Medical School · Year 2 · Renal · includes a quiz and discussion video

Lecture 14: Renal Pharmacology

Unit 2.1: Renal System

Learning Objectives

By the end of this lecture, students will be able to:

1. Describe the mechanisms and clinical uses of diuretics
2. Explain the pharmacology of RAAS-modulating agents
3. Describe drugs affecting uric acid metabolism
4. Explain phosphate binders and vitamin D analogs in CKD
5. Describe immunosuppressive agents used in renal disease
6. Apply principles of drug dosing in kidney disease

Diuretics: Overview

Diuretics constitute one of the most widely prescribed drug classes, used to treat hypertension, edema from heart failure, liver cirrhosis, or nephrotic syndrome, and various electrolyte disorders. Each diuretic class acts at a specific nephron site, blocking distinct transporters or channels to inhibit sodium reabsorption and increase urine output. Understanding the site of action predicts both the efficacy and the characteristic adverse effects of each class.

The thick ascending limb reabsorbs approximately 25% of filtered sodium via the sodium-potassium-2-chloride cotransporter (NKCC2), making loop diuretics that block this transporter the most potent class available. The distal convoluted tubule reabsorbs about 5% of filtered sodium through the thiazide-sensitive sodium-chloride cotransporter (NCC), giving thiazide diuretics moderate potency. The collecting duct reabsorbs only about 2% of filtered sodium through the epithelial sodium channel (ENaC), making potassium-sparing diuretics the least potent but useful adjuncts. Carbonic anhydrase inhibitors act in the proximal tubule, and vasopressin receptor antagonists work in the collecting duct to promote free water excretion.

Diuretic resistance occurs when expected natriuresis fails to materialize despite adequate dosing. Multiple mechanisms contribute. Volume depletion from overly aggressive diuresis reduces delivery of diuretic to the tubule. Low glomerular filtration rate decreases the filtered load of diuretic reaching its site of action, necessitating higher doses. Post-diuretic sodium retention occurs during the dosing interval when drug levels fall, with compensatory sodium reabsorption counteracting the diuresis; continuous infusion may overcome this phenomenon. Chronic diuretic therapy causes nephron adaptation with hypertrophy of downstream segments, leading to enhanced reabsorption that offsets the proximal blockade; combination therapy targeting multiple sites can address this resistance mechanism.

<image>Panel A: Nephron diagram showing diuretic sites from proximal tubule (carbonic anhydrase inhibitors), through thick ascending limb (loop diuretics blocking NKCC2, 25% Na reabsorption), to distal convoluted tubule (thiazides blocking NCC, 5% Na reabsorption). Panel B: Collecting duct diuretics showing potassium-sparing agents blocking ENaC or mineralocorticoid receptor (2% Na reabsorption), and vaptans blocking V2 receptor for free water excretion. Panel C: Potency comparison with relative arrow sizes showing loop diuretics as most potent, thiazides as moderate, and potassium-sparing as least potent. Panel D: Diuretic resistance mechanisms showing volume depletion (reduced delivery), low GFR (decreased filtered load), post-diuretic sodium retention (consider continuous infusion), and nephron adaptation with downstream segment hypertrophy (address with combination therapy).</image>

Loop Diuretics

Loop diuretics act in the thick ascending limb of the loop of Henle, blocking the NKCC2 cotransporter that reabsorbs sodium, potassium, and chloride in a 1:1:2 stoichiometry. This segment normally generates the corticomedullary osmotic gradient essential for urine concentration; loop diuretics disrupt this gradient, impairing concentrating ability in addition to causing natriuresis.

Available agents differ in pharmacokinetics. Furosemide is the most commonly prescribed loop diuretic but has variable oral bioavailability of only about 50%, meaning twice the oral dose may be needed to match intravenous effect. Bumetanide has superior oral bioavailability at approximately 80% with more predictable absorption. Torsemide offers the longest half-life and highest bioavailability, potentially improving consistent diuresis. Ethacrynic acid, a non-sulfonamide loop diuretic, is reserved for patients with severe sulfa allergy and may have less ototoxicity.

Clinical uses center on conditions requiring robust diuresis. Edematous states including heart failure, cirrhosis with ascites, and nephrotic syndrome respond to loop diuretics when volume removal is needed. Acute pulmonary edema requires rapid-onset intravenous administration. Hypercalcemia treatment combines saline volume expansion with loop diuretics to increase calcium excretion (the paracellular calcium reabsorption in the TAL depends on the lumen-positive voltage generated by NKCC2 activity, which loops disrupt). Acute hyperkalemia may transiently benefit from enhanced potassium excretion.

Adverse effects predictably follow from the mechanism of action. Hypokalemia results from increased sodium delivery to the collecting duct, driving potassium secretion. Hypomagnesemia occurs because TAL magnesium reabsorption, like calcium, depends on the lumen-positive potential. Hypocalcemia can develop with chronic use, though acute effects actually include hypercalciuria. Ototoxicity, particularly with rapid intravenous administration or concurrent aminoglycosides, reflects effects on inner ear transporters. Metabolic alkalosis results from volume contraction and chloride depletion. Hyperuricemia occurs because loop diuretics compete with uric acid for secretion in the proximal tubule.

<image>Panel A: NKCC2 mechanism in TAL cell showing Na+, K+, and 2Cl- entering from lumen, K+ recycling through ROMK creating lumen-positive potential that drives paracellular Ca2+ and Mg2+ reabsorption, with loop diuretic blocking NKCC2 and eliminating this potential. Panel B: Agent comparison showing furosemide (50% oral bioavailability, variable), bumetanide (80%, more predictable), torsemide (longest half-life, best bioavailability), and ethacrynic acid (non-sulfonamide for severe sulfa allergy). Panel C: Clinical uses including edematous states (heart failure, cirrhosis, nephrotic syndrome), acute pulmonary edema (IV administration), hypercalcemia (with saline expansion), and acute hyperkalemia. Panel D: Adverse effects showing hypokalemia (increased collecting duct Na delivery driving K secretion), hypomagnesemia (lost voltage-dependent reabsorption), ototoxicity (especially with rapid IV or aminoglycosides), metabolic alkalosis (volume and chloride depletion), and hyperuricemia (proximal tubule secretion competition).</image>

Thiazide Diuretics

Thiazide diuretics act in the distal convoluted tubule by blocking the thiazide-sensitive sodium-chloride cotransporter (NCC). Because only about 5% of filtered sodium reaches this segment, thiazides produce less robust diuresis than loop diuretics but remain effective for hypertension and mild edema.

Available agents have clinically significant differences. Hydrochlorothiazide is the most commonly prescribed but has a relatively short duration of action. Chlorthalidone has a much longer half-life, providing more consistent 24-hour blood pressure control, and evidence suggests superior cardiovascular outcomes. Metolazone maintains efficacy even at very low GFR where other thiazides fail, making it valuable as add-on therapy to loops in resistant edema. Indapamide has more lipophilic properties and may have vasodilatory effects beyond its diuretic action.

Clinical applications extend beyond diuresis. Hypertension treatment with thiazides is supported by extensive outcome data demonstrating cardiovascular mortality reduction. Mild edema responds well, and thiazides synergize with loop diuretics for resistant edema through sequential nephron blockade. Nephrolithiasis prevention exploits the calcium-sparing effect of thiazides, which reduce urinary calcium excretion in hypercalciuric stone formers. Nephrogenic diabetes insipidus paradoxically improves with thiazides, which induce mild volume contraction that enhances proximal tubule reabsorption and reduces urine output. Osteoporosis may benefit from reduced renal calcium losses.

The calcium-sparing effect deserves elaboration. When NCC is blocked, less sodium enters DCT cells, lowering intracellular sodium concentration. This enhances basolateral sodium-calcium exchange (3Na+/1Ca2+ antiporter), increasing calcium reabsorption. The net effect is hypocalciuria, opposite to the hypercalciuria of loop diuretics.

Adverse effects include hypokalemia from increased sodium delivery to the collecting duct. Hyponatremia occurs more frequently with thiazides than loops because thiazides impair diluting capacity without disrupting the medullary gradient needed for water reabsorption; patients continue concentrating urine while losing sodium. Hypercalcemia can develop, particularly in patients with underlying hyperparathyroidism. Hyperuricemia, hyperglycemia, and modest transient hyperlipidemia represent metabolic effects.

<image>Panel A: NCC mechanism in DCT cell showing Na+ and Cl- entering from lumen via NCC, thiazide blocking entry, reduced intracellular Na+ enhancing basolateral Na/Ca exchange (3Na out, 1Ca in), producing the net calcium-sparing effect of hypocalciuria. Panel B: Agent comparison showing hydrochlorothiazide (shorter acting), chlorthalidone (longer half-life with superior cardiovascular outcomes data), metolazone (maintains efficacy at low GFR, synergizes with loops), and indapamide (additional vasodilatory properties). Panel C: Clinical uses including hypertension (extensive outcome data), mild edema, nephrolithiasis prevention (reduced urinary calcium in hypercalciuria), nephrogenic diabetes insipidus (paradoxical benefit from volume contraction), and osteoporosis (reduced renal calcium losses). Panel D: Adverse effects showing hypokalemia, hyponatremia (more common than with loops due to impaired diluting without disrupting concentrating capacity), hypercalcemia, and metabolic effects (hyperglycemia, hyperuricemia, transient hyperlipidemia).</image>

Potassium-Sparing Diuretics

Potassium-sparing diuretics act in the collecting duct through two distinct mechanisms: direct blockade of the epithelial sodium channel (ENaC) or antagonism of the mineralocorticoid receptor (MR). Both mechanisms reduce sodium reabsorption while decreasing the electrical driving force for potassium secretion, hence the potassium-sparing effect.

ENaC blockers include amiloride and triamterene, which directly occlude the channel pore. These agents have modest diuretic potency used alone but serve important roles as adjuncts. Preventing thiazide or loop diuretic-induced hypokalemia represents their most common use. Liddle syndrome, characterized by constitutively active ENaC, responds specifically to amiloride. Lithium-induced nephrogenic diabetes insipidus improves with amiloride because lithium enters collecting duct cells through ENaC, and blocking the channel reduces intracellular lithium accumulation.

Mineralocorticoid receptor antagonists (MRAs) block aldosterone effects at the nuclear receptor level. Spironolactone, the prototypical agent, is non-selective and binds androgen and progesterone receptors, causing gynecomastia, breast tenderness, and menstrual irregularities. Eplerenone offers greater selectivity for the mineralocorticoid receptor with fewer endocrine side effects. Finerenone, a newer non-steroidal MRA, provides potent receptor antagonism with reduced hyperkalemia risk compared to steroidal agents.

Clinical applications for MRAs extend well beyond diuresis. Heart failure with reduced ejection fraction demonstrates mortality benefit with spironolactone or eplerenone, added to standard therapy. Cirrhosis with ascites responds particularly well because secondary hyperaldosteronism contributes prominently to sodium retention; spironolactone is first-line therapy. Primary aldosteronism (Conn syndrome) is treated with MRAs both diagnostically and therapeutically before or instead of surgery. Resistant hypertension often involves subtle volume expansion from aldosterone, and adding an MRA frequently achieves blood pressure control. Emerging data support MRAs for CKD with proteinuria, with finerenone demonstrating renal and cardiovascular benefits in diabetic kidney disease.

Hyperkalemia represents the primary adverse effect of all potassium-sparing diuretics, requiring monitoring especially in patients with CKD or those on RAAS blockade. Gynecomastia with spironolactone can be bothersome. Type 4 RTA-like metabolic acidosis may develop with impaired potassium secretion.

<image>Panel A: Collecting duct principal cell showing ENaC on apical surface for Na entry and Na/K-ATPase on basolateral membrane (3Na out, 2K in), creating lumen-negative potential driving K secretion through ROMK, with ENaC blockers (amiloride, triamterene) occluding the channel pore. Panel B: Mineralocorticoid receptor antagonists blocking aldosterone at the nuclear receptor, showing spironolactone (non-selective with gynecomastia risk), eplerenone (greater MR selectivity, fewer endocrine effects), and finerenone (non-steroidal with reduced hyperkalemia risk). Panel C: MRA clinical applications showing heart failure with mortality benefit, cirrhosis with ascites (first-line), primary aldosteronism (Conn syndrome), resistant hypertension, and CKD/diabetic kidney disease (finerenone renal and cardiovascular benefits). Panel D: Adverse effects showing hyperkalemia as the primary concern (requiring monitoring especially with CKD or RAAS blockade), gynecomastia and menstrual irregularities with spironolactone, and Type 4 RTA-like metabolic acidosis, with ENaC blocker-specific uses for Liddle syndrome and lithium-induced nephrogenic DI.</image>

Other Diuretics

Carbonic anhydrase inhibitors act in the proximal tubule, where carbonic anhydrase (CA) catalyzes the conversion of CO₂ and H₂O to H⁺ and HCO₃⁻, essential for bicarbonate reabsorption and acid secretion. Acetazolamide, the primary agent, inhibits this enzyme, causing bicarbonaturia and metabolic acidosis. Clinical uses include glaucoma treatment (reducing aqueous humor production), altitude sickness prophylaxis and treatment (inducing compensatory respiratory alkalosis), and management of metabolic alkalosis. The diuretic effect is self-limiting because the resulting metabolic acidosis reduces filtered bicarbonate. Side effects include metabolic acidosis, hypokalemia (bicarbonate acts as a non-reabsorbable anion in the collecting duct, enhancing potassium secretion), and paresthesias.

Osmotic diuretics, exemplified by mannitol, are freely filtered at the glomerulus but not reabsorbed, creating an osmotic force that retains water in the tubular lumen and increases urine output. Mannitol is used primarily for cerebral edema reduction (drawing water from brain tissue) and acute glaucoma (reducing intraocular pressure). Its use for acute kidney injury prevention lacks evidence. Side effects include initial volume expansion (mannitol draws water into the vascular space before being excreted), followed by volume depletion. Hyponatremia may occur as water is drawn from cells, though hypernatremia develops if water loss exceeds sodium loss.

Vasopressin receptor antagonists (vaptans) block the V2 receptor in the collecting duct, preventing aquaporin-2 insertion and causing aquaresis (free water excretion without sodium loss). Tolvaptan is an oral V2-selective agent; conivaptan blocks both V1A and V2 receptors and is given intravenously. Clinical uses include euvolemic hyponatremia (SIADH), where vaptans effectively raise serum sodium, and hypervolemic hyponatremia in heart failure or cirrhosis. Tolvaptan also slows cyst growth in autosomal dominant polycystic kidney disease. Risks include overcorrection of hyponatremia (risking osmotic demyelination syndrome), intense thirst, and hepatotoxicity with tolvaptan requiring liver function monitoring.

<image>Panel A: Carbonic anhydrase inhibitor (acetazolamide) showing proximal tubule cell with CA converting CO2 + H2O to H+ and HCO3-, drug blocking enzyme causing bicarbonaturia and metabolic acidosis, with uses for glaucoma, altitude sickness, and metabolic alkalosis, and side effects of acidosis, hypokalemia, and paresthesias. Panel B: Osmotic diuretic (mannitol) showing freely filtered molecule creating osmotic force retaining water in tubule lumen, used for cerebral edema and acute glaucoma, with side effects of initial volume expansion followed by depletion and sodium disturbances. Panel C: Vasopressin receptor antagonists (vaptans) showing V2 receptor in collecting duct normally triggering AQP2 insertion when bound by ADH, with vaptan blocking this to produce aquaresis (free water excretion without sodium loss). Panel D: Vaptan clinical uses showing euvolemic hyponatremia (SIADH), hypervolemic hyponatremia (heart failure, cirrhosis), and ADPKD cyst growth slowing (tolvaptan), with risks of overcorrection causing osmotic demyelination syndrome, intense thirst, and hepatotoxicity requiring liver function monitoring.</image>

RAAS-Modulating Agents

The renin-angiotensin-aldosterone system represents a critical target for cardiovascular and renal pharmacotherapy. Angiotensin-converting enzyme inhibitors (ACE inhibitors) block the conversion of angiotensin I to angiotensin II, reducing vasoconstriction, aldosterone release, and direct tissue effects of angiotensin II. Common agents include lisinopril, enalapril, and ramipril. Beyond RAAS blockade, ACE inhibitors increase bradykinin levels by preventing its degradation, contributing to vasodilation but also causing the characteristic dry cough affecting 5-20% of patients and rare but potentially life-threatening angioedema.

Angiotensin receptor blockers (ARBs) selectively block the AT1 receptor through which angiotensin II exerts most of its deleterious effects. Agents include losartan, valsartan, and irbesartan. Because ARBs do not affect bradykinin metabolism, cough is rare and angioedema less common (though still possible through bradykinin-independent mechanisms). ARBs provide an alternative for patients intolerant of ACE inhibitors due to cough.

Clinical indications for RAAS blockade are extensive. Hypertension treatment benefits from the neurohormonal modulation and end-organ protection beyond blood pressure lowering. Heart failure with reduced ejection fraction demonstrates mortality benefit with ACE inhibitors or ARBs as foundational therapy. Diabetic nephropathy and other proteinuric chronic kidney disease respond to RAAS blockade with reduced proteinuria and slowed progression—the protective effect results from reduced intraglomerular pressure when efferent arteriolar constriction is relieved. Post-myocardial infarction remodeling is attenuated by ACE inhibitors.

Adverse effects require anticipation and monitoring. Hyperkalemia results from reduced aldosterone secretion and direct effects on potassium excretion. Acute kidney injury can occur, particularly in patients with bilateral renal artery stenosis (where efferent tone maintains GFR) or volume depletion. Cough with ACE inhibitors prompts switching to ARBs. Angioedema, though rare, can be delayed by months or years after starting therapy. Teratogenicity is established, with renal agenesis and other fetal abnormalities mandating contraceptive use in women of childbearing potential.

Monitoring requires checking creatinine and potassium 1-2 weeks after initiation or dose increase. A creatinine rise up to 30% is acceptable and reflects reduced intraglomerular pressure; greater increases warrant dose reduction or evaluation for renal artery stenosis. Potassium above 5.5 mEq/L necessitates dose reduction or discontinuation.

<image>Panel A: RAAS cascade showing renin converting angiotensinogen to Ang I, ACE converting Ang I to Ang II, and Ang II acting on AT1 receptor causing vasoconstriction, aldosterone release, and tissue fibrosis, with ACE inhibitor blocking at the ACE step and ARB blocking at the AT1 receptor. Panel B: Bradykinin pathway showing ACE normally degrading bradykinin, ACE inhibitor increasing bradykinin causing vasodilation but also cough (5-20%) and rare angioedema, with ARBs avoiding this pathway. Panel C: Clinical indications showing hypertension (organ protection), heart failure (mortality benefit), diabetic and proteinuric CKD (reduced intraglomerular pressure from efferent arteriolar dilation), and post-MI (reduced remodeling). Panel D: Adverse effects and monitoring showing hyperkalemia, AKI risk (bilateral renal artery stenosis contraindication), cough (ACE inhibitor, switch to ARB), angioedema (rare, can be delayed), teratogenicity (pregnancy contraindication), and monitoring protocol (check creatinine and potassium at 1-2 weeks, acceptable creatinine rise up to 30%).</image>

SGLT2 Inhibitors

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as transformative agents for cardiorenal protection. SGLT2, located in the proximal tubule, normally reabsorbs approximately 90% of filtered glucose along with sodium. Blocking this transporter causes glucosuria of 100-200 grams daily and accompanying natriuresis.

Available agents include empagliflozin, dapagliflozin, and canagliflozin, originally developed for diabetes management but now approved for heart failure and CKD regardless of diabetes status. The renal protective mechanism extends beyond glucose lowering through several pathways. Increased sodium delivery to the macula densa activates tubuloglomerular feedback, causing afferent arteriolar vasoconstriction that reduces intraglomerular pressure. This hemodynamic effect resembles that of RAAS blockade but works through a different mechanism, allowing synergistic protection when the classes are combined. Additional benefits may include reduced inflammation, improved mitochondrial function, and decreased hyperfiltration injury.

Clinical benefits span diabetes, heart failure, and chronic kidney disease. In type 2 diabetes, SGLT2 inhibitors lower HbA1c and promote weight loss through caloric loss in urine. Major cardiovascular outcome trials demonstrated reduced heart failure hospitalizations and cardiovascular death, establishing these agents as essential in diabetes management. In heart failure with reduced ejection fraction, SGLT2 inhibitors reduce hospitalizations and mortality in both diabetic and non-diabetic patients. In chronic kidney disease with proteinuria, the DAPA-CKD and EMPA-KIDNEY trials showed remarkable reduction in CKD progression, dialysis initiation, and death from renal causes in both diabetic and non-diabetic patients.

Adverse effects include genital fungal infections (candidiasis) from glucosuria, affecting approximately 10% of patients and more common in women. Euglycemic diabetic ketoacidosis occurs rarely but requires awareness, particularly in patients with type 1 diabetes (where SGLT2 inhibitors are not generally indicated), acute illness, or reduced carbohydrate intake. Volume depletion from the diuretic effect may cause orthostatic hypotension, particularly when combined with loop diuretics. An initial GFR dip of 3-5 mL/min is expected and reflects the hemodynamic mechanism; this acute reduction paradoxically predicts better long-term renal protection. Fournier's gangrene (necrotizing fasciitis of the perineum) is rare but serious.

<image>Panel A: Proximal tubule mechanism showing SGLT2 on apical membrane normally reabsorbing 90% of filtered glucose with sodium, SGLT2 inhibitor blocking this to cause glucosuria (100-200 g/day) and natriuresis, with increased Na delivery to macula densa activating tubuloglomerular feedback. Panel B: Renal hemodynamic effect showing TGF-mediated afferent arteriolar vasoconstriction reducing intraglomerular pressure, distinct from but synergistic with RAAS blockade mechanism, plus additional benefits of reduced inflammation and improved mitochondrial function. Panel C: Clinical benefits across three domains showing diabetes (HbA1c reduction, weight loss), heart failure (reduced hospitalizations and mortality in HFrEF and HFpEF, diabetic and non-diabetic), and CKD (DAPA-CKD and EMPA-KIDNEY trials showing reduced progression regardless of diabetes status). Panel D: Adverse effects showing genital mycotic infections (approximately 10%, female preponderance), euglycemic DKA (rare, caution with T1DM and acute illness), volume depletion (especially with loop diuretics), expected initial GFR dip of 3-5 mL/min (paradoxically predicts long-term protection), and Fournier's gangrene (rare but serious).</image>

Drugs for CKD-Mineral Bone Disorder

Management of the phosphorus-calcium-PTH axis in chronic kidney disease requires multiple drug classes working in concert. Hyperphosphatemia, hypocalcemia, vitamin D deficiency, and secondary hyperparathyroidism contribute to cardiovascular calcification, bone disease, and mortality in CKD.

Phosphate binders reduce intestinal phosphorus absorption by binding dietary phosphate in the gastrointestinal tract, preventing its absorption and eliminating it in stool. Calcium-based binders including calcium carbonate and calcium acetate are inexpensive and effective but risk hypercalcemia and may contribute to vascular calcification with chronic use. Non-calcium binders avoid this risk: sevelamer is a polymer that also binds bile acids and may improve lipid profiles; lanthanum is an effective alternative. Iron-based binders including sucroferric oxyhydroxide and ferric citrate provide the added benefit of iron supplementation in iron-deficient CKD patients. All phosphate binders must be taken with meals to intercept dietary phosphorus.

Vitamin D therapy addresses deficiency and suppresses PTH secretion. Nutritional vitamin D (cholecalciferol or ergocalciferol) repletes 25-hydroxyvitamin D stores and is appropriate for deficiency in any CKD stage. Active vitamin D (calcitriol) bypasses the deficient renal 1α-hydroxylase and directly activates vitamin D receptors. Active vitamin D analogs including paricalcitol and doxercalciferol may cause less hypercalcemia than calcitriol while maintaining PTH suppression. All forms increase intestinal calcium absorption and can cause hypercalcemia, requiring monitoring.

Calcimimetics address secondary hyperparathyroidism through a different mechanism. Cinacalcet (oral) and etelcalcetide (intravenous, dialysis-only) allosterically activate the calcium-sensing receptor on parathyroid cells, mimicking the effect of elevated calcium and suppressing PTH secretion. Unlike vitamin D, calcimimetics lower rather than raise serum calcium and phosphorus. They are used in dialysis patients with secondary hyperparathyroidism inadequately controlled with phosphate binders and vitamin D.

<image>Panel A: CKD-MBD pathophysiology showing declining kidney function causing hyperphosphatemia (reduced excretion), low calcitriol (reduced 1-alpha-hydroxylase), and hypocalcemia, all stimulating PTH secretion (secondary hyperparathyroidism), with drug intervention points marked. Panel B: Phosphate binders (all taken with meals) showing calcium-based (calcium carbonate, acetate, inexpensive but hypercalcemia and vascular calcification risk), non-calcium (sevelamer also binding bile acids, lanthanum), and iron-based (sucroferric oxyhydroxide, ferric citrate providing additional iron supplementation). Panel C: Vitamin D therapy showing nutritional (cholecalciferol, ergocalciferol for store repletion), active calcitriol (bypasses renal 1-alpha-hydroxylase, directly activates VDR, lowers PTH), and analogs (paricalcitol, doxercalciferol with less hypercalcemia than calcitriol). Panel D: Calcimimetics showing cinacalcet (oral) and etelcalcetide (IV for dialysis patients), mechanism of allosteric activation of calcium-sensing receptor on parathyroid cells mimicking high calcium to suppress PTH, and net effect of lowering PTH, calcium, and phosphorus.</image>

Drugs for Uric Acid

Uric acid management involves agents that either decrease production or increase excretion, with choice depending on the clinical situation and underlying mechanism of hyperuricemia.

Xanthine oxidase inhibitors reduce uric acid production by blocking the enzyme that converts hypoxanthine and xanthine to uric acid. Allopurinol is the classic agent, metabolized to oxypurinol which provides the sustained xanthine oxidase inhibition. Dose reduction is required in CKD because oxypurinol is renally excreted; failure to reduce doses causes accumulation and increased risk of severe hypersensitivity reactions including drug rash with eosinophilia and systemic symptoms (DRESS) and Stevens-Johnson syndrome. HLA-B*5801 testing before initiation is recommended in certain high-risk populations (Korean, Han Chinese, Thai) because this allele confers dramatically increased hypersensitivity risk. Febuxostat is a more potent non-purine xanthine oxidase inhibitor that does not require dose adjustment in moderate CKD; however, cardiovascular safety concerns from the CARES trial led to an FDA boxed warning regarding increased cardiovascular death compared to allopurinol. Clinical indications include chronic gout, prevention of uric acid stones, and tumor lysis syndrome prophylaxis.

Uricosuric agents increase renal uric acid excretion by blocking the urate transporter URAT1 in the proximal tubule, which normally reabsorbs filtered urate. Probenecid is the traditional agent, effective only when renal function is preserved (GFR >50). Lesinurad is a newer uricosuric used in combination with a xanthine oxidase inhibitor. Uricosurics are contraindicated in patients with uric acid nephrolithiasis because the increased uric acid excretion raises stone risk. Adequate hydration is essential.

Rasburicase is a recombinant uricase enzyme that directly converts uric acid to allantoin, a much more soluble compound. This agent produces rapid and dramatic uric acid reduction, making it essential for tumor lysis syndrome treatment. It is contraindicated in G6PD deficiency because the hydrogen peroxide generated during uric acid oxidation causes hemolysis in G6PD-deficient patients. Pegloticase, a pegylated uricase, is used for refractory gout but carries significant immunogenicity and infusion reaction risk.

<image>Panel A: Uric acid metabolic pathway showing purines metabolized through hypoxanthine and xanthine to uric acid via xanthine oxidase, then filtered at kidney and reabsorbed via URAT1, with xanthine oxidase inhibitor and uricosuric intervention sites marked. Panel B: Xanthine oxidase inhibitors showing allopurinol (dose reduction in CKD, hypersensitivity risk including DRESS and SJS, HLA-B*5801 testing in high-risk populations) and febuxostat (no renal adjustment needed, cardiovascular safety concern from CARES trial), with uses for gout, uric acid stones, and tumor lysis prophylaxis. Panel C: Uricosuric agents showing probenecid and lesinurad blocking URAT1 to increase renal uric acid excretion, requiring adequate GFR (greater than 50 for probenecid), contraindicated with uric acid stones, and requiring adequate hydration. Panel D: Rasburicase showing recombinant uricase converting uric acid to highly soluble allantoin for rapid reduction in tumor lysis syndrome, contraindicated in G6PD deficiency (hydrogen peroxide causing hemolysis), and pegloticase for refractory gout with immunogenicity risk.</image>

Drug Dosing in Kidney Disease

Chronic kidney disease profoundly affects drug pharmacokinetics, necessitating systematic dose adjustment for many medications. Understanding the principles enables safe prescribing even when specific guidelines are unavailable.

Renal excretion decreases proportionally with GFR decline for drugs eliminated unchanged by the kidney. Active metabolites of hepatically metabolized drugs may also accumulate when their renal clearance is impaired. Volume of distribution may change in CKD due to altered protein binding (uremic toxins displace drugs from albumin, increasing free fraction) or fluid redistribution. The net effect varies by drug but generally favors accumulation and increased toxicity.

Dose adjustment strategies include reducing the individual dose while maintaining the interval, extending the interval while maintaining the dose, or combining both approaches. The optimal strategy depends on whether efficacy requires high peak concentrations (maintain dose, extend interval) or sustained levels (reduce dose, maintain interval). The CKD-EPI equation provides the GFR estimate for dosing decisions, though some drugs specify adjustments based on creatinine clearance (Cockcroft-Gault equation) for historical reasons.

Drugs commonly requiring adjustment include aminoglycosides (nephrotoxic and ototoxic with accumulation; extended-interval dosing with therapeutic monitoring), vancomycin (nephrotoxic; trough monitoring essential), digoxin (narrow therapeutic index; half the dose when GFR <30), gabapentin (CNS toxicity with accumulation; substantial dose reduction required), metformin (lactic acidosis risk; avoid if GFR <30, caution between 30-45), and direct oral anticoagulants (bleeding risk; agent-specific adjustments).

Drugs to avoid in advanced CKD include NSAIDs (reduce GFR, cause hyperkalemia and AKI), gadolinium-based contrast agents (nephrogenic systemic fibrosis risk if GFR <30), nitrofurantoin (ineffective and causes neuropathy when GFR <30), and metformin at GFR <30. Oral phosphate bowel preparations can cause acute phosphate nephropathy.

<image>Panel A: Pharmacokinetic changes in CKD showing reduced renal excretion with declining GFR, active metabolite accumulation, and altered protein binding with increased free drug fraction from uremic toxin displacement. Panel B: Dose adjustment strategies showing reduced dose with same interval (sustained levels), extended interval with same dose (maintained peaks), or both, with decision based on concentration-dependent versus time-dependent efficacy and CKD-EPI equation for GFR estimation. Panel C: Drugs requiring adjustment with specific recommendations including aminoglycosides (extended interval with level monitoring), vancomycin (trough monitoring), digoxin (halve dose if GFR below 30), gabapentin (substantial reduction for CNS toxicity), metformin (avoid below GFR 30), and DOACs (agent-specific adjustments). Panel D: Drugs to avoid in advanced CKD including NSAIDs (GFR reduction, hyperkalemia, AKI risk), gadolinium below GFR 30 (nephrogenic systemic fibrosis), nitrofurantoin below GFR 30 (ineffective and neuropathy), and oral phosphate bowel preparations (acute phosphate nephropathy).</image>

Summary

Diuretics act at specific nephron segments: loop diuretics block NKCC2 in the TAL (most potent, cause hypokalemia and hypocalciuria), thiazides block NCC in the DCT (moderate potency, cause hypokalemia and hypocalciuria reduction useful for stones), and potassium-sparing agents work in the collecting duct through ENaC blockade or mineralocorticoid receptor antagonism (cause hyperkalemia).

ACE inhibitors and ARBs provide nephroprotection through reduced intraglomerular pressure from efferent arteriolar dilation; monitoring of creatinine and potassium is essential, with up to 30% creatinine rise acceptable. SGLT2 inhibitors provide cardiorenal protection through tubuloglomerular feedback activation and multiple other mechanisms, with benefits extending to non-diabetic heart failure and CKD.

Phosphate binders reduce intestinal phosphorus absorption and must be taken with meals; calcium-based binders risk hypercalcemia while non-calcium alternatives avoid this. Calcimimetics lower PTH by activating the calcium-sensing receptor. Xanthine oxidase inhibitors (allopurinol, febuxostat) reduce uric acid production; allopurinol requires dose adjustment in CKD and carries hypersensitivity risk.

Drug dosing in CKD requires attention to altered pharmacokinetics; renally cleared drugs need dose or interval adjustment. NSAIDs, gadolinium contrast in severe CKD, and nitrofurantoin in advanced CKD should be avoided.

Key Terms

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