Glomerular Chronic Kidney Disease

Glomerular chronic kidney disease is progressive, irreversible loss of kidney function for more than 3 months that arises from a primary or secondary glomerular disease. It is defined by persistent albuminuria or proteinuria (and often haematuria) with or without reduced eGFR, and it is a major cause of end stage kidney disease alongside diabetes and hypertension.

Causes:

• Primary glomerular disease: IgA nephropathy (the commonest primary glomerulonephritis worldwide), focal segmental glomerulosclerosis, membranous nephropathy, minimal change disease (usually not progressive), membranoproliferative disease and C3 glomerulopathy, post-infectious glomerulonephritis with incomplete recovery, fibrillary glomerulonephritis
• Secondary: diabetic kidney disease, lupus nephritis, ANCA-associated glomerulonephritis, amyloidosis, HIV-associated nephropathy, hepatitis B and C related glomerulonephritis, APOL1-associated disease, malaria associated nephropathy, schistosomal glomerulopathy, myeloma and monoclonal immunoglobulin deposition
• Hereditary: Alport syndrome (collagen IV variants), thin basement membrane disease, Fabry disease, congenital nephrotic syndrome

Progression is driven by proteinuria (tubular toxicity from filtered protein and complement), glomerular hypertension and hyperfiltration in surviving nephrons, podocyte loss and focal sclerosis, tubulointerstitial fibrosis and ongoing immune activity. Heavier proteinuria predicts faster decline: loss of eGFR is typically 1 mL/min/1.73 m2 each year in healthy ageing, 2 to 3 in many glomerular diseases and above 5 in rapidly progressive disease.

Staging uses the combination of GFR category and albuminuria category.

GFR categories (eGFR in mL/min/1.73 m2):

• G1: 90 or above
• G2: 60 to 89
• G3a: 45 to 59
• G3b: 30 to 44
• G4: 15 to 29
• G5: below 15

Albuminuria categories (albumin:creatinine ratio):

• A1: below 3 mg/mmol
• A2: 3 to 30 mg/mmol
• A3: above 30 mg/mmol

• Often asymptomatic until eGFR is below 30 mL/min/1.73 m2; found by proteinuria, haematuria, hypertension or raised creatinine on screening
• Frothy urine, oedema, haematuria (macroscopic episodes with infections in IgA nephropathy), hypertension
• Nephrotic syndrome: proteinuria above 3.5 g daily, albumin below 30 g/L, oedema, hyperlipidaemia, thrombosis
• Systemic features: rash, arthralgia, photosensitivity (lupus); purpura (IgA vasculitis); deafness and eye signs (Alport); neuropathic pain and angiokeratoma (Fabry)
• Late features: anaemia, bone and mineral disorder, acidosis, hyperkalaemia, pruritus, fatigue, nausea, restless legs
• Family history of kidney disease, consanguinity, haematuria

Red flags:

• Rapid decline (fall in eGFR above 5 mL/min/1.73 m2 each year or above 25% over 12 months).
• Nephrotic syndrome.
• Haematuria with red cell casts.
• Hypertension refractory to three drugs.
• Onset under 40 years.
• Albumin:creatinine ratio above 70 mg/mmol.
• Systemic disease.
• Unexplained eGFR below 30.

• Confirm chronicity: abnormalities persisting beyond 3 months; use serial eGFR (creatinine based eGFR equation; add cystatin C when creatinine is unreliable) and quantify albuminuria and proteinuria on a first morning sample.
• Urinalysis with microscopy (dysmorphic red cells above 5%, red cell casts), blood pressure, full blood count, electrolytes, bicarbonate, calcium, phosphate, PTH, 25-hydroxyvitamin D, lipids, HbA1c, albumin.
• Immunology: antinuclear antibody, anti-dsDNA, C3, C4, ANCA, anti-GBM antibody, anti-PLA2R antibody, cryoglobulins, serum protein electrophoresis with free light chains, hepatitis B surface antigen, hepatitis C antibody, HIV, syphilis serology.
• Renal ultrasound: kidney length (below 9 cm suggests advanced scarring), cortical thickness, echogenicity; preserved size in diabetes, amyloid and HIV-associated nephropathy.
• Kidney biopsy when it will change treatment: nephrotic syndrome in adults, unexplained proteinuria above 100 mg/mmol (albumin:creatinine ratio above 70 mg/mmol), haematuria with proteinuria, unexplained decline, suspected systemic disease; contraindicated when kidneys are small and echogenic. Light microscopy, immunofluorescence and electron microscopy.
• Genetic testing for suspected inherited disease; family screening.
• Risk prediction with the kidney failure risk equation (age, sex, eGFR, albumin:creatinine ratio) to time referral and access planning.

Differentials: diabetic kidney disease, hypertensive nephrosclerosis, tubulointerstitial disease, obstructive uropathy, ischaemic nephropathy, polycystic kidney disease.

Shared measures (all stages)

• Blood pressure below 130/80 mmHg (below 120 systolic when tolerated, with a consistent measurement technique).
• ACE inhibitor or angiotensin receptor blocker titrated to the maximum tolerated dose in proteinuric disease: ramipril 2.5 mg daily titrated to 10 mg daily; lisinopril 5 mg daily to 40 mg; losartan 50 mg to 100 mg daily; irbesartan 150 mg to 300 mg daily.
• Check creatinine and potassium at 1 to 2 weeks; accept a creatinine rise up to 30%; stop for potassium above 6.0 mmol/L unresolved by binders and diet.
• SGLT2 inhibitor: dapagliflozin 10 mg daily (eGFR at least 25) or empagliflozin 10 mg daily (eGFR at least 20); continue until dialysis. Hold on sick days.
• Finerenone 10 mg daily (20 mg if eGFR at least 60) for type 2 diabetes with albuminuria and potassium below 5.0 mmol/L.
• Sodium restriction below 2 g daily; protein intake 0.8 g/kg daily (avoid high protein diets); weight control; smoking cessation; exercise.
• Statin: atorvastatin 20 mg daily (40 to 80 mg with cardiovascular disease); aspirin 75 mg daily for secondary prevention only.
• Avoid nephrotoxins (NSAIDs, aminoglycosides, contrast when possible, herbal remedies); dose adjust renally cleared drugs; stop metformin below eGFR 30 and halve the dose at eGFR 30 to 44.
• Vaccination: influenza yearly, pneumococcal, hepatitis B for those likely to need dialysis, COVID-19.

Disease specific treatment (specialist)

• IgA nephropathy: maximal supportive care for 3 months.
• If proteinuria stays above 1 g daily with eGFR above 30: targeted release budesonide 16 mg daily for 9 months then 8 mg for 2 months, or a short reduced dose oral glucocorticoid course (methylprednisolone 0.4 mg/kg daily, maximum 32 mg, tapering over 6 to 9 months) with infection prophylaxis.
• Sparsentan 200 mg daily for 14 days then 400 mg daily with monthly liver tests. Tonsillectomy is not routine.
• Focal segmental glomerulosclerosis (primary): prednisolone 1 mg/kg daily (maximum 80 mg) for 4 to 16 weeks; calcineurin inhibitors (tacrolimus 0.05 to 0.1 mg/kg daily in two doses, trough 5 to 8 ng/mL) for steroid dependence or intolerance.
• Membranous nephropathy: rituximab 1 g on days 1 and 15, or cyclophosphamide 2 mg/kg daily with prednisolone for high risk disease; supportive care for 6 months in low risk disease.
• Lupus nephritis class III or IV: methylprednisolone 500 mg intravenously for 3 days, mycophenolate mofetil 1 g twice daily (3 g daily) or cyclophosphamide; hydroxychloroquine 200 to 400 mg daily.
• ANCA vasculitis: rituximab, cyclophosphamide with glucocorticoid and plasma exchange for severe disease.
• Alport syndrome: ACE inhibitor from onset of albuminuria; early treatment in children.
• Fabry disease: agalsidase beta 1 mg/kg every 2 weeks.
• HIV-associated nephropathy: antiretroviral therapy; hepatitis B or C: antiviral therapy; amyloidosis: treat the underlying cause.

CKD complications

• Anaemia: iron (iron sucrose 100 mg intravenously for ferritin below 200 microg/L or transferrin saturation below 20%); epoetin alfa 50 to 100 units/kg three times weekly when haemoglobin is below 100 g/L after iron repletion; target 100 to 120 g/L.
• Mineral and bone disorder: dietary phosphate restriction; sevelamer 800 mg three times daily with meals if phosphate is above 1.5 mmol/L; alfacalcidol 0.25 to 0.5 microg daily for persistent PTH elevation with low 25-hydroxyvitamin D.
• Acidosis: sodium bicarbonate 500 mg to 1 g two to three times daily, to a bicarbonate of 22 to 26 mmol/L.
• Hyperkalaemia: potassium diet, stop contributing drugs, sodium zirconium cyclosilicate 5 to 10 g daily, loop or thiazide diuretic.
• Oedema: furosemide 40 to 120 mg daily; thromboprophylaxis for nephrotic syndrome with albumin below 20 g/L (enoxaparin 40 mg daily).

Monitoring frequency each year by risk (eGFR category with albuminuria category):

• G1 to G2 A1: 1.
• G1 to G2 A2 or G3a A1: 1 to 2.
• G3a A2 or G3b A1: 2.
• G3a A3, G3b A2, G4 A1: 3.
• G3b A3, G4 A2 or A3, G5: 4 or more.

Referral to nephrology.

• eGFR below 30.
• Albumin:creatinine ratio above 70 mg/mmol.
• Haematuria with proteinuria.
• Sustained fall in eGFR above 25% or above 15 mL/min/1.73 m2 in 12 months.
• Hypertension refractory to four drugs.
• Suspected systemic or inherited disease.
• Kidney failure risk above 3% to 5% at 5 years.

Renal replacement planning.

• Begin education when eGFR is below 20 mL/min/1.73 m2 or kidney failure risk is above 10% at 2 years.
• Refer for transplant assessment when eGFR is below 20.
• Create arteriovenous fistula 6 months before anticipated dialysis, or place a peritoneal dialysis catheter 2 to 4 weeks before.
• Start dialysis for uraemic symptoms or complications, typically at eGFR 5 to 10.

Special groups

• Pregnancy: preconception counselling; stop ACE inhibitors, angiotensin receptor blockers, mycophenolate and cyclophosphamide before conception; give aspirin 75 to 150 mg daily from 12 weeks; risk of pre-eclampsia and loss of function rises with eGFR below 60 and proteinuria above 1 g daily.
• Children: assessment of growth, vaccination, and early genetic testing; use age specific blood pressure targets (below the 90th centile or below 120/80 mmHg for adolescents).