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

bloodMast Cell: Granulocyte, binds IgE to membrane,

found in tissueEosinophil: 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 SWarfarin inhibits epoxide reductase

von Willebrand factor carries/protect VIIIBinds GpIb to subendothelial collagen as

well

Coag cascade: anti-coagulation (p.330) Antithrombin III inactivates factors II, VII, IX, X,

and XIHeparin 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 synthesisLead poisioning

○ Inhibits ferrochelatase and ALA dehydrase (heme synthesis)

Some sideroblastic anemiasAnemia 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 hemorrhageEnzyme 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 anemiaAnemia of chronic dz: TIBC, ferritin,

increased storage in marrow macrophages

Lab values in anemiaIDA Chronic

DiseaseHemo-

chroma-tosis

Pregnancy/OCP use

Serum Iron (10) (10) -

Transferrin/ TIBC

(10)

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 genesHb 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 pallorIncreased MCHC and RDWAssociated 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 DICTTP/HUSSLEMalignant 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 countHelmet 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 anemiaDrugs: immunosuppressive agents

Bleeding disorders (p.336) Coagulation Factor Defects/Coagulopathies:

Hemophilia A: factor VIII deficiencyHemophilia B: Factor IX deficiencyVon 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

PT PTT

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 (BS)

N/C N/C

Glanzmann’s thrombansthenia (GT)

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 lymphomaBilobed or binucleate cell appear as “owl

eyes” The cells are CD30+ and CD15+ of B-cell

originNecessary but not sufficient for dx of

Hodgin’s dz

Lymphomas (p.337)

Hodgkin’s Non-Hodgkin’sReed-Sternberg cellsLocalized, single group of nodes

May be associated with HIV and immunosuppression

Extranodal dz is rareContiguous spread (stage is strongest predictor of prognosis)

Multiple peripheral nodesExtranodal dz is commonNon-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 lymphadenopathy50% of cases associated with EBVBimodal 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 RS Lymphocyte Prognosis Comments

Nodular Sclerosing (65-75%) + +++ Excellent

Most commonCollagen banding and lacunar cells Women>men ,10 young adults

Mixed Cellularity

(25%)++++ +++ Intermediate Numerous RS cells

Lymphocyte predominant

(6%)+ ++++ Excellent < 35 year olds

Lymphocyte depleted

(rare)

RS high v. lympho-cyte

+ PoorOlder males with disseminated disease

Non-Hodgkin’s Lymphoma (p.339)

Type Occurs in Cell type Genetics Comments

Small lymphocytic lymphoma

Adults B cellsLike CLL with focal mass

Follicular lymphoma

(small cleaved cell)

Adults B cells t(14:18)

bcl-2 expression

-Difficult to cure-bcl-2 inhibits apoptosis

Diffuse large cell

lymphoma

Usually older adults, but 20% in kids

80% B cells20% T cells

(mature)

- Most common- Aggressive but many are curable

Mantle Cell Lymphoma

Adults B cells t(11:14)Poor prognosis CD5+

Non-Hodgkin’s Lymphoma (p.339)

Type Occurs in Cell type Genetics Comments

Lymphoblastic lymphoma

Most often in kids

T cells (immature)

- Most common in kids, commonly with ALL and mediastinal mass- Very aggressive T-cell lymphoma

Burkitt’s lymphoma

Most often in kids

B cells

t(8:14) c-myc gene moves next to heavy-chain Ig gene (14)

- “Starry-sky” appearance (l-cytes with interspersed macrophages), associated with EBV- 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 leukocytesBone marrow infiltrates of leukemic cellsMarrow failure can cause anemiaInfection (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 smearLarge increase in circulating myeloblastsM3 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 myeloblastsCommonly 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 lineageDefective cells express S-100 and CD1aBirbeck granules (“tennis rackets” on EM)

are characteristicsOlder 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

JAK2 mutations

Polycythemia Vera (PCV)

Neg Pos

Essential Thrombocytosis

-- -- Neg Pos (30-50%)

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 XaMust 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-2Increases 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)

Plasma = ¼ ECF, Interstitial vol = ¾ ECF 60-40-20 rule (% of TB weight) Plasma vol measured by radiolabeled albumin ECF measured by inulin

1/3

2/3

60% TB weight

Osmolarity: 290 mOsm

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 endotheliumFused 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 constantNSAID’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 FxnEffect 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 (Tm)

Amino Acids: reabsorption by 3 different carrier systems, with competitive inhibition with each groupSecondary 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

HCO3If HCO3 > normal then met alkalosis is presentIf HCO3 < normal then NAGMA is presentIf 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: MUDPILESMethanol, 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: RBCBelow: Granular Above: WBC

Below: Hyaline

Nephritic (p. 445)

Acute post-strep glomerulonephritis (GN)

LM-glomeruli enlarged and hypercellular, “lumpy-bumpy”EM-subepithelial immune complex (IC) humpsImmunofluorescence (IF)-granular

Most freq seen in children. Periph and periorbital edema. Resolves spontaneously

Rapidly progressive GN(Cresentic)

LM and IF-crescent moon1.Goodpasture’s-type II hypersensitivity, Ab to GBM=linear IF2.Wegener’s granulomatosis3.Microscopic polyarteritis

Male-dominant dz Hematuria/hemoptysis (lung involved)

c-ANCAp-ANCA

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 (IgA glomerulopathy)

Increased synthesis of IgA. IC’s deposit in mesangium

Often follows URI, often presents as nephrotic syndrome

Alport’s syndrome Mutation in type IV collagen split basement membrane

Nerve disorders, ocular disoders, deafness also 2/2 mutation in type IV collagen

An inflamatory process involves the glomerulus azotemia, hematuria, RBC casts, oliguria, HTN, and proteinuria

Nephrotic (p.445)

Membranous glomerulonephritis (Diffuse membranous glomerulopathy)

LM-diffuse capillary and GBM thickeningEM-”spike dome” appearanceIF-granular SLE nephrotic presentation

Caused by drugs, infections, and SLEMost common cause (MCC) of adult nephrotic syndrome

Minimal change disease (Lipoid nephrosis)

LM- normal glomeruli

EM-foot process effacement

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

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

birefringenceAssociated 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 loopingLM-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 IFEM-”tram-track” appearance due to GBM splitting caused by mesangial ingrowth

Can present as nephritic syndrome Usually progresses slowly to CRFAssociated 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

turnoverE.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’ tumorAniridiaGenitourinary malformationmental motor Retardation

Transitional Cell Ca (p. 447)

Most common tumor of urinary tract systemCan 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/vesselsWhite cell casts are pathognomonic Presentation: fever, CVA tenderness

Chronic:Coars, asymmetric corticomedullary scarringBlunted calyxTubules 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 MellitusAcute pyelonephritisChronic 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

FENaFENa = (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 uremiaClinical 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 ATNChronic: 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 HCO3Uremic encephalopathy confusion, AMS, comaSodium and water excess CHF and pulm edemaChronic pyelonephritisHTNPericarditis

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 High serum conc

Na Disorientation, coma, stupor 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)

HyperKAvoid in bilat renal artery stenosis because ACE inhib

significantly decr GFR by preventing constriction of efferent arterioles

Diuretics: Loop v. ThiazidesLoop Diuretic (furosemide)

Thiazide (HCTZ)

Mechanism

Inhibits cotransport (Na,K,2Cl) of Thick ascending LOH. Abolishes hypertonicity of medulla, prevents urine concentration

Inhibits NaCl resorption in early distal tubule, reduces diluting capacity of the nephron. Decr Ca excretion

Clinical use

Edematous states, (CHF, cirrhosis, nephrotic syndrome, pulm edema) HTN, hyperCa

HTN, CHF, idiopathic hypercalciuria, nephrogenic diabetes insipidus

Toxicity

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!