2.2 Chronic Kidney Disease

Section 2.2: Chronic Kidney Disease

1. Definition, Staging, and Monitoring

Chronic Kidney Disease (CKD) is defined as abnormalities of kidney structure or function, present for more than 3 months, with implications for health. It is diagnosed by the presence of kidney damage markers (such as persistent albuminuria) or an estimated Glomerular Filtration Rate (eGFR) < 60 mL/min/1.73 m² for at least 3 months.

Staging Framework

The KDIGO (Kidney Disease: Improving Global Outcomes) classification system utilizes a dual-staging framework based on GFR (G-stage) and Albuminuria (A-stage).

GFR Categories (G-stage)

• G1: eGFR ≥ 90 mL/min/1.73 m² (Normal or high)
• G2: eGFR 60-89 mL/min/1.73 m² (Mildly decreased)
• G3a: eGFR 45-59 mL/min/1.73 m² (Mildly to moderately decreased)
• G3b: eGFR 30-44 mL/min/1.73 m² (Moderately to severely decreased)
• G4: eGFR 15-29 mL/min/1.73 m² (Severely decreased)
• G5: eGFR < 15 mL/min/1.73 m² (Kidney failure; dialysis-dependent or requiring transplantation)

Albuminuria Categories (A-stage)

Measured via a random spot urine albumin-to-creatinine ratio (ACR):

• A1: ACR < 30 mg/g or < 3 mg/mmol (Normal to mildly increased)
• A2: ACR 30-300 mg/g or 3-30 mg/mmol (Moderately increased; historically termed microalbuminuria)
• A3: ACR > 300 mg/g or > 30 mg/mmol (Severely increased; historically termed macroalbuminuria)

The combination of G-stage and A-stage predicts the risk of CKD progression, cardiovascular events, and all-cause mortality, forming the KDIGO Heat Map. Patients with lower eGFR and higher albuminuria require more frequent clinical monitoring (ranging from once yearly for G1/A1 to four or more times yearly for G4/A3).

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2. Diabetic Nephropathy and Renoprotective Strategies

Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD) globally.

Pathophysiology

Chronic hyperglycemia drives the production of advanced glycation end-products (AGEs) and activates inflammatory cytokines, leading to:

1. Glomerular Hyperfiltration: Driven by afferent arteriole vasodilation and efferent arteriole vasoconstriction.
2. Mesangial Expansion and Glomerular Basement Membrane (GBM) Thickening.
3. Nodular Glomerulosclerosis: Pathognomonic Kimmelstiel-Wilson nodules on histopathology. This progression leads to protein leakage, starting as microalbuminuria (A2) and progressing to overt nephrotic-range proteinuria.

Renoprotective Pharmacotherapy

1. Renin-Angiotensin-Aldosterone System (RAAS) Blockade:
   • Indications: Angiotensin-Converting Enzyme Inhibitors (ACEi; e.g., ramipril, enalapril) or Angiotensin II Receptor Blockers (ARBs; e.g., losartan, valsartan) are indicated for all hypertensive CKD patients with an ACR ≥ 30 mg/g.
   • Mechanism: They selectively dilate the efferent arteriole, which decreases intraglomerular hydrostatic pressure, thereby reducing proteinuria and slowing the rate of GFR decline.
   • Monitoring: Serum creatinine and potassium must be checked 1-2 weeks after starting or increasing the dose. A serum creatinine increase of up to 30% from baseline is expected and acceptable due to altered hemodynamics. If the increase exceeds 30%, or if hyperkalemia is severe (K+ > 5.5 mEq/L) and refractory, the dose should be reduced or discontinued, and the patient evaluated for renal artery stenosis. Do not combine an ACEi and an ARB, as dual blockade increases the risk of acute kidney injury and hyperkalemia without adding clinical benefit.
2. Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors:
   • Indications: SGLT2 inhibitors (e.g., dapagliflozin, empagliflozin) are recommended in patients with type 2 diabetes, CKD, and an eGFR ≥ 20-25 mL/min/1.73 m² (and ACR ≥ 200 mg/g).
   • Mechanism: By blocking sodium-glucose reabsorption in the proximal tubule, they increase sodium delivery to the macula densa. This restores tubuloglomerular feedback, leading to afferent arteriole vasoconstriction, lowering intraglomerular pressure, and providing potent cardiorenal protection.
3. Blood Pressure Target:
   • KDIGO recommends a target systolic blood pressure < 120 mmHg using standardized office blood pressure measurement, unless contraindicated by side effects like orthostatic hypotension.

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3. Staging Complications and Clinical Management

As kidney function declines, complications emerge and must be managed aggressively.

Anemia of CKD

Principally caused by a deficiency in renal erythropoietin (EPO) production.

• Diagnosis: Checked when hemoglobin (Hb) falls below 12 g/dL in adult females and 13 g/dL in adult males.
• Iron Assessment: Prior to starting Erythropoiesis-Stimulating Agents (ESAs; e.g., epoetin alfa, darbepoetin alfa), iron stores must be repleted. The target is a transferrin saturation (TSAT) > 20% and serum ferritin > 100 ng/mL in non-dialysis patients (ferritin > 200 ng/mL in dialysis patients). Repletion is achieved via oral or intravenous iron.
• ESA Therapy: Initiated when Hb is < 10 g/dL. The therapeutic target is 10-11.5 g/dL. Target levels > 11.5 g/dL (or normalized Hb) are avoided because clinical trials demonstrated they do not improve outcomes and instead increase the risk of stroke, venous thromboembolism, and cardiovascular death.

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

CKD-MBD is a systemic disorder that links bone disease (renal osteodystrophy) and vascular calcification.

• Pathophysiology:
  1. Reduced GFR leads to hyperphosphatemia because of impaired renal phosphate excretion.
  2. Loss of functional kidney tissue impairs 1-alpha-hydroxylase activity, preventing the conversion of 25-hydroxyvitamin D to active 1,25-dihydroxyvitamin D (calcitriol).
  3. This deficiency in active vitamin D reduces intestinal calcium absorption, causing hypocalcemia.
  4. Both hyperphosphatemia and hypocalcemia stimulate the parathyroid glands, leading to secondary hyperparathyroidism. High levels of PTH mobilize calcium from bone, leading to high-turnover bone disease (osteitis fibrosa cystica) and calciphylaxis.
• Management:
  • Dietary Phosphate Restriction: Limit intake of high-phosphate foods (dairy, cola, processed foods).
  • Phosphate Binders: Taken with meals to bind dietary phosphate. Calcium-based binders (e.g., calcium carbonate, calcium acetate) are effective but carry a risk of hypercalcemia and vascular calcification. Non-calcium binders (e.g., sevelamer carbonate, lanthanum carbonate) are preferred in patients with pre-existing hypercalcemia, low PTH, or severe vascular/valvular calcification.
  • Vitamin D Therapy: Calcitriol (active vitamin D) or active analogs (e.g., paricalcitol) are used to suppress PTH.
  • Calcimimetics: Cinacalcet increases the sensitivity of calcium-sensing receptors on the parathyroid gland, decreasing PTH secretion without increasing serum calcium or phosphate.

Hyperkalemia and Volume Management

• Hyperkalemia: Chronic hyperkalemia is managed with dietary potassium restriction, loop diuretics, and oral potassium binders (e.g., sodium zirconium cyclosilicate, patiromer).
• Fluid Overload: Managed with loop diuretics (furosemide, torsemide, or bumetanide). In advanced CKD, high doses are required, and combination therapy with thiazide-like diuretics (e.g., metolazone) may be necessary to overcome diuretic resistance.