Renal Anatomy

Kidneys are found against the dorsal wall of abdomen, just beneath the diaphragm and
behind the peritoneum
Renal blood supply is normally 20% of cardiac output

Renal tissues are grossly divided into three major zones

Cortex Approximately 90-95% of blood flow goes to cortex

Medulla 5-10% of blood flow goes to the medulla

Inner medulla

Blood enters kidney through renal artery interlobar artery arcuate artery
interlobular artery afferent arteriole glomerular capillaries efferent arteriole
peritubular capillaries interlobular, arcuate, interlobar veins renal vein
o

Constricting the efferent arteriole will GFR

Angiotensin II preferentially constricts the efferent aterioles [thus ACE-inhibitors

(the -prils) will dilate efferent arterioles and GFR]

Constricting the afferent arteriole will GFR

Kidney produces prostaglandins which is a vasodilator of afferent arteriole

(upregulated when there is ischemia) NSAIDS inhibit prostaglandin synthesis
vasoconstriction ischemia

The kidneys is unique as it has 2 capillary beds arranged in series

o

Glomerular capillaries are high pressure, for filtering

Peritubular capillaries are low pressure, allows filtering and reabsorption

Reuptake of solute and water occurs in peritubular capillaries

Early Proximal Convoluted Tubule

Nephron is the basic unit of the kidney

Early Proximal Convoluted Tubule (PCT): the major location where reabsorption occurs
o

The PCT has a distinctive brush border packed with microvilli when viewed
under a light microscope

Bulk reabsorption of water

Mannitol is an osmotic diuretic that increases tubular fluid osmolarity in the PCT and
thereby increases urine flow

Mannitol toxicity includes possible pulmonary edema and intravascular

dehydration

Na/K ATPase in basolateral membrane functions to maintain a Na gradient. This gradient

allows for passive Na reabsorption into the tubule cell.

Reabsorbs 100% of glucose and amino acids through cotransport with Na

Reabsorption of filtered HCO3- is directly linked to NPT2, a sodium-phosphate

cotransporter which serves as the primary functional regulator of phosphate reabsorption.
o

PTH (parathyroid hormone) induces NPT2 endocytosis reabsorption of

phosphate and reabsorption of HCO3-

Carbonic anhydrase inhibitors (eg, acetazolamide) are diuretics that act in the PCT by
inhibiting the reabsorption of filtered HCO3-.
o

In addition to its use as a diuretic, acetazolamide can also be used:

- To alkalinize the urine
- To treat glaucoma ( secretion of aqueous humor intraocular pressure)
- To treat metabolic alkalosis
- To treat altitude sickness
[1]

Effects of acetazolamide toxicity may include:

- Hyperchloremic metabolic acidosis
- NH3 toxicity
- Neuropathy
- Sulfa allergy (acetazolamide is a sulfa derivative should not be used in
patients allergic to sulfa drugs)
Ammonia is secreted in the PCT, and functions as H+ buffer
o

Glomerulotubular balance maintains a constant fraction (2/3rds or 67%) of filtered Na

and H2O reabsorption in the proximal convoluted tubule
o

Regulated by Starling forces in the peritubular capillaries

Loop Of Henle

Thin Descending Loop of Henle

o Medullar hypertonicity and impermeability to sodium allows only passive
reabsorption of water
o

Urine is hypertonic - osmolality increases dramatically in the descending limb

Epithelium here is simple squamous epithelium (the thick ascending loop has
simple cuboidal)

Thick Ascending Loop of Henle

o

Simple cuboidal epithelium

This region is impermeable to water NaCl is reabsorbed w/o water

Results in urine hypotonicity. This is referred to as the diluting segment.

Active reabsorption of Na, K, and Cl through a co-transporter

Loop diuretics (e.g., furosemide, bumetanide, ethacrynic acid) block the NKCC
(Na+/K+/2Cl-) symporter in the TAL (thick ascending limb) of the loop of Henle
o

Furosemide abolishes the hypertonicity of medulla and prevents concentration of

urine

Furosemides clinical uses include treatment of:

- hypertension
- edematous states e.g., CHF (congestive heart failure); pulmonary edema
- hypercalcemia

Furosemide toxicity includes:

- ototoxicity
- gout
- hypokalemia
- hypocalcemia
- nephritis

K+ leak channels in the luminal membrane allow electrochemical potential gradient to

drive further reabsorption of cations: K+, Mg++ and Ca++

Distal Convoluted Tubule

Distal Convoluted Tubule is lined by simple cuboidal cells with NO brush border.
Contrast this with the proximal convoluted tubule.
Active reabsorption of NaCl by a Na-Cl cotransporter

Thiazide diuretics inhibit Na/Cl cotransporter in the distal convoluted tubule

Thiazides are used to treat:

1. Hypertension
2. CHF (congestive heart failure)
3. Idiopathic hypercalciuriathiazides increase Ca reabsorption in the
distal tubule
4. Nephrogenic DI (diabetes insipidus)Why treat a water-wasting
disease with a diuretic? Thiazides increase renal Na excretion ECF

volume contraction GFR proximal tubular reabsorption of water

and Na less water and Na are lost as urine
[1]

Thiazide toxicity may include:

1. Hypo-{K, H, Na}
- Hypokalemia (low serum K)
- Metabolic alkalosis (low serum H)
- Hyponatremia (low serum Na)
2. Hyper-{glucose, lipids, uric acid, Ca}
- hyperglycemia (high serum glucose)
- hyperlipidemia (high serum lipids)
- hyperuricemia (high serum uric acid)
- hypercalcemia (high serum Ca)Both thiazide diuretics and loop
diuretics can cause hypokalemia, however thiazides cause hypercalcemia,
while loops (eg, furosemide) causes hypocalcemia.

Sodium absorption is mediated by aldosterone

Impermeable to water, thus further diluting tubular fluid

o

Urine becomes more hypotonic

Distal convoluted tubule is the site of action for PTH-driven calcium reabsorption in the
kidney
o

Phosphate excretion is also

Collecting Tubules

Consists of two cell types: principal cells and intercalated cells

Principal cells
o

Reabsorb Na and H2O

Secrete K+

Principal cells: site of action for K sparing diuretics

(amiloride/spironolactone/triamterene) which the secretion of K

Spironolactone is a competitive aldosterone receptor antagonist which functions at the

cortical collecting tubule. It is only pharmacologically active in the presence of
aldosterone.
o

Toxicities of spironolactone include hyperkalemia, gynecomastia, and

antiandrogen effects. It has also been known to cause irregular menses as well as
amenorrhea in female patients.

Principal cells: site of aldosterone control

o

Aldosterone: Na reabsorption and K secretion in principal cells; also H

secretion in intercalated cells

Site of ADH (vasopressin) control

o

Amiloride and triamterene directly block epithelial sodium channels to inhibit

sodium reabsorption in the collecting ducts without depleting potassium. They
function even without the presence of aldosterone.

In the absence of ADH, principal cells are virtually impermeable to water

Intercalated cells
o

Secretes H

Reabsorbs K through H/K ATPase

K+ reabsorption only occurs on a low-K+ diet

Aldosterone further increases H secretion by intercalated cells

Mechanism and location of diuretics

Renal Clearance

Clearance: the volume of plasma cleared of a substance per unit time

o C (x) = U (x) V / P (x)
o

Whereby:

C = clearance (ml/min or ml/24hr)

U (x)= urine concentration of x (mg/ml)

V = urine volume /time (ml/min)

P (x) = plasma concentration (mg/ml)

Of note

If C(x) < GFR, then there is a net tubular reabsorption of X (example: Na,
glucose, amino acids, HCO3-, Cl-)

If C(x) > GFR, then there is a net tubular secretion of X (example: PAH, K)

If C(x) = GFR, then there is no net secretion nor reabsorption of X (example:

Inulin)

Relative clearances:
o

PAH > K+ > inulin > urea > Na+ > glucose, amino acids, and HCO3-

Free Water Clearance (CH2O) is the ability to dilute urine

o

Free Water Clearance (CH2O) = V - Cosm where V = urine flow rate (ml/min) and
Cosm = osmolar clearance (UosmV/Posm)

With ADH: CH2O < 0 (retention of free water)

Without ADH: CH2O > 0 (excretion of free water)

Isotonic urine: CH2O = 0 (seen with loop diuretic

GFR (Glomerular Filtration Rate)

GFR can be expressed in two different ways:

1) GFR is functionally measured by looking at inulin clearance because inulin is filtered,
but neither reabsorbed nor secreted by renal tubules. Therefore:
o

GFR = C (inulin) = U (inulin) V / P (inulin)

GFR decreases with age

o

BUN (blood urea nitrogen) with GFR

plasma [creatinine] with GFR

A decrease in GFR results in increased BUN, extracellular potassium and plasma

creatinine levels. In fact, creatinine clearance is used to estimate GFR.

In prerenal azotemia (hypovolemia), BUN increases more than serum creatinine

increased BUN/creatinine ratio (> 20:1)

2) Another way to express GFR is through use of Starling equation:

o

The driving force for glomerular filtration is the net ultrafiltration pressure across
the glomerular capillaries

GFR = Kf [ (HPgc - HPbs) - (OPgc - OPbs)]

Whereby:

Kf - filtration coefficient of glomerular capillaries

HPgc - glomerular capillary hydrostatic pressure, which is constant along the

length of the capillary

Dilation of afferent arteriole or constriction of efferent arteriole will increase HPgc

HPbs - Bowmans space hydrostatic pressure

Constriction of ureters will increase HPbs

OPgc - glomerular capillary oncotic pressure

OPgc increases along the length of the glomerular capillary

OPgc decreases by decreases in capillary protein concentration, such as in cirrhosis

or nephrotic syndrome. This results in an increased GFR.

OPbs - Bowmans space oncotic pressure

Is usually zero since only a small amount of protein is filtered

GFR (Glomerular Filtration Rate)

GFR can be expressed in two different ways:

1) GFR is functionally measured by looking at inulin clearance because inulin is filtered,
but neither reabsorbed nor secreted by renal tubules. Therefore:
o

GFR = C (inulin) = U (inulin) V / P (inulin)

GFR decreases with age

o

BUN (blood urea nitrogen) with GFR

plasma [creatinine] with GFR

A decrease in GFR results in increased BUN, extracellular potassium and plasma

creatinine levels. In fact, creatinine clearance is used to estimate GFR.

In prerenal azotemia (hypovolemia), BUN increases more than serum creatinine

increased BUN/creatinine ratio (> 20:1)

2) Another way to express GFR is through use of Starling equation:

o

The driving force for glomerular filtration is the net ultrafiltration pressure across
the glomerular capillaries

GFR = Kf [ (HPgc - HPbs) - (OPgc - OPbs)]

Whereby:

Kf - filtration coefficient of glomerular capillaries

HPgc - glomerular capillary hydrostatic pressure, which is constant along the

length of the capillary

Dilation of afferent arteriole or constriction of efferent arteriole will increase HPgc

HPbs - Bowmans space hydrostatic pressure

Constriction of ureters will increase HPbs

OPgc - glomerular capillary oncotic pressure

OPgc increases along the length of the glomerular capillary

OPgc decreases by decreases in capillary protein concentration, such as in cirrhosis

or nephrotic syndrome. This results in an increased GFR.

OPbs - Bowmans space oncotic pressure

Is usually zero since only a small amount of protein is filtered

Glomerulus And Glomerular Filtration Barrier

Glomerulus and its surrounding Bowmans capsule constitute the basic filtration unit of
the kidney
Unlike most other capillary beds, the glomerulus drains into an efferent arteriole rather
than a venule.
The afferent arteriole that supplies the glomerulus is a branch of an interlobular artery in
the cortex
o

Abdominal aorta renal artery lobar artery interlobar artery arcuate

artery interlobular artery afferent arteriole glomerulus efferent
arteriole peritubular capillaries renal vein inferior vena cava

Juxtaglomerular smooth muscle cells contained in the afferent arteriole synthesize renin

The glomerular filtration barrier is made up of:

o

1) The capillary endothelial cells of glomerulus contain numerous large pores

(fenestrae) that allow anything smaller than a RBC (red blood cell) size to pass
through

RBCs are prevented from filtration by this mechanism

2) Below the fenestrated glomerular endothelium sits a fused negatively charged

basement membrane, which repels negatively charged proteins. This helps to
prevent protein passage into Bowmans capsule.

Serum albumin is prevented from filtration by this mechanism

This charged barrier is disturbed in nephrotic syndrome, which results in

proteinuria, hypoalbuminemia and edema

3) Podocytes line the other side of the glomerular basement membrane and form a
tight network of foot processes (pedicles). These pedicles control ultrafiltration of
proteins into Bowmans space.

Only ions (e.g. Na+, K+, Cl-, HCO3-) and small molecules (e.g., glucose, amino
acids, peptides) pass freely here

Renal Blood and Plasma Flow

Renal blood flow

o Directly proportional to pressure difference between the renal artery and the renal
vein; inversely proportional to the resistance of the renal vasculature
o

Autoregulation of RBF is achieved by changing renal vascular resistance; RBF

remains constant over a range of arterial pressures

Myogenic mechanisms of RBF autoregulation: afferent arterioles contract in

response to stretch caused by increased arterial pressure

Tubuloglomerular feedback: increased renal arterial pressure leads to delivery

of fluid to the macula densa. The macula densa secretes paracrine signals that lead
to constriction of the nearby afferent arteriole.

RBF is related to RPF (Renal Plasma Flow) by the expression:

RBF = [ RPF / (1-Hematocrit) ]

Renal plasma flow can be approximated by measuring the clearance of PAH

(paraaminohippuric acid)

PAH is both filtered and secreted by the renal tubules (ie, none is reabsorbed) PAH
clearance is a good representation of effective renal plasma flow (RPF).
However, because it doesn't measure RPF to regions of the kidney not involved in the
filtration and secretion of PAH, PAH clearance underestimates the true RPF by about
10%.

Effective RPF: C (PAH) = [Urine] PAH x V / [Plasma] PAH

Whereby:

Effective RPF = effective renal plasma flow (ml/min or ml/24hr)

C (PAH) = clearance of PAH (ml/min or ml/24hr)

[Urine] PAH = urine concentration of PAH (mg/ml)

V = urine flow rate (ml/min or ml/24hr)

[Plasma] PAH = plasma concentration of PAH (mg/ml)

Effects On GFR, RPF, And Filtration Fraction

Filtration fraction is the fraction of RPF filtered across the glomerular capillaries
o Filtration fraction = GFR / RPF
o

The amount filtered becomes the urine

Normally, 20% of RPF is filtered

80% leaves through efferent arterioles to become peritubular capillary circulation

in FF leads to protein concentration of peritubular capillary blood, which leads

to increased reabsorption in the proximal tubule

in FF leads to in the protein concentration of peritubular capillary blood and

decreased reabsorption in the proximal tubule

Physiological determinants of changes in renal function:

GFR RPF
FF
Afferent arteriole constriction

No change
Efferent arteriole constriction

Increase plasma protein

No change

Glucose Clearance

Filtered load of glucose is directly proportional to plasma [glucose]

Na-glucose cotransport in the proximal convoluted tubule reabsorbs glucose. However,
there are a limited number of these Na-glucose carriers.

Threshold = lowest plasma [glucose] at which glucosuria occurs. Threshold ~180mg/dL.

[1]

Transport maximum (Tm) = glucose reabsorption rate at which all Na-glucose carriers
are saturated Tm is directly proportional to the number of functioning glucose
transporters. Put another way, Tm is directly proportional to the number of functioning
nephrons.

Tm ~375mg/min, which corresponds to a plasma [glucose] of 350mg/dL if GFR is

1.25dL/min.

If plasma [glucose] < 180mg/dL plenty of Na-glucose carriers are available:

- all filtered glucose is reabsorbed excretion of glucose is zero.

If plasma [glucose] > 350mg/dL all Na-glucose carriers are saturated:

- reabsorption is saturated any additional in plasma [glucose] results in glucosuria

If plasma [glucose] is between 180mg/dL and 350mg/dL, some Na-glucose carriers are
saturated while others are not, and the degree of Na-glucose carrier saturation varies from
nephron to nephron. "Splay" represents glucosuria before reabsorption is fully saturated,
and can be explained by:
1) Nephron heterogeneity
2) Relatively low affinity of Na-glucose cotransporters

Juxtaglomerular Apparatus & Renin-Angiotensin System

Macula densa provide signal for the juxtaglomerular apparatus (JGA) smooth muscle
cells of the afferent arteriole to secrete renin
Renin (also known as angiotensinogenase) circulates in blood to cleave a plasma alpha
globulin, angiotensinogen (made in the liver) angiotensin I.

Angiotensin I is then cleaved by ACE (made primarily in the lungs, but also circulates in
plasma) to Angiotensin II

Actions of angiotensin II:

1) potent vasoconstriction blood pressure

2) Na/H exchange and HCO3- - reabsorption in proximal tubules

3) release of aldosterone intravascular volume

4) release of ADH intravascular volume

5) Stimulates hypothalamus to thirst sensation

Renin is produced by the juxtaglomerular apparatus (JGA)modified smooth muscle

cells found in the afferent arterioles. The stimulus for renin release is the JGA cells'
perception of:
o

1) decreased renal blood pressure

2) decreased Na delivery to distal tubule (sensed by macula densa)

3) increased sympathetic tone

Atrial natriuretic peptide (ANP) released from atria asserts negative feedback, causing
decreased renin and increased GFR. The net effect is to increase diuresis and decrease
interstitial edema. Increased ANP levels are seen in patients with pulmonary congestion.

ACE inhibitor drugs (captopril, enalapril, lisinopril) function by inhibiting angiotensinconverting enzyme
serum levels of:
- angiotensin I
- bradykinin
- renin
serum levels of:
- angiotensin II
- aldosterone
o

ACE inhibitors also prevent inactivation of a potent vasodilator, bradykinin

increased bradykinin contributes to edema and cough.

ACE inhibitors are used to treat:

o

1) Hypertension, by decreasing angiotensin II sympathetic activity

2) Congestive heart failure, by decreasing release of aldosterone, thereby

decreasing intravascular volume

3) Diabetic renal disease, early usage of ACE inhibitors in diabetics can be renal
protective

ACE inhibitor toxicity use the mnemonic "CAPTOPRIL":

o

Cough: related to increased bradykinin levels

Angioedema rapid swelling of nose, lips, tongue, mouth, and throat shortly
after first dose

Proteinuria

metallic Taste

hypOtension

contraindicated in Pregnancy: fetal renal damage and possible cardiovascular

anomalies

Rash

Increased renin

Lower angiotensin II

Hyperkalemia: due to decreased aldosterone effect

"-sartan" drugs (e.g., Losartan) block AT1 (angiotensin II type 1) receptors used in the
treatment of hypertension
o

Losartan does not have the same toxic profiles as ACE inhibitors. In particular,
cough is not seen with its usage because it does not prevent the breakdown of
bradykinin.

Aliskerin blocks renin activity

Endocrine Role Of Kidney

Kidney secretes these four products: 1) erythropoietin 2) alpha hydroxylase enzyme 3)

prostaglandin 4) renin
Secretion of erythropoietin
o

Catalyzes active vitamin D production

o

Endothelial cells of peritubular capillaries secrete erythropoietin to assist in red

cell production. Renal failure causes anemia associated with decreased
erythropoietin production.

PTH stimulates the production of -hydroxylase in the kidney which catalyzes the
conversion of 25-OH vitamin D active 1,25 (OH)2 vitamin D.

Prostaglandin mediated vasodilatation of afferent arterioles

o

Prostaglandin is secreted by kidney and functions to vasodilate afferent arterioles

and maintain GFR

NSAIDs may cause acute renal failure by inhibiting renal production of

prostaglandin through the inhibition of cyclooxygenase. This results in
constriction of afferent arterioles and subsequently, a decreased GFR.

Renin secretion
o

Juxtamedullary smooth muscle cells secrete renin, which has an active role in
renin-angiotensin-aldosterone pathway

Acid-Base Balance

Two types of acid are produced in the body: volatile acid and non-volatile
o Volatile acid is CO2
o

Carbonic anhydrase, which is present in most cells, mediates the following

reversible reaction:
CO2 + H2O H2CO3 H+ + HCO3-

Non-volatile acids are called fixed acid. Ex. sulfuric acid (H2SO4) or phosphoric
acid (H3PO4).

Other fixed acids can be overproduced in disease or may be digested: ketoacids,

lactic acid, and salicylic acid

Buffers prevent a change in pH when H+ ions are added to or removed from a solution
o

Most effective within 1.0 pH unit of the pKa

The major extracellular buffer is HCO3- (pKa 6.1). H2PO4-/HPO4-2 is a minor

extracellular buffer (pKa 6.8)

Phosphate (HPO4-2) is most important as a urinary buffer; excretion of H+ as

H2PO4- is called titratable acid

Hemoglobin is a major intracellular buffer. In the physiologic range,

deoxyhemoglobin is a better buffer than oxyhemoglobin

Henderson-Hasselbalch equation: pH = pKa + log[A-]/[HA]

o

Used to calculate pH

When the concentrations of A- (base form of buffer) and HA (acid form of buffer)
are equal, the pH of the solution equals the pKa of the buffer.

Important - The pH of arterial blood can be calculated with the following

equation: pH = pKa + log [HCO3-] / 0.03 x PaCO2 where PaCO2 is the partial
pressure of CO2 in arterial blood

Acid-base disorders
o

Definitions:
Acidemia = pH < 7.35
Alkalemia = pH > 7.45
Respiratory acidosis = PCO2 > 45 mmHg
Respiratory alkalosis = PCO2 < 35 mmHg

pH
Metabolic acidosis
Metabolic alkalosis
Respiratory acidosis
Respiratory alkalosis

PCO2

[HCO3-]

1 disturbance = or
Compensatory response = or

Compensatory Response
Hyperventilation
Hypoventilation
renal [HCO3-] reabsorption
renal [HCO3-] reabsorption

[1]

Respiratory compensation in response to metabolic acidosis can be quantified

with Winter's formula:
PCO2 = 1.5[HCO3-] + 8 +/- 2

Serum anion gap = [Na+] - ([HCO3-] + [Cl-])

Represents unmeasured anions in serum and is normally 8-16 mEq/L.

Serum anion gap is associated with MUDPILERS:

Methanol (formate), Metformin
Uremiaadvanced (chronic) renal failurevs. early renal failure, which may
cause normal anion gap metabolic acidosis
Diabetic ketoacidosis (-hydroxybutyrate, acetoacetate)
Paraldehyde, Phenformin
Iron, Isoniazid
Lactic acidosisshock, hypoxia, poor tissue perfusion; carbon monoxide,
cyanide
Ethanol ketoacidosis (-hydroxybutyrate, acetoacetate), Ethylene glycol
(glycolate, oxalate)
Rhabdomyolysis
Salicylateswith concomitant respiratory alkalosis; prolonged Starvation
ketoacidosis (-hydroxybutyrate, acetoacetate)

Normal anion gap metabolic acidosis (ie, hyperchloremic metabolic acidosis) is

associated with "FUSED CARS":
Fistula (small bowel, pancreatic) loss of HCO3Ureterogastric conduits (eg, urine-diverting colostomy) loss of HCO3Saline administration (ie, saline worsens metabolic acidosis!) gain of ClEndocrineeg, hyperparathyroidism (a cause of type 2 renal tubular acidosis),
Addison's disease (aldosterone deficiency)
Diarrhea loss of HCO3Carbonic anhydrase inhibitors (eg, acetazolamide)(most common cause of type 2
renal tubular acidosis in adults) loss of HCO3Acid infusion (eg, NH4Cl; hyperalimentation with TPN (total parenteral nutrition)
if arginine HCl or lysine HCl are used as amino acids) gain of ClRenal tubular acidosis:
- type 1 ( distal tubule H+ secretion): hypokalemia, urine pH>5.5
- type 2 ( proximal tubule HCO3- reabsorption): hypokalemia, urine pH<5.5
- type 4 (aldosterone deficiency or resistance): hyperkalemia (secondary to NH3
production), urine pH<5.5
Spironolactoneblocks aldosterone receptors

Normal anion gap metabolic acidosis is caused by loss of HCO3- or gain of Cl-,
both of which usually result in hyperchloremic metabolic acidosis:

- gain of Cl- is usually compensated by loss of HCO3- hyperchloremic

metabolic acidosis
- loss of HCO3- is usually compensated by Cl- retention hyperchloremic
metabolic acidosis

Congenital anomalies of the Kidney

Potter phenotype is caused by the Potter sequence (oligohydramnios sequence): Bilateral

renal agenesis failure of fetal renal excretion oligohydramnios ( amniotic fluid)
multiple anomalies (Potter phenotype) and early death:
o 1) Oligohydramnios fails to provide the fetus with adequate amniotic fluid
necessary to fully mature the lungs pulmonary hypoplasia severe
respiratory failure and early neonatal death
o

2) Oligohydramnios allows compression of the fetus within the uterus multiple

deformations (extrinsic disturbances of development):
- Facial deformities: Potter faciesflattened "parrot beak" nose, low-set ears,
micrognathia (recessed chin)
- Limb deformities: rocker-bottom feet, club feet (talipes equinovarus)

3) Oligohydramnios allows contact of fetal skin with amnion amnion

nodosum (nodules of fetal squamous epithelial cells on placental surface)

Maternal abdominal ultrasonography may detect bilateral renal agenesis during

the prenatal period

Horseshoe kidney: right and left kidneys fuse (90% are fused at the inferior pole; 10%
are fused at the superior pole)
o

Horseshoe kidneys become trapped under the inferior mesenteric artery (at
vertebral level L3) remain low in abdomen and may compress ureters, leading
to urinary tract obstruction and possibly urinary stasis incidence of UTIs and
nephrolithiasis, but otherwise normal kidney function

50-60% of girls with Turner syndrome have horseshoe kidney

[1]

Renal ectopia (abnormal location of a kidney)for example: a pelvic kidney

Ureteral abnormalitiesfor example:
- duplicated ureters
- duplication of entire urinary collecting system on one side

ADPKD (autosomal-dominant (adult) polycystic kidney disease)

ADPKD (autosomal-dominant (adult) polycystic kidney disease): most common

genetic cause of renal failure in adults

Development of 100s to 1000s of large, round expanding cysts by 20-25 years

of age massive bilateral kidney enlargement, destruction of renal
parenchyma, and ultimately renal failure

85% of ADPKD cases are caused by mutations in the PKD1 gene (polycystin-1)
on chromosome 16.
15% of ADPKD cases are caused by mutations in the PKD2 gene (polycystin-2)
on chromosome 4.

Mutations in PKD1 are associated with more severe disease, resulting in ESRD
(end-stage renal disease) at an earlier age: ESRD at ~55 years of age for PKD1
mutations vs. ~75 years of age for PKD2 mutations

Patients are often asymptomatic with normal renal function until their 40s and 50s, when
they often present with:
o

HUGE kidneysoften discovered as abdominal masses on palpation of the

anterior abdomen

Renal insufficiencychronic renal failure begins at 40-60 years of age, and is

the most common cause of death in patients with ADPKD

Hypertension ( renin)

Hematuria

Flank pain (due to progressive dilation of cysts or hemorrhage into cysts).

PKD1 gene (chromosome 16):

o

PKD1 encodes polycystin-1: a transmembrane protein important for connective

tissue adhesion between renal tubular epithelial cells (esp. the distal nephron) as
well as other cells throughout the body.

Therefore, mutation in PKD1 weak connective tissue which breaks down

over years pathogenesis of ADPKD is similar to connective tissue disorders
such as Ehler-Danlos syndrome and Marfan syndrome. [Note: there is an
incidence of mitral valve prolapse in ADPKD, Marfan syndrome, and EhlerDanlos syndrome]

PKD2 gene (chromosome 4):

o

PKD2 encodes polycystin-2: a transmembrane protein that functions as a Ca++

channel.

Therefore, mutation in PKD2 defective regulation of intracellular Ca++ levels.

Pathogenesis: mutations of PKD1 (polycystin-1) or PKD-2 (polycystin-2)

Defective cilia-centrosome complex on apical surface of renal tubular epithelial

cells

Defective regulation of intracellular Ca++ within renal tubular cells

fluid secretion and proliferation/ apoptosis of renal tubule cells

Cysts arise from the tubular structure in any part of the nephron in the
cortex and medulla

Although cysts involve < 10% of nephrons, progressive enlargement of 100s to

1000s of large round cysts over many years eventually compresses the
surrounding nephrons, compromising renal function

Extrarenal congenital anomalies associated with ADPKD:

o

1) Extrarenal cysts: liver (polycystic liver disease occurs in 40% of ADPKD

patients) > pancreas > spleen

2) Intracranial berry (saccular) aneurysm, most commonly in the circle of

Willis at the junction of the ACommA (anterior communicating artery) and the
ACA (anterior cerebral artery) 10% of ADPKD patients die from rupture of
intracranial berry aneurysm and subsequent subarachnoid hemorrhage

3) Mitral valve prolapse (midsystolic click)

4) Colonic diverticula, most commonly sigmoid diverticulosis (bright red blood

per rectum)

[ Extra pathogenesis detailsbeyond the scope of Step 1, only for the curious ]
o

Cilia on the apical surface of renal tubular cells function as mechanosensors that
detect changes in shear stress (and thus fluid flow) in renal tubules

Polycystin-1 and polycystin-2 (both localized to the primary cilium on the apical
surface of renal tubular cells) interact to form a complex that regulates
intracellular levels of Ca++, which in turn acts as a second messenger to coordinate
downstream cellular effects (e.g., cell proliferation/apoptosis/secretory function)

Normally:
in fluid flow within renal tubules in ciliary bending appropriate in Ca+
+
-channel opening appropriate in intracellular Ca++ levels within renal tubular
cells appropriate fluid secretion proliferation/apoptosis rate of renal tubule
cells

ADPKD (mutations of PKD1 (polycystin-1) or PKD-2 (polycystin-2)):

in fluid flow within renal tubules in ciliary bending abnormal in Ca++channel opening abnormal in intracellular Ca++ levels within renal tubular
cells fluid secretion and proliferation/ apoptosis of renal tubule cells
cyst formation with progressive cyst enlargement

ARPKD (autosomal-recessive (childhood) polycystic kidney disease)

ARPKD (autosomal-recessive (childhood) polycystic kidney disease): renal pathology

is evident at birthbilaterally enlarged kidneys with smooth external surface and
multiple small radiating cysts in the cortex and medulla [1]
o Most ARPKD cases are caused by mutations in the PKHD1 gene (fibrocystin) on
chromosome 6.
o

Patients present with progressive, often fatal renal failure, most commonly during
the perinatal or neonatal period.

Patients who survive infancy may develop:

- Multiple hepatic cysts
- Congenital hepatic fibrosis (periportal fibrosis + proliferation of portal bile
ducts) portal hypertension with splenomegaly

Renal failure in utero oligohydramnios ( amniotic fluid) Potter's facies

(flattened "parrot beak" nose, low-set ears, micrognathia), limb defects (rockerbottom feet, talipes equinovarus) and lung hypoplasia

Compare:
- ARPKDsmall radiating cysts which originate from the collecting ducts of nephrons
(cylindrical dilation of collecting ducts dilated elongated cysts oriented in radial
fashion with their long axis perpendicular to the cortical surface)
- ADPKDlarge round cysts which originate from any part of the nephron

Other cystic diseases of the Kidney

Medullary sponge kidney: benign congenital disorder characterized by cystic dilations

of medullary collecting ducts ("swiss cheese" appearance of medulla on intravenous
pyelogram); renal cortex is spared
o Most patients are asymptomatic. Most common symptoms/complications include:
1) Recurrent kidney stones (60% of cases)
2) Hematuria
3) UTI

Localized (simple) renal cysts: benign cysts usually located in the renal cortex of
normal-sized kidneys.
o

Most patients are asymptomatic. Microscopic hematuria is occasionally a

benign, incidental finding on urinalysis.

Acquired renal cystic disease: multiple cysts in cortex and medulla associated with endstage renal disease and chronic dialysis therapy
o

Slightly risk of developing renal cell carcinoma

Acute Kidney Injury

AKI (acute kidney injury) is now the preferred term to describe acute injury to the
kidney. Note: AKI has replaced the older term "acute renal failure".
o AKI = abrupt in serum creatinine or an abrupt in urine output
o

Therefore, AKI can be:

- Oliguric (urine output <400mL/day); or
- Non-oliguric (urine output 400mL/day)please remember that AKI is not
always accompanied by oliguria!

Prerenal azotemia (prerenal AKI):

blood flow to kidney, kidneys are intrinsically normal
o

Prerenal AKI = most common cause of AKI

blood flow to kidney (w/o parenchymal damage) GFR

1) clearance of BUN, Cr, and other metabolites
2) reabsorption of Na and H2O (kidney parenchyma and tubular function
(concentrating ability) are intact) oliguria is always present in prerenal AKI

Causes of prerenal AKI include:

o

1) Hypovolemia:
- dehydration, inadequate oral fluid intake
- hemorrhage, burns
- vomiting, diarrhea, excessive use of diuretics

2) Hypotension:
- cardiogenic shock (eg, myocardial infarction)
- massive peripheral vasodilation: septic shock (eg, gram-negative sepsis due to
UTI), neurogenic shock (eg, spinal cord injury), anaphylactic shock (eg, bee
sting)

3) Low cardiac output:

- CHF (congestive heart failure)
- constrictive pericarditis
- coarctation of aorta (decreased cardiac output to lower extremities, including the
kidneys)

4) Hypoalbuminemia:
- cirrhosis
- nephrotic syndrome
- burns
- malabsorption

5) Renal artery stenosis

6) Hepatorenal syndrome

7) Hepatopulmonary syndrome

Renal azotemia (intrarenal AKI):

kidneys are damaged impaired glomerular filtration and/or renal tubular function

Causes of intrarenal AKI include:

1) Glomerular diseaseacute glomerulonephritis, usually due to RPGN (rapidly

proliferative glomerulonephritis):
- Type I RPGN: Goodpasture syndrome
- Type II RPGN: Poststreptococcal glomerulonephritis, Lupus nephritis, IgA
nephropathy
- Type III RPGN: Wegener granulomatosis

2) Tubulointerstitial disease:
- Acute tubular necrosis (epithelial casts degenerate to form pigmented, muddybrown renal tubular casts in urine) = most common cause of intrarenal AKI
- Drug-induced interstitial nephritis

3) Vascular disease:
- Intrarenal vascular occlusioneg, renal artery/vein thrombosis, thrombotic
microangiopathies: HUS (hemolytic uremic syndrome), TTP (thrombotic
thrombocytopenic purpura)
- Intrarenal vasculitiseg, Wegener granulomatosis

Postrenal azotemia (postrenal AKI):

obstruction of urine outflow, kidneys are intrinsically normal
o

Postrenal AKI = least common cause of AKI

Causes of postrenal AKI include:

o

Obstruction of urethra:
- BPH (benign prostatic hyperplasia) = most common cause of postrenal AKI
- Nephrolithiasis (kidney stones in urethra or impacted at bladder neck)

Obstruction due to neoplastic invasion/extension (eg, neoplasia of cervix,

prostate, bladder)

Bilateral obstruction of ureters (eg, retroperitoneal fibrosisureters are

retroperitoneal structures)

Bilateral obstruction of kidneys (eg, bilateral staghorn stones)

Lab findings:
o

Prerenal
Azotemia

AGN

ATN

Postrenal
Azotemia
(prolonged

obstruction)
UOsm

>500

>500

<350

<350

UNa

<20

<20

>40

>40

>15

>15

15

15

<1

<1

>2

>2

BUN:Cr ratio
FENa

Hyaline casts Hemat- "Muddy brown" casts,

Normal urine
(or normal
uria, RBC renal tubular cell casts,
UA
sediment
urine sediment) casts
granular casts
o Table abbreviations:
- AGN: Acute Glomerulonephritis
- ATN: Acute Tubular Necrosis
- UOsm: urine osmolality (mOsm/kg)
- UNa: urine Na+ (mEq/L)
- FENa: Fractional Excretion of Na+ (%)
- UA: Urinalysis
o

In prerenal azotemia and AGN, tubular function remains intactthese two

conditions have similar UOsm (>500), UNa (<20), serum BUN:Cr ratio (>15:1),
FENa (<1).
Urinalysis can help distinguish one from the other:
- Normal sediment or hyaline casts are seen on urinalysis in patients with prerenal
azotemia
- RBC casts and hematuria are seen on urinalysis in patients with AGN

In ATN (acute tubular necrosis) and postrenal azotemia secondary to prolonged

obstruction, tubular function is dysfunctionalthey have similar UOsm (<350),
UNa (>40), serum BUN:Cr ratio (15), FENa (>2).
Urinalysis can help distinguish one from the other:
- "Muddy brown" casts, renal tubular cell casts, and granular casts are seen on
urinalysis in patients with ATN
- Normal urine sediment is seen on urinalysis in patients with postrenal azotemia
secondary to prolonged obstruction.

Note: postrenal azotemia of short duration has UOsm, UNa, BUN:Cr, and FENa
similar to prerenal azotemia.

Chronic Renal Failure

Chronic renal failure: irreversible loss of nephrons glomerular capillary pressure in

remaining nephrons hyperfiltration damage fibrosis, scarring, loss of additional
nephrons
o Most common primary causes of chronic renal failure are diabetes mellitus (40%
of cases) and hypertension (30%). Less common causes include chronic
glomerulonephritis (15%), interstitial nephritis (5%), cystic renal disease (5%)
o

Urinalysis:
- Tubular dysfunction isosthenuria (inability to concentrate or dilute urine)
fixed specific gravity, free water clearance = zero
- Broad/waxy casts

Consequences of chronic renal failure include:

o

Azotemia: BUN and serum Cr

anion gap metabolic acidosis due to:

1) renal excretion of H+ as NH4+ (hence the metabolic acidosis)
2) renal excretion of sulfate, phosphate, urate, hippurate, etc. (hence the anion
gap)

Retention of Na and H2O hypertension and accelerated atherosclerosis,

peripheral edema, congestive heart failure

erythropoietin production normochromic, normocytic anemia

1--hydroxylase 1,25-dihydroxyvitamin D production reabsorption of

Ca from GI tract hypocalcemia secondary hyperparathyroidism ( PTH)
bone turnover resorptive cystic bone lesions (osteitis fibrosa cystica, which
is a type of renal osteodystrophy)

renal excretion of phosphate hyperphosphatemia, which also contributes to

the hypocalcemia by combining with calcium to precipitate out into tissues
(metastatic calcification)

renal excretion of Mg hypermagnesemia

renal excretion of K hyperkalemia (peaked T waves on EKG)

1) inhibits NH3 synthesis in proximal tubule renal excretion of H+ as NH4+
2) inhibits insulin release from pancreatic -cells insulin deficiency glucose
intolerance

risk of infection due to uremia-induced dysfunction of neutrophils and other

white blood cells

risk of bleeding due to uremia-induced platelet dysfunction ( bleeding time)

Uremia is a syndrome of severe renal failure with azotemia ( BUN and serum
Cr) + manifestations described above (e.g., acidosis, hypertension, fluid overload,
anemia, hyperkalemia, hypocalcemia, bleeding diathesis, etc) + the following:

- nausea, vomiting
- neurologic dysfunction: mental status changes, encephalopathy, asterixis,
coma
- hemorrhagic fibrinous pericarditis
o

Additional abnormalities associated with chronic renal failure include:

- pruritis
- hyperuricemia
- libido secondary to low testosterone levels

Acute Tubular Necrosis

ATN (acute tubular necrosis):

o ATN = most common cause of intrarenal AKI. Recall that AKI is defined as an
abrupt in serum creatinine or an abrupt in urine output.

There are 2 major categories of ATN: ischemic ATN and nephrotoxic ATN. Regardless of
etiology, the pathophysiology of ATN involves (1) disturbances in renal blood flow and
(2) tubular injury.

For example, the pathophysiology of ischemic ATN: Ischemia

o

1) Intrarenal vasoconstriction (net effect = afferent arteriolar

vasoconstriction) GFR oliguria

2) Damage of tubules in outer renal medulla, especially the straight portion of

proximal tubule (part of nephron that is most susceptible to hypoxic injury due to
high ATP demand) and thick ascending limb of Henle's loop (part of nephron that
is 2nd most susceptible to hypoxic injury to high ATP demand) renal tubular
cells necrosis, detachment from the basement membrane luminal
obstruction by pigmented renal tubular cell casts (Tamm-Horsfall protein +
entrapped cells) intratubular pressure GFR oliguria

How does ischemia cause intrarenal vasoconstriction? By 2 different

mechanisms:
Mechanism 1: ischemia loss of tubule cell polarity redistribution of
basolateral Na-K-ATPase to luminal tubular cell surface Na delivery to
macula densa in distal tubules stimulates renin secretion by juxtaglomerular
apparatus angiotensin II intrarenal vasoconstriction
Mechanism 2: ischemia endothelial damage vasoconstrictors (endothelin)
(vasoconstrictor) and vasodilators (NO, PGI2) intrarenal vasoconstriction

Regardless of etiology (ischemic vs. nephrotoxic), ATN is characterized by 3 phases:

1) Initiation phase
2) Maintenance (oliguric) phase
3) Recovery (polyuric) phase

Initiation phase (first ~36 hours):

Inciting ischemic event or nephrotoxin exposure slight in urine output with

an in BUN

Maintenance (oliguric) phase:

o

Sustained oliguria (40-400mL/day)

ECF (extracellular) volume weight gain, edema, pulmonary vascular

congestion

Hyperkalemia EKG changes (peaked T waves, depressed ST segment,

prolonged PR interval, wide QRS complex), heart block, arrhythmias (eg,
ventricular fibrillation) risk of sudden cardiac death

Retention of H+ and unmeasured anions (sulfate, phosphate, urate) anion gap

metabolic acidosis

Recovery (polyuric) phase (2-3 weeks after inciting event if patients survive the oliguric
maintenance phase):
o

Brisk diuresis (up to 3L/day) urinary loss of K+, Ca2+, Mg2+, PO43- (because the
renal tubules are still damaged at this point)

Hypokalemia (one of most serious complications of recovery phase of ATN)

EKG changes (flattening or inversion of T waves, U waves, depressed ST
segment), premature atrial/ventricular contractions, arrhythmias (eg, atrial
fibrillation)

Renal tubular function (concentrating ability) eventually recovers BUN and

serum Cr return to baseline

Ischemic ATN is most commonly caused by prerenal failure, which can be caused by
anything that compromises renal perfusion, including:
o

1) effective circulating blood volume (preload):

- Hypovolemiaeg, vomiting, diarrhea, burns, hemorrhage, dehydration, diuretic
overuse
- Systemic vasodilationeg, septic shock
- Cirrhosis ( albumin production colloid oncotic pressure
intravascular volume)

2) cardiac outputeg, CHF (congestive heart failure)

3) NSAIDs ( PGI2 vasodilation of afferent arteriole GFR) or ACE

inhibitors ( angiotensin II vasoconstriction of efferent arteriole GFR)
can precipitate prerenal failure in patients who already have poor renal perfusion

Nephrotoxic ATN can be caused by a variety of exogenous and endogenous

nephrotoxins, including:

Aminoglycosides (#1 cause of nephrotoxic ATN)

Heavy metals: lead, mercury

Radiographic contrast media

Gram negative sepsis

Myoglobulinuria as a result of trauma / crush injuries or intense exercise

(exercise-induced myoglobinuria): myoglobulin collects in tubular cells and
decreases perfusion

Direct injury to proximal convoluted tubule from gentamicin, mercuric chloride

or ethylene glycol (antifreeze). Note, most other drugs cause an interstitial
nephritis.

In ethylene glycol acute tubular necrosis: one would see massive intratubular
oxalate crystal deposits with a polarized light

Drug-Induced Interstitial Nephritis

Acute drug-induced interstitial nephritis: acute inflammation of renal interstitium

(edema + prominent mononuclear and eosinophilic infiltrate) that resolves following
withdrawal of offending drug
o Abrupt onset of signs and symptoms ~15 days (range of 2-40 days) after the first
dose of the inciting drug:
- Fever, rash, joint pain
- Eosinophilia, serum IgE
- Hematuria, mild proteinuria, pyuria (eosinophiluria)
- 50% of patients develop acute renal failure with azotemia (BUN:Cr ratio15)
and oliguria
o

Drug acts as a hapten (most drugs are too small to induce immune responses by
themselves) by covalently binding to a carrier (e.g., an extracellular or
cytoplasmic protein of renal tubular cells) hapten-carrier conjugate serves as
an immunogen, triggering a hypersensitivity reaction (type I and/or type IV)
injury of tubular cells and/or their basement membrane

Type I or Type IV hypersensitivity:

- Some patients have serum IgE levels, suggesting Type I hypersensitivity
- Other patients have mononuclear/granulomatous infiltrate on renal biopsy and
positive skin tests to drugs, suggesting Type IV hypersensitivity

Acute drug-induced interstitial nephritis may be caused by several drugssome of the

more classic culprits can be remembered using the mnemonic "Please Note All Drugs
that Can Possibly Scar Renals"
o

Penicillin derivativeseg, methicillin, ampicillin

NSAIDs

Allopurinol

Sulfa-derived Diureticseg, thiazides, furosemide, acetazolamide

Cephalosporins

Proton pump inhibitors

Sulfonamide antibioticssulfamethoxazole, sulfisoxazole

Sulfasalazineused to treat Crohn disease, ulcerative colitis, rheumatoid arthritis

RifampinRNA polymerase inhibitor used mainly to treat TB

Analgesic nephropathy: long term (years) excessive intake of analgesics chronic

tubulointerstitial nephritis + renal papillary necrosis
o

Long term combination use of acetaminophen and aspirin are the major causes.

Major association/complication with renal papillary necrosis

Leads to chronic renal failure, anemia, & hypertension.

Renal Papillary Necrosis

Renal papillary necrosis: ischemic coagulative necrosis of tips of the renal papillae of
one of more renal pyramids sloughing off of dead renal papillae urinary obstruction
obstructive atrophy (sparing the cortical columns of Bertin) with depressed areas of
renal cortex overlying subjacent necrotic papillae [1]
o Renal papillary necrosis with sloughing off of dead renal papillae
1) hyposthenuria (inability to concentrate urine) due to damage of renal
tubules within necrotic papillae
2) hematuria, proteinura, colicky flank pain may result if entire tips of necrotic
papillae are excreted
3) urine outflow due to obstruction by sloughed papillae
o

Sloughing of papilla can be seen as a "ring defect" on intravenous pyelogram

(IVP): dark lesion surrounded by bright rings of excreted contrast material.

Renal papillary necrosis is observed in several diseases. Mnemonic: "SO sAAD"Renal

papillary necrosis is "so sad" (think of the sloughing renal papillae as giant tears falling
into a pool of urine) [2]
o

Sickle cell trait or disease (remember, these patients have multiple vasoocclusive
episodes causing organ ischemia)

Obstruction of the urinary tract

Acute pyelonephritis (especially problematic in a diabetic patient)

Analgesic nephropathy: chronic excessive analgesic intake chronic

tubulointerstitial nephritis + renal papillary necrosis
Inciting analgesics may contain mixtures of:
- Phenacetin (an analgesic that was once popular, but no longer prescribed due to
its side effect profile; it can still appear on exams because it is a classic cause of
ATN)
- Acetaminophen (a metabolite of phenacetin)
- Aspirin
- Caffeine
- Codeine

Diabetes mellitus (most common etiology of renal papillary necrosis)

Diffuse Cortical Necrosis

Diffuse cortical necrosis: acute pale ischemic infarction (coagulative necrosis) sharply
limited to the renal cortex and columns of Bertin; the medulla is spared
o Occurs most commonly following an obstetric emergency (e.g., abruptio
placentae), septic shock, or major surgery with extensive blood loss.
o

May be caused by ischemic hypoperfusion secondary to coagulopathy (e.g.,

microangiopathic thrombosis, disseminated intravascular coagulation)

Prognosis is based on extent of renal cortex involvement:

- If patchy or unilateral: patients may survive
- If extensive and bilateral: rapidly fatal course with sudden anuria acute
renal failure uremic death.

Do not confuse it with Waterhouse Friderichsen syndrome, which is a disease of the

adrenal glands (not the renal cortex) due to similar etiologies

Nephrotic syndrome & systemic etiologies

Clinical manifestations of nephrotic syndrome:

o 1) Massive proteinuriaurinary loss of >3.5 grams of protein per day
o

2) Hypoalbuminemiaserum albumin < 3g/dL (the lower limit of normal is

3.4g/dL). Hypoalbuminemia results in plasma colloid oncotic pressure
compensatory in 2-macroglobulin synthesis to maintain oncotic pressure.

3) Generalized pitting edema (anasarca if severe)primarily due to

hypoalbuminemia and the resultant in plasma colloid oncotic pressure. This
generalized edema is further aggravated by Na and H2O retention due to
hypovolemia:
- Compensatory aldosterone secretion (hypovolemia renin angiotensin
II aldosterone)

- Sympathetic stimulation (hypovolemia SNS outflow)

- Natriuresis (hypovolemia atrial natriuretic peptide Na excretion)
o

4) Hyperlipidemia and hypercholesterolemiaas a result of hepatic synthetic

activity, including synthesis of albumin and lipoprotein synthesis:
VLDL IDL LDL cholesterol
Hyperlipidemia and hypercholesteremia Lipiduriaurinalysis reveals fatty
casts (oval fat bodies) which demonstrate "maltese cross" interference pattern
under polarized light due to cholesterol

5) Hypogammaglobulinemia due to loss of immunoglobulins in urine

humoral immunodeficiency with susceptibility to infection, especially
staphylococcal and pneumococcal infections

6) Hypercoagulable state due to loss of proteinaceous anticoagulants like

antithrombin III, protein C and protein S in urine risk of thrombosis (eg,
renal vein thrombosis, especially in membranous nephropathy) and risk of
thromboembolic complications

Primary Nephrotic Syndromes:

- Minimal Change diseasemost common nephrotic syndrome in Children
- Focal segmental glomerulosclerosismost common nephrotic syndrome in adults in
US
- Membranous nephropathy (membranous glomerulonephritis)2nd most common
nephrotic syndrome in adults in US
- Membranoproliferative glomerulonephritis

Systemic diseases that can cause nephrotic syndrome"SAD"

- Systemic lupus erythematosus (can also present as nephritic)
- Amyloidosis
- Diabetic nephropathy

Lupus Nephritis: 5 subtypes of renal involvement

Type IV is the prototype and most severe form of the disease

Combination of nephrotic and nephritic syndromes

Subendothelial, subepithelial, and mesangial immune complex deposits

Endothelial cell proliferation, mesangial proliferation, focal thrombosis, and

extensive scarring

Amyloidosis:
o

Subendothelial and mesangial amyloid deposits

Identified by Congo red stain. Under polarized light will show apple green
birefringence.

Primary amyloidosis of the amyloid light chain (AL) type is associated with
plasma cell disorders such as multiple myeloma

Protein AA type is associated with inflammatory diseases such as rheumatoid

arthritis

Diabetic Nephropathy: [1]

o

Thickening of basement membrane as seen by electron microscopy

mesangial matrix either in a nodular pattern (nodular glomerulosclerosis, also

known as Kimmelstiel-Wilson disease) or a diffuse pattern (diffuse mesangial
sclerosis)

More common in type I diabetics than type II.

[2]

Poor glycemic control nonenzymatic glycosylation of renal vasculature

(hyalinization):
1) Efferent arterioles (hyaline arteriolosclerosis) increases glomerular filtration
rate hyperfiltration damage mesangial proliferation.
2) Widespread thickening and permeability of the glomerular basement
membrane and renal tubular basement membrane early disease presents with
microalbuminuria
Note: nodular formation (arrows shown in image) due to deposition of type IV
collagen (aka microangiopathy)
Note: hyalinization of the afferent arteriole occurs later which eventually GFR

Nephrotic syndromeMinimal-change disease

Minimal-Change Disease (Lipoid Nephrosis; Nil disease):

- Most common cause nephrotic syndrome in children.
o Pathophysiology:
- T cells and cytokines injure visceral epithelial cells (podocytes) podocytes
and podocyte foot processes lose their negative charge and become effaced
"highly selective" proteinuria with hypoalbuminemiaie, most of the protein
lost in urine is albumin (albumin has low molecular weight and abundant negative
charge easily filtered by a damaged charge barrier that has lost a significant
amount of its native negative charge)
Note:
- Effacement of podocyte foot processes = simplification (flattening, retraction,
swelling) of podocyte foot process architecture
- "Effacement" of podocyte foot processes is often incorrectly called "fusion" of
podocyte foot processes

[1]

Defective glomerular filtration charge barrier filtration and subsequent

tubular resorption of lipoproteins lipid-laden proximal tubular cellshence
the name "lipoid nephrosis"
Light microscopy:
- Normal-appearing glomeruli, lipid-laden proximal tubular cells
Immunofluorescence:
- No deposits
Electron microscopy:
- Diffuse effacement of podocyte (visceral epithelial cell) foot processes
- Normal-appearing glomerular basement membrane, no electron-dense deposits

Clinical features:
- Young child (most commonly 2-6 years of age), sometimes with a recent history
of respiratory infection or routine prophylactic immunization presents with
massive proteinuria and S/Sx of nephrotic syndrome, however renal function is
usually good and there is usually no hematuria or hypertension
- Good response to corticosteroid therapy, excellent prognosis

Nephrotic syndromeFSGS (focal segmental glomerulosclerosis)

FSGS (focal segmental glomerulosclerosis):

- Most common cause of nephrotic syndrome in adults in the US. [1]
o Why "Focal Segmental"?
- Sclerosis of some (but not all) glomerulihence, "Focal"
- Within affected glomeruli, there is sclerosis of some (but not all) of the
glomerulushence, "Segmental"
o

Pathophysiology:
- Damage (possibly cytokine-mediated) and focal disruption of podocytes
(visceral epithelial cells) foci of permeability entrapment of plasma
proteins sclerosis, hyalinosis
Note: There are no immune complex deposits in FSGS.

Light microscopy:
- Sclerosis (but no deposits) within some juxtamedullary glomeruli; some
glomeruli appear normal and unaffected
Immunofluorescence microscopy:
- IgM and C3 may be observed in sclerotic areas and/or in the mesangium,
however no immune complex deposits are visualized
Electron microscopy:

- Diffuse effacement of foot processes may be observed in sclerotic and

nonsclerotic areas
o

Associations with FSGS:

- Black race
- HIV infection
- IV drug abuse (eg, Heroin)
- Sickle-cell disease
- Obesity
- Pamidronic acid therapy

Treatment & Prognosis:

- Poor response to corticosteroid therapy
- Poor prognosis: >50% of patients develop end-stage renal disease within 10
years
- High rate of disease recurrence (25-50%) in patients receiving renal transplants

Nephrotic syndromeMembranous nephropathy (membranous

glomerulonephritis)

Membranous nephropathy (membranous glomerulonephritis):

- 2nd most common cause of nephrotic syndrome in adults in the US (focal segmental
glomerulosclerosis is now the most common)
o Pathophysiology:
- Circulating immune complexes are believed to bind to in situ antigens on the
glomerular epithelial basement membrane activation of complement cascade
C5b-C9 membrane attack complex damages glomerular epithelial and
mesangial cells, causing their release of proteases and oxidants which further
contribute to glomerular capillary wall damage nephrotic-range proteinuria.
o

Light microscopy:
- Normal-appearing glomeruli (early stages of the disease) or diffuse glomerular
capillary wall thickening (later stages of the disease)
- Silver stain spike and dome patternthe spikes are basement membrane
material (colored black by the silver stain) and the domes are immune complex
deposits (not colored by the silver stain).
Immunofluorescence microscopy:
- Granular deposits of IgG and/or C3
Electron microscopy:
- Subepithelial (subpodocyte) immune complex deposits

May cause renal vein thrombosis

Although 85% of cases of membranous nephropathy are primary idiopathic, there are a
variety of causes of secondary membranous nephropathy:

Infectious diseases:
- Hepatitis B
- Hepatitis C
- Syphilis
- Malaria

Autoimmune diseases:
- SLE (systemic lupus erythematosus)
- RA (rheumatoid arthritis)
- SS (sjgren's syndrome)
- Hashimoto thyroiditis

Drugs:
- Penicillamine
- Captopril
- NSAIDs
- Gold

Malignancies:
- Solid tumorseg, colon carcinoma, lung carcinoma, melanoma
- Chronic lymphocytic leukemia

Nephrotic syndromeMPGN (membranoproliferative glomerulonephritis)

Note: MPGN is not a pure nephrotic syndrome the clinical presentation includes both
nephritic and nephrotic features.
MPGN (membranoproliferative glomerulonephritis):
o

Adolescents/young adults with nephrotic syndrome and a nephritic component

(eg, hematuria) slow progression to renal failure

Common to both MPGN type I and MPGN type II:

1) Glomeruli are large and hypercellular due to WBC infiltrate, proliferation of
mesangial cells and endothelial cells, and mesangial matrix
2) Mesangial ingrowth and new GBM (glomerular basement membrane) synthesis
in response to deposition of immune complexes duplication/splitting of GBM
thick GBM w/ "tram-track" or "double contour" appearance (esp. evident
w/ silver or PAS stains)

MPGN type 1:
- Subendothelial immune complex deposits
- Activates both classical and alternative complement serum C1, C4, C3

MPGN type 2 (dense deposit disease, MPGN II):

- Intramembranous immune complex deposits
- Activates alternative complement only serum C3; normal C1 and C4
- Associated with C3 nephritic factor, an IgG autoantibody that stabilizes C3bBb

(alternative complement C3 convertase) persistent C3 activation serum

C3
o

Causes of membranoproliferative glomerulonephritis include:

1) Autoimmune disease with chronic immune complex depositionfor example:
- SLE (systemic lupus erythematosus)
- SS (sjgren's syndrome)
2) Infectionfor example:
- Hepatitis C, usually with cryoglobulinemia
- Hepatitis B
- HIV
- Schistosomiasis
3) 1-Antitrypsin deficiency
4) Malignancy:
- CLL (chronic lymphocytic leukemia)
- Lymphoma

Nephritic syndrome

Signs and symptoms of nephritic syndrome are all due to inflamed, damaged glomeruli

o 1) Hematuria:
- Patients often report "smoky" or "tea-colored" or "cola-colored" urine
- 4+ blood on urine dipstick
- RBC casts, dysmorphic RBCs on urinalysis
o

2) Mild to moderate proteinuriausually <1g/day (>150mg/day but <3.5g/day)

GFR, yet renal tubular function (concentrating ability) is still intact

3) Oliguria
4) Clearance of BUN, Cr, and uremic toxins Azotemia ( BUN and serum
Cr) with BUN:Cr ratio >15
5) Salt retention Mild to moderate hypertension
6) Salt retention Periorbital edema (more generalized pitting edema may
occur, but usually only in severe cases)

Nephritic syndrome vs. nephrotic syndrome:

o

Hematuria (4+ blood on urine dipstick) is a prominent feature of nephritic

syndrome, with dysmorphic RBCs & RBC casts on urinalysisvs. nephrotic
syndrome: urinalysis reveals fatty casts (oval fat bodies) which demonstrate
"maltese cross" interference pattern under polarized light due to cholesterol

Hallmark of nephritic syndrome: RBC casts

o

Proteinuria may be present in nephritic syndrome but is usually mild (<3.5g/day)

vs. nephrotic syndrome: >3.5g/day (4+ protein on urine dipstick)

Edema may be present in nephritic syndrome but is usually mild (eg, periorbital
edema) and is due to salt retentionvs. nephrotic syndrome: generalized edema
(anasarca) due to hypoalbuminemia

Nephritic syndrome is characterized by neutrophil-mediated glomerular injury

vs. nephrotic syndrome: T-cells and cytokines damage podocytes and cause
podocytes to lose their negative charge, in turn causing them to fuse and
decreasing their effectiveness as a filtration barrier to negatively charged
macromolecules like albumin

Nephritic syndromePSGN (poststreptococcal glomerulonephritis)

PSGN (poststreptococcal glomerulonephritis):

- also known as acute proliferative poststreptococcal glomerulonephritis
o If the strain of S. pyogenes is nephritogenic (eg, serotype M12, M4, or M1)
risk of developing PSGN as a complication 1-4 weeks following common strep
infections, including upper respiratory tract infections (eg, pharyngitis) or skin
infections (eg, impetigo, erysipelas, scarlet fever).

Pathophysiology:

URI or skin infection with a nephritogenic strain of group A -hemolytic

Streptococcus pyogenes (especially serotype M12, M4, or M1)

1-4 weeks to make antibodies ( anti-streptolysin O, anti-DNAse B) and form

immune complexes

Subepithelial (subpodocyte) immune complex deposition (type III

hypersensitivity) in glomeruli with subsequent activation of alternative
complement
1) serum C3 level; normal C1 and C4 levels
2) C5a recruits neutrophils glomerular damage/inflammation (ie,
glomerulonephritis) with large hypercellular glomeruli due to WBC infiltrate and
proliferation of mesangial and endothelial cells

Note: renal tubules are not the primary target during acute attacks of
glomerulonephritis renal tubular function (concentrating ability) remains largely
intact

Microscopic appearance of renal biopsy:

o

Light microscopy:
- Large hypercellular glomeruli

Immunofluorescence microscopy:
- Granular/coarse deposits of IgG, IgM, and C3 along the GBM (glomerular
basement membrane) and in the mesangium

Electron microscopy:
- Large subepithelial (subpodocyte) electron-dense depositsprominent
"bumps and humps"
- Subendothelial, intramembranous, and mesangial electron-dense deposits may
also be visualized but are less common and less prominent than the subepithelial
deposits

Classic clinical presentation:

o

Young child (most commonly 6-10 years of age) with history of upper respiratory
tract infection (eg, pharyngitis) or skin infection (eg, impetigo, erysipelas, scarlet
fever) 1-4 weeks ago

Sudden development of fever, nausea, malaise, and S/Sx of nephritic syndrome:

- Hematuria (4+ blood on urine dipstick)"smoky" or "tea-colored" or "colacolored" urine; RBC casts and dysmorphic RBCs on urinalysis
- Mild to moderate proteinuriausually <1g/day (always <3.5g/day)
- Oliguria
- Azotemia with BUN:Cr ratio >15 because renal tubular function (concentrating
ability) is still intact
- Mild to moderate hypertension
- Mild edema (eg, periorbital edema)

Nephritic syndromeRPGN (rapidly progressive glomerulonephritis)

RPGN (rapidly progressive glomerulonephritis):

- also known as crescentic glomerulonephritis
o Light microscopy:
Crescents and collapsed glomerular tufts
Immunofluorescence microscopy:
Depends on the type of RPGN:
- Type I (anti-GBM antibody) RPGNsmooth linear staining of IgG and/or C3
- Type II (immune complex) RPGNgranular staining of IgG and/or C3
- Type III (pauci-immune) RPGNweak or absent staining
Electron microscopy:
- Ruptures in the GBM (glomerular basement membrane)
o

Pathophysiology:
1) Ruptures in the GBM triggers the formation of crescents by:
- Allowing infiltration of leukocytes into Bowman space (the urinary space lined
by visceral epithelium (ie, podocytes) and parietal epithlieum)

- Allowing leakage of fibrinogen into Bowman space where it is converted into

fibrin
- Triggering proliferation of parietal epithelial cells lining the Bowman space
2) Eventually, crescents fill the entire Bowman space compression/collapse of
the glomerular tuft

Type I RPGN:
- Mediated by anti-GBM (glomerular basement membrane) antibodies
- ANCA-negative in most cases
- Immunofluorescence microscopy: smooth linear staining of IgG and/or C3
o

Type II RPGN:
- Mediated by immune complex deposition
- ANCA-negative in most cases
- Immunofluorescence microscopy: granular staining of IgG and/or C3
o

2 possible clinical presentations of Type I RPGN:

1) If the anti-GBM antibodies cross-react with pulmonary alveolar basement
membranes renal + pulmonary involvementie, Goodpasture syndrome
- or 2) If the anti-GBM antibodies do NOT cross-react with pulmonary alveolar
basement membranes "renal limited" (ie, isolated renal involvement)

Although sometimes idiopathic, many cases of type II RPGN represent a

complication of one of the immune complex-mediated nephritidesFor example:
- PSGN (poststreptococcal glomerulonephritis)
- Lupus nephritis
- IgA nephropathy
- HSP (Henoch-Schnlein purpura)

Type III RPGN:

- Pauci-immuneie, lack of anti-GBM (glomerular basement membrane) antibodies or
immune complexes
- ANCA-positive
- Immunofluorescence microscopy: weak or absent staining [1]
o

Although usually idiopathic, some cases of type III RPGN are caused by a
systemic vasculitisFor example:
- Wegener granulomatosisc-ANCA (anti-proteinase 3 antibodies)
- Churg-Strauss syndromep-ANCA (anti-myeloperoxidase antibodies)
- Microscopic polyangiitisp-ANCA (anti-myeloperoxidase antibodies)

Note: Recent research indicates that immune complexes may play a role in
ANCA-associated Wegeners granulomatosis

Nephritic syndromeGoodpasture syndrome

Goodpasture syndrome:

Epidemiology: males > females, young adults in their 20s and 30s

S/Sx:
1) Pulmonary hemorrhage hemoptysis (1st presenting symptom), cough,
dyspnea
Followed by a couple weeks later by
2) Rapidly progressive renal failure with S/Sx of nephritic syndromehematuria
(2nd presenting symptom), RBC casts, azotemia, oliguria, mild/moderate
hypertension, mild/moderate proteinuria and edema

Tx: steroids; plasmapheresis for weeks until steroids take effect

Pathophysiology:
o

Type II hypersensitivity reaction: anti-GBM antibodies react with the

Goodpasture antigen (a peptide within the noncollagenous portion of the 3 chain
of type IV collagen) in GBMs (glomerular basement membranes) and also crossreact with pulmonary alveolar basement membranes pulmonary hemorrhage
(hemoptysis) + renal failure (hematuria)

Goodpasture syndrome usually leads to Type 1 (anti-GBM antibody) RPGN

(rapidly progressive (cresentic) glomerulonephritis)crescents fill Bowman's
space due to the proliferation of parietal epithelial cells, fibrin deposition and
infiltration of leukocytes.

Microscopic appearance of renal biopsy:

o

Light microscopy:
- Crescents may or may not be visualized, depending on the stage of the disease
process

Immunofluorescence microscopy:
- Smooth linear deposits of IgG and C3 which outline the entire glomerular
basement membrane
- ANCA negative

Nephritic syndromeAlport syndrome

Alport syndrome:
1) Hereditary nephritis (which may progress to chronic renal failure)
2) Hearing loss
3) Ocular abnormalities
o 85% of cases of Alport syndrome are due to an X-linked recessive defect in the 5
chain of type IV collagen.
The remaining 15% of cases are autosomal recessive or autosomal dominant

defects in the 3 chain or the 4 chain of type IV collagen.

[Note: the 3 chain of type IV collagen contains the Goodpasture antigen]
o

Regardless of inheritance pattern or the specific defect involved, all cases of

Alport syndrome are caused by defective type IV collagen assembly structuralfunctional defects in the:
- GBM (glomerular basement membrane) nephritis (hematuria, RBC casts)
- Cochlear hair cells of the inner ear sensorineural hearing loss
- Lens and cornea of the eye ocular abnormalities (eg, lens dislocation,
posterior cataracts, corneal dystrophy)

Most common presentation:

- hematuria (gross or microscopic), frequently with RBC casts

Electron microscopy:
- Irregular thickening/thinning of the GBM (glomerular basement membrane)
with splitting/lamination of the lamina densa this often gives the GBM a
unique "basketweave" appearance

Note: GBM splitting is also seen in membranoproliferative glomerulonephritis

(MPGN) type I

Nephritic syndromeIgA nephropathy

IgA nephropathy (Bergers disease):

- Most common cause of nephritic syndrome worldwide
- An important cause of recurrent hematuria (gross or microscopic)
o Light microscopy:
- May show normal-appearing glomeruli or mesangial widening due to mesangial
proliferation and/or deposition of immune complexes
Immunofluorescence microscopy:
- Mesangial deposition of IgA1, often with C3 and properdin
Electron microscopy:
- Confirms the presence of mesangial deposits
o

Characterized by painless recurrent hematuria in children that occurs 1-2 days

after an infection of mucosal tissue (eg, genitourinary tract, gastrointestinal tract).
[Memory Aid: IgA is produced by mucosal tissue & follows infections of mucosal
tissue.]
Note:
Differentiate IgA nephropathy from PSGN (post-streptococcal
glomerulonephritis).
PSGN:
- Occurs in kids 1-2wks post-infection (vs. 1-2 days post-infection)

- IgG immune complexes (vs. IgA)

- serum C3 levels (vs. IgA which cannot fix complement normal C3 levels in
IgA nephropathy)
o

IgA nephropathy is associated with:

- Henoch Schnlein purpurapurpuric skin rash (IgA-mediated small vessel
vasculitis), hematuria (IgA-mediated kidney disease), abdominal pain (GI
involvement), arthritis/arthralgia (joint involvement).
- Celiac sprueIgA-mediated bowel disease (anti-gliadin IgA)
- Dermatitis herpetiformisgrouped vesicles on extensor surfaces

EM: Sub-Endothelial vs. Sub-Epithelial Deposits - Summary

Sub-Endothelial Deposits:
o Diffuse proliferative glomerulonephritis (Nephritic)
-Due to SLE (there is also a less common nephrotic subtype that is subepithelial)
o

Type I Membranoproliferative Glomerulonephritis (Type I MPGN) EM also

shows tram-tracking due to mesangial proliferation.
[More commonly presents as nephrotic syndrome w/ hematuria]

Sub-Epithelial Deposits:
o

Post-streptococcal glomerulonephritis (nephritic)

Membranous glomerulonephritis aka. diffuse membranous glomerulopathy

(nephrotic syndrome) "spike and dome" appearance.

Other Type Of Deposits:

o

Mesangial Deposits: IgA Nephropathy (Berger's disease)

Intramembranous Deposits (within the GBM): MPGN type II (dense-deposit

disease) EM also shows "tram-tracking"

No Visible Deposits By EM:

o

Minimal Change Disease (nephrotic) EM shows podocyte fusion

Focal Segmental Glomerulosclerosis (nephrotic) EM shows podocyte fusion

and focal detachment of visceral epithelial cells

Alport Syndrome (Hereditary Nephritis) EM shows alternating thickening and

thinning of GMB with splitting "Basket weave appearance"

Goodpastures (RPGN: Rapidly Progressive Glomerulonephritis aka Type I

Crescentic Glomerulonephritis nephritic)

[Note: there are antibodies to GBM but there are no electron dense electron
deposits visible by EM, diagnose by IF]

Chronic Glomerulonephritis

Chronic glomerular disease

o Is not always preceded by inflammatory injury
o

Rapidly progressive glomerulonephritis (RPGN) is the most common cause,

followed by focal segmental glomerulosclerosis

Gross appearance: kidneys are symmetrically shrunken, and diffusely granular

Microscopically:

Scarring of the glomeruli trichrome stain shows blue-staining collagen in

glomeruli

Interstitial fibrosis trichrome will show blue-staining collagen between

glomeruli

Hyaline arteriolosclerosis (thickening of wall of arterioles and narrowed lumen)

secondary to hypertension.

Tubular atrophy

Lymphocytic infiltrate

Clinical presentation:
o

Hypertension

Anemia (secondary to lack of erythropoietin) fatigue/malaise

Proteinuria

Azotemia

Grossly bloody urine is rare (although microscopically it is present)

Oliguria and waxy casts

Without treatment uremia and death

Treatment: Hemodialysis or renal transplant

Infection of the Urinary Tract and Kidney

Urinary tract infection: General characteristics

Higher incidence in women due to shorter length of female urethra

Higher incidence during pregnancy

Most frequently involves normal flora of colon, such as E. coli

[1]

Lower UTI: cystitis, prostatitis, urethritis

Upper UTI: pyelonephritis (pyelo = "pelvis")

Pyelonephritis can be caused by: [2]
o

1) Ascending infection from the lower urinary tract:

- E. coli accounts for about 85% of community-acquired UTIs and 50% of
hospital-acquired UTIs.

2) Hematogenous dissemination to the kidney (e.g., tuberculosis, staph)

- Most common form of nonpulmonary tuberculosis (after lymphadenopathy) is
genitourinary disease; genitourinary tuberculosis is usually asymptomatic
[3] [4]

Risk factors:
o Catheters inserted through urethra into bladder
#1 cause UTI/sepsis in hospitals.
o

Surgery on kidney or urinary tract

Obstruction of urinary flow (i.e. benign prostate hyperplasia)

Vesicoureteral reflux: incompetent vesicoureteral orifice (b/w ureter and bladder)

urine refluxes into ureters when bladder is under pressure bacteria can
ascend the ureter to the kidney

Uro-gynecological structural abnormalities

Immunocompromised states, such as diabetes or transplant patients

Pregnancy
[5]

Clinical manifestations:
o Urinary frequency
o

Dysuria

Pyuria: neutrophils in urine

Hematuria: blood in urinehowever, unlike bacteria in urine cultures, urinary red

cells are a nonspecific finding
Hematuria can also be associated with:
- Renal disease
- Kidney or bladder stones
- Trauma to the urinary tract or the prostate
- Disorders involving the body's clotting system
- Cancer along the urinary tract
- Medication side effectse.g., warfarin (Coumadin), clopidogrel (Plavix),
aspirin
[6]

Bacteriuriaurine culture to confirm UTI:

>105 colonies per mL of a single species of bacteria is generally considered

diagnostic of UTI
Acute pyelonephritis: bacterial infection of renal pelvis & parenchyma
o

In addition to ascending infection by E. Coli there are other common enteric gram
- rods: Proteus, Enterobacter, Klebsiella, Pseudomonas

Fever, flank tenderness, leukocytosis, urinary white cells, and white cell casts in
urine (pathognomonic)

Gross appearance: Patchy pale abscesses on the cortex and medulla

Histologically: abscess formation which starts in the interstitial tissue and

eventually ruptures into tubules intratubular neutrophils white cell
(leukocyte) casts in urine. Glomeruli usually not affected.
[remember: casts only form in the tubules]

Complications:
-chronic pyelonephritis
-papillary necrosis (w/ diabetics or w/ obstruction)

Treatment:
Uncomplicated: Oral Ciprofloxacin
Hospitalization: IV Ciprofloxacin
Note: Fluoroquinolones (cipro) and TMP-SMX are used because they can reach
high concentrations in the renal medulla.

Chronic pyelonephritis:

Risk factors: diabetes, vesicoureteral reflux (in children), urinary tract obstruction
(stones, tumors)

Reflux type: coarse asymmetric corticomedullary scarring directly overlaying the

deformity of renal pelvis and calyces: blunting of calyces. This blunting is not
seen in acute pyelonephritis.

Chronic infection due to incompetent vesicoureteral junction causing

vesicoureteral reflux (reflux type) and/or chronic distal obstruction (e.g. BPH)
causing hydronephrosis (obstructive type).

Obstructive type: hydronephrosis dilation of calyces and thinning of cortex

In the later stages, tubular atrophy with eosinophilic proteinaceous casts which
appear like thyroid follicles: thyroidization of the kidneys

Can lead to renal hypertension and end stage renal disease

Cystitis
o

Bladder inflammation (part of the lower urinary tract) from fecal flora, drugs,
and/or radiation.

Dysuria, urgency, hematuria ( uncommon in vaginitis/urethritis), suprapubic pain

(distinguish from flank pain/CVA tenderness of pyelonephritis), urinary white
cells with NO white cell casts (distinguish from WBC casts found in
pyelonephritis), fever is uncommon (unlike pyelonephritis), lack of vaginal
discharge (distinguish from vaginitis/urethritis)

Hemorrhagic cystitis due to anti-cancer agents (ifosfamide or

cyclophosphamide) use mesna as an adjunct for prevention.
Also due to adenovirus.

Radiation cystitis post radiation therapy

Treat with TMP-SMX for susceptible bacterial infection can also use a muscarinic
antagonist (oxybutynin) to reduce urgency.

Infection of the Urinary Tract and Kidney

Urinary tract infection: General characteristics

o Higher incidence in women due to shorter length of female urethra
o

Higher incidence during pregnancy

Most frequently involves normal flora of colon, such as E. coli

[1]

Lower UTI: cystitis, prostatitis, urethritis

Upper UTI: pyelonephritis (pyelo = "pelvis")

Pyelonephritis can be caused by: [2]
o

1) Ascending infection from the lower urinary tract:

- E. coli accounts for about 85% of community-acquired UTIs and 50% of
hospital-acquired UTIs.

2) Hematogenous dissemination to the kidney (e.g., tuberculosis, staph)

- Most common form of nonpulmonary tuberculosis (after lymphadenopathy) is
genitourinary disease; genitourinary tuberculosis is usually asymptomatic
[3] [4]

Risk factors:
o Catheters inserted through urethra into bladder
#1 cause UTI/sepsis in hospitals.
o

Surgery on kidney or urinary tract

Obstruction of urinary flow (i.e. benign prostate hyperplasia)

Vesicoureteral reflux: incompetent vesicoureteral orifice (b/w ureter and bladder)

urine refluxes into ureters when bladder is under pressure bacteria can
ascend the ureter to the kidney

Uro-gynecological structural abnormalities

Immunocompromised states, such as diabetes or transplant patients

Pregnancy
[5]

Clinical manifestations:
o Urinary frequency
o

Dysuria

Pyuria: neutrophils in urine

Hematuria: blood in urinehowever, unlike bacteria in urine cultures, urinary red

cells are a nonspecific finding
Hematuria can also be associated with:
- Renal disease
- Kidney or bladder stones

- Trauma to the urinary tract or the prostate

- Disorders involving the body's clotting system
- Cancer along the urinary tract
- Medication side effectse.g., warfarin (Coumadin), clopidogrel (Plavix),
aspirin
[6]

Bacteriuriaurine culture to confirm UTI:

>105 colonies per mL of a single species of bacteria is generally considered

diagnostic of UTI
Acute pyelonephritis: bacterial infection of renal pelvis & parenchyma
o

In addition to ascending infection by E. Coli there are other common enteric gram
- rods: Proteus, Enterobacter, Klebsiella, Pseudomonas

Fever, flank tenderness, leukocytosis, urinary white cells, and white cell casts in
urine (pathognomonic)

Gross appearance: Patchy pale abscesses on the cortex and medulla

Histologically: abscess formation which starts in the interstitial tissue and

eventually ruptures into tubules intratubular neutrophils white cell
(leukocyte) casts in urine. Glomeruli usually not affected.
[remember: casts only form in the tubules]

Complications:
-chronic pyelonephritis
-papillary necrosis (w/ diabetics or w/ obstruction)

Treatment:
Uncomplicated: Oral Ciprofloxacin
Hospitalization: IV Ciprofloxacin
Note: Fluoroquinolones (cipro) and TMP-SMX are used because they can reach
high concentrations in the renal medulla.

Chronic pyelonephritis:
o

Risk factors: diabetes, vesicoureteral reflux (in children), urinary tract obstruction
(stones, tumors)

Reflux type: coarse asymmetric corticomedullary scarring directly overlaying the

deformity of renal pelvis and calyces: blunting of calyces. This blunting is not
seen in acute pyelonephritis.

Chronic infection due to incompetent vesicoureteral junction causing

vesicoureteral reflux (reflux type) and/or chronic distal obstruction (e.g. BPH)
causing hydronephrosis (obstructive type).

Obstructive type: hydronephrosis dilation of calyces and thinning of cortex

In the later stages, tubular atrophy with eosinophilic proteinaceous casts which
appear like thyroid follicles: thyroidization of the kidneys

Can lead to renal hypertension and end stage renal disease

Cystitis
o

Bladder inflammation (part of the lower urinary tract) from fecal flora, drugs,
and/or radiation.

Dysuria, urgency, hematuria ( uncommon in vaginitis/urethritis), suprapubic pain

(distinguish from flank pain/CVA tenderness of pyelonephritis), urinary white
cells with NO white cell casts (distinguish from WBC casts found in
pyelonephritis), fever is uncommon (unlike pyelonephritis), lack of vaginal
discharge (distinguish from vaginitis/urethritis)

Hemorrhagic cystitis due to anti-cancer agents (ifosfamide or

cyclophosphamide) use mesna as an adjunct for prevention.
Also due to adenovirus.

Radiation cystitis post radiation therapy

Treat with TMP-SMX for susceptible bacterial infection can also use a muscarinic
antagonist (oxybutynin) to reduce urgency.

Hydronephrosis

Obstruction of urine outflow which leads to dilation of renal pelvis/calyces/ureter

o The excess pressure causes compression atrophy of the renal parenchyma (renal
medulla and cortex).
o

Bilateral hydronephrosis occurs when obstruction is below the ureters

Etiology
o

Congential (typically presents in children):

- Atresia of urethra
- Bladder neck obstruction

Acquired (Adults):
- Stones (most common)
- Tumors in pelvic area (BPH, cervical cancer tumors)

- Inflammatory (retroperitoneal fibrosis, prostatis)

- Neurogenic (spinal cord injury bladder paralysis)
- Pregnancy

Tubules are affected first impaired concentrating ability

Chronic nephritis is a common complication

Benign Tumors of the Kidney

Adenoma:
o Often small and asymptomatic
o

But may be precursor lesion to renal carcinoma

Angiomyolipoma:
o

Hamartoma consisting of fat, smooth muscle and blood vessel

May be associated with tuberous sclerosis

Malignant Tumors of the Kidney

Renal cell carcinomaalso known as clear cell carcinoma of the kidney,

hypernephroma, or Grawitz tumor
o Most common renal malignancy
o

Higher incidence in men and smokers

Associated with invasion of renal veins or inferior vena cava

Associated with gene deletions in chromosome 3 and Von Hippel Lindau

syndrome

Results in early hematogenous dissemination

Histology:
- clear polygonal cells derived from proximal tubule
- cells are "clear" due to high glycogen and lipid content

Clinical triad:
1) flank pain
2) palpable mass
3) hematuria

May manifest with paraneoplastic syndromes: PTHrP, EPO, ACTH, Renin

Wilms Tumor:
o

Most common renal malignancy of early childhood

Originates from primitive metanephric tissue with embryonic glomeruli and

mesenchymal elements

Presents with large palpable flank mass, hemihypertrophy, hypertension

May be part of WAGR complex:

- Wilms tumor (due to deletion of the WT1 tumor suppressor gene on
chromosome 11)
- Aniridia (due to mutation/deletion of the PAX6 gene on chromosome 11)
- Genitourinary malformation
- Mental-motor Retardation

Associated with deletions on short arm of chromosome 11 (11p), specifically the

WT gene.

Transitional Cell Carcinoma:

o

Most common tumor of urinary collecting system

Can occur in renal calyces, pelvis, ureters, or bladder

Tends to spread by local extension to surrounding tissue. Contrast this with renal
cell carcinoma, which spreads hematogenously.

Most common initial complaint (leading to this diagnosis): painless hematuria

Associated risk factors include:

- cigarette smoking
- cyclophosphamide
- aniline dyes
- phenacetin