5.2 Chronic Kidney Disease & Renal Replacement Therapy
Key Takeaways
- Chronic kidney disease (CKD) is defined as abnormalities of kidney structure or function present for >3 months, staged by eGFR (G1-G5) and Albuminuria categories (A1 <3 mg/mmol, A2 3-30 mg/mmol, A3 >30 mg/mmol).
- SGLT2 inhibitors (e.g., dapagliflozin, empagliflozin) reduce intraglomerular pressure by restoring tubuloglomerular feedback, slowing CKD progression and reducing cardiovascular mortality in patients with eGFR ≥20 mL/min/1.73m².
- CKD-Mineral and Bone Disorder (CKD-MBD) develops from hyperphosphatemia, impaired 1-α-hydroxylation of vitamin D (low active 1,25-(OH)2D3), hypocalcemia, and compensatory secondary hyperparathyroidism.
- Anemia of CKD is predominantly due to deficient renal erythropoietin production by peritubular interstitial cells, managed with erythropoiesis-stimulating agents (ESAs) to maintain hemoglobin at 100-115 g/L once iron stores are replete (ferritin >100 μg/L, TSAT >20%).
- Absolute emergency indications for renal replacement therapy (RRT) follow the AEIOU mnemonic: refractory Acidosis (pH <7.15), refractory Hyperkalemia (>6.5 mmol/L), Intoxication (SLIME), Fluid Overload, and Uremic complications (pericarditis, encephalopathy).
Chronic Kidney Disease & Renal Replacement Therapy
Chronic Kidney Disease (CKD) is defined by KDIGO guidelines as abnormalities of kidney structure or function, present for $> 3$ months, with implications for health. It affects over 10% of the global adult population and represents a potent independent risk factor for cardiovascular events, heart failure, and all-cause mortality.
KDIGO Staging & Classification System
CKD classification utilizes a two-dimensional grid based on eGFR (G-stage) and Albuminuria (A-stage), which together predict the risks of progression, cardiovascular events, and mortality.
| eGFR Category | eGFR Range ($\text{mL/min/1.73m}^2$) | Clinical Description |
|---|---|---|
| G1 | $\ge 90$ | Normal or high (requires structural/histological evidence of kidney damage) |
| G2 | $60\text{--}89$ | Mildly decreased (requires structural/histological evidence of kidney damage) |
| G3a | $45\text{--}59$ | Mildly to moderately decreased |
| G3b | $30\text{--}44$ | Moderately to severely decreased |
| G4 | $15\text{--}29$ | Severely decreased |
| G5 | $< 15$ | Kidney failure (End-Stage Renal Disease / ESRD) |
| Albuminuria Category | ACR Range ($\text{mg/mmol}$) | ACR Range ($\text{mg/g}$) | Clinical Description |
|---|---|---|---|
| A1 | $< 3.0$ | $< 30$ | Normal to mildly increased |
| A2 | $3.0\text{--}30.0$ | $30\text{--}300$ | Moderately increased (microalbuminuria) |
| A3 | $> 30.0$ | $> 300$ | Severely increased (macroalbuminuria) |
Disease-Modifying Pharmacotherapy in CKD
The goal of CKD management is to slow disease progression, reduce albuminuria, and minimize cardiovascular risk.
1. Renin-Angiotensin-Aldosterone System (RAAS) Inhibition
- Agents: ACE inhibitors (e.g., ramipril, enalapril) or Angiotensin Receptor Blockers (ARBs, e.g., losartan, valsartan).
- Mechanism: Preferentially dilate the efferent arteriole of the glomerulus, reducing intraglomerular hydrostatic pressure and glomerular hyperfiltration.
- Monitoring: Expect an initial serum creatinine rise up to $30%$ within 4 weeks of initiation; this reflects hemodynamic pressure reduction and does not warrant drug cessation unless creatinine continues to rise or refractory hyperkalemia occurs.
2. Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors
- Agents: Dapagliflozin, empagliflozin, canagliflozin.
- Mechanism: Block glucose and sodium reabsorption in the proximal convoluted tubule. Increased sodium delivery to the macula densa restores tubuloglomerular feedback, inducing afferent arteriolar constriction and reducing intraglomerular hypertension.
- Clinical Evidence: Landmark trials (DAPA-CKD, EMPA-KIDNEY) demonstrate significant reductions in CKD progression, kidney failure, cardiovascular death, and heart failure hospitalizations down to an eGFR of $20,\text{mL/min/1.73m}^2$.
3. Non-Steroidal Mineralocorticoid Receptor Antagonists
- Finerenone: Demonstrates additive antiproteinuric and cardiorenal protective benefits in patients with type 2 diabetes and CKD already taking maximum tolerated doses of ACEi/ARB and SGLT2 inhibitors.
Management of Systemic CKD Complications
1. CKD-Mineral and Bone Disorder (CKD-MBD)
As eGFR declines below $45,\text{mL/min/1.73m}^2$, phosphorus excretion drops, leading to hyperphosphatemia. Concurrently, renal peritubular cells fail to produce $1\text{-}\alpha\text{-hydroxylase}$, resulting in calcitriol ($1,25(\text{OH})_2\text{D}_3$) deficiency.
-
Pathophysiology Pathway:
- Decreased eGFR ($<45,\text{mL/min}$) $\rightarrow$ Phosphate retention $\rightarrow$ Hyperphosphatemia
- Reduced $1\text{-}\alpha\text{-hydroxylase}$ $\rightarrow$ Low $1,25(\text{OH})_2\text{D}_3$ $\rightarrow$ Reduced intestinal $\text{Ca}^{2+}$ absorption $\rightarrow$ Hypocalcemia
- Hypocalcemia + Hyperphosphatemia + Low Calcitriol $\rightarrow$ Secondary Hyperparathyroidism (High PTH) $\rightarrow$ Bone resorption (Osteitis Fibrosa Cystica)
-
Management:
- Dietary Phosphate Restriction: Limit dairy, nuts, processed foods.
- Phosphate Binders: Non-calcium-based binders (Sevelamer, Lanthanum) are preferred over calcium-based binders (calcium acetate, calcium carbonate) to avoid accelerating vascular calcification.
- Active Vitamin D Analogs: Alfacalcidol or Calcitriol (native vitamin D / cholecalciferol cannot be hydroxylated by the kidney in advanced CKD).
- Calcimimetics: Cinacalcet activates calcium-sensing receptors on the parathyroid gland, suppressing PTH secretion without causing hypercalcemia.
2. Anemia of Chronic Kidney Disease
- Pathophysiology: Deficient production of erythropoietin (EPO) by peritubular interstitial cells of the renal cortex. Additional factors include hepcidin-mediated iron sequestration, uremic toxins reducing RBC lifespan, and frequent blood loss.
- Diagnostic Target: Normocytic, normochromic anemia. Iron stores must be evaluated prior to Erythropoiesis-Stimulating Agent (ESA) therapy:
- Serum Ferritin: Target $> 100,\mu\text{g/L}$ ($> 200,\mu\text{g/L}$ in hemodialysis).
- Transferrin Saturation (TSAT): Target $> 20%$.
- ESA Therapy: Epoetin alfa/beta or Darbepoetin alfa. Target hemoglobin level is $100\text{--}115,\text{g/L}$.
Exam Pearl: Normalizing hemoglobin to $> 120,\text{g/L}$ with ESAs increases the risk of stroke, myocardial infarction, arteriovenous access thrombosis, and hypertension without conferring quality-of-life benefit.
Renal Replacement Therapy (RRT)
When eGFR drops below $15,\text{mL/min/1.73m}^2$ (G5), patients require planning for RRT.
Absolute Indications for Emergency RRT (The "AEIOU" Mnemonic)
- Acidosis: Severe metabolic acidosis ($\text{pH} < 7.15$) refractory to medical management (e.g., sodium bicarbonate).
- Electrolytes: Severe hyperkalemia ($[\text{K}^+] > 6.5,\text{mmol/L}$) refractory to intravenous insulin-dextrose and potassium binders.
- Intoxication: Poisoning with dialyzable toxins (SLIME: Salicylates, Lithium, Isopropanol, Methanol, Ethylene glycol).
- Overload: Refractory volume overload / acute pulmonary edema resistant to high-dose loop diuretics.
- Uremia: Uremic encephalopathy, uremic pericarditis (pericardial rub), uremic neuropathy, or uremic bleeding.
Dialysis Modalities Comparison
| Feature | Hemodialysis (HD) | Peritoneal Dialysis (PD) |
|---|---|---|
| Access | Arteriovenous (AV) fistula (preferred), AV graft, or central venous catheter | Permanent Tenckhoff peritoneal catheter |
| Mechanism | Solute diffusion and ultrafiltration across semipermeable synthetic membrane | Peritoneal membrane acts as natural semipermeable membrane; dextrose dialysate |
| Schedule | Thrice weekly (4 hours per session in center) | Daily (CAPD: 4 manual exchanges/day; APD: overnight machine) |
| Primary Complication | Vascular access thrombosis/infection, dialysis disequilibrium syndrome, $\beta_2$-microglobulin amyloidosis | Peritonitis (Staph epidermidis, Staph aureus, Gram-negative bacilli; cloudy dialysate, $\text{WBC} > 100/\mu\text{L}$ with $> 50%$ PMNs) |
Kidney Transplantation
Kidney transplantation is the treatment of choice for ESRD, offering superior survival and quality of life compared to maintenance dialysis.
- Immunosuppression Regimens: Triple therapy consisting of a Calcineurin Inhibitor (Tacrolimus or Cyclosporine), an Antimetabolite (Mycophenolate Mofetil or Azathioprine), and Corticosteroids (Prednisolone).
- Calcineurin Inhibitor Toxicity: Causes afferent arteriolar vasoconstriction, presenting with hypertension, tremor, hypomagnesemia, hyperkalemia, and dose-dependent nephrotoxicity (striped interstitial fibrosis on biopsy).
A 54-year-old man with end-stage renal disease secondary to diabetic nephropathy is admitted to the emergency department. He missed his last two hemodialysis sessions. He reports severe dyspnea and nausea. On examination, blood pressure is 182/104 mmHg, pulse rate is 96 bpm, respiratory rate is 28 breaths/min, and oxygen saturation is 88% on room air. Diffuse bilateral pulmonary crackles are heard. Electrocardiogram reveals peaked T waves across precordial leads. Laboratory results show serum potassium of 7.2 mmol/L, bicarbonate of 11 mmol/L, arterial pH of 7.12, and urea of 38 mmol/L. Which of the following represents the definitive treatment for this patient's clinical deterioration?
A 62-year-old woman with Stage 4 CKD (eGFR 22 mL/min/1.73m²) presents for routine outpatient review. Laboratory testing reveals: serum calcium 2.02 mmol/L (normal 2.15–2.55), phosphate 2.18 mmol/L (normal 0.8–1.45), parathyroid hormone (PTH) 38 pmol/L (normal 1.6–6.9), and 25-hydroxyvitamin D 68 nmol/L. She is currently taking ramipril and empagliflozin. What is the most appropriate next step in managing her mineral and bone disorder?
A 59-year-old man with Stage 3b CKD (eGFR 34 mL/min/1.73m²) secondary to hypertensive nephrosclerosis has a routine complete blood count demonstrating hemoglobin of 88 g/L (normocytic, normochromic). Investigations reveal: serum ferritin 420 μg/L (reference 30–300), transferrin saturation (TSAT) 28% (reference 20–50%), vitamin B12 340 pmol/L, and folate 18 nmol/L. Stool occult blood is negative. The physician decides to initiate epoetin alfa (ESA) therapy. What is the target hemoglobin range for this patient?