretics (furosemide + spironolactone) for oedema
• IV albumin 20% (100mL) + furosemide: for severe hypovolaemic oedema
• Statins: for persistent hyperlipidaemia
• Prophylactic penicillin V: during active nephrotic syndrome in children

Referral Criteria

• All adults with nephrotic syndrome → nephrology
• Steroid-resistant children → paediatric nephrology
• Frequently relapsing (≥2 relapses in 6 months or ≥4 in 12 months)

• Children: 90-95% achieve complete remission with steroids; 50-70% relapse
• Adults: 70-80% respond to steroids (but slower, over weeks-months)
• Steroid-resistant cases (~5% children, ~20% adults): re-biopsy to exclude FSGS
• Progression to ESRD: very rare (<5% overall)
• Remission off all treatment: achieved by >80% by adulthood
• Mortality from complications (infection, thromboembolism) is rare with modern management
• Cyclophosphamide induces sustained remission in 70-80% of frequently relapsing cases

Nephrotic Syndrome – Key Complications

PREDNOS Trial

• Compared 8-week vs 16-week prednisolone course in childhood nephrotic syndrome
• Extended course significantly reduced relapse rate at 2 years

Steroid-Sparing Agent Comparison

Key Facts

FSGS is a histological pattern rather than a single disease. It represents a common pathway of podocyte injury from various causes. Primary FSGS is thought to be caused by a circulating permeability factor.

Epidemiology

• Increasing incidence worldwide; now accounts for 20-25% of adult nephrotic syndrome
• Most common glomerular cause of ESRD in the US (particularly Afro-Caribbean populations)
• APOL1 gene variants (G1/G2 alleles) confer 5-15 fold increased risk in African populations
• Peak age: 25-45 years; M:F ratio 1.5:1

Aetiology

• Primary (idiopathic): circulating permeability factor (possibly suPAR, cardiotrophin-like cytokine-1)
• Secondary (adaptive): obesity, reduced nephron mass, vesicoureteric reflux, sickle cell, HIV (collapsing variant)
• Genetic: mutations in podocyte genes (NPHS1, NPHS2/podocin, ACTN4, TRPC6, INF2)
• Drug-induced: heroin, interferon, lithium, pamidronate

Pathophysiology

• Sclerosed segments obstruct capillary flow → further nephron loss
• Focal and segmental distribution means lesions may be missed on biopsy (sampling error)

Presentation

• Nephrotic syndrome in 60-70%: heavy proteinuria, oedema, hypoalbuminaemia
• Subnephrotic proteinuria with haematuria in 30-40%
• Hypertension at presentation in 30-50%
• Renal impairment at presentation in 20-30%
• Microscopic haematuria in 30-50%

Variants (Columbia Classification)

• NOS (not otherwise specified): most common
• Tip variant: better prognosis, more steroid-responsive
• Collapsing variant: worst prognosis, associated with HIV and APOL1; aggressive course
• Perihilar variant: associated with secondary/adaptive FSGS
• Cellular variant: rare, intermediate prognosis

Red Flags

• Collapsing variant → screen for HIV, APOL1; poor prognosis
• Steroid resistance → check compliance, consider genetic testing
• Post-transplant recurrence → early presentation with heavy proteinuria

Bloods

• Serum albumin: low
• Urine PCR: nephrotic-range
• U&Es: may show renal impairment
• Lipid profile: hyperlipidaemia
• C3/C4: normal (distinguishes from complement-mediated GN)
• HIV test: essential (collapsing variant)
• HbA1c: exclude diabetes

Imaging

• Renal USS: normal or slightly enlarged kidneys; echogenic in advanced disease

Special Tests

• Renal biopsy (essential for diagnosis):
  • LM: segmental sclerosis in some glomeruli; may be missed if few glomeruli sampled
  • IF: IgM and C3 trapping in sclerosed segments (non-specific)
  • EM: diffuse foot process effacement (primary) or focal effacement (secondary)
• Genetic testing: NPHS2, NPHS1 mutations if familial, steroid-resistant, or childhood-onset
• Minimum 20 glomeruli recommended on biopsy to avoid sampling error

Non-pharmacological

• Sodium restriction and fluid management for oedema
• Weight loss if obesity-related (secondary FSGS)
• Treat underlying cause in secondary FSGS (e.g., antiretrovirals for HIV)

Pharmacological

Primary FSGS:

• Prednisolone 1mg/kg/day (max 80mg) for ≥16 weeks before declaring steroid resistance
• 30-50% achieve complete or partial remission
• Calcineurin inhibitors (steroid-resistant or steroid-dependent):
  • Ciclosporin 3-5mg/kg/day (target trough 100-175 ng/mL) for ≥12 months
  • Tacrolimus 0.05-0.1mg/kg/day as alternative
  • 50-60% achieve partial/complete remission
• Mycophenolate mofetil 1g BD + dexamethasone: alternative if CNI intolerant
• Rituximab: emerging evidence for steroid-dependent FSGS

Secondary FSGS:

• RAAS blockade (ACEi/ARB) to reduce proteinuria
• Treat underlying cause
• Immunosuppression generally NOT indicated

Supportive:

• ACEi/ARB for all patients with proteinuria
• Diuretics for oedema
• Statins for hyperlipidaemia
• Thromboprophylaxis if albumin <20 g/L

Referral Criteria

• All cases → nephrology
• Steroid resistance → tertiary nephrology/genetic testing
• Planning for transplantation → discuss recurrence risk

• Untreated primary FSGS: 50-70% progress to ESRD within 5-10 years
• Complete remission: <5% progress to ESRD (regardless of treatment modality)
• Partial remission: significantly better than no remission
• Steroid-resistant FSGS: ~60% reach ESRD within 6-8 years
• Collapsing variant: worst prognosis; median time to ESRD ~2-3 years
• Tip variant: best prognosis; behaves similarly to MCD
• Post-transplant recurrence: 20-40%; higher if rapid ESRD from native disease

Columbia Classification of FSGS Variants

Primary vs Secondary FSGS

Key Facts

Membranous nephropathy is an autoimmune disease where antibodies (mainly anti-PLA2R) target podocyte antigens, forming subepithelial immune complexes that activate complement and damage the filtration barrier.

Epidemiology

• Peak incidence: age 50-60 years; M:F 2:1
• Accounts for 25-30% of adult nephrotic syndrome
• Incidence: 1-2 per 100,000/year in the UK
• Rare in children (<5% of nephrotic syndrome)

Aetiology

• Primary (75%): anti-PLA2R antibodies (most common), anti-THSD7A antibodies (~3%)
• Secondary (25%):
  • Malignancy: lung, colon, breast, prostate, lymphoma (especially age >60)
  • Autoimmune: SLE (class V lupus nephritis), RA
  • Infections: hepatitis B, hepatitis C, syphilis, malaria
  • Drugs: NSAIDs, gold, penicillamine, captopril

Pathophysiology

• Anti-PLA2R IgG4 antibodies bind PLA2R on podocyte foot processes
• In situ immune complex formation on the subepithelial surface of GBM
• Complement activation (C5b-9 membrane attack complex) → podocyte injury
• GBM remodelling with spike formation between deposits
• Progressive GBM thickening → nephrotic-range proteinuria

Classic Presentation

• Nephrotic syndrome: peripheral oedema, frothy urine, weight gain
• Insidious onset over weeks to months
• Preserved renal function at diagnosis in most patients

Features

• Heavy proteinuria (often >10g/day)
• Hypoalbuminaemia (<25 g/L)
• Hyperlipidaemia
• Microscopic haematuria (30-50%)

Complications

• Thromboembolism: highest risk of all nephrotic syndromes
  • Renal vein thrombosis (5-8%): flank pain, haematuria, sudden increase in proteinuria
  • DVT/PE
• Infection (loss of immunoglobulins)
• AKI (rare unless complications)

Red Flags

• Age >60 → mandatory malignancy screening (CT chest/abdomen/pelvis)
• Anti-PLA2R negative → higher likelihood of secondary cause
• Low complement → consider SLE or hepatitis
• Constitutional symptoms (weight loss, malaise) → malignancy screen

Bloods

• Anti-PLA2R antibodies: positive in 70-80% of primary MN; titre correlates with disease activity and predicts treatment response
• Anti-THSD7A: if PLA2R negative
• Serum albumin, lipids, U&Es, urine PCR: standard nephrotic syndrome workup
• C3/C4: normal in primary; low in lupus
• ANA, dsDNA: exclude SLE
• Hepatitis B/C serology: mandatory
• Age-appropriate cancer screening: CT CAP, PSA, mammography

Imaging

• Renal USS: normal kidney size
• CT chest/abdomen/pelvis: malignancy screening (age >60 or PLA2R negative)
• Renal Doppler: if renal vein thrombosis suspected

Special Tests

• Renal biopsy (diagnostic):
  • LM: diffuse GBM thickening, GMS stain shows spike pattern
  • IF: granular IgG4 and C3 along GBM
  • EM: subepithelial electron-dense deposits with GBM spike formation
  • PLA2R staining on biopsy: more sensitive than serum antibody

Non-pharmacological

• Risk stratification based on anti-PLA2R titre, proteinuria, and eGFR
• Low risk (proteinuria <3.5g/day, normal eGFR, low PLA2R): observation with supportive care for 6 months
• Dietary sodium restriction, fluid management

Pharmacological

Supportive (all patients):

• ACEi/ARB: maximised for proteinuria reduction
• Statins: for hyperlipidaemia
• Anticoagulation: prophylactic LMWH or warfarin if albumin <20g/L (some advocate <25g/L given high thrombotic risk)

Immunosuppression (high risk or progressive):

• Rituximab 1g IV on days 1 and 15: now considered first-line (MENTOR trial – non-inferior to ciclosporin with better sustained remission)
• Modified Ponticelli regimen: alternating months of IV methylprednisolone/oral prednisolone and oral cyclophosphamide for 6 months
• Calcineurin inhibitors: ciclosporin 3.5-5mg/kg/day or tacrolimus (high relapse rate on cessation)
• Mycophenolate mofetil: limited evidence, used in some centres

Referral Criteria

• All patients with membranous nephropathy → nephrology
• Age >60 or anti-PLA2R negative → malignancy screening
• Thrombotic complications → haematology/anticoagulation clinic

• Rule of thirds: spontaneous remission (30-40%), stable disease (30%), progressive to ESRD (30-40%)
• Anti-PLA2R negative at presentation or early decline: associated with better outcomes
• Spontaneous remission may take up to 3-5 years
• With immunosuppression: 60-80% achieve complete/partial remission
• 5-year renal survival: ~85-90% with modern treatment
• Transplant recurrence: 30-40% but significant graft loss in only ~10%
• Secondary MN: prognosis depends on treating underlying cause

Staging (Ehrenreich-Churg Classification)

MENTOR Trial (2019)

• Rituximab vs ciclosporin for primary membranous nephropathy
• Complete/partial remission at 24 months: rituximab 60% vs ciclosporin 20%
• Rituximab now preferred first-line over CNIs

Anti-PLA2R Antibodies

Key Facts

MPGN represents a pattern of glomerular injury with shared morphological features but distinct pathogenic mechanisms. Modern classification focuses on immunopathogenesis rather than ultrastructural appearance.

Epidemiology

• Rare; <5% of primary glomerulonephritis
• Most common in young adults and adolescents
• Incidence declining in Western countries due to HCV treatment

Aetiology

Immune complex-mediated:

• Hepatitis C with cryoglobulinaemia (most common cause overall)
• Hepatitis B, SLE, monoclonal gammopathy (MGRS)
• Bacterial endocarditis, shunt nephritis

Complement-mediated (C3 glomerulopathy):

• C3 nephritic factor (autoantibody stabilising C3 convertase)
• Factor H deficiency or antibodies
• Genetic complement mutations

Pathophysiology

• Immune complex deposition or complement dysregulation activates complement cascade within glomeruli
• Mesangial and endocapillary proliferation
• Mesangial cell interposition between endothelium and GBM → double-contour (tram-track) GBM
• Progressive glomerulosclerosis

Presentation

• Nephrotic syndrome (40-50%) or nephritic-nephrotic overlap
• Nephritic syndrome (20-30%): haematuria, proteinuria, hypertension, renal impairment
• Asymptomatic urinary abnormalities: microscopic haematuria and proteinuria
• Acute nephritis: rare, can mimic post-infectious GN

Associated Features

• Hepatitis C: arthralgia, purpura, neuropathy (cryoglobulinaemia)
• SLE: rash, arthritis, serositis
• Lipodystrophy: associated with C3 glomerulopathy
• Drusen (retinal deposits): dense deposit disease

Red Flags

• Low C3 in older adult → screen for monoclonal gammopathy
• Cryoglobulinaemia → test for hepatitis C
• Rapidly declining GFR → urgent biopsy

Bloods

• C3: low in both forms; C4: low in immune complex-mediated, normal in C3 glomerulopathy
• Hepatitis B/C serology: mandatory
• Cryoglobulins: if HCV positive or vasculitis suspected
• ANA, dsDNA: exclude SLE
• Serum protein electrophoresis and free light chains: exclude monoclonal gammopathy
• C3 nephritic factor, Factor H/I levels: if C3 glomerulopathy suspected
• FBC, U&Es, albumin, lipids: standard workup

Imaging

• Renal USS: normal kidney size initially

Special Tests

• Renal biopsy (essential):
  • LM: lobular glomeruli, mesangial proliferation, GBM double contours
  • IF: distinguishes immune complex (IgG/IgM + C3) from C3 glomerulopathy (C3 dominant, Ig negative)
  • EM: subendothelial deposits (type I), intramembranous dense deposits (dense deposit disease/type II), subepithelial/subendothelial (type III)
• Complement genetics: if C3 glomerulopathy confirmed

Non-pharmacological

• Treat underlying cause: antiviral therapy for HCV (direct-acting antivirals), treat SLE, treat monoclonal gammopathy
• Supportive care: RAAS blockade, sodium restriction

Pharmacological

Immune complex-mediated:

• Treat underlying disease (HCV: sofosbuvir-based DAAs; SLE: immunosuppression; MGRS: haematological treatment)
• Rituximab: for cryoglobulinaemic MPGN refractory to antiviral therapy

C3 glomerulopathy:

• Mycophenolate mofetil 1-2g/day: first-line for progressive disease
• Eculizumab (anti-C5 monoclonal): for refractory cases with evidence of terminal complement activation
• Plasma exchange: for Factor H antibodies

Supportive (all):

• ACEi/ARB for proteinuria
• Statins, anticoagulation if nephrotic

Referral Criteria

• All cases → nephrology
• C3 glomerulopathy → tertiary centre with complement expertise

• 50% progress to ESRD within 10 years
• Immune complex-mediated: prognosis depends on treating underlying cause; HCV cure can induce remission
• C3 glomerulopathy: generally poorer prognosis; dense deposit disease worst
• Transplant recurrence: 30-65% (higher for C3 glomerulopathy)
• C3GN post-transplant: ~50% graft loss from recurrence at 10 years

Modern Classification of MPGN

Complement Profile in GN

Key Facts

RPGN is a nephrological emergency requiring urgent investigation and treatment. The key is to identify the underlying cause (anti-GBM, immune complex, or ANCA-associated) to guide specific therapy.

Epidemiology

• Rare; overall incidence ~7 per million/year
• ANCA-associated is the most common cause (55-60%)
• Anti-GBM disease: 0.5-1 per million/year
• Peak incidence: bimodal – young adults (20-30) and elderly (60-70)

Aetiology

Pathophysiology

• Severe glomerular injury → fibrin deposition in Bowman's space
• Proliferation of parietal epithelial cells and macrophages forms crescents
• Crescents compress glomerular tuft → loss of filtration
• Irreversible fibrotic crescents develop within 1-2 weeks if untreated
• Tubulointerstitial inflammation accelerates damage

Presentation

• Rapidly declining renal function (days to weeks)
• Haematuria (macroscopic or microscopic with red cell casts)
• Proteinuria (usually subnephrotic)
• Oliguria/anuria in advanced cases
• Constitutional symptoms: malaise, fever, weight loss, arthralgia

Type-Specific Features

• Anti-GBM: haemoptysis (Goodpasture syndrome), young males or elderly
• Immune complex: features of underlying disease (SLE, IgA nephropathy)
• ANCA-associated: upper/lower respiratory tract involvement, purpura, neuropathy

Red Flags

• Haemoptysis + renal failure → anti-GBM disease or ANCA vasculitis (pulmonary-renal syndrome)
• Rapidly rising creatinine with active sediment → do not delay treatment
• Anuria → urgent dialysis + biopsy

Urgent Investigations

• Urinalysis: haematuria with red cell casts (nephritic sediment), proteinuria
• U&Es: rapidly rising creatinine
• Immunology (urgent):
  • ANCA: c-ANCA/PR3 (GPA), p-ANCA/MPO (MPA)
  • Anti-GBM antibodies: positive in type I
  • ANA, dsDNA, C3/C4: lupus screen
  • Immunoglobulins, complement: immune complex disease
• FBC: anaemia, thrombocytopenia (TMA), eosinophilia (EGPA)
• CRP/ESR: elevated
• Blood film: fragmentation if TMA
• Chest X-ray: pulmonary haemorrhage

Renal Biopsy

• Urgent (within 24-48 hours)
• LM: crescents in >50% of glomeruli
• IF: linear IgG (anti-GBM), granular (immune complex), pauci-immune/negative (ANCA)
• Proportion of fibrous vs cellular crescents guides treatment (fibrous = irreversible)

Emergency Management

• Start treatment empirically if high clinical suspicion – do not wait for biopsy
• IV methylprednisolone 500mg-1g daily for 3 days, then oral prednisolone 1mg/kg/day tapering

Anti-GBM Disease (Type I)

• Plasma exchange (daily for 14 days or until antibodies clear) – removes circulating anti-GBM antibodies
• Cyclophosphamide 2-3mg/kg/day PO for 3 months
• Prednisolone 1mg/kg/day tapering over 6 months
• Prognosis: if dialysis-dependent at presentation, renal recovery is unlikely (<10%)

ANCA-Associated (Type III)

• Cyclophosphamide (IV pulses 15mg/kg every 2 weeks × 3, then every 3 weeks × 3-6) OR rituximab 375mg/m² weekly × 4 (RAVE trial showed non-inferiority)
• Prednisolone 1mg/kg/day tapering; consider avacopan (complement C5a receptor inhibitor, ADVOCATE trial) as steroid-sparing
• Plasma exchange: consider if creatinine >500 µmol/L or pulmonary haemorrhage (PEXIVAS trial showed no overall benefit for renal outcomes but may help in severe pulmonary haemorrhage)
• Maintenance: azathioprine or rituximab for 18-24 months minimum

Immune Complex (Type II)

• Treat underlying cause (SLE, infection)
• Immunosuppression as per specific disease

Referral Criteria

• All cases → urgent nephrology (same day)
• Pulmonary haemorrhage → ICU
• Dialysis-dependent → renal team for RRT

• Untreated: almost 100% progress to ESRD within weeks
• Anti-GBM: renal survival ~30-40% overall; <10% if dialysis-dependent at presentation
• ANCA-associated: 60-80% renal survival at 5 years with treatment
• Creatinine at presentation is the strongest predictor of renal outcome
• Proportion of fibrous crescents: higher = worse prognosis
• Relapse rate: anti-GBM <5%, ANCA-associated 30-50% (PR3 > MPO)

Classification of Crescentic GN

Pulmonary-Renal Syndromes

Key Facts

Nephrotic syndrome results from increased glomerular permeability to protein, predominantly albumin. The underlying cause determines treatment and prognosis.

Epidemiology

• Childhood incidence: 2-7 per 100,000 children/year
• Adult incidence: 3 per 100,000/year
• Males more commonly affected in childhood; equal in adults

Aetiology

Children: MCD (80%), FSGS (10%), membranous (5%), MPGN (5%) Adults: Membranous (25-30%), FSGS (20-25%), MCD (10-15%), MPGN (5-10%), diabetic (25%), amyloid (5%) Secondary causes: diabetes, SLE, amyloidosis, drugs (NSAIDs, gold), infections (HBV, HCV, HIV), malignancy

Pathophysiology

• Glomerular basement membrane damage → loss of charge-selective and size-selective barriers

• In many patients, primary sodium retention by nephrons also contributes (overfill hypothesis)
• Hepatic response to hypoalbuminaemia: increased lipoprotein synthesis → hyperlipidaemia
• Loss of antithrombin III, protein C/S, increased fibrinogen → prothrombotic state
• Loss of immunoglobulins (especially IgG) → increased infection susceptibility

Classic Features

• Generalised oedema: periorbital (morning), peripheral (dependent), ascites, pleural effusions
• Frothy urine: due to heavy proteinuria
• Weight gain: fluid retention

Complications

• Thromboembolism: DVT, PE, renal vein thrombosis (5-8%)
  • Most common with membranous nephropathy
  • Suspect RVT: sudden flank pain, worsening proteinuria, haematuria
• Infection: spontaneous bacterial peritonitis (children), cellulitis, pneumonia
  • Encapsulated organisms (pneumococcus) particularly dangerous
• Hyperlipidaemia: raised total cholesterol, LDL, triglycerides
• AKI: hypovolaemia, sepsis, bilateral renal vein thrombosis

Red Flags

• Rapidly declining renal function → exclude RPGN or bilateral RVT
• Haematuria with nephrotic syndrome → consider FSGS, MPGN, lupus (not typical MCD)
• Low complement → SLE, MPGN, post-infectious GN
• Adult >60 with nephrotic syndrome → malignancy screening (especially membranous)

Bedside

• Urinalysis: 3-4+ protein, assess for blood
• Blood pressure: may be normal or elevated
• Daily weight: monitor fluid status
• Fluid balance: strict input/output

Bloods

• Urine PCR or 24h urine protein: >350 mg/mmol or >3.5 g/day
• Serum albumin: <25 g/L
• Lipid profile: raised cholesterol, triglycerides
• U&Es: renal function
• FBC: haemoconcentration (raised Hb/Hct)
• Immunoglobulins: low IgG
• C3/C4: low in MPGN, lupus; normal in MCD, FSGS, membranous
• ANA, dsDNA: lupus screen
• Anti-PLA2R: membranous nephropathy
• HbA1c: diabetes
• Hepatitis B/C, HIV: infection screen
• Serum/urine electrophoresis: myeloma/amyloid

Imaging

• Renal USS: kidney size, exclude other pathology
• Chest X-ray: pleural effusions
• Renal Doppler: if renal vein thrombosis suspected

Special Tests

• Renal biopsy: mandatory in adults; not routine in typical childhood nephrotic syndrome

Non-pharmacological

• Sodium restriction (<2g/day) and fluid restriction if oedematous
• Dietary protein: adequate but not high-protein diet
• Leg elevation, compression stockings
• Pneumococcal vaccination (loss of IgG)

Pharmacological

Oedema management:

• Loop diuretics: furosemide 40-120mg PO/IV
• Spironolactone 25-100mg as adjunct
• IV albumin 20% (100mL) + IV furosemide: for severe/resistant oedema

Thromboprophylaxis:

• Prophylactic LMWH or warfarin if albumin <20 g/L
• Full anticoagulation if documented VTE

Hyperlipidaemia:

• Statins (atorvastatin 20-80mg): for persistent hyperlipidaemia

Specific treatment:

• Directed by underlying cause (see individual conditions)
• Children: empirical prednisolone for presumed MCD
• Adults: guided by biopsy result

Supportive:

• ACEi/ARB: reduce proteinuria
• Infection prophylaxis: consider prophylactic penicillin V in children

Referral Criteria

• All adults → nephrology for biopsy
• Children not responding to 4 weeks of steroids → paediatric nephrology
• Complications (VTE, AKI, severe infection) → urgent admission

• Depends entirely on underlying cause
• MCD in children: 90-95% remission with steroids; excellent long-term prognosis
• Membranous nephropathy: rule of thirds (remission/stable/progressive)
• FSGS: 50-70% progress to ESRD if untreated
• Diabetic nephropathy: leading cause of ESRD
• Thromboembolic events: major cause of morbidity/mortality in acute phase
• Infection: leading cause of mortality in childhood nephrotic syndrome

Nephrotic vs Nephritic Syndrome

Causes by Age Group

Key Facts

Nephritic syndrome reflects acute glomerular inflammation with disruption of the glomerular capillary wall, allowing passage of red blood cells and protein into the urine.

Epidemiology

• Post-streptococcal GN: peak age 5-12 years; rare in adults in developed countries
• IgA nephropathy: most common cause of GN worldwide (but presents as nephritic-nephrotic overlap)
• Incidence of post-infectious GN declining in UK/developed world

Aetiology

Post-infectious (most common in children):

• Group A streptococcus (S. pyogenes) – pharyngitis (1-3 weeks) or impetigo (3-6 weeks)
• Staphylococcal: endocarditis, shunt infections
• Viral: hepatitis B/C

Non-infectious:

• IgA nephropathy
• SLE (class III/IV)
• ANCA-associated vasculitis (GPA, MPA)
• Anti-GBM disease
• MPGN
• Henoch-Schönlein purpura (IgA vasculitis)

Pathophysiology

• Immune complex deposition (subepithelial humps in post-streptococcal) or in situ formation

• Proteinuria results from increased GBM permeability but is usually subnephrotic

Classic Presentation (Post-Streptococcal)

• 1-3 weeks after pharyngitis or 3-6 weeks after skin infection
• Dark/cola-coloured urine (macroscopic haematuria)
• Periorbital oedema (particularly morning)
• Hypertension (can be severe in children)
• Oliguria
• Mild loin/abdominal pain

Other Causes

• IgA nephropathy: haematuria within 1-2 days of URTI (synpharyngitic)
• Lupus nephritis: arthralgia, rash, serositis, multi-system disease
• ANCA vasculitis: constitutional symptoms, pulmonary involvement

Red Flags

• Haemoptysis + renal failure → pulmonary-renal syndrome (anti-GBM, ANCA)
• C3 not normalising after 8 weeks → consider MPGN or C3 glomerulopathy
• Adult with nephritic syndrome → higher likelihood of serious pathology; biopsy needed

Bedside

• Urinalysis: blood +++, protein +/++, red cell casts on microscopy
• Blood pressure: often elevated
• Throat swab: may isolate group A streptococcus

Bloods

• U&Es: creatinine (may be elevated), potassium
• C3/C4: low C3 in post-infectious GN, MPGN, SLE; normal in IgA, ANCA
• ASO titre: elevated 1-3 weeks after streptococcal pharyngitis
• Anti-DNase B: more sensitive for skin infections
• ANA, dsDNA: SLE screen
• ANCA: GPA/MPA screen
• Anti-GBM: Goodpasture screen
• FBC: anaemia (CKD, MAHA), thrombocytopenia (HUS/TTP)
• Blood cultures: if endocarditis-related GN suspected

Imaging

• Renal USS: normal-sized kidneys (acute process)
• Chest X-ray: pulmonary haemorrhage, fluid overload

Special Tests

• Renal biopsy: NOT required for typical post-streptococcal GN in children; indicated in adults, atypical presentation, or failure to improve within 4-6 weeks

Non-pharmacological

• Fluid and sodium restriction during acute phase
• Bed rest: during acute phase
• Monitor fluid balance, daily weights, BP

Pharmacological

Post-streptococcal GN (children):

• Supportive: fluid/salt restriction, antihypertensives (amlodipine, nifedipine)
• Loop diuretics (furosemide): for oedema and hypertension
• Antibiotics: penicillin V for 10 days (eradicate streptococcal carriage; does not alter disease course)
• No immunosuppression required – self-limiting

Other causes:

Referral Criteria

• All adults with nephritic syndrome → nephrology
• Children with atypical features, failure to improve, or declining renal function
• Suspected RPGN → urgent nephrology

• Post-streptococcal GN in children: >95% make full recovery; complement normalises within 8 weeks
• Adults with post-streptococcal GN: 15-30% develop chronic renal impairment
• IgA nephropathy: 20-40% ESRD at 20 years
• Lupus nephritis: depends on class; class IV has 80-90% renal survival at 10 years with treatment
• ANCA vasculitis: 60-80% renal survival at 5 years
• Anti-GBM: poor if dialysis-dependent at presentation

Complement Levels in Glomerulonephritis

Timing of Haematuria After Infection

Key Facts

Lupus nephritis is one of the most serious manifestations of SLE and requires prompt diagnosis and treatment to prevent irreversible renal damage. Renal biopsy is critical for classification.

Epidemiology

• Affects 30-50% of SLE patients; higher in Afro-Caribbean, Hispanic, and Asian populations
• F:M ratio 9:1 (reflecting SLE demographics)
• Peak onset: 20-40 years
• Afro-Caribbean patients have more severe disease and worse outcomes

Aetiology

• Autoimmune disease with loss of tolerance to nuclear antigens
• Anti-dsDNA antibodies form immune complexes that deposit in glomeruli
• Genetic factors: complement deficiency (C1q, C2, C4), Fcγ receptor polymorphisms
• Environmental triggers: UV light, infections, drugs

Pathophysiology

• Circulating anti-dsDNA immune complexes deposit in glomerular subendothelial, subepithelial, and mesangial locations
• In situ immune complex formation also occurs
• Complement activation (classical pathway) → low C3 and C4
• Inflammatory cell infiltration → proliferative GN
• Full house immunofluorescence: IgG, IgA, IgM, C3, C1q deposition

Presentation

• Proteinuria (ranges from mild to nephrotic)
• Haematuria (microscopic, with red cell casts in proliferative classes)
• Hypertension
• Oedema: nephrotic syndrome (particularly class V)
• Declining renal function: especially class III/IV

SLE Systemic Features

• Malar rash, discoid lupus, photosensitivity
• Arthralgia/arthritis, serositis, oral ulcers
• Cytopenias, lymphadenopathy

Red Flags

• Rapidly declining eGFR → urgent biopsy (may be class IV with crescents)
• Nephrotic-range proteinuria → class V or IV+V
• Rising anti-dsDNA and falling complement → flare
• Thrombocytopenia + renal failure → consider TTP-like syndrome (antiphospholipid)

Bloods

• ANA: positive (>95% sensitive for SLE)
• Anti-dsDNA: correlates with disease activity and renal involvement
• C3/C4: low (correlates with flare)
• Anti-C1q antibodies: correlate with lupus nephritis specifically
• U&Es: creatinine, eGFR
• Urine ACR/PCR: quantify proteinuria
• FBC: cytopenias (lymphopenia, thrombocytopenia)
• ESR: typically elevated; CRP may be normal (unless co-infection)
• Anti-Sm antibodies: specific for SLE
• Antiphospholipid antibodies: lupus anticoagulant, anticardiolipin, anti-β2GP1

Imaging

• Renal USS: normal or slightly enlarged kidneys

Special Tests

• Renal biopsy: essential for classification
  • IF: "full house" pattern (IgG, IgA, IgM, C3, C1q)
  • LM: varies by class (mesangial, proliferative, membranous)
  • Activity and chronicity indices guide treatment decisions

Class I/II (Mesangial)

• Supportive: ACEi/ARB for proteinuria, hydroxychloroquine 200-400mg/day (reduces flares by 50%)
• No specific immunosuppression required

Class III/IV (Proliferative) – Induction

• Mycophenolate mofetil 2-3g/day for 6 months (ALMS trial: non-inferior to cyclophosphamide, better side-effect profile) + prednisolone 0.5-1mg/kg/day tapering
• OR IV cyclophosphamide: Euro-Lupus protocol (500mg every 2 weeks × 6 doses) + prednisolone
• Hydroxychloroquine 200-400mg/day: continue in all patients (reduces flares and mortality)
• Voclosporin 23.7mg BD + MMF: improves complete renal response (AURORA trial)
• Belimumab (anti-BLyS): can be added to standard therapy (BLISS-LN trial)

Class III/IV – Maintenance

• MMF 1-2g/day or azathioprine 2mg/kg/day for ≥3-5 years
• Continue hydroxychloroquine
• Gradual steroid taper to ≤5mg/day

Class V (Membranous)

• If subnephrotic: ACEi/ARB + hydroxychloroquine
• If nephrotic: MMF ± calcineurin inhibitor or rituximab

Supportive

• ACEi/ARB for proteinuria
• Vitamin D and calcium supplementation
• Thromboprophylaxis if nephrotic
• Cardiovascular risk management

Referral Criteria

• All suspected lupus nephritis → nephrology + rheumatology
• Class III/IV → tertiary centre
• Treatment-resistant disease → consider belimumab, voclosporin, or rituximab

• Class I/II: excellent prognosis; rarely progresses to ESRD
• Class III/IV: 10-year renal survival 80-90% with modern treatment; 20-30% may relapse
• Class V: 10-year renal survival ~85%; chronic disease with risk of thromboembolic events
• Class VI: advanced sclerosis; not responsive to immunosuppression; plan RRT
• Afro-Caribbean patients: worse outcomes; higher relapse rates
• Flare rate: 30-50% over 5 years on maintenance therapy
• SLE patients on dialysis do relatively well; lupus tends to become quiescent once on RRT

ISN/RPS Classification of Lupus Nephritis

Landmark Trials

Key Facts

Anti-GBM disease is a medical emergency. The speed of diagnosis and initiation of treatment directly determines renal outcome. Every hour of delay before treatment reduces the chance of renal recovery.

Epidemiology

• Rare: 0.5-1 per million/year
• Bimodal age distribution: young males (20-30) and older females (60-70)
• Young patients more likely to have pulmonary involvement
• ~30% of anti-GBM patients are also ANCA positive (double positive – better prognosis)

Aetiology

• Autoimmune: loss of tolerance to alpha-3(IV) collagen (specifically the NC1 domain)
• Triggers: smoking (major risk factor for pulmonary involvement), hydrocarbons, infections, lithotripsy
• HLA-DR15 (DRB1*1501) associated with susceptibility
• HLA-DR1 and DR7 may be protective

Pathophysiology

• Anti-GBM IgG antibodies bind to the NC1 domain of alpha-3(IV) collagen

• Same collagen is present in alveolar basement membrane → pulmonary haemorrhage if membrane disrupted
• Smoking, infection, or fluid overload disrupts alveolar integrity, exposing the antigen
• Rapid progression to irreversible renal failure within days-weeks if untreated

Renal Manifestations

• RPGN: rapidly declining renal function, oliguria/anuria
• Haematuria: macroscopic or microscopic with red cell casts
• Proteinuria: usually subnephrotic
• Hypertension: variable

Pulmonary Manifestations (Goodpasture Syndrome)

• Haemoptysis: ranging from mild to massive life-threatening
• Dyspnoea, cough
• Bilateral alveolar infiltrates on CXR
• Hypoxia
• More common in smokers and young males

Constitutional

• Malaise, fatigue, weight loss
• Fever (less common than in ANCA vasculitis)

Red Flags

• Massive haemoptysis → ICU, emergency plasma exchange
• Rapidly rising creatinine → start treatment immediately (do not wait for biopsy results)
• Anuric at presentation → renal recovery unlikely but still treat to preserve residual function

Urgent Investigations

• Anti-GBM antibodies (serum ELISA): positive in >95%; result within hours in many labs
• ANCA: 30% of anti-GBM patients are also ANCA positive
• U&Es: rapidly rising creatinine
• Urinalysis: haematuria, red cell casts, proteinuria
• FBC: anaemia (blood loss or chronic disease)
• CXR: bilateral alveolar infiltrates (pulmonary haemorrhage)
• ABG: hypoxia if pulmonary involvement
• Carbon monoxide transfer factor (KCO): raised (trapped CO in haemoglobin within alveoli) – most sensitive marker of alveolar haemorrhage

Renal Biopsy

• Urgent (within 24 hours)
• LM: crescentic GN (>50% crescents)
• IF: linear IgG along GBM – pathognomonic
• IF may also show linear C3
• EM: no electron-dense deposits (unlike immune complex disease)
• Proportion of fibrous vs cellular crescents: key prognostic indicator

Emergency Treatment (Start Immediately)

Triple therapy:

1. Plasma exchange: 4L exchanges daily or alternate days for 14 sessions (removes circulating anti-GBM antibodies); replace with 5% albumin (FFP if recent biopsy or active haemorrhage)
2. Cyclophosphamide: 2-3mg/kg/day PO for 3 months (prevents new antibody production)
3. Prednisolone: 1mg/kg/day (max 60mg) tapering over 6 months; often preceded by IV methylprednisolone 500mg-1g × 3 days

Supportive

• Dialysis: if required for fluid overload, hyperkalaemia, uraemia
• Mechanical ventilation: if massive pulmonary haemorrhage
• Smoking cessation: essential
• PCP prophylaxis: co-trimoxazole during immunosuppression

Duration and Monitoring

• Treatment typically 3-6 months total (shorter than ANCA vasculitis)
• Monitor anti-GBM titre: aim for negative
• Relapse is very rare (<5%); long-term maintenance NOT required

Transplantation

• Can be considered once anti-GBM antibodies negative for >6 months
• Recurrence in transplant: very rare (<5%)
• Wait at least 12 months after antibodies clear

Referral Criteria

• All cases → urgent nephrology (same day)
• Pulmonary haemorrhage → ICU
• Dialysis-dependent → renal team

• Overall renal survival: 30-40% at 1 year
• Creatinine <500 µmol/L at presentation: 80-90% renal recovery
• Creatinine >500 µmol/L and dialysis-dependent: <10% renal recovery (particularly if 100% crescents on biopsy)
• Patient survival: >90% at 1 year with treatment
• Pulmonary haemorrhage mortality: ~10% with treatment; higher if massive
• Double-positive (anti-GBM + ANCA): better renal prognosis than anti-GBM alone (30-40% more likely to recover renal function); but higher relapse risk (ANCA-related)
• Relapse: very rare (<5%) – one of the few advantages of this disease vs ANCA vasculitis

Anti-GBM Disease vs ANCA Vasculitis

Prognostic Factors

Key Facts

AAV is characterised by necrotising small-vessel vasculitis, predominantly affecting kidneys, lungs, and upper airways. ANCA testing has revolutionised diagnosis, and rituximab has transformed treatment.

Epidemiology

• Combined incidence: ~20 per million/year in the UK
• GPA and MPA are most common; EGPA is rarer (~2 per million/year)
• Peak age: 60-70 years; rare in children
• M:F roughly equal
• More common in Northern European populations

Aetiology

• Autoimmune with environmental triggers
• ANCA directed against neutrophil granule proteins: PR3 (proteinase 3) or MPO (myeloperoxidase)
• Genetic: HLA associations (HLA-DP for GPA, HLA-DQ for MPA)
• Environmental: silica exposure, infections, drugs (hydralazine, propylthiouracil, minocycline)

Pathophysiology

• Necrotising vasculitis with fibrinoid necrosis of vessel walls
• In kidneys: focal necrotising glomerulonephritis with crescent formation
• Pauci-immune: minimal immunoglobulin/complement deposition (unlike immune complex GN)
• Granuloma formation in GPA (necrotising granulomatous inflammation)
• Eosinophilic infiltration in EGPA

General Features

• Constitutional: fever, malaise, weight loss, night sweats, myalgia, arthralgia
• Renal: haematuria, proteinuria, rapidly declining GFR (RPGN)
• Pulmonary: cough, dyspnoea, haemoptysis, pulmonary infiltrates/haemorrhage

GPA-Specific

• ENT: nasal crusting, epistaxis, saddle-nose deformity, sinusitis, otitis media, subglottic stenosis
• Pulmonary: cavitating lung nodules, pulmonary haemorrhage
• Renal: crescentic GN
• Eyes: scleritis, orbital pseudotumour (proptosis)

MPA-Specific

• Renal: most commonly affected organ; RPGN
• Pulmonary: haemorrhage (no granulomata)
• Skin: purpura, livedo reticularis
• Neuropathy: mononeuritis multiplex

Red Flags

• Pulmonary haemorrhage: life-threatening, requires ICU admission
• Rapidly rising creatinine with active sediment: urgent biopsy and treatment
• Subglottic stenosis: airway compromise in GPA

Bloods

• ANCA: c-ANCA/PR3 (GPA), p-ANCA/MPO (MPA, EGPA)
• U&Es: creatinine, eGFR
• FBC: anaemia, eosinophilia (EGPA), thrombocytosis
• CRP/ESR: elevated
• Urine PCR: proteinuria
• Urinalysis: haematuria with red cell casts
• Anti-GBM: exclude dual positivity (30% overlap)
• C3/C4: normal (unlike lupus)
• LFTs, hepatitis serology: baseline before treatment

Imaging

• CT chest: cavitating nodules (GPA), ground-glass opacification (haemorrhage)
• CT sinuses: mucosal thickening, bony destruction (GPA)
• Renal USS: normal-sized kidneys

Special Tests

• Renal biopsy: pauci-immune crescentic GN; focal segmental necrotising lesions
• Lung biopsy: necrotising granulomatous vasculitis (GPA)
• Nerve biopsy: vasculitic neuropathy

Induction (Severe/Organ-Threatening)

• Rituximab 375mg/m² IV weekly × 4 doses (RAVE trial: non-inferior to CYC; superior for relapsing disease)
• OR IV cyclophosphamide: 15mg/kg every 2 weeks × 3, then every 3 weeks × 3 (Euro-Vasculitis/CYCLOPS)
• Prednisolone 1mg/kg/day (max 60mg) tapering to 5mg by 5 months
• IV methylprednisolone 500mg-1g × 3 days for severe presentations
• Avacopan 30mg BD: C5a receptor inhibitor; steroid-sparing (ADVOCATE trial – non-inferior to steroids with fewer side effects)
• Plasma exchange: consider for severe pulmonary haemorrhage or creatinine >500 µmol/L (PEXIVAS showed no benefit for renal outcome but may help pulmonary haemorrhage)

Maintenance (≥18-24 months minimum)

• Rituximab 500mg IV every 6 months (MAINRITSAN: superior to azathioprine for preventing relapse)
• OR Azathioprine 2mg/kg/day (check TPMT before starting)
• Continue low-dose prednisolone (aim to wean off)

Supportive

• PCP prophylaxis: co-trimoxazole 480mg OD during immunosuppression (also reduces ENT relapse in GPA)
• Bone protection: calcium/vitamin D, consider bisphosphonate
• BP control: ACEi/ARB for renal protection

Referral Criteria

• All suspected AAV → urgent nephrology/rheumatology
• Pulmonary haemorrhage → ICU
• Subglottic stenosis → ENT

• 5-year survival: 75-80% (improved dramatically with rituximab)
• Renal survival at 5 years: 70-80%
• Relapse rate: 30-50% within 5 years; PR3 > MPO
• Mortality: infections (from immunosuppression) and cardiovascular disease are leading causes
• ANCA negativity during remission associated with lower relapse risk
• Dialysis-dependent at presentation: ~30% recover enough to discontinue dialysis
• MPA has lower relapse rate but higher mortality than GPA

ANCA-Associated Vasculitis Comparison

Landmark Trials

Key Facts

ADPKD is a systemic ciliopathy with progressive cyst formation in kidneys and other organs. It is the most common genetic cause of renal failure.

Epidemiology

• Prevalence: 1 in 400-1,000
• Accounts for 5-10% of ESRD in the UK
• Autosomal dominant with near-complete penetrance
• 5-10% of cases are de novo mutations (no family history)

Aetiology

• PKD1 (85%): encodes polycystin-1; earlier, more severe disease
• PKD2 (15%): encodes polycystin-2; later onset, milder
• Autosomal recessive PKD (ARPKD): PKHD1 gene; presents in neonates/infants

Pathophysiology

• Polycystins are expressed in renal tubular cilia and regulate intracellular calcium signalling

• Two-hit hypothesis: inherited mutation + somatic second hit → cyst initiation
• Cysts gradually enlarge (1-2% per year volume increase), compressing normal parenchyma
• Vasopressin (ADH) stimulates cAMP and cyst growth → rationale for tolvaptan
• Progressive renal enlargement: kidneys can reach >30 cm in length

Renal Manifestations

• Bilateral palpable kidneys (often ballotable)
• Hypertension: earliest and most common manifestation (develops before GFR decline)
• Loin/flank pain: cyst haemorrhage, infection, or mass effect
• Haematuria: cyst rupture or infection; can be macroscopic
• UTI/cyst infection: more common in women; cyst infections can be difficult to treat
• Renal stones: 20-30% (uric acid and calcium oxalate)
• Progressive CKD: gradual decline to ESRD

Extra-renal Manifestations

• Hepatic cysts: 70-80% (usually asymptomatic; more common/larger in women)
• Intracranial aneurysms: 5-10% (risk of SAH; screen if family history of aneurysm/SAH)
• Mitral valve prolapse: 25%
• Aortic root dilatation, aortic regurgitation
• Diverticular disease: increased prevalence
• Abdominal/inguinal herniae

Red Flags

• Sudden severe headache → subarachnoid haemorrhage (ruptured aneurysm)
• Fever with loin pain → cyst infection (may not show on standard cultures)
• Rapidly declining GFR → cyst haemorrhage, obstruction, or superimposed disease

Bedside

• Blood pressure: often elevated before renal impairment
• Family history: essential (autosomal dominant pattern)
• Urinalysis: haematuria

Bloods

• U&Es: eGFR, creatinine
• FBC: polycythaemia (increased EPO production by cysts)
• Urine ACR: proteinuria assessment

Imaging

• Renal ultrasound: first-line diagnostic tool; bilateral enlarged cystic kidneys
  • Ravine criteria (at-risk individuals): ≥3 cysts aged 15-39; ≥2 cysts per kidney aged 40-59
• MRI with TKV (total kidney volume): best predictor of progression; used for Mayo classification (1A-1E)
• MR angiography (brain): screen for intracranial aneurysms if family history of aneurysm/SAH (screening from age 20)

Special Tests

• Genetic testing: PKD1/PKD2 mutation analysis; useful if equivocal imaging, young living donor candidates, or reproductive counselling
• CT/MRI: complicated cyst assessment (haemorrhage, infection, malignancy)
• PET-CT: may help differentiate cyst infection from haemorrhage

Non-pharmacological

• Adequate hydration: 2.5-3L/day (suppresses vasopressin and may slow cyst growth)
• Sodium restriction: <6g/day
• Regular exercise: maintain cardiovascular fitness
• Avoid contact sports: risk of cyst rupture with enlarged kidneys
• Genetic counselling: 50% transmission risk

Pharmacological

Blood pressure:

• ACEi (ramipril) or ARB (candesartan): first-line
• Target <130/80 (HALT-PKD trial: intensive BP control slowed TKV growth in early disease)

Tolvaptan (V2 receptor antagonist):

• NICE TA876: approved for adults with ADPKD and evidence of rapidly progressive disease
• Criteria: CKD stages 2-3, TKV growth >5%/year or eGFR decline >2.5 mL/min/year
• Dose: titrated from 45/15mg to 90/30mg (split dosing)
• TEMPO 3:4 trial: reduced TKV growth by 49% and eGFR decline by 26%
• Monitoring: LFTs monthly for 18 months then 3-monthly (risk of hepatotoxicity ~5%)
• Side effects: polyuria, polydipsia, nocturia, hepatotoxicity

Other:

• Pain management: paracetamol, avoid NSAIDs; consider nerve blocks for chronic pain
• Cyst infection: lipophilic antibiotics penetrate cysts better (ciprofloxacin, co-trimoxazole); prolonged course 4-6 weeks
• Renal stones: treat as per standard guidelines

Surgical

• Cyst aspiration/sclerotherapy: for symptomatic large cysts
• Nephrectomy: prior to transplant if very large kidneys (space, infection risk)
• Hepatic cyst fenestration: for massive hepatomegaly

Renal Replacement Therapy

• Transplantation is treatment of choice for ESRD
• Living related donors must be screened (genetic testing/USS)
• Peritoneal dialysis or haemodialysis as bridge to transplant

Referral Criteria

• All diagnosed ADPKD → nephrology
• Rapidly progressive disease → assess for tolvaptan
• Family history of intracranial aneurysm → MRA screening

• PKD1: median age to ESRD 54 years
• PKD2: median age to ESRD 74 years
• TKV >1500 mL: strong predictor of progression to ESRD
• Tolvaptan delays ESRD by an estimated 4-7 years
• Intracranial aneurysm rupture: mortality 50% (justifies screening in high-risk families)
• Post-transplant outcomes: excellent; ADPKD patients tend to do well on transplant
• CKD complications (anaemia, bone disease) may develop later than other causes of CKD due to preserved EPO production

Mayo Classification for ADPKD Prognosis

PKD1 vs PKD2

Key Facts

Alport syndrome results from defective type IV collagen in basement membranes of kidneys, cochlea, and eyes. Early ACEi therapy significantly delays ESRD.

Epidemiology

• Incidence: 1 in 5,000-10,000
• Accounts for 1-2% of ESRD
• X-linked (80%): COL4A5 mutations; affects males severely
• Autosomal recessive (15%): COL4A3/4 mutations; both sexes equally
• Autosomal dominant (5%): milder, later onset

Aetiology

• Mutations in alpha-3, alpha-4, or alpha-5 chains of type IV collagen
• These chains form the collagen IV network of GBM, cochlear basement membrane, and lens capsule
• X-linked: hemizygous males have no functional alpha-5(IV) collagen; heterozygous females have mosaic expression

Pathophysiology

• Defective collagen IV → structurally abnormal GBM
• GBM initially thin (childhood) → progressive thickening, splitting, and lamellation (basket-weave)
• Secondary FSGS develops as disease progresses
• Absence of alpha-3/4/5(IV) collagen network from GBM confirmed on immunohistochemistry
• Cochlear basement membrane abnormalities → progressive sensorineural hearing loss

Renal

• Persistent microscopic haematuria from early childhood (often from birth in males)
• Episodic macroscopic haematuria (often with infections)
• Progressive proteinuria developing in adolescence/early adulthood
• Hypertension as CKD develops
• ESRD: X-linked males by age 20-30; autosomal recessive by 20-30; X-linked females variable (10-15% ESRD)

Hearing

• Bilateral sensorineural hearing loss: high-frequency initially, progressive
• Develops in late childhood/adolescence
• Not present at birth (unlike congenital deafness)
• Affects 80% of X-linked males

Ocular

• Anterior lenticonus: pathognomonic (cone-shaped lens protrusion); 25-40% of X-linked males
• Dot-and-fleck retinopathy: perimacular region
• Posterior polymorphous corneal dystrophy

Red Flags

• Family history of haematuria + deafness + early renal failure → strong suspicion
• Young male with unexplained haematuria → consider Alport
• Proteinuria developing in childhood with haematuria → initiate ACEi

Bloods

• U&Es: eGFR, creatinine
• Urine ACR/PCR: quantify proteinuria
• Urinalysis: persistent haematuria
• Audiometry: bilateral high-frequency sensorineural hearing loss

Imaging

• Renal USS: normal initially; may become small in advanced disease
• Slit-lamp examination: anterior lenticonus, retinal flecks

Special Tests

• Genetic testing: now first-line for diagnosis (NGS panels for COL4A3/4/5)
• Renal biopsy (if genetic testing inconclusive):
  • EM: GBM thickening, thinning, splitting with basket-weave lamellation (pathognomonic)
  • IF: absence of alpha-5(IV) collagen staining in GBM (X-linked males)
  • Skin biopsy: absence of alpha-5(IV) in epidermal basement membrane (non-invasive alternative for X-linked)
• Family screening: urinalysis, audiometry, and genetic testing for at-risk relatives

Non-pharmacological

• Genetic counselling: essential for family planning
• Hearing aids: for sensorineural hearing loss
• Regular ophthalmology review: monitor for lens abnormalities

Pharmacological

• ACE inhibitors (ramipril): started at first sign of proteinuria (even in childhood)
  • EARLY-PROTECT trial: ACEi in children with haematuria-only delays proteinuria onset
  • Significantly delays progression to ESRD by years to decades
• ARBs: alternative if ACEi intolerant
• BP control: target <130/80 in adults
• Standard CKD management: as disease progresses (anaemia, bone disease, etc.)

Renal Replacement Therapy

• Transplantation: treatment of choice for ESRD
• Risk of anti-GBM disease in transplant (~3-5%): recipient develops antibodies against "normal" alpha-3/4/5(IV) collagen in the allograft
• Patients should be counselled about this risk
• Living related donors: must be screened genetically (heterozygous females may be carriers)

Referral Criteria

• All suspected Alport syndrome → paediatric/adult nephrology + clinical genetics
• Hearing loss → audiology/ENT
• Ocular symptoms → ophthalmology

• X-linked males: ESRD by age 20-30 without treatment; ACEi can delay ESRD by 10-15 years
• X-linked females (carriers): 10-15% develop ESRD (usually later in life); variable severity
• Autosomal recessive: ESRD by age 20-30 (both sexes equally affected)
• Autosomal dominant: later onset, ESRD uncommon before age 50
• Post-transplant anti-GBM disease: 3-5% of X-linked males; usually early post-transplant
• Hearing loss: progressive but does not improve with renal transplantation

Alport Syndrome Genetics

Thin Basement Membrane Disease vs Alport Syndrome

Key Facts

RCC is the most common solid renal tumour. The incidental detection rate has increased due to widespread cross-sectional imaging, improving stage at diagnosis.

Epidemiology

• ~13,000 new cases/year in the UK (7th most common cancer)
• Peak age 60-70 years; M:F 2:1
• Incidence increasing (partly due to incidental detection)
• 5th most common cancer in males in the UK

Aetiology

• Risk factors: smoking (30% increased risk), obesity, hypertension, chronic dialysis (acquired cystic disease)
• Genetic syndromes: VHL syndrome (clear cell), hereditary papillary RCC (MET mutations), BHD syndrome

Pathophysiology

• Arises from renal tubular epithelium
• Clear cell (70-80%): VHL inactivation → HIF-driven angiogenesis; highly vascular tumour
• Papillary (10-15%): type 1 (MET) and type 2
• Chromophobe (5%): arises from intercalated cells; better prognosis
• Collecting duct (<1%): aggressive

Local Symptoms

• Haematuria: painless, macroscopic (most common presenting symptom)
• Loin/flank pain: dull aching
• Palpable mass: in advanced disease
• Classic triad present in <10% of cases

Systemic/Paraneoplastic

• Pyrexia of unknown origin (20%)
• Weight loss, fatigue, anorexia
• Polycythaemia: ectopic EPO (3-5%)
• Hypercalcaemia: PTHrP secretion
• Hypertension: renin secretion
• Stauffer syndrome: non-metastatic hepatic dysfunction (raised ALP, hepatosplenomegaly)
• Left varicocele: left renal vein obstruction (pathognomonic for left RCC)
• Amyloidosis: AA type (rare)

Metastatic Disease (25% present with metastases)

• Lung (75%), bone (20%), liver (18%), brain (8%)
• Cannonball metastases on CXR (classic)

Red Flags

• Painless haematuria in adults → urgent investigation (2-week wait referral)
• New left varicocele → left renal mass
• Unexplained PUO + raised ESR → consider RCC

Bedside

• Urinalysis: haematuria
• BP: hypertension

Bloods

• FBC: polycythaemia (EPO) or anaemia (chronic disease)
• U&Es: renal function
• Calcium: hypercalcaemia (PTHrP)
• LFTs: Stauffer syndrome (raised ALP)
• ESR/CRP: often elevated
• LDH: prognostic marker

Imaging

• CT abdomen with contrast (triphasic): gold standard; characterises mass, staging, vascular invasion
  • Bosniak classification for cystic lesions (I-IV)
• CT chest: lung metastases
• MRI: if IVC thrombus suspected; superior for vascular detail
• Bone scan: if bone pain or raised ALP
• CT/MRI brain: if neurological symptoms

Special Tests

• Renal biopsy: not routine for surgical candidates; indicated if lymphoma suspected, small renal mass in comorbid patient, or if metastatic disease with unknown primary
• PET-CT: limited role in RCC (variable FDG uptake); more useful for detecting recurrence

Localised Disease (T1-T3)

• Partial nephrectomy: T1a (≤4cm); nephron-sparing; preferred when technically feasible
• Radical nephrectomy: T1b-T3; includes kidney, Gerota's fascia, ± adrenalectomy, ± lymph node dissection
• Active surveillance: small renal masses (≤3cm) in elderly/comorbid patients; growth rate monitoring with serial imaging
• Ablation (radiofrequency/cryoablation): alternative for small tumours in patients unfit for surgery

Locally Advanced (T3-T4 with IVC Thrombus)

• Radical nephrectomy with IVC thrombectomy (may require cardiopulmonary bypass for right atrial extension)

Metastatic RCC

• Cytoreductive nephrectomy: consider in selected patients with good performance status
• First-line systemic therapy (NICE approved):
  • Nivolumab + ipilimumab (CheckMate 214): intermediate/poor risk
  • Pembrolizumab + axitinib (KEYNOTE-426): all risk groups
  • Cabozantinib (METEOR): all risk groups
  • Sunitinib 50mg/day (4 weeks on, 2 weeks off): TKI; historical standard
  • Pazopanib 800mg/day: alternative TKI
• Second-line: nivolumab monotherapy, cabozantinib, lenvatinib + everolimus

Referral Criteria

• Any suspicious renal mass → urology 2-week wait
• Painless macroscopic haematuria → urgent referral
• Metastatic disease → oncology MDT

• Stage I: 5-year survival ~90%
• Stage II: 5-year survival ~75%
• Stage III: 5-year survival ~60%
• Stage IV: 5-year survival 10-15% (improved with immunotherapy)
• Checkpoint inhibitors have improved median OS in metastatic RCC from ~15 months to >45 months
• Late recurrence can occur >10 years after nephrectomy (lifelong surveillance recommended)
• Spontaneous regression of metastases after nephrectomy: extremely rare (<1%) but well-documented

RCC Subtypes

IMDC Prognostic Criteria (Metastatic RCC)

Favourable (0 factors), Intermediate (1-2), Poor (3-6)

Key Facts

RAS is an important but often over-treated cause of secondary hypertension. The ASTRAL and CORAL trials changed practice, demonstrating that most atherosclerotic RAS should be managed medically.

Epidemiology

• Atherosclerotic RAS: found in 7% of patients >65 years at autopsy; 15-30% of patients with peripheral vascular disease
• FMD: much rarer; predominantly young women
• Prevalence increases with age and cardiovascular risk factors

Aetiology

• Atherosclerosis (90%): ostial/proximal stenosis; associated with generalised atherosclerosis
• FMD (10%): medial fibroplasia (most common subtype); mid/distal renal artery; "string-of-beads" appearance
• Other rare causes: Takayasu arteritis, neurofibromatosis, radiation, aortic dissection

Pathophysiology

• Stenosis reduces renal perfusion → activation of RAAS

• Bilateral RAS or RAS in solitary kidney: severe renal impairment

Hypertension

• Resistant hypertension: uncontrolled on 3+ antihypertensives
• Severe/accelerated hypertension: particularly if onset age >55 or <30
• Abrupt onset of hypertension in previously normotensive patient

Renal

• AKI precipitated by ACEi/ARBs: >20-30% rise in creatinine
• Asymmetric kidney size (>1.5cm difference on USS)
• Progressive CKD despite good BP control

Cardiovascular

• Flash pulmonary oedema: bilateral RAS; recurrent sudden-onset APO
• Abdominal bruit: heard in 40-50% (epigastric/flank)
• Generalised atherosclerosis: peripheral vascular disease, coronary artery disease, carotid disease

Red Flags

• Flash pulmonary oedema → bilateral RAS
• AKI on ACEi → stop and investigate
• Young woman with severe hypertension → FMD

Bloods

• U&Es: creatinine (may be elevated), potassium (hypokalaemia suggests secondary hyperaldosteronism)
• Lipid profile: cardiovascular risk
• Plasma renin and aldosterone: elevated renin (but not routinely measured)

Imaging

• Duplex renal ultrasound: first-line screening; peak systolic velocity >180cm/s suggests >60% stenosis; resistance index >0.8
• MR angiography (gadolinium-enhanced): gold standard non-invasive; 90-95% sensitivity/specificity
• CT angiography: alternative if MRI contraindicated; excellent for atherosclerotic disease
• Catheter angiography: gold standard but invasive; reserved for intervention
• Captopril renography: functional test; sensitivity ~90% for unilateral RAS; less used now

Special Tests

• Renal USS: asymmetric kidney size (>1.5cm difference suggests significant RAS on the smaller side)
• 24h ambulatory BP: confirm resistant hypertension

Medical Management (First-Line for Atherosclerotic RAS)

• Antihypertensives: calcium channel blocker (amlodipine) + thiazide-like diuretic (indapamide) first-line
• ACEi/ARB: can be used cautiously for unilateral RAS (monitor creatinine/K+ at 1-2 weeks); contraindicated in bilateral RAS or single kidney with RAS
• Statin: atorvastatin 80mg for cardiovascular risk reduction
• Antiplatelet: aspirin 75mg or clopidogrel
• Smoking cessation: essential

Revascularisation

Atherosclerotic RAS:

• ASTRAL (2009) and CORAL (2014) trials: stenting provided no additional benefit over medical therapy for BP control or renal function preservation
• Stenting reserved for: flash pulmonary oedema, rapidly declining renal function despite medical therapy, failure of medical BP control, or recurrent AKI

Fibromuscular dysplasia:

• Percutaneous transluminal angioplasty (PTA) without stenting: curative in 60-80%
• First-line treatment for FMD
• Screen for FMD in other vascular beds (carotid, iliac)

Referral Criteria

• Suspected RAS → nephrology/vascular
• FMD → specialist vascular centre
• Flash pulmonary oedema with suspected bilateral RAS → urgent referral

• Atherosclerotic RAS: progressive; 10-20% of stenoses progress to occlusion over 5 years
• Medical therapy: adequate BP control achieved in 70-80% with multi-drug regimen
• FMD after angioplasty: cure of hypertension in 30-50%, improvement in 30-40%
• Ischaemic nephropathy: progressive CKD despite treatment in many patients with bilateral disease
• Cardiovascular events: leading cause of death in atherosclerotic RAS patients

Atherosclerotic RAS vs FMD

ASTRAL and CORAL Trials

Key Facts

UTIs are among the most common bacterial infections. Most uncomplicated lower UTIs in women can be managed empirically without urine culture. Appropriate antibiotic stewardship is essential.

Epidemiology

• Lifetime incidence in women: ~50%; recurrence in 25-30%
• UTI in men: uncommon before age 50; usually indicates underlying pathology
• Incidence increases with age, catheterisation, and institutionalisation
• Most common cause of Gram-negative bacteraemia

Aetiology

• E. coli: 70-80% (community), 50% (hospital)
• Other Gram-negatives: Klebsiella (8%), Proteus (5% – alkaline urine, staghorn calculi)
• Staphylococcus saprophyticus: second most common in young women
• Enterococcus: associated with catheterisation
• Pseudomonas: catheterised/hospitalised patients

Pathophysiology

• Ascending infection from perineum via urethra to bladder (cystitis) and potentially to kidneys (pyelonephritis)
• Short female urethra explains female predominance
• Bacterial virulence factors: P-fimbriae (pyelonephritis), type 1 fimbriae (cystitis)
• Risk factors: female sex, sexual activity, pregnancy, menopause (atrophic vaginitis), catheterisation, urinary obstruction, vesicoureteric reflux, diabetes

Lower UTI (Cystitis)

• Dysuria: burning/stinging on urination
• Frequency and urgency
• Suprapubic pain/discomfort
• Cloudy, malodorous urine
• Haematuria (30% of cases)
• No systemic features

Upper UTI (Pyelonephritis)

• Fever (>38°C), rigors
• Loin/flank pain (unilateral)
• Nausea, vomiting
• Costovertebral angle tenderness
• Symptoms of lower UTI may or may not be present

In Elderly

• May present atypically: confusion, falls, functional decline, incontinence
• Do not treat asymptomatic bacteriuria in the elderly

Red Flags

• Sepsis (high NEWS2 score, tachycardia, hypotension) → IV antibiotics
• Pyelonephritis not responding to oral antibiotics within 48 hours → consider abscess/obstruction
• Recurrent UTI in men → urological investigation
• Haematuria after UTI treated → urological referral to exclude malignancy

Bedside

• Urine dipstick: nitrites (specific) + leucocytes (sensitive); both positive = high PPV
• NEWS2 score: assess for sepsis

Bloods (if systemic features/pyelonephritis)

• FBC, CRP: raised WCC and CRP
• U&Es: renal function
• Blood cultures: if systemically unwell
• Lactate: if sepsis suspected

Microbiology

• MSU for culture and sensitivity: indicated for complicated UTI, treatment failure, recurrent UTI, pregnancy, males, catheterised
• Significant bacteriuria: ≥10⁵ CFU/mL (symptomatic: ≥10³ may be significant)

Imaging

• Not routine for uncomplicated UTI
• Renal USS: if pyelonephritis not responding to treatment (exclude abscess/obstruction)
• CT KUB: if renal stones suspected
• DMSA scan: scarring assessment in children with recurrent UTI

Uncomplicated Lower UTI in Women (NICE NG109)

• First-line: nitrofurantoin 100mg MR BD for 3 days (if eGFR >45)
• Second-line: trimethoprim 200mg BD for 3 days (check local resistance – E. coli resistance ~30% in some areas)
• Third-line: pivmecillinam 400mg stat then 200mg TDS for 3 days
• Empirical treatment without MSU is appropriate in typical presentations

Lower UTI in Men

• Trimethoprim 200mg BD or nitrofurantoin 100mg MR BD for 7 days
• Always send MSU
• Consider prostatitis (14-28 day course of trimethoprim or ciprofloxacin)

Pyelonephritis

• Mild (oral): cefalexin 500mg TDS for 7-10 days or co-amoxiclav 500/125mg TDS
• Severe (IV): IV co-amoxiclav 1.2g TDS or IV piperacillin-tazobactam 4.5g TDS (per local protocol)
• Switch to oral when clinically improving for 24-48 hours

UTI in Pregnancy

• Always treat (including asymptomatic bacteriuria)
• Nitrofurantoin (avoid at term – neonatal haemolysis) or cefalexin 500mg BD for 7 days
• Trimethoprim: avoid first trimester (folate antagonist)
• Send MSU for culture

Recurrent UTIs (≥3/year or ≥2 in 6 months)

• Behavioural measures: adequate hydration, post-coital voiding, avoid constipation
• Vaginal oestrogen cream (postmenopausal women): effective in reducing recurrence
• Antibiotic prophylaxis: nitrofurantoin 50-100mg nocte or trimethoprim 100mg nocte for 6 months
• Post-coital prophylaxis: single-dose antibiotic after intercourse
• Self-start therapy: patient-initiated course at symptom onset
• D-mannose, cranberry products: limited evidence

Referral Criteria

• Recurrent UTI in men → urology
• Recurrent UTI in women → further investigation (USS, cystoscopy if haematuria)
• UTI not responding to treatment → imaging for complications

• Uncomplicated cystitis: >95% cure rate with appropriate antibiotics
• Pyelonephritis: full recovery expected with prompt treatment; 10-20% develop bacteraemia
• Untreated pyelonephritis in pregnancy: 20-40% develop sepsis
• Recurrent UTIs: 25-30% of women experience recurrence within 6 months
• Catheter-associated UTIs: most common healthcare-associated infection; increases morbidity and length of stay

NICE NG109 Antibiotic Choice Summary

Common UTI Organisms

Key Facts

Pyelonephritis requires prompt antibiotic therapy and assessment for complications. It can rapidly progress to urosepsis, particularly in patients with obstruction or immunosuppression.

Epidemiology

• Incidence: 15-17 per 10,000 women/year; 3-4 per 10,000 men/year
• Peak age: reproductive years (women), elderly (both sexes)
• Pregnancy: 1-2% of pregnancies; 20-40% of untreated asymptomatic bacteriuria progresses to pyelonephritis

Aetiology

• Ascending infection from lower urinary tract (most common route)
• Haematogenous spread (rare): Staphylococcus aureus from distant focus
• Organisms: E. coli (70-80%), Klebsiella, Proteus, Enterococcus, Pseudomonas

Pathophysiology

• Bacteria ascend from bladder via ureters to renal pelvis and parenchyma
• Vesicoureteric reflux facilitates ascent
• Infection causes acute inflammation with neutrophil infiltration, tubular damage, and interstitial oedema
• Can lead to abscess formation, papillary necrosis (particularly in diabetics), and renal scarring

Typical Presentation

• Fever (>38°C), rigors, chills
• Loin/flank pain (unilateral, dull aching)
• Costovertebral angle tenderness on examination
• Nausea and vomiting
• Lower urinary tract symptoms may or may not be present (dysuria, frequency)

Severe/Complicated

• Sepsis: tachycardia, hypotension, confusion
• Renal abscess: swinging fever, failure to respond to antibiotics
• Emphysematous pyelonephritis: gas within renal parenchyma (diabetics); surgical emergency

Red Flags

• Sepsis (NEWS2 ≥5) → IV antibiotics, fluid resuscitation, senior review
• No improvement after 48-72 hours → imaging for abscess/obstruction
• Pregnant with pyelonephritis → hospital admission, IV antibiotics
• Known urinary obstruction + infection → emergency nephrostomy/drainage (pyonephrosis)

Bedside

• Urine dipstick: nitrites, leucocytes, blood
• Observations: temperature, NEWS2 score

Bloods

• FBC: raised WCC (neutrophilia)
• CRP: elevated
• U&Es: renal function (AKI risk)
• Blood cultures: before antibiotics (positive in 20-30%)
• Lactate: if sepsis suspected

Microbiology

• MSU: for culture and sensitivity before antibiotics

Imaging

• Not routine for uncomplicated pyelonephritis
• Renal USS or CT: indicated if:
  • No clinical improvement after 48-72 hours IV antibiotics
  • Suspected obstruction (pyonephrosis)
  • Recurrent pyelonephritis
  • Atypical presentation
• CT abdomen with contrast: best for abscess, emphysematous pyelonephritis
• DMSA scan: assess renal scarring (particularly in children with VUR)

Mild Pyelonephritis (Outpatient)

• Cefalexin 500mg TDS or co-amoxiclav 500/125mg TDS for 7-10 days (NICE NG111)
• Trimethoprim 200mg BD for 14 days if culture-sensitive
• Adequate oral fluids, regular paracetamol
• Safety-netting: return if worsening, vomiting, unable to take oral medications

Severe Pyelonephritis (Inpatient)

• IV co-amoxiclav 1.2g TDS or IV piperacillin-tazobactam 4.5g TDS (per local antibiotic guidelines)
• IV gentamicin 5-7mg/kg (single dose, OD dosing): for sepsis or resistant organisms
• IV-to-oral switch when: afebrile for 24-48 hours, improving clinically, tolerating oral intake
• Total course: 7-14 days

Complicated Pyelonephritis

• Obstruction with infection (pyonephrosis): emergency nephrostomy or ureteric stent + IV antibiotics
• Renal abscess (>3cm): percutaneous drainage + prolonged antibiotics (4-6 weeks)
• Emphysematous pyelonephritis: IV antibiotics ± nephrectomy (high mortality 20-40%)

In Pregnancy

• Hospital admission for IV antibiotics
• IV cefuroxime 1.5g TDS or IV amoxicillin + gentamicin (per local protocol)
• Monitor for preterm labour
• Follow-up urine cultures to confirm clearance

Referral Criteria

• Recurrent pyelonephritis → urology (structural assessment)
• Failure to respond to treatment → imaging for abscess/obstruction
• Sepsis → acute medicine/ICU

• Uncomplicated pyelonephritis: full recovery in >95% with appropriate treatment
• Bacteraemia: occurs in 20-30%; increases ICU admission risk
• Renal scarring: risk increases with recurrent infections, VUR, and delayed treatment
• Emphysematous pyelonephritis: mortality 20-40% even with treatment
• Pyelonephritis in pregnancy: risk of preterm delivery; 20-40% bacteraemia rate if untreated
• Chronic pyelonephritis: repeated infections can lead to CKD and hypertension

Emphysematous Pyelonephritis Classification

Risk Factors for Complicated Pyelonephritis

Key Facts

Renal stones are common and recurrent. Prevention through dietary modification and increased fluid intake is key to reducing recurrence, which occurs in 50% within 5 years.

Epidemiology

• Lifetime prevalence: 10-15% in UK; increasing incidence
• M:F 3:1 (gap narrowing)
• Peak age: 30-50 years
• Recurrence rate: 50% within 5 years, 80% within 10 years

Aetiology

Stone types:

• Calcium oxalate (70-80%): most common; radiopaque
• Calcium phosphate (10-15%): often mixed with oxalate
• Uric acid (5-10%): radiolucent on X-ray; associated with gout, acidic urine
• Struvite/triple phosphate (5-10%): "infection stones" (Proteus, Klebsiella); form staghorn calculi
• Cystine (1-2%): hexagonal crystals; autosomal recessive cystinuria

Pathophysiology

• Supersaturation of urine with stone-forming substances

• Inhibitors of crystallisation: citrate, pyrophosphate, Tamm-Horsfall protein
• Risk factors: dehydration, high-sodium diet, animal protein, low fluid intake, hot climate, CKD, RTA, hyperparathyroidism

Acute Presentation (Ureteric Colic)

• Sudden-onset severe colicky pain: loin → groin (follows dermatomes T10-L2)
• Pain comes in waves; patient often writhing/unable to lie still
• Haematuria (microscopic or macroscopic; present in 85%)
• Nausea and vomiting
• Referred pain: testicular/labial if distal ureter

Location-Specific Features

• PUJ stones: loin pain
• Mid-ureter: radiates to flank/iliac fossa
• Vesicoureteric junction: frequency, urgency, suprapubic pain
• Bladder stones: intermittent stream, strangury

Complicated Stones

• Infected obstructed kidney: fever + loin pain + sepsis (EMERGENCY – requires immediate drainage)
• Staghorn calculus: large branching stone filling renal pelvis and calyces
• Bilateral obstruction or single kidney: AKI

Red Flags

• Bilateral stones with AKI → urgent urology

Bedside

• Urinalysis: haematuria (85%), nitrites/leucocytes if infection
• Pregnancy test: women of childbearing age (before CT)
• Observations: NEWS2 (sepsis assessment)

Bloods

• FBC, CRP: infection markers
• U&Es: renal function (AKI if obstructed)
• Calcium: hypercalcaemia (hyperparathyroidism)
• Urate: hyperuricaemia (uric acid stones)
• Blood cultures: if febrile

Imaging

• Non-contrast CT KUB: gold standard (>95% sensitivity/specificity); reveals stone size, location, hydronephrosis
• KUB X-ray: first-line in some centres; identifies radiopaque stones (calcium, struvite); misses uric acid and cystine
• Renal USS: alternative in pregnancy and children; detects hydronephrosis but limited stone detection

Special Tests

• Stone analysis: send passed/retrieved stones for composition analysis
• Metabolic workup (recurrent stone formers): serum calcium, PTH, urate, bicarbonate; 24h urine collection (calcium, oxalate, citrate, urate, creatinine, pH, volume)
• Cystine screen: spot urine cystine in young patients

Acute Management (NICE NG118)

• Analgesia: diclofenac 75mg IM or 100mg PR (first-line; superior to opioids for renal colic)
  • IV paracetamol as adjunct
  • Avoid NSAIDs in AKI, pregnancy, or peptic ulcer disease → morphine 10mg IM/IV alternative
• Antiemetics: ondansetron 4mg IV or metoclopramide 10mg IV
• IV fluids: if dehydrated or vomiting; NOT forced diuresis
• Medical expulsive therapy: tamsulosin 400mcg OD for distal ureteric stones 5-10mm (up to 4 weeks)

Intervention Criteria

• Stone >10mm unlikely to pass → intervention
• Stone not passed after 4 weeks
• Persistent pain despite analgesia
• Infected obstructed system → emergency nephrostomy/stent
• Bilateral obstruction or single kidney

Interventional Options

• ESWL: first-line for renal stones <20mm; non-invasive
• Ureteroscopy (URS): preferred for ureteric stones; allows laser lithotripsy
• PCNL (percutaneous nephrolithotomy): for large renal stones >20mm or staghorn calculi
• Open/laparoscopic surgery: rarely needed

Prevention of Recurrence

• Fluid intake: ≥2.5L/day (target urine output >2L/day)
• Dietary: reduce sodium (<6g/day), moderate animal protein, normal calcium intake (low calcium paradoxically increases oxalate stones)
• Calcium oxalate stones: potassium citrate (alkalinises urine, inhibits crystallisation)
• Uric acid stones: allopurinol 100-300mg OD + potassium citrate (target urine pH 6.5-7.0)
• Cystine stones: high fluid intake (>3L/day) + potassium citrate ± D-penicillamine/tiopronin
• Struvite stones: treat underlying infection; complete stone clearance essential

Referral Criteria

• Stone >5mm not passing → urology
• Recurrent stones → metabolic workup
• Infected obstructed kidney → emergency urology

• Stones <5mm: 80-90% pass spontaneously within 4 weeks
• Stones 5-10mm: ~50% pass spontaneously
• Stones >10mm: <10% pass spontaneously
• Recurrence: 50% within 5 years without preventive measures; reduced to 10-15% with lifestyle modifications
• ESWL success rate: 70-90% for stones <20mm
• Ureteroscopy success rate: 90-95% for ureteric stones
• Staghorn calculi: if untreated, can cause loss of kidney function and sepsis

Stone Types Summary

Metabolic Causes to Investigate

Key Facts

Urinary retention is common in older men and can cause significant morbidity if unrecognised. High-pressure chronic retention is a medical emergency due to the risk of renal failure.

Epidemiology

• Lifetime incidence: 10% of men by age 70, 30% by age 80
• Much less common in women
• BPH is present in 50% of men aged 50 and 80% by age 80

Aetiology

Men:

• BPH (most common), prostate cancer, urethral stricture, phimosis Women:
• Pelvic organ prolapse, gynaecological malignancy, urethral stricture Both sexes:
• Constipation, drugs (anticholinergics, opioids, sympathomimetics, antihistamines)
• Neurological: cauda equina syndrome, MS, spinal cord injury, diabetic neuropathy
• Post-surgical (especially pelvic/spinal surgery)
• Blood clot retention (post-haematuria)

Pathophysiology

• Acute: sudden increase in bladder outlet resistance or loss of detrusor function
• Chronic low-pressure: detrusor failure → progressive bladder distension with low intravesical pressure; renal function preserved

Acute Retention

• Sudden inability to pass urine with increasing urgency
• Suprapubic pain (severe, often described as unbearable)
• Palpable/percussable bladder (tender)
• Distress and agitation
• May be precipitated by: anaesthesia, opioids, anticholinergics, alcohol, UTI, constipation

Chronic Retention

• Painless progressive difficulty voiding
• Overflow incontinence (constant dribbling)
• Large palpable bladder (may extend to umbilicus or beyond)
• Nocturia, poor stream, incomplete emptying

High-Pressure Chronic Retention

• Bilateral hydronephrosis
• Renal impairment (raised creatinine)
• Peripheral oedema (fluid overload)
• Post-obstructive diuresis risk after catheterisation

Red Flags

• Bilateral loin pain + renal impairment → high-pressure chronic retention
• Bilateral leg weakness, saddle anaesthesia, loss of anal tone → cauda equina syndrome (neurosurgical emergency)
• Post-obstructive diuresis >200mL/hr → requires IV fluid replacement

Bedside

• Bladder scan: post-void residual volume; >300mL significant, >1000mL chronic retention
• DRE: prostate size (BPH), nodularity/hardness (malignancy)
• Neurological examination: perineal sensation (S2-S4), anal tone, lower limb neurology (cauda equina)

Bloods

• U&Es: renal function (AKI from obstructive uropathy)
• PSA: after DRE (or before, as DRE can falsely elevate); prostate cancer screening
• FBC: anaemia of chronic disease
• Calcium: hypercalcaemia can cause retention

Imaging

• Renal USS: hydronephrosis, kidney size (bilateral hydronephrosis in high-pressure retention)
• MRI spine: if cauda equina suspected (EMERGENCY)
• Transrectal USS/MRI prostate: staging if prostate cancer suspected

Special Tests

• Urodynamic studies: flow rate, detrusor pressure; differentiates obstruction from detrusor failure
• Flexible cystoscopy: urethral stricture assessment
• IPSS (International Prostate Symptom Score): quantify LUTS severity

Acute Retention

• Immediate urethral catheterisation (12-16Fr Foley catheter)
• If urethral catheter fails: suprapubic catheter insertion
• Record residual volume; send CSU for culture
• Monitor for post-obstructive diuresis: if output >200mL/hr, replace with IV 0.9% NaCl (match output)
• Start tamsulosin 400mcg OD (alpha-blocker) to facilitate TWOC
• TWOC (trial without catheter): after 2-3 days of alpha-blocker; success rate 40-50%

Chronic Retention

• Catheterisation (often gradual decompression preferred to reduce risk of haemorrhage, though evidence is limited)
• Monitor renal function closely after decompression
• Replace post-obstructive diuresis fluids with IV saline
• Urgent urology referral if high-pressure retention with renal impairment

Medical Management (BPH)

• Alpha-blockers: tamsulosin 400mcg OD, alfuzosin 10mg OD (relax smooth muscle)
• 5-alpha reductase inhibitors: finasteride 5mg OD (reduces prostate volume; takes 6 months for effect; reduces PSA by 50%)
• Combination therapy: tamsulosin + finasteride for large prostates (CombAT trial)
• Anticholinergics (solifenacin): only for OAB symptoms, NOT for obstruction

Surgical Management

• TURP (transurethral resection of prostate): gold standard for BPH refractory to medical therapy
• HoLEP (holmium laser enucleation): alternative for large prostates
• TUVP, UroLift, Rezum: newer minimally invasive options
• Clean intermittent self-catheterisation (CISC): for neurogenic bladder/detrusor failure

Referral Criteria

• Acute retention → urology
• Chronic retention with renal impairment → urgent urology + nephrology
• Suspected cauda equina → emergency MRI + neurosurgery
• Failed TWOC → urology for surgical assessment

• TWOC success: 40-50% after first episode with alpha-blocker
• Recurrence after successful TWOC: 50% within 2 years
• TURP: symptom improvement in 85-90%; 10-15% require repeat procedure within 10 years
• High-pressure retention: renal function usually recovers after decompression (if not end-stage)
• Post-obstructive diuresis: usually self-limiting within 48-72 hours
• Long-term catheterisation: associated with increased UTI, encrustation, quality of life impact

Drugs Causing Urinary Retention

IPSS Scoring

Key Facts

HUS is a medical emergency requiring urgent recognition. The distinction between typical (STEC) and atypical (complement-mediated) HUS is critical as management differs fundamentally.

Epidemiology

• Typical HUS: peak age 6 months to 5 years; incidence ~1.5 per 100,000 children/year in the UK
• aHUS: much rarer; ~0.5 per million/year; any age
• Leading cause of AKI in children

Aetiology

Typical HUS:

• STEC (Shiga toxin-producing E. coli) O157:H7 (most common), O104:H4
• Source: undercooked beef, unpasteurised milk, contaminated water/produce
• 5-15% of STEC infections develop HUS

Atypical HUS:

• Complement dysregulation: mutations in Factor H (25%), Factor I, MCP (CD46), C3, Factor B
• Anti-Factor H antibodies (especially children)
• Acquired: pregnancy, drugs (ciclosporin, tacrolimus, quinine), transplant

Pathophysiology