Medical Specialty

Nephrology

Every renal diagnosis, electrolyte disorder, acid-base disturbance, dialysis modality, transplant protocol, glomerular disease, classification system, and management strategy in one place.

01 Renal Anatomy & Physiology

The kidneys are paired retroperitoneal organs located at the T12–L3 vertebral levels, each weighing approximately 120–170 g in adults and measuring 10–12 cm in length. They receive ~20–25% of cardiac output (~1,000–1,200 mL/min) despite constituting only 0.5% of body weight, making them the most highly perfused organs per gram of tissue. The kidneys regulate fluid and electrolyte balance, acid-base homeostasis, blood pressure (via the renin-angiotensin-aldosterone system), erythropoiesis (EPO production), and vitamin D activation (1,25-dihydroxyvitamin D).

Gross Anatomy

Each kidney is surrounded by a fibrous renal capsule, perinephric fat, and Gerota's fascia. The parenchyma consists of an outer cortex (containing glomeruli, proximal and distal convoluted tubules) and an inner medulla (containing loops of Henle and collecting ducts arranged in 8–18 renal pyramids). The pyramids drain into minor calyces → major calyces → renal pelvis → ureter. The renal hilum transmits the renal artery, renal vein, ureter, lymphatics, and nerves. The left renal vein is longer and crosses anterior to the aorta (relevant for nutcracker syndrome and as a surgical landmark).

Cross-section of the human kidney showing cortex, medulla, renal pyramids, calyces, renal pelvis, and ureter — **Figure 1 — Kidney Cross-Section.** Cross-sectional view showing the cortex, medulla with renal pyramids, calyces, renal pelvis, and ureter. The cortex contains glomeruli while the medulla contains loops of Henle and collecting ducts. Source: Wikimedia Commons. Public domain.

The Nephron

Each kidney contains approximately 1 million nephrons — the functional unit of the kidney. Each nephron consists of a glomerulus (capillary tuft within Bowman's capsule), proximal convoluted tubule (PCT), loop of Henle (thin descending limb, thin ascending limb, thick ascending limb), distal convoluted tubule (DCT), and collecting duct. Cortical nephrons (~85%) have short loops; juxtamedullary nephrons (~15%) have long loops that penetrate deep into the medulla, critical for the countercurrent concentrating mechanism.

Detailed diagram of a nephron showing glomerulus, proximal tubule, loop of Henle, distal tubule, and collecting duct — **Figure 2 — The Nephron.** Detailed anatomy of the nephron showing the glomerulus, proximal convoluted tubule, loop of Henle (descending and ascending limbs), distal convoluted tubule, and collecting duct. Each segment has distinct transport functions. Source: Wikimedia Commons. Public domain.

Nephron Segment Functions

Segment	Key Functions	Transporters	Drugs Acting Here
Proximal tubule	Reabsorbs ~65% Na+, HCO3−, glucose, amino acids, phosphate, uric acid; secretes organic acids/bases	Na+/H+ exchanger (NHE3), SGLT2, Na-phosphate cotransporter	SGLT2 inhibitors, carbonic anhydrase inhibitors (acetazolamide)
Thin descending limb	Permeable to water, impermeable to solute → concentrates tubular fluid	Aquaporin-1	—
Thick ascending limb (TAL)	Reabsorbs ~25% Na+, K+, Cl−; impermeable to water ("diluting segment"); generates medullary gradient	Na-K-2Cl cotransporter (NKCC2)	Loop diuretics (furosemide, bumetanide)
Distal convoluted tubule	Reabsorbs ~5% NaCl; Ca2+ reabsorption (PTH-sensitive)	Na-Cl cotransporter (NCC)	Thiazide diuretics
Collecting duct (principal cells)	Na+ reabsorption, K+ secretion (aldosterone-mediated); water reabsorption (ADH-mediated)	ENaC (epithelial Na channel), ROMK, Aquaporin-2	K-sparing diuretics (amiloride, spironolactone)
Collecting duct (intercalated cells)	Type A: H+ secretion, HCO3− reabsorption; Type B: HCO3− secretion, H+ reabsorption	H+-ATPase, H+/K+-ATPase, pendrin	—

Glomerular Filtration

The glomerular filtration barrier consists of three layers: fenestrated endothelium, glomerular basement membrane (GBM), and podocyte foot processes with slit diaphragms. Normal GFR is ~120 mL/min/1.73 m² in young adults. The GBM carries a negative charge that repels albumin (anionic); loss of this charge barrier (e.g., in minimal change disease) leads to proteinuria. Starling forces govern filtration: GFR = K_f × [(P_GC − P_BS) − (π_GC − π_BS)], where P_GC = glomerular capillary hydrostatic pressure (~60 mmHg), P_BS = Bowman's space hydrostatic pressure (~15 mmHg), and π_GC = glomerular capillary oncotic pressure (~28 mmHg).

Key renal formulas: GFR ≈ U_Cr × V / P_Cr (creatinine clearance); CKD-EPI equation (preferred for eGFR); FENa = (U_Na × P_Cr) / (P_Na × U_Cr) × 100; Cockcroft-Gault: CrCl = [(140 − age) × weight] / (72 × S_Cr) (× 0.85 if female).

Renal Blood Flow & Autoregulation

Blood enters via the renal artery → segmental → interlobar → arcuate → interlobular arteries → afferent arteriole → glomerular capillaries → efferent arteriole → peritubular capillaries (cortex) or vasa recta (medulla). The kidney autoregulates RBF and GFR over MAP 80–180 mmHg via two mechanisms: myogenic reflex (afferent arteriolar constriction in response to stretch) and tubuloglomerular feedback (macula densa senses NaCl delivery; increased delivery causes afferent constriction via adenosine). ACE inhibitors/ARBs dilate the efferent arteriole, reducing intraglomerular pressure — this is renoprotective long-term but can acutely reduce GFR (especially in bilateral renal artery stenosis).

A >30% rise in creatinine after starting an ACEi/ARB should raise suspicion for bilateral renal artery stenosis or a solitary kidney with unilateral stenosis. A modest rise of up to 30% is expected and acceptable — do NOT stop the medication.

Countercurrent Mechanism

The countercurrent multiplier (loop of Henle) creates the medullary osmotic gradient (300 mOsm at the corticomedullary junction up to 1,200 mOsm at the papillary tip). The thick ascending limb actively transports NaCl without water, diluting tubular fluid and concentrating the interstitium. The countercurrent exchanger (vasa recta) maintains the gradient by passively exchanging solutes and water in a hairpin arrangement. ADH (vasopressin) inserts aquaporin-2 channels into the collecting duct, allowing water to be reabsorbed along the medullary gradient, producing concentrated urine (up to 1,200 mOsm/kg). Without ADH, dilute urine (<100 mOsm/kg) is excreted.

02 The Renal Physical Exam & Assessment

Volume Status Assessment

Finding	Hypovolemia	Euvolemia	Hypervolemia
JVP	Flat (<5 cm H₂O)	5–8 cm H₂O	Elevated (>8 cm H₂O)
Mucous membranes	Dry	Moist	Moist
Skin turgor	Decreased (tenting)	Normal	Normal or taut
Orthostatics	Positive (SBP drop ≥20 or HR rise ≥20)	Negative	Negative
Edema	Absent	Absent	Peripheral, sacral, pulmonary
Urine output	Oliguria (<400 mL/day)	Normal (800–2000 mL/day)	Variable
BUN/Cr ratio	>20:1	10–20:1	Variable

Edema Grading

Grade	Depth	Rebound Time	Location
1+	2 mm	Immediate	Feet/ankles
2+	4 mm	15 seconds	Below knee
3+	6 mm	30 seconds	Above knee
4+	8+ mm	>30 seconds	Anasarca (generalized)

Urinalysis Interpretation

Parameter	Normal	Abnormal Significance
Color	Pale to dark yellow	Red/brown: hematuria or myoglobin; cola-colored: glomerulonephritis
Specific gravity	1.005–1.030	<1.005: dilute (DI, water excess); >1.030: concentrated (dehydration); fixed at 1.010: tubular damage
pH	4.5–8.0	Persistently alkaline: UTI (urease organisms), RTA type 1
Protein	Negative to trace	Detects albumin primarily; false positive with concentrated/alkaline urine
Blood	Negative	Positive without RBCs on microscopy: myoglobinuria or hemoglobinuria
Glucose	Negative	Positive: DM (glucose >180 mg/dL), Fanconi syndrome, SGLT2 inhibitors
Leukocyte esterase	Negative	Suggests pyuria/UTI
Nitrites	Negative	Positive: gram-negative bacteria (Enterobacteriaceae)

Urine Electrolytes & Fractional Excretion

Test	Prerenal	Intrinsic Renal (ATN)	Interpretation
FENa	<1%	>2%	Most useful in oliguric AKI; unreliable with diuretics
FEUrea	<35%	>50%	Preferred when patient is on diuretics
Urine Na	<20 mEq/L	>40 mEq/L	Low = avid Na retention (prerenal)
Urine osmolality	>500 mOsm/kg	<350 mOsm/kg	High = concentrating ability intact (prerenal)
BUN/Cr ratio	>20:1	10–15:1	Elevated in prerenal, GI bleed, steroids

FENa is unreliable in patients on diuretics — always calculate FEUrea instead. FENa can also be <1% in contrast nephropathy, myoglobinuria, and early obstructive uropathy despite intrinsic injury.

Urine Microscopy — Key Casts

Cast Type	Appearance	Associated Condition
Hyaline	Transparent, low refractive index	Normal (concentrated urine, dehydration); nonspecific
Granular ("muddy brown")	Coarse or fine granules, dark	Acute tubular necrosis (ATN)
RBC casts	Red/orange, intact RBCs in cast matrix	Glomerulonephritis (pathognomonic)
WBC casts	White cells within cast	Pyelonephritis, acute interstitial nephritis
Waxy	Broad, waxy, sharply defined edges	Advanced CKD, severe stasis
Fatty (Maltese cross)	Fat globules, birefringent under polarized light	Nephrotic syndrome

03 Key Terminology & Abbreviations

Nephrology employs a dense vocabulary of abbreviations spanning renal physiology, dialysis, transplant, and electrolyte disorders. Mastery of these terms is essential for interpreting renal panels, urinalyses, biopsy reports, and dialysis prescriptions.

Abbreviation	Meaning
GFR / eGFR	Glomerular filtration rate / estimated GFR
CrCl	Creatinine clearance
BUN	Blood urea nitrogen
AKI / CKD / ESRD	Acute kidney injury / chronic kidney disease / end-stage renal disease
ATN / AIN	Acute tubular necrosis / acute interstitial nephritis
FENa / FEUrea	Fractional excretion of sodium / urea
UACR / UPCR	Urine albumin-to-creatinine ratio / urine protein-to-creatinine ratio
RRT / KRT	Renal replacement therapy / kidney replacement therapy
HD / PD / CRRT	Hemodialysis / peritoneal dialysis / continuous renal replacement therapy
AVF / AVG / CVC	Arteriovenous fistula / arteriovenous graft / central venous catheter
Kt/V	Dialysis adequacy measure (K=clearance, t=time, V=volume of distribution)
KDIGO	Kidney Disease: Improving Global Outcomes
RAAS	Renin-angiotensin-aldosterone system
ACEi / ARB	ACE inhibitor / angiotensin receptor blocker
MRA	Mineralocorticoid receptor antagonist
EPO / ESA	Erythropoietin / erythropoiesis-stimulating agent
CKD-MBD	CKD-mineral and bone disorder
PTH / iPTH	Parathyroid hormone / intact PTH
FSGS / MCD / MN	Focal segmental glomerulosclerosis / minimal change disease / membranous nephropathy
RPGN	Rapidly progressive glomerulonephritis
ANCA / GBM	Anti-neutrophil cytoplasmic antibody / glomerular basement membrane
GPA / MPA / EGPA	Granulomatosis with polyangiitis / microscopic polyangiitis / eosinophilic GPA
TTP / HUS / aHUS	Thrombotic thrombocytopenic purpura / hemolytic uremic syndrome / atypical HUS
ADPKD	Autosomal dominant polycystic kidney disease
RTA	Renal tubular acidosis
SIADH / DI	Syndrome of inappropriate ADH / diabetes insipidus
ADH (AVP)	Antidiuretic hormone (arginine vasopressin)

04 AKI: Classification & Etiologies Critical

Acute kidney injury (AKI) is defined as an abrupt decline in kidney function over hours to days. It is classified by the KDIGO criteria based on serum creatinine rise and/or urine output decline. AKI occurs in ~10–15% of hospitalized patients and up to 50% of ICU patients, and is independently associated with increased mortality, length of stay, and progression to CKD.

KDIGO AKI Staging

Stage	Serum Creatinine	Urine Output
1	Rise ≥0.3 mg/dL within 48 h OR 1.5–1.9× baseline within 7 days	<0.5 mL/kg/h for 6–12 h
2	2.0–2.9× baseline	<0.5 mL/kg/h for ≥12 h
3	≥3.0× baseline OR ≥4.0 mg/dL OR initiation of RRT	<0.3 mL/kg/h for ≥24 h OR anuria for ≥12 h

AKI Etiologies

Category	Mechanism	Common Causes	Diagnostic Clues
Prerenal (~55–60%)	Decreased renal perfusion with intact tubular function	Hypovolemia (hemorrhage, dehydration, GI losses), heart failure (cardiorenal), sepsis (early), hepatorenal syndrome, NSAIDs, ACEi/ARB	FENa <1%, UOsm >500, BUN/Cr >20:1, bland sediment
Intrinsic (~35–40%)	Direct parenchymal damage to tubules, glomeruli, interstitium, or vessels	ATN (ischemic or nephrotoxic), AIN (drug-induced), glomerulonephritis, TMA, atheroembolic disease	FENa >2%, muddy brown casts (ATN), RBC casts (GN), WBC casts (AIN), eosinophiluria (AIN)
Postrenal (~5%)	Urinary tract obstruction	BPH, bilateral ureteral stones, pelvic malignancy, neurogenic bladder, retroperitoneal fibrosis	Hydronephrosis on US, high post-void residual, rapid improvement with decompression

Hepatorenal Syndrome

Type 1 (HRS-AKI): Rapid decline in GFR (Cr doubling to >2.5 mg/dL in <2 weeks) in advanced cirrhosis. Pathophysiology: splanchnic vasodilation → decreased effective circulating volume → intense renal vasoconstriction. Diagnostic criteria: cirrhosis + ascites, AKI without improvement after 48 h of volume expansion with albumin (1 g/kg/day, max 100 g/day) and withdrawal of diuretics, no nephrotoxins, no parenchymal disease. Treatment: midodrine + octreotide + albumin (or norepinephrine in ICU); terlipressin (approved outside US); definitive treatment is liver transplantation. Median survival without treatment: 2 weeks.

Always obtain a renal ultrasound in new AKI to rule out obstruction — it is the single most important first imaging study. Postrenal AKI is the most rapidly reversible cause and should never be missed.

05 Acute Tubular Necrosis

ATN is the most common cause of intrinsic AKI, accounting for ~85% of intrinsic renal failure. It results from ischemic or nephrotoxic injury to tubular epithelial cells, particularly in the S3 segment of the proximal tubule and the medullary thick ascending limb — areas with high metabolic demand and borderline oxygen supply.

ATN Classification

Type	Mechanism	Common Causes
Ischemic ATN	Prolonged renal hypoperfusion exceeding autoregulatory capacity	Shock (septic, cardiogenic, hemorrhagic), major surgery (especially cardiac with CPB), aortic cross-clamping
Nephrotoxic ATN	Direct tubular cell toxicity	Aminoglycosides, cisplatin, amphotericin B, radiocontrast, vancomycin, tenofovir, IV immunoglobulin (sucrose-based)

Phases of ATN

Phase	Duration	Features
Initiation	Hours to days	Insult occurs; rising creatinine, declining urine output
Extension	1–2 days	Ongoing ischemia and inflammation; apoptosis and necrosis
Maintenance	1–2 weeks	Established AKI; oliguric or nonoliguric; complications (hyperkalemia, acidosis, volume overload)
Recovery	Days to weeks	Tubular regeneration; polyuric phase (may lose large volumes of water and electrolytes); gradual GFR improvement

Non-oliguric ATN (typically from nephrotoxins like aminoglycosides) has a better prognosis than oliguric ATN. During the polyuric recovery phase, watch for hypokalemia and volume depletion — replace losses aggressively.

Management

Treatment is primarily supportive: optimize volume status, discontinue nephrotoxins, avoid further hemodynamic insults, manage complications (hyperkalemia, acidosis, fluid overload). There is no proven pharmacologic therapy to accelerate recovery. Initiate RRT for refractory hyperkalemia, severe metabolic acidosis, volume overload unresponsive to diuretics, or uremic complications (encephalopathy, pericarditis, bleeding).

06 Acute Interstitial Nephritis

AIN is a hypersensitivity-mediated inflammation of the renal interstitium, most commonly drug-induced (~70–75% of cases). It accounts for 15–20% of all AKI. The classic triad of fever, rash, and eosinophilia is present in only ~10–15% of cases (more common with methicillin, now rarely used).

Etiologies

Category	Common Agents / Causes
Antibiotics	Penicillins (classic), cephalosporins, sulfonamides (TMP-SMX), fluoroquinolones, rifampin
NSAIDs	All NSAIDs (onset may be delayed weeks to months; often with nephrotic-range proteinuria)
PPIs	Omeprazole, pantoprazole (increasingly recognized; may have insidious onset)
Other drugs	Allopurinol, phenytoin, checkpoint inhibitors (nivolumab, pembrolizumab)
Infections	Pyelonephritis, Legionella, CMV, EBV, Mycobacterium tuberculosis
Autoimmune	Sarcoidosis, SLE, Sjögren syndrome, IgG4-related disease, TINU syndrome

Diagnosis & Management

Urinalysis: sterile pyuria, WBC casts, eosinophiluria (detected by Hansel stain; sensitivity only ~60–70%). Mild proteinuria is typical; nephrotic-range proteinuria suggests NSAID-associated AIN with concurrent MCD. Renal biopsy is the gold standard: interstitial edema and inflammatory infiltrate (lymphocytes, eosinophils, monocytes) with tubulitis. Treatment: withdraw offending agent (most important step). If no improvement in 5–7 days, consider prednisone 1 mg/kg/day for 2–4 weeks with taper. Earlier steroid initiation (within 7 days of diagnosis) is associated with better renal recovery.

07 Contrast-Induced & Pigment Nephropathy

Contrast-Induced Nephropathy (CIN)

CIN is defined as a rise in serum creatinine ≥0.5 mg/dL or ≥25% above baseline within 48–72 hours of contrast administration. Mechanism: renal vasoconstriction + direct tubular toxicity + oxidative stress. Risk factors: CKD (eGFR <30 highest risk), diabetes, volume depletion, heart failure, large contrast volumes, concurrent nephrotoxins.

Prevention Strategy	Evidence
IV isotonic saline (1–1.5 mL/kg/h for 6–12 h pre and post)	Strong evidence; cornerstone of prevention
Use low-osmolar or iso-osmolar contrast; minimize volume	Contrast volume / eGFR ratio <3.7 associated with lower risk
Hold metformin (restart 48 h post if renal function stable)	Prevents lactic acidosis if AKI develops; does not prevent CIN itself
NAC (N-acetylcysteine)	PRESERVE trial showed no benefit; not recommended
Withhold NSAIDs, diuretics if possible	Reduces additive nephrotoxic/hemodynamic insult

Pigment Nephropathy

Rhabdomyolysis: skeletal muscle breakdown releases myoglobin, which causes AKI via direct tubular toxicity, intratubular cast formation, and renal vasoconstriction. Labs: CK >5,000 U/L (often >10,000), hyperkalemia, hyperphosphatemia, hypocalcemia (early), hyperuricemia, elevated LDH. Urine dipstick positive for blood but no RBCs on microscopy (myoglobin cross-reacts). Treatment: aggressive IV NS (200–300 mL/h targeting UOP 200–300 mL/h); bicarbonate infusion is controversial (may alkalinize urine to prevent myoglobin cast formation, but no RCT evidence of benefit). Monitor for compartment syndrome.

Crush Syndrome

In rhabdomyolysis, the most life-threatening early complication is hyperkalemia from massive intracellular K+ release. Check K+ immediately and prepare for emergency management. Calcium should be given cautiously — it may deposit in damaged muscle, worsening injury. The early hypocalcemia typically self-corrects; avoid aggressive calcium replacement unless symptomatic or severe hyperkalemia requires it.

08 CKD Staging & Progression

CKD is defined as abnormalities of kidney structure or function present for >3 months, with implications for health. The most common causes in the US are diabetes mellitus (~45%) and hypertension (~28%). KDIGO classifies CKD by both GFR category and albuminuria category to determine risk and management.

KDIGO GFR Categories

Stage	GFR (mL/min/1.73 m²)	Description
G1	≥90	Normal or high (kidney damage with normal GFR)
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 (ESRD)

KDIGO Albuminuria Categories

Category	UACR (mg/g)	Description
A1	<30	Normal to mildly increased
A2	30–300	Moderately increased (formerly "microalbuminuria")
A3	>300	Severely increased (formerly "macroalbuminuria")

The combination of GFR category and albuminuria category determines the "heat map" of risk for CKD progression and cardiovascular events. A patient with G2A3 (GFR 75 but UACR 500) is at higher risk than G3aA1 (GFR 55 but UACR 15) — albuminuria is a powerful independent predictor.

Slowing CKD Progression

Intervention	Target / Details	Evidence
ACEi or ARB	Titrate to max tolerated dose; accept up to 30% Cr rise	RENAAL, IDNT, REIN trials
SGLT2 inhibitor	Dapagliflozin 10 mg or empagliflozin 10 mg daily; initiate if eGFR ≥20	DAPA-CKD, EMPA-KIDNEY, CREDENCE
Finerenone (nsMRA)	10–20 mg daily (requires K+ <5.0, eGFR ≥25)	FIDELIO-DKD, FIGARO-DKD
Blood pressure control	<130/80 mmHg (SPRINT); <120 systolic may confer additional benefit	SPRINT, ACCORD-BP
Glycemic control (DKD)	HbA1c <7%; avoid hypoglycemia in advanced CKD	DCCT, UKPDS, ADVANCE
Dietary protein restriction	0.8 g/kg/day for CKD 3–5 (not on dialysis)	MDRD study (modest benefit)
Avoid nephrotoxins	NSAIDs, aminoglycosides, excess contrast	Universal recommendation

09 CKD Complications Management

Anemia of CKD

Normocytic normochromic anemia develops primarily from decreased erythropoietin (EPO) production, typically when eGFR <30–45. Iron deficiency is common (reduced absorption, chronic blood loss from uremia-related platelet dysfunction, dialysis losses). Workup: CBC, reticulocytes, iron studies (TSAT and ferritin).

Parameter	Target in CKD	Treatment
Iron stores	TSAT >20% and ferritin >100 ng/mL (non-dialysis); ferritin >200 (HD)	IV iron (ferric carboxymaltose, iron sucrose) preferred in HD patients; oral iron for CKD ND
Hemoglobin	10–11.5 g/dL (do NOT target normalization)	ESAs: epoetin alfa 50–100 U/kg SC 3×/week or darbepoetin alfa 0.45 mcg/kg SC q2weeks
ESA response	Hb rise 1–2 g/dL over 4 weeks	ESA hyporesponsiveness: check iron stores, infection, inflammation, B12/folate, secondary hyperPTH

ESA Safety Warning

Targeting Hb >13 g/dL with ESAs increases risk of stroke, cardiovascular events, and death (CHOIR, CREATE, TREAT trials). Always replete iron first before initiating ESAs. HIF-PHIs (e.g., roxadustat, daprodustat) are newer oral alternatives that stimulate endogenous EPO production.

CKD-Mineral Bone Disorder (CKD-MBD)

The pathophysiology begins with phosphate retention in CKD → stimulates FGF23 → decreased 1,25(OH)₂D production → hypocalcemia → secondary hyperparathyroidism → bone disease (osteitis fibrosa cystica from high-turnover). Over time, vascular calcification occurs.

Abnormality	Target	Treatment
Hyperphosphatemia	Phosphorus 3.5–5.5 mg/dL (CKD 3–5); keep within normal range	Dietary restriction (<800 mg/day); phosphate binders: sevelamer, lanthanum (non-calcium); calcium acetate (limit if Ca elevated)
Hypocalcemia	Correct albumin-adjusted calcium; avoid aggressive supplementation	Calcitriol (0.25–0.5 mcg/day) or paricalcitol if PTH elevated
Secondary hyperPTH	PTH 2–9× upper limit of normal for CKD G5D	Calcitriol, active vitamin D analogs (paricalcitol, doxercalciferol), cinacalcet (calcimimetic 30–180 mg daily)
Vitamin D deficiency	25(OH)D >30 ng/mL	Ergocalciferol or cholecalciferol supplementation

Metabolic Acidosis in CKD

Impaired ammoniagenesis and reduced HCO3− regeneration lead to non-anion-gap metabolic acidosis in CKD (typically serum HCO3− 12–20 mEq/L). Acidosis accelerates muscle catabolism, bone demineralization, and CKD progression. Treatment: oral sodium bicarbonate 650–1300 mg TID (target serum HCO3− ≥22 mEq/L). Monitor for volume overload from sodium load.

Hyperkalemia in CKD

Reduced renal K+ excretion, metabolic acidosis, and medications (ACEi/ARB, spironolactone) predispose to hyperkalemia. Chronic management: dietary K+ restriction (<2 g/day), loop diuretics (enhance K+ excretion), potassium binders (patiromer 8.4 g daily or sodium zirconium cyclosilicate (SZC) 10 g TID × 48 h then 5–10 g daily). These newer binders allow continued RAAS inhibitor use.

10 Diabetic Kidney Disease

Diabetic kidney disease (DKD) is the leading cause of ESRD in the US (~45% of new dialysis initiations). It develops in ~30–40% of patients with type 1 or type 2 diabetes. Natural history: glomerular hyperfiltration → microalbuminuria (UACR 30–300) → overt proteinuria (>300) → declining GFR → ESRD (typically over 10–20 years in type 1 DM, often faster in type 2).

Pathology

Key histologic findings: mesangial expansion (earliest), GBM thickening, Kimmelstiel-Wilson nodules (nodular glomerulosclerosis, pathognomonic but not always present), and diffuse glomerulosclerosis. Afferent and efferent arteriolar hyalinosis is characteristic (afferent alone is seen in hypertension).

Management of DKD

Intervention	Dosing / Target	Key Evidence
ACEi or ARB (first-line)	Titrate to max tolerated dose	RENAAL (losartan), IDNT (irbesartan) — 16–20% reduction in renal endpoints
SGLT2 inhibitor	Empagliflozin 10 mg, dapagliflozin 10 mg, canagliflozin 100 mg daily	CREDENCE: 30% reduction in renal composite; DAPA-CKD: 39% reduction; EMPA-KIDNEY: 28% reduction
Finerenone (nsMRA)	10–20 mg daily (add to ACEi/ARB + SGLT2i)	FIDELIO-DKD: 18% reduction in kidney composite; FIGARO-DKD: 13% reduction in CV composite
GLP-1 receptor agonist	Semaglutide, liraglutide	FLOW trial (semaglutide): 24% reduction in kidney events
Blood pressure	<130/80 mmHg	UKPDS, ACCORD-BP
Glycemic control	HbA1c <7% (individualize; <8% in advanced CKD/elderly)	DCCT, UKPDS, ADVANCE

The current standard of care for DKD is "four pillars": ACEi/ARB + SGLT2 inhibitor + finerenone + GLP-1 RA. SGLT2 inhibitors reduce intraglomerular pressure by restoring tubuloglomerular feedback (constricting the afferent arteriole). Expect an initial eGFR dip of 3–5 mL/min, which is hemodynamic and reversible — do NOT discontinue.

11 Hypertensive Nephrosclerosis

Hypertensive nephrosclerosis is the second leading cause of ESRD in the US. Two forms exist: benign nephrosclerosis (chronic, slowly progressive) and malignant nephrosclerosis (accelerated hypertension with rapid GFR decline).

Benign Nephrosclerosis

Chronic hypertension causes arteriolar hyalinosis and intimal fibrosis of small renal vessels → ischemic injury to glomeruli and tubulointerstitium → global glomerulosclerosis. Clinical features: slowly progressive CKD, mild proteinuria (usually <1 g/day), small kidneys on imaging (bilateral), bland urine sediment. More common and more aggressive in African Americans (APOL1 risk variants).

Malignant Hypertension / Hypertensive Emergency

BP typically >180/120 mmHg with end-organ damage: AKI (fibrinoid necrosis of arterioles, "onion-skinning"), microangiopathic hemolytic anemia (schistocytes), retinopathy (flame hemorrhages, papilledema), encephalopathy. Treatment: IV antihypertensives (nicardipine, nitroprusside, labetalol); reduce MAP by no more than 25% in first hour, then gradually to 160/100 over 24 h.

APOL1 and Kidney Disease

Variants in the APOL1 gene (G1 and G2 alleles) are carried by ~13% of African Americans and confer a 7–10× increased risk of hypertensive nephrosclerosis, FSGS, and HIV-associated nephropathy. These variants evolved as protection against Trypanosoma brucei (sleeping sickness). APOL1-mediated kidney disease tends to be more aggressive with faster progression to ESRD.

12 Nephrotic Syndrome

Nephrotic syndrome is defined by: proteinuria >3.5 g/day (or UPCR >3,500 mg/g), hypoalbuminemia (<3.0 g/dL), peripheral edema, hyperlipidemia, and lipiduria (fatty casts, oval fat bodies, Maltese crosses). Complications include venous thromboembolism (loss of antithrombin III, protein C, protein S), infections (loss of immunoglobulins), and accelerated atherosclerosis.

Major Causes of Nephrotic Syndrome

Disease	Epidemiology	Pathology	Key Features	Treatment
Minimal Change Disease (MCD)	Most common in children (77%); 10–15% in adults	LM: normal; IF: negative; EM: podocyte foot process effacement	Abrupt nephrotic syndrome, often post-URI or atopy; highly steroid-responsive	Prednisone 1 mg/kg/day × 4–8 weeks then taper; 90% adults remit; relapsers: cyclophosphamide, rituximab, CNIs
FSGS	Most common primary GN causing ESRD in African Americans; increasing incidence	LM: segmental sclerosis in some glomeruli; IF: IgM/C3 trapping; EM: foot process effacement	Nephrotic syndrome + hypertension + hematuria; poor steroid response; APOL1-associated; can recur post-transplant (especially collapsing variant)	Prednisone × 4–6 months (only 30–50% respond); CNIs (cyclosporine, tacrolimus); rituximab for relapsing
Membranous Nephropathy (MN)	Most common primary nephrotic syndrome in white adults; M:F 2:1	LM: GBM thickening ("spike and dome"); IF: granular IgG/C3; EM: subepithelial deposits	~70% have anti-PLA2R antibodies; secondary causes: hepatitis B, malignancy (lung, colon, stomach), SLE, drugs (NSAIDs, gold, penicillamine)	Rule of thirds: 1/3 spontaneous remission, 1/3 stable, 1/3 progress. Immunosuppression for high risk: rituximab (now first-line), cyclophosphamide + steroids (Ponticelli), CNIs
Diabetic Nephropathy	Most common cause of nephrotic syndrome overall	Mesangial expansion, GBM thickening, Kimmelstiel-Wilson nodules	Progressive proteinuria in longstanding DM; usually bilateral enlarged kidneys (early); retinopathy in 90% of T1DM	ACEi/ARB + SGLT2i + finerenone + GLP-1 RA; glycemic control
Amyloidosis (AL or AA)	AL: plasma cell dyscrasia; AA: chronic inflammatory conditions	Congo red stain: apple-green birefringence under polarized light; amyloid deposits in mesangium and GBM	Nephrotic syndrome + cardiomyopathy + neuropathy (AL); hepatosplenomegaly (AA)	AL: treat underlying plasma cell clone (bortezomib, daratumumab); AA: treat underlying inflammation

Always check anti-PLA2R antibodies in adult nephrotic syndrome — if positive, it confirms primary membranous nephropathy and can be used to monitor treatment response (declining titers correlate with remission). A negative PLA2R should prompt workup for secondary causes including malignancy screening.

13 Nephritic Syndrome

Nephritic syndrome is characterized by: hematuria (often with RBC casts and dysmorphic RBCs), hypertension, edema, oliguria, and a mild-to-moderate rise in creatinine. Proteinuria is usually subnephrotic (<3.5 g/day) but can overlap. The hallmark on biopsy is inflammatory injury to the glomerulus.

Major Causes of Nephritic Syndrome

Disease	Pathology	Key Features	Complement	Treatment
IgA Nephropathy (Berger disease)	Mesangial IgA deposits (IF); mesangial proliferation (LM)	Most common GN worldwide; episodic gross hematuria 1–2 days after URI ("synpharyngitic"); persistent microscopic hematuria	Normal	ACEi/ARB + SGLT2i; steroids if persistent proteinuria >1 g/day despite 3–6 months RAAS blockade; budesonide (Tarpeyo); consider fish oil
Post-Streptococcal GN	Subepithelial "humps" (EM); "lumpy-bumpy" IgG/C3 (IF); diffuse proliferative (LM)	Children 6–10 y/o; 1–3 weeks after pharyngitis or 3–6 weeks after skin infection; cola-colored urine, periorbital edema	Low C3 (normal C4)	Supportive (self-limited in children; >95% recover); adults have worse prognosis
RPGN (crescentic GN)	Crescents (>50% of glomeruli) in Bowman's space	Rapidly progressive renal failure over days to weeks; nephritic sediment	Varies by type	Emergency: pulse methylprednisolone + cyclophosphamide ± plasmapheresis; type-specific therapy
Anti-GBM disease (Goodpasture)	Linear IgG staining along GBM (IF); crescentic GN (LM)	RPGN + pulmonary hemorrhage (Goodpasture syndrome); anti-GBM antibodies positive; young males (20–30) or elderly (60–70)	Normal	Plasmapheresis (remove circulating antibodies) + cyclophosphamide + steroids; poor prognosis if Cr >5.7 or requiring dialysis at presentation
MPGN	GBM double contour ("tram-tracking"); mesangial/endocapillary proliferation	Mixed nephritic-nephrotic features; secondary causes: HCV, cryoglobulinemia, monoclonal gammopathy, C3 glomerulopathy	Low C3 ± C4	Treat underlying cause; immunosuppression for C3 glomerulopathy

RPGN Classification

Type I (anti-GBM) ~10%: linear IgG on IF; anti-GBM antibodies. Type II (immune complex) ~45%: granular IF; includes lupus nephritis, IgA nephropathy, post-infectious GN. Type III (pauci-immune) ~45%: negative/minimal IF; ANCA-positive (GPA, MPA, EGPA). Treatment must be initiated empirically before biopsy results if RPGN is suspected clinically.

14 Lupus Nephritis

Lupus nephritis (LN) occurs in ~50–60% of SLE patients and is a major determinant of morbidity and mortality. Renal biopsy is essential for classification and treatment decisions. The ISN/RPS classification guides therapy.

ISN/RPS Classification of Lupus Nephritis (2003/2018 Revised)

Class	Name	Pathology	Clinical Features	Treatment
I	Minimal mesangial	Normal LM; mesangial immune deposits on IF/EM only	Normal UA, normal renal function	Treat extrarenal SLE only
II	Mesangial proliferative	Mesangial hypercellularity; mesangial deposits	Microscopic hematuria, mild proteinuria	Treat extrarenal SLE; ACEi/ARB if proteinuria
III	Focal (proliferative)	<50% glomeruli with endocapillary ± extracapillary proliferation; subendothelial deposits	Hematuria, proteinuria, possible AKI; active sediment	Induction: mycophenolate mofetil (MMF) or IV cyclophosphamide + steroids; maintenance: MMF or azathioprine
IV	Diffuse (proliferative)	≥50% glomeruli affected; "full house" IF (IgG, IgA, IgM, C3, C1q); wire loop lesions	Nephritic syndrome, heavy proteinuria, hypertension, renal insufficiency; most severe form	Same as III; consider adding belimumab or voclosporin; plasmapheresis if concurrent anti-GBM or TMA
V	Membranous	GBM thickening with subepithelial deposits; may coexist with III or IV	Nephrotic syndrome; may have "pure" nephrotic picture	If combined with III/IV: treat as proliferative. Pure V: MMF + steroids; consider rituximab, CNIs
VI	Advanced sclerosing	≥90% globally sclerosed glomeruli	CKD/ESRD; minimal active disease	No immunosuppression; RRT; LN rarely recurs in transplant

Lupus Nephritis Induction Regimens

MMF-based (preferred for most): MMF 2–3 g/day + methylprednisolone 500–1000 mg IV × 3 days then oral prednisone 0.5–1 mg/kg/day taper. Euro-Lupus cyclophosphamide: IV CYC 500 mg q2weeks × 6 doses (lower dose than NIH protocol; similar efficacy, less toxicity). Voclosporin (AURORA trial): add to MMF + steroids for improved complete remission rates. Belimumab (BLISS-LN trial): add to standard induction for improved renal response. Maintenance: MMF 1–2 g/day for ≥3–5 years.

"Full house" immunofluorescence (IgG, IgA, IgM, C3, C1q all positive) is virtually pathognomonic of lupus nephritis. Low complement (C3 and C4) and elevated anti-dsDNA antibodies correlate with active renal disease and can be followed serially to monitor response.

15 ANCA-Associated Vasculitis

The ANCA-associated vasculitides (AAV) are small-vessel vasculitides that frequently involve the kidney as pauci-immune crescentic glomerulonephritis (type III RPGN). They include GPA (granulomatosis with polyangiitis), MPA (microscopic polyangiitis), and EGPA (eosinophilic granulomatosis with polyangiitis).

AAV Classification

Disease	ANCA Pattern	Upper Airway	Lung	Kidney	Unique Features
GPA (Wegener's)	c-ANCA / anti-PR3 (~80%)	Sinusitis, nasal crusting, saddle nose deformity, subglottic stenosis	Nodules, cavitary lesions, hemorrhage	Crescentic GN (RPGN)	Granulomatous inflammation; "limited" (no renal) or "severe" (renal/lung)
MPA	p-ANCA / anti-MPO (~60%)	Rare	Pulmonary hemorrhage (no nodules/cavities)	Crescentic GN (most common AAV renal involvement)	No granulomas; higher proportion of renal-limited disease
EGPA (Churg-Strauss)	p-ANCA / anti-MPO (~40%); 60% ANCA-negative	Allergic rhinitis, nasal polyps	Asthma (precedes vasculitis by years), eosinophilic infiltrates	Less frequent (~25%); when present, usually less severe	Peripheral eosinophilia >1,500/μL; cardiac involvement (myocarditis); mononeuritis multiplex

Renal Management of AAV

Induction: Pulse methylprednisolone (500–1000 mg IV × 3 days) + rituximab 375 mg/m² × 4 weekly doses (RAVE, RITUXVAS trials) OR IV cyclophosphamide. Rituximab is preferred for relapsing disease and PR3-ANCA positive disease. Plasmapheresis: Consider for severe renal disease (Cr >5.7 mg/dL) or concurrent pulmonary hemorrhage; PEXIVAS trial showed no benefit for renal recovery but remains standard for pulmonary hemorrhage. Maintenance: Rituximab 500 mg q6months for ≥2 years (MAINRITSAN); alternatively azathioprine 2 mg/kg/day. Avacopan (C5a receptor inhibitor) can be added to reduce steroid exposure (ADVOCATE trial).

Anti-PR3 (c-ANCA) is associated with GPA and a higher relapse rate. Anti-MPO (p-ANCA) is associated with MPA and generally lower relapse rates but can have more chronic renal damage at presentation. A patient with RPGN and positive ANCA should be treated empirically before biopsy confirmation.

16 Thrombotic Microangiopathies

The thrombotic microangiopathies (TMAs) are characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and organ injury (especially kidney and brain). The hallmark pathology is endothelial injury with fibrin-platelet thrombi in arterioles and capillaries.

TMA Classification

Disease	Mechanism	Key Labs	Clinical Features	Treatment
TTP	Severe ADAMTS13 deficiency (<10%) — acquired (autoantibody) or congenital	ADAMTS13 activity <10%; schistocytes on smear; LDH elevated; indirect bilirubin elevated; haptoglobin low	Classic pentad (rare): MAHA, thrombocytopenia, AKI, fever, neurologic symptoms; mortality >90% without treatment	Emergent plasma exchange (PEX); do NOT wait for ADAMTS13 results; caplacizumab (anti-vWF); steroids; rituximab for refractory
Typical HUS	Shiga toxin-producing E. coli (STEC) O157:H7; toxin causes endothelial injury	Stool culture, Shiga toxin PCR; ADAMTS13 normal	Children (peak 1–5 y/o); bloody diarrhea 5–7 days before MAHA/AKI; often severe AKI requiring dialysis	Supportive care (IV fluids, dialysis PRN); NO antibiotics (may increase toxin release); NO plasma exchange; >90% children recover
Atypical HUS (aHUS)	Complement dysregulation (mutations in complement regulators: CFH, CFI, MCP, C3, CFB)	Low C3 (sometimes); normal ADAMTS13; genetic testing for complement mutations	No preceding diarrhea; recurrent TMA episodes; AKI; can occur at any age; high recurrence in transplant	Eculizumab (anti-C5 monoclonal antibody) or ravulizumab (long-acting); meningococcal vaccination required before use

TTP Emergency

If TTP is suspected (MAHA + thrombocytopenia + neurologic symptoms), initiate plasma exchange immediately — every hour of delay increases mortality. The PLASMIC score can help differentiate TTP from other TMAs (score ≥6 = high probability of ADAMTS13 <10%). Do NOT transfuse platelets — this can precipitate fatal thrombosis ("fuel on the fire").

17 Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease (1:400–1,000), caused by mutations in PKD1 (85%, chromosome 16, worse prognosis) or PKD2 (15%, chromosome 4, milder). It accounts for ~5% of ESRD. Bilateral renal cysts develop and enlarge progressively, destroying normal parenchyma.

Clinical Features

Manifestation	Details
Renal	Bilateral enlarged kidneys with innumerable cysts; flank/back pain; hematuria; nephrolithiasis (uric acid, calcium oxalate in 20–30%); UTIs and cyst infections; hypertension (onset 20–30s); progressive CKD → ESRD (median age: 54 for PKD1, 74 for PKD2)
Hepatic	Hepatic cysts (most common extrarenal manifestation, ~80%); rarely cause liver failure; can cause mass effect
Cardiovascular	Mitral valve prolapse (25%); intracranial aneurysms (~8%, screen if family history of SAH or prior to major surgery); aortic root dilation
Other	Pancreatic cysts; seminal vesicle cysts; diverticular disease; inguinal and abdominal wall hernias

Diagnosis & Management

Diagnosis: Ultrasound criteria (Ravine criteria, age-dependent): age 15–39, ≥3 cysts total; age 40–59, ≥2 cysts per kidney; age ≥60, ≥4 cysts per kidney. MRI is more sensitive for cyst counting and total kidney volume (TKV) measurement, used for Mayo classification (1A–1E) to predict progression.

Tolvaptan (TEMPO 3:4, REPRISE trials): V2 receptor antagonist that slows TKV growth and GFR decline. Indicated for patients at risk of rapid progression (Mayo class 1C–1E, eGFR >25). Dosing: 45/15 mg → titrate to 90/30 mg daily (split AM/PM). Monitoring: liver function tests monthly × 18 months then q3months (risk of hepatotoxicity in ~5%); ensure adequate water intake (2–4 L/day) due to aquaresis. Avoid in pregnancy.

Pain management in ADPKD is challenging. Avoid NSAIDs (nephrotoxic). Cyst decompression (aspiration + sclerotherapy) or laparoscopic cyst fenestration for refractory pain. Cyst infections require lipophilic antibiotics that penetrate cysts: fluoroquinolones or TMP-SMX (not cephalosporins or aminoglycosides, which do not penetrate).

18 Renal Artery Stenosis

Renal artery stenosis (RAS) causes renovascular hypertension and ischemic nephropathy. Two main etiologies exist with distinct demographics and management approaches.

Feature	Atherosclerotic RAS	Fibromuscular Dysplasia
Epidemiology	Older adults (>50); men; atherosclerosis risk factors	Young women (15–50 years)
Location	Proximal 1/3 of renal artery (ostial)	Mid-to-distal renal artery
Pathology	Atherosclerotic plaque	Medial fibroplasia ("string of beads" on angiography)
Bilateral	30–40%	35% (may also involve carotid, vertebral arteries)
Treatment	Medical therapy (ACEi/ARB + statin + antihypertensives); revascularization (stenting) only for refractory HTN, flash pulmonary edema, or progressive CKD	Percutaneous transluminal angioplasty (PTA) WITHOUT stenting; ~90% cure or improvement

Diagnostic Clues for RAS

Suspect RAS when: resistant hypertension (uncontrolled on ≥3 drugs); flash (recurrent) pulmonary edema with bilateral RAS; AKI after starting ACEi/ARB (Cr rise >30%); asymmetric kidney size (>1.5 cm difference); abdominal bruit. Diagnosis: CTA or MRA (preferred noninvasive); duplex Doppler US (operator-dependent but useful for screening); catheter angiography is the gold standard.

The CORAL trial showed no benefit of stenting over medical therapy alone for atherosclerotic RAS in most patients. Reserve revascularization for: (1) flash pulmonary edema (Pickering syndrome), (2) refractory heart failure, (3) progressive CKD despite optimal medical therapy, or (4) failure of medical therapy to control BP.

19 Renal Tubular Acidosis

Renal tubular acidosis (RTA) refers to a group of disorders characterized by non-anion-gap metabolic acidosis due to impaired renal acid excretion or bicarbonate reabsorption, with a disproportionately preserved GFR.

RTA Classification

Feature	Type 1 (Distal)	Type 2 (Proximal)	Type 4 (Hyperkalemic)
Defect	Impaired H+ secretion in collecting duct (alpha-intercalated cells)	Impaired HCO3− reabsorption in proximal tubule	Aldosterone deficiency or resistance
Urine pH	>5.5 (cannot acidify urine)	<5.5 (once serum HCO3− below reabsorptive threshold ~15 mEq/L)	<5.5
Serum K+	Low (hypokalemia)	Low (hypokalemia)	High (hyperkalemia)
Serum HCO3−	May be very low (<10 mEq/L)	Moderately low (12–18 mEq/L)	Mildly low (17–22 mEq/L)
Complications	Nephrolithiasis (calcium phosphate), nephrocalcinosis, osteomalacia	Osteomalacia, rickets (children), Fanconi syndrome	Hyperkalemia-related cardiac risk
Causes	Sjögren, SLE, amphotericin B, toluene, sickle cell, lithium, medullary sponge kidney	Fanconi syndrome (multiple myeloma, tenofovir, ifosfamide, Wilson disease), carbonic anhydrase inhibitors	Diabetic nephropathy (hyporeninemic hypoaldosteronism), ACEi/ARB, spironolactone, TMP, Addison disease, heparin
Treatment	Oral sodium bicarbonate or sodium citrate (1–2 mEq/kg/day); potassium citrate if hypokalemic	High-dose bicarbonate (10–15 mEq/kg/day); thiazides may help (enhance proximal reabsorption by volume contraction)	Fludrocortisone (if truly aldosterone deficient); dietary K+ restriction; loop diuretics; discontinue offending drugs; sodium bicarbonate

A helpful mnemonic: Type 1 = cannot excrete acid (urine pH always >5.5); Type 2 = cannot reabsorb bicarb (loses HCO3− until serum level drops below threshold, then urine pH drops); Type 4 = cannot excrete potassium (hyperkalemia is the defining feature). The urine anion gap (Na+ + K+ − Cl−) is positive in RTA (impaired NH4+ excretion) and negative in GI bicarbonate losses (intact renal NH4+ excretion).

20 Sodium Disorders Critical

Hyponatremia (Na+ <135 mEq/L)

The most common electrolyte disorder in hospitalized patients (~15–30%). Always assess serum osmolality first to exclude pseudohyponatremia (isotonic: hyperlipidemia/hyperproteinemia) and hypertonic hyponatremia (hyperglycemia: corrected Na+ = measured Na+ + 1.6 × [(glucose − 100)/100]).

Volume Status	Etiology	Urine Na+	Treatment
Hypovolemic	GI losses, diuretics, cerebral salt wasting, burns, third-spacing	<20 (extrarenal loss); >20 (renal loss: diuretics, CSW)	Isotonic saline (NS); treats both volume and Na+
Euvolemic	SIADH (most common), hypothyroidism, adrenal insufficiency, psychogenic polydipsia, beer potomania, tea-and-toast	>40 (in SIADH)	Fluid restriction (500–1000 mL/day); salt tablets + loop diuretic; tolvaptan (V2 receptor antagonist); urea
Hypervolemic	Heart failure, cirrhosis, nephrotic syndrome, advanced CKD	<20 (HF, cirrhosis); >20 (CKD)	Fluid + salt restriction; loop diuretics; treat underlying cause

Hyponatremia Correction Rates

Critical safety limit: Correct Na+ by no more than 8 mEq/L in any 24-hour period (some experts say 6–8 for high-risk patients: alcoholism, malnutrition, liver disease, hypokalemia). Overcorrection causes osmotic demyelination syndrome (ODS) — central pontine myelinolysis: dysarthria, dysphagia, quadriparesis, "locked-in" syndrome. If overcorrecting: administer DDAVP 2 mcg IV q8h + D5W to re-lower Na+. Acute symptomatic hyponatremia (<48 h): can correct faster, give 3% hypertonic saline 100–150 mL bolus over 10–20 min (may repeat ×2); target 4–6 mEq/L rise in first 6 hours.

Hypernatremia (Na+ >145 mEq/L)

Always represents a water deficit. Patients either lost water or cannot access/drink water (ICU patients, elderly, infants).

Etiology	Mechanism	Urine Osmolality
Insensible/GI losses	Fever, burns, diarrhea (osmotic: lactulose)	>700 mOsm/kg (appropriate ADH response)
Central DI	Decreased ADH production (post-pituitary surgery, trauma, tumors)	<300 mOsm/kg; responds to desmopressin
Nephrogenic DI	Kidney resistance to ADH (lithium, hypercalcemia, hypokalemia, demeclocycline)	<300 mOsm/kg; does NOT respond to desmopressin
Osmotic diuresis	Glucosuria, mannitol, urea	300–600 mOsm/kg (inappropriately low for hypernatremia)

Treatment: Calculate free water deficit = TBW × [(Na+/140) − 1], where TBW = 0.6 × weight (males) or 0.5 × weight (females). Replace with D5W or free water enterally. Correct no faster than 10–12 mEq/L per 24 h (risk of cerebral edema with rapid correction). Central DI: desmopressin (DDAVP) 1–4 mcg IV/SC q12h. Nephrogenic DI: treat underlying cause; thiazides (paradoxical effect), amiloride (for lithium-induced), low-sodium diet.

21 Potassium Disorders Critical

Hyperkalemia (K+ >5.0 mEq/L)

K+ Level	Severity	EKG Changes (progressive)
5.5–6.0	Mild	Peaked T waves (earliest sign, best seen in precordial leads)
6.0–7.0	Moderate	Prolonged PR interval; flattened P waves; widened QRS
7.0–8.0	Severe	Loss of P waves; further QRS widening; sine wave pattern
>8.0	Life-threatening	Sine wave → ventricular fibrillation → asystole

Emergency Hyperkalemia Management

Step 1 — Cardiac membrane stabilization: Calcium gluconate 10% 10 mL IV over 2–3 min (or calcium chloride via central line); onset 1–3 min, lasts 30–60 min. Does NOT lower K+ but protects the heart. Repeat if EKG changes persist. Step 2 — Shift K+ intracellularly: Regular insulin 10 units IV + D50W 25 g (to prevent hypoglycemia); onset 15–30 min, lasts 4–6 h. Albuterol 10–20 mg nebulized; onset 15–30 min. Sodium bicarbonate 50 mEq IV (only if acidotic; minimal effect alone). Step 3 — Remove K+ from body: Loop diuretics (furosemide 40–80 mg IV); SZC (sodium zirconium cyclosilicate) 10 g PO; patiromer 8.4 g PO; hemodialysis (definitive for severe/refractory cases). Kayexalate (sodium polystyrene sulfonate) is falling out of favor due to GI necrosis risk and slow onset.

Hypokalemia (K+ <3.5 mEq/L)

Causes: GI losses (diarrhea, vomiting/NG suction — via metabolic alkalosis and renal K+ wasting), renal losses (diuretics, hyperaldosteronism, RTA type 1 and 2, hypomagnesemia), transcellular shifts (insulin, beta-agonists, alkalosis). EKG changes: flattened T waves, ST depression, U waves, prolonged QT, predisposition to arrhythmias (especially with digoxin).

Treatment: Oral KCl 40–80 mEq/day (preferred; each 10 mEq raises K+ ~0.1 mEq/L). IV KCl for severe (<3.0) or symptomatic: max rate 10–20 mEq/h via peripheral line, 40 mEq/h via central line with continuous monitoring. Always check and correct magnesium — hypomagnesemia causes refractory hypokalemia by increasing ROMK-mediated K+ secretion in the collecting duct.

The relationship between K+ and Mg2+ is critical: you cannot correct hypokalemia without first correcting hypomagnesemia. This is one of the most commonly tested and clinically relevant electrolyte principles. Always check Mg2+ in any patient with refractory hypokalemia.

22 Calcium & Phosphorus Disorders

Hypercalcemia

The two most common causes account for ~90%: primary hyperparathyroidism (outpatient) and malignancy (inpatient — via PTHrP, osteolytic metastases, or 1,25(OH)₂D production by lymphoma). Symptoms: "stones, bones, groans, thrones, and psychiatric overtones" (nephrolithiasis, bone pain, abdominal pain/constipation, polyuria, confusion/depression).

Severity	Corrected Ca2+ (mg/dL)	Management
Mild	10.5–12.0	Hydration; address cause; monitor
Moderate	12.0–14.0	IV NS (200–300 mL/h); loop diuretics (after volume repleted); calcitonin 4 IU/kg q12h (rapid but tachyphylaxis in 48 h)
Severe / symptomatic	>14.0 or symptomatic	Aggressive IV NS; calcitonin; zoledronic acid 4 mg IV (onset 2–4 days, duration weeks) or denosumab; hemodialysis for refractory/life-threatening

Hypocalcemia

Symptoms: perioral/digital paresthesias, carpopedal spasm, Chvostek sign (facial twitching with tapping CN VII), Trousseau sign (carpal spasm with BP cuff inflation × 3 min), QT prolongation, seizures, laryngospasm. Common causes: hypoparathyroidism (post-surgical most common), vitamin D deficiency, CKD, acute pancreatitis, hyperphosphatemia, hypomagnesemia, hungry bone syndrome (post-parathyroidectomy).

Treatment: Symptomatic/severe: calcium gluconate 1–2 g IV over 10–20 min (10–20 mL of 10% solution) then continuous infusion. Always correct hypomagnesemia. Chronic: oral calcium carbonate/citrate + calcitriol.

Phosphorus Disorders

Hyperphosphatemia: CKD (most common), rhabdomyolysis, tumor lysis syndrome, hypoparathyroidism. Treatment: dietary restriction, phosphate binders (sevelamer, lanthanum, calcium acetate), dialysis. Hypophosphatemia: refeeding syndrome (most dangerous), respiratory alkalosis (shifts into cells), antacids (bind phosphorus), hyperparathyroidism, vitamin D deficiency. Severe (<1.0 mg/dL): IV sodium/potassium phosphate 0.08–0.16 mmol/kg over 6 h.

23 Magnesium Disorders

Hypomagnesemia (Mg2+ <1.8 mg/dL)

Common in hospitalized patients (~12%). Causes: GI losses (diarrhea, malabsorption, PPI use), renal losses (loop/thiazide diuretics, alcohol, aminoglycosides, cisplatin, amphotericin B, calcineurin inhibitors), hungry bone syndrome. Effects: refractory hypokalemia, refractory hypocalcemia (impairs PTH secretion and action), QT prolongation, torsades de pointes.

Treatment: Mild (1.2–1.8): oral magnesium oxide 400–800 mg BID (poorly absorbed; causes diarrhea) or magnesium glycinate/taurate (better tolerated). Severe (<1.2) or symptomatic: magnesium sulfate 1–2 g IV over 1 h; for torsades de pointes: 2 g IV push. Renal excretion is rapid, so sustained repletion requires multiple doses over 24–48 h.

Hypermagnesemia (Mg2+ >2.5 mg/dL)

Almost exclusively in CKD/ESRD patients receiving magnesium-containing medications (antacids, laxatives). Progressive symptoms: hyporeflexia (4–7 mg/dL) → somnolence (7–10) → respiratory depression, cardiac arrest (ECG: prolonged PR, widened QRS, heart block) (>10–12). Treatment: stop Mg-containing agents; IV calcium gluconate (antagonizes cardiac effects); IV saline + furosemide (enhance excretion); hemodialysis for severe cases.

24 Metabolic Acidosis

Metabolic acidosis is defined by low pH (<7.35) with low HCO3− (<22 mEq/L). The first step is to calculate the anion gap (AG) = Na+ − (Cl− + HCO3−); normal = 12 ± 4. Adjust for albumin: corrected AG = AG + 2.5 × (4.0 − albumin).

Anion Gap Metabolic Acidosis (AGMA)

Mnemonic: MUDPILES

Letter	Etiology	Key Features
M	Methanol	Visual changes ("snowfield" vision), osmol gap elevated, formic acid
U	Uremia	Advanced CKD (eGFR <15); retained organic acids
D	Diabetic ketoacidosis	Hyperglycemia, ketonemia/ketonuria, AG often >20
P	Propylene glycol / Paraldehyde	IV lorazepam infusion (propylene glycol vehicle), osmol gap elevated
I	Isoniazid / Iron	INH: seizures + lactic acidosis; treat with pyridoxine
L	Lactic acidosis	Type A: tissue hypoxia (shock, sepsis); Type B: metformin, liver failure, malignancy, thiamine deficiency
E	Ethylene glycol	Flank pain, calcium oxalate crystals in urine, osmol gap elevated, AKI
S	Salicylates	Mixed AG metabolic acidosis + respiratory alkalosis; tinnitus; ferric chloride test

Winter's formula: Expected pCO2 = 1.5 × [HCO3−] + 8 (±2). If actual pCO2 is HIGHER than predicted → concurrent respiratory acidosis. If LOWER → concurrent respiratory alkalosis. Delta-delta: ΔAG / ΔHCO3−; ratio <1 = concurrent non-AG acidosis; ratio >2 = concurrent metabolic alkalosis. Osmol gap = measured − calculated osm; >10 suggests toxic alcohol ingestion.

Non-Anion Gap Metabolic Acidosis (NAGMA)

AG is normal; the acidosis results from HCO3− loss or impaired acid excretion. Calculate the urine anion gap (UAG) = U_Na + U_K − U_Cl.

UAG	Interpretation	Causes
Negative (U_Cl > U_Na + U_K)	Appropriate renal NH4+ excretion (GI HCO3− loss)	Diarrhea, external pancreatic/biliary fistula, ureteral diversion
Positive	Impaired renal acid excretion	RTA (types 1, 2, 4), CKD (early)

25 Metabolic Alkalosis

Metabolic alkalosis (pH >7.45, HCO3− >28 mEq/L) requires both a generation phase (HCO3− gain or H+ loss) and a maintenance phase (impaired renal HCO3− excretion, usually from volume depletion, chloride depletion, or hypokalemia). Check urine chloride to classify.

Category	Urine Cl−	Causes	Treatment
Saline-responsive (chloride-responsive)	<20 mEq/L	Vomiting/NG suction (loss of HCl), diuretics (after effect), post-hypercapnia, chloride-losing diarrhea	IV normal saline (provides Cl− for renal HCO3− excretion); KCl replacement; treat underlying cause
Saline-resistant (chloride-resistant)	>20 mEq/L	Primary hyperaldosteronism (Conn), Cushing syndrome, renal artery stenosis, Bartter syndrome, Gitelman syndrome, licorice ingestion, Liddle syndrome	Treat underlying cause; spironolactone/eplerenone for mineralocorticoid excess; amiloride for Liddle; acetazolamide (enhances HCO3− excretion) for refractory cases

In metabolic alkalosis from vomiting, the kidney initially tries to excrete HCO3− (alkaline urine), but volume and chloride depletion eventually force the kidney to reabsorb Na+ with HCO3− instead of Cl− — perpetuating the alkalosis. This is why saline (volume + chloride) is the treatment. The "paradoxically acidic urine" in severe vomiting occurs because the kidney prioritizes Na+ reabsorption over acid-base correction.

26 Hemodialysis

Indications for Dialysis (AEIOU)

Letter	Indication	Details
A	Acidosis	Severe metabolic acidosis (pH <7.1) refractory to bicarbonate therapy
E	Electrolytes	Refractory hyperkalemia (K+ >6.5 with EKG changes, or resistant to medical therapy)
I	Intoxication	Dialyzable toxins: methanol, ethylene glycol, lithium, salicylates, metformin, isopropanol
O	Overload	Volume overload refractory to diuretics (pulmonary edema)
U	Uremia	Uremic symptoms: encephalopathy, pericarditis, neuropathy, bleeding diathesis

Vascular Access Types

Access	Description	Maturation	Advantages	Disadvantages
AVF (preferred)	Surgical anastomosis of artery to vein (radiocephalic > brachiocephalic > brachiobasilic)	2–4 months ("Rule of 6s": flow >600 mL/min, diameter >6 mm, <6 mm deep, >6 cm length)	Lowest infection rate; best patency; best long-term outcomes	Long maturation time; primary failure rate 20–50% (especially radiocephalic)
AVG	Synthetic graft (usually PTFE) connecting artery to vein	2–4 weeks	Faster maturation than AVF; usable in patients with poor native vessels	Higher infection and thrombosis rates than AVF; requires surgical revision
CVC (tunneled catheter)	Dual-lumen catheter (internal jugular preferred; avoid subclavian if possible)	Immediate	Immediate use; no maturation needed; bridge to permanent access	Highest infection rate (catheter-related bloodstream infection); central venous stenosis risk; lower blood flow rates

Dialysis Adequacy

Kt/V is the standard measure: K = dialyzer clearance, t = treatment time, V = urea distribution volume. Target: Kt/V ≥1.4 per session (KDOQI); minimum adequate: Kt/V ≥1.2. URR (urea reduction ratio) = (pre-BUN − post-BUN) / pre-BUN × 100; target ≥65%. Standard prescription: 3–4 h sessions, 3×/week.

The "fistula first" initiative prioritizes AVF creation; refer patients to vascular surgery when eGFR <20–25 mL/min or within 1 year of anticipated dialysis need. Avoid venipuncture and IV catheter placement in the non-dominant arm to preserve veins for future AVF creation.

27 Peritoneal Dialysis

Peritoneal dialysis (PD) uses the peritoneal membrane as the dialysis membrane. Dialysate is instilled into the peritoneal cavity via a Tenckhoff catheter; solutes diffuse from blood to dialysate, and water is removed by osmotic ultrafiltration (using dextrose or icodextrin in dialysate).

PD Modalities

Modality	Description	Typical Prescription
CAPD (Continuous Ambulatory PD)	Manual exchanges, no machine; 4–5 exchanges/day with 4–6 h dwells	2–2.5 L exchanges × 4/day
APD (Automated PD / CCPD)	Machine (cycler) performs exchanges overnight; patient free during day	10–15 L total over 8–10 h overnight ± daytime dwell

PD Adequacy

Weekly Kt/V target ≥1.7 (total: peritoneal + residual renal function). PET (peritoneal equilibration test) classifies membrane transport: high transporters (rapid solute equilibration, poor ultrafiltration — best for APD with short dwells), low transporters (slow solute clearance, excellent ultrafiltration — best for CAPD with long dwells).

PD Peritonitis

Diagnosed by ≥2 of 3: abdominal pain/cloudy effluent, WBC >100/μL in effluent (with >50% PMNs), positive effluent culture. Most common organisms: coagulase-negative Staphylococcus (~30%), S. aureus (~15%), gram-negatives (~20%). Treatment: empiric intraperitoneal antibiotics covering gram-positive (vancomycin or cefazolin) + gram-negative (ceftazidime or gentamicin). Catheter removal for: refractory peritonitis (>5 days without response), fungal peritonitis, relapsing peritonitis, or tunnel infection with peritonitis.

28 Continuous Renal Replacement Therapy

CRRT provides slow, continuous solute clearance and fluid removal over 24 hours, making it ideal for hemodynamically unstable ICU patients who cannot tolerate intermittent HD. It requires ICU-level monitoring and continuous anticoagulation of the circuit.

CRRT Modalities

Modality	Mechanism	Primary Clearance	Replacement Fluid
CVVH (continuous veno-venous hemofiltration)	Convection (large-volume ultrafiltration with replacement fluid)	Middle molecules + small solutes	Pre- or post-filter replacement
CVVHD (continuous veno-venous hemodialysis)	Diffusion (dialysate flows countercurrent to blood)	Small solutes (urea, creatinine, K+)	Dialysate only
CVVHDF (continuous veno-venous hemodiafiltration)	Convection + diffusion (combined)	Both small and middle molecules	Replacement fluid + dialysate

CRRT Prescribing

Recommended dose: 20–25 mL/kg/h of effluent (RENAL, ATN trials showed no benefit from higher doses). Anticoagulation: regional citrate anticoagulation (preferred; chelates calcium in the circuit; calcium infused back into the patient) or systemic heparin. Citrate contraindicated in severe liver failure (impaired citrate metabolism → metabolic alkalosis, ionized hypocalcemia). Monitor ionized calcium, acid-base, electrolytes q4–6h.

CRRT vs Intermittent HD

CRRT advantages: better hemodynamic stability, more precise fluid management, continuous drug clearance (important for antibiotics). Disadvantages: requires ICU stay, continuous anticoagulation, immobilization, higher cost, nurse-intensive. Major RCTs (RENAL, ATN) show no mortality difference between CRRT and intermittent HD in AKI, but CRRT is preferred for hemodynamically unstable patients.

29 Dialysis Emergencies

Dialysis Disequilibrium Syndrome

Occurs during or shortly after first HD sessions in severely uremic patients (BUN >150 mg/dL). Mechanism: rapid urea removal from blood creates an osmotic gradient between plasma and brain → cerebral edema. Symptoms: headache, nausea, confusion, seizures, rarely fatal herniation. Prevention: short initial sessions (2 h), slow blood flow rates (200 mL/min), use high-sodium dialysate, consider mannitol infusion. Treatment: stop dialysis, mannitol, supportive care.

Access-Related Emergencies

Emergency	Presentation	Management
Access thrombosis	Loss of thrill/bruit in AVF/AVG; inability to dialyze	Urgent thrombectomy (surgical or pharmacomechanical); catheter placement for next HD
Access infection	Erythema, warmth, tenderness; fever, positive blood cultures	AVF: antibiotics (usually IV vancomycin); AVG: may need partial/complete graft excision if infected; CVC: exchange over wire vs removal + new site
Access hemorrhage	Bleeding from puncture sites or aneurysmal dilation	Direct pressure; protamine if post-heparin; surgical evaluation for pseudoaneurysm
Air embolism	Dyspnea, chest pain, "mill-wheel" murmur, cardiovascular collapse	Clamp catheter; left lateral decubitus + Trendelenburg position; aspirate air via catheter; 100% O2; hyperbaric O2 if available

Pulmonary Edema in ESRD

Flash pulmonary edema in a dialysis patient is a medical emergency. If the patient missed dialysis: emergent hemodialysis (or CRRT if unstable). Bridge therapy while arranging HD: high-dose IV nitroglycerin (reduces preload), BIPAP/CPAP, IV furosemide 200–400 mg (may have minimal effect in anuric patients). Consider continuous ultrafiltration. If bilateral renal artery stenosis is suspected (recurrent flash pulmonary edema between dialysis sessions in a patient with normal EF), evaluate with renal artery imaging.

30 Pre-Transplant Evaluation & Listing

Kidney transplantation is the optimal renal replacement therapy for eligible ESRD patients, offering superior survival, quality of life, and cost-effectiveness compared to dialysis. Pre-emptive transplantation (before dialysis initiation) has the best outcomes.

Evaluation Workup

Domain	Assessment
Cardiovascular	EKG, echocardiogram; stress testing if ≥3 risk factors or prior cardiac history; coronary angiography if indicated
Malignancy screening	Age-appropriate cancer screening; 2–5 year cancer-free interval required for most malignancies
Infections	Hepatitis B/C, HIV, CMV, EBV, TB (quantiferon), syphilis, toxoplasma; vaccination update (live vaccines BEFORE transplant)
Immunologic	ABO blood typing, HLA typing, PRA (panel reactive antibody — measures degree of sensitization); crossmatch
Urologic	Voiding cystourethrogram if bladder dysfunction suspected; native nephrectomy if recurrent infections or massive PKD
Psychosocial	Adherence assessment, substance abuse screening, social support evaluation

Allocation & Donor Types

Deceased donor: UNOS allocation based on EPTS (Estimated Post-Transplant Survival) score and KDPI (Kidney Donor Profile Index). Higher KDPI kidneys have shorter expected graft survival. Living donor: ABO-compatible or ABO-incompatible (with desensitization); paired kidney exchange for incompatible pairs. Living donor transplants have superior outcomes (graft half-life ~15–20 years vs 10–12 years for deceased donor).

Contraindications to transplantation: active malignancy, active infection, severe cardiac/pulmonary disease with life expectancy <5 years, active substance abuse, documented non-adherence, BMI >40 (relative). Age alone is NOT a contraindication — patients in their 70s and 80s can be successfully transplanted.

31 Immunosuppression Protocols

Induction Therapy (perioperative)

Agent	Mechanism	Indication	Key Side Effects
Basiliximab	Anti-IL-2R (CD25) monoclonal antibody; blocks T-cell proliferation	Low immunologic risk patients	Generally well-tolerated; low infection risk
Anti-thymocyte globulin (ATG)	Polyclonal antibody causing T-cell depletion	High immunologic risk (high PRA, repeat transplant, AA recipients)	Leukopenia, thrombocytopenia, serum sickness, cytokine release syndrome; increased infection and malignancy risk
Alemtuzumab	Anti-CD52; depletes T and B cells	Some steroid-avoidance protocols	Profound lymphopenia; increased infection risk

Maintenance Immunosuppression (Triple Therapy Standard)

Agent	Mechanism	Typical Dose	Monitoring	Key Toxicities
Tacrolimus (FK506)	Calcineurin inhibitor; blocks IL-2 transcription	0.05–0.1 mg/kg BID; target trough 8–12 ng/mL (early), 5–8 (maintenance)	Trough levels; renal function; glucose; K+; Mg2+	Nephrotoxicity, diabetes (NODAT), tremor, hyperkalemia, hypomagnesemia, posterior reversible encephalopathy
Mycophenolate mofetil (MMF)	IMPDH inhibitor; blocks purine synthesis in lymphocytes	1000 mg BID (or mycophenolic acid 720 mg BID)	CBC (for leukopenia); GI symptoms	GI toxicity (diarrhea, nausea), leukopenia, teratogenic (pregnancy category X)
Prednisone	Anti-inflammatory; suppresses multiple immune pathways	Taper from 30 mg to 5 mg daily by 3–6 months; some protocols withdraw completely	Glucose; bone density; BP	Diabetes, osteoporosis, weight gain, cataracts, avascular necrosis, adrenal suppression

Tacrolimus trough levels must be monitored closely — the therapeutic window is narrow. Drug interactions are extensive: azole antifungals and diltiazem increase levels (CYP3A4 inhibition); rifampin, phenytoin decrease levels (CYP3A4 induction). Always check interactions before prescribing new medications.

32 Transplant Complications

Rejection Types

Type	Timing	Mechanism	Biopsy Findings	Treatment
Hyperacute	Minutes to hours	Preformed donor-specific antibodies (ABO or HLA); complement activation	Fibrin thrombi, neutrophilic infiltration, cortical necrosis	Nephrectomy (irreversible); prevented by crossmatch testing
Acute T-cell mediated (TCMR)	Days to months (usually first 6 months)	T-cell infiltration of tubules and interstitium (tubulitis)	Banff classification: tubulitis + interstitial inflammation; graded IA, IB, IIA, IIB, III	Pulse methylprednisolone 500 mg × 3 days; ATG for steroid-resistant rejection
Acute antibody-mediated (ABMR)	Days to years	Donor-specific antibodies (DSA) against HLA; complement-mediated endothelial injury	C4d staining of peritubular capillaries; microvascular inflammation; glomerulitis	Plasmapheresis + IVIG ± rituximab; increase baseline immunosuppression; eculizumab for refractory
Chronic (CAMR/IFTA)	Months to years	Both immune (chronic ABMR) and non-immune (CNI toxicity, recurrent disease) factors	Interstitial fibrosis and tubular atrophy (IF/TA); transplant glomerulopathy (double contours)	No proven treatment for chronic changes; optimize immunosuppression; minimize CNI; control BP and proteinuria

Infectious Complications (Timeline)

Period	Infections	Prophylaxis
0–1 month	Surgical site infections, UTI, C. difficile, donor-derived infections	Perioperative antibiotics
1–6 months	CMV, BK virus (nephropathy), PJP (Pneumocystis), EBV, fungal	Valganciclovir (CMV) × 3–6 months; TMP-SMX (PJP) × 6–12 months
>6 months	Community-acquired infections; opportunistic infections if over-immunosuppressed; PTLD (EBV-driven)	Annual influenza vaccine; continued monitoring

BK Virus Nephropathy

BK polyomavirus reactivation occurs in ~5–10% of transplant recipients (due to immunosuppression), causing BK nephropathy with graft dysfunction. Screen with BK viremia (PCR) monthly for first 6 months, then q3months through 2 years. Viremia >10,000 copies/mL suggests active nephropathy. Treatment: reduce immunosuppression (first step — typically decrease MMF by 50% or switch tacrolimus to lower target); cidofovir and IVIG have limited evidence. No antiviral with proven efficacy.

Post-Transplant Lymphoproliferative Disorder (PTLD)

EBV-driven lymphoproliferation occurring in ~1–3% of adult kidney transplant recipients (higher in EBV-seronegative recipients). Spectrum ranges from benign polyclonal B-cell proliferation to aggressive monomorphic lymphoma (usually diffuse large B-cell). Treatment: reduce immunosuppression (may be curative for early lesions); rituximab for CD20+ disease; chemotherapy (R-CHOP) for advanced/monomorphic PTLD.

33 Kidney Biopsy

Indications

Unexplained AKI, nephrotic syndrome in adults, nephritic syndrome, rapidly progressive GN, persistent proteinuria >1 g/day, unexplained hematuria with proteinuria, systemic disease with renal involvement (SLE, vasculitis, amyloid), transplant dysfunction (to differentiate rejection from other causes).

Contraindications

Absolute	Relative
Uncontrolled bleeding diathesis (INR >1.5, platelets <50,000)	Uncontrolled hypertension (correct to <160/90 before biopsy)
Solitary functioning kidney (unless transplant biopsy)	Small kidneys (<9 cm) suggesting advanced CKD (findings unlikely to change management)
Active renal or urinary tract infection	Obesity (technical difficulty)
Uncooperative patient	Multiple bilateral cysts (ADPKD)

Biopsy Technique

Performed percutaneously under ultrasound guidance with the patient prone. Target the lower pole of the left kidney (or the transplant kidney in the iliac fossa). Use a 16- or 18-gauge automated spring-loaded biopsy needle. Obtain 2 cores (adequate if ≥10 glomeruli for LM). Specimens sent for: light microscopy (H&E, PAS, trichrome, silver stain), immunofluorescence (IgG, IgA, IgM, C3, C1q, kappa, lambda, fibrinogen), and electron microscopy. Post-procedure: bed rest × 6–8 h, serial vitals and Hb checks.

Complications

Gross hematuria (~3–5%); perinephric hematoma (~15% by imaging, most clinically insignificant); need for blood transfusion (~1–2%); need for angiographic intervention (<0.5%); nephrectomy (extremely rare, <0.01%); death (<0.02%).

34 Urinalysis & Urine Studies

Complete UA Interpretation

The urinalysis is the "poor man's kidney biopsy" and remains the most important initial test in nephrology. A complete UA includes: dipstick analysis (chemical), microscopy (cellular elements, casts, crystals), and quantitative studies (protein, albumin).

Urine Crystals

Crystal	Appearance	Urine pH	Clinical Significance
Calcium oxalate (monohydrate)	Dumbbell or oval-shaped	Acidic	Ethylene glycol poisoning; hyperoxaluria; most common kidney stone type
Calcium oxalate (dihydrate)	Envelope or bipyramidal	Any	Often incidental; hypercalciuria
Uric acid	Rhomboid or rosette; yellow-brown	Acidic (<5.5)	Gout, tumor lysis syndrome, uric acid nephrolithiasis
Triple phosphate (struvite)	"Coffin lid" shape	Alkaline (>7.0)	UTI with urease-producing organisms (Proteus); staghorn calculi
Cystine	Hexagonal plates	Acidic	Cystinuria (autosomal recessive); recurrent stones
Calcium phosphate	Wedge-shaped prisms; amorphous	Alkaline	RTA type 1; hyperparathyroidism

Quantifying Proteinuria

Method	Normal	Significance
Dipstick protein	Negative to trace	Semi-quantitative; detects albumin only; misses light chains (Bence Jones)
UACR (spot)	<30 mg/g	Preferred screening for DKD; 30–300 = moderately increased; >300 = severely increased
UPCR (spot)	<150 mg/g	Approximates 24-h protein excretion (UPCR of 3,500 ≈ 3.5 g/day)
24-h urine protein	<150 mg/day	Gold standard but cumbersome; >3,500 mg = nephrotic range
Sulfosalicylic acid (SSA) test	Negative	Detects all proteins including light chains; positive dipstick + negative SSA = false positive; negative dipstick + positive SSA = light chains

35 Pregnancy & the Kidney

Normal Renal Changes in Pregnancy

GFR increases ~50% by second trimester (hyperfiltration) → serum creatinine normally decreases to 0.4–0.6 mg/dL. A "normal" Cr of 0.9 mg/dL may indicate renal impairment in pregnancy. Physiologic hydronephrosis (R > L, due to dextrorotated uterus compressing right ureter) is common and does not require treatment. Mild proteinuria up to 300 mg/day is normal.

Preeclampsia

Affects 5–8% of pregnancies; defined as new hypertension (≥140/90 after 20 weeks gestation) + proteinuria (≥300 mg/day) OR end-organ damage (thrombocytopenia, elevated LFTs, creatinine >1.1, cerebral/visual symptoms). Pathophysiology: abnormal placentation → placental ischemia → anti-angiogenic factors (sFlt-1) → endothelial dysfunction. Renal pathology: glomerular endotheliosis. HELLP syndrome: Hemolysis, Elevated Liver enzymes, Low Platelets — a severe variant. Treatment: delivery (definitive); magnesium sulfate (seizure prophylaxis); antihypertensives (labetalol, nifedipine, hydralazine). Prevention: low-dose aspirin (81 mg daily from 12–16 weeks) in high-risk women.

CKD in Pregnancy

CKD Stage	Risk	Key Considerations
CKD 1–2 (eGFR >60)	Moderate	Generally favorable outcomes; increased monitoring; switch ACEi/ARB to labetalol/nifedipine (ACEi/ARB are teratogenic)
CKD 3–4	High	30–40% risk of preeclampsia; accelerated CKD progression; preterm delivery in ~50%
CKD 5 / Dialysis	Very high	Fertility reduced; if pregnant on dialysis: intensified HD (6×/week, target BUN <50); multidisciplinary management

Medications Contraindicated in Pregnancy

ACE inhibitors / ARBs: fetotoxic (renal dysgenesis, oligohydramnios, skull defects) — discontinue immediately upon confirmed pregnancy. MMF: teratogenic (pregnancy category X); switch to azathioprine ≥6 weeks before conception. Cyclophosphamide, methotrexate, mTOR inhibitors: all contraindicated. Safe immunosuppressants in pregnancy: azathioprine, calcineurin inhibitors (tacrolimus, cyclosporine), prednisone.

36 Imaging in Nephrology

Modality	Indication	Advantages	Limitations
Renal Ultrasound	First-line for all renal pathology; AKI (rule out obstruction); CKD (kidney size); cysts; transplant evaluation	No radiation, no contrast; bedside availability; Doppler for RAS screening	Operator-dependent; limited by body habitus; cannot differentiate medical renal disease etiologies
CT Abdomen/Pelvis	Nephrolithiasis (non-contrast); renal masses (with contrast); renal artery evaluation (CTA)	High sensitivity for stones and masses; fast acquisition	Radiation; iodinated contrast risk in CKD; cannot characterize some cystic lesions
MRI / MRA	Renal artery stenosis; complex cystic lesions (Bosniak); RCC staging; ADPKD volume measurement	No radiation; excellent soft tissue contrast; gadolinium-enhanced MRA for RAS	Gadolinium contraindicated if eGFR <30 (risk of nephrogenic systemic fibrosis with group 1 agents); cost; availability
Nuclear Renal Scan	MAG3 (differential function, obstruction with furosemide washout); DMSA (cortical scarring); captopril renogram (RAS)	Functional assessment (split function); can diagnose obstruction vs dilation	Radiation; low spatial resolution; time-consuming
Renal Angiography	Gold standard for RAS; therapeutic (angioplasty/stenting); AV malformations; bleeding	Diagnostic and therapeutic; highest resolution	Invasive; contrast exposure; access site complications; atheroembolic risk

Non-contrast CT is the gold standard for nephrolithiasis (sensitivity >95%). Renal ultrasound is always the first imaging in AKI — it takes 2 minutes and rules out hydronephrosis. For gadolinium MRI in CKD: group II agents (gadoteridol, gadobutrol) are considered safe even with low eGFR — the risk of NSF was primarily with older group I agents (gadodiamide, gadopentetate).

37 Classification Systems (All)

KDIGO AKI Staging

Stage	Creatinine Criteria	Urine Output Criteria
1	≥0.3 mg/dL rise in 48 h OR 1.5–1.9× baseline	<0.5 mL/kg/h × 6–12 h
2	2.0–2.9× baseline	<0.5 mL/kg/h × ≥12 h
3	≥3.0× baseline OR Cr ≥4.0 OR RRT initiation	<0.3 mL/kg/h × ≥24 h OR anuria ≥12 h

KDIGO CKD GFR & Albuminuria Classification

GFR Category	GFR Range	Albuminuria A1 (<30)	Albuminuria A2 (30–300)	Albuminuria A3 (>300)
G1 (≥90)	Normal/high	Low risk	Moderate risk	High risk
G2 (60–89)	Mildly decreased	Low risk	Moderate risk	High risk
G3a (45–59)	Mild-mod decreased	Moderate risk	High risk	Very high risk
G3b (30–44)	Mod-sev decreased	High risk	Very high risk	Very high risk
G4 (15–29)	Severely decreased	Very high risk	Very high risk	Very high risk
G5 (<15)	Kidney failure	Very high risk	Very high risk	Very high risk

ISN/RPS Lupus Nephritis Classification

Class	Name	Key Features
I	Minimal mesangial	Normal LM; mesangial deposits on IF/EM
II	Mesangial proliferative	Mesangial hypercellularity
III	Focal proliferative	<50% glomeruli; endocapillary ± extracapillary
IV	Diffuse proliferative	≥50% glomeruli; most severe; wire loops
V	Membranous	Subepithelial deposits; nephrotic picture
VI	Advanced sclerosing	≥90% sclerosed glomeruli

Oxford Classification for IgA Nephropathy (MEST-C)

Score	Feature	Definition	Prognostic Significance
M0/M1	Mesangial hypercellularity	≤50% / >50% of glomeruli	M1 predicts worse outcome
E0/E1	Endocapillary hypercellularity	Absent / Present	E1 may respond to immunosuppression
S0/S1	Segmental sclerosis	Absent / Present	S1 predicts worse outcome
T0/T1/T2	Tubular atrophy/interstitial fibrosis	≤25% / 26–50% / >50%	Strongest predictor of progression
C0/C1/C2	Crescents	Absent / <25% / ≥25% of glomeruli	C2 predicts rapid progression

38 Medications Master Table

Immunosuppressants

Drug	Mechanism	Dose	Key Toxicity	Monitoring
Cyclophosphamide	Alkylating agent; crosslinks DNA	IV: 0.5–1 g/m² monthly; Euro-Lupus: 500 mg q2wk × 6	Hemorrhagic cystitis (give MESNA), leukopenia, infections, gonadal toxicity, bladder cancer	CBC q1–2 weeks; UA for hematuria
Mycophenolate mofetil	IMPDH inhibitor (purine synthesis)	500–1500 mg BID	GI (diarrhea), leukopenia, teratogenic	CBC; MPA levels if available
Rituximab	Anti-CD20 (B-cell depletion)	375 mg/m² weekly × 4 or 1 g × 2 (days 1, 15)	Infusion reactions, infections, PML (rare), HBV reactivation	CD19/CD20 counts; HBV screen before use
Tacrolimus	Calcineurin inhibitor	0.05–0.1 mg/kg BID	Nephrotoxicity, NODAT, tremor, hyperkalemia, hypomagnesemia	Trough level (goal varies by indication)
Cyclosporine	Calcineurin inhibitor	3–5 mg/kg/day divided BID	Nephrotoxicity, hypertension, hirsutism, gingival hyperplasia	Trough or C2 level

Phosphate Binders

Drug	Type	Dose	Advantages	Disadvantages
Sevelamer carbonate	Non-calcium, non-metal polymer	800–1600 mg TID with meals	No calcium loading; may lower LDL; no aluminum toxicity	GI (bloating, constipation); large pill burden; cost
Lanthanum carbonate	Non-calcium metal binder	500–1000 mg TID with meals	Effective; chewable	GI symptoms; long-term lanthanum tissue deposition (unclear significance)
Calcium acetate	Calcium-based	667 mg (1–2 tabs) TID with meals	Inexpensive; effective	Hypercalcemia; vascular calcification risk; avoid if Ca >10.2 or PTH suppressed
Sucroferric oxyhydroxide	Iron-based	500 mg TID with meals (chewable)	Low pill burden; provides some iron	Dark stools; GI side effects

Diuretics in Nephrology

Class	Drug	Site of Action	Typical Dose	Key Notes
Loop	Furosemide	TAL (NKCC2)	20–400 mg IV/PO; ceiling effect in CKD	Most potent diuretic; ototoxic at high doses; hypoK, hypoMg, hypoCa
Loop	Bumetanide	TAL (NKCC2)	0.5–10 mg; 1 mg bumetanide ≈ 40 mg furosemide	Better oral bioavailability than furosemide (80% vs 50%)
Loop	Torsemide	TAL (NKCC2)	10–200 mg PO; 20 mg ≈ 40 mg furosemide	Longest acting loop; best oral absorption; may reduce HF readmissions
Thiazide	Chlorthalidone / HCTZ	DCT (NCC)	12.5–50 mg daily	Ineffective if eGFR <30 (except metolazone); hypoK, hypoNa, hyperCa, hyperuricemia
Thiazide-like	Metolazone	DCT + proximal tubule	2.5–10 mg (give 30 min before loop)	Sequential nephron blockade with loop; effective in advanced CKD; potent — monitor closely
K-sparing	Spironolactone / Eplerenone	Collecting duct (MR antagonist)	25–100 mg daily	Hyperkalemia risk; gynecomastia (spironolactone); eplerenone more selective
K-sparing	Amiloride	Collecting duct (ENaC blocker)	5–20 mg daily	Used for lithium-induced NDI; Liddle syndrome; hyperkalemia risk
Osmotic	Mannitol	Proximal tubule / loop	0.25–1 g/kg IV	Used in cerebral edema; dialysis disequilibrium; check osmol gap
CA inhibitor	Acetazolamide	Proximal tubule	250–500 mg BID	Metabolic acidosis (desired in alkalosis treatment); altitude sickness; glaucoma

Diagram showing sites of action of different diuretic classes along the nephron — **Figure 3 — Diuretic Sites of Action.** Loop diuretics act on the Na-K-2Cl transporter in the thick ascending limb; thiazides on the Na-Cl cotransporter in the distal convoluted tubule; K-sparing agents on the ENaC or mineralocorticoid receptor in the collecting duct. Source: Wikimedia Commons. Public domain.

39 Abbreviations Master List

General Nephrology

GFRGlomerular filtration rate eGFREstimated GFR CrClCreatinine clearance BUNBlood urea nitrogen SCrSerum creatinine AKIAcute kidney injury CKDChronic kidney disease ESRDEnd-stage renal disease KDIGOKidney Disease: Improving Global Outcomes KDOQIKidney Disease Outcomes Quality Initiative RRT / KRTRenal / kidney replacement therapy

Tubular & Electrolyte

FENaFractional excretion of sodium FEUreaFractional excretion of urea ATNAcute tubular necrosis AINAcute interstitial nephritis RTARenal tubular acidosis SIADHSyndrome of inappropriate ADH secretion DIDiabetes insipidus ADH / AVPAntidiuretic hormone / arginine vasopressin AGAnion gap UAGUrine anion gap ODSOsmotic demyelination syndrome

Glomerular Disease

GNGlomerulonephritis RPGNRapidly progressive glomerulonephritis FSGSFocal segmental glomerulosclerosis MCDMinimal change disease MNMembranous nephropathy MPGNMembranoproliferative glomerulonephritis ANCAAnti-neutrophil cytoplasmic antibody GBMGlomerular basement membrane PLA2RPhospholipase A2 receptor ISN/RPSInternational Society of Nephrology / Renal Pathology Society LNLupus nephritis

Dialysis & Transplant

HDHemodialysis PDPeritoneal dialysis CRRTContinuous renal replacement therapy CVVHContinuous veno-venous hemofiltration CVVHDContinuous veno-venous hemodialysis CVVHDFContinuous veno-venous hemodiafiltration AVFArteriovenous fistula AVGArteriovenous graft CVCCentral venous catheter Kt/VDialysis adequacy measure URRUrea reduction ratio PETPeritoneal equilibration test CAPDContinuous ambulatory peritoneal dialysis APDAutomated peritoneal dialysis DSADonor-specific antibody PRAPanel reactive antibody TCMRT-cell mediated rejection ABMRAntibody-mediated rejection PTLDPost-transplant lymphoproliferative disorder NODATNew-onset diabetes after transplant

Medications

ACEiAngiotensin-converting enzyme inhibitor ARBAngiotensin receptor blocker MRA / nsMRAMineralocorticoid receptor antagonist / non-steroidal MRA SGLT2iSodium-glucose cotransporter 2 inhibitor ESAErythropoiesis-stimulating agent EPOErythropoietin CNICalcineurin inhibitor MMFMycophenolate mofetil ATGAnti-thymocyte globulin CYCCyclophosphamide SZCSodium zirconium cyclosilicate

40 Risk Scores & Guidelines

Kidney Failure Risk Equation (KFRE)

Predicts 2- and 5-year probability of kidney failure requiring dialysis or transplant, using four variables: age, sex, eGFR, and UACR. Validated in >30 countries and >700,000 patients. Used to guide referral timing and dialysis planning. An 8-variable version adds serum calcium, phosphorus, bicarbonate, and albumin for improved accuracy in CKD G4–5.

KFRE 5-Year Risk	Clinical Action
<3%	Continue primary care management; annual nephrology review if CKD G3b+
3–5%	Nephrology referral; education about KRT modalities
5–15%	Active KRT preparation; vascular access planning; transplant evaluation
>15%	Imminent dialysis planning; access creation; consider pre-emptive transplant listing

UACR Thresholds & Management

UACR (mg/g)	Category	Management Implications
<30	A1 (normal)	Standard cardiovascular risk management
30–300	A2 (moderately increased)	ACEi/ARB indicated; add SGLT2i if DKD; screen annually
>300	A3 (severely increased)	Aggressive RAAS blockade; SGLT2i; finerenone; nephrology referral; monitor q3–6 months

Nephrology Referral Criteria (KDIGO)

Indication	Details
eGFR <30 mL/min (CKD G4–5)	Mandatory referral for KRT planning
Persistent UACR >300 mg/g	Evaluation for underlying glomerular disease
Rapid GFR decline	>5 mL/min/year sustained decline
AKI of uncertain etiology	Especially with active sediment or systemic features
Resistant hypertension	Uncontrolled on ≥3 agents including a diuretic
Persistent hematuria with proteinuria	After urologic evaluation excludes structural causes
Hereditary kidney disease	ADPKD, Alport syndrome, Fabry disease
Recurrent nephrolithiasis	Metabolic evaluation and prevention

Key Clinical Trial Summary

Trial	Drug / Intervention	Population	Key Finding
CREDENCE (2019)	Canagliflozin	T2DM + CKD (eGFR 30–90, UACR >300)	30% reduction in renal composite; stopped early for efficacy
DAPA-CKD (2020)	Dapagliflozin	CKD (eGFR 25–75, UACR 200–5000); 33% non-diabetic	39% reduction in renal composite; benefit in non-diabetic CKD
EMPA-KIDNEY (2022)	Empagliflozin	CKD (eGFR 20–45, or 45–90 with UACR ≥200)	28% reduction in progression; broadest CKD population studied
FIDELIO-DKD (2020)	Finerenone	T2DM + CKD (UACR 30–5000, on ACEi/ARB)	18% reduction in kidney composite
FIGARO-DKD (2021)	Finerenone	T2DM + CKD (broader, earlier CKD)	13% reduction in CV composite
FLOW (2024)	Semaglutide	T2DM + CKD	24% reduction in kidney events; stopped early
RAVE (2010)	Rituximab vs cyclophosphamide	ANCA vasculitis	Non-inferior for remission induction; superior for relapsing disease
PEXIVAS (2020)	Plasma exchange in AAV	ANCA vasculitis with severe renal disease	No benefit for death or ESRD composite
SPRINT (2015)	Intensive BP control	High CV risk (no diabetes)	SBP <120 vs <140: 25% reduction in CV events; eGFR decline faster but less clinical kidney disease
PRESERVE (2018)	NAC + sodium bicarb for CIN prevention	CKD undergoing angiography	No benefit of NAC or IV sodium bicarbonate over IV saline

References

Figures

Figure 1 — Kidney Cross-Section. Source: Wikimedia Commons. Public domain.
Figure 2 — The Nephron. Source: Wikimedia Commons. Public domain.
Figure 3 — Diuretic Sites of Action. Source: Wikimedia Commons. Public domain.

Key Trials & Guidelines

KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl. 2013;3(1):1–150.
KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1–S276.
KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of CKD. Kidney Int. 2024;105(4S):S117–S314.
Perkovic V et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy (CREDENCE). N Engl J Med. 2019;380(24):2295–2306.
Heerspink HJL et al. Dapagliflozin in Patients with Chronic Kidney Disease (DAPA-CKD). N Engl J Med. 2020;383(15):1436–1446.
The EMPA-KIDNEY Collaborative Group. Empagliflozin in Patients with Chronic Kidney Disease (EMPA-KIDNEY). N Engl J Med. 2023;388(2):117–127.
Bakris GL et al. Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes (FIDELIO-DKD). N Engl J Med. 2020;383(23):2219–2229.
Pitt B et al. Cardiovascular Events with Finerenone in Kidney Disease and Type 2 Diabetes (FIGARO-DKD). N Engl J Med. 2021;385(24):2252–2263.
Perkovic V et al. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes (FLOW). N Engl J Med. 2024;391(2):109–121.
Stone JH et al. Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis (RAVE). N Engl J Med. 2010;363(3):221–232.
Walsh M et al. Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis (PEXIVAS). N Engl J Med. 2020;382(7):622–631.
Weisbord SD et al. Outcomes after Angiography with Sodium Bicarbonate and Acetylcysteine (PRESERVE). N Engl J Med. 2018;378(7):603–614.
SPRINT Research Group. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med. 2015;373(22):2103–2116.
Torres VE et al. Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease (TEMPO 3:4). N Engl J Med. 2012;367(25):2407–2418.

Textbooks & Core References

Brenner BM, ed. Brenner & Rector's The Kidney. 11th ed. Elsevier; 2019.
Johnson RJ, Feehally J, Floege J, eds. Comprehensive Clinical Nephrology. 7th ed. Elsevier; 2024.
Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders. 5th ed. McGraw-Hill; 2001.
Daugirdas JT, Blake PG, Ing TS, eds. Handbook of Dialysis. 5th ed. Wolters Kluwer; 2015.
National Kidney Foundation. KDOQI Clinical Practice Guidelines. Available at: kidney.org.