5.2 Chronic Kidney Disease & Glomerular Disorders

Chronic Kidney Disease & Glomerular Disorders

Chronic Kidney Disease (CKD) is defined as an abnormality of kidney structure or function persisting for greater than 3 months, with implications for overall health. It is characterized by progressive, irreversible nephron loss leading to glomerulosclerosis, tubulointerstitial fibrosis, and loss of homeostatic capacity. In the United Kingdom, CKD affects approximately 10% of the adult population and is a powerful independent risk factor for cardiovascular morbidity, end-stage renal disease, and premature death.

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1. CKD Classification & NICE Staging Matrix

According to NICE Guideline NG203, CKD is staged using a dual classification matrix combining estimated Glomerular Filtration Rate (eGFR, the "G" category) and the urinary Albumin-to-Creatinine Ratio (ACR, the "A" category). Measurement of urine ACR is significantly more sensitive than protein dipsticks or total protein-to-creatinine ratio (PCR) for detecting low-grade nephron injury.

The KDIGO / NICE Staging Grid

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2. Strategies to Retard CKD Progression

Interventions aimed at retarding progressive nephron decline focus on tight blood pressure control, reduction of intraglomerular hyperfiltration, and metabolic optimisation.

Blood Pressure Targets (NICE NG203)

• Standard Target: In adults with CKD and urine ACR < 70 mg/mmol, target clinic systolic BP is 120–139 mmHg and diastolic BP is < 90 mmHg (clinic target < 140/90 mmHg).
• Proteinuric Target: In adults with CKD and significant proteinuria (ACR ≥ 70 mg/mmol), with or without diabetes, target clinic systolic BP is 120–129 mmHg and diastolic BP is < 80 mmHg (clinic target < 130/80 mmHg).

Renin-Angiotensin-Aldosterone System (RAAS) Blockade

Angiotensin-Converting Enzyme (ACE) inhibitors (e.g. ramipril) or Angiotensin Receptor Blockers (ARBs, e.g. losartan) represent first-line pharmacotherapy for renal protection. They preferentially dilate the efferent arteriole, reducing intraglomerular capillary hydrostatic pressure and decreasing albumin leak.

• Indications:
  • CKD with diabetes and ACR over 3 mg/mmol.
  • CKD with hypertension and ACR over 30 mg/mmol.
  • CKD with ACR 70 mg/mmol or more, irrespective of hypertension or cardiovascular disease.
  • Titrate to the highest licensed dose the person can tolerate. Do not routinely start an ACEi/ARB if pre-treatment potassium is above 5.0 mmol/L, and stop it if potassium rises to 6.0 mmol/L or more despite stopping other potassium-raising drugs (NICE NG203).
• Monitoring U&Es Post-Initiation: Serum creatinine and potassium must be re-checked 1–2 weeks after initiating or up-titrating an ACEi/ARB.
• The "Acceptable Rise" Rule: An initial rise in serum creatinine of up to 30% from baseline (or a fall in eGFR of up to 25%) is an expected physiological hemodynamic consequence of efferent arteriolar vasodilation. Do not stop the medication! If creatinine rises by 30% or more (or eGFR falls by 25% or more), investigate other causes such as volume depletion, concurrent NSAID use or bilateral renal artery stenosis, and if none is found, stop the drug or reduce to a previously tolerated dose.

SGLT2 Inhibitors (Sodium-Glucose Cotransporter-2 Inhibitors)

Large cardiovascular and renal outcome trials (DAPA-CKD, EMPA-KIDNEY) have established dapagliflozin and empagliflozin as standard therapy for patients with CKD and persistent albuminuria (ACR ≥ 22.6 mg/mmol or eGFR 20–45 mL/min/1.73m²), irrespective of diabetes status. SGLT2 inhibitors restore tubuloglomerular feedback by increasing sodium delivery to the macula densa, promoting afferent arteriolar constriction and dampening glomerular hyperfiltration.

Cardiovascular Risk Reduction

Offer atorvastatin 20 mg daily for primary or secondary prevention of cardiovascular disease in adults with CKD. Increase the dose if non-HDL cholesterol has not fallen by more than 40% and eGFR is 30 mL/min/1.73m² or more; agree higher doses with a renal specialist if eGFR is below 30 (NICE).

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3. Systemic Complications of CKD & Management

As functional nephron mass declines below 30–45 mL/min/1.73m², endocrine and metabolic derangements manifest across multiple organ systems.

A. Anaemia of Chronic Kidney Disease

• Pathophysiology: Normochromic, normocytic anaemia caused primarily by deficient production of erythropoietin (EPO) by peritubular interstitial capillary fibroblasts in the renal cortex. Uraemic toxins also shorten red cell lifespan, and chronic inflammation elevates hepcidin, sequestering reticuloendothelial iron.
• Diagnostic Threshold (NICE NG8): Consider investigating and managing anaemia of CKD if Hb is 110 g/L or less (105 g/L or less in children under 2) or there are symptoms of anaemia. An eGFR below 60 should prompt consideration of CKD as the cause; with higher eGFRs, look harder for other causes.
• Step 1: Replenish Iron Stores First! Erythropoiesis-Stimulating Agents (ESAs) are ineffective in iron deficiency and induce functional iron deficiency. Ensure serum ferritin > 100 µg/L and transferrin saturation (TSAT) > 20% prior to commencing ESAs. In non-dialysis CKD, trial oral iron; in dialysis-dependent patients or oral intolerance, intravenous iron (e.g. ferric derisomaltose) is mandatory.
• Step 2: Erythropoiesis-Stimulating Agents (ESAs): Recombinant human EPO (epoetin alfa, epoetin beta) or long-acting darbepoetin alfa. Aspirational Haemoglobin Range: 100–120 g/L (NICE NG8; do not aim above 120 g/L, as normalising Hb above 120 g/L significantly increases risks of stroke, cardiovascular death, and arteriovenous fistula thrombosis).

B. CKD Mineral and Bone Disorder (CKD-MBD)

Declining renal function disrupts mineral homeostasis through the following sequence:

1. Phosphate Retention: Reduced GFR diminishes fractional phosphate clearance, leading to hyperphosphataemia.
2. Deficient 1-Alpha-Hydroxylase: Loss of functional renal proximal tubular mass impairs conversion of 25-hydroxyvitamin D to active 1,25-dihydroxycholecalciferol (calcitriol).
3. Hypocalcaemia: Calcitriol deficiency decreases intestinal calcium and phosphate absorption, precipitating hypocalcaemia.
4. Secondary Hyperparathyroidism: Both hypocalcaemia and hyperphosphataemia directly stimulate the calcium-sensing receptor (CaSR) on parathyroid glands, stimulating parathyroid hyperplasia and massive secretion of Parathyroid Hormone (PTH).
5. Renal Osteodystrophy: Chronic high PTH stimulates relentless osteoclast activity, resorbing bone matrix and producing osteitis fibrosa cystica (subperiosteal bone resorption, "salt-and-pepper" skull, brown tumours). Conversely, oversuppression of PTH leads to adynamic bone disease.
6. Vascular Calcification & Calciphylaxis: Calcium-phosphate precipitation in blood vessel walls causes medial calcification (Mönckeberg's arteriosclerosis) and ischemic skin necrosis (calcific uraemic arteriolopathy / calciphylaxis).

Therapeutic Management of CKD-MBD

• Dietary Phosphate Restriction: Restrict dairy products, processed foods, and carbonated beverages.
• Phosphate Binders (Taken with meals):
  • Non-calcium binders (e.g. sevelamer hydrochloride, lanthanum carbonate) are preferred if serum calcium is elevated or normal, or if vascular calcification is documented.
  • Calcium-based binders (e.g. calcium acetate) may be used if hypocalcaemic.
• Active Vitamin D Analogues: Administer alfacalcidol or calcitriol orally to suppress parathyroid hyperplasia. Standard colecalciferol (nutritional vitamin D) cannot be converted to active form in advanced CKD.
• Calcimimetics: Cinacalcet binds allosterically to the calcium-sensing receptor on parathyroid chief cells, increasing receptor sensitivity to extracellular calcium and directly suppressing PTH release without causing hypercalcaemia or hyperphosphataemia.

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4. Glomerular Diseases: Nephrotic vs. Nephritic Syndromes

Glomerular diseases present along a clinical continuum anchored by two classical prototypes: nephrotic syndrome (podocyte injury with massive selective or non-selective proteinuria) and nephritic syndrome (inflammatory, destructive endocapillary injury with haematuria).

Distinct Glomerular Entities for PLAB 1

1. Minimal Change Disease (MCD)

• Most common cause of nephrotic syndrome in children (peak age 2–6 years).
• Light microscopy: normal glomeruli ("minimal change"). Electron microscopy: diffuse effacement (fusion) of podocyte foot processes.
• Presentation: Sudden severe periorbital and peripheral oedema following a mild respiratory illness.
• Management: Exquisitely responsive to high-dose oral corticosteroids (prednisolone 60 mg/m²/day). Renal biopsy is unnecessary in children unless steroid-resistant.

2. Membranous Nephropathy (MN)

• Most common cause of primary nephrotic syndrome in non-diabetic adults (peak age 40–60 years).
• Etiology: 70–80% primary, driven by autoantibodies against the M-type phospholipase A2 receptor (anti-PLA2R). Secondary causes include solid organ malignancies (bronchial, colon, stomach), hepatitis B/C, NSAIDs, and SLE.
• Histology: Silver stain demonstrates diffuse basement membrane thickening with characteristic "spike-and-dome" subepithelial immune deposits.

3. Focal Segmental Glomerulosclerosis (FSGS)

• Common cause of adult nephrotic syndrome, particularly in patients of African descent. Secondary causes include HIV infection, heroin use, morbid obesity, and nephron loss.
• Steroid resistance is frequent; high rate of recurrence in kidney allografts post-transplantation.

4. IgA Nephropathy (Berger's Disease)

• The most common primary glomerulonephritis worldwide.
• Classical Presentation: Young male presenting with episodic macroscopic haematuria 1–2 days after an upper respiratory tract infection ("synpharyngitic haematuria"). In contrast to PSGN, the latency period is very short (24–48 hours) and serum complement (C3/C4) levels are completely normal.
• Histology: Mesangial proliferation with intense mesangial IgA deposition on immunofluorescence.

5. Post-Streptococcal Glomerulonephritis (PSGN)

• Immune-complex mediated glomerulonephritis occurring 1–3 weeks after Group A beta-haemolytic streptococcal pharyngitis, or 3–6 weeks after streptococcal impetigo.
• Laboratory Findings: "Smoky" or "tea-coloured" urine with red cell casts, elevated antistreptolysin O (ASOT) or anti-DNase B titres, and characteristically low serum C3 complement (which normalises within 6–8 weeks).
• Electron microscopy: Subepithelial electron-dense "humps".

6. Anti-GBM Disease (Goodpasture's Syndrome)

• Rapidly progressive crescentic glomerulonephritis (RPGN) caused by circulating IgG antibodies directed against the alpha-3 chain of type IV collagen in the glomerular and alveolar basement membranes.
• Clinical Presentation: Dual pulmonary-renal syndrome featuring life-threatening pulmonary haemorrhage (haemoptysis) and acute oliguric kidney injury.
• Histology: Crescent formation on light microscopy; pathognomonic smooth linear IgG deposition along the glomerular basement membrane on direct immunofluorescence.
• Emergency Management: Immediate plasmapheresis (to remove circulating anti-GBM antibodies) combined with high-dose intravenous methylprednisolone and oral cyclophosphamide.