Renal Pharmacology  ·  Module 3 of 5

Chronic Kidney Disease Pharmacology

Drug dosing adjustments · RAAS blockade and SGLT2 inhibitors · Anemia management · CKD-MBD pharmacology

• CKD reduces renal drug clearance proportional to GFR decline. Key agents requiring dose adjustment or avoidance: metformin — entirely renally excreted by tubular secretion; accumulates → inhibits hepatic lactate clearance → metformin-associated lactic acidosis; hold when eGFR <30 mL/min, dose-reduce and monitor 30–45 mL/min, withhold before contrast procedures. Direct oral anticoagulants by renal risk: dabigatran 80% renally eliminated — contraindicated at eGFR <30 (highest renal risk); apixaban ~27% renal — safest in advanced CKD; rivaroxaban and edoxaban intermediate. Active metabolite accumulation: morphine → morphine-6-glucuronide (potent respiratory depressant); hydromorphone, oxycodone, codeine similar; meperidine → normeperidine (pro-convulsant) — avoid entirely in CKD.
• RAAS blockade: angiotensin II preferentially constricts the efferent arteriole → raises intraglomerular capillary pressure → forces protein across filtration barrier → tubular injury + interstitial inflammation. ACEi and ARBs dilate the efferent arteriole → lower intraglomerular pressure → reduce proteinuria independently of systemic BP effect. Acute creatinine rise up to 30% on initiation is expected and acceptable (efferent dilation reduces hydraulic filtration pressure); >30% rise or bilateral renal artery stenosis suspected → investigate. ACEi reduce CKD progression in diabetic nephropathy independently of BP (AIPRI data); ARBs equivalent in type 2 diabetic nephropathy (IDNT, RENAAL). ACEi + ARB combination: no added renoprotection but substantially higher hyperkalemia and AKI risk (ONTARGET) — never combine. Hold when eGFR <30 + K⁺ >5.5 mEq/L, volume depletion, pre-contrast, perioperatively.
• SGLT2 inhibitors in CKD: hyperfiltrating surviving nephrons over-reabsorb Na⁺ in PCT → ↓ Na delivery to macula densa → TGF signals afferent dilation → ↑ intraglomerular pressure → nephron loss accelerated. SGLT2 inhibitors block glucose-coupled Na⁺ reabsorption → restore Na delivery to macula densa → afferent constriction via TGF → ↓ intraglomerular pressure. Effect is independent of diabetes. CREDENCE (canagliflozin, type 2 DM + CKD): −30% ESKD/creatinine doubling/renal-CV death composite. DAPA-CKD (dapagliflozin, diabetic + non-diabetic CKD): −39% composite across both populations. Now standard of care in CKD. Glycosuric efficacy diminishes as GFR ↓ (less filtered glucose); but renoprotective TGF mechanism persists at lower GFR. AEs: genital mycotic infections (5–10%, manageable); euglycemic DKA (glucose near-normal but ketosis elevated); Fournier's gangrene (black box warning).
• CKD anemia arises from deficient erythropoietin production by peritubular fibroblasts as nephron mass decreases → normochromic normocytic anemia. ESAs: epoetin alfa (SC/IV 2–3×/week) and darbepoetin alfa (hyperglycosylated → 3× longer t½ → weekly or q2w dosing). Black box warning: hemoglobin targets above 11–12 g/dL increase stroke, MI, thrombosis, and death (CHOIR, TREAT trials); current guideline: maintain Hb 10–11.5 g/dL at lowest effective dose. Iron is an absolute co-requirement — ESAs drive erythropoiesis and rapidly deplete iron stores → functional iron deficiency → ESA hyporesponsiveness; IV iron preferred in dialysis patients (GI absorption limited by inflammation and hepcidin-mediated block; IV bypasses both). HIF-PHI inhibitors (roxadustat, daprodustat): block prolyl hydroxylase domain enzymes → HIF-1α accumulates (mimics hypoxia) → upregulates endogenous EPO transcription; oral dosing advantage; phase 3 non-inferior to ESAs; cardiovascular safety under ongoing scrutiny; positioned as alternative when ESA inadequate.
• CKD-MBD: ↓ phosphate excretion → hyperphosphatemia; ↓ renal 1α-hydroxylase → ↓ calcitriol; hypocalcemia + hyperphosphatemia → secondary hyperparathyroidism (PTH mobilizes Ca²⁺ and PO₄ from bone). Treatment targets: normalize serum phosphorus, restore active vitamin D, suppress PTH without adynamic bone disease. Phosphate binders (with meals — must bind dietary phosphate in gut): calcium carbonate/acetate (effective, cheap; risk of vascular calcification from positive Ca²⁺ balance); sevelamer (non-calcium polymer; also lowers LDL); lanthanum carbonate (non-calcium metal binder). Active vitamin D: calcitriol (natural active form; suppresses PTH via VDR in parathyroid chief cells); paricalcitol/doxercalciferol (synthetic analogs; greater parathyroid vs intestinal selectivity → less hypercalcemia + hyperphosphatemia). Cinacalcet (calcimimetic): allosterically activates calcium-sensing receptor on parathyroid chief cells → sensitizes to Ca²⁺ → suppresses PTH without raising serum Ca²⁺; use when hypercalcemia limits vitamin D analog use; EVOLVE trial: no CV mortality reduction overall; AEs: nausea, vomiting, hypocalcemia.