Transcript USMLE STEP I Review Week 6: Renal and Hematology Physiology

Steven Katz, MSIV
Part 1: Hematology and Oncology
(p.326-347)

Blood Cell Differentiation
Heme Terms (p. 327)

Erythrocyte: anucleate, biconcave cell with
large surface area for gas exchange.

Macrophage: mature monocyte, phagocytic
cell found in tissues

Platelet: cytoplasmic fragment of
megakaryocyte, involved in primary
hemostasis. Aggregates and interacts with
fibrinogen to form hemostatic plug. 1/3
platelet pool stored in the spleen.
Heme terms (p.327)

Leukocyte: two types granulocytes and
mononuclear cells. Involved in defense against
infections
 Basophil: Granulocyte, mediates allergic rxn, in
blood
 Mast Cell: Granulocyte, binds IgE to membrane,
found in tissue
 Eosinophil: Granulocyte, causes of eosinophilia
(NAACP) Neoplasm, Asthma, Allergy, Collagen
Vasc. Dz, Parasites
 Neutrophil: Granulocyte, acute inflammatory
response cell
 Monocyte: mononuclear cell, “frosted glass
cytoplasm”
Heme Terms (p.327)

Dendritic Cells: APC, has MHC II and Fc
receptor, main inducer of 10 Ab response

Lymphocyte: mononuclear cells mature
into:
 B lymphocyte: humoral immunity
 Plasma cell: mature B Lymphocyte, produce
Ab. (multiple myeloma is a plasma cell
neoplasm)
 T lymphocyte: cellular immunity, matures in
thymus
○ MHC x CD=8 (MHC2 x CD4 & MHC1 x CD1)
Intrinsic Pathway
Extrinsic Pathway
*
*
*
TF = thromboplastin
*
*
Factor II is prothrombin (IIa is
thrombin)
* = Ca required
Thrombogenesis
Coag Cascade and platelet plug
(p.330)

Platelet plug formation
1. Adhesion: vWF mediates linking of platelet
Gp1b receptor to subendothelial collagen
2. Aggregation: balance btw pro-aggregation and
anti-aggregation factors


TxA2 released by platelets incr aggregation
PGI2 and NO from endothelial cells decr aggregation
3. Swelling: binding of ADP on platelet receptor

 insertion of G2b/3a on platelet memb which
allows platelet cohesion, Ca strengthens
platelet plug
ASA inhibits cyclooxygenase which inhibits TxA2
synthesis
Coag cascade: pro-coagulation
(p.330)

Vitamin K becomes activated by epoxide
reductase and acts as a co-factor in the
maturation of Factors II, VII, IX,, X, C,
and S
 Warfarin inhibits epoxide reductase

von Willebrand factor carries/protect VIII
 Binds GpIb to subendothelial collagen as
well
Coag cascade: anti-coagulation
(p.330)

Antithrombin III inactivates factors II, VII,
IX, X, and XI
 Heparin activates ATIII
Protein C is activated by Protein S and
thrombomodulin (endothelial cells).
 APC (activated protein C) cleaves and
inactivates Va and VIIIa

 Factor V Leiden mutation produces APC
resistant Factor V

Plasminogen –tPA-> plasmin
cleavage of fibrin mesh
Coag cascade and kinin (p.331)
Hereditary Thrombosis Syndromes (p.329)
Factor V Leiden: mutant factor V cannot be
degraded by protein C
 Prothrombin gene mutation: Mutation in 3’
untranslated region associated with venous
clots
 AT III deficiency: inherited deficiency of
ATIII, reduced increase of PTT with heparin
admin
 Protein C or S deficiency: decreased ability
to inactivate factors V and VIII. Increased
risk of hemorrhagic skin necrosis following
warfarin admin

Blood groups (p.331)
Type A: has A Ag on RBC and B Ab in
plasma
 Type B: has B Ag on RBC and A Ab in
plasma
 Type AB: A and B Ag on RBC, no Ab in
plasma “universal RECIEPIENT”
 Type O: No Ag on RBC, both AB in plasma,
“universal DONOR”


Rh: + indicates Ag is present, mothers who are
neg, may make anti-Rh IgG that can cross the
placenta and cause hemolytic dz of the newborn
(in the subsequent pregnancy)
RBC pathologies (p.332)
Type
Biconcave
Spherocyte
Elliptocyte
Macro-ovalocyte
Helmet cell, shistocyte
Sickle Cell
Bite Cell
Teardrop cell
Acanthocyte (spur cell)
Target cell
Burr Cell
Basophilic stippling
Pathology
Normal
spherocytosis, autoimmune hemolysis
Hereditary elliptocytosis
Megaloblastic anemia, marrow failure
DIC, TTP/HUS, traumatic, hemolysis
Sickle Cell anemia
G6PD deficiency
Myeloid metaplasia with myelofibrosis
“Spiny”, in liver dz and abetalipoproteinemia
HbC dz, Asplenia, Liver dz, Thalassemia (HALT)
TTP/HUS
Thalassemia, Anemia of chronic dz, IDA, Lead
(TAIL)
Anemias-VERY IMPORTANT (p.332)

Microcytic Hypochromic: MCV <80
 Iron deficiency anemia: serum iron, TIBC,
ferritin (intracellular iron store)
○ Decreased heme synthesis
 Thalassmia: target cells
○ Mut leads to decr globin synthesis
 Lead poisioning
○ Inhibits ferrochelatase and ALA dehydrase (heme
synthesis)
 Some sideroblastic anemias
 Anemia of chronic dz: release of iron to transferrin
Anemias-VERY IMPORTANT
(p.332)

Macrocytic: MCV >100
 Megaloblastic-vit B12 and/or folate
deficiency
 Drugs that block DNA synthesis (e.g sulfa,
phenytoin, AZT)
 Marked reticulocytosis (bigger than mature
RBC’s)
Anemias-VERY IMPORTANT
(p.332)

Normocytic, normochromic
 Acute hemorrhage
 Enzyme defects (e.g. G6PD)
 RBC membrane defects (e.g. spherocytosis)
 Bone marrow disorders (e.g. aplastic
anemia, leukemia) (macrocytic as well)
 Hemoglobinopathies (e.g. sickle cell)
 Autoimmune hemolytic anemia
 Anemia of chronic dz: TIBC, ferritin,
increased storage in marrow macrophages
Lab values in anemia
IDA
Serum Iron
Chronic
Disease
(10)
(10)
Transferrin/
TIBC
Ferritin
% transferrin
saturation
(serum
Fe/TIBC)
Ferritin=iron storage; Transferrin=iron transport in blood
Hemo- Pregnancy
chroma- /OCP use
tosis
(10)
-
Porphyria (p.333)
Lead poisioning: build up coproporphyrin
and ALA 2/2 inhibition of ferrochelatase
and ALAL dehydrase
 Acute intermittent porphyria: build up of
porphobilinogen and d-ALA 2/2 inhibition
of iroporphyrinogen I synthase
 Porphyria Cutanea Tarda: build up of
uroporphyrin (tea-colored) 2/2 inhibition
of uroporphyrinogen decarboxylase

Hemoglobin synthesis
Blood Dyscrasias (p.334)

Sickle Cell: mut of beta-globin chain. Low O2 or
dehydration precipitates sickling.
 Complications:
○ aplastic anemia (parvo B19)
○ Autosplenectomy
○ incr risk of encapsulated org infect
○ Salmonella osteomyelitis
○ vaso-occlusive crises
○ renal papillary necrosis, etc.
 Therapies include hydroxyurea (incr HbF),
bone marrow transplant, folate, etc.


“Crew cut” on skull XR 2/2 marrow expansion from incr
erythropoeisis
Newborns are initially asymptomatic 2/2 high HbF levels
Blood Dyscrasias (p.334)

a-thalassemia: there are 4 a-globin
chains and clinical dz depends on how
many chains are under-produced.
 HbH: b4-tetramers, lacks 3 a-globin genes
 Hb Barts: g4-tetramers, lacks all 4 a-globin
genes
○ Results in hydrops fetalis and intrauterine fetal
death

Most prevalent in Asian and African
populations
Blood Dyscrasias (p.334)

b-thalassemia:
 Minor (heterozygotes): beta-chain is under-
produced
 Major (homozygotes): beta-chain is absent
○ Require transfusions and get 2ndary
hemochromatosis (need iron chelator)
HbF production is increased but
inadequate
 HbS/B-thal heterozygotes have
increased propensity to have sickling.

Hemolytic Anemias (p.335)

Usually results in increased serum bilirubin
(indirect/unconjugated) and reticulocytosis

INTRAvascular hemolysis  hemoglobinuria

EXTRAvascular  jaundice
Hemolytic Anemias (p.335)

Autoimmune
 Warm agglutinin (IgG) chronic anemia seen
in SLE, CLL, and with certain drugs (e.g. amethyldopa). Mostly extravascular
hemolysis (RBC’s destroyed by Kupffer cells
and spleen)
 Cold agglutinin (IgM) ACUTE anemia
triggered by cold, seen with Mycoplasma
pneumoniae or mono (EBV).
 Erythroblastosis fetalis: in newborns 2/2 Rh
or other blood group incompatibility. Ab from
Mom destroy baby’s RBC’s.
Hemolytic Anemias (p.335)

Hereditary spherocytosis: Extravascular
hemolysis 2/2/ defect in ankyrin, band
3.1, or spectrin.
 RBC are round and have no central pallor
 Increased MCHC and RDW
 Associated with splenomegaly, aplastic
crisis, and Howell-Jolly bodies

Coombs negative, use osmotic fragility
test for confirmation of disease
Howell-Jolly Body
Hemolytic Anemias (p.335)

Paroxysmal nocturnal hemoglobinuria:
 Intravascular hemolysis 2/2 membrane
defect. The RBC’s have an increased
sensitivity to the lytic activity of complement
(impaired synthesis of GPI anchor/decayaccelerating factor in RBC membranes)

Lab tests show increased urine
hemosiderin (iron storage complex
similar to ferritin)
Hemolytic Anemias (p.335)
 Microangiopathic Anemia:
Intravasular hemolysis seen in
 DIC
 TTP/HUS
 SLE
 Malignant hypertension
Disseminated Intravascular Coagulation
(DIC) (p.335)

Activation of the coagulation cascade leading to
microthrombi and global consumption of
platelets, fibrin, and coagulation factors.

Causes:
 Sepsis, Trauma, Obstetric complications, acute
Pancreatitis, Malignancy, Nephrotic syndromes,
Transfusion (STOP Making New Thrombi)

Lab Findings:
 Incr PT, PTT, fibrinogen, and fibrin split products
(D-dimer)
 Decr platelet count
 Helmet cells and shistocytes on blood smear
Bleeding disorders (p.336)

Platelet abnormality causes:
 ITP: peripheral platelet destruction, anti-GpIIb/IIIa
Ab, incr megakaryocytes)
○ May have onset after a viral infection
○ Definitive treatment in splenectomy
 TTP: deficiency in vWF cleaving metalloproteinase,
incr platelet aggregation, thrombosis and shistocyte
formation, incr LDH, neurologic and renal sx, fever
 Aplastic anemia
 Drugs: immunosuppressive agents
Bleeding disorders (p.336)

Coagulation Factor Defects/Coagulopathies:
 Hemophilia A: factor VIII deficiency
 Hemophilia B: Factor IX deficiency
 Von Willebrand’s disease: fairly mild it is the most
common bleeding disorder
○ Cause of bleeding is deficiency of von Willebrand’s
factor which leads to a defect of platelet adhesion and
decreased factor VIII survival
○ *Remember vWF helps protect Factor VIII!
Hemorrhagic Disorders (p.336)
DISORDER
Platelet
count
Bleeding
time
Thrombocytopenia
Hemophilia A or B
N/C
von Willebrand’s disease
N/C
N/C
PT
PTT
N/C
N/C
N/C
N/C
*
N/C or
DIC
Vitamin K deficiency
N/C
Bernard-Soulier disease
(BS)
Glanzmann’s
thrombansthenia (GT)
N/C
N/C
N/C
N/C
N/C
N/C
Hemorrhagic Disorders

Defects in platelet plug formation lead to
increased bleeding time
 GT: decr GpIIb/IIIa (defect in platelet-platelet adhesion)
 BS: decr GpIb (defect in platelet-collagen adhesion)
 vWD: decr vWF (defect in platelet-collagen adhesion)
 DIC and thombrocytopenia: decreased platelet count
Defects in extrinsic coag cascade lead to
increased PT
 Defects in intrinsic coag cascade lead to
increased PTT

Reed-Sternberg cells (p. 337)

Distinctive giant cell associate with
Hodgkin’s lymphoma
 Bilobed or binucleate cell appear as “owl
eyes”
 The cells are CD30+ and CD15+ of B-cell
origin
 Necessary but not sufficient for dx of
Hodgin’s dz
Lymphomas (p.337)
Hodgkin’s
Non-Hodgkin’s
Reed-Sternberg cells
Localized, single group of nodes
May be associated with HIV and
immunosuppression
Extranodal dz is rare
Contiguous spread (stage is strongest
predictor of prognosis)
Multiple peripheral nodes
Extranodal dz is common
Non-contiguous spread
Constitutional “B” si/sx: low grade
feve, night sweats, weight loss
Majority involve B cells (except those
of lymphoblastic T cell origin)
Mediastinal lymphadenopathy
50% of cases associated with EBV
Bimodal distribution—young and old
Fewer constitutional si/sx
More common in men except for
nodular sclerosing type
Peak incidence for certain subtypes at
20-40 years of age
Good prognosis = increased
lymphocytes and decreased RS
Hodgkin’s Lymphoma (p. 337)
Type
Nodular
Sclerosing
(65-75%)
RS
Lymphocyte Prognosis
Comments
Most common
Collagen banding and
lacunar cells
Women>men ,10
young adults
+
+++
Excellent
Mixed
Cellularity
(25%)
++++
+++
Intermediate Numerous RS cells
Lymphocyte
predominant
(6%)
+
++++
Excellent
< 35 year olds
RS
high v.
lympho
-cyte
+
Poor
Older males with
disseminated disease
Lymphocyte
depleted
(rare)
Non-Hodgkin’s Lymphoma (p.339)
Type
Small
lymphocytic
lymphoma
Follicular
lymphoma
(small cleaved
cell)
Diffuse large
cell
lymphoma
Mantle Cell
Lymphoma
Occurs in
Adults
Adults
Cell type
Genetics
Like CLL with
focal mass
B cells
B cells
-Difficult to
t(14:18)
cure
bcl-2 expression -bcl-2 inhibits
apoptosis
- Most
common
- Aggressive
but many are
curable
Usually older 80% B cells
adults, but
20% T cells
20% in kids
(mature)
Adults
B cells
Comments
t(11:14)
Poor
prognosis
CD5+
Non-Hodgkin’s Lymphoma (p.339)
Type
Lymphoblastic
lymphoma
Burkitt’s
lymphoma
Occurs in
Cell type
Genetics
Comments
Most often in T cells
kids
(immature)
- Most common in
kids, commonly with
ALL and mediastinal
mass
- Very aggressive Tcell lymphoma
Most often in
B cells
kids
- “Starry-sky”
appearance (l-cytes
with interspersed
macrophages),
associated with EBV
- Jaw lesions
endemic in Africa
t(8:14) c-myc
gene moves
next to
heavy-chain
Ig gene (14)
Multiple Myeloma (p.338)



Monoclonal plasma cell cancer that arises in
the marrow and produces IgG (55%) or IgA
(45%).
Most common 10 tumor arising within the bone
in the elderly (> 40-50 y/o)
Symptoms:
 destructive bone lesions and consequent hypercalcemia
 Renal insufficiency
 Increased susceptibility to infection
 Anemia
 Also associated with 10 amyloidosis and punched out lytic
lesions on x-ray.

Think CRAB: hyperCalcemia, Renal insuff,
Anemia, Back and Bone pain
Multiple Myeloma (p.338)

Labs:
 SPEP (serum protein electrophoresis) shows
monoclonal Ig spike (M protein)
 UPEP (urine protein electrophoresis) shows Ig light
chains (aka Bence Jones protein)
 Peripheral Smear shows RBC’s stacked like poker
chips (Rouleaux formation)

Compare to Waldenström’s macroglobulinemia
 M spike is IgM (not IgG or IgA)
 Also hyperviscosity symptoms, no lytic bone lesions

If asymptomatic dx is monoclonal gammopathy
of undetermined significance (MGUS)
Chromosomal Translocations
(p. 339)
Translocation
Associated Disorder
t(9;22) Philadelphia chromosome
CML (bcr-abl hybrid)
t(8;14)
Burkitt’s lymphoma (c-myc activation)
t(14;18)
Follicular lymphoma (bcl-2 activation)
t(15;17)
M3 type of AML (responsive to alltrans retinoic acid)
t(11;22)
Ewing’s sarcoma
t(11;14)
Mantle cell lymphoma
Leukemoid Rxn (p.340)
Increased white blood count with LEFT
shift (e.g. 80% bands)
 Increased leukocyte alkaline
phosphatase

Leukemias (p.340)

General signs and symptoms:
 Increased number of circulating leukocytes
 Bone marrow infiltrates of leukemic cells
 Marrow failure can cause anemia
 Infection (decreased mature WBC’s)
 Hemorrhage (decreased platelets)
 Leukemic cell infiltrates in liver, spleen and
lymph nodes are possible as well
Leukemias (p.340)

ALL: Most common in < 15 y/o
 Bone marrow replaced by large increase in
lymphoblasts
 TdT+ (marker of pre-T and pre-B cells)
 Most responsive to therapy
 May spread to CNS and testes

AML: Median onset ~60 y/o, Auer rods
seen on smear
 Large increase in circulating myeloblasts
 M3 responds to all-trans retinoic acid (Vit A)
(induces differentiation of myeloblasts)
Leukemias (p.340)

CLL: seen in > 60 y/o
 Lymphadenopathy, hepatosplenomegaly
 Few symptoms and generally indolent course
 Smudge cells on smear
 Warm Ab autoimmune anemia
 Similar to SLL (small lymphocytic lymphoma)

CML: Age range 30-60 y/o
 Defined by the Philadelphia chrom, myeloid stem cell




proliferation
Presents with increased neutrophils, metamyelocytes,
basophils, splenomegaly
May accelerate and transform into ALL (1/3) or AML (2/3) “blast
crisis”
Left shift with all stages of myeloid maturation on smear
Very low leukocyte alk phos (vs. leukomoid rxn)
○ Responds to imatinib (anti bcr-abl)
Leukemias (p.340)

Hairy cell leukemia—mature B-cell tumor in the
eldery. Cells have filamentous, hair like
projections.
 Stains TRAP (tartrate-resistant acid phosphatase) positive
Auer rods (p.340)

Peroxidase positive cytoplasmic
inclusions in granulocytes and
myeloblasts
 Commonly seen in acute promyelocytic
leukemia (M3)
 Treatment of M3 AML can release Auer rods
Langerhans cell histiocytoses/
Histocytosis X (p.340)

Proliferative disorders of dendritic
(Langerhans) cells from the monocyte
lineage
 Defective cells express S-100 and CD1a
 Birbeck granules (“tennis rackets” on EM)
are characteristics
 Older terms for different clinical conditions
with same basic disorder
○ Letterer-Siwe dz, Hand-Schuller-Christian dz,
eosinophilic granulomas
Myeloproliferative disorders (p.341)
RBC’s
WBC
Platelets Philadelphia
chromosome
Polycythemia
Vera (PCV)
Essential
Thrombocytosis
Myelofibrosis
CML
--
-Variable
Variable
JAK2
mutations
Neg
Pos
Neg
Pos (30-50%)
Neg
Pos (30-50%)
Pos
Neg
 The myelofibroproliferative disorders represents an overlapping spectrum classic
findings below:
 PCV-Abnl hematopoeitic stem cells that are sensitive to growth factors
 ET-Similar to PCV, but specific for megakaryocytes
 Myelofibrosis-Fibrotic obliteration of bone marrow
 CML-bcr-abl transformation leads to incr cell division and inhib of apoptosis.
JAK2 is involved in hematopoeitic growth factor signaling. Mutations are
important in disorders other than CML
Heme Pharmacology

Heparin: catalyzes the activation of ATIII, decr
thrombin, and Xa
 Must monitor PTT

LMWH: Acts more on Xa, can be administered
subQ, can not be given to renal failure pts.
 PTT monitoring not needed


Warfarin: interferes with Vit K dependant
clotting factors. Increases PT
ASA: Irreversibly inhibits COX-1 and COX-2
 Increases bleeding time
Part 2: Renal (p.436-452)

Quick Anatomy Review
Ureters: Course (p.436)

Ureters pass UNDER the uterine artery
and UNDER the ductus (vas) deferens
(retroperitoneal)

Water UNDER the bridge
Fluid Compartments (p.437)
1/3
60% TB weight
2/3
Osmolarity:
290 mOsm
Plasma = ¼ ECF, Interstitial vol = ¾ ECF
 60-40-20 rule (% of TB weight)
 Plasma vol measured by radiolabeled albumin
 ECF measured by inulin

Renal Clearance (p.437)
Cx = UxV/Px = volume of plasma from
which the substance is completely
cleared per unit time
 Cx < GFR: net tubular reabsorption of X
 Cx > GFR net tubular secretion of X
 Cx= GRF no net secretion of X





Cx = clearance of X (units are mL/min)
Ux = urine concentration of X
Px = plasma concentration of X
V = urine flow rate
Glomerular Filtration (p.437)
Barrier: responsible for filtration of
plasma according to size and net charge
 Composed of:

 Fenestrated capillary endothelium
 Fused BM with heparan sulfate (neg charge)
 Epithelial layer with podocyte foot processes

Charge barrier is LOST in nephrotic
syndromes  albuminuria,
hypoproteinemia, edema (generalized),
and hyperlipidemia
Glomerular Filtration (p.437)
Rate: Use inulin to calculate as it is not
secreted or resorbed and it is FREELY
filtered.
 GFR = Uinulin x V/Pinulin = Cinulin =
 Kf[(PGC – PBS) – (pGC - pBS)]


Kf = filtration coefficient/GC = glomerular capillary/BS = Bowman’s space

Creatinine clearance slightly
overestimates GFR as it is secreted in
the renal tubules
Effective Renal Plasma Flow
(ERPF) (p.437)

ERPF can be estimated using PAH
clearance as it is both filtered and
actively secreted by the tubule.
 ALL PAH entering the kidney is excreted
RBF = RPF/(1-HCT)
 ERPF underestimates true RPF by
about 10%

Filtration (p.438)
Filtration fraction = GFR/RPF
 Filtered load = GFR x plasma conc
 Prostaglandins dilate afferent arteriole

 Increase RPF and GFR so FF constant
 NSAID’s block this action

Angiotensin II preferentially constricts
efferent arteriole
 Decr RPF but incr GFR so FF increases
 ACE inhibitor blocks this action
Changes in Renal Fxn
Effect
RPF
Afferent arteriole constriction
GFR
FF
NC
Efferent arteriole constriction
Incr plasma protein conc
NC
Decr plasma protein conc
NC
Constriction of ureter
NC
Clearance (p.438)

Free Water: Ability to dilute urine
 CH
20
= V- Cosm
 V = urine flow rate; Cosm = UosmV/Posm
 With ADH: CH
<
20
0 (retention of free water)
 Without ADH CH 0 > 0 (excretion of free water)
2
 Isotonic urine CH 0 = 0 (seen with loop diuretics)
2
Clearance (p.438)

Glucose is FULLY reabsorbed in the
proximal tubule at normal plasma levels
 At or above 200 mg/dL glucosuria begins
(threshold)
 At 350 mg/dL transport mechanism is saturated
(Tm)

Amino Acids: reabsorption by 3 different
carrier systems, with competitive inhibition
with each group
 Secondary active transport occurs in in
proximal tubule and is SATURABLE
(p. 439)
Early Proximal Tubule:
•Contains brush border which resorbs
•ALL of the glucose and amino acids
•MOST of the HCO3, Na, and water
•ISOtonic absorption
• Secretes ammonia  acts as buffer for
secreted hydrogen ions
PTH: Inhibits Na/PO4 co-transport 
phosphate excretion
ATII: stimulates Na/H exchange 
Increased Na and water excretion
(can cause contraction alkalosis)
reabsorption
(p. 439)
Thick ascending loop of Henle:
• Actively resorbs Na, K,
and Cl
• Indirectly induces the
paracellular reabsorption of
Mg and Ca
• Impermeable to water
• DILUTING seegment
• Makes urine HYPOtonic
(p. 439)
• Passively resorbs
water via medullary
hypertonicity.
Thin
descending
loop of
Henle:
• The walls are
impermeable to
sodium
• Makes urine
HYPERtonic
(p. 439)
Early DCT:
•Actively resorbs Na,
Cl
•Diluting segment
•Makes urine
HYPOtonic
PTH: Increases Ca/Na
exchange 
Increased Ca resorption
(p. 439)
Collecting Tubule:
•Resorbs Na in exchange for K and
H (regulated by aldosterone)
Aldosterone:
•Leads to insertion of Na channel
on LUMINAL side
ADH: acts at V2 receptors
•Insertion of aquaporin channel on
LUMINAL side
Relative concentrations along renal tubule (p. 440)
Renin-Angiotensin-Aldosterone
System (p.440)
Juxtaglomerular apparatus (p.441)
JG cells (modified smooth muscle of
afferent arteriole) and macula densa (Na
sensor, part of DCT)
 JG cells secrete renin (leading to
increased angiotensisn II and
aldosterone levels) in response to
decreased renal BP, decreased Na
delivery to distal tubule, and increased
sympathetic tone.

Endocrine Fxns of the Kidney (p. 441)
Endothelial cells of the peritubular capillaries
secrete EPO in response to hypoxia
 Prox tubule cells convert Vit D to its active form
(indirect stim from PTH)

 PTH acts directly on the kidney to increase Ca
reabsorption and decr PO4 reabsorption

JG cells secrete renin in response to decr renal
arterial pressure and increase sympathetic
discharge (B1 effect)
Endocrine Fxns of the Kidney (p. 441)
 Secretion
of prostaglandins to
vasodilate afferent arterioles to incr
GFR.
 NSAID’s can cause renal failure by
inhibiting the renal production of
prostaglandins.
Hormones acting on the kidney (p. 442)
Acid/Base—VERY IMPORTANT
(p.442)
pH
PCO2
[HCO3]
Compensatory mech
Met acidosis
Hyperventilation
Met alkalosis
Hypoventilation
Resp acidosis
Increase renal HCO3
reabsorption
Resp alkalosis
Decrease renal HCO3
reabsorption
Henderson-Hasselbach equation pH= pKa + log [HCO3]/0.03*PCO2
Approach to Acid/Base (p.442)
NORMAL VALUES:


1.
pH = 7.40
HCO3 = 24 mEq/L
AG = 12
Does the pH indicate an alkalosis or
acidosis?
○
2.
PCO2 = 40mmHg
Acidosis pH < 7.40; Alkalosis pH >7.40
Is the primary disorder respiratory or
metabolic?
○
Acidosis:


○
Respiratory if PCO2 > 40
Metabolic if HCO3 < 24
Alkalosis:


Respiratory if PCO2 < 40
Metabolic if HCO3 > 24
Approach to Acid/Base (p.442)
3.
What is the Anion gap?
Na – (Cl + HCO3)
If AG > 20, AGMA is present regardless of pH
○
○
4.
Is there proper compensation?
Winter’s Formula: used to check for resp. compensation when
met. acid is present
○




○
○
○
Expected PCO2 = 1.5 (HCO3) + 8 +/- 2
< expected resp alkalosis is present
> expected resp acid is present
Quick and Dirty method: if last two digits of pH = PCO2 then there is
likely appropriate compensation
Met alkalosis: increase in PCO2 = 0.75(DHCO3)
Acute Resp: change in PCO2 of 10 = pH change of
0.08 in opposite direction
Chronic Resp: change in PCO2 of 10 = pH change of
0.03 in opposite direction
Approach to Acid Base:
5. If there is an AGMA, is there another
disorder?
 Use the corrected serum HCO3 equation:
○ Excess anion gap = measured – normal
○ Corrected HCO3 = Excess AG + measured
HCO3
 If HCO3 > normal then met alkalosis is present
 If HCO3 < normal then NAGMA is present
 If HCO3 = normal then no other disorder is present
Common Causes of Each Disorder

Respiratory acidosis:
 CNS depression, neuromuscular d/o, airway
obstruction, severe PNA, lung dz (acute and
chronic), opioids and narcotics

Respiratory alkalosis:
 Hyperventilation (high altitude), pregnancy,
sepsis, mechanical ventilation, ASA ingestion
(early)

AGMA: MUDPILES
 Methanol, Uremia, DKA/starvation, Paraldehyde
or Phenformin, INH or Iron, Ethylene glycol
(oxalic acid), Salicylates
Common Causes of Each Disorder

NAGMA:
 GI bicarb loss (diarrhea), or renal bicarb loss
(early renal failure, RTA, aldosterone
inhibitors), Glue sniffing, hyperchloremia

Metabolic Alkalosis:
 Vomiting, NG suction, diuretics, volume
contraction, mineralocorticoid excess,
antacid use
Renal Tubular Acidosis (p.444)

Type 1:
 Defect in H/K ATPase of collecting tubules 
inability to secrete H.
○ Can lead to hypokalemia

Type 2:
 Defect in proximal tubule HCO3 reabsoprtion.
○ Can lead to hypokalemia

Type 4:
 Hypoaldosteronism  hyperK  inhibition of
ammonia excretion in proximal tubule.
○ Leads to decreased urine pH 2/2 decr buffering
capacity
Casts and what they mean (p.444)

RBC casts:
 Glomerular inflammation (nephritic syndromes)
 Ischemia
 Malignant hypertension

WBC casts:
 Tubulointerstitial dz
 Acute pyleonephritis
 Glomerular disorders

Granular “muddy Brown” casts: Acute tubular necrosis

Waxy casts: advanced renal dz/CRF
Hyaline casts: nonspecific


MISCELLANEOUS:
 Bladder Ca: RBC no casts
 Acute cystitis: WBC no casts
Casts continued (p.444)
Above: RBC
Below: Granular
Above: WBC
Below: Hyaline
Nephritic (p. 445)
An inflamatory process involves the glomerulus  azotemia, hematuria,
RBC casts, oliguria, HTN, and proteinuria
Acute post-strep
glomerulonephritis
(GN)
LM-glomeruli enlarged and
hypercellular, “lumpy-bumpy”
EM-subepithelial immune complex
(IC) humps
Immunofluorescence (IF)-granular
Most freq seen in children.
Periph and periorbital
edema.
Resolves spontaneously
Rapidly progressive
GN
(Cresentic)
LM and IF-crescent moon
1. Goodpasture’s-type II
hypersensitivity, Ab to
GBM=linear IF
2. Wegener’s granulomatosis
3. Microscopic polyarteritis
Male-dominant dz
Hematuria/hemoptysis (lung involved)
Diffuse proliferative
GN (due to SLE)
Subendothelial DNA-anti-DNA IC’s
 “wire-looping” of capillaruies
IF-granular
Most common cause of death in SLE.
SLE can present as nephrotic
syndrome
Berger’s disease
Increased synthesis of IgA.
IC’s deposit in mesangium
Often follows URI, often presents as
nephrotic syndrome
Mutation in type IV collagen  split
basement membrane
Nerve disorders, ocular disoders,
deafness also 2/2 mutation in type IV
collagen
(IgA glomerulopathy)
Alport’s syndrome
c-ANCA
p-ANCA
Nephrotic (p.445)
Nephrotic syndrome presents with passive
proteinuria (>3.0-3.5 g/day, frothy urine),
hyperlipemia, edema
 Also can have increased coagulation as
proteins C and S are lost in urine as well

Membranous
glomerulonephritis
(Diffuse
membranous
glomerulopathy)
LM-diffuse capillary and GBM
thickening
EM-”spike dome” appearance
IF-granular
SLE nephrotic presentation
Minimal change
disease
(Lipoid nephrosis)
LM- normal glomeruli
EM-foot process effacement
Caused by drugs, infections,
and SLE
Most common cause (MCC)
of adult nephrotic syndrome
Nephrotic pics (p. 445)
Granular IF in membranous GN
“spike and dome” on EM
Minimal change dz: note appearance is fairly
normal
Nephrotic (p.445)
Amyloidosis
LM-Congo red stain, apple-green
birefringence
Associated with
multiple myeloma,
chronic conditions,
TB and RA
Diabetic
glomerulonephropathy
Non-enzymatic glycosylation (NEG)
of GBM  permeability, thickening,
NEG of efferent arterioles  GFR
 mesangial damage, wire looping
LM-Kimmelsteil-Wilson “wire loop”
lesions
Focal segmental
glomerulosclerosis
LM- segmental sclerosis and
hyalinosis
Most common
glomerular dz in HIV
pts. More severe in
these pts as well.
Membranoproliferative
glomerulonephritis
Subendothelial IC with granular IF
EM-”tram-track” appearance due to
GBM splitting caused by mesangial
ingrowth
Can present as
nephritic syndrome
Usually progresses
slowly to CRF
Associated with
HBV > HCV
Glomerular histopathology (p.446)
1. Subepi: membranous
nephropathy
2. Large irregular subepi
“humps”: acute GN
3. Subendo deposits in
lupus GN
4. Mesangial deposits in
IgA nephropathy
5. Ab binding to GBM—
linear pattern on IF
(Goodpasture’s)
6. Effacement of
epithelial foot
processes (in all with
proteinuria, imp for
minimal change dz
(may be only sign on
EM))
Kidney Stones (p.446)

Can lead to severe complications (e.g. pyelonephritis,
and hydronephrosis)

4 Major types:
 Calcium: Most common stone and tend to recur
(75-85%)
○ Radio-opaque and contain CaPO4 and/or Ca oxalate
○ Conditions that cause hyperCa (cancer, PTH, Vit D, milk-alkali
syndrome) can lead to hypercalciuria and stones.
 Ammonium magnesium phosphate (struvite):
○ 2nd most common
○ Caused by infection with urease-positive bugs (Proteus, Staph,
Klebsiella)
○ Can form staghorn calculi that can be a nidus for UTI’s
○ Rasio-opaque or lucent. Worse with alkauria
Kidney Stones (p.446)

Can lead to severe complications (e.g. pyelonephritis,
and hydronephrosis)

4 Major types:
 Uric Acid: Radio-lucent
○ Strong association with hyperuricemia (e.g. gout)
○ Often seen as a result of disease with increased cell
turnover
 E.g. Leukemia and myeloproliferative disorders
 Cystine: Faintly radio-opaque, treat with urine
alkalinization
○ Most often secondary to cystinuria.
○ Hexagonal shape
○ Rarely may form cystine staghorn calculi
Renal cell carcinoma (p.447)






Most common renal malignancy and in men age 50-70
Originates in renal tubule cells  polygonal clear cells
Invades IVC and spreads hematogenously.
Associated with von Hippel-Lindau and chromosome 3
gene deletion, increased incidence w/smoking and
obesity
Clinically manifests with hematuria, palpable mass,
secondary polycythemia, flank pain, fever, and weight
loss
Also associated with paraneoplastic syndromes
 Ectopic EPO, ACTH, PTHrP, and prolactin
Wilms’ tumor (p.447)





Most common renal malignancy of early childhood
(ages 2-4)
Genetic: Deletion of tumor suppressor gene WT1 on
chromosome 11
Contains embryonic glomerular structures
Clinically presents with huge palpable flank mass,
hemihypertrophy.
May be associated with WAGR copmplex
 Wilms’ tumor
 Aniridia
 Genitourinary malformation
 mental motor Retardation
Transitional Cell Ca (p. 447)

Most common tumor of urinary tract system
 Can occur in renal calyces, renal pelvis, ureters, and
bladder (all places where there are transitional cells)
Painless hematuria is suggestive of bladder
cancer
 Associated with problems in Pee SAC:

 Phenacetin, Smoking, Aniline dyes, and
Cyclophosphamide
Pyelonephritis (p. 447)

Acute:
 Affects cortex with relative sparing of
glomeruli/vessels
 White cell casts are pathognomonic
 Presentation: fever, CVA tenderness

Chronic:
 Coars, asymmetric corticomedullary scarring
 Blunted calyx
 Tubules can contain eosinophilic casts
Diffuse Cortical Necrosis (p.447)
Acute generalized infarction of cortices of
both kidneys
 Likely 2/2 combo of vasospasm and DIC
 Associated with obstetric catastrophes
(e.g. abruptio placentae) and septic shock

Drug-Induced Interstitial Nephritis
(p.447)
Acute interstitial renal inflammation
 Causes: Drugs (e.g. PCN derivatives,
NSAID’s, diuretics) act as haptens (a

small molecule that can elicit an immune
response) inducing hypersensitivity

Signs/Symptoms: Fever, rash,
eosiniophilia, hematuria 2 WEEKS after
administration
Acute Tubular Necrosis (p.447)

Cellular:
 Loss of cell polarity, epithelial cell detachment, necrosis,
granular “muddy brown” casts
 3 stages: Inciting event  maintenance (low urine) 
recovery





MCC of iatrogenic ARF
Reversible but fatal if untreated (tx with dialysis)
Associated with renal ischemia, crush injury
(myoglobinuria), and toxins
Death occurs most often during initial oliguric phase
Recovery in 2-3 weeks
Renal Papillary Necrosis (p.447)

Sloughing of renal papillae
 Gross hematuria and proteinuria

Associated with
 Diabetes Mellitus
 Acute pyelonephritis
 Chronic phenacetin use (acetaminophen is
derivative)
 Sickle Cell Anemia
Acute Renal Failure (p.448)
Normally BUN is reabsorbed but Cr is
NOT
 ARF is defined as an abrupt decrease in
renal fxn with increase in Cr and BUN
over a period of several days.

Acute Renal Failure (p.448)
1.
2.
Prerenal azotemia: decr RBF  decr GFR.
Na/water and urea retained by the kidney , so
BUN/Cr ratio incr in attempt to comserve volume
Intrinsic renal: generally due to acute tubular
necrosis or ischemia/toxins.
1.
2.
3.
3.
Patchy necrosis leads to debris obstructing the tubule and
fluid backflow across necrotic tubule  decreased GFR
Urine has epithelial/granular casts.
BUN resorption is impaired  decreased BUN/Cr ratio
Postrenal: outflow obstruction (stones, BPH,
neoplasia)
1.
Stones as cause only develops with bilateral obstruction
Acute Renal Failure (p.448)
Variable
Prerenal
Renal
Postrenal
Urine osmolality
> 500
< 350
< 350
Urine Na
< 10
> 20
> 40
FENa
< 1%
> 2%
> 4%
> 20
< 15
> 15
FENa = (UNa * PCr/ PNa * UCr) x 100
Serum BUN/Cr
Renal Failure (p.448)
Inability to make urine and make
nitrogenous waste.
 Leads to uremia

 Clinical syndrome marked by increased Bun
and Cr and other associated sx’s (confusion,
HTN, coma, fibrinous pericarditis, etc.)

2 forms of renal failure
 Acute: often due to ATN
 Chronic: MCC’s diabetes and HTN
Renal Failure (p.448)

Consequences:
 Anemia (failure of EPO production)
 Renal osteodystrophy (failure of Vit D production)
 HyperK  cardiac arrhythmias (peaked T waves)
 Metabolic Acidosis: 2/2 decreased acid secretion





and decreased production of HCO3
Uremic encephalopathy  confusion, AMS, coma
Sodium and water excess  CHF and pulm edema
Chronic pyelonephritis
HTN
Pericarditis
Fanconi’s syndrome (p.448)



Decreases tubule
transport of AA,
glucose, PO4, Uric
acid, protein and
electrolytes
Can be acquired or
congenital
Causes include
Wilson’s Dz,
glycogen storage dz,
and drugs (cisplatin,
expired tetracycline)
Defect
Complications
Decr PO4
reabsorption
Rickets
Decr HCO3
reabsorption
Metabolic
acidosis
Decr early
Na
reabsorption
Incr distal Na
reabsorption 
hypoK
Cysts (p.449)
ADPKD
-Multiple, large b/l cysts that ultimately destroy the
parenchyma. Enlarged kidneys.
-Presents with flank pain, hematuria, HTN, UTI,
progressive renal failure.
-AD mut in APKD1 or APKD2.
-Death from uremia or HTN
ARPKD
Infantile presentation in parenchyma. AR, associated
with hepatic cysts and fibrosis
Dialysis cysts
Cortical and medullary cysts resulting from long
standing dialysis
Medullary
cystic dz
Medullary cysts. U/S shows small kidneys. POOR
prognosis
Medullary
sponge dz
Collecting duct cysts. GOOD prognosis
Simple Cysts
Benign, incidental finding. Cortex only
Electrolyte Disturbances (p.449)
Electrolyte Low serum conc
Disorientation, coma, stupor
Na
High serum conc
Neurologic: irritability,
delirium, coma
Cl
2/2 met alk, hypoK, hypovol,
incr aldosterone
2/2 NAGMA
K
U waves in EKG, flattened T
waves, arrhythmias,
paralysis
Peaked T waves, wide
QRS, arrhythmias
Ca
Tetany, neuromuscular
irritability
Delirium, renal stones,
abd pain, not necessary
calciuria
Mg
neuromuscular irritability,
arrhythmias
Delirium, decreased
DTR, cardiopulm arrest
PO4
Low-mineral ion product
causes bone loss,
osteomalacia
High-mineral ion
product causes renal
stones, metastatic
calcifications
Diuretics: Site of Action
ACE inhibitors “-pril”(p.452)

Mechanism:
 Inhibits ACE  reduces levels of AGII and prevents
inactivation of bradykinin (a potent vasodilator)
 Renin release is increased 2/2 loss of feedback inhibition.

Clinical use:
 HTN, CHF, diabetic renal dz

Toxicity:
 Cough, Angioedema, Proteinuria, Taste changes,
hypOtension, Pregnancy problems (fetal renal damage),
Rash, Increased renin, Lower AGII (CAPTOPRIL)
 HyperK
 Avoid in bilat renal artery stenosis because ACE inhib
significantly decr GFR by preventing constriction of efferent
arterioles
Diuretics: Loop v. Thiazides
Loop Diuretic
(furosemide)
Inhibits cotransport
(Na,K,2Cl) of Thick
Mechanism ascending LOH. Abolishes
hypertonicity of medulla,
prevents urine concentration
Clinical
use
Toxicity
Thiazide (HCTZ)
Inhibits NaCl resorption in
early distal tubule, reduces
diluting capacity of the
nephron. Decr Ca excretion
Edematous states, (CHF,
cirrhosis, nephrotic
syndrome, pulm edema)
HTN, hyperCa
HTN, CHF, idiopathic
hypercalciuria, nephrogenic
diabetes insipidus
Ototoxicity, HypoK,
Dehydration, Allergy (sulfa),
Nephritis, Gout
OH DANG!
Hypokalemic met alk,
hypoNa, hyperGlycemia,
hyperLipidemia,
hyperUricemia,
hyperCalcemia. Sulfa
allergy. hyperGLUC
Diuretics: K+ sparing


Spironolactone, Triamterene, Amiloride
Mechanism:
 Spironolactone is a competitive aldosterone receptor
antagonist in the cortical collecting tubule (CCT).
 Triamterene and amiloride act at the same part of the tubule
by blocking Na channels in the CCT.

Clinical Use:
 Hyperaldosteronism, K depletion, CHF

Toxicity:
 HyperK, endocrine effects of aldosterone antagonists
○ Gynecomastia, antiandrogen effects

Note: Spironolactone can also be used to treat acne
in females, it is from the anti-androgen side effect!