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Mechanisms of Action: All Nephrology Drugs (Detailed)

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I. DIURETICS

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1. Carbonic Anhydrase Inhibitors (CAIs)

• The proximal tubule is richly endowed with carbonic anhydrase (CA), found in both the luminal brush border (type IV, membrane-bound) and cytoplasm (type II, cytosolic).
• Normally, the Na+-H+ antiporter (NHE3) in the luminal membrane secretes H+ into the lumen. Luminal H+ reacts with filtered HCO3- to form H2CO3, which is rapidly decomposed to CO2 + H2O by brush-border CA IV.
• CO2 diffuses into the cell, where cytosolic CA II catalyzes its rehydration back to H2CO3, which dissociates into H+ (recycled to NHE3) and HCO3- (exits via basolateral NBC1 cotransporter with Na+ into blood).
• CAIs competitively inhibit both CA IV and CA II, blocking this entire cycle. The result is:
  • Decreased H+ secretion into the lumen
  • Reduced HCO3- reabsorption (HCO3- is lost in urine)
  • Reduced Na+ reabsorption (coupled to H+)
  • Increased delivery of NaHCO3, Cl-, K+, water to distal segments
  • Net effect: bicarbonate diuresis, alkaline urine, and metabolic acidosis with continued use
• Because CAIs cause a self-limiting diuresis (tubular fluid becomes rich in Cl- while HCO3- is depleted), they are weak diuretics.

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2. Osmotic Diuretics

• Osmotic diuretics are freely filtered at the glomerulus but are NOT reabsorbed (or minimally reabsorbed) by the tubular epithelium.
• Their presence in tubular fluid raises the osmolality of that fluid, opposing water reabsorption in the proximal tubule and descending loop of Henle (which are freely water-permeable).
• Consequently, tubular fluid volume remains high, carrying Na+, Cl-, K+, and other solutes along with it into the collecting system - preventing their reabsorption by an osmotic "dilution" effect.
• In the thick ascending limb (TAL) - which is water-impermeable - osmotic diuretics increase flow rate, reducing the capacity for countercurrent concentration.
• Osmotic diuretics also expand plasma volume initially (drawing water from the intracellular space), which can increase RBF and GFR.

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3. Loop Diuretics (High-Ceiling Diuretics)

• The TAL is the major diluting segment. It actively reabsorbs ~25% of filtered NaCl but is impermeable to water, so this segment normally dilutes the tubular fluid and generates the medullary osmotic gradient.
• The primary transporter in the TAL luminal membrane is the Na+-K+-2Cl- cotransporter (NKCC2/SLC12A1). It uses the energy of the Na+ gradient (maintained by basolateral Na+/K+-ATPase) to simultaneously move 1 Na+, 1 K+, and 2 Cl- from the lumen into the cell.
• Loop diuretics bind to and block NKCC2 from the luminal side. Because these drugs are organic acids, they are actively secreted into the proximal tubule lumen via OAT1/3 transporters and MRP2/4, reaching high luminal concentrations.
• Blocking NKCC2 has cascading effects:
  • Na+, K+, Cl- are no longer reabsorbed in the TAL - all delivered to the distal tubule
  • K+ that normally recycles back into the lumen via luminal ROMK channels (to maintain NKCC2 function) is blocked, abolishing the positive lumen potential. This positive lumen potential normally drives paracellular reabsorption of Ca2+ and Mg2+, so loop diuretics cause hypercalciuria and hypomagnesemia.
  • The medullary osmotic gradient is abolished, impairing urinary concentrating ability
  • Large Na+ delivery to the collecting duct stimulates aldosterone-mediated K+ and H+ secretion → hypokalemia and metabolic alkalosis
• Loop diuretics also increase renal prostaglandin synthesis, which contributes to renal vasodilation and increased RBF (the venodilatory effect of furosemide in acute pulmonary edema).
• Ethacrynic acid is structurally distinct (a phenoxyacetic acid derivative vs. sulfonamide) - it alkylates the -SH group of NKCC2. It is used in patients with sulfonamide allergy.

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4. Thiazide and Thiazide-Like Diuretics

• The DCT (early portion) reabsorbs ~5-8% of filtered NaCl via the luminal Na+-Cl- cotransporter (NCC/SLC12A3) - the "thiazide-sensitive" cotransporter. NCC cotransports Na+ and Cl- electroneutrally.
• Thiazides bind to and block NCC from the luminal side. Like loop diuretics, they are secreted into the proximal tubule lumen via OAT1/3 (basolateral) and MRP4 (luminal) to reach their site of action.
• Effects of NCC blockade:
  • Reduced Na+ and Cl- reabsorption in DCT → natriuresis
  • Increased Na+ delivery to collecting duct → aldosterone activation → ↑ K+ and H+ secretion → hypokalemia, metabolic alkalosis
  • Paradoxical hypocalciuria: Blocking NCC reduces intracellular Na+, which enhances basolateral Na+/Ca2+ exchanger (NCX1) activity, increasing Ca2+ reabsorption from the cell into blood. Also, PTH-stimulated apical TRPV5 Ca2+ channels are upregulated. Net: less Ca2+ in urine - used to treat calcium nephrolithiasis.
  • ↑ Mg2+ excretion
  • Uric acid retention: Thiazides compete with urate for OAT3-mediated secretion in the proximal tubule, reducing uric acid excretion → hyperuricemia.
  • Insulin resistance and glucose intolerance: hypokalemia reduces pancreatic beta-cell insulin secretion; also direct metabolic effects.

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5. Potassium-Sparing Diuretics

5a. Mineralocorticoid (Aldosterone) Receptor Antagonists

• Aldosterone normally enters principal cells, binds to the mineralocorticoid receptor (MR) in the cytoplasm, and the aldosterone-MR complex translocates to the nucleus where it acts as a transcription factor.
• Aldosterone increases transcription of the epithelial sodium channel (ENaC) and the Na+/K+-ATPase pump, as well as accessory proteins (serum- and glucocorticoid-inducible kinase, SGK1) that traffic ENaC to the apical membrane.
• ENaC allows luminal Na+ to flow into the principal cell down its electrochemical gradient, creating a lumen-negative potential. This drives K+ secretion (via ROMK channels) and H+ secretion (by type A intercalated cells).
• Spironolactone and eplerenone are competitive antagonists at the MR. They compete with aldosterone for binding to the cytoplasmic MR, preventing formation of the aldosterone-MR complex and blocking downstream transcription of ENaC, Na+/K+-ATPase, and ROMK. Net effect: ↓ Na+ reabsorption and ↓ K+ secretion in the CCD → potassium sparing + mild natriuresis.
• Spironolactone also has anti-androgenic activity (binds androgen receptor) causing gynecomastia and menstrual irregularities. Eplerenone is more selective for MR, with fewer sex hormone side effects.
• Finerenone is a newer, non-steroidal MRA with high MR selectivity, balanced renal/cardiac distribution, and no active metabolites; approved for CKD with type 2 diabetes (reduces kidney disease progression and cardiovascular events).

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5b. ENaC Blockers (Direct)

• Amiloride and triamterene act independently of aldosterone by directly blocking the luminal ENaC channel (epithelial sodium channel, composed of α, β, γ subunits).
• These drugs are organic bases that are positively charged at physiologic pH. They physically enter and occlude the pore of ENaC from the luminal side, blocking Na+ entry into the principal cell.
• Reduced Na+ entry → less lumen-negative potential → reduced electrochemical driving force for K+ secretion (via ROMK) and H+ secretion → K+ sparing, mild Na+ excretion.
• Their effect is not dependent on aldosterone levels - effective even in adrenal insufficiency (where spironolactone is ineffective).
• Amiloride also blocks Na+-H+ exchanger NHE1 at higher concentrations and is used to treat Liddle syndrome (gain-of-function ENaC mutation).

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II. RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS) INHIBITORS

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6. ACE Inhibitors (ACEIs)

• Angiotensin-converting enzyme (ACE, also called kininase II) is a zinc metallopeptidase located on the luminal surface of vascular endothelium (especially pulmonary) and on the brush border of proximal tubular cells.
• ACE cleaves a dipeptide from the C-terminus of angiotensin I (a 10-amino acid peptide) to produce angiotensin II (an 8-amino acid vasoactive peptide). ACE also degrades bradykinin (a vasodilator).
• ACEIs bind to the active site zinc of ACE, competitively inhibiting the conversion of Ang I → Ang II.
• Reduced Ang II → multiple renal effects:
  • Efferent arteriolar dilation: Ang II normally preferentially constricts the efferent arteriole. ACEIs dilate the efferent arteriole → ↓ intraglomerular pressure (↓ GFR in the short term, but long-term renoprotection by reducing hyperfiltration and proteinuria).
  • Reduced aldosterone secretion: Ang II is the primary stimulus for adrenal aldosterone release. ACEIs → ↓ aldosterone → ↓ Na+ and water retention, ↑ K+ retention (hyperkalemia risk).
  • Reduced proximal tubular Na+ reabsorption: Ang II normally directly stimulates NHE3. ACEIs reduce this.
  • Reduced ADH release and sympathetic activation (secondary effects via reduced Ang II).
• Bradykinin accumulation (due to ACE inhibition of bradykinin degradation) → vasodilation (via NO, prostacyclin) and also causes the characteristic dry cough and risk of angioedema.
• Renoprotective mechanism: Reduction in intraglomerular hypertension reduces proteinuria and slows progression of diabetic nephropathy and proteinuric CKD.

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7. Angiotensin II Receptor Blockers (ARBs)

• Ang II acts on two receptor subtypes: AT1R and AT2R.
• AT1R mediates all major vasoconstrictor, pro-inflammatory, pro-fibrotic, and sodium-retaining effects of Ang II (vasoconstriction, aldosterone release, proximal tubule Na+ reabsorption, sympathetic stimulation, mesangial cell contraction, TGF-β induction).
• AT2R mediates opposing vasodilatory and anti-proliferative effects.
• ARBs are selective competitive antagonists at AT1R. They do not prevent Ang II formation (Ang II levels actually rise due to loss of negative feedback via AT1R), but they block AT1R-mediated effects.
• Unlike ACEIs: ARBs do NOT inhibit bradykinin degradation, so they do not cause cough or angioedema (much lower risk). However, both classes equally reduce intraglomerular pressure and proteinuria.
• AT2R remains unblocked and may be activated by the elevated Ang II levels, contributing to vasodilation and organ protection.

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8. Renin Inhibitors

• Renin is the rate-limiting enzyme that cleaves angiotensinogen (produced by the liver) to produce angiotensin I - the first and committed step of the RAAS cascade.
• Aliskiren is a direct renin inhibitor (DRI) - it binds to the active site of renin, blocking cleavage of angiotensinogen → prevents generation of both Ang I and Ang II (and all downstream effects).
• Unlike ACEIs/ARBs, aliskiren suppresses plasma renin activity (PRA) whereas ACEIs and ARBs cause a reflex rise in PRA (reactive hyperreninemia). Aliskiren reduces PRA by >80%.
• Not used in combination with ACEIs or ARBs (increased adverse effects without added benefit - ALTITUDE trial).

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9. Mineralocorticoid Receptor Antagonists (MRAs)

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III. DRUGS FOR HYPERKALEMIA

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10. Sodium Bicarbonate / Insulin + Glucose / Calcium Gluconate

• Calcium gluconate: Directly stabilizes the cardiac membrane potential by raising the threshold potential, counteracting the depolarizing effect of hyperkalemia on cardiomyocytes. Does NOT lower serum K+.
• Insulin + Glucose: Insulin activates the Na+/K+-ATPase in skeletal muscle and liver, driving K+ intracellularly. Glucose prevents hypoglycemia. Rapid onset (15-30 min).
• Sodium bicarbonate: Corrects acidosis; in acidosis, H+ moves into cells in exchange for K+ (via H+/K+ exchanger); correcting acidosis reverses this, shifting K+ back into cells. Moderate efficacy.

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11. Cation-Exchange Resins / Potassium Binders

• Sodium polystyrene sulfonate (SPS): An exchange resin that, in the gastrointestinal tract (primarily colon), releases Na+ in exchange for K+. The resin-bound K+ is then excreted in feces. Slow onset; may cause bowel necrosis.
• Patiromer: A non-absorbed, non-systemic polymeric potassium binder. It binds K+ in exchange for Ca2+ primarily in the distal colon (where K+ secretion occurs). Patiromer has a high selectivity for K+ over other cations. Onset ~7 hours.
• Sodium Zirconium Cyclosilicate (SZC/ZS-9): An inorganic crystalline compound with a microporous structure that preferentially captures K+ ions (and NH4+) in exchange for H+ and Na+ throughout the GI tract (predominantly small intestine). It mimics the K+ selectivity of a biological ion channel, with onset within 1-2 hours. Very high capacity and K+ selectivity.

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IV. DRUGS FOR HYPERPHOSPHATEMIA (Renal Failure / CKD-MBD)

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12. Phosphate Binders

• Calcium-based: Calcium carbonate, Calcium acetate (PhosLo)
• Non-calcium-based: Sevelamer (hydrochloride/carbonate), Lanthanum carbonate, Sucroferric oxyhydroxide (Velphoro), Ferric citrate

• All phosphate binders work in the gastrointestinal lumen - they are not absorbed systemically.
• They bind dietary phosphate (from food) in the GI lumen, forming insoluble complexes that are excreted in stool, preventing phosphate absorption.
• Calcium carbonate/acetate: Ca2+ ions bind PO4 to form calcium phosphate precipitates. Calcium acetate is more efficient per gram of calcium. Risk: calcium loading, hypercalcemia, vascular calcification.
• Sevelamer: A non-absorbable polymeric resin (crosslinked polyallylamine). It binds phosphate via ionic/hydrogen bonding. Additional benefits: binds bile acids (↓ LDL cholesterol) and does not cause hypercalcemia. Also reduces FGF-23 levels.
• Lanthanum carbonate: La3+ (rare earth metal) has extremely high affinity for phosphate; binds to form insoluble lanthanum phosphate in the stomach (works best with meals). Minimal systemic absorption.
• Sucroferric oxyhydroxide: A polynuclear iron(III)-oxyhydroxide that binds phosphate via ligand exchange in the GI lumen. Lower pill burden. May darken stool.
• Ferric citrate: Fe3+ binds phosphate in GI tract; absorbed iron contributes to treating iron-deficiency anemia in HD patients (dual benefit).

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V. DRUGS FOR CKD-MINERAL BONE DISEASE (CKD-MBD)

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13. Active Vitamin D Analogues / Vitamin D Receptor Activators (VDRAs)

• CKD causes loss of renal 1α-hydroxylase (CYP27B1) activity, reducing conversion of 25(OH)D to active 1,25(OH)2D3 (calcitriol).
• Calcitriol directly activates the vitamin D receptor (VDR), a nuclear receptor/transcription factor. VDR-calcitriol heterodimer + retinoid X receptor (RXR) binds to vitamin D response elements (VDREs) in DNA.
• Genomic actions: ↑ intestinal Ca2+ and phosphate absorption (via TRPV6 channels, calbindin-D9k), ↑ renal Ca2+ reabsorption, ↑ PTH gene suppression.
• Suppression of secondary hyperparathyroidism (SHPT): Calcitriol directly suppresses PTH gene transcription by binding to a VDRE in the PTH gene promoter, reducing PTH synthesis and parathyroid cell hyperplasia.
• Paricalcitol (19-nor-1,25(OH)2D2): Selectively activates VDR with reduced calcemic/phosphatemic potency vs. calcitriol - lower risk of hypercalcemia/hyperphosphatemia while still suppressing PTH.
• Alfacalcidol: A prodrug; 25-hydroxylated to calcitriol by liver CYP27A1 (bypasses the deficient renal 1α-hydroxylation).

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14. Calcimimetics

• The calcium-sensing receptor (CaSR) is a G-protein coupled receptor (Gq family) expressed on the parathyroid gland chief cells. It senses extracellular Ca2+ and suppresses PTH secretion when Ca2+ is elevated.
• In SHPT, parathyroid glands become hyperplastic and the set-point for Ca2+-mediated PTH suppression is shifted upward (the CaSR is desensitized).
• Calcimimetics are positive allosteric modulators (allosteric activators) of CaSR. They bind to a hydrophobic pocket in the transmembrane domain of CaSR and increase the receptor's sensitivity to extracellular Ca2+, shifting the Ca2+-PTH curve leftward. This mimics the effect of hypercalcemia even at normal or low Ca2+ levels.
• Result: ↓ PTH secretion, ↓ parathyroid cell proliferation; over time, can cause parathyroid gland involution.
• Cinacalcet also activates CaSR in C-cells of the thyroid → ↑ calcitonin release (minor effect).
• Etelcalcetide is a synthetic peptide (D-amino acid) calcimimetic administered IV with hemodialysis; it covalently binds (via disulfide bond) to extracellular cysteine residues of CaSR, activating it independently of Ca2+.

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VI. ERYTHROPOIESIS-STIMULATING AGENTS (ESAs)

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15. ESAs

• Epoetin alfa: Recombinant human erythropoietin (EPO). EPO is normally produced by peritubular interstitial cells (fibroblasts) of the renal cortex in response to hypoxia, mediated by HIF-1α (hypoxia-inducible factor 1α). EPO binds to the EPO receptor (EPOR) on erythroid progenitors (CFU-E/BFU-E) in the bone marrow. EPOR is a homodimeric cytokine receptor that activates JAK2/STAT5 signaling → proliferation, differentiation, and survival of erythroid precursors → increased RBC production.
• Darbepoetin alfa: A hyperglycosylated EPO analogue with extra N-linked oligosaccharide chains, giving it a ~3x longer half-life (t½ ~25 h vs. ~8 h for epoetin). Same mechanism via EPOR/JAK2/STAT5.
• CERA (Methoxy PEG-epoetin beta): PEGylated EPO with extremely prolonged t½ (~130 h); can be dosed monthly. Same receptor mechanism.
• HIF-Prolyl Hydroxylase Inhibitors (HIF-PHIs): Roxadustat, Daprodustat, Vadadustat, Molidustat.
  • Under normoxia, prolyl hydroxylase domain enzymes (PHD1/2/3) hydroxylate HIF-1α/HIF-2α on conserved proline residues, targeting them for ubiquitination by VHL E3 ligase → proteasomal degradation.
  • HIF-PHIs are competitive inhibitors of PHDs (competing with their co-substrate 2-oxoglutarate). They stabilize HIF-1α and HIF-2α, which translocate to the nucleus, dimerize with HIF-1β (ARNT), and bind hypoxia response elements (HREs) in the EPO gene and other genes involved in iron metabolism (↑ EPO, ↑ TFRC, ↓ hepcidin).
  • Net: Endogenous EPO production is stimulated; hepcidin suppression improves iron mobilization. Oral administration (unlike injectable ESAs).

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VII. IMMUNOSUPPRESSANTS (Transplant / Glomerulonephritis)

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16. Calcineurin Inhibitors (CNIs)

• Cyclosporine binds to cyclophilin (a cytosolic immunophilin) → the cyclosporine-cyclophilin complex inhibits calcineurin (a Ca2+/calmodulin-dependent phosphatase).
• Tacrolimus binds to FKBP12 (FK binding protein 12) → the tacrolimus-FKBP12 complex also inhibits calcineurin (same target, different drug-immunophilin complex; ~100x more potent than cyclosporine).
• Calcineurin normally dephosphorylates NFAT (nuclear factor of activated T cells), allowing NFAT to translocate into the nucleus and activate IL-2, IL-4, IL-5, IFN-γ gene transcription.
• CNI blockade of calcineurin → NFAT remains phosphorylated and cytoplasmic → ↓ IL-2 transcription → ↓ T-cell activation and proliferation (especially CD4+ helper T cells).
• Nephrotoxicity of CNIs: Calcineurin inhibition in afferent arterioles → increased endothelin and thromboxane → afferent arteriolar vasoconstriction → reduced RBF and GFR (reversible, calcineurin-dependent) and chronic structural changes (TGF-β mediated interstitial fibrosis, tubular atrophy - CAN: chronic allograft nephropathy).

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17. mTOR Inhibitors

• Sirolimus binds to FKBP12 (same immunophilin as tacrolimus) → the sirolimus-FKBP12 complex binds to and inhibits mTORC1 (mechanistic target of rapamycin complex 1).
• mTORC1 phosphorylates S6 kinase (S6K1) and 4E-BP1, promoting ribosomal biogenesis, protein synthesis, and cell-cycle progression (G1 → S phase transition).
• Inhibition of mTORC1 → cell cycle arrest at G1 phase → reduced lymphocyte (T and B cell) proliferation in response to cytokine signals (IL-2, IL-4, IL-15) - acts downstream of IL-2 signaling, complementing calcineurin inhibitors.
• Also inhibits smooth muscle cell proliferation (used to prevent coronary restenosis), and has anti-tumor properties.
• Does NOT cause nephrotoxicity via vasoconstriction (unlike CNIs), but can cause proteinuria (by disrupting podocyte mTOR signaling), impaired wound healing, dyslipidemia, and myelosuppression.

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18. Antiproliferative Agents

• A prodrug; hydrolyzed by esterases in the gut wall and liver to mycophenolic acid (MPA).
• MPA is a reversible, non-competitive inhibitor of inosine monophosphate dehydrogenase (IMPDH), specifically IMPDH II (the isoform expressed in activated lymphocytes).
• IMPDH II catalyzes the rate-limiting step in the de novo purine synthesis pathway: conversion of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) → guanosine monophosphate (GMP) → deoxyGTP, needed for DNA synthesis.
• Unlike other cells which can use the salvage pathway (HGPRT) for guanine nucleotide synthesis, lymphocytes (T and B cells) are uniquely dependent on the de novo pathway.
• MPA selectively depletes dGTP in lymphocytes → inhibits T-cell and B-cell proliferation, antibody production, and expression of adhesion molecules.

• Prodrug; converted to 6-mercaptopurine (6-MP) and then to 6-thioguanine nucleotides (6-TGN) by HGPRT.
• 6-TGN is incorporated into DNA, causing DNA strand breaks and inhibiting purine synthesis (also inhibits PRPP amidotransferase - the first committed step of de novo purine synthesis).
• Less selective than MMF; myelosuppression is the main toxicity. Metabolized by xanthine oxidase (XO) and thiopurine methyltransferase (TPMT). Co-administration with allopurinol (XO inhibitor) causes severe toxicity by blocking 6-MP degradation.

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19. Corticosteroids

• Bind to the intracellular glucocorticoid receptor (GR), which translocates to the nucleus.
• Activate/repress gene transcription via glucocorticoid response elements (GREs):
  • Trans-repression: ↓ NF-κB and AP-1 activity → ↓ transcription of pro-inflammatory cytokines (IL-1, IL-6, TNF-α, IL-12), ↓ COX-2, ↓ iNOS.
  • Trans-activation: ↑ anti-inflammatory proteins (IκBα, annexin-1).
  • Non-genomic effects (rapid): Suppress T-cell activation, ↓ B-cell function, ↓ complement activation, ↓ neutrophil and macrophage function.
• Used in: nephrotic syndrome (MCD, FSGS, membranous), lupus nephritis, ANCA vasculitis, IgA nephropathy, transplant rejection.

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20. Rituximab

• A chimeric monoclonal antibody (murine variable + human constant regions) targeting CD20 expressed on pre-B and mature B lymphocytes (but not plasma cells or stem cells).
• Binding to CD20 → B-cell depletion via:
  1. Complement-dependent cytotoxicity (CDC) - Fc region activates complement (C1q binding).
  2. Antibody-dependent cell-mediated cytotoxicity (ADCC) - Fc region engages NK cells and macrophages.
  3. Direct apoptosis induction via CD20 signaling.
• Used in: ANCA vasculitis (GPA, MPA), membranous nephropathy (anti-PLA2R antibodies), lupus nephritis, MCD in adults, refractory nephrotic syndrome.

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21. Belimumab

• Monoclonal antibody against BAFF (B-cell activating factor, also called BLyS) - a TNF superfamily cytokine essential for B-cell survival, maturation, and differentiation.
• Blocks BAFF binding to its receptors (BAFF-R, TACI, BCMA) on B cells → ↓ B-cell survival and ↓ auto-antibody production.
• Used in: Lupus nephritis (Class III/IV) in combination with standard-of-care.

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VIII. SGLT2 INHIBITORS (Nephroprotective)

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22. SGLT2 Inhibitors

• Sodium-glucose cotransporter 2 (SGLT2/SLC5A2) is located on the luminal membrane of the S1 segment of the proximal tubule. It reabsorbs ~90% of the filtered glucose (and some Na+) using the electrochemical Na+ gradient - it is a secondary active transporter (1 Na+ : 1 glucose, low affinity, high capacity).
• SGLT2 inhibitors competitively and reversibly block SGLT2, causing glucosuria (even in non-diabetics) and natriuresis.
• Tubuloglomerular feedback (TGF) restoration: In early diabetes/CKD, SGLT2 is upregulated, causing excess Na+ and glucose reabsorption in the PCT. This reduces NaCl delivery to the macula densa → blunted TGF → afferent arteriolar vasodilation → glomerular hyperfiltration and raised GFR. SGLT2 inhibition restores NaCl delivery to the macula densa → restores TGF → afferent arteriolar vasoconstriction → ↓ intraglomerular pressure → renoprotection (this is the primary nephroprotective mechanism, independent of glycemic control).
• Additional mechanisms: ↓ glomerular hypertension, ↓ proteinuria, ↓ oxidative stress and inflammation in tubular cells (via ↓ NLRP3 inflammasome), ↓ tubular oxygen consumption, ↓ uric acid (mild uricosuric effect via URAT1 competition), ↓ sympathetic tone, ↓ blood pressure (mild osmotic diuresis), possible anti-fibrotic effects.
• Evidence: DAPA-CKD and CREDENCE trials demonstrated significant reduction in CKD progression (sustained ≥40% decline in eGFR, ESRD, CV death) in patients with CKD with and without diabetes.

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IX. DRUGS FOR GOUT AND URIC ACID (Nephropathy / Stones)

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23. Xanthine Oxidase Inhibitors

• Xanthine oxidase (XO) (also called xanthine dehydrogenase, XDH) catalyzes the last two steps of purine catabolism: hypoxanthine → xanthine → uric acid.
• Allopurinol is converted by XO to oxypurinol, which forms a tight, slowly reversible (pseudo-irreversible) complex with the reduced form of XO, inhibiting it. Allopurinol itself is a competitive inhibitor of XO for xanthine, while oxypurinol is a non-competitive inhibitor of the reduced enzyme.
• Result: Accumulation of hypoxanthine and xanthine (more soluble than uric acid), ↓ uric acid production → ↓ serum urate → ↓ urate deposition in joints and kidneys.
• Febuxostat: A non-purine selective inhibitor of XO. It occupies the substrate-binding channel and molybdopterin cofactor region of both oxidized and reduced forms of XO, providing more complete inhibition. Metabolized hepatically (not renally), unlike allopurinol - safer in CKD.

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24. Uricosuric Agents

• Uric acid reabsorption in the proximal tubule is mediated primarily by URAT1 (SLC22A12) and OAT4 on the luminal membrane, and GLUT9 on the basolateral membrane.
• Probenecid and benzbromarone inhibit URAT1 and OAT4, blocking uric acid reabsorption → uricosuria (↑ uric acid excretion in urine) → ↓ serum urate.
• Lesinurad: A selective URAT1 inhibitor with additional inhibition of OAT4, approved for use with XO inhibitors.
• Risk: Uricosuria increases urinary urate, risking uric acid nephrolithiasis (especially if urine is acidic and not adequately hydrated).
• Probenecid also inhibits OAT-mediated secretion of many drugs in the proximal tubule (penicillins, cephalosporins, methotrexate, loop diuretics, NSAIDs), forming many clinically important drug interactions.

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X. ANTIHYPERTENSIVES (Renal-Specific Context)

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25. Vasopressin (ADH) Receptor Antagonists (Vaptans)

• Arginine vasopressin (AVP/ADH) acts on:
  • V2 receptors (Gs-coupled) on the basolateral membrane of principal cells of the collecting duct → activates adenylate cyclase → ↑ cAMP → PKA phosphorylates aquaporin-2 (AQP2) vesicles → AQP2 inserts into the apical membrane → water permeability of the collecting duct ↑ (antidiuresis).
  • V1a receptors on vascular smooth muscle → vasoconstriction.
• Tolvaptan and lixivaptan: Selective V2 receptor antagonists → block AVP-induced AQP2 insertion → free water diuresis (aquaresis) without significant Na+ loss → ↑ serum Na+ in hyponatremia.
• Used in: Autosomal dominant polycystic kidney disease (ADPKD) (tolvaptan - TEMPO 3:4 trial: slows cyst growth and eGFR decline by blocking V2R-mediated cAMP-driven cyst epithelial proliferation and fluid secretion), SIADH, heart failure (hyponatremia).
• Conivaptan: Non-selective V1a/V2 antagonist (IV only).

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26. Endothelin Receptor Antagonists

• Endothelin-1 (ET-1) is a potent vasoconstrictor that acts on ETA receptors (vasoconstriction, fibrosis, mesangial contraction) and ETB receptors (vasodilation, NO release, Na+ excretion).
• ETA antagonism → ↓ mesangial contraction → ↓ intraglomerular pressure → ↓ proteinuria.
• Sparsentan: Dual antagonist of AT1R (like an ARB) and ETA receptor - used in IgA nephropathy (DUPLEX trial) and focal segmental glomerulosclerosis (FSGS) (DUET trial) - reduces proteinuria significantly more than irbesartan alone.
• Atrasentan: Selective ETA antagonist (SONAR trial - reduced kidney events in diabetic nephropathy).

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XI. COMPLEMENT INHIBITORS (Glomerulonephritis / aHUS / C3G)

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27. Complement Inhibitors

• Eculizumab/Ravulizumab: Monoclonal antibodies that bind complement C5, preventing its cleavage into C5a (anaphylatoxin → inflammation, neutrophil recruitment) and C5b (initiates membrane attack complex, MAC). Used in: atypical HUS (aHUS) (caused by dysregulation of the alternative complement pathway) and C3 glomerulopathy (C3G).
• Avacopan: A small-molecule antagonist of the C5a receptor 1 (C5aR1) on neutrophils and monocytes. Blocks C5a-mediated neutrophil activation and tissue infiltration. Used in ANCA vasculitis (GPA, MPA) - the ADVOCATE trial showed non-inferiority to high-dose glucocorticoids for remission induction and superiority for sustained remission.
• Pegcetacoplan/Iptacopan: Act upstream at C3/factor B level to inhibit the alternative complement pathway.

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XII. DRUGS FOR NEPHROGENIC SYSTEMIC/SPECIFIC CONDITIONS

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28. Sodium Bicarbonate

• Provides exogenous HCO3- to buffer excess H+ and correct metabolic acidosis.
• In CKD, reduced renal ammoniagenesis and HCO3- reclamation cause metabolic acidosis. Supplemental NaHCO3 raises plasma HCO3- directly, reduces acid load on bone (slowing bone mineral buffering and dissolution), and may slow CKD progression by reducing acid-induced tubulointerstitial injury (activation of complement, endothelin, renin-angiotensin by acid).

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29. Acetylcysteine (NAC)

• N-acetylcysteine is a precursor to glutathione (GSH). It reduces oxidative stress by replenishing intracellular GSH and directly scavenging reactive oxygen species (ROS) generated by iodinated contrast agents in renal tubular cells.
• Also causes renal vasodilation (via ↑ NO synthesis).

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30. Dopamine (Low-dose) / Fenoldopam

• Dopamine (0.5-2 mcg/kg/min): Acts on D1 receptors on proximal tubular cells and renal vasculature → adenylate cyclase activation → ↑ cAMP → vasodilation of afferent arterioles, ↑ RBF and GFR, inhibition of proximal tubular NHE3 and Na+/K+-ATPase (mild natriuresis). Also acts on D2 receptors to inhibit norepinephrine and aldosterone release. Evidence for renal protection in AKI is NOT established.
• Fenoldopam: Selective D1 receptor agonist; increases renal perfusion without systemic vasodilation-related reflexes. Used in hypertensive crises with renal involvement.

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Summary Table

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Nephrology Drugs: Complete Drug Reference

Mechanism of Action | Uses | Dosage | ADRs | Contraindications

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I. DIURETICS

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1. Carbonic Anhydrase Inhibitors (CAIs)

• Metabolic alkalosis (especially in ICU/diuretic-induced)
• Glaucoma (reduces aqueous humor production)
• Altitude sickness / acute mountain sickness (prophylaxis and treatment)
• Renal tubular acidosis (type 1 - alkalinizes urine to prevent stone formation)
• Epilepsy (absence seizures, adjunct)
• Idiopathic intracranial hypertension (pseudotumor cerebri)

• Acetazolamide: 250-1000 mg/day orally in divided doses; for altitude sickness: 125-250 mg twice daily starting 1-2 days before ascent; IV: 250-500 mg
• Methazolamide: 50-100 mg 2-3 times daily

• Acetazolamide: 5 mg/kg/day orally (glaucoma/epilepsy); altitude sickness: 2.5 mg/kg every 12 h; max 125-250 mg/dose

• Metabolic acidosis (hyperchloremic, non-anion gap) - limits long-term use (self-limiting diuresis)
• Hypokalemia
• Renal calculi (urinary alkalinization precipitates calcium phosphate stones; reduced citrate excretion)
• Paresthesias (tingling in extremities and face - very common, due to metabolic acidosis)
• Drowsiness, malaise, anorexia, altered taste (especially for carbonated beverages)
• Thrombocytopenia, agranulocytosis, aplastic anemia (rare, idiosyncratic)
• Sulfonamide hypersensitivity reactions (fever, rash, Stevens-Johnson syndrome)
• Transient myopia

• Hyponatremia, hypokalemia
• Hepatic cirrhosis (risk of hepatic encephalopathy - ammonia metabolism depends on renal acidification)
• Renal insufficiency (metabolic acidosis accumulates)
• Adrenocortical insufficiency
• Sulfonamide hypersensitivity
• Long-term use in closed-angle glaucoma

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2. Osmotic Diuretics

• Raised intracranial pressure (cerebral edema, head injury, Reye's syndrome)
• Raised intraocular pressure (acute angle-closure glaucoma, pre-operatively)
• Prevention/treatment of oliguric AKI (maintains tubular flow - evidence debated)
• Forced diuresis in drug/toxin poisoning
• Rhabdomyolysis (maintains urine flow to prevent renal tubular obstruction by myoglobin)

• Mannitol (IV): 0.25-2 g/kg over 30-60 min (ICP control); repeated q6-8 h as needed; urine output should be maintained >30-50 mL/h; maximum single dose: 200 g

• Mannitol: 0.25-1 g/kg IV over 20-30 min; may repeat q4-6 h; max 6 g/kg/24 h

• Initial ECF volume expansion (risk of acute pulmonary edema in CHF patients)
• Hyponatremia (dilutional, from water drawn into ECF from ICF)
• Hypernatremia and dehydration (late, with excessive water loss)
• Headache, nausea, vomiting (common)
• Thrombophlebitis at infusion site
• Rebound ICP increase (if blood-brain barrier is disrupted, mannitol may accumulate in brain)
• Acute kidney injury with high doses (osmotic nephrosis - vacuolization of proximal tubular cells)
• Hypo/hyperkalemia

• Anuria / severe renal failure (drug accumulates)
• Active intracranial bleeding (urea and mannitol both)
• Severe dehydration
• Pulmonary edema or severe CHF
• Urea: hepatic failure (↑ blood ammonia risk)

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3. Loop Diuretics

• Acute pulmonary edema (first-line: IV furosemide)
• Chronic heart failure with fluid overload
• Nephrotic syndrome (resistant edema)
• Hepatic cirrhosis with ascites (usually combined with spironolactone)
• Hypertension with CKD (GFR <30 mL/min - thiazides are ineffective)
• Hypercalcemia (with IV saline - forced calciuresis)
• Hyperkalemia (enhances K+ excretion)
• Forced diuresis in poisoning
• Hyponatremia of SIADH (with fluid restriction)
• Resistant/refractory hypertension

• Furosemide: Oral: 1-2 mg/kg/dose every 6-12 h; IV: 0.5-1 mg/kg/dose; max 6 mg/kg/day; neonates: 1-2 mg/kg IV q12-24 h (avoid in premature infants - risk of nephrocalcinosis, ototoxicity)
• Bumetanide: 0.015-0.1 mg/kg/dose every 6-24 h; IV/IM/PO
• Torsemide: Not well established in children <18 years

• Hypokalemia (most common - enhanced K+ secretion at the collecting duct via aldosterone activation)
• Metabolic alkalosis (H+ loss in collecting duct)
• Hyponatremia (free water loss if not replaced)
• Hypomagnesemia (loss of lumen-positive potential)
• Hypocalciuria → hypocalcemia (loss of paracellular Ca2+ reabsorption in TAL; calciuric - used to treat hypercalcemia)
• Ototoxicity - sensorineural hearing loss, tinnitus (dose-dependent; more with ethacrynic acid; risk increased with aminoglycosides, vancomycin)
• Hyperuricemia (compete with urate for OAT3-mediated secretion)
• Volume depletion, hypotension, prerenal azotemia
• Hyperglycemia (less than thiazides)
• Sulfonamide hypersensitivity (furosemide, bumetanide, torsemide - NOT ethacrynic acid)
• Photosensitivity
• Interstitial nephritis (rare, idiosyncratic)

• Anuria
• Severe electrolyte depletion (hypokalemia, hyponatremia, dehydration)
• Sulfonamide hypersensitivity (use ethacrynic acid instead)
• Hepatic coma/pre-coma (risk of electrolyte disturbance precipitating encephalopathy)
• Concurrent aminoglycoside therapy (ototoxicity risk)
• First trimester pregnancy (teratogenic potential, though used cautiously in pregnancy-related hypertension)

• Aminoglycosides/vancomycin: additive ototoxicity and nephrotoxicity
• NSAIDs: reduce diuretic response (inhibit prostaglandin-mediated renal vasodilation)
• Lithium: toxicity due to enhanced proximal tubular Li+ reabsorption (volume contraction)
• Digoxin: hypokalemia potentiates digoxin toxicity
• Probenecid: competes for OAT3 secretion → reduces diuretic effect
• ACEIs/ARBs + loop diuretics: first-dose hypotension

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4. Thiazide and Thiazide-Like Diuretics

• Hypertension (first-line, especially as part of combination therapy)
• Mild-moderate edema (CHF, liver disease, renal disease)
• Calcium nephrolithiasis (recurrent - reduces urinary Ca2+)
• Nephrogenic diabetes insipidus (paradoxical - reduces urine volume by 30-50%)
• Osteoporosis prevention (reduces Ca2+ urinary loss)
• Idiopathic hypercalciuria

• HCTZ: 1-2 mg/kg/day orally in 1-2 divided doses; infants <6 months: up to 3 mg/kg/day; max 37.5 mg/day (children 1 month-2 years); max 100 mg/day (children 2-12 years)
• Chlorthalidone: 0.3 mg/kg/day; max 2 mg/kg/day (not well established)

• Hypokalemia (2nd most common electrolyte problem; potentiates QT prolongation)
• Hyponatremia (sometimes severe/fatal, especially in elderly women; thiazides impair free water excretion)
• Hyperuricemia (compete with urate for OAT3 secretion; can precipitate gout)
• Hyperglycemia / new-onset diabetes (↓ insulin secretion via hypokalemia; direct metabolic effects; less CV risk than expected)
• Hypercalcemia (enhanced Ca2+ reabsorption - use this effect therapeutically in hypercalciuria)
• Hypomagnesemia
• Hyperlipidemia (↑ LDL, total cholesterol, triglycerides with prolonged use - less relevant clinically)
• Metabolic alkalosis
• Erectile dysfunction
• Photosensitivity, skin rash
• Acute pancreatitis (rare)
• Acute interstitial nephritis (rare)
• Sulfonamide hypersensitivity (all thiazides contain sulfonamide moiety)
• Acute angle-closure glaucoma (rare, within first weeks)
• Potentially fatal hyponatremia (especially elderly, low body weight females)

• Anuria
• Sulfonamide hypersensitivity
• Severe renal impairment (GFR <30 mL/min - most thiazides ineffective; metolazone/indapamide work)
• Severe hepatic failure
• Hypercalcemia
• Hyponatremia
• Pregnancy (causes fetal thrombocytopenia, neonatal jaundice - avoid unless essential)
• Co-administration with lithium (reduces lithium clearance)

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5a. Potassium-Sparing Diuretics: ENaC Blockers

• Prevention/treatment of hypokalemia caused by loop or thiazide diuretics (combined use)
• Hypertension (in combination)
• CHF and ascites (with loop diuretics)
• Liddle syndrome (amiloride - gain-of-function ENaC mutation)
• Primary hyperaldosteronism (second-line to spironolactone)
• Cystic fibrosis lung disease (amiloride - reduces Na+ reabsorption from airway surface)

• Amiloride: 5-10 mg once daily; max 20 mg/day
• Triamterene: 50-100 mg twice daily; max 300 mg/day

• Amiloride: 0.1-0.4 mg/kg/day orally in 1-2 divided doses; max 20 mg/day
• Triamterene: 2-4 mg/kg/day orally in divided doses; not widely used in children

• Hyperkalemia (most dangerous - life-threatening; especially in renal impairment, concurrent ACEI/ARB, K+ supplements, NSAIDs, diabetes)
• Nausea, vomiting, diarrhea, headache (amiloride)
• Nausea, vomiting, leg cramps, dizziness (triamterene)
• Triamterene-specific: Renal stones (triamterene crystals); interstitial nephritis; folic acid antagonism (megaloblastic anemia in cirrhosis); photosensitization; ↓ glucose tolerance
• Metabolic acidosis (type IV RTA pattern)
• Hyponatremia

• Hyperkalemia (serum K+ >5.5 mEq/L)
• Severe/chronic renal failure (CrCl <30 mL/min) - accumulation + hyperkalemia
• Concurrent K+-sparing diuretics, ACEIs, ARBs, K+ supplements
• Diabetic nephropathy
• Triamterene: hepatic cirrhosis (folic acid antagonism → megaloblastic anemia)
• NSAIDs + amiloride: hyperkalemia risk

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5b. Mineralocorticoid Receptor Antagonists (MRAs)

• Primary hyperaldosteronism (Conn's syndrome) - spironolactone is drug of choice
• Refractory hypertension (4th-line agent)
• Heart failure with reduced ejection fraction (HFrEF) - RALES trial (spironolactone), EMPHASIS-HF (eplerenone) - reduces mortality
• Ascites in hepatic cirrhosis (spironolactone first-line, ratio 100:40 with furosemide)
• Nephrotic syndrome (adjunct)
• Prevention of hypokalemia with loop/thiazide diuretics
• Hirsutism, acne, polycystic ovary syndrome (PCOS) (spironolactone - anti-androgenic)
• Finerenone: CKD with type 2 diabetes (FIDELIO-DKD, FIGARO-DKD trials - reduces composite kidney + cardiovascular events)
• Adrenal hyperplasia

• Spironolactone: 1-3.3 mg/kg/day orally in 1-4 divided doses; max 100-400 mg/day depending on indication

• Hyperkalemia (most serious - same risk factors as ENaC blockers)
• Spironolactone-specific antiandrogenic effects: Gynecomastia (up to 10-15% of men), impotence, decreased libido, menstrual irregularities, breast pain, feminization (due to cross-reactivity with androgen receptor and progesterone receptor)
• Eplerenone: Much more selective for MR → minimal gynecomastia; mild hypertriglyceridemia
• Metabolic acidosis
• Dizziness, headache
• GI upset, nausea, vomiting, cramping
• Spironolactone has been associated with a small ↑ in risk of breast cancer with long-term use (limited evidence)
• Finerenone: Hyperkalemia; no sex hormone effects

• Hyperkalemia
• Renal failure (CrCl <30 mL/min for eplerenone; use with caution with spironolactone)
• Concurrent use of other K+-sparing diuretics or K+ supplements
• Addison's disease
• Finerenone: concurrent strong CYP3A4 inhibitors (ketoconazole, itraconazole); eGFR <25 mL/min/1.73m2 + serum K+ >5 mEq/L at initiation

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II. RAAS INHIBITORS

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6. ACE Inhibitors (ACEIs)

• Hypertension (first-line, especially in diabetic nephropathy, CKD with proteinuria)
• Diabetic nephropathy (renoprotective - CAPTOPRIL trial, MICRO-HOPE)
• Non-diabetic proteinuric CKD (slows progression)
• Chronic heart failure (HFrEF) - reduces mortality and morbidity
• Post-MI (especially with reduced EF)
• Prevention of progressive renal insufficiency
• Secondary prevention of cardiovascular events
• Scleroderma renal crisis (captopril - treatment of choice)

• Enalapril: 0.05-0.08 mg/kg/day in 1-2 divided doses; max 0.5 mg/kg/day (neonates: use with extreme caution - profound hypotension risk)
• Lisinopril: 0.07-0.1 mg/kg once daily; max 0.6 mg/kg/day or 40 mg/day (children ≥6 years)
• Captopril: 0.1-0.5 mg/kg/dose 2-3x daily (neonates: 0.01-0.05 mg/kg/dose)

• Dry, persistent cough (10-15% of patients; due to bradykinin and substance P accumulation in airways; more in Asian patients; reason to switch to ARB)
• Angioedema (1% - potentially life-threatening; bradykinin-mediated swelling of face, tongue, larynx; more in Black patients and those with hereditary angioedema; C1-inhibitor deficiency)
• Hyperkalemia (blocked aldosterone → ↓ K+ excretion; serious in CKD, diabetes, concurrent K+-sparing diuretics)
• First-dose hypotension (especially in volume-depleted patients, heart failure with high RAAS activation)
• Acute deterioration of renal function (↓ GFR due to efferent dilation → acceptable rise in creatinine up to 30% within first 2 months; contraindicated in bilateral renal artery stenosis)
• Fetotoxicity / teratogenicity (ACE inhibitor fetopathy: renal dysgenesis, oligohydramnios, fetal renal failure, skull hypoplasia; contraindicated in pregnancy)
• Rash, dysgeusia (altered taste) - captopril (contains sulfhydryl group)
• Neutropenia (captopril, rare - sulfhydryl-related)
• Proteinuria / membranous nephropathy (captopril, rare)

• Pregnancy (all trimesters - fetotoxic/teratogenic)
• Bilateral renal artery stenosis (or unilateral RAS in a solitary kidney) - causes acute renal failure
• Hyperkalemia (K+ >5.5 mEq/L)
• History of ACEI-induced angioedema
• Hereditary or idiopathic angioedema
• Severe aortic stenosis (hemodynamic instability)
• Concurrent aliskiren in patients with diabetes or CKD (eGFR <60) - ALTITUDE trial showed harm
• Anuria due to renal artery stenosis
• Not to be combined with ARBs (dual RAAS blockade - ONTARGET trial - increased adverse effects)

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7. Angiotensin Receptor Blockers (ARBs)

• Hypertension (especially patients intolerant of ACEI cough)
• Diabetic nephropathy type 2 (irbesartan - IDNT trial; losartan - RENAAL trial)
• Heart failure (valsartan - Val-HeFT; candesartan - CHARM)
• Post-MI with LV dysfunction (valsartan - VALIANT)
• Stroke prevention (losartan - LIFE trial)
• IgA nephropathy (reduces proteinuria)
• Non-diabetic proteinuric CKD

• Losartan: 0.7 mg/kg once daily (max 50 mg/day) for children 6-16 years; not recommended for GFR <30 mL/min in children
• Valsartan: 1.3 mg/kg once daily (max 40 mg/day); children ≥1 year
• Candesartan: < 1 year not recommended; 1-6 years: 0.05-0.4 mg/kg/day

• No cough (major advantage over ACEIs)
• Angioedema (rare, <0.1% - much less than ACEIs)
• Hyperkalemia (same mechanism as ACEIs)
• Hypotension (first-dose, volume-depleted patients)
• Acute kidney injury in bilateral RAS (same as ACEIs)
• Fetotoxicity (same as ACEIs - contraindicated in pregnancy)
• Olmesartan-associated enteropathy (sprue-like diarrhea, weight loss, villous atrophy - rare but serious; often years after initiation)
• Dizziness, headache (well tolerated overall)

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8. Direct Renin Inhibitor

• Hypertension (monotherapy or combination; limited use due to safety concerns)
• CKD with proteinuria (investigational, not widely used now)

• Hyperkalemia
• Hypotension (first dose)
• Diarrhea, GI upset
• Angioedema (rare)
• Elevated serum creatinine (in bilateral RAS)
• Cough (rare, <1%)

• Pregnancy (like ACEIs/ARBs)
• Concurrent ACEIs or ARBs in patients with diabetes or CKD (eGFR <60) - increased renal failure, stroke, hyperkalemia
• Bilateral renal artery stenosis

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III. DRUGS FOR HYPERKALEMIA

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9. Calcium Gluconate / Calcium Chloride

• Calcium gluconate 10%: 10-20 mL (1-2 g) IV over 5-10 min (cardiac protection); repeat in 5 min if ECG changes persist
• Calcium chloride 10%: 5-10 mL IV (more elemental calcium, central line preferred)

• Calcium gluconate: 0.5-1 mL/kg (max 10 mL) of 10% solution IV slowly

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10. Insulin + Glucose

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11. Patiromer (Veltassa)

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12. Sodium Zirconium Cyclosilicate (SZC / ZS-9 / Lokelma)

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13. Sodium Polystyrene Sulfonate (Kayexalate / SPS)

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IV. DRUGS FOR CKD-MINERAL BONE DISEASE (CKD-MBD)

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14. Phosphate Binders

Calcium Carbonate / Calcium Acetate

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Sevelamer (Hydrochloride / Carbonate)

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Lanthanum Carbonate (Fosrenol)

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15. Active Vitamin D Analogues (VDRAs)

• Calcitriol: CKD: 0.25 mcg/day orally; HD/PD: 0.5-1 mcg 3x/week IV (HD); peritoneal dialysis: 0.5-1.5 mcg/day
• Alfacalcidol: 0.25-1 mcg/day orally
• Paricalcitol: PTH <500 pg/mL: 1 mcg/day or 2 mcg 3x/week (oral or IV); PTH ≥500 pg/mL: 2 mcg/day or 4 mcg 3x/week

• Calcitriol: CKD: 0.01-0.05 mcg/kg/day (typical 0.25 mcg/day); dialysis: higher doses under nephrology guidance
• Alfacalcidol: 0.04-0.08 mcg/kg/day

• Hypercalcemia (primary concern - nausea, vomiting, polyuria, nephrocalcinosis, metastatic calcification, arrhythmias)
• Hyperphosphatemia (↑ intestinal PO4 absorption)
• Adynamic bone disease (over-suppression of PTH)
• Vascular/soft tissue calcification (with high Ca-PO4 product)
• Nausea, headache, pruritus

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16. Calcimimetics

• Secondary hyperparathyroidism in dialysis patients (HD and PD)
• Primary hyperparathyroidism (where surgery is not possible)
• Parathyroid carcinoma
• Etelcalcetide: secondary HPT specifically in hemodialysis patients (IV administration with HD sessions)

• Cinacalcet: start 30 mg once daily; titrate every 2-4 weeks to max 180 mg/day; monitor PTH and Ca2+ monthly
• Etelcalcetide: 5 mg IV 3x/week at end of HD sessions; titrate by 2.5 mg increments; range 2.5-15 mg 3x/week

• Cinacalcet: Not FDA-approved for children; limited data in pediatric HPT; doses ~0.5-1 mg/kg/day have been used

• Hypocalcemia (most important; monitor Ca2+ regularly; risk of QTc prolongation at very low Ca2+; seizures at severe hypocalcemia)
• Nausea, vomiting (30-40% of patients with cinacalcet - take with food; etelcalcetide: less GI toxicity)
• Muscle cramps, paresthesias, spasms (hypocalcemia-related)
• Headache, dizziness
• Adynamic bone disease (over-suppression of PTH)
• Etelcalcetide: injection site reactions, antibody formation

• Hypocalcemia (corrected Ca2+ <8.4 mg/dL - do not initiate)
• Not used in non-dialysis CKD patients (lacks outcome data; risk of hypocalcemia)
• Cinacalcet: seizure disorder (threshold lowered by hypocalcemia)

• Strong CYP3A4 inhibitors (ketoconazole, ritonavir): increase cinacalcet levels → lower dose
• Strong CYP3A4 inducers (rifampicin): reduce cinacalcet levels
• Cinacalcet is a strong CYP2D6 inhibitor → increases levels of tricyclic antidepressants, flecainide, metoprolol

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V. ERYTHROPOIESIS-STIMULATING AGENTS (ESAs) & RELATED

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17. Erythropoiesis-Stimulating Agents (ESAs)

• Epoetin alfa: 50-100 units/kg SC/IV 3x/week (CKD); adjust to maintain Hb 10-11.5 g/dL (do NOT target Hb >13 g/dL - TREAT trial)
• Darbepoetin alfa: 0.45 mcg/kg SC once weekly; or 0.75 mcg/kg once every 2 weeks; or monthly dosing
• CERA: 0.6 mcg/kg IV/SC every 2 weeks (correction); 1.2 mcg/kg once monthly (maintenance)

• Epoetin alfa: 50-300 units/kg SC/IV 3x/week; adjust based on Hb response (CKD children); neonatal anemia: 200-400 units/kg/dose SC 3x/week
• Darbepoetin: 0.45 mcg/kg SC/IV once weekly; adjust based on response

• Hypertension (most common; especially with rapid increase in Hb; reduced NO availability; ESRD patients)
• Thromboembolism (DVT, PE, vascular access thrombosis in HD patients; risk ↑ with higher Hb targets)
• Pure red cell aplasia (PRCA) (rare; anti-EPO antibodies neutralize endogenous and exogenous EPO; especially with SC route of epoetin alfa; present with sudden anemia, absent reticulocytes)
• Headache, flu-like symptoms (fever, myalgia, arthralgia)
• Stroke and cardiovascular events (with Hb >13 g/dL - TREAT, CREATE, CHOIR trials - reason for conservative Hb targets)
• Iron depletion (functional iron deficiency as erythropoiesis increases; supplement iron routinely)
• Seizures (rare, with rapid Hb rise)
• Tumor progression (theoretical - EPO receptors on some tumor cells)

• Uncontrolled hypertension
• Pure red cell aplasia (history of)
• Hypersensitivity to EPO products
• Hb >11.5 g/dL (do not initiate)
• Avoid targeting Hb >11.5 g/dL in CKD patients (increased CV risk)

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18. HIF-Prolyl Hydroxylase Inhibitors (HIF-PHIs)

• Roxadustat: 70-200 mg 3x/week (non-dialysis: 70 mg 3x/week initial; HD: 100-200 mg 3x/week based on weight)
• Daprodustat: 4-24 mg once daily
• Vadadustat: 300-600 mg once daily

• Thromboembolism (slightly higher risk noted in some trials - ongoing monitoring)
• Hypertension (less than ESAs)
• Cardiovascular events (roxadustat - non-inferior to darbepoetin in dialysis; daprodustat/vadadustat - FDA label includes cardiovascular warning)
• Hyperkalemia
• Metabolic acidosis
• Nausea, diarrhea
• Hepatotoxicity (monitor LFTs)
• Tumor promotion (theoretical - HIF upregulates multiple oncogenes; caution in malignancy)

• Pregnancy (animal teratogenicity data)
• Active malignancy (relative)
• Uncontrolled hypertension
• Severe hepatic impairment

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VI. IMMUNOSUPPRESSANTS

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19. Calcineurin Inhibitors (CNIs)

• Cyclosporine binds cyclophilin → cyclosporine-cyclophilin complex inhibits calcineurin → blocks NFAT dephosphorylation → ↓ IL-2 gene transcription → ↓ T cell activation
• Tacrolimus binds FKBP12 → tacrolimus-FKBP12 complex inhibits calcineurin (100x more potent than cyclosporine) → same downstream mechanism

• Kidney, liver, heart, lung transplant (maintenance immunosuppression - backbone of most protocols)
• Nephrotic syndrome: FSGS, membranous nephropathy (corticosteroid-resistant)
• Lupus nephritis (tacrolimus)
• Minimal change disease (refractory)
• IgA nephropathy
• Autoimmune hepatitis

• Cyclosporine: Initial: 6-12 mg/kg/day PO in 2 divided doses; trough target 150-400 ng/mL (early post-transplant), 50-150 ng/mL (maintenance); microemulsion formulation (Neoral) preferred
• Tacrolimus: Initial: 0.05-0.15 mg/kg/day PO in 2 divided doses; trough 10-15 ng/mL (early), 5-10 ng/mL (maintenance); extended-release once daily formulations available

• Cyclosporine: 6-15 mg/kg/day PO in 2 divided doses (children often need higher mg/kg doses than adults due to faster metabolism); monitor troughs
• Tacrolimus: 0.1-0.3 mg/kg/day PO in 2 divided doses; children have higher clearance

• Nephrotoxicity (most important and common - afferent arteriolar vasoconstriction → acute decline in GFR; chronic: TGF-β mediated tubulointerstitial fibrosis)
• Hypertension (calcineurin inhibition in renal vasculature → vasospasm)
• Neurotoxicity (tremor, headache, paresthesias, posterior reversible encephalopathy syndrome - PRES)
• Hyperlipidemia (↑ LDL, total cholesterol)
• Hirsutism, gingival hyperplasia (cyclosporine-specific)
• Hyperuricemia and gout (reduced renal urate excretion)
• Hyperkalemia (type IV RTA pattern - blocks K+ secretion)
• Hypomagnesemia
• Hyperglycemia
• Hepatotoxicity (↑ LFTs)
• Increased risk of opportunistic infections (CMV, fungal, PCP)
• Malignancy risk (especially skin cancers, PTLD - post-transplant lymphoproliferative disorder; EBV-associated)

• More neurotoxicity and diabetogenic (new-onset diabetes after transplant - NODAT: 15-30% with tacrolimus)
• Less hirsutism, less gingival hyperplasia
• Less hyperlipidemia
• Similar nephrotoxicity (though slightly less severe)
• Similar infections and malignancy risk

• Hypersensitivity to polyoxyl 60 hydrogenated castor oil (IV cyclosporine vehicle)
• Uncontrolled hypertension
• Active malignancy (relative)
• Concurrent nephrotoxic drugs without close monitoring
• Pregnancy: use only if benefit > risk; tacrolimus is preferred if transplant immunosuppression needed during pregnancy

• Both metabolized by CYP3A4 and P-glycoprotein:
  • CYP3A4 inhibitors (azoles, erythromycin, calcium channel blockers - diltiazem, verapamil, grapefruit juice): ↑ CNI levels → toxicity
  • CYP3A4 inducers (rifampicin, phenytoin, phenobarbitone, carbamazepine, St John's wort): ↓ CNI levels → rejection
• Nephrotoxic drugs (aminoglycosides, NSAIDs, amphotericin B, contrast agents): additive nephrotoxicity
• Statins + cyclosporine: ↑ statin levels → rhabdomyolysis risk

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20. mTOR Inhibitors

• Kidney transplant (CNI-sparing or conversion regimens)
• Liver transplant (everolimus)
• Renal angiomyolipoma in tuberous sclerosis (sirolimus/everolimus - anti-tumor mTOR effect)
• Autosomal dominant polycystic kidney disease (ADPKD) - reduces cyst volume (limited clinical benefit in trials)
• Lymphangioleiomyomatosis (LAM)
• Subependymal giant cell astrocytoma (SEGA) in tuberous sclerosis
• Oncology: renal cell carcinoma, breast cancer, pancreatic NET (everolimus)

• Sirolimus: Loading 6 mg; then 2 mg/day; target trough 5-15 ng/mL; higher targets (10-20 ng/mL) early post-transplant
• Everolimus: 0.75 mg twice daily; trough 3-8 ng/mL

• Sirolimus: 1 mg/m2/day loading; then 1 mg/m2/day; trough monitoring essential
• Everolimus: 0.8 mg/m2 twice daily; adjust to trough

• Proteinuria (inhibits podocyte mTOR signaling → podocyte injury → collapsing FSGS pattern in some patients)
• Impaired wound healing (mTOR is important for cell migration and proliferation - delay initiation until wounds heal post-transplant)
• Dyslipidemia (↑ LDL, total cholesterol, triglycerides - more marked than CNIs)
• Myelosuppression (thrombocytopenia, leukopenia, anemia)
• Mouth ulcers (aphthous stomatitis) - very common
• Interstitial pneumonitis (non-infectious, immune-mediated; present with cough, dyspnea; resolve on drug withdrawal)
• Edema (peripheral and lymphedema)
• Acneiform rash
• Increased infections (different spectrum - more fungal; less CMV than CNIs)
• Potential for acute rejection (especially if CNI removed rapidly)
• Impaired glucose tolerance

• Active serious infection
• Active malignancy (relative - paradoxically inhibits some tumor growth but immunosuppressive)
• Pregnancy (teratogenic in animals)
• Recent transplant with poor wound healing (delay use until 4-8 weeks post-transplant)
• Severe hyperlipidemia unresponsive to statins

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21. Antiproliferative Agents

Mycophenolate Mofetil (MMF) / Mycophenolate Sodium (MPS)

• Kidney, liver, heart transplant (standard maintenance triple therapy with CNI + steroid)
• Lupus nephritis (with steroids - first-line for class III/IV)
• ANCA vasculitis (maintenance after remission induction)
• Membranous nephropathy
• IgA nephropathy
• Refractory nephrotic syndrome

• MMF (CellCept): 1-1.5 g twice daily (2-3 g/day); Black/African-American renal transplant recipients: 1.5 g twice daily
• MPS (Myfortic, enteric-coated): 720-1080 mg twice daily (360 mg MPS = 500 mg MMF approximately)
• Lupus nephritis: MMF 2-3 g/day

• MMF: 600 mg/m2 twice daily (max 1 g twice daily); or 15-23 mg/kg/dose twice daily in children 3 months - 18 years
• MPS: 450 mg/m2 twice daily

• GI toxicity: Diarrhea (30-45%), nausea, vomiting, abdominal pain (enteric-coated MPS may reduce GI side effects)
• Myelosuppression: Leukopenia, neutropenia (can be severe), anemia, thrombocytopenia
• Increased infections: CMV, herpes viruses, fungal, PML (JC virus - rare)
• Teratogenicity / embryotoxicity (category D - FDA REMS program required; causes cleft lip/palate, ear and eye malformations; avoid in pregnancy - switch to azathioprine if transplant patient becomes pregnant)
• Malignancy (lymphoma, skin cancers - PTLD)

• Pregnancy (FDA REMS required; effective contraception mandatory)
• Hypersensitivity to mycophenolate or polysorbate 80
• Concurrent use of cholestyramine (reduces MMF entero-hepatic cycling, reduces AUC by 40%)
• Severe active GI disease (relative)

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Azathioprine

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22. Corticosteroids

• Prednisolone: Nephrotic syndrome: 1 mg/kg/day (max 80 mg) for 4-8 weeks, then slow taper; Lupus nephritis induction: 0.5-1 mg/kg/day; Transplant: high-dose induction (500 mg methylprednisolone IV for 3 days), then maintenance prednisolone 5-10 mg/day
• ANCA vasculitis induction: 1 mg/kg/day prednisolone (max 60 mg) + rituximab or cyclophosphamide; then taper

• Nephrotic syndrome (MCD): 60 mg/m2/day (max 60 mg) for 4-6 weeks, then 40 mg/m2 alternate-day for 4-6 weeks then taper

• Infections (opportunistic - Pneumocystis jirovecii, fungal, CMV, TB reactivation; prophylaxis required)
• Cushingoid features (moon face, buffalo hump, weight gain, striae)
• Hypertension (mineralocorticoid effects)
• Hyperglycemia / new-onset diabetes (NODAT)
• Osteoporosis (requires Ca2+ + vitamin D + bisphosphonate with long-term use)
• Avascular necrosis (osteonecrosis) of femoral/humeral head
• Growth retardation in children (especially with continuous dosing)
• Adrenal suppression (HPA axis suppression with >3 weeks of treatment → do not stop abruptly)
• Cataract, glaucoma
• Psychiatric effects (euphoria, psychosis, depression)
• Poor wound healing, thin skin, easy bruising
• Peptic ulcer disease (use PPI prophylaxis)
• Myopathy (proximal)
• Hypokalemia, fluid retention (mineralocorticoid effects)

• Systemic fungal infections (untreated)
• Live vaccines (during immunosuppressive doses)
• Active untreated TB (unless anti-TB cover given)
• Active peptic ulceration (relative - use PPI cover)
• Psychosis (relative)

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23. Rituximab

• ANCA vasculitis (GPA, MPA) - induction and maintenance (RAVE/RITUXVAS trials)
• Membranous nephropathy (anti-PLA2R antibody positive - MENTOR trial)
• Lupus nephritis (refractory Class III/IV)
• Minimal change disease (adults, refractory)
• Refractory nephrotic syndrome

• ANCA vasculitis induction: 375 mg/m2 IV weekly x 4, or 1 g IV x 2 doses (2 weeks apart)
• Membranous nephropathy (MENTOR protocol): 1 g IV x 2 doses, 2 weeks apart; repeat at 6 months
• Maintenance: 500 mg every 6 months (titrate to CD19/CD20 counts and ANCA titers)

• 375 mg/m2 IV weekly x 4 (for steroid-resistant/dependent nephrotic syndrome and ANCA vasculitis)

• Infusion reactions (fever, chills, nausea, hypotension, bronchospasm - first infusion; premedicate with methylprednisolone, acetaminophen, diphenhydramine)
• Progressive multifocal leukoencephalopathy (PML) (JC virus reactivation - rare but life-threatening)
• Hypogammaglobulinemia (IgG levels fall; risk of bacterial infections; monitor levels)
• Serious infections (bacterial, viral, fungal - especially herpes zoster, hepatitis B reactivation)
• Hepatitis B reactivation (screen all patients before rituximab; give antiviral prophylaxis to HBsAg+/anti-HBc+ patients)
• Prolonged B-cell depletion (months to years)
• Cytokine release syndrome
• Tumor lysis syndrome (in lymphoma patients)
• Neutropenia (late-onset)

• Active severe infection
• Unscreened/untreated hepatitis B (risk of severe reactivation hepatitis)
• Hypersensitivity to murine proteins or rituximab
• Live vaccines during treatment and until B-cell recovery

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VII. SGLT2 INHIBITORS

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24. SGLT2 Inhibitors

• CKD with or without T2DM (dapagliflozin - DAPA-CKD trial; empagliflozin - EMPA-KIDNEY trial)
• T2DM with CV disease or high CV risk
• Heart failure with reduced or preserved ejection fraction
• Prevention of contrast-associated AKI (emerging data)
• Reduction of ESRD progression

• Dapagliflozin: 10 mg once daily (CKD/T2DM/HF); can be started if eGFR ≥25 mL/min/1.73m2 (CKD indication)
• Empagliflozin: 10-25 mg once daily (T2DM); 10 mg once daily (HF/CKD); can be used if eGFR ≥20 mL/min/1.73m2 (EMPA-KIDNEY)
• Canagliflozin: 100-300 mg once daily (T2DM); 100 mg/day (CKD - CREDENCE trial); can be used if eGFR ≥30 mL/min/1.73m2

• Genital mycotic infections (very common - 10-15%; vulvovaginal candidiasis in women, balanitis in men; due to glucosuria providing substrate for fungal growth)
• Urinary tract infections (increased risk - especially pyelonephritis; canagliflozin most, dapagliflozin least)
• Diabetic ketoacidosis (DKA) with near-normal glucose (euglycemic DKA - present with vomiting, abdominal pain, high anion-gap; glucose may only be mildly elevated; hold SGLT2i perioperatively and during illness)
• Volume depletion and hypotension (especially elderly, on loop diuretics, ACEIs/ARBs)
• Acute kidney injury (mostly volume-related; reversible on stopping)
• Fournier's gangrene (necrotizing fasciitis of genitalia/perineum - rare but serious; FDA class warning)
• Hypoglycemia (only if combined with insulin or sulfonylureas)
• Lower limb amputations (canagliflozin - CANVAS trial; not clearly a class effect)
• Bone fractures (canagliflozin - reduced bone mineral density)
• Increased hematocrit (hemoconcentration + erythropoiesis stimulation via EPO)
• Transient eGFR dip of 10-20% (expected hemodynamic effect on initiation - do NOT discontinue; eGFR recovers and long-term trajectory is improved)
• Hyperkalemia (minor, via natriuresis)
• Elevated LDL (minor)

• eGFR <20-25 mL/min/1.73m2 (glycemic efficacy lost; renoprotection trials allow lower eGFR but not ESRD/dialysis)
• T1DM (high DKA risk - except investigational use)
• Recurrent genitourinary infections
• Perioperative/periprocedural period (hold 3-4 days before surgery - DKA risk)
• Severe hepatic impairment (canagliflozin)
• Pregnancy (limited safety data; avoid)
• Prior Fournier's gangrene (relative)

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VIII. DRUGS FOR HYPERURICEMIA / GOUT NEPHROPATHY

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25. Xanthine Oxidase Inhibitors

• Gout (prophylaxis and treatment - NOT acute attacks)
• Uric acid nephrolithiasis (prevention)
• Urate nephropathy / tumor lysis syndrome (prevention)
• Recurrent calcium oxalate stones with hyperuricemia

• Allopurinol: Start 100 mg/day; increase by 100 mg every 2-4 weeks; target serum urate <6 mg/dL; max 800 mg/day. Dose-reduce in CKD (e.g., CrCl 30-60: 200 mg/day; CrCl 10-30: 100 mg/day; CrCl <10: 50-100 mg every 48-72 h). Test for HLA-B*5801 in South/Southeast Asians before starting (severe cutaneous reactions).
• Febuxostat: 40-80 mg once daily; no dose adjustment needed in mild-moderate CKD; max 120 mg/day.

• Allopurinol: Tumor lysis syndrome prophylaxis: 10 mg/kg/day (max 300 mg/day) in 2-3 divided doses; children <6 years: 150 mg/day; 6-10 years: 300 mg/day

• Allopurinol hypersensitivity syndrome (AHS): fever, rash, eosinophilia, hepatitis, renal failure (SJS/TEN risk especially in HLA-B*5801 carriers - Korean, Han Chinese, Thai populations - screen before prescribing)
• Gout flare on initiation (mobilization of urate crystals - use colchicine or NSAID prophylaxis for first 3-6 months)
• GI upset, nausea
• Hepatotoxicity (elevated LFTs)
• Febuxostat: Cardiovascular events (CARES trial - increased CV mortality vs. allopurinol in patients with established CV disease; FDA added boxed warning; FAST trial subsequently showed lower CV mortality - controversy ongoing)
• Arthralgia, diarrhea, headache (febuxostat)

• Allopurinol: concurrent azathioprine/6-MP (without dose reduction - severe myelosuppression); known hypersensitivity; acute gout attack (wait until attack resolves)
• Febuxostat: concurrent azathioprine/6-MP (similar concern); established CV disease (relative - use with caution per FDA boxed warning)
• Both: avoid initiating during acute gout flare

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26. Rasburicase

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IX. VASOPRESSIN (V2) RECEPTOR ANTAGONISTS (Vaptans)

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27. Tolvaptan

• ADPKD (tolvaptan - TEMPO 3:4 trial: slows total kidney volume growth and eGFR decline by 30% over 3 years)
• Euvolemic/hypervolemic hyponatremia (SIADH, heart failure, cirrhosis)

• ADPKD: 45 mg in AM + 15 mg in PM; up to 90 mg + 30 mg daily; split-dose schedule
• Hyponatremia: 15 mg once daily; max 60 mg/day; correct Na+ no faster than 10-12 mEq/L in 24 h

• Polyuria and polydipsia (pharmacological effect - patients must have unrestricted access to water)
• Thirst (90%+ of patients)
• Hepatotoxicity (serious; ↑ ALT/AST; FDA restriction: only via REMS program - RISK MAP; avoid if hepatic disease; check LFTs regularly; limit use to ≤3 years for ADPKD with certain restrictions)
• Overly rapid serum Na+ correction → osmotic demyelination syndrome (central pontine myelinolysis) - most feared complication; initiate in hospital with Na+ monitoring q6-8 h for first 24-48 h
• Dizziness, fatigue
• Hyperkalemia (mild)
• Dry mouth

• Inability to sense/respond to thirst (unconscious patients, severe dementia) - cannot regulate water intake → lethal hypernatremia
• Hypovolemic hyponatremia
• Anuria
• Hepatic impairment (serious hepatotoxicity risk - avoid in liver disease)
• Concurrent strong CYP3A inhibitors (greatly increase tolvaptan levels)
• Pregnancy

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X. COMPLEMENT INHIBITORS

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28. Eculizumab / Ravulizumab

• Atypical HUS (aHUS) - primary indication in nephrology; life-saving; prevents TMA progression
• Paroxysmal nocturnal hemoglobinuria (PNH)
• Anti-complement therapy in C3 glomerulopathy (C3G) - investigational

• Eculizumab (aHUS): 900 mg IV weekly x 4 weeks, then 1200 mg at week 5, then 1200 mg every 2 weeks
• Ravulizumab (longer t½ - q8 week dosing): Weight-based loading + maintenance; doses 2400-3000 mg every 8 weeks

• Eculizumab: Weight-based dosing (10-40 kg range: 600 mg induction, 300 mg maintenance; >40 kg: adult doses)

• Meningococcal infections (most serious - Neisseria meningitidis septicemia; complement C5b-9 is essential for killing encapsulated bacteria; must vaccinate against meningococcus (MenACWY + MenB) ≥2 weeks before starting; if urgent treatment needed before vaccination - give prophylactic penicillin/ciprofloxacin)
• Headache, nasopharyngitis, upper respiratory infections
• Infusion reactions (fever, rigors, nausea)
• Increased risk of other encapsulated bacterial infections (Haemophilus influenzae, Streptococcus pneumoniae - ensure relevant vaccinations)

• Unresolved Neisseria meningitidis infection
• Unvaccinated patients (give meningococcal vaccine first; if urgent, start with antibiotic prophylaxis simultaneously)
• Hypersensitivity to murine proteins

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29. Avacopan (Tavneos)

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XI. MISCELLANEOUS NEPHROPROTECTIVE DRUGS

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30. Sodium Bicarbonate

• Metabolic acidosis in CKD
• Renal tubular acidosis (all types)
• Type I (distal) RTA: alkalinize urine, prevent nephrocalcinosis
• Type II (proximal) RTA: large doses needed (5-15 mEq/kg/day - loss from kidney)
• Prevention of contrast-induced nephropathy (debated - not superior to NS hydration)
• Uric acid nephropathy (alkalinize urine - increases urate solubility)

• CKD metabolic acidosis: 0.5-1 mEq/kg/day orally; target serum HCO3- >22 mEq/L
• Acute severe acidosis: IV NaHCO3 (1-3 mEq/kg IV), with caution (risk of volume overload, paradoxical intracellular acidosis, overshoot alkalosis)

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31. Cyclophosphamide

• ANCA vasculitis induction (especially severe disease with renal involvement - EUVAS trials)
• Severe lupus nephritis (proliferative - Class III/IV)
• Membranous nephropathy (refractory)
• Minimal change disease (refractory)
• FSGS (refractory)

• IV pulse: 0.75-1 g/m2 monthly for 6 months (NIH protocol - lupus)
• Oral: 2 mg/kg/day for 3-6 months (ANCA vasculitis - CYCLOPS trial showed IV pulse = oral efficacy with less leukopenia)
• Reduced in renal impairment (cyclophosphamide is renally cleared)

• Hemorrhagic cystitis (acrolein metabolite damages urothelium → dysuria, hematuria; prevent with MESNA, aggressive hydration, frequent voiding)
• Gonadal toxicity (ovarian failure, premature menopause, azoospermia - dose-dependent; particularly severe with cumulative doses >150 mg/kg; consider sperm/egg banking)
• Myelosuppression (nadir at 10-14 days post-pulse; risk of severe infections)
• Transitional cell carcinoma of bladder (long-term risk with cumulative exposure)
• Opportunistic infections (PCP prophylaxis with cotrimoxazole required)
• Nausea, vomiting, alopecia (dose-dependent)
• SIADH (high-dose IV)

• Urinary outflow obstruction (hemorrhagic cystitis risk)
• Pregnancy
• Active serious infection
• Severely depressed bone marrow function

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Summary Reference Table

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