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 Pathology
Biconcave Normal
Spherocyte spherocytosis, autoimmune hemolysis
Elliptocyte Hereditary elliptocytosis
Macro-ovalocyte Megaloblastic anemia, marrow failure
Helmet cell, shistocyte DIC, TTP/HUS, traumatic, hemolysis
Sickle Cell Sickle Cell anemia
Bite Cell G6PD deficiency
Teardrop cell Myeloid metaplasia with myelofibrosis
Acanthocyte (spur cell) “Spiny”, in liver dz and abetalipoproteinemia
Target cell HbC dz, Asplenia, Liver dz, Thalassemia (HALT)
Burr Cell TTP/HUS
Basophilic stippling 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 Chronic Hemo- Pregnancy
Disease chroma- /OCP use
tosis
Serum Iron (10) (10) -

Transferrin/ (10)
TIBC
Ferritin -
% transferrin -
saturation
(serum
Fe/TIBC)
Ferritin=iron storage; Transferrin=iron transport in blood
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 -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)
 -thalassemia: there are 4 -globin
chains and clinical dz depends on how
many chains are under-produced.
HbH: 4-tetramers, lacks 3 -globin genes
Hb Barts: 4-tetramers, lacks all 4 -globin
genes
○ Results in hydrops fetalis and intrauterine fetal
death
 Most prevalent in Asian and African
populations
Blood Dyscrasias (p.334)
 -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. -
methyldopa). 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/decay-
accelerating 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 Bleeding PT PTT
count time
Thrombocytopenia N/C N/C

Hemophilia A or B N/C N/C N/C

von Willebrand’s disease N/C N/C *

N/C or
DIC

Vitamin K deficiency N/C N/C

Bernard-Soulier disease N/C N/C

(BS)
Glanzmann’s N/C N/C N/C
thrombansthenia (GT)
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
Reed-Sternberg cells
Localized, single group of nodes
Extranodal dz is rare
Contiguous spread (stage is strongest
predictor of prognosis)
Constitutional “B” si/sx: low grade
feve, night sweats, weight loss
Mediastinal lymphadenopathy
50% of cases associated with EBV
Bimodal distribution—young and old
More common in men except for
nodular sclerosing type
Good prognosis = increased
lymphocytes and decreased RS
Non-Hodgkin’s
May be associated with HIV and
immunosuppression
Multiple peripheral nodes
Extranodal dz is common
Non-contiguous spread
Majority involve B cells (except those
of lymphoblastic T cell origin)
Fewer constitutional si/sx
Peak incidence for certain subtypes at
20-40 years of age
Hodgkin’s Lymphoma (p. 337)
Type RS Lymphocyte Prognosis Comments

Nodular Most common

Sclerosing Collagen banding and
(65-75%) + +++ Excellent lacunar cells
Women>men ,10
young adults
Mixed
Cellularity ++++ +++ Intermediate Numerous RS cells
(25%)
Lymphocyte
predominant + ++++ Excellent < 35 year olds
(6%)
Lymphocyte RS
depleted high v. Older males with
+ Poor
(rare) lympho disseminated disease
-cyte
Non-Hodgkin’s Lymphoma (p.339)
Type Occurs in Cell type Genetics Comments

Small Like CLL with

lymphocytic Adults B cells focal mass
lymphoma
Follicular -Difficult to
lymphoma t(14:18) cure
Adults B cells
(small cleaved bcl-2 expression -bcl-2 inhibits
cell) apoptosis
- Most
Diffuse large Usually older 80% B cells common
cell adults, but 20% T cells - Aggressive
lymphoma 20% in kids (mature) but many are
curable
Poor
Mantle Cell
Adults B cells t(11:14) prognosis
Lymphoma CD5+
Non-Hodgkin’s Lymphoma (p.339)
Type Occurs in Cell type Genetics Comments

- Most common in
kids, commonly with
Lymphoblastic Most often in T cells ALL and mediastinal
lymphoma kids (immature) mass
- Very aggressive
T-cell lymphoma

- “Starry-sky”
t(8:14) c-myc appearance (l-cytes
gene moves with interspersed
Burkitt’s Most often in
B cells next to macrophages),
lymphoma kids
heavy-chain associated with EBV
Ig gene (14) - Jaw lesions
endemic in Africa
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 all-

trans 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 JAK2
chromosome mutations
Polycythemia
Neg Pos
Vera (PCV)
Essential
-- -- Neg Pos (30-50%)
Thrombocytosis
Myelofibrosis Variable Variable Neg Pos (30-50%)
CML 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) – (GC - BS)]
 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 GFR FF

Afferent arteriole constriction 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
CH20 = V- Cosm
 V = urine flow rate; Cosm = UosmV/Posm
With ADH: CH20 < 0 (retention of free water)
Without ADH CH20 > 0 (excretion of free water)
Isotonic urine CH20 = 0 (seen with loop diuretics)
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 (T m)
 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)
(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:
 pH = 7.40 PCO2 = 40mmHg HCO3 = 24 mEq/L AG = 12

1. Does the pH indicate an alkalosis or

acidosis?
○ Acidosis pH < 7.40; Alkalosis pH >7.40
2. 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(HCO3)
○ 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
Above: WBC
Below: Granular
Below: Hyaline
 Nephritic (p. 445)
An inflamatory process involves the glomerulus  azotemia, hematuria,
RBC casts, oliguria, HTN, and proteinuria
Acute post-strep LM-glomeruli enlarged and Most freq seen in children.
glomerulonephritis hypercellular, “lumpy-bumpy” Periph and periorbital edema.
(GN) EM-subepithelial immune complex Resolves spontaneously
(IC) humps
Immunofluorescence (IF)-granular

Rapidly progressive LM and IF-crescent moon Male-dominant dz

1.Goodpasture’s-type II Hematuria/hemoptysis (lung involved)
GN
(Cresentic) hypersensitivity, Ab to GBM=linear
IF
2.Wegener’s granulomatosis c-ANCA
3.Microscopic polyarteritis p-ANCA

Diffuse proliferative Subendothelial DNA-anti-DNA IC’s Most common cause of death in SLE.
 “wire-looping” of capillaruies SLE can present as nephrotic
GN (due to SLE) syndrome
IF-granular

Berger’s disease Increased synthesis of IgA. Often follows URI, often presents as
(IgA glomerulopathy) IC’s deposit in mesangium nephrotic syndrome

Alport’s syndrome Mutation in type IV collagen  split Nerve disorders, ocular disoders,
basement membrane deafness also 2/2 mutation in type IV
collagen
 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 LM-diffuse capillary and GBM Caused by drugs, infections,
glomerulonephritis thickening and SLE
(Diffuse EM-”spike dome” appearance Most common cause (MCC)
membranous IF-granular of adult nephrotic syndrome
glomerulopathy) SLE nephrotic presentation
Minimal change LM- normal glomeruli
disease
(Lipoid nephrosis) EM-foot process effacement
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 Associated with
birefringence multiple myeloma,
chronic conditions,
TB and RA
Diabetic Non-enzymatic glycosylation (NEG)
glomerulonephropathy of GBM  permeability, thickening,
NEG of efferent arterioles  GFR
 mesangial damage, wire looping
LM-Kimmelsteil-Wilson “wire loop”
lesions
Focal segmental LM- segmental sclerosis and Most common
glomerulosclerosis hyalinosis glomerular dz in HIV
pts. More severe in
these pts as well.
Membranoproliferative Subendothelial IC with granular IF Can present as
glomerulonephritis EM-”tram-track” appearance due to nephritic syndrome
GBM splitting caused by mesangial Usually progresses
ingrowth 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. Prerenal azotemia: decr RBF  decr GFR.
Na/water and urea retained by the kidney , so
BUN/Cr ratio incr in attempt to comserve volume
2. Intrinsic renal: generally due to acute tubular
necrosis or ischemia/toxins.
1. Patchy necrosis leads to debris obstructing the tubule and
fluid backflow across necrotic tubule  decreased GFR
2. Urine has epithelial/granular casts.
3. BUN resorption is impaired  decreased BUN/Cr ratio
3. 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
FENa = (UNa * PCr/ PNa * UCr)  x 100 < 1% > 2% > 4%

Serum BUN/Cr > 20 < 15 > 15

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, Defect Complications
glucose, PO4, Uric
acid, protein and
electrolytes Decr PO4
Rickets
 Can be acquired or reabsorption
congenital
Decr HCO3 Metabolic
 Causes include
Wilson’s Dz, reabsorption acidosis
glycogen storage dz, Decr early Incr distal Na
and drugs (cisplatin, Na reabsorption 
expired tetracycline)
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 Medullary cysts. U/S shows small kidneys. POOR
cystic dz prognosis
Medullary Collecting duct cysts. GOOD prognosis
sponge dz
Simple Cysts Benign, incidental finding. Cortex only
Electrolyte Disturbances (p.449)
Electrolyte Low serum conc High serum conc
Na Disorientation, coma, stupor Neurologic: irritability,
delirium, coma

Cl 2/2 met alk, hypoK, hypovol, 2/2 NAGMA

incr aldosterone

K U waves in EKG, flattened T Peaked T waves, wide

waves, arrhythmias, QRS, arrhythmias
paralysis
Ca Tetany, neuromuscular Delirium, renal stones,
irritability abd pain, not necessary
calciuria
Mg neuromuscular irritability, Delirium, decreased
arrhythmias DTR, cardiopulm arrest

PO4 Low-mineral ion product High-mineral ion

causes bone loss, product causes renal
osteomalacia 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
Edematous states, (CHF,
Clinical cirrhosis, nephrotic
use syndrome, pulm edema)
HTN, hyperCa
Ototoxicity, HypoK,
Dehydration, Allergy (sulfa),
Nephritis, Gout
Toxicity
OH DANG!
Thiazide (HCTZ)
Inhibits NaCl resorption in
early distal tubule, reduces
diluting capacity of the
nephron. Decr Ca excretion
HTN, CHF, idiopathic
hypercalciuria, nephrogenic
diabetes insipidus
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!