14.1 Acute Kidney Injury & Chronic Kidney Disease

Renal medicine forms a high-yield component of the MRCP(UK) Part 1 examination. Mastery of acute kidney injury (AKI) staging, the physiological discrimination between prerenal and intrinsic renal failure, emergency indications for renal replacement therapy (RRT), and the multimodal management of chronic kidney disease (CKD) and its mineral-bone complications is clinically vital and frequently examined.

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1. Acute Kidney Injury: KDIGO Classification & Staging

Acute kidney injury is defined by the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines as any of the following:

1. An increase in serum creatinine by >= 26.5 µmol/L (>= 0.3 mg/dL) within 48 hours; OR
2. An increase in serum creatinine to >= 1.5x baseline, known or presumed to have occurred within the prior 7 days; OR
3. Urine volume < 0.5 mL/kg/h for 6 consecutive hours.

KDIGO stages AKI according to the severity of biochemical and oliguric derangement, with staging determined by the parameter representing the worse degree of insult.

Baseline Creatinine Pearl: When a pre-admission creatinine is unavailable, UK guidelines recommend using the lowest creatinine recorded within the preceding 3 months (or up to 12 months). If completely absent, a baseline value can be back-calculated using the MDRD or CKD-EPI formula assuming an average normal eGFR of 75 mL/min/1.73 m².

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2. Prerenal AKI vs. Acute Tubular Necrosis (ATN) vs. Postrenal AKI

Distinguishing transient renal hypoperfusion (prerenal uraemia) from established parenchymal damage (acute tubular necrosis) is essential for guiding fluid therapy versus volume restriction.

Pathophysiological Distinction

• Prerenal AKI: Renal parenchymal integrity is intact. Systemic hypovolaemia, cardiogenic shock, sepsis-induced vasodilation, or renal autoregulatory failure (e.g. concurrent NSAIDs constricting afferent arterioles and ACEi/ARBs dilating efferent arterioles) decreases glomerular hydrostatic pressure. Intact proximal and collecting tubules avidly reabsorb sodium and water under intense angiotensin II and aldosterone stimulation, generating concentrated, sodium-poor urine.
• Intrinsic ATN: Ischaemic or nephrotoxic injury causes swelling, sloughing, and necrosis of renal tubular epithelial cells (particularly in the metabolically vulnerable straight S3 segment of the proximal tubule and medullary thick ascending limb). Loss of tubular epithelial cell polarity, brush-border detachment, cast obstruction, and transtubular backleak of glomerular filtrate impair the ability of the kidney to concentrate urine or conserve sodium, producing isotonic, sodium-rich urine.
• Postrenal AKI: Mechanical obstruction of urinary outflow (prostatic hypertrophy, retroperitoneal fibrosis, pelvic malignancy, bilateral ureteric calculi). Intraluminal pressure rises retrograde into Bowman's space, opposing glomerular filtration. Renal ultrasonography demonstrates pelvicalyceal dilation (hydronephrosis). Catheterisation or urgent percutaneous nephrostomy/ureteric stenting is diagnostic and therapeutic. Beware false-negative ultrasound in the hyperacute phase (< 24 hours) or in retroperitoneal fibrosis (which encases and prevents ureteric dilation).

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3. Emergency Indications for Renal Replacement Therapy (RRT)

In acute kidney injury, the decision to initiate emergency RRT (haemodialysis or continuous venovenous haemofiltration [CVVH]) is governed by the clinical and metabolic state rather than arbitrary creatinine numbers. The classical mnemonic is AEIOU:

1. A — Acidosis: Severe refractory metabolic acidaemia (pH < 7.20 or bicarbonate < 10–12 mmol/L) failing medical management (e.g. sodium bicarbonate infusion limited by volume overload or hypernatraemia).
2. E — Electrolytes: Life-threatening, refractory hyperkalaemia (K⁺ > 6.5 mmol/L) with ECG abnormalities (peaked T waves, broadened QRS, sine-wave pattern) unresponsive to insulin-dextrose, calcium gluconate, and potassium-wasting resins.
3. I — Ingestion (Dialysable Toxins): The "SLIME" toxins:
   • Salicylates (aspirin): Indicated for levels > 500 mg/L (> 3.6 mmol/L) or lower if severe pulmonary oedema, coma, or refractory acidosis exist.
   • Lithium: Indicated for acute intoxication > 4.0 mmol/L or chronic toxicity > 2.5 mmol/L with severe neurotoxicity (ataxia, seizures, delirium).
   • Isopropanol: Converted to acetone; causes ketosis without metabolic acidosis.
   • Methanol: Toxic metabolite formic acid causes retinal damage and blindness; massive high anion gap metabolic acidosis.
   • Ethylene Glycol: Toxic metabolite oxalic acid precipitates calcium oxalate crystals in tubules causing ATN, severe acidosis, and hypocalcaemia.
4. O — Overload: Refractory pulmonary oedema unresponsive to escalating high-dose intravenous loop diuretics (e.g. furosemide bolus/infusions).
5. U — Uraemic Complications:
   • Uraemic Pericarditis: Friction rub, pleuritic chest pain; high risk of haemorrhagic tamponade (anticoagulation and systemic thrombolysis strictly contraindicated; hemodialysis without heparin is the treatment of choice).
   • Uraemic Encephalopathy: Asterixis (flapping tremor), cognitive decline, seizures, coma.
   • Uraemic Bleeding: Qualitative platelet dysfunction driven by guanidinosuccinic acid and uraemic toxins disrupting glycoprotein Ib-IX and von Willebrand factor interaction. Managed acutely with desmopressin (DDAVP 0.3 μg/kg IV), cryoprecipitate, and dialysis.

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4. Chronic Kidney Disease: KDIGO Staging & Progression Retardants

Chronic kidney disease is defined by abnormalities of kidney structure or function persisting for > 3 months. KDIGO 2024 guidance mandates dual staging using eGFR (G category) and urinary albumin-to-creatinine ratio (ACR; A category).

Evidence-Based Renoprotection & Progression Retardants

• Blood Pressure Targets: Under NICE NG203 guidelines, target systolic BP < 140/90 mmHg if ACR < 30 mg/mmol; tighten to < 130/80 mmHg if ACR >= 30 mg/mmol (or ACR >= 3 mg/mmol in diabetic kidney disease).
• RAAS Inhibition: First-line therapy is an ACE inhibitor (e.g. ramipril) or ARB (e.g. losartan). They preferentially dilate efferent arterioles, reducing intraglomerular hypertension and slowing sclerosis. Monitoring: Check serum creatinine and potassium at 1–2 weeks. An increase in creatinine up to 30% (or drop in eGFR up to 25%) from baseline is physiologically expected and acceptable; discontinue only if the rise exceeds 30% or unmanageable hyperkalaemia occurs.
• SGLT2 Inhibitors: Dapagliflozin and empagliflozin (DAPA-CKD, EMPA-KIDNEY) inhibit proximal tubular glucose/sodium co-transport, restoring tubuloglomerular feedback and reducing hyperfiltration. Recommended for adults with CKD (eGFR 20–45 mL/min or eGFR 45–90 with ACR >= 22.6 mg/mmol) regardless of diabetes status.
• Non-Steroidal Mineralocorticoid Receptor Antagonist (Finerenone): Selectively blocks aldosterone-driven inflammation and fibrosis. Demonstrated in the FIDELIO-DKD and FIGARO-DKD trials to significantly reduce CKD progression and cardiovascular events in patients with type 2 diabetes and persistent albuminuria on maximum tolerated ACEi/ARB.

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5. Systemic Complications: Anaemia of CKD & CKD-MBD

Anaemia of Chronic Kidney Disease

• Aetiology: Relative deficiency of renal erythropoietin (EPO) produced by peritubular capillary interstitial cells (fibroblasts) in the deep cortex and outer medulla. Compounded by elevated circulating hepcidin (decreased renal clearance and chronic microinflammation), which degrades ferroportin, trapping iron inside macrophages and hepatocytes and producing functional iron deficiency.
• Morphology: Typically normochromic, normocytic anaemia with a low reticulocyte production index.
• Therapeutic Algorithm:
  1. Iron Repletion First: Prior to initiating erythropoiesis-stimulating agents (ESAs), optimize iron stores to ensure adequate substrate for erythropoiesis. Targets: serum ferritin > 100 µg/L (or > 200 µg/L in haemodialysis) and transferrin saturation (TSAT) > 20%. Intravenous iron (ferric carboxymaltose or ferric derisomaltose) is superior to oral iron in non-dialysis and dialysis CKD.
  2. Erythropoiesis-Stimulating Agents (ESAs): Initiated if Hb < 100 g/L despite replete iron stores. Agents include recombinant human EPO (epoetin alfa/beta) or darbepoetin alfa.
  3. Strict Target Haemoglobin: The target Hb is 100–115 g/L (never normalize Hb > 120–130 g/L). Landmark randomized controlled trials (CHOIR, CREATE, TREAT) demonstrated that targeting normal haemoglobin levels causes a statistically significant increase in stroke, deep vein thrombosis, cardiovascular death, and accelerated vascular access thrombosis.

Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD)

CKD-MBD represents a systemic triad of biochemical abnormalities, bone disease (renal osteodystrophy), and vascular/valvular soft-tissue calcification.

Reduced GFR --> Phosphate Retention (Hyperphosphataemia)
                    |
                    v
  Stimulation of Osteocytes --> Elevated FGF23 (with Klotho co-factor)
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                                    v
      Inhibition of Renal 1-alpha-hydroxylase (CYP27B1)
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                    v
       Decreased Active 1,25-(OH)2 Vitamin D (Calcitriol)
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                    v
         Decreased Intestinal Ca2+ Absorption --> Hypocalcaemia
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                                                       v
          Parathyroid Gland Hyperplasia --> SECONDARY HYPERPARATHYROIDISM
                                            (High PTH, Low/Normal Ca2+, High PO43-)

• Renal Osteodystrophy Spectrum:
  • Osteitis Fibrosa Cystica: High-turnover bone disease driven by excessive PTH; subperiosteal bone resorption, brown tumours (osteoclastomas), "rugger-jersey spine" on spinal radiography.
  • Osteomalacia: Defective bone mineralization due to severe calcitriol deficiency or historical aluminium binder toxicity.
  • Adynamic Bone Disease: Low-turnover bone disease caused by excessive suppression of PTH (iatrogenic overtreatment with active vitamin D analogues or calcium salts); prone to fracture and accelerated vascular calcification.
• Tertiary Hyperparathyroidism: Following years of chronic end-stage kidney disease, prolonged parathyroid hyperplasia transitions to autonomous, monoclonal parathyroid adenomas that escape negative feedback. Characterized biochemically by markedly elevated PTH in the presence of HYPERCALCAEMIA and hyperphosphataemia.
• Management Strategies:
  • Dietary Phosphate Restriction: First-line non-pharmacological step.
  • Phosphate Binders: Taken with meals. Non-calcium-based binders (sevelamer carbonate, lanthanum carbonate) are strongly preferred over calcium-based binders (calcium acetate, calcium carbonate) in patients with hypercalcaemia or arterial calcification, as calcium-containing salts accelerate vascular stiffening and calciphylaxis.
  • Active Vitamin D Analogues: Oral alfacalcidol or calcitriol; directly suppress pre-pro-PTH gene transcription. Caution: can precipitate hypercalcaemia and hyperphosphataemia by enhancing intestinal absorption.
  • Calcimimetics (Cinacalcet): An allosteric activator of the calcium-sensing receptor (CaSR) on chief cells of the parathyroid gland. Increases receptor sensitivity to extracellular calcium, thereby suppressing PTH secretion without raising serum calcium or phosphate levels (in fact, it lowers both). Indicated for refractory secondary hyperparathyroidism or tertiary hyperparathyroidism awaiting parathyroidectomy.