Pocket Medicine (Pocket Notebook Series)

ACID-BASE DISTURBANCES

GENERAL

Definitions

• Acidemia → pH <7.36, alkalemia → pH >7.44; pH = 6.10 + log([HCO₃]/[0.03xPCO₂])

• Acidosis → process that ↑ [H⁺] or ↓ pH by ↓ HCO₃ or ↑ PaCO₂

• Alkalosis → process that ↓ [H⁺] or ↑ pH by ↑ HCO₃ or ↓ PaCO₂

• Primary disorders: metabolic acidosis or alkalosis, respiratory acidosis or alkalosis

• Compensation

Respiratory: hyper/hypoventilation alters P_aCO₂ to counteract 1° metabolic process

Renal: excretion/retention of H⁺/HCO₃^– to counteract 1° respiratory process

Respiratory compensation occurs in mins-hrs; renal compensation takes days

Compensation usually never fully corrects pH; if pH normal, consider mixed disorder

Consequences of Severe Acid-Base Disturbances (NEJM 1998;338:26 & 107)
Organ System	Acidemia (pH <7.20)	Alkalemia (pH >7.60)
Cardiovascular	↓ contractility, arteriolar vasodilation ↓ MAP & CO; ↓ response to catecholamines ↑ risk of arrhythmias	Arteriolar vasoconstriction ↓ coronary blood flow ↑ risk of arrhythmias
Respiratory	Hyperventilation, ↓ resp. muscle strength	Hypoventilation
Metabolic	↑ K (resp. > metab.), insulin resistance	↓ K, Ca, Mg, PO4
Neurologic	Δ MS	Δ MS, seizures, tetany

Workup (NEJM 2014;371:1434)

• Traditional or physiologic approach (Brønsted-Lowry definition of acids & bases)

Determine primary disorder: ✓ pH, P_aCO₂, HCO₃

Determine if degree of compensation is appropriate

Compensation for Acid-Base Disorders (NEJM 2014;371:1434)
Primary Disorder	Expected Compensation
Metabolic acidosis	↓ PaCO2 = 1.2 × ΔHCO3 or PaCO2 = (1.5 × HCO3) + 8 ± 2 (Winters’ formula) (also, PaCO2 ≈ last 2 digits of pH)
Metabolic alkalosis	↑ PaCO2 = 0.7 × ΔHCO3 or PaCO2 = 0.7 (HCO3–24) + 40 ± 2 or HCO3 + 15
Acute respiratory acidosis	↑ HCO3 = 0.1 × ΔPaCO2 (also, ↓ pH = 0.008 × ΔPaCO2)
Chronic respiratory acidosis	↑ HCO3 = 0.35 × ΔPaCO2 (also, ↓ pH = 0.003 × ΔPaCO2)
Acute respiratory alkalosis	↓ HCO3 = 0.2 × ΔPaCO2 (also, ↑ pH = 0.008 × ΔPaCO2)
Chronic respiratory alkalosis	↓ HCO3 = 0.4 × ΔPaCO2

• Alternative approaches

Base excess/deficit (NEJM 2018;378:1419)

Strong ion difference or “Stewart Method” (NEJM 2014;371:1821)

Mixed disorders (more than one primary disorder at the same time)

• If compensation less or greater than predicted, may be two disorders:

P_aCO₂ too low → concomitant 1° resp. alk.; P_aCO₂ too high → concomitant 1° resp. acid.

HCO₃ too low → concomitant 1° met. acid.; HCO₃ too high → concomitant 1° met. alk.

• Normal pH, but...

↑ P_aCO₂ + ↑ HCO₃ → resp. acid. + met. alk.

↓ P_aCO₂ + ↓ HCO₃ → resp. alk. + met. acid.

Normal P_aCO₂ & HCO₃, but ↑ AG → AG met. acid. + met. alk.

Normal P_aCO₂, HCO₃, & AG → no disturbance or non-AG met. acid. + met. alk.

• Cannot have resp. acid. (hypoventilation) and resp. alk. (hyperventilation) simultaneously

(Adapted from Brenner BM, ed., Brenner & Rector’s The Kidney, 8th ed., 2007; Ferri F, ed. Practical Guide to the Care of the Medical Patient, 7th ed., 2007)

• ABG vs. VBG: concordant for pH (~0.04), HCO₃ (~2 mEq) but not PCO₂ (~8±17 mmHg)

VBG can be used to screen for hypercarbia w/ PCO₂ cutoff ≥45 mmHg (100% Se),

but may not accurately assess degree of hypercarbia (Am J Emerg Med 2012;30:896)

METABOLIC ACIDOSIS

Initial workup (NEJM 2014;371:1434)

• ✓ anion gap (AG) = Na⁺ – (Cl^– + HCO₃^–) = unmeasured anions – unmeasured cations

If ↑ glc, use measured not corrected Na

Expected AG is [albumin] × 2.5 (ie, 10 if albumin is 4 g/dL, 7.5 if albumin is 3 g/dL)

↑ AG → ↑ unmeasured anions such as organic acids, phosphates, sulfates

↓ AG → ↓ alb or ↑ unmeasured cations (Ca, Mg, K, Li, Ig), bromide/iodine toxicity

• If ↑ AG, ✓ delta-delta (Δ/Δ = ΔAG/ΔHCO₃) to assess if there is an additional metabolic

acid-base disturbance; ΔAG = (calculated AG – expected AG), ΔHCO₃ = (24 – HCO₃)

Δ/Δ = 1–2 → pure AG metabolic acidosis

Δ/Δ <1 → AG metabolic acidosis and simultaneous non-AG acidosis

Δ/Δ >2 → AG metabolic acidosis and simultaneous metabolic alkalosis

For pure lactic acidosis Δ/Δ 1.6 b/c of slow lactate clearance

Etiologies of AG Metabolic Acidosis
Ketoacidosis	Diabetes mellitus, alcoholism, starvation (NEJM 2015;372:546)
Lactic acidosis (NEJM 2014; 371:2309)	Type A: hypoxic (eg, shock, mesenteric ischemia, CO poisoning, cyanide) Type B: nonhypoxic. ↓ clearance (eg, hepatic dysfxn) or ↑ generation [eg, malig, EtOH, thiamine def., meds (metformin, NRTIs, salicylates, propylene glycol, propofol, isoniazid, linezolid)] D-lactic acidosis: short bowel syndrome → precip by glc ingest → metab by colonic bacteria to d-lactate; not detected by standard lactate assay
Renal failure	Accumulation of organic anions (eg, phosphates, sulfates, etc.)
Ingestions (NEJM 2020; 382:2544)	Glycols: Ethylene (antifreeze) → metab to glycolic and oxalic acids Propylene (pharmaceutical solvent, eg, IV diazepam, lorazepam, and phenobarbital; antifreeze) → lactic acidosis Diethylene (brake fluid) → diglycolic acid 5-oxoproline (pyraglutamic acid): acetaminophen → ↑ organic acid 5- oxoproline in susceptible Pts (malnourished, female, renal failure) Methanol (windshield fluid, antifreeze, solvents, fuel): metab to formic acid Aspirin: early resp alkalosis (CNS stim) + late metab acidosis (impairs oxidative phosphorylation → inorganic acids (eg, ketones, lactate)

“GOLD MARK” = Glycols, Oxoproline, Lactic, D-Lactic, Methanol, ASA, Renal, Ketoacidosis

Workup for AG metabolic acidosis (AJKD 2021;78:A16)

• ✓ for ketonuria (dipstick acetoacetate) or plasma β-hydroxybutyrate (βOHB)

nb, urine acetoacetate often not present in early ketoacidosis due to shunting to βOHB; ∴ acetoacetate may later turn ⊕ but does not signify worsening disease

• If ⊖ ketones, ✓ renal function, lactate, toxin screen, and osmolal gap

• If obtunded or ↑↑ AG, check osmolal gap (OG) = measured osmoles – calculated osmoles

Calculated osmoles = (2 × Na) + (glucose/18) + (BUN/2.8) (+ [EtOH/4.6] if ↑ EtOH level and want to test if other ingestions)

OG >10 → suggests ingestion (see below) but lacks specificity (can be elevated in lactic acidosis, DKA, and alcoholic ketoacidosis due to acetone)

High-dose lorazepam (>10 mg/h) a/w propylene glycol intoxication

OG & AG vary based on timing, initially OG ↑, then ↓ w/ metabolism as AG ↑

Ingestions (NEJM 2018;378:270) Call poison control for guidance (800-222-1222)
AG	OG	Ingestion	Other Manifestations
↑	nl	Acetaminophen	Hepatitis
		Salicylates	Fever, tachycardia, tinnitus; met. acid. + resp. alkalosis
↑	↑	Methanol	ΔMS, blurred vision, pupillary dilation, papilledema
↑	↑	Ethylene glycol	ΔMS, cardiopulm. failure, hypoCa. Ca oxalate crystals → AKI. Urine fluoresces under UV light.
nl/↑	↑	Propylene glycol	AKI, liver injury
↑	nl/↑	Diethylene glycol	AKI, N/V, pancreatitis, neuropathy, lactic acidosis
nl/↑	↑	Isopropyl alcohol	ΔMS, fruity breath (acetone), pancreatitis, lactic acidosis
		Ethanol	Alcoholic fetor, ΔMS, hepatitis; keto + lactic acidosis ± met. alk. (vomiting)

Etiologies of Non-AG Metabolic Acidosis
GI losses of HCO3	Diarrhea, intestinal or pancreatic fistulas or drainage
RTAs	See section on renal tubular acidoses below
Early renal failure	Impaired generation of ammonia
Ingestions	Acetazolamide, sevelamer, cholestyramine, toluene
Dilutional	Due to rapid infusion of bicarbonate-free IV fluids
Posthypocapnia	Respiratory alkalosis → renal wasting of HCO3; rapid correction of resp. alk. → transient acidosis until HCO3 regenerated
Ureteral diversion	Colonic Cl–/HCO3– exchange, ammonium reabsorption

Workup for non-AG metabolic acidosis

• Evaluate history for causes (see above)

• ✓ urine anion gap (UAG) = (U_Na + U_K) – U_Cl

UAG = unmeasured anions – unmeasured cations; NH₄⁺ is primary unmeasured cation (represented by U_Cl). UAG is indirect assay for renal H⁺ excretion.

• ⊖ UAG → ↑ renal NH₄⁺ excretion → appropriate renal response to acidemia

Ddx: GI causes (diarrhea, fistulas, ureteral diversion), IV NS, ingestions

• ⊕ UAG → failure of kidneys to generate NH₄⁺

Ddx: distal (type 1, usually ↓ K) or hypoaldo (type IV, usually ↑ K) RTA, early renal failure

• UAG unreliable in AKI/CKD, polyuria, Na depletion (U_Na <20), U_pH >6.5 & HAGMA (causes ⊕ UAG b/c excretion of organic anions) and less useful in prox RTA as variable. Then use U_Osm gap = measured U_Osm – [2×(Na⁺ + K⁺) + BUN + glc (mmol/L)]. U_Osm gap <40 mmol/L indicates impaired NH₄⁺ excretion

Renal tubular acidoses (RTAs) (Adv Ther 2021;38:949)

• Proximal (Type II): ↓ proximal reabsorption of HCO₃

1° (Fanconi’s syndrome) = ↓ proximal reabsorption of HCO₃, PO₄, glc, amino acids

Acquired: paraprotein (MM, amyloidosis), metals (Pb, Cd, Hg, Cu), ↓ vit D, PNH, renal Tx

Meds: acetazolamide, aminoglycosides, ifosfamide, cisplatin, topiramate, tenofovir

• Distal (Type I): defective distal H⁺ secretion

1°, autoimmune (Sjögren’s, RA, SLE), hypercalciuria, meds (ampho, Li, ifosfamide); normally a/w ↓ K; if with ↑ K → sickle cell, obstruction, renal transplant

• Hypoaldo (Type IV): hypoaldo → ↑ K → ↓ NH₃ synthesis → ↓ urine acid-carrying capacity

↓ renin: diabetic nephropathy, NSAIDs, chronic interstitial nephritis, calcineurin inh, HIV

↓ aldo production: 1° AI, ACEI/ARBs, heparin, severe illness, inherited (↓ 21-hydroxylase)

↓ response to aldosterone

Meds: K-sparing diuretics, TMP-SMX, pentamidine, calcineurin inhibitors

Tubulointerstitial disease: sickle cell, SLE, amyloid, DM

• Combined (Type III): rarely discussed or clinically relevant, also called juvenile RTA, has distal & proximal features, can be due to carbonic anhydrase II deficiency

^aUrine pH will rise above 5.3 in the setting of HCO₃ load

^bFe_HCO3 should be checked after an HCO₃ load

^cSee above for causes of distal RTA (Type I) associated with hyperkalemia

Treatment of severe metabolic acidoses (pH <7.2) (Nat Rev Nephrol 2012;8:589)

• DKA: insulin, IVF, K repletion (NEJM 2015;372:546); AKA: dextrose, IVF, replete K, Mg, PO₄

• Lactic acidosis: treat underlying condition, avoid vasoconstrictors, avoid “Type B” meds

• Renal failure: hemodialysis

• Methanol & ethylene glycol: fomepizole (20 mg/dL), vit. B₁ & B₆ (ethylene glycol), folate (methanol), dialysis (if AKI, VS unstable, vision Δ or >50 mg/dL) (NEJM 2018;378:270)

• Alkali therapy: if pH <7.1 or <7.2 and co-existing AKI (may ↓ mortality; Lancet 2018;392:31)

• NaHCO₃: amps by IV push or infusion of three 50-mmol amps in 1 L D₅W if less urgent

Can estimate mmol of HCO₃ needed as [desired-current HCO₃]_serum × wt (kg) × 0.4

Side effects: ↑ volume, ↑ Na, ↓ ICa, ↑ P_aCO₂ (& ∴ intracellular acidosis; ∴ must ensure adequate ventilation to blow off CO₂)

METABOLIC ALKALOSIS

Pathophysiology (CJASN 2020;15:1848)

• Saline-responsive etiologies require initiating event and maintenance phase

• Initiating event: net HCO₃⁻ reabsorption (due to loss of volume, Cl^-, and/or K⁺) or loss of H⁺

Loss of H⁺ (± Cl^-) from GI tract, kidneys, or transcellular shift in hypokalemia

Contraction alkalosis: loss of HCO₃^--poor fluid → extracellular fluid “contracts” around fixed amount of HCO₃^- → ↑ HCO₃^- concentration

Exogenous alkali: iatrogenic HCO₃^- (with renal impairment), milk-alkali syndrome

Posthypercapnia: resp. acidosis → compensation with H⁺ excretion and HCO₃^- retention; rapid correction of hypercapnia (eg, intubation) → transient excess HCO₃^-

• Maintenance phase

Volume depletion → ↑ ATII → ↑ PCT reabsorption of HCO₃^- & ↑ aldosterone (see below)

Cl^- depletion → ↓ Cl^- uptake in macula densa → ↑ RAS & ↑ CCD Cl^-/HCO₃^- exchanger

Hypokalemia → transcellular K⁺/H⁺ exchange; intracellular acidosis → HCO₃^- reabsorption and ammoniagenesis & ↑ distal H⁺-K⁺-ATPase activity → HCO₃^- retention

Hyperaldosteronism (1° or 2°) → ↑ CCD α-intercalated H⁺ secretion w/ HCO₃^- retention & Na⁺ reabsorption in principal cell → H⁺ secretion (for electrical neutrality)

Etiologies of Metabolic Alkalosis
Saline responsive UCl <25	GI loss of H+: emesis, NGT suction, villous adenoma, chloridorrhea Renal loss: loop/thiazide, ↓ Cl intake, milk-alkali, Pendred syndrome Posthypercapnia, sweat losses in cystic fibrosis
Saline resistant UCl >40	Hypertensive (mineralocorticoid excess) 1° hyperaldosteronism (eg, Conn’s) 2° hyperaldosteronism (eg, renovascular dis., renin-secreting tumor) Non-aldo (Cushing’s, Liddle’s, exogenous mineralocorticoids, licorice) Normotensive Severe hypokalemia (K<2); exogenous alkali load (w/ AKI or ↓ vol) Bartter’s syndrome (loop-like); Gitelman’s syndrome (thiazide-like)

Workup

• Check volume status and U_Cl

U_Cl <25 mEq/L → saline responsive

U_Cl >40 mEq/L → saline resistant (unless currently receiving diuretics)

(U_Na unreliable determinant of volume status in alkalemia → ↑ HCO₃^- excretion → ↑ Na excretion; negatively charged HCO₃^- w/ Na⁺ maintaining electrical neutrality)

If U_Cl >40 and volume replete, ✓ U_K; U_K <20 laxative abuse; U_K >30, ✓ blood pressure

Treatment of severe metabolic alkalosis (pH >7.6) (JASN 2012;23:204)

• If saline responsive: resuscitate with Cl-rich solution (NS), replete K, d/c diuretics cardiopulmonary disease precludes hydration, can use KCl, acetazolamide, HCl

• Hyperaldosteronism: treat underlying condition, K-sparing diuretic, resect adenoma if 1^o

RESPIRATORY ACIDOSIS (NEJM 1989;321:1223; Crit Care 2010;14:220)

Etiologies (also see “Hypercapnia”; P_aCO₂ = VCO₂/V_E(1-V_D/V_T); V_E = RR x V_T)

• ↑ CO₂ production (↑ VCO₂): fever, thyrotoxicosis, sepsis, steroids, overfeeding (carbs)

• CNS depression (↓ RR and/or V_T): sedatives (opiates, benzos, etc.), CNS trauma, central sleep apnea, obesity, hypoventilation, hypothyroidism

• Neuromuscular disorders (↓ V_T): Guillain-Barré, poliomyelitis, ALS, MS, paralytics, myasthenia gravis, muscular dystrophy, severe ↓ P & K, high spinal cord injury

• Chest wall (↓ V_T): PTX, hemothorax, flail chest, kyphoscoliosis, ankylosing spondylitis

• Upper airway (↓ V_T): foreign body, laryngospasm, OSA, esophageal intubation

• Lower airway (gas exchange) (↑ V_D and/or ↓ V_T): asthma, COPD, pulm edema, IPF

Often hypoxia → ↑ RR → resp. alk., but muscle fatigue → resp. acid

• Post infusion of bicarbonate in acidemic Pt w/ limited ability to ↑ minute ventilation

RESPIRATORY ALKALOSIS

Etiologies (NEJM 2002;347:43; Crit Care 2010;14:220)

• Hypoxia → hyperventilation: pneumonia, CHF, PE, restrictive lung disease, anemia

• Primary hyperventilation

CNS stimulation, pain, anxiety, trauma, stroke, CNS infection, pontine tumors

drugs: salicylates toxicity (early), β-agonists, progesterone, methylxanthines, nicotine

pregnancy, sepsis, hepatic failure, hyperthyroidism, fever

• Pseudorespiratory alkalosis: ↓ perfusion w/ preserved ventilation (eg, CPR, severe HoTN) → ↓ delivery of CO₂ to lungs for excretion; low P_aCO₂ but ↑ tissue CO₂

SODIUM AND WATER HOMEOSTASIS

OVERVIEW

General (NEJM 2015;372:55 & 373:1350)

• Disorders of serum sodium are generally due to Δs in total body water, not sodium

• Hyper- or hypo-osmolality → rapid water shifts → Δs in brain cell volume → Δ MS, seizures

Key hormones

• Antidiuretic hormone (ADH): primary hormone that regulates sodium concentration

Stimuli: hyperosmolality (290–295 mOsm), ↓↓ effective arterial volume, angiotensin II

Action: insertion of aquaporin-2 channels in principal cells → passive water reabsorption

urine osmolality is an indirect functional assay of the ADH-renal axis

U_osm range: 50 mOsm/L (no ADH) to 1200 mOsm/L (maximal ADH)

• Aldosterone: primary hormone that regulates total body sodium (and ∴ volume)

Stimuli for secretion: hypovolemia (via renin and angiotensin II), hyperkalemia

Action: iso-osmotic principal cell reabsorption of Na via epithelial Na channel (ENaC) in exchange for K⁺ or H⁺

HYPONATREMIA

Pathophysiology (JASN 2008;19:1076; NEJM 2015;372:1349)

• Excess H₂O relative to Na, usually due to ↑ ADH

• ↑ ADH may be appropriate (eg, hypovolemia or hypervolemia with ↓ EAV)

• ↑ ADH may be inappropriate (SIADH)

• Rarely, ↓ ADH (appropriately suppressed), but kidneys unable to maintain nl [Na]_serum

at steady state, solute intake = solute excretion; urine output = solute excretion/U_osm

nl dietary solute load ~750 mOsm/d, min U_osm = 50 mOsm/L, ∴ UOP can be up to ~15 L

↑ H₂O intake (1° polydipsia): ingestion of massive quantities (usually >15 L/d) of free H₂O overwhelms diluting ability of kidney → H₂O retention

↓ solute intake (“tea & toast” & beer potomania): ↓↓ daily solute load → insufficient solute to excrete H₂O intake (eg, if only 250 mOsm/d, minimum U_osm = 50 mOsm/L → excrete in ~5 L; if H₂O ingestion exceeds this amount → H₂O retention)

Workup (JASN 2012;23:1140 & 2017;28:1340; Crit Care 2013;17:206; NEJM 2015;372:55)

• History: (1) acute vs. chronic (>48 h); (2) sx severity; (3) risk for neuro complications (alcoholism, malnourished, cirrhosis, older women on thiazides, hypoxia, hypoK)

• Measure plasma osmolality

Hypotonic (P_osm <280) most common scenario; true excess of free H₂O relative to Na

Isotonic (P_osm 280–295): rare lab artifact from hyperlipidemia or hyperproteinemia

Hypertonic (P_osm >295): excess of another effective osmole (eg, glucose, mannitol) that draws H₂O intravascularly; for each 100 mg/dL ↑ glc >100 mg/dL → ↓ [Na] by ~2 mEq/L

• For hypotonic hyponatremia, ✓ volume status (JVP, skin turgor, dry axilla, mucous membranes, edema, ascites), effusions, vital signs, orthostatics, BUN/Cr, FE_UricAcid, U_Na

• Measure U_osm, although useful for dx in limited circumstances, b/c almost always >300

U_osm <100 in ↑ H₂O intake (1^o polydipsia) or ↓ solute intake (beer potomania, “tea & toast”)

U_osm >300 does not mean SIADH; must determine if ↑ ADH appropriate or inappropriate

however, U_osm can be important when deciding on treatment (see below)

• If euvolemic and ↑ U_osm, evaluate for glucocorticoid insufficiency and hypothyroidism

• If available, consider FE_UricAcid as >12% suggests SIADH (J Clinc Endo 2008;93:2991)

Hypovolemic hypotonic hyponatremia (ie, ↓↓ total body Na, ↓ TBW)

• Renal losses (U_Na >20 mEq/L, FE_Na >1%): diuretics (esp. thiazides, because loop diuretics

↓ tonicity of medullary interstitium, Δ for H₂O absorption, & ∴ urine concentrating ability), salt-wasting nephropathy, cerebral salt wasting, mineralocorticoid deficiency

• Extrarenal losses (U_Na <10 mEq/L, U_Cl <10 mEq/L if alkalemia, FE_Na <1%): hemorrhage, GI loss (diarrhea or vomiting), third-spacing (pancreatitis), ↓ PO intake, insensible losses

Euvolemic hypotonic hyponatremia (ie, ↑ TBW relative to total body Na)

• SIADH (euvolemia or mild hypervolemia, typically inapprop U_osm >100, U_Na >20 mEq/L)

Malignancy: lung (SCLC), brain, GI, GU, lymphoma, leukemia, thymoma, mesothelioma

Pulmonary: pneumonia, TB, aspergillosis, asthma, COPD, PTX, mechanical ventilation

Intracranial: trauma, stroke, SAH, seizure, infxn, hydrocephalus, Guillain-Barré

Drugs: antipsychotics, antidepress. (SSRI, TCA, MAOi), haloperidol, chemo (vincristine, cisplatin), AVP, MDMA, NSAIDs, opiates, amiodarone (Am J Kidney Dis 2008;52:144)

Miscellaneous: pain, nausea, postoperative state

• Endocrinopathies: ↑ ADH activity seen in glucocorticoid deficiency (co-secretion of ADH & CRH) and severe hypothyroidism/myxedema coma (↓ CO/SVR → ADH release & ↓ GFR)

• Psychogenic polydipsia (U_osm <100, ↓ FE_{Uric Acid}): usually intake >15 L/d

• Low solute (↓ U_Na, ↓ U_osm) “tea & toast”; beer potomania

• Reset osmostat: chronic malnutrition (↓ intracellular osmoles) or pregnancy (hormonal

effects) → ADH physiology reset to regulate a lower [Na]_serum

Hypervolemic hypotonic hyponatremia (ie, ↑ total body Na, ↑ ↑ TBW)

• ↓ EAV → ↑ RAAS → ↑ aldosterone & ↑ adrenergic tone → ↑↑ ADH (Am J Med 2013;126:S1)

• CHF (↓ CO & renal venous congestion → ↓ EAV; U_Na <10 mEq/L, FE_Na <1%)

• Cirrhosis (splanchnic arterial vasodilation + ascites → ↓ EAV; U_Na <10 mEq/L, FE_Na <1%)

• Nephrotic syndrome (hypoalbuminemia → edema → ↓ EAV; U_Na <10 mEq/L, FE_Na <1%)

• Advanced renal failure (diminished ability to excrete free H₂O; U_Na >20 mEq/L)

Treatment (NEJM 2015;372:55; JASN 2017;28:1340; CJASN 2018;13:641 & 984)

• Approach: depends on volume status, acuity of hyponatremia, and if symptomatic

Acute sx: initial rapid correction of [Na]_serum (2 mEq/L/h for the first 2–3 h) until sx resolve

Asx or chronic symptomatic: correct [Na]_serum at rate of ≤0.5 mEq/L/h

Rate ↑ Na should not exceed 6 (chronic) to 8 (acute) mEq/L/d to avoid central pontine myelinolysis/osmotic demyelination (CPM/ODS: paraplegia, dysarthria, dysphagia)

If severe (<120) or neuro sx: consider 3% NaCl. dDAVP 1-2 µg q8h in consultation with nephrology (to prevent rapid overcorrection) (AJKD 2013;61:571; CJASN 2018; 13:641)

• Frequent lab draws and IVF rate adjustments are cornerstones of treatment

• Rapid correction: can lead to CPM/ODS (esp if chronic or Na <120 mEq/L). Should be emergently reversed w/ dDAVP ± D₅W; partial neuro recovery possible (CJASN 2014;9:229).

• Effect of IV fluids: complex as depends not only on [Na]_infusate but also UOP and U_osm

Scenario	Formula to estimate new [Na]serum after 1 L infusion
If minimal UOP and none of infused Na excreted
If euvolemic (eg, in SIADH) & all infused Na excreted

In SIADH “fixed” high U_osm. ∴ in SIADH w/ U_osm 616, 1 L NS (154 mEq Na or 308 mOsm solute in 1 L H₂O) will be excreted in 0.5 L H₂O → net gain 0.5 L H₂O. ∴ NS worsens [Na]_serum if U_osm >infusate_osm. In contrast, 1 L 3% NaCl (1026 mOsm) would be excreted in ~1.7 L urine → net loss 0.7 L H₂O. ∴ 3% saline ↑ [Na]_serum.

Effect of 1 L infusion in 70-kg male w/ [Na]serum 110 mEq/L & Uosm 616 mOsm/kg
IVF Type	[Na]content	No UOP	Infused Na excreted
0.9% NaCl	154 mEq/L	+1.0 mEq/L	-1.3 mEq/L
3% NaCl	513 mEq/L	+9.4 mEq/L	+1.8 mEq/L

• Hypovolemic hyponatremia: volume repletion with isotonic 0.9% saline at a slow rate. Once volume replete → stimulus for ADH removed (w/ very short ADH t_½) → kidneys excrete free H₂O → serum Na will correct rapidly (D₅W ± dDAVP if overcorrection)

• SIADH (NEJM 2007;356:2064; AJKD 2020;76:203): fluid restrict + treat underlying cause

hypertonic saline (± loop diuretic; AJKD 2020;76:203) if sx or Na fails to ↑ w/ fluid restriction Intermittent bolus of 3% saline (~2 mL/kg q6h) vs. continuous infusion (~0.5 mL/kg/h) similar (JAMA IM 2021;181:81) when moderate symptoms. Must recheck serum Na frequently during hypertonic use (at least q2h).

NaCl tabs if chronic and no CHF. Consider urea 0.25–0.5 g/kg/d (CJASN 2018;13:1627)

aquaresis: vaptans (vasopressin receptor antag) for refractory SIADH (NEJM 2015;372:23)

• Hypervolemic hyponatremia: free water restrict (1^st line), diurese w/ loop diuretics (avoid thiazides) & ↑ EAV (vasodilators to ↑ CO in CHF, colloid infusion in cirrhosis)

vaptans sometimes used; however, no mortality benefit, hypoNa recurs after stopping drug, high risk of overcorrection, contraindicated in cirrhosis (NEJM 2015;372:2207)

HYPERNATREMIA

Pathophysiology (Crit Care 2013;17:206; NEJM 2015;372:55)

• Deficit of water relative to sodium; by definition, all hypernatremic Pts are hypertonic

• Usually loss of hypotonic fluid (ie, “dehydration”); occasionally infusion of hypertonic fluid, post-ATN diuresis w/ loss of low or electrolyte-free water (Am J Neph 2012;36:97)

• And impaired access to free water (eg, intubation, Δ MS, elderly): hypernatremia is a powerful thirst stimulus, ∴ usually only develops in Pts w/o access to H₂O or ill

Workup

• ✓ U_osm, U_Na, volume status (vital signs, orthostatics, JVP, skin turgor, BUN, Cr)

Extrarenal H₂O loss (U_osm >700–800)

• GI H₂O loss: vomiting, NGT drainage, osmotic diarrhea, fistula, lactulose, malabsorption

• Insensible loss: fever, exercise, ventilation, burns

Renal H₂O loss (U_osm <700–800)

• Diuresis: osmotic (glucose, mannitol, urea), loop diuretics

• Diabetes insipidus (Nature Reviews Nephrology 2015;11:576)

ADH deficiency (central) or resistance (nephrogenic)

Central: hypothalamic or posterior pituitary disease (congenital, trauma/surgery, infiltrative/IgG4); also idiopathic, hypoxic/ischemic encephalopathy (shock, Sheehan’s syndrome), anorexia, sarcoidosis, histiocytosis, drugs: EtOH, phenytoin, snake venom, tumors: craniopharyngioma, germinoma, lymphoma, leukemia, meningioma, pituitary

Nephrogenic (Annals 2006;144:186)

congenital (ADH receptor V2 mutation, aquaporin-2 mutation; Pediatric Clinics 2019;66:227)

drugs: lithium, amphotericin, demeclocycline, foscarnet, cidofovir, ifosfamide

metabolic: hypercalcemia, severe hypokalemia, protein malnutrition, congenital

tubulointerstitial: postobstruction, recovery phase of ATN, PKD, sickle cell, Sjögren’s, amyloid, pregnancy (placental vasopressinase)

DI usually presents as severe polyuria and mild hypernatremia

Other (U_osm >700–800)

• Na overload: hypertonic saline (eg, resuscitation w/ NaHCO₃), mineralocorticoid excess

• Seizures, ↑ exercise: ↑ intracellular osmoles → H₂O shifts → transient ↑ [Na]_serum

Treatment (NEJM 2015;372:55)

• Restore access to H₂O or supply daily requirement of H₂O (≥1 L/d)

• Replace free H₂O deficit (also replace concurrent volume deficit if appropriate):

eg, 1 L D₅W given to 70-kg man w/ [Na] = 160 mEq/L will ↓ [Na]_serum by 3.7 mEq

nb, do not forget to correct Na if hyperglycemia also present

• Rate of correction depends on acuity of onset and risk:

chronic (>48 hr): ~12 mEq/d appears safe w/o risk of cerebral edema (CJASN 2019;14:656)

acute (<48 hr): may ↓ Na by 2 mEq/L/h until Na 145

hyperacute (min-hrs) & life threatening (ICH, seizure): rapidly infuse D₅W ± emergent HD

• Estimate: in 70-kg man, 125 mL/h of free H₂O will ↓ [Na] by ~0.5 mEq/L/h

• ½ NS (77 mEq/L) or ¼ NS (38 mEq/L) provides both volume & free H₂O (500 or 750 mL of free H₂O per L, respectively); can give free H₂O via NGT/OGT

• Formulas provide only estimates; ∴ recheck serum Na frequently

• DI and osmotic diuresis: see “Polyuria” section below

• Na overload: D₅W + diuretic. Consider HD if life threatening (ICH, hypertonia, seizures).

POLYURIA

Definition and pathophysiology

• Polyuria defined as >3 L UOP per day

• Due to an osmotic or a water diuresis; almost always due to osmotic diuresis in inpatients

Workup

• Perform a timed urine collection (6 h sufficient) and measure U_osm

• 24-h osmole excretion rate = 24-h UOP (actual or estimate) × U_osm

>1000 mOsm/d → osmotic diuresis; <800 mOsm/d → water diuresis

Osmotic diuresis

• Etiologies

Hyperglycemia (>180 exceeds PCT reabsorption), mannitol, propylene glycol

Na: NaCl IVF, recovering AKI (eg, post obstruction)

Urea: ↑ protein feeds, hypercatabolism (burns, steroids), GI bleed, resolving azotemia

Water diuresis

• Etiologies: DI (Na_serum >143) or 1° polydipsia (Na_serum <136)

see “Hypernatremia” above for list of causes of central and nephrogenic DI

• Workup of DI: U_osm <300 (complete) or 300–600 (partial)

water deprivation test (rarely used)

hypertonic saline-stimulated plasma copeptin >4.9 pmoL/L indicates 1° polydipsia (97% accuracy vs. 77% for water deprivation; NEJM 2018;379:428)

Treatment

• 1° polydipsia: treat psychiatric illness, check meds, restrict access to free H₂O

• Osmotic diuresis: address underlying cause, replace free H₂O deficit (see “Hypernatremia” for formula to calculate) and ongoing losses

• DI:

Central DI: desmopressin (dDAVP, 1^st line), low Na/protein diet + HCTZ, chlorpropamide

Nephrogenic DI: treat underlying cause if possible; Na restriction + HCTZ (mild volume depletion → ↓ delivery of filtrate for free H₂O absorption), consider amiloride for Li- induced DI (Kid Int 2009;76:44), indomethacin (NEJM 1991;324:850) or trial desmopression

Pregnancy-induced DI: due to vasopressinase from placenta, ∴ Rx w/ dDAVP

POTASSIUM HOMEOSTASIS

Overview (NEJM 2015;373:60)

• Renal: K excretion regulated at distal nephron (CCD) by principal & α-intercalated cells

Distal Na delivery & urine flow: Na absorption → lumen electronegative → K secretion

Metabolic alkalemia and aldosterone: increase Na absorption and K secretion

nb, diurnal urinary K excretion (day >night), ∴ 24-h sample preferred over spot

• Transcellular shifts: most common cause of acute ∆ in serum K (98% intracellular)

Acid-base disturbance: K⁺/H⁺ exchange across cell membranes

Insulin → stimulates Na-K ATPase → hypokalemia (mitigates postprandial ↑ K)

Catecholamines → stimulate Na-K ATPase → hypokalemia; reversed by β-blockers

Massive necrosis (eg, tumor lysis, rhabdo, ischemic bowel) → release of intracellular K

Hypo- or hyperkalemic periodic paralysis: rare disorders due to channel mutations

• Diet: alone rarely causes ↑ or ↓ K (total body store ~3500 mEq, daily intake ~100 mEq)

HYPOKALEMIA

Transcellular shifts (U_K:Cr <13 mEq/g)

• Alkalemia, insulin, catecholamines, β₂-agonists, hypothermia, hypokalemic/thyrotoxic periodic paralysis, acute ↑ hematopoiesis (megaloblastic anemia Rx w/ B₁₂, AML crisis), chloroquine; overdose: Ba/Cs, antipsychotics (risperidone, quetiapine), theophylline

GI potassium losses (U_K:Cr <13 mEq/g)

• GI losses plus metabolic acidosis: diarrhea, laxative abuse, villous adenoma

• Vomiting & NGT drainage usually manifest as renal losses due to 2° hyperaldo & met. alk.

Renal potassium losses (U_K:Cr >13 mEq/g)

• Hypotensive or normotensive

acidosis: DKA, RTA [distal RTAs (type I) >proximal RTAs (type II)]

alkalosis: diuretics (thiazide >loop), vomiting/NGT drainage (via 2° hyperaldosteronism)

Bartter’s syndrome (loop of Henle dysfxn→ furosemide-like effect; JASN 2017;28:2540)

Gitelman’s syndrome (DCT dysfxn→ thiazide-like effect (KI 2017;91:24)

drugs: acetaminophen overdose, PCN, gent., ampho, foscarnet, cisplatin, ifosfamide

↓ Mg: less Mg to inhibit principal cell ROMK channel, ∴ ↑ K secretion (JASN 2010;21:2109)

• Hypertensive: mineralocorticoid excess

1° hyperaldosteronism (eg, Conn’s syndrome, glucocorticoid-remediable aldosteronism)

2° hyperaldosteronism (eg, renovascular disease, renin-secreting tumor)

Nonaldosterone mineralocorticoid (eg, Cushing’s, Liddle’s [↑ ENaC], exogenous, licorice)

Clinical manifestations

• Nausea, vomiting, ileus, weakness, muscle cramps, rhabdomyolysis, ↓ insulin secretion

• Renal: ammoniagenesis, phosphaturia, hypocitraturia, NaCl & HCO₃ retention, polyuria

• ECG: may see U waves, ↑ QT, flat Tw, ST depression, ventricular ectopy (PVCs, VT, VF)

Workup (JAMA 2021;12:1216)

• Identify transcellular shifts & treat. TTKG validity questioned (Curr Op Nephro 2011;20:547).

• ✓ U_K:Cr: >13 mEq/g → renal loss; <13 mEq/g → extrarenal loss (AJKD 2019;74:682)

• If renal losses, ✓ BP, acid-base, U_Cl (U_Na unreliable), U_Ca/Cr, renin, aldosterone, cortisol

Treatment (JAMA 2000;160:2429)

• If true potassium deficit: potassium repletion (↓ 1 mEq/L ≈ 200 mEq total body loss)

Dosage: 40 mEq PO q4h, 10 mEq/h (IV), 20 mEq/h (central line), 40 mEq in 1 L IVF

• Replete K⁺ to >3 or >4 mEq/L if high-risk (HTN, CHF, arrhythmias, MI, digoxin, cirrhosis)

• Beware of excessive potassium repletion if transcellular shift cause of hypokalemia

• Treat underlying cause (if ↓ vol: avoid dextrose as ↑ insulin → intracellular potassium shifts)

• Consider Rx that ↓ K loss: ACEI/ARB, K⁺-sparing diuretics, βB

• Replete Mg if <2 mEq/L: IV Mg-SO₄ 1–2 g q2h and oral Mg-oxide (limited by diarrhea).

Causes of low Mg: GI loss (diarrhea, bypass, pancreatitis, malnutrition, PPI); renal loss (diuretics, nephrotoxic drugs, EtOH, ↑ Ca, 1° wasting syndromes, volume expansion)

HYPERKALEMIA

Transcellular shifts (BMJ 2009;339:1019)

• Acidemia, ↓ insulin (DM), cell lysis (tumor, rhabdo, ischemic bowel, hemolysis, transfusions, resorbing hematomas, hyperthermia, rewarming), hyperkalemic periodic paralysis, ↑ osmolality. Drugs: succinylcholine, aminocaproic acid, digoxin, β-blockers.

Decreased GFR

• Any cause of oliguric or anuric AKI or any cause of end-stage renal disease

Normal GFR but with ↓ renal K excretion

• Normal aldosterone function

↓ EAV (K excretion limited by ↓ distal Na delivery & urine flow): CHF, cirrhosis

Excessive K intake: in conjunction with impairment in K excretion or transcellular shift

Ureterojejunostomy (absorption of urinary K in jejunum)

• Hypoaldosteronism: same as etiologies of hypoaldo RTA (type IV)

↓ renin: DM, NSAIDs, chronic interstitial nephritis, HIV, multiple myeloma, Gordon’s

Normal renin, ↓ aldo synthesis: 1° adrenal disorders, ACEI, ARBs, heparin, ketoconazole

↓ response to aldosterone

Meds: K-sparing diuretics, TMP-SMX, pentamidine, calcineurin inhibitors

Tubulointerstitial disease: sickle cell, SLE, amyloid, diabetes

Clinical manifestations

• Weakness, nausea, paresthesias, palpitations; Renal: ↓ NH₄⁺ secretion → acidosis

• ECG: ST depression, peaked T waves, ↓ QT, ↑ PR interval, ↑ QRS width, loss of P wave, sine wave pattern, PEA/VF (ECG: low sens., cardiac arrest can be first manifestation!)

Workup (Crit Care Med 2008;36:3246)

• Rule out pseudohyperkalemia (IVF w/ K, tourniquet, hemolysis, ↑ plt or WBC), rule out transcellular shift

Treatment of Hyperkalemia
Intervention	Dose	Onset	Comment
Ca gluconate Ca chloridea	1–2 amps IV	<3 min	Transient effect (30–60 min) Stabilizes cell membrane
Insulin	reg insulin 5–10 U IV + 1–2 amps D50W	15–30 min	Peak 30–60 min, lasts 4–6 h ↓ K 0.5–1.2 mEq/L
Bicarbonate (esp. if acidemic)	1–2 amps IV 150 mEq in 1 L D5W	15–30 min	Exchange K for H+ in cells Lasts 5–6 h; ↓ K 0.7 mEq/L
β2 agonists	albuterol 10–20 mg inh. or 0.5 mg IV	30–90 min	Peak 90 min, lasts 2–6 h ↓ K 0.5–1.4 mEq/L (IV >inh)
K-binding resins	SPSb 15–60 g PO/PR patiromer 8.4–25.2 g/d PO Na zirconium 5–10 g PO	4–24 hrs hrs-d hrs	Exchange K for cations in gut (Na, Ca, H); ↓ K 0.8–1 mEq/L/d. Edema & HTN w/ Na zirconium.
Diuretics	furosemide ≥40 mg IV	30 min	↓ total body K
Hemodialysis	Most rapid in 1st hr (1 mEq/L)		↓ total body K (JASN 2017;28:3441)

^aCaCl contains more calcium and is typically reserved for codes (↑ risk of tissue necrosis) or via central line

^b~0.4% intestinal necrosis esp. postop, ileus, SBO/LBO, bowel disease (UC), renal txp (Clin Nephro 2016;85:38)

• Assess GFR, if normal, then ✓U_K, U_Na (<25 mEq/d ↓ distal Na delivery). ✓ U_K:Cr (<13 favors ↓ renal K excretion).

• Rate of onset important to note when establishing a treatment plan (Mayo Clinic 2020;96:744)

• Stabilize (initial): 10% CaCl (central) or gluconate (IV). ↑ memb. potential → ↓ excitability

• Redistribute: insulin + dextrose (continuous if NPO), HCO₃, β₂-agonists

• Eliminate: SPS, patiromer, Na zirconium, diuretics (w/ saline if preserved renal fxn), consider emergent HD in life-threatening situations

• Patient information for diet education: http://www.kidney.org/atoz/content/potassium

KIDNEY DISEASE

ACUTE KIDNEY INJURY (AKI)

Definition (KDIGO 2012;2:1)

• Stages in ICU correspond to ↑ hospital mortality and LOS (Crit Care Med 2009;37:2552)

Stage 1: Cr ≥0.3 mg/dL in 2d or ↑ Cr ≥50%, or UOP <0.5 mL/kg/h for ≥6h

Stage 2: ↑ Cr 2–3x baseline in 7d or UOP <0.5 mL/kg/h for ≥12h

Stage 3: ↑ 3x baseline in 7d, UOP <0.3 mL/kg/h for ≥24h, anuria ≥12h, or Cr >4

• Cannot estimate GFR using Cr in setting of AKI or ∆’ing Cr (requires steady state)

Workup (NEJM 2014;371:55)

• H&P: meds, contrast, or other nephrotoxins; ↓ PO intake, HoTN, infxn/sepsis; trauma, myalgias; BPH/retention. Search for insult 24–48 hr prior ↑ Cr. VS, vol status, rash.

• Urine evaluation: output, urinalysis, sediment, electrolytes, and osmolality

• Fractional excretion Na (FE_Na) = (U_Na/P_Na)/(U_Cr/P_Cr); if diuretic, ✓ FE_UN=(U_UN/P_UN)/(U_Cr/P_Cr)

• Renal U/S or CT: r/o obstruction & cortical atrophy in chronic kidney disease

• Serologies (if indicated): see “Glomerular Disease”

• Renal biopsy (microscopy, IF, and EM): if etiology unclear (esp. if proteinuria/hematuria). Relative contraindic.: SBP>150, ASA/NSAID, anticoag, cirrhosis. DDAVP if GFR <45.

Etiologies and Diagnosis of Acute Kidney Injury (Ann Inter Med 2017;9:66)
Etiologies		UA, Sediment, Indices
Prerenal	↓ Effective arterial volume (NEJM 2007;357:797) Hypovolemia, ↓ CO (CHF), ↓ oncotic pressure (cirrhosis, nephrotic), vasodilation (sepsis) Δ local renal perfusion: NSAIDs, ACEI/ARB, contrast, calcineurin inhib, HRS, hyperCa Large vessel: RAS (bilateral + ACEI), VTE, dissection, abd compart. synd. (renal vs. compress), vasculitis	Bland Transparent hyaline casts FENa <1%, BUN/Cr >20 FEUN ≤35%
Intrinsic	Acute tubular necrosis (ATN) Severe ischemia, sepsis, CIN (↓ RBF + toxin) Toxins Drugs: vanc, AG, cisplatin, foscarnet, HES (starch), IVIG, pentamidine, amphotericin, tenofovir Pigments: Hb, myoglobin (NEJM 2009;361:62) Monoclonal: Ig light chains (Blood 2010;116:1397) Crystals: UA, ACV, MTX, indinavir, oral NaPO4	Pigmented granular muddy brown casts ± RBCs & protein from tubular damage FENa >2%, BUN/Cr <20 (except pigment, CIN) FEUN >50%
	Acute interstitial nephritis (AIN) Allergic: β-lactams, sulfa drugs, NSAIDs, PPIs Infection: pyelo, viral, legionella, TB, leptospirosis Infiltrative: sarcoid, lymphoma, leukemia Autoimmune: Sjögren’s, TINU, IgG4, SLE, ICIs	WBCs, WBC casts, ± RBCs w/ neg UCx ⊕ urine eos in abx ⊕ lymphs in NSAIDs
	Small-med vessel: chol emboli, PAN, TMAs (TTP, HUS, atypical HUS, DIC, preeclampsia, APS, malignant HTN, scleroderma renal crisis)	± RBCs ⊕ urine eos in chol emboli
	Glomerulonephritis (see “Glomerular Disease”)	Dysmorphic RBCs, RBC casts
Post	Bladder neck: BPH, prostate cancer, neurogenic bladder, anticholinergic meds Ureteral (bilateral or unilateral in single kidney): malig, LAN, retroperitoneal fibrosis, nephrolithiasis	Bland ± non-dysmorphic RBCs, WBC, crystals

General treatment (CJASN 2008;3:962)

• Prerenal: isotonic IVF ≈ alb (NEJM 2004;350:22). No clear benefit of balanced crystalloids (eg, LR) over normal saline (NEJM 2018;378:829 & 2022;386:815).

• Avoid nephrotoxic insults (meds and contrast); renally dose medications

• Optimize hemodynamics (both MAP & CO) and maintain euvolemia (NEJM 2007;357:797)

• No benefit to dopamine (Annals 2005;142:510), diuretics (JAMA 2002;288:2547), or mannitol

Managing complications

• May take 1–3 wk to recover from ATN; anticipate volume overload, ↑ K, ↑ PO₄, acidosis

• Episodes of AKI ↑ risk of CKD progression, even after recovery (NEJM 2014;371:58)

• Indications for urgent dialysis (when condition refractory to conventional therapy)

Acid-base disturbance: refractory acidemia

Electrolyte disorder: hyperK; hyperCa, hyperPO₄, tumor lysis syndrome

Intoxications (http://www.extrip-workgroup.org/): Poison Control (1-800-222-1222)

Indicated for: methanol, ethylene glycol, metformin, Li, valproic acid, salicylates, barbiturates, theophylline, thallium

Consider for: carbamazepine, APAP, dig (Rx Digibind), dabigatran (Rx idarucizumab)

Overload: refractory hypervolemia → hypoxemia (eg, CHF)

Uremia: pericarditis, encephalopathy, bleeding

• In stage 3 AKI, wait until above indication or oliguria >72 hrs (NEJM 2016;375:122; Lancet 2020;395:1506). If oliguria >72 hrs, further delaying until urgent indication ↑ mortality (Lancet 2021;397:1293).

DISEASE-SPECIFIC MANAGEMENT

Acute interstitial nephritis (AIN) (CJASN 2017;12:2046 & JASN 2020;31:435)

• Commonly drug-induced: β-lactams, sulfa drugs, NSAIDs, PPIs, quinolones, allopurinol

• If suspected, prompt removal of offending drug; ? early steroids w/in 7d of dx

• Rechallenging after suspected ICI-induced AIN may depend on oncology natural history

Cardiorenal syndrome (CRS) (CJASN 2017;12:1624)

• Multifactorial pathophys including: 1) ↓ CO, 2) ↑ renal venous congestion, 3) ↑ RAAS

• Bidirectionality: acute CHF → AKI, and oliguric AKI can worsen CHF (JACC 2008;52:1527)

• Rx: IV loop diuretics (bypass gut edema; dosing below); no diff. between high vs. low dose and bolus vs. gtt (NEJM 2011;364:797). No clinical benefit: dopa, nesiritide, ultrafilt.

• Prognosis: 7% ↑ mortality a/w each 10 mL/min ↓ eGFR in ADHF (JACC 2006;47:1987)

Contrast-induced acute kidney injury (CIAKI) (NEJM 2019;380:2146)

• Risk factors: CKD, DM, CHF, age, hypotension, ↑ contrast volume (JACC 2004;44:1393)

• AKI 24–48 h post contrast, peaks 3–5 d, resolves 7–10 d (consider chol emboli if does not)

• Prevention: consider if eGFR <60 (espec. w/ proteinuria), DM, MI, HoTN (CJASN 2013;8:1618)

Isotonic IV fluids: may be helpful if high risk (Lancet 2017;389:1312)

Outpatients: 3 mL/kg/h × 1 h prior, 1–1.5 mL/kg/h × 6 h after (JAMA 2004;291:2328)

Inpatients: 1 mL/kg/h × 6–12 h pre, intra, post-procedure (Lancet 2014;383:1814)

Hold ACEI/ARB (AJKD 2012;60:576), NSAIDs, diuretics. Min. contrast & use iso-osmolar.

• Nephrogenic systemic fibrosis: fibrosis of skin, joints, internal organs ~2–4 wk post gado exposure in CKD 4–5 (JACC 2009;53:1621). Postgado HD encouraged, though limited data.

Hepatorenal syndrome (HRS; see “Cirrhosis”; AJKD 2013;62:1198)

• Albumin + either IV vasopressors (norepi, terlipressin) or octreotide & midodrine

Obstructive diseases

• Dx: renal U/S if undifferentiated or CT abd/pelvic (I^–) if suspect nephrolithiasis

• Rx: Foley if urethra vs. perc. nephrostomy if above ureters (eg, stones), tamsulosin/finasteride

• Watch for post-obstructive diuresis after relieving blockage, replace ½ UOP w/ ½ NS.

Hemorrhagic cystitis (rapid ∆ in size of bladder vessels); avoid by decompressing slowly.

Polycystic kidney disease (NEJM 2008;359:1477; 2017;377:1988)

• Mostly AD PKD1/PKD2 mutations → renal cysts. PKD1 (85%) younger-onset ESRD.

• Rx: hydration, low-salt diet; tolvaptan reduces GFR decline. Family genetic screening.

Rhabdomyolysis (NEJM 2009;361:62)

• Pathophys: myoglobin-induced oxidant injury, vasoconstriction, myoglobin precipitation & pre-renal (extravasation). Can lead to ↓ Ca, ↑ K, and ↑ PO₄.

• Diagnosis: UA ⊕ for heme but 0 RBCs (ie, myoglobinuria)

• Risk of AKI when CK >20,000. Rhabdo and mortality risk score: JAMA Int Med 2013;173:1821.

• Aggressive IVF (tailor IVF to target UOP ~3 mL/kg). If urine pH <6.5, consider NaHCO₃ ✓ K & Ca frequently, trend CK. Monitor for compartment syndrome.

Scleroderma renal crisis (Nature Neph 2016;12:678)

• 5–20% diffuse cutaneous SSc w/ narrowing glomerular vessels. Sx: renal failure, severe HTN, encephalopathy. Rx: max ACEi for BP control.

COVID-19 associated AKI (Am J Physiol Renal Physiol 2021;4:403)

• 17% of inPts. ATN >collapsing FSGS (high-risk APOL1 genotype). ↑ clotting risk w/ RRT

Thrombotic microangiopathies (TMAs): see “Hematology”

CHRONIC KIDNEY DISEASE (CKD)

Definition and etiologies (Lancet 2021;10302:786)

• GFR <60 for ≥3 mo and/or kidney damage (albuminuria, structural abnormality)

• Prevalence 15% in U.S.

• Albuminuria predicts all-cause & CV mortality, CKD progression (NEJM 2004;351:1296)

• Cr poor estimate of GFR, use equation (https://www.kidney.org/professionals/kdoqi/gfr_calculator)

Cystatin-C–based formula less influenced by race than Cr-based (NEJM 2021;385:1737)

• Etiologies: DM (45%), HTN/RAS (27%), glomerular (10%), interstitial (5%), PKD (2%), congenital, drugs, myeloma, repeated insults (eg, Mesoamerican nephropathy)

• Progression to ESRD: kidney failure risk equation (JAMA 2016;315:164; kidneyfailurerisk.com)

Stages of CKD (Kid Int 2013;3[Suppl]:5)
GFR Stage	GFR mL/min/1.73 m2	Goals
1 (nl or ↑ GFR)	>90	Dx/Rx of underlying condition & comorbidities, slow progression; cardiovascular risk reduction
2 (mild)	60–89	Estimate progression
3a (mild-mod)	45–59	Evaluate and treat complications
3b (mod-severe)	30–44	Evaluate and treat complications
4 (severe)	15–29	Prepare for renal replacement therapy (RRT)
5 (kidney failure)	<15 or dialysis	Dialysis if uremic/volume overload; Tx
Albuminuria stage based on albuminuria (mg/d) or spot urine alb (mg) to Cr (g) ratio Stages: A1 = <30 (normal/mild); A2 = 30–300 (moderate); A3 = >300 (severe)

Signs and Symptoms of Uremia (NEJM 2018;379:669)
General	Nausea, anorexia, malaise, uremic fetor, metallic taste, hypothermia
Skin	Uremic frost (white crystals in & on skin), pruritus, calciphylaxis
Neurologic	Encephalopathy (Δ MS, ↓ memory & attention), seizures, neuropathy, impaired sleep, restless leg syndrome
Cardiovascular	Pericarditis, atherosclerosis, HTN, CHF, cardiomyopathy (LVH)
Hematologic	Anemia, bleeding (due to platelet dysfunction and Epo deficiency)
Metabolic	↑ K, ↑ PO4, acidosis, ↓ Ca, 2° hyperparathyroidism, osteodystrophy

Complications & treatment (JAMA 2019;322:1294; KI 2021;99:S1)

• General: renal referral when GFR <30 or proteinuria, access planning (avoid subclavian lines, preserve an arm by avoiding phlebotomy, BP measurements, IVs)

• CV risk reduction: consider usual preventive Rx including statin, βB, etc.

• Dietary restrictions: Na (if HTN), K (if oliguric or hyperkalemic), PO₄, mod protein.

• Diabetes: strict glc control; ACEI/ARB, SGLT2i and MRA (NEJM 2020;383:2219) slow CKD progression (↓ glomerular pressure)

• SGLT2i: in proteinuric CKD (min eGFR 25-30) w/ or w/o DM, transient ↓ in eGFR (<5) but then 30-40% ↓ risk of CKD progression & ↓ mortality (NEJM 2019;380:2295 & 2020;383:1436)

• BP control: goal ideally <120/80, a/w ↓ mortality. ACEI or ARB, not both. For outPts, ✓ Cr & K in 1–2 wk, d/c if Cr ↑ 30% or K >5.4 (after dietary Δ & loop diuretic).

• Metabolic acidosis: sodium bicarbonate or sodium citrate if low HCO₃ (JASN 2015;26:515)

• Hyperkalemia: 2-g K diet, see “Potassium Homeostasis”

• Anemia: goal Hb 10–11.5 g/dL, worse outcomes if target higher (NEJM 2009;361:2019)

epoetin (start 80–120 U/kg SC, divided 3×/wk) or darbepoetin (0.75 mg/kg q 2 wk)

iron supplementation to keep transferrin sat >20% (often given IV in HD Pts).

HIF inhib. ↑ endogenous EPO production, not yet approved (NEJM 2021;385:2313 & 2325).

• Uremic bleeding: desmopressin (dDAVP) 0.3 μg/kg IV or 3 μg/kg intranasally

• 2° hyperPTH: ↑ PO₄, ↑ FGF-23, ↓ calcitriol, & ↓ Ca → ↑ PTH → renal osteodystrophy

CKD stage	3	4	5
Target PTH (pg/mL)	35–70	70–110	150–600

Phosphorus binders (take with meals!) (NEJM 2010;362:1312). Non-Ca–based binders (eg, sevelamer) a/w ↓ mort. compared to Ca-based (Lancet 2013;382:1268).

If PTH above goal then start vit. D (if 25-(OH)D <30) or 1,25-(OH)D analogue (calcitriol); stop if ↑ Ca (AJKD 2009;53:408)

Cinacalcet (parathyroid Ca-sensing receptor agonist) if ↑ PTH despite phosphorus binders ± vit. D analogue (CJASN 2016;11:161); consider parathyroidectomy

• Calciphylaxis (calcific uremic arteriopathy, NEJM 2018;378:1704)

Pathophys: calcification of media in dermal small- to med-sized blood vessels & SC fat → ischemia and skin necrosis w/ painful lesions (NEJM 2007;356:1049)

Risk factors: ESRD, ♀>♂, DM, vit K def, obesity, warfarin, local trauma, thrombophilias

Dx: skin bx, but limitations (Kidney Int 2018;94:390); bone scan used in support of dx

Rx: ↓ risk factors, wound care/surgical debridement, manage hyperPTH, d/c vit D, Ca, & warfarin (DOAC okay). Pain control, palliative care, ? Na thiosulfate.

Prognosis: 60% 1-y mortality in ESRD Pts (AJKD 2015;66:133)

• Anticoag: ESRD at ↑ bleed risk; if using DOAC, consider apixiban >rivaroxaban >dabigatran due to protein binding/renal clearance (JASN 2017;28:2241)

• Transplant evaluation

DIURESIS

General considerations

• ↑ Na & H₂O excretion for treatment of HTN or edema in CHF, renal failure, and cirrhosis

• Daily wt most effective method of documenting successful diuresis

Loop diuretics (NEJM 2017;377:1964)

• Drugs: furosemide (Lasix), torsemide, bumetanide (Bumex), ethacrynic acid

• Mech: inhib NaK2Cl cotransporter in thick ascending limb (ThAL, site of 25% Na reabsorp) → ↓ medullary osmotic gradient & ↓ free H₂O reabsorption via ADH

Transient venodilation may aid in pulmonary congestion (NEJM 1973;288:1087)

Response is fxn of amt of drug excreted; ∴ ↑ dose needed in renal insufficiency, CHF

Sigmoidal dose response curve; ∴ ↑ dose until induce diuresis, ↑↑ dose beyond that point yields diminishing returns compared with ↑ frequency of dosing

• Dosing: bioavailability PO furosemide ~50%, PO torsemide & bumetanide ~90%

40 mg IV = 80 mg PO Lasix = 20 mg PO/IV torsemide = 1 mg IV/PO bumetanide

Dose furosemide bid-qid; qd dosing can yield initial diuresis, but then anti-natriuresis. Cont. vs. bolus IV similar in acute CHF (NEJM 2011;364:797). Ethacrynic acid if sulfa allergy.

? ↑ diuresis w/ co-administration of albumin if ↓ serum albumin (Crit Care Med 2005;33:1681)

• Adverse effects: ↑ Na, ↓ K, ↓ Mg, ↓ Ca, hyperuricemia, ototoxicity, hypersensitivity (sulfa)

Thiazide diuretics (JASN 2017;28:3414)

• Drugs: hydrochlorothiazide (HCTZ), chlorothiazide (Diuril), metolazone (Zaroxolyn)

• Mech: inhib Na-Cl cotransporter in the distal convoluted tubule (DCT); 5% Na reabsorp

synergistic with loop diuretic, esp. if chronic loop use

↓ effect when GFR <30, except metolazone, which is still effective in renal insufficiency

• Dosing: give 30 min prior to loop diuretic

• Adverse effects: ↓ Na, ↓ K, ↓ Mg, ↑ Ca, HLD, pancreatitis, ↑ glc, hypersensitivity

K-sparing diuretics (NEJM 2017;377:1964)

• Drugs: spironolactone (Aldactone), amiloride, triamterene, eplerenone

• Mech: ↓ Na reabsorption (~1%) in collecting duct (amiloride/triamterene inhibit principal cell Na channel [ENaC]; spironolactone/eplerenone inhibit mineralocorticoid receptor).

Relatively weak natriuretic activity, useful in combination with thiazide or in cirrhosis.

• Adverse effects: ↑ K (esp. w/ ACEI), metabolic acidosis, gynecomastia (spironolactone)

Approach to Diuresis (if inadequate diuresis, go to next step)
Step	Action
1	Loop diuretic PO: ✓ response at 1–3 h, redose at 2× prior dose if needed
2	Add thiazide diuretic PO (potentiates response to loop diuretic)
3	Loop diuretic IV: bolus bid–qid ± thiazide (may start here if inPt) ↑ dose w/ ↑ Cr; initial effective IV Lasix dose ≈ 30 × Cr (ie, if Cr = 4 → 120 mg IV)
4	Loop diuretic infusion: bolus + continuous IV infusion ± thiazide (PO or IV)
5	RRT: consider ultrafiltration, CRRT, or HD

Disease state specific regimens

• Renal insufficiency: loop diuretic (↑ dose to achieve effective delivery to ThAL) ± thiazide

• CHF: loop diuretic (↑ frequency over ↑ dose), IV for gut edema + thiazide (watch K & Mg)

• Nephrotic syndrome: urinary albumin binds secreted loop diuretic, use 2–3× normal dose

• Cirrhosis: spironolactone (blocks 2° hyperaldosteronism) + Lasix in 2.5:1 ratio

• Severe metabolic alkalosis: acetazolamide & treat underlying cause

RENAL REPLACEMENT AND DIALYSIS

General

• Acute indications: see “AKI”; choices CVVH vs. HD

• Chronic indications: timing of RRT initiation should factor in Pt QoL, uremic sx, risk of development of urgent/acute indications; modalities PD vs. HD (no clear diff in outcomes)

• Outcomes of ESRD: death from CVD (50%), infxn (30%), withdrawal of care (20%)

Modalities
	HD	CVVH	PD
Physiology	Diffusion	Convection	Diffusion
Access	AV fistula/graft or CVC	CVC	Peritoneal catheter
Prescription	Duration, volume goal; K, Na, Ca, HCO3 in bath, anticoag	Volume goal, K & Ca in replacement fluid (HCO3 vs. citrate)	PD fluid (dextrose, icodextrin), dwell time, # cycles
Complic.	HoTN, arrhythmia, disequilibrium syndrome* if very high BUN, ↑ CO HF	HoTN, ↓ PO4, ↓ iCa (citrate toxicity in hepatic dysfxn)	Peritonitis, ↑ glc, ↓ albumin, R pleural effusion

^*Disequilibrium syndrome: sx cerebral edema due to H₂O shifts after urea removal

Hemodialysis (HD) (NEJM 2010;363:1833)

• Solute removal across semipermeable membrane, countercurrent blood & dialysate flow

Volume removal: Na/H₂O ultrafiltered via transmembrane pressure (TMP) gradient

Solutes: Cr, urea, K diffuse from blood → dialysate, HCO₃ from dialysate → blood

Solute removal inversely proportional to size ∴ effective removal of K, urea, Cr, not PO₄

• 6× vs. 3×/wk improved HTN, LV mass, QoL, but ↑ vasc issues (NEJM 2010;363:2287); w/ 3×/wk HD, ↑ mortality risk during 2-d interval (Sa–Tu or Fri–Mo) (NEJM 2011;365:1099)

• Fever w/ catheter: empiric abx (vanc + GNR coverage qHD). GPC >GNR >mixed/fungal. Remove/replace catheter (depends on organism), “lock” abx (JASN 2014;25:2927).

• Central vein stenosis: assoc. with longer HD duration, tunneled catheters. HeRO grafts bypass subclavian stenosis with flow into central vein (J Vasc Access 2016;17:138).

Vascular Access
	Advantages	Disadvantages
AV fistula	Highest patency Lowest risk of bacteremia Lowest mortality (JASN 2013;24:465)	Long maturation time (2–6 mo) Primary nonfunction (20%)
AV graft	Easier to create than AVF Maturation time (2–3 wk)	Poor 1° patency, often requiring thrombectomy or angioplasty
Catheter	Immediate use Use as bridge to AVF/AVG	Highest risk of bacteremia ↓ blood flow → ↓ HD efficiency

Continuous veno-venous hemofiltration (CVVH) (NEJM 2012;367:26)

• Hemofiltration rather than dialysis. Blood under pressure passes down one side highly permeable membrane filtering H₂O and solutes via TMP gradient (convective clearance); filtrate discarded. Replacement fluid infused (solute concentration similar to plasma, except no urea, Cr, PO₄). Fluid balance by adjusting filtrate/replacement fluid.

• Replacement fluid rate determines clearance. Choice of replacement fluid buffer:

HCO₃ (+ heparin to prevent clotting, although can be run heparin-free)

citrate: hepatically metabolized to HCO₃, ∴ cannot be given in cirrhosis/liver failure. Provides anticoag w/in machine via Ca chelation. Citrate toxicity: ↓ iCa but nl/ ↑ serum Ca and AG met acidosis.

Dose adjust for solute and volume removal (AJKD 2016;68:645)

• Other CRRT modalities: CVVHD (dialysis), CVVHDF (filtration & dialysis) (AJKD 2016;68:645)

• Benefits compared w/ HD: ↓ gross fluid shift (preferred in HoTN), but slower clearance of solutes and toxins

Peritoneal dialysis (PD) (JAMA 2017;317:1864)

• Fluid removed via convection using oncotic pressure (eg, dextrose). ↑ concentrations and dwell times removes more fluid (less as glc equilibrates).

• PD fluid: dextrose (1.5%, 2.5%, or 4.25%), buffer (lactate), Na⁺, Ca²⁺, Mg²⁺

• Infuse 10 min, dwell 90 min–5.5 h, drain 20 min; exchanges done manually or using cycler at night (automated or cont. ambulatory peritoneal dialysis APD, CAPD)

• PD peritonitis: abd pain & cloudy drainage (WBC >100 & >50% PMNs). 60–70% GPC, 15–20% GNR. Rx: abx IV or in PD, catheter removal for certain org (yeast, Pseudomonas).

• Sclerosing peritonitis, a rare long-term complication (NEJM 2002; 347:737)

• Hyperglycemia: exacerbated by inflammation, long dwell times, and higher [glucose]

• Benefits: lower cost, independence, preservation of residual kidney function. No Δ mortality vs. HD (AJKD 2018;71:344).

Kidney transplantation (Med Clin N Am 2016;100:435)

• Refer when GFR <20. Contraindic: active malig, infxn, ischemia, noncompl, subst use

• 5-yr survival: living donor 91%; deceased donor 70–84% (AJKD 2016;23:281). Donors have minor ↑ risk of ESRD (Am J Transplant 2014;14:2434).

• Immunosuppression: calcineurin inhib (tacrolimus>CsA) or CTLA4 inhib (belatacept) (NEJM 2016;374:333), antimetabolite (MMF>AZA), prednisone, mTOR inhib (sirolimus) if others contraindicated

• Rejection: Ab (ABMR) or T-cell mediated (TCMR), a/w poor graft survival; BANFF criteria (Am J Transplant 2018;18:293). Rx options: ↑ immunosupp., pulse steroids, IVIG, rituximab.

• Late renal dysfxn: usual AKI causes + calcineurin tox, rejection (NEJM 2010;363:1451), BK virus, recurrence of 1° disease; usual w/u + immunosupp levels, donor-specific antigen (DSA), BK virus load, U/S, then bx if no other cause (CJASN 2008;3:S56; CJASN 2011;6:1774)

• ↑ infxn (incl opportunistic such as CMV, JC, BK viruses; CJASN 2012;7:2058) & cancer (PTLD)

• ↑ CVD risk due to HTN (calcineurin inhib, RAS), DM & dyslipidemia (immunosupp meds)

GLOMERULAR DISEASE

GLOMERULONEPHRITIS (GN)

Definition (Lancet 2016;387:2036; JASN 2016;27:1278)

• ↑ glomerular inflammation → endothelial & podocyte injury

• Histology: proliferative (↑ cells), sclerosing (scar), necrotizing (areas cell death). Focal (<50% of glomeruli) to diffuse to crescentic. Segmental (<50% tuft) to global (100%).

• Clinically: hematuria w/ dysmorphic RBCs or RBC casts, ± subnephrotic proteinuria often w/ AKI, HTN, edema

• Progression: acute ≈ days; rapidly progressive (RPGN) ~6 wk; chronic ≈ mos; can be asx

^aPredominant type; can see either type (NEJM 2012;367:214); ^bGPA (Wegener’s); EGPA (Churg-Strauss)

Anti-GBM Disease (linear staining) <15% of total (CJASN 2017;12:1162)
Disease	Glomerulonephritis	Pulm Hemorrhage	Anti-GBM
Goodpasture’s	⊕	⊕	⊕
Anti-GBM disease	⊕	—	⊕

Immune Complex (IC) Disease (granular staining) ~40–45% of total (CJASN 2018;13:128)
Renal-Limited Diseases	Systemic Diseases
Infection-Related GN (Staph & Strep; ↓ C3, ± ASLO)	SLE (CJASN 2017;12:825) (⊕ ANA, ⊕ anti-dsDNA, ⊕ anti-Sm, ↓ C3, ↓ C4)
Membranoproliferative GN (MPGN) (↓ C3)	Cryoglobulinemia (⊕ cryocrit, ⊕ RF, ⊕ HCV, SPEP, ↓ C3, ↓ C4)
Fibrillary and immunotactoid GN (normal C3/C4)	Endocarditis (fever, ⊕ BCx, valvular disease, ↓ C3)
IgA nephropathy (normal C3, ±↑ IgA) (NEJM 2013;368:2402; CJASN 2017;12:677)	Henoch-Schönlein purpura (IgA nephropathy + syst. vasculitis w/ IgA deposits, nl C3, ±↑ IgA)

Oncology-related glomerulopathy (CJASN 2016;11:1681)

• Associations between malig (solid tumors & heme) and/or their Rx (HSCT & chemo- therapeutics) and GN, nephrotic syndrome, and thrombotic microangiopathies (TMA)

• Most common associations: membranous (solid tumors, HSCT), MCD (Hodgkin’s, solid tumors), MPGN (CLL, MM), TMA (HSCT, VEGF, anti-EGFR, CNIs, TKIs, mTOR)

• Monoclonal glomerulopathy of renal significance: Ig-mediated kidney disease by nonmalignant B or plasma cells. Workup: SPEP, sFLC, flow cytometry, IFE, BMBx.

Workup (JAMA 2017;318:1276)

• Acute GN/RPGN ± lung hemorrhage is an emergency → requires early Dx and Rx

• UA + sediment (dysmorphic RBCs) ✓ ANCA, anti-GBM, C3/C4, SPEP, serum FLC

• Depending on hx: ANA, anti-dsDNA/Sm, RF, Hep B&C, HIV, ASLO, BCx, cryocrit, skin bx

• Consider GN mimics: thrombotic microangiopathies (qv), myeloma, AIN, cholesterol emboli

• Renal biopsy with immunofluorescence (IF) + electron microscopy (EM)

Treatment (AJKD 2020;75:124 & 2020;76:265)

• If acute GN/RPGN suspected, give 500–1000 mg methylpred. IV qd × 3d ASAP while awaiting bx results.

• SLE nephritis: induction w/ steroids + cyclophosphamide (CYC) or MMF (CJASN 2017;12:825)

• ANCA ⊕ or anti-GBM: pulse steroids + CYC (or rituximab). Plasma exchange if ⊕ anti-GBM. Controversial in ANCA ⊕ only, even w/ GN or pulm hemor. (NEJM 2020;382:622).

• See “Vasculitis” for further disease-specific Rx details (eg, eculizumab for atypical HUS)

ASYMPTOMATIC GLOMERULAR HEMATURIA

Definition and etiologies

• Hematuria ± proteinuria of glomerular origin w/o renal insufficiency or systemic disease (nonglomerular more common; see “Hematuria”)

• Ddx: any cause of GN (esp. IgA); also consider Alport’s (X-linked, deafness, renal failure), thin basement membrane nephropathy (autosomal dominant, benign; JASN 2013;23:364)

IgA nephropathy (CJASN 2017;12:677; AJKD 2021;78:429)

• Most common cause of GN; ♂ pred; peak incidence 20–30s; can also be post-infectious

• Wide range of clinical presentations: asx hematuria (30–40%), gross hematuria ~1–3 d after URI (10–15%), chronic GN (10%), nephrotic syndrome (5%), RPGN (<5%)

• Though clinical presentation can be highly suggestive, definitive dx only w/ bx

• Prognosis: ↑Cr, HTN, proteinuria a/w poor prog. (AJKD 2012;59:865). 20–40% ESRD w/in 20 y.

• Rx: ACEI/ARB; if persistent proteinuria (> 1g/d), clinical trial enrollment or shared decision for steroids, consider SGLT2i (NEJM 2020;383:1436); ± cytotoxic Rx for GN; ? fish oil

NEPHROTIC SYNDROME

Definition (JASN 2014;25:2393)

• Podocyte injury (effacement) → loss of proteins (albumin, ATIII, Ig)

• Clinically: proteinuria >3.5 g/d, albumin <3 g/dL, edema, ↑ chol., VTE (25%), infection

Primary glomerular diseases (grouped by pathology)

• Focal segmental glomerulosclerosis (40%; CJASN 2017;12:502). Primary: permeability factor. Secondary: adaptive (hyperfiltration, sickle cell, obesity, anabolic steroids, OSA, ↑ protein, vesico-ureteral reflux); meds/toxins (IFN, bisphosphonates, NSAIDs, heroin), viral (COVID-19, HIV) or genetic (ApoL1 mutation in AA; JASN 2015;26:1443).

• Membranous nephropathy (30%; CJASN 2017;12:938, JASN 2021;32:268): Primary: Ab to PLA2R [70%], THSD7A [5%], other (EXT1-2, NELL1, Sema3B). Secondary: infxn (HBV, HCV, HIV, syphilis); autoimmune (eg, SLE); carcinomas; drugs (NSAIDs, penicillamine).

• Minimal change disease (20%, more common in children; CJASN 2017;12:332) allergies, NSAIDs, ampicillin, Hodgkin’s disease, SLE, DM, MG, celiac disease

• Membranoproliferative GN (5%, mixed nephrotic/nephritic features; CJASN 2014;9:600)

Immune complex mediated: infection (esp. HCV ± cryos, IE, HBV, “shunt” nephritis, other chronic infxns), SLE, cryos, Sjögren’s, lymphomas, dysproteinemia, idiopathic

Complement mediated (rare); dense deposit disease (DDD), C3GN

• Fibrillary-immunotactoid glomerulopathy (1%; JASN 2008;19:34)

• Mesangial proliferative GN (? atypical forms of MCD/FSGS, 5%) IgM, C1q nephropathy

Systemic diseases with secondary glomerular involvement

• Diabetes mellitus (CJASN 2017;12:2032): nodular glomerulosclerosis (Kimmelstiel-Wilson lesion); glomerular hyperfiltration → microalbuminuria → dipstick ⊕ → nephrotic range (10–15 y). Proliferative retinopathy seen in 90% of type 1 and 60% of type 2.

• Amyloidosis: AL or light-chain amyloid or AA amyloid secondary to inflammation

• SLE (CJASN 2017;12:825): typically membranous nephropathy (WHO class V)

• Cryoglobulinemia (AJKD 2016;67): a/w HCV, monoclonal gammopathy. Typically MPGN.

Workup (BMJ 2008;336:1185)

• U/A + sediment: usually benign; ± oval fat bodies (“Maltese crosses”; NEJM 2007;357:806)

• Measure proteinuria: 24-h urine or spot urine protein/Cr ratio (not accurate in AKI), renal bx

• 2° causes: ↑ Hb_A1C + retinop. → DM; ✓ ANA, anti-dsDNA, tox screen, C3/C4, SPEP/light chains, fat pad bx, cryocrit, HBV/HCV, HIV, RPR, APLA2R Ab, age-approp. CA screen

Treatment (NEJM 2013;368:10)

• General: protein suppl.; diuretics for edema; treat hyperlipidemia, Na restriction (<2 g/d)

• ACEI or ARB: ↓ proteinuria → slow nonimmunologic progression of renal disease

• 1° glomerular: steroids ± rituximab or cytotoxic therapy (CJASN 2014;9:1386; NEJM 2019;381:36)

• Secondary causes: treat underlying disease

• Watch for malnutrition (protein loss), consider anticoag if albumin <2.5 in membranous (KI 2014;85:1412), infection (esp. encapsulated organisms b/c loss of Ig)

URINALYSIS

Urine Dipstick
Metric	Significance and Uses
Specific gravity	Estimate Uosm: each 0.001 above 1 ≈ 30 osm (SG 1.010 → Uosm ≈ 300) SG and Uosm useful in evaluating AKI, dysnatremias, polyuria Heavy substances (glucose, contrast) ↑ SG more than Uosm
pH	Range: 4.5–8.5; useful in evaluation of stones, RTAs, infection (urease UTI)
Protein	Detects albuminuria (>300 mg/d); see “Proteinuria.” False ⊖: dilute urine
Blood	See “Hematuria”; ⊕ from RBCs, free Hgb, or free myoglobin (eg, rhabdo) False ⊕: semen, dilute urine (→ osmotic cell lysis), ↑ pH, vaginal blood False ⊖: vit C
WBC	Suggests inflammation (UTI, interstitial nephritis, GN)
Ketones	Detects acetoacetate (ie, ketoacidosis) but not β-hydroxybutyrate
Leuk est	Lysed PMNs. Se 80% for UTI. FN: proteinuria, glycosuria FP: ↓ pH or SG
Nitrite	Suggests presence of nitrate reductase ⊕ bacteria (most enteric GNRs)
Bilirubin	↑ in biliary or hepatic disease
Glucose	⊕ in hyperglycemia (>180 mg/dL), pregnancy, Fanconi’s syndrome, SGLT2i

Urine Sediment (microscopic examination) (Am J Kidney Dis 2008;51:1052)
Method: Centrifuge fresh sample (prox. port if Foley) × 3–5 min at 1500–3000 rpm; pour off supernatant in one motion; resuspend pellet by agitating base of tube; pour suspension onto slide w/ coverslip; view under “high dry” power; phase contrast for RBC morphology
Cells	RBCs: assess amount & morphology (many dysmorphic → glomerular) WBCs: PMNs (UTI) vs. eosinophils (AIN; may require special stain) Epithelial cells: tubular (ATN), transitional (bladder or ureters), squamous
Casts (see urinalysis photo inserts in appendix)	Proteins molded in lumen of renal tubule ± entrapped cellular elements RBC → GN WBC → AIN, pyelonephritis, GN Granular (“muddy brown”): degenerating cellular casts → ATN Tubular cell → ATN Hyaline: Tamm-Horsfall protein (nonspecific) Waxy and broad → advanced chronic kidney disease
Crystals (see urinalysis photo inserts in appendix)	Calcium oxalate monohydrate: spindle, oval, or dumbbell shaped Calcium oxalate dihydrate: envelope shaped or octahedral Uric acid: variable shape; polychromatic under polarized light Cystine: hexagon shaped Struvite: coffin-lid shaped; seen in chronic UTI with urea-splitting organisms Drugs: sulfa, protease inhibitors: “shocks of wheat”; acyclovir: fine needles

PROTEINURIA

Etiologies of Proteinuria
Category	Description	Etiologies
Glomerular (can be >3.5 g/d)	Disruption of filtration barrier → lose albumin	Glomerulonephritis Nephrotic syndrome
Tubulointerstitial (usually <1–2 g/d)	↓ reabsorption of freely filtered proteins → lose globulins	ATN; AIN Fanconi’s syndrome
Overflow	↑ production of freely filtered proteins	Multiple myeloma Myoglobinuria
Isolated	By def’n: asx, normal renal fxn, sed, & imaging, no h/o renal disease	Functional (fever, exercise, CHF) Orthostatic (only when upright) Idiopathic (transient or persistent)

• Urine dipstick

1+ ≈30 mg/dL, 2+ ≈100 mg/dL, 3+ ≈300 mg/dL, 4+ >2 g/dL; interpretation depends on SG; eg, 3+ in very concentrated urine might not indicate heavy proteinuria

Insensitive for microalbuminuria and myeloma light chains (Bence-Jones protein)

• Spot urine: protein (mg/dL)/creatinine (mg/dL) ≈ g/d of proteinuria (NEJM 1983;309:1543) unlike urine dipstick, will accurately measure myeloma light chains

reliable surrogate for 24-hr urine, esp. 1^st morning void (JASN 2009;20:436); inaccurate if AKI depends on Cr production, ∴ underestimates if muscular, overestimates if cachectic

• Moderate albuminuria (30–300 mg/d or mg/L or mg/g Cr): early sign of glomerular vascular disease; marker for ↑ risk of CV adverse outcomes (KI 2013;3:19)

• Orthostatic proteinuria: typically in adolescents; ~90% of young ♂ with isolated proteinuria have orthostatic proteinuria; typically resolves spontaneously

HEMATURIA

Etiologies of Hematuria
Extrarenal (far more common)	Intrarenal
Nephrolithiasis Neoplasm: transitional cell, prostate Infxn: cystitis, urethritis, prostatitis Foley trauma BPH Schistosoma haematobium	Nephrolithiasis or crystalluria Neoplasm Trauma/exercise Vascular: renal infarcts, renal v. thromb., sickle cell Glomerular: IgA, thin BM, others PKD (NEJM 2008;359:1477)

• Wide, overlapping ages for various etiologies, but general guide for common causes:

<20 y: GN, UTI, congenital; 20–60 y: UTI, nephrolithiasis, cancer

>60 y ♂: prostatitis, cancer, UTI; >60 y ♀: UTI, cancer

Workup (NEJM 2021;385:153)

• Urine dipstick: ⊕ if ≥3 RBCs; ⊕ dipstick and ⊖ sediment → myo- or hemoglobinuria

• Urine sediment: dysmorphic RBCs or RBC casts → GN → consider renal bx

• If suggestive sx, r/o UTI or nephrolithiasis

• Low cancer risk: repeat U/A in 4–6 wks; if still ⊕ → cystoscopy + imaging

• Intermediate risk (eg, ♂ 40–59 yrs or ♀ 50–59 yrs or 10–30 pack-yrs): cystoscopy + U/S

• High risk (eg, age ≥60 or >30 pack-yrs): CT urography (Se 96%, Sp 98%) + cystoscopy

• Rx: if obstruction: bladder irrigation and 3-way Foley on CBI

NEPHROLITHIASIS

Types of stones and risk factors (Nat Rev Dis Prim 2016;2:16008)

• Calcium (Ca oxalate >Ca phosphate): 70–90% of kidney stones (NEJM 2010;363:954)

Urine findings: ↑ Ca, ↑ oxalate (Ca-ox only), ↑ pH (Ca-phos only), ↓ citrate, ↓ volume

2° hypercalciuria: 1° hyperparathyroidism, distal RTA, sarcoid, Li use

2° hyperoxaluria: Crohn’s, ileal disease w/ intact colon, gastric bypass, pancreatic insuffic.

Diet: ↑ animal protein, ↑ sucrose, ↑ Na, ↓ K, ↓ fluid, ↓ fruits/vegetables, ↑ vit. C, ↓ Ca

• Uric acid: 5–10% of kidney stones, radiolucent on plain film

Urine findings: ↑ uric acid, ↓ pH (eg, from chronic diarrhea)

• Magnesium ammonium phosphate (“struvite” or “triple phosphate”)

Chronic upper UTI w/ urea-splitting organisms (eg, Proteus, Klebs) → ↑ urine NH₃, pH >7

• Cystine: inherited defects of tubular amino acid reabsorption

Clinical manifestations

• Hematuria (absence does not exclude diagnosis), flank pain, N/V, dysuria, frequency

• Ureteral obstruction (stones >5 mm unlikely to pass spont.) → AKI if solitary kidney

• UTI: ↑ risk of infection proximal to stone; urinalysis of distal urine may be normal

Workup

• Non-contrast CT 97% Se, 96% Sp (ureteral dilation w/o stone suggests recent passage); U/S (Se 57%, Sp 98%) may serve as initial test in stable patient (NEJM 2014;371:1100)

• Strain urine for stone to analyze; U/A & UCx; electrolytes, BUN/Cr, Ca, PO₄, PTH

• 24-h urine × 2 (>6 wk after acute setting) for Ca, PO₄, oxalate, citrate, Na, Cr, pH, K, vol.

Acute treatment (JAMA 2020;323:1961)

• Analgesia (narcotics ± NSAIDs; combination superior, Ann Emerg Med 2006;48:173), ensure adequate fluid repletion, antibiotics if UTI

• α-blocker >CCB to pass stone if ≤10 mm (Cochrane; 2014:CD008509, Lancet 2006;368:1171)

• Indications for immediate urologic eval and/or hosp: obstruction (esp. solitary or transplant kidney), urosepsis, intractable pain or vomiting, significant AKI

• Urologic Rx: lithotripsy (NEJM 2012:367:50), ureteroscopic removal, lap/perc nephrolithotomy

Chronic treatment (CJASN 2016;11:1305 & 2017;12:1699)

• Increase fluid intake (>2 L/d) for goal UOP 2 L/d (J Nephrol 2016;29:211)

• Calcium stones: 24-h urine identifies specific urinary risk factors to treat

Diet: ↓ Na and meat (NEJM 2002;346:77), ↓ oxalate foods & sucrose/fructose

Meds: thiazides (↓ urine Ca), K-citrate if low urine citrate, allopurinol if high urine uric acid

Avoid low dietary Ca as ↑ oxalate absorp (NEJM 2002;346:77), unclear role of Ca suppl.

• Uric acid: fluid intake, urine alkalinization (K-citrate) to pH 6.5–7, allopurinol

• Magnesium ammonium phosphate (struvite): antibiotics for UTI; urologic intervention; acetohydroxamic acid; urease inhibitor reserved for experienced clinician, poorly tolerated

• Cystine: fluid, urine alkaliniz (K-citrate) to 7–8, d-penicillamine, tiopronin (KI 2006;69:1041)