USMLE ENDPOINT BY DR.

AHMED SHEBL RENAL SYSTEM

Embryology
Kidney embryology:
Pronephros—week 4; then degenerates.
Mesonephros—functions as interim kidney for 1st trimester; later contributes to
male genital system (Wolffian duct).
Metanephros—permanent; first appears in 5th week of gestation; nephrogenesis
continues
through weeks 32–36 of gestation.
 Ureteric bud—derived from caudal end of mesonephric duct; gives rise to ureter,
pelvises, calyces, and collecting ducts; fully canalized by 10th week.
 Metanephric mesenchyme (i.e., metanephric blastema)—ureteric bud interacts with this
tissue; interaction induces differentiation and formation of glomerulus through to
distal convoluted tubule (DCT).
 Aberrant interaction between these 2 tissues may result in several congenital
malformations of the kidney (Multicystic dysplastic kidney).
 Ureteropelvic junction—last to canalize  most common site of obstruction (can be
detected on prenatal ultrasound as hydronephrosis).

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Potter sequence (syndrome):

 Oligohydramnios  compression of developing fetus  limb deformities (club

feet), facial anomalies (eg, low-set ears and retrognathia A, flattened nose),
compression of chest and lack of amniotic fluid aspiration into fetal lungs 
pulmonary hypoplasia (cause of death).
 Causes include ARPKD, obstructive uropathy (eg, posterior urethral valves),
bilateral renal agenesis, and chronic placental insufficiency.

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Horseshoe kidney:
 Inferior poles of both kidneys fuse abnormally A.
 As they ascend from pelvis during fetal development, horseshoe kidneys get trapped
under inferior mesenteric artery and remain low in the abdomen.
 Kidneys function normally.
 Associated with hydronephrosis (eg,
ureteropelvic junction obstruction), renal
stones, infection, chromosomal aneuploidy
syndromes (eg, Turner syndrome; trisomies 13,
18, 21), and rarely renal cancer.

Congenital solitary functioning kidney:

 Condition of being born with only one functioning kidney.
 Majority asymptomatic with compensatory hypertrophy of contralateral kidney, but
anomalies in contralateral kidney are common. Often diagnosed prenatally via ultrasound.
 Unilateral renal agenesis:
 Ureteric bud fails to develop and induce differentiation of metanephric
mesenchyme  complete absence of kidney and ureter.
 Multicystic dysplastic kidney:
 Ureteric bud fails to induce differentiation of metanephric mesenchyme 
nonfunctional kidney consisting of cysts and connective tissue.
 Predominantly nonhereditary and usually unilateral; bilateral leads to Potter
sequence.

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Duplex collecting system:

 Bifurcation of ureteric bud before it enters the metanephric blastema creates a Y-
shaped bifid ureter.
 Duplex collecting system can alternatively occur through two ureteric buds reaching and
interacting with metanephric blastema.
 Strongly associated with vesicoureteral reflux and/or ureteral obstruction,  risk for
UTIs.

Posterior urethral valves:

 Membrane remnant in the posterior urethra in males; its persistence can lead to urethral
obstruction.
 Can be diagnosed prenatally by hydronephrosis (Bilateral) and dilated or thick-
walled bladder on ultrasound.
 Most common cause of bladder outlet obstruction in male infants.

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Anatomy
Kidney anatomy and glomerular structure:
Kidney surface anatomy:
 UW: Fracture 12th rib  risk for kidney injury.
 The 12th rib overlies the parietal pleura medially and the kidney laterally.
 The left 9th, 10th, and 11th ribs overlie the spleen.
 The right 8th-11th ribs overlie the liver's posterior surface.

 Left kidney is taken during donor transplantation because it has a longer renal vein.

Renal blood flow:

Renal artery  segmental artery  interlobar artery  arcuate artery
 interlobular artery  afferent arteriole  glomerulus  efferent arteriole  vasa
recta/ peritubular capillaries  venous outflow.
Afferent = Arriving.
Efferent = Exiting.
 Peritubular capillaries  cortex.
 Vasa recta  medulla.

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Course of ureters:

 It courses anterior to the iliac vessels (area of resection of the pelvic nodes, which drain
the uterus and cervix) and just posterior to the uterine artery near the lateral fornix of the
vagina.
 Ureters pass under uterine artery or under vas deferens (retroperitoneal).
 Gynecologic procedures (eg, ligation of uterine or ovarian vessels) may damage ureter
 ureteral obstruction or leak  hydronephrosis and flank pain due to distension
of the ureter and renal pelvis.
 ―Water (ureters) under the bridge (uterine artery or vas deferens).‖

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UW: Layers traversed during suprapubic cystostomy:

 Skin  superficial fascia  aponeurosis  transversalis fascia  bladder wall.
 The bladder is extraperitoneal. In placement of a suprapubic cystostomy, the trocar and
cannula will pierce the layers of the abdominal wall but will not enter the peritoneum.
 The superior surface of the bladder is covered with peritoneum and is related to coils of
ileum or sigmoid colon. Along the lateral margins of this surface, the peritoneum is
reflected onto the lateral pelvic walls. The bladder is therefore extraperitoneal.

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 USMLE ENDPOINT BY DR. AHMED SHEBL RENAL SYSTEM

Physiology
Fluid compartments:

Volume
where:
Volume = volume of distribution, or volume of the body fluid compartment (L)
Amount = amount of substance present (mg)
Concentration = concentration in plasma (mg/L)

Plasmaosm = (2 × Na) + (Glucose/18) + (BUN/2.8)

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Glomerular filtration barrier:

 Responsible for filtration of plasma according to size and charge selectivity.
 Composed of:
 Fenestrated capillary endothelium.
 Basement membrane with type IV collagen chains and heparan sulfate.
 Epithelial layer consisting of podocyte foot processes A.
 Charge barrier—all 3 layers contain ⊝ charged glycoproteins preventing ⊝ charged
molecule entry (eg, albumin).
 Size barrier—fenestrated capillary epithelium (prevent entry of > 100 nm
molecules/blood cells); podocyte foot processes interpose with basement membrane; slit
diaphragm (prevent entry of molecules > 50–60 nm).

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Function of the nephron:

Renal clearance:
 Cx = UxV/Px = volume of plasma from
which the substance is completely cleared
per unit time.
 If Cx < GFR: net tubular reabsorption of X.
 If Cx> GFR: net tubular secretion of X.
 If Cx= GFR: no net secretion or reabsorption.

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UW: Glucose reabsorption and PAH secretion is carrier-mediated transport; can be

saturated at high blood concentrations.

Glomerular filtration rate:

 Inulin clearance can be used to calculate
GFR because it is freely filtered and is
neither reabsorbed nor secreted.
 Normal GFR ≈ 100 mL/min.
 Creatinine clearance is an approximate
measure of GFR. Slightly overestimates GFR because creatinine is moderately secreted
by renal tubules.

Serum creatinine and GFR:

 UW: The relationship between serum
creatinine and GFR is nonlinear.
 A person's serum creatinine can be essentially
normal even after a 50% loss of kidney
function (i.e. following kidney donation or
unilateral nephrectomy).
 UW: Serum creatinine levels begin to rise
significantly as the GFR declines to <60
mL/min.
 UW: Serum creatinine is therefore an
insensitive indicator for decreasing GFR when
creatinine levels are normal.
 Incremental reductions in GFR define the stages of chronic kidney disease.

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Effective renal plasma flow:

 Effective renal plasma flow (eRPF) can be
estimated using para-aminohippuric acid
(PAH) clearance.
 Between filtration and secretion, there is nearly
100% excretion of all PAH that enters
the kidney.
 eRPF = UPAH × V/PPAH = CPAH.
 Renal blood flow (RBF) = RPF/ (1 - Hct).
 Plasma = 1 - hematocrit.
 eRPF underestimates true renal plasma flow
(RPF) slightly.

Filtration:
 Filtration fraction (FF) = GFR/RPF. Normal FF = 20%.
 Filtered load (mg/min) = GFR (mL/min) × plasma concentration (mg/mL).
 GFR can be estimated with creatinine clearance.
 RPF is best estimated with PAH clearance.
 Prostaglandins Dilate Afferent arteriole (PDA)
ACE inhibitors Constrict Efferent arteriole (ACE).

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Changes in glomerular dynamics:

 UW: Acute ureteral constriction or obstruction  ↓GFR & ↓FF.

 K. Effect of sympathetic stimulation: VC of both afferent and efferent which are
both considered connected as a resistance in series  ↓↓RPF & ↓hydrostatic pressure
 ↓GFR & so, ↑FF.

 K: What would happen if you gave NSAIDs to the 75-year-old man who is
hemorrhaging?
 During a stress state the increase in sympathetic tone causes vasoconstriction
of the afferent arterioles. The same stimuli activate a local production of
prostaglandins.
 Prostaglandins lead to vasodilation of the afferent arterioles, thus modulating
the vasoconstriction.
 Unopposed, the vasoconstriction from the sympathetic nervous system and
angiotensin II can lead to a profound reduction in RPF and GFR, which in
turn, could cause renal failure.
 NSAIDs inhibit synthesis of prostaglandins and interfere with these protective
effects.

 BRS: Increases in the filtration

fraction produce increases in the protein
concentration of peritubular capillary
blood, which leads to increased
reabsorption in the proximal tubule.
■ Decreases in the filtration fraction
produce decreases in the protein
concentration of peritubular capillary blood
and decreased reabsorption in the
proximal tubule.

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Calculation of reabsorption and secretion rate:

 Filtered load = GFR × Px.  rate in.
 Excretion rate = V × Ux  rate out.

 Reabsorption rate = filtered – excreted.

 Secretion rate = excreted – filtered.

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Glucose clearance:
 Glucose at a normal plasma level (range
60–120 mg/dL) is completely reabsorbed
in proximal convoluted tubule (PCT) by
Na+/glucose cotransport.
 In adults, at plasma glucose of ∼ 200
mg/dL, glucosuria begins (threshold).
 At rate of ∼ 375 mg/min, all transporters
are fully saturated (Tm).
 Normal pregnancy may decrease ability of
PCT to reabsorb glucose and amino acids
 glucosuria and aminoaciduria.
 Sodium-glucose cotransporter 2 (SGLT2) inhibitors (eg, -flozin drugs) permit
glucosuria at plasma concentrations < 200 mg/dL.
 Glucosuria is an important clinical clue to diabetes mellitus.
 Splay is the region of substance clearance between threshold and Tm; (between threshold
and Tm) due to the heterogeneity of nephrons.

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Nephron physiology:

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Renal tubular defects:

Fanconi syndrome is first (PCT), the rest are in alphabetic order.
 Fanconi syndrome:
1. Generalized reabsorptive defect in PCT.
2. Associated with ↑ excretion of nearly all amino acids, glucose, HCO3–, and
PO43.
3. May result in metabolic acidosis (proximal renal tubular acidosis).
4. Causes include: hereditary defects (eg, Wilson disease, tyrosinemia, glycogen
storage disease, and cystinosis), ischemia, multiple myeloma,
nephrotoxins/drugs (eg, ifosfamide, cisplatin, tenofovir, and expired
tetracyclines), and lead poisoning.
 Bartter syndrome:
1. Reabsorptive defect in thick ascending loop of Henle. Affects Na+/K+/2Cl-
cotransporter.
2. Results in hypokalemia and metabolic alkalosis with hypercalciuria.
3. Presents similarly to chronic loop diuretic use.
4. Autosomal recessive.
 Gitelman syndrome:
1. Reabsorptive defect of NaCl in.
2. Leads to hypokalemia, hypomagnesaemia, metabolic alkalosis,
hypocalciuria.
3. Similar to using life-long thiazide diuretics.
4. Autosomal recessive.
5. Less severe than Bartter syndrome.
 Liddle syndrome:
1. Gain of function mutation  ↑ Na+ reabsorption in collecting tubules (↑
activity of Na+ channel).
2. Results in hypertension, hypokalemia, metabolic alkalosis, ↓ aldosterone.
3. Presents like hyperaldosteronism, but aldosterone is nearly undetectable.
4. Autosomal dominant.
5. Treatment: amiloride.

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 Syndrome of Apparent Mineralocorticoid Excess:

1. Hereditary deficiency of 11β-hydroxysteroid dehydrogenase, which
normally converts cortisol (can activate mineralocorticoid receptors) to
cortisone (inactive on mineralocorticoid receptors) in cells containing
mineralocorticoid receptors.
2. Excess cortisol in these cells from enzyme deficiency  ↑ mineralocorticoid
receptor activity  hypertension, hypokalemia, metabolic alkalosis.
3. Low serum aldosterone levels.
4. Can be acquired disorder from glycyrrhetinic acid (present in licorice), which
blocks activity of 11β-hydroxysteroid dehydrogenase.
5. Treatment: corticosteroids (exogenous corticosteroids ↓ endogenous cortisol
production  ↓ mineralocorticoid receptor activation).
6. Cortisol tries to be the SAME as aldosterone.

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Concentration and dilution of the urine:

UW: Permeability of the

nephron to water:
 Regardless of the patient's
hydration status, the majority
of water reabsorption in the
nephron occurs in the
proximal tubule passively
with the reabsorption of
solutes.
 In the presence of ADH: the
collecting ducts contain the
most concentrated fluid in
the nephron, while the thick
ascending limb of the loop
of Henle and distal
convoluted tubule contain
the most dilute fluid.
 In the absence of ADH: the
tubular fluid is most
concentrated at the junction between the descending and ascending limbs of the
loop of Henle and most dilute in the collecting ducts.

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 UW: ADH acts on the medullary segment of the collecting duct to increase urea
and water reabsorption, allowing for the production of maximally concentrated
urine.

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Relative concentrations along proximal convoluted tubules:

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 Tubular inulin ↑ in concentration (but not amount) along the PCT as a result of water
reabsorption.
 Cl- reabsorption occurs at a slower rate than Na+ in early PCT and then matches the
rate of Na+ reabsorption more distally. Thus, its relative concentration ↑ before it
plateaus.
 UW: Where is the lowest concentration of PAH?
PAH is primarily secreted into the nephron by the proximal tubule, but some is also
freely filtered by the glomerulus. PAH is not reabsorbed by any portion of the
nephron. Therefore, tubular fluid concentration of PAH is lowest in Bowman's space.

Na+ reabsorption along the nephron

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Renin-angiotensin-aldosterone system:

 Renin:
 Secreted by JG cells in response to ↓ renal arterial pressure, ↑ renal
sympathetic discharge (β1 effect), and ↓ Na+ delivery to macula densa cells.
 AT II:
 Helps maintain blood volume and blood pressure.
 Affects baroreceptor function; limits reflex bradycardia, which would
normally accompany its pressor effects.
 ANP, BNP:
 Released from atria (ANP) and ventricles (BNP) in response to ↑ volume;
 may act as a “check” on renin-angiotensin-aldosterone system;
 Relaxes vascular smooth muscle via cGMP  ↑ GFR, ↓ renin.
 Dilates afferent arteriole, constricts efferent arteriole  promotes natriuresis.
 ADH:
 Primarily regulates osmolarity; also responds to low blood volume states.
 Aldosterone:
 Primarily regulates ECF volume and Na+ content;
 Responds to low blood volume states.
 Responds to hyperkalemia by ↑ K+ excretion.

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Juxtaglomerular apparatus:

 Consists of mesangial cells, JG cells (modified smooth muscle of afferent arteriole)

and the macula densa (NaCl sensor, part of DCT).
 JG cells secrete renin in response to ↓ renal blood pressure and ↑ sympathetic tone
(β1).
 Macula densa cells sense ↓ NaCl delivery to DCT  ↑ renin release  efferent
arteriole vasoconstriction  ↑ GFR.
 JGA maintains GFR via renin-angiotensin aldosterone system.
 β-blockers can decrease BP by inhibiting β1-receptors of the JGA  ↓ renin release.

Kidney endocrine functions:

 Erythropoietin:
 Released by interstitial cells in peritubular capillary bed in response
to hypoxia.
 Stimulates RBC proliferation in bone marrow.
 Erythropoietin often supplemented in chronic kidney disease.
 Calciferol (vitamin D):
 PCT cells convert 25-OH vitamin D3 to 1,25- (OH)2 vitamin D3
(calcitriol, active form.)

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 Prostaglandins:
 Paracrine secretion which vasodilates the afferent arterioles to ↑
RBF.
 NSAIDs block renal-protective prostaglandin synthesis  constriction
of afferent arteriole and ↓ GFR; this may result in acute renal failure in
low renal blood flow states.
 Dopamine:
 Secreted by PCT cells, promotes natriuresis.
 At low doses, dilates interlobular arteries, afferent arterioles, efferent
arterioles  ↑RBF, little or no change in GFR.
 At higher doses, acts as vasoconstrictor.

Hormones acting on kidney:

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Potassium shifts:

 Potassium regulation in distal tubule and collecting duct: Either reabsorb or

secrete K+, depending on dietary K+ intake.
 Reabsorption of K+:
 Involves an H+, K+-ATPase in the luminal membrane of the α-
intercalated cells.
 Occurs only on a low-K+ diet (K+ depletion). Under these conditions,
K+ excretion can be as low as 1% of the filtered load because the
kidney conserves as much K+ as possible.
 Secretion of K+:
 Occurs in the principal cells.
 Variable and accounts for the wide range of urinary K+ excretion.
 Depends on factors such as dietary K+, aldosterone levels, acid–base
status, and urine flow rate.

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UW: K depletion  stimulates α-intercalated cells to reabsorb extra potassium.

Normal or increased K load  stimulate principal cells secrete K.

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Electrolyte disturbances

• Tetany in the absence of hypocalcemia and alkalosis = hypomagnesaemia.

• Diarrhea & diuretics cause hypomagnesaemia and hypokalemia.

Acid-base physiology:

Acid
production

Nonvolatile
Volatile acid
acids (fixed
(Co2)
acids)

1. Volatile acid:
 Is Co2.
 Produced from the aerobic metabolism of cells.
 CO2 combines with H2O to form the weak acid H2CO3, which dissociates
into H+ and HCO3- by the following reactions:
 Co2 + H2O ↔ H2CO3 ↔ H+ + HCO3-
 Carbonic anhydrase, which is present in most cells, catalyzes the reversible
reaction between CO2 and H2O.
2. Nonvolatile acids (fixed acids):
 Include sulfuric acid (a product of protein catabolism) and phosphoric acid
(a product of phospholipid catabolism).
 Normally produced at a rate of 40 to 60 mmoles/day.
 Other fixed acids that may be overproduced in disease or may be ingested
include ketoacids, lactic acid, and salicylic acid.

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Renal regulation of acid base balance:

UW: Urinary acid excretion occurs primarily in the form of NH4 and titratable acids
(H2PO4). In metabolic acidosis, urinary pH decreases due to increased excretion of free H+,
NH4; and H2PO4. Bicarbonate is completely reabsorbed from the tubular fluid in
acidotic states.

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 Predicted respiratory compensation for a simple metabolic acidosis can be calculated

using the Winter’s formula.
 If measured Pco2 > predicted Pco2  concomitant respiratory acidosis;
 If measured Pco2 < predicted Pco2  concomitant respiratory alkalosis:
o Pco2(predicted) = 1.5 [HCO3–] + 8 ± 2

Acidosis and alkalosis:

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A normal AG acidosis is characterized by

a lowered bicarbonate concentration,
which is counterbalanced by an equivalent
increase in plasma chloride concentration.
For this reason, it is also known as
hyperchloremic metabolic acidosis.

Metabolic response to vomiting:

UW: Aspirin toxicity (suspected in a patient with the triad of fever, tinnitus,
and tachypnea): causes 2 different acid-base abnormalities simultaneously:
 Respiratory alkalosis: is the first disturbance to occur, as salicylates directly
stimulate the medullary respiratory center. The resulting increase in ventilation
leads to increased loss of CO2 in the expired air.
 Anion gap metabolic acidosis: begins to develop shortly afterward, as high
concentrations of salicylates increase lipolysis, uncouple oxidative
phosphorylation, and inhibit the citric acid cycle. This results in the
accumulation of organic acids in the blood (eg, ketoacids, lactate and
pyruvate).

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Metabolic alkalosis:
 UW: The next step in a patient with metabolic alkalosis  urine chloride.

 Loss of Cl (hypochloremia) impairs HCO3 excretion by the kidney (by β-

intercalated cells), worsening the metabolic alkalosis.
 ↑mineralocorticoids  loss of H+  ↑lumen negativity  chloride co-secreted 
↑urinary chloride.

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Renal tubular acidosis:

A disorder of the renal tubules that leads to normal anion gap (hyperchloremic)
metabolic acidosis.
 Distal renal tubular acidosis (type 1):
a) Urine pH > 5.5.
b) Defect in ability of H/K pump in α intercalated cells to secrete H+ 
no new HCO3- is generated  metabolic acidosis.
c) Associated with hypokalemia, ↑ risk for calcium phosphate kidney
stones (due to ↑ urine pH and ↑ bone turnover).

Why hypokalemia in type I RTA?  The defect here is in H/K PUMP which normally excrete H and
reabsorb K  its failure will lead to acidosis + hypokalemia.

d) Causes: amphotericin B toxicity, analgesic nephropathy, congenital

anomalies (obstruction) of urinary tract.
 Proximal renal tubular acidosis (type 2):
a) Defect in PCT HCO3- reabsorption  ↑ excretion of HCO3- in urine
and subsequent metabolic acidosis.
b) Urine is acidified by α-intercalated cells in collecting tubule  Urine
PH < 5.5
c) Associated with hypokalemia, ↑ risk for hypophosphatemic rickets.
d) Causes: Fanconi syndrome and carbonic anhydrase inhibitors.
 Hyperkalemic renal tubular acidosis (type 4):
a) Urine pH < 5.5.
b) Hypoaldosteronism  hyperkalemia  ↓ NH3 synthesis in PCT 
↓ NH4+ excretion  ↓buffer system for H+ excretion  acidic urine.
When urinary potassium excretion is impaired, some of the excess potassium enters the cells, with
electroneutrality being maintained in part by the movement of cellular sodium and hydrogen ions into the
extracellular fluid. The ensuing intracellular alkalosis in the kidney would then diminish ammonium
production in the proximal tubule.

c) Causes: ↓ aldosterone production (eg, diabetic hyporeninism, ACE

inhibitors, ARBs, NSAIDs, heparin, cyclosporine, adrenal
insufficiency) or aldosterone resistance (eg, K+-sparing diuretics,
nephropathy due to obstruction, TMP/SMX).

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Pathology
Casts in urine:
 Presence of casts indicates that hematuria/pyuria is of glomerular or renal tubular
origin.
 Bladder cancer, kidney stones  hematuria, no casts.
 Acute cystitis  pyuria, no casts.
 RBC casts: A Glomerulonephritis, malignant hypertension.
 WBC casts: B Tubulointerstitial inflammation, acute pyelonephritis, transplant
rejection.
 Fatty casts (“oval fat bodies”): Nephrotic syndrome. Associated with ―Maltese
cross‖ sign.
 Granular (“muddy brown”) casts C Acute tubular necrosis.
 Waxy casts: D are seen in advanced renal disease (chronic renal failure).
They are shiny, translucent tubular structures formed in the dilated tubules of enlarged
nephrons that undergo compensatory hypertrophy in response to reduced renal mass.
 Hyaline casts: E Nonspecific, can be a normal finding, often seen in concentrated
urine samples.

Nomenclature of glomerular disorders

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Glomerular diseases:

Nephritic syndrome:
NephrItic syndrome = Inflammatory process. When glomeruli are involved, leads to
hematuria and RBC casts in urine. Associated with azotemia, oliguria, hypertension (due to
salt retention), and proteinuria.

1) Acute poststreptococcal glomerulonephritis (PSGN):

a. Most frequently seen in children. Occurs ∼ 2–4 weeks after group A
streptococcal infection of pharynx or skin. Resolves spontaneously. Note:
Once again in contrast with rheumatic fever, the incidence of PSGN is not
decreased by antibiotic administration.
b. Type III hypersensitivity reaction.
c. Presents with peripheral and periorbital edema, cola-colored urine,
hypertension.
d. LM—glomeruli enlarged and hypercellular A due to a combination of
leukocyte infiltration (neutrophils and monocytes) and mesangial and
endothelial cell proliferation.

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e. IF—(―starry sky‖) granular appearance (―lumpy-bumpy‖) B due to IgG,

IgM, and C3 deposition along GBM and mesangium.
f. EM—subepithelial immune complex (IC) humps due to deposition of
immune complexes composed of IgG. IgM, and C3.
g. Lab findings:
i. Elevated titers of anti-streptococcal antibodies (anti-streptolysin O,
anti-DNase B, anti-cationic proteinase).
ii. Low C3 concentration.
iii. Cryoglobulins may also be present in the serum.

UW: Age is an important prognostic factor in poststreptococcal glomerulonephritis.

95% of affected children, but only 60% of affected adults recover completely.

2) Rapidly progressive (crescentic) glomerulonephritis

a. LM and IF—crescent moon shape...
b. Crescents consist of fibrin and plasma proteins (eg, C3b) with glomerular
parietal cells, monocytes, macrophages. Due to fibrinoid necrosis of the
glomeruli  fibrin escape into Bowman's space.
c. Poor prognosis. Rapidly deteriorating renal function (days to weeks).
d. Several disease processes may result in this pattern, in particular:

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3) Diffuse proliferative glomerulonephritis:

a. Often due to SLE or
membranoproliferative
glomerulonephritis.
b. LM—―wire looping‖ of capillaries.
c. EM—subendothelial and sometimes
intramembranous IgG-based ICs often
with C3 deposition.
d. IF—granular.
e. A common cause of death in SLE (think ―wire lupus‖).
f. DPGN and MPGN often present as nephrotic syndrome and nephritic
syndrome concurrently.

 UW: Infective endocarditis may affect the kidney by 2 ways:

1) Immune complex deposition  diffuse proliferative GN  acute
renal insufficiency  ↑Creatinine.
2) Emboli from vegetations  renal infarction or abscess  flank
pain + normal creatinine.

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4) IgA nephropathy (Berger disease):

a. LM—mesangial proliferation (hypercellularity).
b. EM—mesangial IC deposits.
c. IF—IgA-based IC deposits in mesangium.
d. Renal pathology of Henoch-Schönlein purpura.
e. Episodic gross hematuria that occurs concurrently with respiratory or GI
tract infections (IgA is secreted by mucosal linings). In contrast, post-
streptococcal glomerulonephritis is seen 1-3 weeks after streptococcal
pharyngitis and is usually not recurrent.
Not to be confused with Buerger disease (thromboangiitis obliterans).

UW: Painless hematuria within 5-7 days of an upper respiratory tract Infection 
IgA nephropathy.
UW: When IgA nephropathy is accompanied by extra renal symptoms (eg
abdominal pain, arthralgias, purpuric skin lesions), the syndrome is called Henoch-
Schönlein purpura.

5) Alport syndrome:
a. Mutation in type IV collagen  thinning and splitting of glomerular
basement membrane.
b. Most commonly X-linked dominant.
c. Eye problems (eg, retinopathy, lens dislocation), glomerulonephritis, and
sensorineural deafness; “can’t see, can’t pee, can’t hear a bee.”
d. “Basket-weave” appearance on EM  Lamellated appearance.

6) Membranoproliferative glomerulonephritis:
a. Type I—subendothelial immune complex (IC)
deposits with granular IF; “tram-track” appearance
on PAS stain D and H&E stain E due to GBM
splitting caused by mesangial ingrowth. Causes:
Idiopathic or may be 2° to hepatitis B or C
infection.
b. Type II—also called dense deposit disease 
deposition within the basement membrane.
i. Type II is associated with C3 nephritic factor
(IgG antibody that stabilizes C3 convertase 
persistent activation of C3  persistent
complement activation  ↓ C3 levels).
c. MPGN is a nephritic syndrome that often copresents
with nephrotic syndrome.

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Nephrotic syndrome
 The initial event is an increased permeability of the glomerular capillary wall to
plasma proteins caused by structural or physicochemical changes  massive urine
protein loss.
 Massive prOteinuria (> 3.5 g/day) with hypoalbuminemia, resulting edema,
hyperlipidemia.
 Frothy urine with fatty casts. Due to podocyte damage disrupting glomerular
filtration charge barrier.
 May be 1° (eg, direct sclerosis of podocytes) or 2° (systemic process [eg, diabetes]
secondarily damages podocytes).
 Associated with hypercoagulable state (eg, thromboembolism) due to antithrombin
(AT) III loss in urine and ↑ risk of infection (due to loss of immunoglobulins in
urine and soft tissue compromise by edema).

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Renal vein thrombosis as a result of nephrotic syndrome:

 Due to loss of antithrombin III  hypercoagulable state.
 Sudden-onset abdominal or flank pain and gross hematuria with elevated lactate
dehydrogenase as a result of renal infarction.
 Left-sided varicoceles are relatively common.
Nephrotic syndrome ↑ risk of infection:
 The loss of immunoglobulins and low-molecular-weight components of
complement (such as factor B) makes patients with nephrotic syndrome
vulnerable to infections, especially pneumococcal infections.
Hyperlipidemia in nephrotic syndrome:
 To compensate for the decreased plasma albumin concentration, the liver
increases its synthesis of proteins, including lipoproteins.
 This increase in lipoprotein production, along with the decrease in lipid catabolism
due to low plasma levels of lipoprotein lipase and abnormal transport of circulating
lipid particles, contributes to the increased cholesterol triglyceride, VLDL, LDL,
Lp(a) lipoprotein, and apoprotein concentrations seen in nephrotic syndrome.
Lipiduria:
 Increased glomerular capillary wall permeability leads to lipid loss in the urine in
the form of free fat and oval fat bodies (with characteristic Maltese cross
appearance under polarized light).
Causes of edema in nephrotic syndrome:
 ↓ Serum albumin  ↓ plasma oncotic pressure  fluid shift to the interstitium 
↓intravascular volume  ↓ renal perfusion pressure  ↑RAAS  ↑aldosterone
(secondary hyperaldosteronism)  sodium retention.
 The decreased intravascular volume also stimulates antidiuretic hormone (ADH) a
secretion, which increases water retention in the collecting ducts.

 Severe nephritic syndrome may present with nephrotic syndrome features (nephritic-
nephrotic syndrome) if damage to GBM is severe enough to damage charge barrier.

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1) Minimal change disease (lipoid nephrosis):

 Most common cause of nephrotic syndrome in children.
 Often 1° (idiopathic) and may be triggered by recent infection, immunization,
immune stimulus, insect stings.
 Rarely, may be 2° to lymphoma (eg, cytokine-mediated damage).
 1° disease has excellent response to corticosteroids.
 Pathogenesis:
 MCD is caused by a primary defect in immunologic function as
suggested by its association with respiratory infections, immunizations,
and atopic disorders, as well as its excellent response to steroid therapy.
 This immune dysfunction leads to overproduction of a specific cytokine
(possibly IL-13) that causes direct damage to the podocytes leading to
retraction and fusion of the foot processes with reduced numbers of slit
diaphragms.
 This damage causes increased translocation of albumin, but not other
serum proteins, through the podocyte barrier, resulting in selective
proteinuria (loss of albumin not Igs).
 LM—normal glomeruli (lipid may be seen in PCT cells).
 IF ⊝.
 EM—effacement of foot processes A.

 Low-molecular weight proteins, such as albumin and transferrin, are excreted.

Large proteins such as IgG and macroglobulin are not lost.
 Occurs mainly in minimal change disease.
 Size selectivity is due to fenestrated endothelial cells.
 Charge selectivity is due to heparan sulfate in the GBM.
 Albumin has small size and can pass through the endothelium but it is –ve charged
and prevented by the charge selectivity.
 Charge selectivity are lost from the glomerular basement membrane in minimal
change disease.

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2) Focal segmental glomerulosclerosis (FSGN):

 Most common cause of nephrotic syndrome in African Americans and
Hispanics.
 Can be 1° (idiopathic) or 2° to other conditions (eg, HIV infection, sickle cell
disease, heroin abuse, massive obesity, interferon treatment, chronic kidney
disease due to congenital malformations).
 LM—segmental sclerosis and hyalinosis B.
 IF—often ⊝, but may be ⊕ for nonspecific focal deposits of IgM, C3, C1.
 EM—effacement of foot process similar to minimal change disease.
 1° disease has inconsistent response to steroids. May progress to chronic renal
disease.

Nephrotic + effacement of foot process + no response to steroids  FSGN

3) Membranous nephropathy (membranous glomerulonephritis):

 Most common cause of 1° nephrotic syndrome in Caucasian adults.
 Causes:
 85% 1° (eg, antibodies to phospholipase A2 receptor PLA2R).
 2° to drugs (eg, NSAIDs, penicillamine, gold), infections (eg, HBV, HCV,
and syphilis), SLE, or solid tumors. {NB: the MCCO death in SLE is renal
failure}
 LM—diffuse capillary and GBM thickening C. without ↑ in cellularity.
 IF—granular as a result of immune complex deposition. Nephrotic presentation
of SLE.
 EM—“spike and dome” appearance with subepithelial deposits.
 UW: Nephrotic + malignancy  Membranous glomerulonephritis.
 1° disease has poor response to steroids. May progress to chronic renal disease.
 UW: lgG4 antibodies to the phospholipase A2 receptor (PLA2R), a
transmembrane protein abundant on podocytes  primary idiopathic
Membranous nephropathy.

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4) Amyloidosis:
 LM—Congo red stain shows apple-green birefringence under polarized light due
to amyloid deposition in the mesangium.
 Kidney is the most commonly involved organ (systemic amyloidosis).
 Associated with chronic conditions that predispose to amyloid deposition (eg, AL
amyloid, AA amyloid).
5) Diabetic glomerulonephropathy:
 Most common cause of end-stage renal disease in the United States.
 Pathogenesis:
 Non enzymatic glycosylation of GBM  ↑ permeability, thickening.
 Nonenzymatic glycosylation of efferent arterioles (hyaline
arteriosclerosis)  hyperfiltration  ↑GFR  mesangial expansion.

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 UW: Microalbuminuria in diabetic nephropathy (DN):

 In diabetes, there is progressive loss of this negative charge due to
upregulation of heparanase expression by renal epithelial cells, which
results in leakage of albumin.
 In the initial stages of DN, only small amounts of albumin (<300 mg/day)
are lost.
 This moderately increased albuminuria is detected with the use of an
albumin-specific urine dipstick as it is not detected by regular dipstick
analysis.
 Early administration of ACE inhibitors in patients with diabetes and
albuminuria has been shown to reduce urinary albumin excretion and slow
progression to overt diabetic nephropathy.
 UW: microalbuminuria is defined as urine albumin loss of 30-300 mg/day and is
indicative of nephropathy in diabetic patients.
 LM:
 Increased mesangial matrix deposition.
 GBM thickening.
 Eosinophilic nodular glomerulosclerosis (Kimmelstiel-Wilson lesions,
arrows in D)  the nodules compress the glomerular capillaries and cause
loss of glomerular function.

 UW: KW nodules have the following characteristics:

o Located in the peripheral mesangium.
o Ovoid or spherical in shape.
o Lamellated appearance.
o Eosinophilic on hematoxylin and eosin stain.
o Periodic acid-Schiff (+).
 UW: The urinary sediment is typically bland (no red or white cells or casts) in
diabetic nephropathy.

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Kidney stones
 Can lead to severe complications such as hydronephrosis, pyelonephritis.
 Presents with unilateral flank tenderness, colicky pain radiating to groin, hematuria.
 Treat and prevent by encouraging fluid intake.
 Most common kidney stone presentation: calcium oxalate stone in patient with
hypercalciuria and normocalcemia.

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 Most common cause of calcium stones is idiopathic hypercalciuria; hypercalcemia

and its related causes must be excluded.
 Citrate acts in the tubular lumen by combining with calcium to form a nondissociable
but soluble complex. As a result, there is less free calcium available to combine with
oxalate  ↓Ca Oxalate stones.

Hydronephrosis
 Distention/dilation of renal pelvis and calyces A.
 Usually caused by urinary tract obstruction (eg, renal stones, severe BPH, cervical
cancer, injury to ureter); other causes include retroperitoneal fibrosis, vesicoureteral
reflux.
 Dilation occurs proximal to site of pathology.
 Serum creatinine becomes elevated if obstruction is bilateral or if patient has only
one kidney. Leads to compression and possible atrophy of renal cortex and medulla.

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Tumor lysis syndrome

 It often develops during chemotherapy for high-grade lymphomas, leukemias, and

other tumors that have rapid cell turnover and high sensitivity to chemotherapy.
 Pathophysiology:
1) When a large number of tumor cells are destroyed during chemotherapy,
intracellular ions, such as potassium, phosphorous, and uric acid (a metabolite
of tumor nucleic acid), are released into the serum and are then filtered by the
kidneys.
2) Uric acid is soluble at physiologic pH, but precipitates in an acidic
environment.
3) The lowest pH along the nephron is found in the distal tubules and
collecting ducts; so these are the segments of the nephron that become
obstructed by uric acid crystals.
4) Obstructive uropathy and acute renal failure follow.
 Prevention and treatment:
1) Urine alkalinization and hydration.
2) Allopurinol (a xanthine oxidase inhibitor) is used to reduce uric acid
production during the breakdown of tumor cells.

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Renal
cancers

Collecting
Parenchyma system &
urinary tract

Transitional Squamous
Adults Children cell cell
carcinoma carcinoma

Renal cell Renal

Wilm’s tumor
carcinoma oncocytoma

Renal cell carcinoma

 Most common 1° renal malignancy.
 Pathology:
1) Originates from PCT cells  polygonal clear cells filled with accumulated
lipids and carbohydrates.
2) Often golden-yellow due to ↑ lipid content.
 Clinical picture:
1) Most common in men 50–70 years old. ↑ Incidence with smoking and obesity.
2) Triad: Hematuria, flank mass, renal pain.
3) Invades renal vein (may develop varicocele if left sided) then IVC and spreads
hematogenously; metastasizes to lung and bone.
4) Associated with paraneoplastic syndromes (eg, ectopic EPO, ACTH,
PTHrP, and renin).
5) Metastasis to the retroperitoneal LN.
 Pathogenesis: involves loss of VHL (tumor suppressor gene on chromosome 3),
which leads to increased IGF-1 (promotes growth) and increased HIF transcription
factor (increases VEGF and PDGF).

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 Tumors may be hereditary or sporadic:

1) Sporadic tumors classically arise in adult males (average age is 60 years) as a
single tumor in the upper pole of the kidney; major risk factor for sporadic
tumors is cigarette smoke.
2) Hereditary tumors arise in younger adults and are often bilateral. Von
Hippel-Lindau disease is an autosomal dominant disorder associated with
inactivation of the VHL gene leading to increased risk for hemangioblastoma
of the cerebellum and renal cell carcinoma.
 Treatment:
1) Surgery/ablation for localized disease.
2) Immunotherapy (eg, aldesleukin  recombinant IL-2) or targeted therapy for
metastatic disease, rarely curative.
3) Resistant to chemotherapy and radiation therapy.

Renal oncocytoma
 Benign epithelial cell tumor arising from collecting ducts (arrows in A point to well
circumscribed mass with central scar).
 Large eosinophilic cells with abundant mitochondria without perinuclear clearing B
(vs chromophobe renal cell carcinoma).
 Presents with painless hematuria, flank pain, and abdominal mass.
 Often resected to exclude malignancy (eg, renal cell carcinoma).

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Nephroblastoma (Wilms tumor)

 Most common renal malignancy of early childhood
(ages 2–4).
 Contains embryonic glomerular structures.
 Presents with large, palpable, unilateral flank mass A
and/or hematuria.
 “Loss of function” mutations of tumor suppressor
genes WT1 or WT2 on chromosome 11.
 May be a part of several syndromes:
1) WAGR complex: Wilms tumor, Aniridia
(absence of iris), Genitourinary malformations, mental Retardation/intellectual
disability (WT1 deletion).
2) Denys-Drash: Wilms tumor, early-onset nephrotic syndrome, male
pseudohermaphroditism (WT1 mutation).
3) Beckwith-Wiedemann: Wilms tumor, macroglossia, organomegaly,
hemihyperplasia (WT2 mutation).

Urinary Painless hematuria

tract
cancers

Transitional Squamous
cell cell
carcinoma carcinoma

Transitional cell carcinoma:

 Most common tumor of urinary tract system (can occur in renal calyces, renal pelvis,
ureters, and bladder) A B.
 Can be suggested by painless hematuria (no casts).
 Multifocal sessile or papillary tumors.
 Risk factors:
1) Associated with problems in your Pee SAC:
Phenacetin, Smoking, Aniline dyes, and Cyclophosphamide.
2) Occupational exposure to rubber, plastics, aromatic amine-containing dyes,
textiles, or leather.

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Squamous cell carcinoma of the bladder

 Chronic irritation of urinary bladder  squamous metaplasia  dysplasia and
squamous cell carcinoma.
 Risk factors include: Schistosoma haematobium infection (Middle East), chronic
cystitis, smoking, chronic nephrolithiasis.
 Presents with painless hematuria.

Myeloma cast nephropathy ("myeloma kidney")

 C/P of multiple myeloma (MM):

 Should be suspected when an elderly patient has one or more of the
following:
1. Fatigability (due to anemia)
2. Constipation (due to hypercalcemia)
3. Bone pain, most commonly in the back and ribs (bone lysis due to
production of osteoclast-activating factor by myeloma cells)
4. Elevated serum protein (monoclonal proteins)
5. Renal failure.
 Cause of MM nephropathy:
 Excess excretion of free light chains (Bence Jones proteins).
 These proteins are filtered by the glomerulus in small amounts and then
reabsorbed in the tubules.
 When levels exceed reabsorptive capacity, light chains precipitate with Tamm
Horsfall protein and form casts that cause tubular obstruction and epithelial
injury, leading to impaired renal function.
 LM:
 Large glassy casts that stain intensely eosinophilic composed of Bence-Jones
proteins.
 Deposition of light chain fragments in the glomerular mesangium and
capillary loops can also cause renal failure in MM (AL amyloidosis).

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Urinary incontinence

 Stress incontinence:
1) Outlet incompetence (urethral hypermobility or intrinsic sphincteric
deficiency)  leak with ↑ intra-abdominal pressure (eg, sneezing, lifting).
2) ↑ Risk with obesity, vaginal delivery, prostate surgery.
3) UW: It is almost twice as common in women because external urethral
sphincter (EUS) trauma or pudendal nerve (innervates EUS) injury is common
during vaginal child birth. Postmenopausal women have estrogen deficiency,
which can cause laxity and weakness of pelvic floor support.
4) ⊕ Bladder stress test (directly observed leakage from urethra upon coughing
or Valsalva maneuver).
5) Treatment: pelvic floor muscle strengthening (Kegel) exercises, weight loss,
pessaries.

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 Urgency incontinence = spastic bladder = overactive bladder = uninhibited

bladder.
1) The bladder does not distend/relax properly due to loss of descending
inhibitory control from the upper motor neuron (e.g. frontal lobe and internal
capsule infarcts or Multiple sclerosis)  detrusor hyperreflexia and urge
incontinence.
2) Overactive bladder (detrusor instability)  leak with urge to void
immediately.
 UW: Multiple sclerosis + incontinence  urgency incontinence
3) Triggers can include running water, hand washing, or exposure to cold
weather.
4) Urodynamic studies: show little or no residual urine after emptying as
bladder contractility is normal but distensibility is poor.
5) Treatment: Kegel exercises, bladder training (timed voiding, distraction or
relaxation techniques), antimuscarinics (eg, oxybutynin).
6) UW: Bladder infection (cystitis) can cause irritation of the bladder wall and
findings similar to urge incontinence with urinary urgency, frequency, and
incontinence.

 Mixed incontinence:
1) Features of both stress and urgency incontinence.

 Overflow incontinence:
1) Incomplete emptying (detrusor underactivity or outlet obstruction)  leak
with overfilling.
2) UW: Overflow incontinence is due to:
 Impaired detrusor contractility (eg. diabetic autonomic neuropathy) or
 Bladder outlet obstruction (eg, tumor obstructing urethra) causing
incomplete bladder evacuation.
3) Constant involuntary dribbling or urinary incontinence at the end of the day.
Pelvic floor relaxation at night combined with a full bladder can lead to
nocturnal enuresis.
4) ↑ Postvoid residual (urinary retention) on catheterization or ultrasound.
5) Treatment: catheterization, relieve obstruction (eg, α-blockers for BPH).

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Urinary tract infection (acute bacterial cystitis)

 Inflammation of urinary bladder.
 Presents as suprapubic pain, dysuria, urinary frequency, urgency.
 Systemic signs (eg, high fever, chills) are usually absent.
 Risk factors include female gender (short urethra), sexual intercourse (―honeymoon
cystitis‖), indwelling catheter, diabetes mellitus, and impaired bladder emptying.
 Causes:
1) E coli (most common).
2) Staphylococcus saprophyticus—seen in sexually active young women (E
coli is still more common in this group).
3) Klebsiella.
4) Proteus mirabilis—urine has ammonia scent.
 Lab fndings: ⊕ leukocyte esterase. ⊕ Nitrites (indicate gram ⊝ organisms).
Sterile pyuria and ⊝ urine cultures suggest urethritis by Neisseria gonorrhea or
Chlamydia trachomatis.

 UW: Catheter-associated urinary tract infection (UTI ):

 The diagnosis is based on a positive urine culture and ruling out other
systemic infections (eg pneumonia).
 Duration of catheterization is the most significant risk factor for UTI.
 Preventive measures include:
 Avoiding unnecessary catheterization.
 Using sterile technique when inserting the catheter.
 Removing the catheter promptly when no longer needed.

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Pyelonephritis: Acute pyelonephritis

 Neutrophils infiltrate renal interstitium A.
 Affects cortex with relative sparing of glomeruli/vessels.
 Presents with fevers, flank pain (costovertebral angle
tenderness), nausea/vomiting, chills.
 Causes: include
1) Ascending UTI (E coli is most common),
2) Hematogenous spread to kidney.
 Lab findings: WBCs in urine +/- WBC casts. CT would
show striated parenchymal enhancement B.
 Risk factors include: indwelling urinary catheter,
urinary tract obstruction, vesicoureteral reflux, diabetes
mellitus, and pregnancy.
 Complications include: chronic pyelonephritis, renal
papillary necrosis, perinephric abscess, and urosepsis.
 Treatment: antibiotics.

Chronic pyelonephritis
 The result of recurrent episodes of acute pyelonephritis.
 Typically requires predisposition to infection such as vesicoureteral reflux or
chronically obstructing kidney stones.
 Coarse, asymmetric corticomedullary scarring, blunted calyx. Scarring of the upper
pole and the lower pole is a characteristic of the VUR.
 Tubules can contain eosinophilic casts resembling thyroid tissue C (thyroidization of
kidney).
 Xanthogranulomatous pyelonephritis—rare; grossly orange nodules that can mimic
tumor nodules; characterized by widespread kidney damage due to granulomatous
tissue containing foamy macrophages.

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Diffuse cortical necrosis

 Acute generalized cortical infarction of
both kidneys.
 Likely due to a combination of vasospasm
and DIC.
 Associated with obstetric catastrophes (eg,
abruptio placentae), septic shock.

Renal osteodystrophy
 Hypocalcemia, hyperphosphatemia,
and failure of vitamin D
hydroxylation associated with chronic
renal disease  2°
hyperparathyroidism.
 Hyperphosphatemia also
independently ↓ serum Ca2+ by
causing tissue calcifcations, whereas ↓
1,25-(OH)2 D3  ↓ intestinal Ca2+
absorption.
 Causes subperiosteal thinning of
bones.

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Acute kidney injury (acute renal failure)

 Acute kidney injury is defined as an abrupt decline in renal function as measured by
↑ creatinine and ↑ BUN or by oliguria/anuria.
 Prerenal azotemia:
 Due to ↓ RBF (eg, hypotension)  ↓ GFR.
 Na+/H2O and BUN retained by kidney in an attempt to conserve volume  ↑
BUN/creatinine ratio (BUN is reabsorbed, creatinine is not).
 Tubular function remains intact (fractional excretion of sodium (FENa) <
1% and urine osmolality > 500 mOsm/kg).
 Intrinsic renal failure:
 Generally due to acute tubular necrosis or ischemia/toxins; less commonly
due to acute glomerulonephritis (eg, RPGN, hemolytic uremic syndrome) or
acute interstitial nephritis.
 In ATN, patchy necrosis  debris obstructing tubule and fluid backflow
across necrotic tubule  ↓ GFR.
 Urine has epithelial/granular casts.
 BUN reabsorption is impaired  ↓ BUN/creatinine ratio.
 Decreased the ability to reabsorb Na  FENa > 2%.
 Decreased the ability to concentrate the urine  urine osm < 500 mOsm/kg.
 Postrenal azotemia:
 Due to outflow obstruction (stones, BPH, neoplasia, congenital anomalies).
 Tubular function remains intact in early obstruction (fractional excretion
of sodium (FENa) < 1% and urine osmolality > 500 mOsm/kg).
 Develops only with bilateral obstruction.

 Azotemia refers to increased BUN and creatinine in an asymptomatic person.

 Uremia = symptomatic azotemia.

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Consequences of renal failure:

 Inability to make urine and excrete nitrogenous wastes.
 Consequences (MAD HUNGER):
 Metabolic Acidosis
 Dyslipidemia (especially ↑ triglycerides) D2 lipoprotein lipase
inactivation in uremia.
 Hyperkalemia
 Uremia—clinical syndrome marked by:
 ↑ BUN:
o Nausea and anorexia
o Pericarditis  fibrinous type.
o Asterixis
o Encephalopathy
o Platelet dysfunction
 Na+/H2O retention (HF, pulmonary edema, hypertension)
 Growth retardation and developmental delay
 Erythropoietin failure (anemia)
 Renal osteodystrophy.

Hemolytic uremic syndrome (HUS)

Clinical
Etiology
features
• Shiga toxin producing bacteria: • Antecedent diarrheal illness (often bloody).
• E. coli O157:H7 • Hemolytic anemia with schistocytes
• Shigella • Thrombocytopenia
• Acute kidney injury

Pathogenesis of HUS:
These toxins (Shiga toxin) injure the endothelium of preglomerular arterioles and
glomerular capillaries leading to platelet activation and aggregation and the
formation of microthrombi.
Platelet consumption causes thrombocytopenia (platelets <140,000/mm), but there is
typically no purpura or active bleeding.
Erythrocytes passing through the damaged capillaries suffer shear injury and are
broken down to schistocytes causing microangiopathic hemolytic anemia.
Extensive damage to the renal vasculature results in acute kidney injury
(oliguria/anuria, hematuria, increased creatinine).

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Thrombocytopenic thrombotic purpura (TTP)

 C/P: pentad of fever, neurologic symptoms, renal failure, anemia (Microangiopathic
hemolytic anemia with schistocytes) and thrombocytopenia in the setting of a
gastrointestinal illness.
 TTP is almost always characterized by normal PT and aPTT (Vs DIC)

Acute interstitial nephritis (AIN) (Tubulointerstitial nephritis):

 Acute interstitial renal inflammation.

 Pyuria (classically eosinophils) and azotemia occurring after administration of drugs
that act as haptens, inducing hypersensitivity (eg, diuretics, penicillin derivatives,
proton pump inhibitors, sulfonamides, rifampin, NSAIDs).
 Less commonly may be 2° to other processes such as systemic infections (eg,
mycoplasma) or autoimmune diseases (eg, Sjögren syndrome, SLE, sarcoidosis).
 Presentation: Fever, rash, and peripheral eosinophilia in a setting of acute renal
failure (ARF) after introduction of a new drug.
 Urine eosinophils clinch the diagnosis.

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Chronic interstitial nephritis:

 Cause: chronic use of NSAIDs  analgesic nephropathy.
 Pathogenesis: NSAIDs concentrate in the renal medulla along the medullary
osmotic gradient with higher levels in the papillae. These drugs uncouple oxidative
phosphorylation and are thought to cause glutathione depletion with subsequent lipid
peroxidation, resulting in damage to tubular and vascular endothelial cells.
 Pathology:
 Patchy interstitial inflammation with subsequent fibrosis.
 Tubular atrophy, papillary necrosis and scarring.
 Caliceal architecture distortion.
 Calcium may deposit in areas of chronic inflammation and this calcification is
visible on renal imaging.
 C/P:
 Modest elevation in serum creatinine.
 Mild proteinuria.
 Evidence of tubular dysfunction (polyuria, nocturia).
 Microscopic hematuria and sterile pyuria may also be seen on urinalysis.

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Acute tubular necrosis (ATN)

 Most common cause of acute kidney injury in hospitalized
patients.
 Spontaneously resolves in many cases. Can be fatal,
especially during initial oliguric phase.
 ↑ FENa.
 Key findings: granular (“muddy brown”) casts A.
 3 stages:
1) The initiation phase of ATN:
 Corresponds with the original ischemic or
toxic insult.
 Lasts about 36 hours.
 During this phase there is only a slight decrease in urine output as
renal tubular cell damage begins.
2) Maintenance phase (oliguric phase): <risk for hyperkalemia>
 Tubular damage is fully established.
 Patients commonly have oliguria, fluid overload, electrolyte
abnormalities (hyperkalemia, metabolic acidosis) and uremia.
 Lasts 1-3 weeks.
 ↓GFR, ↑Creatinine.
 LM: tubular epithelial necrosis, denudation of the tubular basement
membrane, and casts containing degenerating cells and debris.
3) The recovery phase (polyuric phase): <risk for hypokalemia>
 Re-epithelization of tubules.
 The GFR recovers relatively quickly as the tubules clear of casts and
debris.
 However, the tubular cells recover more gradually, resulting in
transient polyuria and loss of electrolytes (risk of hypokalemia) due
to impaired tubular resorption and decreased renal concentrating
ability.
 The majority of patients eventually experience complete restoration of
renal function
 Can be caused by ischemic or nephrotoxic injury:
1) Ischemic—2° to r renal blood flow (eg, hypotension, shock, sepsis,
hemorrhage, HF). Results in death of tubular cells that may slough into tubular
lumen (PCT and thick ascending limb are highly susceptible to injury).
2) Nephrotoxic—2° to injury resulting from toxic substances (eg,
aminoglycosides, radiocontrast agents, lead, cisplatin, ethylene glycol), crush
injury (myoglobinuria), hemoglobinuria. PCT is particularly susceptible to
injury.

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 Histologically:
1) Flattening or ballooning of the proximal tubular epithelial cells with loss of
the brush border, and subsequent cell necrosis and denudation of the tubular
basement membrane.

UW: Ischemic injury predominately affects the renal medulla, which has low blood supply
even under normal conditions. The straight portion of the proximal tubule and the thick
ascending limb of Henles loop are particularly susceptible to hypoxia, as they participate in the
active (ATP-consuming) transport of ions and have high oxygen demand.

UW: When ATN is associated with multiorgan failure, renal function may be permanently
impaired (foci of interstitial scarring can be seen on light microscopy).

Ethylene glycol poisoning:

 Rapidly absorbed from the gastrointestinal tract and metabolized to:
1) Glycolic acid  toxic to renal tubules  ATN.
2) Oxalic acid  precipitate as calcium oxalate crystals.
 Ethylene glycol is found in automobile antifreeze, engine coolants, and
hydraulic brake fluids, ingestion may be accidental or intentional (used as a
substitute for alcohol in alcohol abusers).

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Renal papillary necrosis

 Sloughing of necrotic renal papillae A  gross hematuria
and proteinuria with renal pain.
 May be triggered by recent infection or immune stimulus.
 Associated with sickle cell disease or trait, acute
pyelonephritis, NSAIDs, diabetes mellitus.
SAAD papa with papillary necrosis:
Sickle cell disease or trait
Acute pyelonephritis
Analgesics (NSAIDs)
Diabetes mellitus
 UW: NSAIDs decrease prostaglandin synthesis causing constriction of medullary
vasa recta and ischemic papillary necrosis.
 UW: NSAID-associated chronic renal injury is morphologically characterized by
chronic interstitial nephritis and papillary necrosis.

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Renal cyst disorders: Autosomal dominant polycystic kidney disease

(ADPKD)
 Most common hereditary cause of renal failure in adults.
 Numerous cysts in cortex and medulla A causing bilateral enlarged kidneys
ultimately destroy kidney parenchyma.
 Pathogenesis:
 Mutation in PKD1 (85% of cases, chromosome 16) or PKD2 (15% of cases,
chromosome 4)  tubular cell proliferation and fluid secretion.
 Cyst formation occurs at any point in the nephron, but < 5% of nephrons are
affected.
 Microscopic cysts present at birth progressively enlarge over the decades.
 Enlarged cysts compress the renal parenchyma, causing atrophy and fibrosis.
 C/P:
 Presents with flank pain (due to dilation of the cysts and stretching of the
renal capsule), hematuria, hypertension (due to ↑renin), urinary infection,
progressive renal failure in ~ 50% of individuals.
 Renal cysts can usually be seen on imaging by the 3rd to 4th decade of life.
 Death from complications of chronic kidney disease or hypertension (caused
by ↑renin production).
 Associated with berry aneurysms, mitral valve prolapse, benign hepatic cysts,
and diverticulosis.
(ADPKD Cyst in the kidney + cyst in the liver + cyst in the brain)
 Treatment: ACE inhibitors or ARBs.

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Autosomal recessive polycystic kidney disease (ARPKD) (juvenile)

 Cystic dilation of collecting ducts B.
 Often presents in infancy.
 Associated with congenital hepatic fibrosis.
 Significant oliguric renal failure in utero can lead to Potter sequence.
 Concerns beyond neonatal period include systemic hypertension, progressive renal
insufficiency, and portal hypertension from congenital hepatic fibrosis.

UW: Fibrocystin is found in the epithelial cells of both the renal tubule and the bile
ducts; deficiency leads to the characteristic polycystic dilation of both structures.

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Medullary cystic kidney disease

 Autosomal dominant cyst formation in medullary collecting ducts (PKD has both
in cortex and medulla).
 Inherited disease causing tubulointerstitial fibrosis and progressive renal
insufficiency with inability to concentrate urine.
 Medullary cysts usually not visualized; shrunken kidneys on ultrasound (Vs PKD
enlarged kidney).
 Poor prognosis.

Multicystic dysplastic kidney

 Noninherited, congenital malformation of the renal parenchyma characterized by
cysts and abnormal tissue (eg, cartilage).
 Ureteric bud fails to induce differentiation of metanephric mesenchyme 
nonfunctional kidney consisting of cysts and connective tissue.
 Usually unilateral; bilateral leads to Potter sequence (must be distinguished from
PKD).
 Absence of a normal pelvicaliceal system  associated with ureteral or
ureteropelvic atresia, with the affected kidney essentially rendered nonfunctional.
 Abdominal ultrasound of the fetus or newborn is diagnostic.

Renal cysts

Inherited Non-inherited

Enlarged kidneys Shrunken kidney Multicystic

with cysts in with cysts in the dysplastic
medulla & cortex medulla kidney

Medullary cystic
PKD
kidney

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Simple vs complex renal cysts

 Simple cysts:
 Are filled with ultrafiltrate (anechoic on
ultrasound C).
 Very common and account for majority of all
renal masses.
 Found incidentally and typically asymptomatic.
 Complex cysts:
 Including those that are septated, enhanced, or
have solid components on imaging.
 Require follow-up or removal due to risk of renal cell carcinoma.

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Pharmacology
Diuretics site of action

Mannitol
 MECHANISM: Osmotic diuretic. ↑ Tubular fluid osmolarity  ↑ urine flow, ↓
intracranial/intraocular pressure.
 CLINICAL USE: Drug overdose, elevated intracranial/intraocular pressure.
 ADVERSE EFFECTS: Pulmonary edema, dehydration.
 Contraindicated in anuria, HF.

Acetazolamide
 MECHANISM: Carbonic anhydrase inhibitor. Causes self-limited NaHCO3 diuresis
and ↓ total body HCO3 stores.
 CLINICAL USE: Glaucoma, urinary alkalinization, metabolic alkalosis, altitude
sickness, pseudo tumor cerebri.

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Loop diuretics: Furosemide, bumetanide, torsemide

 MECHANISM: Sulfonamide loop diuretics.
1) Inhibit cotransport system (Na+/K+/2Cl-) of
thick ascending limb of loop of Henle.
2) Abolish hypertonicity of medulla, preventing
concentration of urine.
3) Stimulate PGE release (vasodilatory effect
on afferent arteriole); inhibited by NSAIDs.
4) ↑ Ca2+ excretion. Loops Lose Ca2+.
 CLINICAL USE: Edematous states (HF, cirrhosis, nephrotic syndrome, pulmonary
edema), hypertension, hypercalcemia.
 ADVERSE EFFECTS: OtSotoxicity (tinnitus, vertigo, hearing impairment, or
deafness), Hypokalemia, Hypomagnesemia, Dehydration, Allergy (sulfa), metabolic
Alkalosis, Nephritis (interstitial), Gout. OHH DAANG!
 UW: Ototoxicity secondary to loop diuretics usually occurs with higher dosages, pre-
existing chronic renal disease, rapid intravenous administration, or when used in
combination with other ototoxic agents (aminoglycosides salicylates and cisplatin).
Hearing impairment is usually reversible but may be permanent in some cases.

Loop diuretics: Ethacrynic acid

 MECHANISM: Non sulfonamide inhibitor of cotransport system (Na+/K+/2Cl-) of
thick ascending limb of loop of Henle.
 CLINICAL USE: Diuresis in patients allergic to sulfa drugs.
 ADVERSE EFFECTS: Similar to furosemide, but more ototoxic.

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Thiazide diuretics: Hydrochlorothiazide, chlorthalidone, metolazone.

 MECHANISM:
1. Inhibit NaCl reabsorption in early
DCT  ↓ diluting capacity of
nephron.
2. ↓ Ca2+ excretion.
 CLINICAL USE: Hypertension, HF,
idiopathic hypercalciuria, nephrogenic
diabetes insipidus, osteoporosis.
 ADVERSE EFFECTS: Hypokalemic
metabolic alkalosis, hyponatremia, hyperGlycemia, hyperLipidemia, hyperUricemia,
hyperCalcemia. Sulfa allergy.

 UW: Thiazides increase Ca+2 reabsorption through 2 major mechanisms:

1. Inhibition of the Na /Cl cotransporter on the apical side of DCT cells decreases
intracellular Na- concentrations. This activates the basolateral Na/Ca+2 antiporter,
which pumps Na into the cell in exchange for Ca+2. The resulting decrease in
intracellular Ca+2 concentration enhances luminal Ca+2 reabsorption across the apical
membrane.
2. Hypovolemia induced by thiazides increases Na and H2O reabsorption in the
proximal tubule, leading to a passive increase in paracellular Ca+2 reabsorption.

 UW: Thiazide diuretics decrease intravascular fluid volume which stimulates

aldosterone secretion and leads to increased excretion of potassium and hydrogen
ions in the urine. This results in hypokalemia and metabolic alkalosis.

 UW: Chlorthalidone appears to be more potent in lowering blood pressure than

other thiazides (eg. hydrochlorothiazide) but is also associated with more metabolic
abnormalities.

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Potassium-sparing diuretics: Spironolactone and eplerenone; Triamterene,

and Amiloride.
The K+ STAys.
 MECHANISM:
1. Spironolactone and eplerenone are
competitive aldosterone receptor
antagonists in cortical collecting
tubule. Eplerenone is a more selective
aldosterone antagonist with fewer side
effects.
2. Triamterene and amiloride act at the
same part of the tubule by blocking
Na+ channels in the cortical collecting tubule.
 CLINICAL USE: Hyperaldosteronism, K+ depletion, HF, hepatic ascites
(spironolactone), nephrogenic DI (amiloride), antiandrogen.
 ADVERSE EFFECTS: Hyperkalemia (can lead to arrhythmias), endocrine effects
with spironolactone (eg, gynecomastia, antiandrogen effects).

 UW: In heart failure, aldosterone is also produced in the myocardium and acts
locally, leading to fibrosis and myocardial hypertrophy. The resulting cardiac
remodeling worsens left ventricular dysfunction in heart failure patients.
Spironolactone effectively blocks aldosterone's detrimental cardiac effects.

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Diuretics: electrolyte changes

 Urine NaCl: ↑ with all diuretics (strength varies based on potency of diuretic effect).
Serum NaCl may decrease as a result.
 Urine K+: ↑ especially with loop and thiazide diuretics. Serum K+ may decrease as a
result.
 Blood pH:
1. ↓ (acidemia):
a) Carbonic anhydrase inhibitors: ↓ HCO3- reabsorption.
b) K+ sparing: aldosterone blockade prevents K+ secretion and H+
secretion. Additionally, hyperkalemia leads to K+ entering all cells (via
H+/K+ exchanger) in exchange for H+ exiting cells.
2. ↑ (alkalemia):
a) loop diuretics and thiazides: cause alkalemia through several
mechanisms:
 Volume contraction  ↑ AT II  ↑ Na+/H+ exchange in PCT
 ↑ HCO3- reabsorption (―contraction alkalosis‖).
 K+ loss leads to K+ exiting all cells (via H+/K+ exchanger) in
exchange for H+ entering cells.
 In low K+ state, H+ (rather than K+) is exchanged for Na+ in
cortical collecting tubule  alkalosis and ―paradoxical
aciduria‖.
 2+
Urine Ca :
1. ↑ with loop diuretics: ↓ paracellular Ca2+ reabsorption  hypocalcemia.
2. ↓ with thiazides: enhanced Ca2+ reabsorption.

Angiotensin converting enzyme inhibitors: Captopril, enalapril, lisinopril,

ramipril.

 MECHANISM:
1. Inhibit ACE  ↓ AT II  ↓ GFR by preventing constriction of efferent
arterioles.
2. ↑ Renin due to loss of negative feedback.
3. Inhibition of ACE also prevents inactivation of bradykinin, a potent
vasodilator.
 CLINICAL USE: Hypertension, HF (↓ mortality), proteinuria, diabetic nephropathy.
Prevent unfavorable heart remodeling as a result of chronic hypertension. In chronic
kidney disease (eg, diabetic nephropathy), ↓ intraglomerular pressure, slowing GBM
thickening.
 ADVERSE EFFECTS: Cough, Angioedema (due to ↑ bradykinin; contraindicated in
C1 esterase inhibitor deficiency), Teratogen (fetal renal malformations), ↑ Creatinine
(↓ GFR), Hyperkalemia, and Hypotension. Used with caution in bilateral renal artery
stenosis because ACE inhibitors will further ↓ GFR  renal failure.
Captopril’s CATCHH.

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Angiotensin II receptor blockers: Losartan, candesartan, valsartan.

 MECHANISM: Selectively block binding of angiotensin II to AT1 receptor. Effects

similar to ACE inhibitors, but ARBs do not increase bradykinin.
 CLINICAL USE: Hypertension, HF, proteinuria, or chronic kidney disease (eg,
diabetic nephropathy) with intolerance to ACE inhibitors (eg, cough, angioedema).
 ADVERSE EFFECTS: Hyperkalemia, r GFR, hypotension; teratogen.
 K: ACE inhibitors and ARBs may cause a type IV RTA because they block
aldosterone (leading to hyperkalemia); in this case they must both be held. If ACE
inhibitors cause hyperkalemia, so will ARBs.
 K: Switch from ACE inhibitor to ARB in cases with ACE-inhibitor cough, not for
hyperkalemia.

Aliskiren

 MECHANISM: Direct renin inhibitor, blocks conversion of angiotensinogen to

angiotensin I.
 CLINICAL USE: Hypertension.
 ADVERSE EFFECTS: Hyperkalemia, ↓ GFR, hypotension, angioedema. Relatively
contraindicated in patients already taking ACE inhibitors or ARBs.

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 Vesicoureteral reflux P. 4
Retrograde flow of urine from bladder toward upper urinary tract. Can be 1° due to abnormal/insufficient
insertion of the ureter within the vesicular wall (ureterovesical junction [UVJ]) or 2° due to abnormally high
bladder pressure resulting in retrograde flow via the UVJ. risk of recurrent UTIs.

Kidney anatomy and glomerular structure P.5

Renal tubular acidosis P. 34

Uremia, FGF23 P. 59
- Normal phosphate levels are maintained during early stages of CKD due to levels of fibroblast growth
factor 23 (FGF23), which promotes renal excretion of phosphate.
- Uremia: syndrome resulting from high serum urea. Can present with nausea, anorexia, encephalopathy
(seen with asterixis), pericarditis, platelet dysfunction.
- Management : dialysis.

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  Renovascular disease P. 5
Unilateral or bilateral renal artery stenosis (RAS) renal perfusion renin angiotensin HTN. Most common
cause of 2° HTN in adults.
Main causes of RAS:

1. Atherosclerotic plaques: proximal 1/3 of renal artery, usually in older males, smokers.
2. Fibromuscular dysplasia: distal 2/3 of renal artery or segmental branches, usually young or middle-
aged females For unilateral RAS, affected kidney can atrophy asymmetric kidney size. Renal venous
sampling will show renin in affected kidney, renin in unaffected kidney.

For bilateral RAS, patients can have a sudden rise in creatinine after starting an ACE inhibitor, ARB, or renin
inhibitor, due to their interference on RAAS-mediated renal perfusion.
Can present with severe/refractory HTN, flash pulmonary edema, epigastric/flank bruit. Patients with RAS
may also have stenosis in other large vessels.

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  Mention the blood supply of different segments of the ureter:
- Upper 1/3: renal artery
- Middle 1/3: gonadal artery
- Lower 1/3: common iliac, internal iliac, superior vesical artery

 Relation of ureter to iliac vessels:

- Ureter descend posterior to gonadal vessels at upper portion just anterior to psoas muscle
- Then pass anterior to the iliac vessels.

 Volume Expansions and Contractions – “Lost in the Desert” = Diabetes Insipidus, SIADH = Primary
Polydipsia (i.e. same effects)

 L/M of different stages of renal transplant rejection:

- Hyperacute rejection (occur within min – hours) → vascular fibrinoid necrosis & neutrophil
infiltration of the arterioles.
- Acute rejection (< 6months, after stoppage of immunosuppressant) → interstitial.
 L/M of Cyclosporine induced nephrotoxicity:
- cause nephrotoxicity by renal vasoconstriction and tubular cell damage
- it show early arteriolar hyalinization, tubularvacuolization

 What is the effect of co-administration of NSAIDs with furosemide:

- Because furosemide act by ↑↑ PG so vasodilatation of the afferent arterioles
- NSAIDs ↓the PGs release → ↓↓ GFR

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  Net filtration pressure is net pressure of hydrostatic pressures and oncotic pressure (mmHg), while
filtration coefficient used to determine net fluid movement in given area (ml/min).
 In normal conditions (normal ADH):
- Lowest tubular fluid osmolarity is at collecting tubule
- Highest tubular fluid osmolarity is at descending loop of Henle (esp. its tip)
 In DHD (↑ADH):
- Lowest tubular fluid osmolarity is at early DCT.
- Highest tubular fluid osmolarity is at collecting tubule.


 L/M of Kimmelstiel Wilson nodules:

- DM cause initially GBM thickening, ↑↑ mesangial matrix deposition → overtime, expansion of
mesangium → nodules that compress the capillaries, damage GBM.
- KW noduels has characters:
1- Located in peripheral mesangium
2- Ovoid, spherical
3- Lamellated appearance
4- Eosinophilic on H&E
5- PAS positive

 Why patients on chronic diarrhea → have urate stones as specific:

- Chronic diarrhea → ↓↓ bicarbonate reabsorption → chronic metabolic acidosis
- The body response by ↑↑ release of H+ as NH4, H2PO4 and reabsorption of HCO3 (ammonia
buffer system) → this acidic urine promote the precipitation of urate stones
- As dehydration → ↑↑ concentrated urine.

 What are the changes of plasma osmolality, ICF, ECF in case of diabetes insipidus, dehydration,
profound sweating (hypotonic sweat) : Hyperosmolar volume contraction.

 L/M of different stages of renal transplant rejection:

- Hyperacute rejection (occur within min – hours) → vascular fibrinoid necrosis & neutrophil
infiltration of the arterioles.
- Acute rejection (< 6months, after stoppage of immunosuppressant) → interstitial mononuclear
infiltrate due to sensitized T-cells (B-cells may be applied in antibody mediated acute rejection, but
with different L/M findings).
- Chronic rejection (>3 months)→ fibrous intimal thickening of the vessels, mononuclear infiltrates
→ ischemia.

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 Carbonic anhydrase enzyme is present in PCT, eye (aquous humor production), pancreas, GIT, CNS,
RBCs

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