The Renal System

Acute kidney injury — localize before you treat

• Postrenal causes (accounts for under 5% of AKI): bilateral ureteral obstruction from stones or tumor, prostatic hyperplasia, bladder neck obstruction, urethral stricture, neurogenic bladder

Acute tubular necrosis

• Most common intrinsic cause of acute kidney injury in hospitalized patients
• Two big buckets of cause: ischemic (prolonged prerenal hypoperfusion — proximal tubule and thick ascending limb are most vulnerable, highest oxygen demand) and nephrotoxic
• Exogenous nephrotoxins: IV contrast, aminoglycosides, cyclosporine, ethylene glycol, acetaminophen (overdose), heavy metals
• Endogenous nephrotoxins: myoglobin (rhabdomyolysis), uric acid (tumor lysis syndrome), oxalate
• Hallmark urine finding: muddy brown granular casts
• Clinical course: oliguric phase → diuretic phase (tubules regenerate but can't yet concentrate urine, risk of dehydration) → recovery phase

Two more named patterns of acute kidney injury

• Diffuse cortical necrosis: acute infarction of both renal cortices from combined vasospasm and DIC — classically follows an obstetric catastrophe (e.g., placental abruption) or septic shock
• Renal papillary necrosis: the renal papillae slough off and cause gross hematuria, often triggered by infection or an immune stimulus — remember the four risk factors with SAAD (papa with papillary necrosis): Sickle cell disease/trait, Acute pyelonephritis, Analgesics (NSAIDs), Diabetes mellitus

Urine casts — reading the sediment

• A cast means blood or pus originated somewhere in the nephron itself, not the bladder/lower tract — bladder cancer and stones cause hematuria without casts, and simple cystitis causes pyuria without casts
• All casts share a matrix of Tamm–Horsfall protein (uromodulin), normally secreted by tubular cells

Nephrotic vs. nephritic — the defining split

Nephrotic diseases

Nephritic diseases

Cystitis vs. pyelonephritis

• E. coli causes the large majority of uncomplicated UTIs
• Staphylococcus saprophyticus — second most common cause in young sexually active women
• Proteus mirabilis — urease-positive, alkalinizes urine, associated with struvite stones
• Klebsiella and Enterobacter are also common colonic-flora causes of cystitis
• Nosocomial (catheter-associated) cystitis is more often caused by Pseudomonas or Staphylococcus aureus
• Risk factors: female urethral anatomy, sexual activity, pregnancy, catheterization, vesicoureteral reflux, obstruction, diabetes
• Diagnostic threshold: pyuria (>8 leukocytes/high-power field) plus >10⁵ CFU/mL on culture with compatible symptoms

Chronic pyelonephritis

• Results from recurrent or inadequately treated infection, often with underlying vesicoureteral reflux or obstruction
• Scarring and deformity of the renal pelvis and calyces
• Interstitial fibrosis with tubular atrophy
• Tubular ischemia can produce a microscopic pattern resembling thyroid follicles ("thyroidization" of the kidney) — atrophic tubules filled with eosinophilic, colloid-like casts

Acute interstitial nephritis

• Hypersensitivity reaction in the renal interstitium — classically drug-induced
• Common culprits, grouped by the mnemonic DRAINS: Diuretics, Rifampin, Antibiotics (penicillins, cephalosporins), proton pump Inhibitors, NSAIDs, Sulfa drugs — can also follow infection or be idiopathic
• Classic (but insensitive) triad: fever, rash, eosinophilia
• Urinalysis: white cells, white cell casts, and eosinophils; sterile pyuria
• Usually reversible with withdrawal of the offending drug

• Cardinal presentation: sudden-onset severe flank pain radiating to groin, hematuria, restlessness (contrast with the still posture of peritonitis)
• Natural inhibitors of stone formation: citrate, nephrocalcin, Tamm–Horsfall protein (uromodulin), and uropontin — low urine citrate is a common, treatable driver of calcium stone formation
• First-line imaging: noncontrast CT (most sensitive); ultrasound preferred in pregnancy
• Cystinuria transporter defect: the same PCT carrier that fails to reabsorb cystine also fails to reabsorb COLA — Cystine, Ornithine, Lysine, Arginine; cystine itself is the only one of the four poorly soluble enough to precipitate into stones. Treatment: high fluid intake, urinary alkalinization, and chelating agents (e.g., penicillamine) if refractory
• Struvite stones form only in the presence of urease-producing bacteria (Proteus, Klebsiella, Staphylococcus saprophyticus) that split urea into ammonia and alkalinize the urine — treatment requires eradicating the infection, often alongside surgical stone removal since antibiotics alone won't dissolve an existing staghorn calculus
• Uric acid stones are one of the few types that can be dissolved medically — alkalinizing the urine (raising pH) plus allopurinol to lower uric acid production

Cystic kidney disease

Hydronephrosis

• Distention of the renal pelvis and/or calyces, almost always from downstream urinary tract obstruction — stones, severe BPH, congenital narrowing, tumor, or ureteral injury
• Dilation occurs proximal to (upstream of) the blocked segment
• Serum creatinine only rises if the obstruction is bilateral, or the patient has just one working kidney — a unilaterally obstructed kidney in someone with two functioning kidneys can hide behind a normal creatinine
• Prolonged obstruction leads to compression and eventual atrophy of the renal cortex and medulla

Urinary incontinence — three mechanisms

Chronic kidney disease

• Leading causes worldwide: diabetes mellitus and hypertension, by a wide margin
• Defined by ≥3 months of reduced GFR or kidney damage markers
• Overt uremic symptoms typically emerge once GFR falls to roughly 50–65% of normal — by-products of protein and amino acid metabolism (especially urea) start driving the multi-system findings below
• Imaging clue: bilateral small, echogenic kidneys (contrast with normal/enlarged kidneys in ADPKD or diabetic nephropathy)

Uremic syndrome — systems affected, one line each

• Cardiovascular: hypertension, uremic pericarditis, accelerated atherosclerosis
• Hematologic: normocytic normochromic anemia (↓ erythropoietin), lymphocytopenia and leukopenia (↑ infection risk), platelet dysfunction (bleeding despite normal platelet count), burr cells (RBCs with irregular spiny projections) on smear
• Neurologic: asterixis, headache, fatigue, seizures, encephalopathy, peripheral neuropathy
• GI: nausea, anorexia, peptic ulcer, uremic fetor, increased GI bleeding risk
• Endocrine/metabolic: secondary hyperparathyroidism from phosphate retention and low active vitamin D → renal osteodystrophy/osteomalacia; impaired growth and development; infertility and sexual dysfunction
• Dermatologic: pallor, pruritus, uremic frost (rare, advanced)
• Electrolyte: hyperkalemia, hyperphosphatemia, hypertriglyceridemia, hyperuricemia, hypocalcemia, metabolic acidosis

Renal osteodystrophy — the chain reaction

Renovascular disease — a common, correctable cause of hypertension

• Renal artery stenosis → reduced renal perfusion is misread by the kidney as systemic hypotension → renin rises → angiotensin II rises → secondary hypertension, one of the most common identifiable causes in adults
• Atherosclerotic plaque: proximal third of the renal artery — typically older males with other vascular risk factors
• Fibromuscular dysplasia: distal two-thirds of the artery or its segmental branches — typically younger or middle-aged women, giving a classic "string of beads" appearance on angiography
• Unilateral stenosis lets the affected kidney atrophy over time and shows higher renin on that side specifically when sampled
• Bilateral stenosis is the setting where starting an ACE inhibitor or ARB can precipitate a sharp rise in creatinine, because the drug removes the angiotensin-mediated efferent constriction both kidneys were relying on to maintain filtration pressure

Renal oncocytoma — the benign look-alike

• Benign epithelial tumor arising from collecting-duct intercalated cells — large eosinophilic cells packed with mitochondria
• Grossly shows a well-circumscribed mass with a characteristic central scar; on histology the cells lack the perinuclear clearing/halo seen in chromophobe RCC, which is the main lesion it has to be distinguished from
• Presents with painless hematuria, flank pain, or an abdominal mass — indistinguishable from RCC by symptoms alone, so it's usually resected just to rule malignancy out

Wilms tumor syndromes, spelled out

• WAGR complex (WT1 gene deletion): Wilms tumor, Aniridia (missing iris), Genitourinary malformations, Range of developmental delays
• Denys-Drash syndrome (WT1 point mutation): Wilms tumor, early-onset nephrotic syndrome from diffuse mesangial sclerosis, and gonadal dysgenesis (male pseudohermaphroditism)
• Beckwith-Wiedemann syndrome (WT2/imprinting defect on chromosome 11, causing genetic overexpression): Wilms tumor, organomegaly, macroglossia, hemihyperplasia, omphalocele

Bladder cancer — two histologic types, different risk factors

• Urothelial (transitional cell) carcinoma: the most common bladder tumor by far, and the most common tumor of the urinary tract overall (renal calyces, pelvis, ureters, or bladder). Suggested by Painless hematuria (no casts, since it's a lower-tract lesion). Risk factors spell "Pee SAC": tobacco Smoking, Aromatic amines (dye/rubber industry exposure), Cyclophosphamide
• Squamous cell carcinoma of the bladder: arises from chronic irritation → squamous metaplasia → dysplasia. Four "S" risk factors: Schistosoma haematobium infection (endemic to parts of the Middle East/Africa), chronic cystitis, smoking, and chronic bladder stones. Also presents with painless hematuria and no casts

Site of action along the nephron

RAAS blockers

ADH-axis drugs

• Desmopressin (DDAVP): ADH analog — treats central diabetes insipidus and some bleeding disorders (releases vWF)
• Demeclocycline / lithium: ADH antagonists at the collecting duct — used to treat SIADH; lithium's use here also explains why it can cause nephrogenic diabetes insipidus as a side effect
• Central DI responds to desmopressin; nephrogenic DI does not (the receptor/channel machinery itself is broken) — a fast way to distinguish the two on a vignette

Core quantities

Starling forces across the glomerular capillary

• Filtration is always net-favored across the glomerulus (unlike systemic capillaries)
• Hydrostatic pressure in the capillary (P_GC) pushes fluid out — raised by afferent dilation or efferent constriction
• Hydrostatic pressure in Bowman space (P_BS) opposes filtration — raised by ureteral obstruction
• Oncotic pressure in the capillary (π_GC) opposes filtration and rises along the capillary length as protein concentrates
• Oncotic pressure in Bowman space (π_BS) is normally ~0 (protein doesn't cross an intact filter)

Other variables that shift filtration fraction

• Ureteral obstruction → raises Bowman-space pressure → decreases FF
• Increased plasma protein (e.g., multiple myeloma) → raises capillary oncotic pressure → decreases FF
• Decreased plasma protein (e.g., liver failure, nephrotic syndrome) → lowers capillary oncotic pressure → increases FF

Arteriolar tone and GFR — the pairs students mix up

Clearance logic for individual solutes

• Substance cleared faster than GFR → net tubular secretion (e.g., PAH, most organic acids/bases)
• Substance cleared slower than GFR (or zero) → net tubular reabsorption or non-filtration (e.g., glucose normally, plasma proteins)
• Substance cleared equal to GFR → freely filtered, neither reabsorbed nor secreted (inulin — the definition of an ideal GFR marker)
• Reabsorption of actively-transported solutes (glucose, amino acids) is saturable — described by a transport maximum (T_m); above T_m, the excess spills into urine
• Glucose T_m is reached around a plasma level of ~350–375 mg/dL — above that, filtered glucose exceeds reabsorptive capacity and drives an osmotic diuresis, the mechanism behind polyuria in uncontrolled diabetic hyperglycemia
• Glucosuria actually begins earlier, around a plasma level of ~200 mg/dL (the "threshold") — the gap between threshold and T_m is the splay, a gradual rather than all-or-nothing transition caused by natural variation in transporter capacity across different nephrons
• Normal pregnancy raises GFR, which filters more glucose at any given plasma level and effectively lowers the threshold — mild glucosuria at a normal plasma glucose is common in pregnancy and isn't necessarily diabetes
• SGLT2 inhibitors (the "-flozin" drugs) block the same PCT transporter directly, causing glucosuria even at plasma glucose levels below 200 mg/dL — this is their intended mechanism, not a side effect

Renin–angiotensin–aldosterone axis

• Angiotensin II: constricts efferent arteriole, stimulates aldosterone (zona glomerulosa), stimulates ADH and ACTH release, drives thirst, and directly increases proximal Na⁺/H⁺ exchange
• Angiotensin II is the most potent endogenous vasoconstrictor acting on renal arterioles at physiologic levels
• Aldosterone acts on principal cells: reabsorb Na⁺ (and water follows), secrete K⁺; acts on intercalated cells to secrete H⁺
• Angiotensin II is further broken down to angiotensin III — still a potent aldosterone stimulator, but a much weaker vasoconstrictor than angiotensin II
• ACE inhibitors (e.g., captopril, enalapril) lower blood pressure by blocking the angiotensin I → II conversion, which also reduces aldosterone release; ARBs (e.g., losartan, valsartan) instead block angiotensin II from reaching its receptor, preventing efferent arteriolar constriction

Antidiuretic hormone (ADH / vasopressin)

• Released from posterior pituitary in response to ↑ plasma osmolality (sensed by hypothalamic osmoreceptors) or severe volume depletion
• Binds V2 receptors on principal cells → ↑ cAMP → inserts aquaporin-2 channels → ↑ water reabsorption, concentrated urine
• Governs water balance; aldosterone governs solute (Na⁺/K⁺) balance — a useful one-line distinction

Atrial natriuretic peptide (ANP) & BNP

• Released by atrial (ANP) / ventricular (BNP) myocytes in response to stretch from volume overload
• Dilates afferent arteriole, constricts efferent → raises GFR
• Inhibits renin and aldosterone → promotes natriuresis and diuresis — a physiologic counterweight to RAAS

Parathyroid hormone & vitamin D on the nephron

• PTH acts on PCT: inhibits phosphate reabsorption (phosphaturic) and activates 1α-hydroxylase → more active vitamin D
• PTH acts on DCT: increases Ca²⁺ reabsorption
• Active vitamin D (1,25-dihydroxyvitamin D) increases both intestinal and renal Ca²⁺/phosphate reabsorption

Juxtaglomerular apparatus

• Sits where the distal tubule loops back to touch its own glomerulus's afferent arteriole
• Juxtaglomerular cells: modified smooth muscle in the afferent arteriole wall — sense arteriolar pressure directly and secrete renin
• Macula densa: specialized DCT cells sitting right against the arterioles — sense NaCl delivery and signal the JG cells via paracrine communication
• Function: short-term, this apparatus is the effector arm of tubuloglomerular autoregulation; long-term, it's the trigger for the whole renin–angiotensin–aldosterone cascade

Kidney as an endocrine/paracrine organ

• Erythropoietin: released by peritubular interstitial cells in response to hypoxia — stimulates RBC production in bone marrow; this is why chronic kidney disease causes a normocytic anemia, and why replacement EPO can raise blood pressure as a side effect
• Calcitriol (active vitamin D): PCT cells convert 25-OH vitamin D to the active 1,25-(OH)₂ form via 1α-hydroxylase, a step stimulated by PTH — increases intestinal calcium absorption
• Prostaglandins: locally vasodilate the afferent arteriole to protect renal blood flow, especially when systemic pressure drops — this is exactly the protective effect NSAIDs block, which is why NSAIDs are risky in volume-depleted patients
• Dopamine: secreted locally by proximal tubule cells, promotes natriuresis; at low concentrations it dilates the renal vasculature and raises renal blood flow with little GFR change, but at higher doses it becomes a vasoconstrictor instead

Potassium shifts — what pushes K⁺ into vs. out of cells

How these hormones reshape the fluid compartments

Reasoning through six scenarios by whether volume is gained/lost and whether the fluid is isotonic, hypertonic, or hypotonic:

• Rule of thumb: water always shifts to equalize osmolarity between ICF and ECF — trace the water, not the solute, to get ICF volume right
• An isotonic fluid shift never moves water across cell membranes, so ICF volume never changes in the top two rows

Anion gap

• AG = Na⁺ − (Cl⁻ + HCO₃⁻); normal range roughly 8–12 mEq/L
• Elevated AG means an unmeasured acid has accumulated (lactate, ketoacids, toxin anions)
• Normal AG (hyperchloremic) acidosis means bicarbonate was lost directly and chloride rose to compensate — GI loss (diarrhea) or renal tubular acidosis

Working up metabolic alkalosis by urine chloride

• Check urine Cl⁻ once you've confirmed metabolic alkalosis — it separates the two mechanisms driving it
• Saline-responsive (urine Cl⁻ <20 mEq/L): volume-depleted, chloride-avid state — vomiting, recent loop/thiazide use, antacid overuse; corrects with volume/chloride repletion
• Saline-resistant (urine Cl⁻ >20 mEq/L): mineralocorticoid excess is driving it independent of volume status — hyperaldosteronism, Bartter/Gitelman syndrome, current diuretic use; volume repletion alone won't fix it

Clinical presentation by disturbance type

Renal tubular acidosis at a glance

Inherited tubular transport defects

Order to memorize them in, working from proximal tubule to collecting duct: Fanconi → Bartter → Gitelman → Liddle → SAME.

Widening the differential — renin/aldosterone patterns across renal disorders

Electrolyte disturbances — symptoms at a glance

Compensation — expected direction, not full correction

• Metabolic acidosis → respiratory compensation is hyperventilation (↓ PCO₂)
• Metabolic alkalosis → respiratory compensation is hypoventilation (↑ PCO₂)
• Respiratory acidosis/alkalosis → renal compensation (↑ or ↓ HCO₃⁻ handling) takes days, so chronic respiratory disturbances are far better compensated than acute ones
• Use Winter's formula for expected PCO₂ in metabolic acidosis: PCO₂ ≈ (1.5 × HCO₃⁻) + 8 ± 2 — a measured PCO₂ outside this range means a second, superimposed acid–base disorder
• The relationship between pH, bicarbonate, and PCO₂ is formalized by the Henderson-Hasselbalch equation: pH = 6.1 + log([HCO₃⁻] ÷ (0.03 × PCO₂)) — worth recognizing rather than memorizing, since it's just the algebraic version of "more bicarbonate or less CO₂ raises pH"

Where the nephron handles acid–base

• PCT: reabsorbs ~85–90% of filtered HCO₃⁻ via carbonic anhydrase; generates new bicarbonate by metabolizing glutamine, excreting the byproduct as NH₄⁺
• DCT: also generates "new" bicarbonate through H⁺ secretion coupled to filtered phosphate buffering (titratable acid)
• Distal nephron / collecting duct: intercalated cells actively secrete H⁺ (type A, generating new HCO₃⁻) or secrete HCO₃⁻ (type B, during alkalosis)
• Ammoniagenesis is the kidney's main adaptive mechanism to excrete a chronic acid load
• Normal urine is mildly acidic (pH ≈ 6) at baseline, reflecting net daily acid excretion

Approximate nephron reabsorption budget (freely filtered load)

• PCT: ~67% of filtered Na⁺, water, and K⁺ regardless of GFR ("glomerulotubular balance"); ~100% of filtered glucose and amino acids; ~50% of urea; ~85% of filtered phosphate
• Thick ascending limb: ~20–25% of filtered Na⁺/K⁺ via the Na⁺-K⁺-2Cl⁻ cotransporter; essentially impermeable to water
• DCT: ~5–7% of filtered Na⁺ via the Na⁺-Cl⁻ cotransporter; still impermeable to water
• Collecting duct: final ~5% of Na⁺ (aldosterone-dependent) and up to ~15% of filtered water (ADH-dependent)

Direction of change in each primary disturbance

• Respiratory compensation for a metabolic problem is fast (minutes); renal compensation for a respiratory problem is slow (days) — this is why acute respiratory disturbances show near-uncompensated pH swings while chronic ones look much closer to normal

Fast differentiators worth drilling

• Hematuria + recent sore throat (1–2 weeks ago) → think poststreptococcal GN; hematuria within 1–2 days of a URI → think IgA nephropathy
• Nephrotic child under 5 with no other findings → minimal change disease until proven otherwise
• Young man with hemoptysis + hematuria → Goodpasture syndrome
• Flank pain + palpable kidneys + family history → ADPKD
• Painless gross hematuria in an older smoker → transitional cell carcinoma (bladder/ureter/pelvis) or RCC depending on location
• Muddy brown casts → ATN; WBC casts → pyelonephritis or interstitial nephritis; RBC casts → glomerulonephritis; fatty/waxy casts → nephrotic syndrome/advanced CKD

Common examination traps

• "Increased anion gap" and "decreased anion gap" questions almost always hinge on whether bicarbonate was lost with chloride replacing it (normal gap) versus consumed by buffering an unmeasured acid (high gap)
• A rising creatinine after starting an ACE inhibitor is expected and mild (efferent dilation drops GFR) — a large rise (>30%) instead suggests underlying bilateral renal artery stenosis
• Distinguish SIADH (euvolemic hyponatremia, concentrated urine) from cerebral salt wasting (hypovolemic hyponatremia) — both can occur after CNS injury but require opposite management (fluid restriction vs. fluid/salt repletion)
• "Nephrotic-range proteinuria" is a lab threshold (>3.5 g/day), not proof of full-blown nephrotic syndrome — the full syndrome also needs hypoalbuminemia and edema

Glomerular filtration barrier — three layers, two jobs

• Fenestrated capillary endothelium: size barrier — keeps blood cells in, lets plasma solutes through
• Glomerular basement membrane: made of type IV collagen and heparan sulfate — the heparan sulfate carries a negative charge that repels other negatively charged proteins like albumin
• Podocyte foot processes with slit diaphragms: the final size filter, blocking anything larger than a small protein from getting through
• Losing the negative charge barrier (e.g., podocyte effacement in minimal change disease) lets albumin leak through even though the physical pores haven't changed size — this is why nephrotic syndromes are fundamentally charge-barrier diseases

Nephron segments — one-line function of each

• Glomerulus: filtration barrier — size- and charge-selective
• Proximal convoluted tubule: bulk isosmotic reabsorption of Na⁺, water, glucose, amino acids, bicarbonate
• Thin descending limb: water-permeable only — concentrates filtrate
• Thick ascending limb: impermeable to water, active NaCl reabsorption — dilutes filtrate, builds medullary gradient
• Distal convoluted tubule: fine-tunes Na⁺/Ca²⁺ under aldosterone/PTH control
• Collecting duct: final water reabsorption (ADH) and K⁺/H⁺ handling (aldosterone)

Total body water and its compartments

• Measure TBW with a tracer that crosses all membranes (tritiated water)
• Measure ECF with a tracer confined to extracellular space (inulin, mannitol)
• Measure plasma volume with a tracer that stays intravascular (labeled albumin)
• ICF = TBW − ECF (calculated, not measured directly)
• Normal serum osmolality runs about 275–295 mOsm/kg H₂O
• Plasma volume = total blood volume × (1 − hematocrit)

Three successive kidney systems

Ascent and rotation

• Kidney originates in the pelvis, "ascends" to the abdomen as the fetus grows caudally away from it (not true migration)
• Rotates 90° so the hilum faces medially
• Blood supply is sequentially taken over by higher aortic branches during ascent

Lower urinary tract

• Urogenital sinus divides into the bladder and urethra
• Bladder is continuous with the allantois → allantois regresses to the median umbilical ligament (urachus remnant)
• Urethra: proximal part from endoderm/urogenital sinus, distal-most part from ectoderm