4.1 Nephrology & Renal Pharmacotherapy
Key Takeaways
- KDIGO guidelines classify AKI based on serum creatinine and urine output, and CKD based on GFR and albuminuria categories.
- Management of CKD-MBD involves controlling hyperphosphatemia with binders, followed by calcimimetics or vitamin D analogs for secondary hyperparathyroidism.
- Acute hyperkalemia with EKG changes requires immediate membrane stabilization with IV calcium, followed by intracellular shifting and elimination.
- Chronic hyperkalemia can be managed with newer potassium binders like patiromer or sodium zirconium cyclosilicate.
- Renal drug dosing must account for the specific dialysis modality, taking note of drug molecular weight, protein binding, and volume of distribution.
4.1 Nephrology & Renal Pharmacotherapy
Acute Kidney Injury (AKI) Staging and Management
Acute kidney injury is characterized by a rapid and potentially reversible decline in renal function, leading to the accumulation of nitrogenous waste products. The Kidney Disease: Improving Global Outcomes (KDIGO) criteria define AKI based on changes in serum creatinine (SCr) and urine output (UOP).
| Stage | Serum Creatinine (SCr) Criteria | Urine Output (UOP) Criteria |
|---|---|---|
| 1 | Increase of >=0.3 mg/dL within 48 hours OR 1.5-1.9x baseline | <0.5 mL/kg/h for 6-12 hours |
| 2 | Increase of 2.0-2.9x baseline | <0.5 mL/kg/h for >=12 hours |
| 3 | Increase of 3.0x baseline OR SCr >=4.0 mg/dL OR RRT initiation | <0.3 mL/kg/h for >=24 hours OR anuria for >=12 hours |
Management primarily involves hemodynamic support, optimizing fluid status, and removing nephrotoxic agents (e.g., NSAIDs, aminoglycosides, contrast media, amphotericin B). For contrast-induced nephropathy (CIN) prevention, isotonic intravenous saline is the cornerstone of therapy; N-acetylcysteine and sodium bicarbonate are no longer routinely recommended due to lack of proven efficacy. Diuretics should not be used to prevent AKI. However, loop diuretics (e.g., furosemide, bumetanide) can be utilized to manage volume overload in oliguric AKI patients, though they do not improve mortality or renal recovery. Urgent indications for renal replacement therapy (RRT) are remembered by the mnemonic AEIOU: Acidosis (refractory metabolic acidosis), Electrolyte abnormalities (severe, symptomatic hyperkalemia), Intoxication (dialyzable toxins like salicylates, lithium, methanol, ethylene glycol), Overload (refractory fluid overload), and Uremia (uremic pericarditis, encephalopathy, or bleeding).
Chronic Kidney Disease (CKD) Progression
CKD is defined as abnormalities of kidney structure or function present for >3 months. KDIGO staging relies on a two-dimensional grid using Glomerular Filtration Rate (GFR) and albuminuria.
GFR Categories (mL/min/1.73m2)
- G1: >=90 (Normal or high)
- G2: 60-89 (Mildly decreased)
- G3a: 45-59 (Mild to moderately decreased)
- G3b: 30-44 (Moderate to severely decreased)
- G4: 15-29 (Severely decreased)
- G5: <15 (Kidney failure)
Albuminuria Categories (mg/g creatinine)
- A1: <30 (Normal to mildly increased)
- A2: 30-300 (Moderately increased)
- A3: >300 (Severely increased)
Slowing progression relies heavily on blood pressure control and reducing intraglomerular pressure. KDIGO recommends a target systolic BP <120 mmHg for most patients with CKD, balancing the risks of hypotension and falls. ACE inhibitors or ARBs are first-line agents for patients with albuminuria (A2 or A3 categories). Upon initiation, a transient increase in SCr up to 30% is a normal physiological response due to efferent arteriole vasodilation; they should not be discontinued unless the increase exceeds 30% or if severe hyperkalemia (>=5.5 mEq/L) occurs and is refractory to management. SGLT2 inhibitors (e.g., dapagliflozin, empagliflozin) have shown significant benefit in slowing CKD progression and reducing cardiovascular events, independent of diabetes status. They are recommended for patients with an eGFR >=20 mL/min/1.73m2. Finerenone, a non-steroidal mineralocorticoid receptor antagonist (MRA), is also indicated to reduce the risk of eGFR decline, end-stage kidney disease, and cardiovascular death in adult patients with CKD associated with type 2 diabetes.
Renal Replacement Therapy: Hemodialysis vs. Peritoneal Dialysis
Hemodialysis (HD) is typically performed 3 times weekly. It provides rapid clearance of small molecular weight solutes. Vascular access is best achieved via an arteriovenous (AV) fistula due to lower infection and thrombosis rates compared to AV grafts or central venous catheters. Complications include intradialytic hypotension (managed with midodrine, fluid restriction, or cool dialysate) and muscle cramps (managed with vitamin E or quinine). Catheter-related bloodstream infections require empiric coverage for MRSA (vancomycin) and Pseudomonas (cefepime or ceftazidime).
Peritoneal Dialysis (PD) involves continuous dwell of dialysate via the peritoneal membrane. It preserves residual renal function better than HD, provides continuous clearance, and allows for a more liberal diet. However, it carries a risk of peritonitis (typically presenting as cloudy effluent and abdominal pain). Most peritonitis cases are caused by Gram-positive organisms (Staphylococcus epidermidis, Staphylococcus aureus). Treatment is initiated empirically with intraperitoneal cefazolin or vancomycin plus ceftazidime or an aminoglycoside to cover Gram-negative pathogens.
CKD-Mineral and Bone Disorder (CKD-MBD)
Secondary hyperparathyroidism develops due to a complex cascade: phosphate retention, decreased renal 1-alpha hydroxylase activity (leading to decreased active vitamin D/calcitriol production), and subsequent hypocalcemia. This cascade stimulates increased parathyroid hormone (PTH) secretion.
- Phosphate Binders: Given strictly with meals to bind dietary phosphate.
- Calcium-based: Calcium acetate and calcium carbonate. Effective but carry a risk of hypercalcemia. Total elemental calcium intake should not exceed 2,000 mg/day.
- Non-calcium-based: Sevelamer carbonate (can lower LDL cholesterol), lanthanum carbonate (chewable tablet, must not be swallowed whole), sucroferric oxyhydroxide, and ferric citrate (can increase systemic iron indices, reducing IV iron needs).
- Vitamin D Analogs: Used to directly suppress PTH synthesis.
- Active Vitamin D: Calcitriol. It has a high risk of inducing hypercalcemia and hyperphosphatemia by increasing intestinal absorption of both.
- Analogs: Paricalcitol and doxercalciferol. These have a lower incidence of hypercalcemia compared to calcitriol.
- Calcimimetics: Increase the sensitivity of the calcium-sensing receptor on the parathyroid gland, reducing PTH secretion.
- Cinacalcet (oral) and etelcalcetide (IV). These can cause significant hypocalcemia and should be avoided if corrected serum calcium is below the lower limit of normal. They are particularly useful in patients with high PTH and concurrent hypercalcemia.
Calciphylaxis (calcific uremic arteriolopathy) is a severe, rare complication characterized by systemic medial calcification of arterioles leading to ischemia and subcutaneous necrosis. Management involves rigorous control of calcium and phosphate, often utilizing sodium thiosulfate.
Hyperkalemia: Acute vs. Chronic Management
Hyperkalemia is a life-threatening complication of renal impairment, defined generally as a serum potassium >5.0 mEq/L, with severe cases >6.5 mEq/L or any level with EKG changes.
Acute Management
- Membrane Stabilization: IV calcium gluconate or calcium chloride (preferably via central line to avoid necrosis) is indicated immediately if EKG changes (peaked T waves, widened QRS, loss of P wave) are present. Calcium antagonizes the membrane actions of potassium but does not lower serum potassium levels.
- Intracellular Shifting: Regular insulin (typically 10 units IV) plus dextrose 50% (to prevent hypoglycemia), nebulized albuterol (10-20 mg), and IV sodium bicarbonate (most effective if the patient has concurrent metabolic acidosis).
- Elimination: Loop diuretics (e.g., furosemide), hemodialysis (most rapid and definitive method), or GI potassium binders.
Chronic Management
- Sodium Polystyrene Sulfonate (SPS): Exchanges sodium for potassium in the gut. Carries a black box warning for colonic necrosis, especially when given with sorbitol.
- Patiromer (Veltassa): Exchanges calcium for potassium. Given daily; must be separated from other oral drugs by 3 hours to prevent decreased absorption of concurrent medications.
- Sodium Zirconium Cyclosilicate (Lokelma): Exchanges sodium and hydrogen for potassium. Has a rapid onset of action and must be separated from other drugs by 2 hours.
Renal Drug Adjustments
Drug pharmacokinetics are profoundly altered in CKD.
- Absorption: Increased gastric pH due to ammonia buffering can alter the absorption of weak acids and bases.
- Distribution: Decreased protein binding occurs, especially for acidic drugs like phenytoin to albumin, leading to higher free (active) fractions. The volume of distribution often increases for water-soluble drugs due to edema and fluid overload.
- Metabolism & Elimination: Reduced renal clearance necessitates dose reductions or extended intervals for renally eliminated medications. Notable examples include gabapentin (dose reduction required to prevent neurotoxicity), enoxaparin (contraindicated or adjusted if CrCl <30 mL/min), Direct Oral Anticoagulants (DOACs like rivaroxaban are avoided in CrCl <15-30 mL/min depending on indication, while apixaban can be used in ESRD with specific criteria), and beta-lactam antibiotics (which can cause seizures if accumulated).
Drugs efficiently removed by hemodialysis generally possess a small volume of distribution (<1 L/kg), low protein binding, and low molecular weight. Supplemental doses or post-dialysis dosing may be necessary for these medications (e.g., aminoglycosides, vancomycin).
A patient with an eGFR of 40 mL/min/1.73m2 and a urine albumin-to-creatinine ratio (UACR) of 450 mg/g is started on lisinopril. Two weeks later, the patient's serum creatinine has increased by 20% from baseline, and serum potassium is 4.8 mEq/L. What is the most appropriate action?
Which of the following medications used for the chronic management of hyperkalemia exchanges calcium for potassium in the gastrointestinal tract and requires separation from other oral medications by 3 hours?
A 54-year-old male with CKD Stage 4 (eGFR 22 mL/min/1.73m2) presents to the clinic. His labs show: Serum Potassium 5.2 mEq/L, Calcium 9.5 mg/dL, Phosphorus 6.8 mg/dL, and PTH 450 pg/mL. Which of the following is the most appropriate initial therapy to manage this patient's CKD-MBD?