L35,36,37 CKD Pharmacology, Therapeutics, Labs

Three determinants of renin release: 1. Decreased [blank_start]Na+ concentration[blank_end] sensed by kidney 2. Decreased BP or renal [blank_start]blood flow[blank_end] 3. [blank_start]Beta 2[blank_end] receptor activation

Angiotensin causes profound vasoconstriction and aldosterone release.

Both ACEIs and ARBS will decrease systemic vascular resistance and increase renal perfusion.

Diuretics for CKD: 1. Loop diuretics inhibit the activity of the Na-K-2Cl symporter in the [blank_start]thick ascending loop of Henle[blank_end]. Therefore maximum effect is ~[blank_start]20-25[blank_end]%. 2. Thiazide diuretics inhibit the activity of the Na-Cl symporter in the [blank_start]distal tubule[blank_end]. Maximum effect is ~[blank_start]5[blank_end]%. 3. K-sparing diuretics inhibit the activity of epithelial Na+ channels in the [blank_start]late distal tubule and collecting duct[blank_end]. Maximum effect is ~[blank_start]2[blank_end]%. 4. Aldosterone antagonists competitively inhibit the binding of [blank_start]aldosterone[blank_end] to the mineralocorticoid receptor. The only class of diuretics that do not enter the tubule cell from the apical ([blank_start]tubular[blank_end]) side, and instead from the basolateral ([blank_start]blood[blank_end]) side.

Classification of CKD: • Normal/ CKD 1: GFR >90 mL/min • Mild/ CKD 2: GFR [blank_start]60-90[blank_end] mL/min • Moderate/ CKD 3: GFR [blank_start]30-60[blank_end] mL/min • Severe/ CKD 4: GFR [blank_start]15-30[blank_end] mL/min • End-stage/ CKD 5: GFR <15 mL/min

Non-pharmacological treatment of CKD entails dietary sodium restriction, and protein restriction if GFR < 30mL/min.

When using ACEIs and ARBs in CKD the target is a reduction in urine [blank_start]albumin[blank_end] of 30-50%. Starting can [blank_start]reduce[blank_end] GFR; start at a [blank_start]low[blank_end] dose and titrate the dose slowly to effect. Other Important side effects to consider: • [blank_start]Hyper[blank_end]kalaemia • [blank_start]Acute[blank_end] renal impairment • Dry cough (fairly [blank_start]common[blank_end]) • Angioedema ([blank_start]rare[blank_end], but serious)

Methods of estimating renal function: 1. Creatinine-based methods (CLcr, eGFR) • Collection of 24 hour urine samples ([blank_start]creatinine[blank_end] clearance) • Cockcroft-Gault [blank_start]Equatoin[blank_end] (an estimate of creatinine clearance) • MDRD • CKD-EPI All these are reported by the lab as “[blank_start]eGFR[blank_end]”. 2. Cystatin C clearance 3. Clearance of a [blank_start]xenobiotic[blank_end]: Inulin (NOT insulin), 51Cr EDTA (radioisotope)

Creatinine is freely filtered by the glomerulus and so its clearance lets us estimate GFR.

Cockcroft & Gault equation: CLcr = ( (140 - [blank_start]Age[blank_end]) x [blank_start]ideal body weight[blank_end] x K* ) / [blank_start]serum creatinine[blank_end] * K = 1.23 for males, 1.04 for females

All creatinine-based methods; • Are poor predictors of GFR if malnourished or low [blank_start]muscle[blank_end] mass • Over-estimate GFR in the elderly, [blank_start]obese[blank_end] (using total body weight), severe or end-stage renal disease • Not for <[blank_start]18[blank_end] years old • Unreliable when renal function [blank_start]changing[blank_end] rapidly (acute renal failure) • Drugs [blank_start]inhibiting[blank_end] tubular secretion can raise creatinine conc (e.g. probenecid, trimethoprim, spironolactone)

In CKD, K+ secretion is [blank_start]reduced[blank_end] resulting in accumulation. Concentrations above [blank_start]5.5-6[blank_end]mmol/L become symptomatic. Hyperkalaemia is more likely to be observed in CKD 4 or 5, and is exacerbated by [blank_start]ACE-I, ARBs[blank_end] and K-sparing diuretics.

Match the ranges. - Creatinine (plasma): Adult male: 50-[blank_start]110[blank_end] µmol/L, Adult female: 45-[blank_start]90[blank_end] µmol/L - Urea (plasma): Adults: [blank_start]3.2-7.7[blank_end] mmol/L - Sodium (plasma) [blank_start]135-145[blank_end] mmol/L - Osmolality (plasma) 280-[blank_start]300[blank_end] mmol/kg - Osmolality (urine) 300-[blank_start]1200[blank_end] mmol/kg