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: procoagulation (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: anticoagulation (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 RBCs)

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 Disease Hemo- Pregnancy chroma- /OCP use tosis (10)

Serum Iron
Transferrin/ TIBC Ferritin % transferrin saturation (serum Fe/TIBC)

(10)

(10)
-

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 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 (RBCs 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 babys RBCs.

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 RBCs 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 Willebrands disease: fairly mild it is the most

common bleeding disorder

Cause of bleeding is deficiency of von Willebrands

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
Hemophilia A or B von Willebrands disease DIC Vitamin K deficiency Bernard-Soulier disease (BS) N/C N/C N/C N/C N/C

N/C
N/C N/C

N/C

* N/C or

N/C

N/C

Glanzmanns 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

Hodgkins 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 Hodgins dz

Lymphomas (p.337)
Hodgkins
Reed-Sternberg cells Localized, single group of nodes

Non-Hodgkins
May be associated with HIV and immunosuppression

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 distributionyoung and old More common in men except for nodular sclerosing type Good prognosis = increased lymphocytes and decreased RS

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

Hodgkins Lymphoma (p. 337) RS Lymphocyte Prognosis Comments Type

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

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

Mixed Cellularity (25%)

Lymphocyte predominant (6%) Lymphocyte depleted (rare)

++++

+++

Intermediate Numerous RS cells

+ RS high v. lympho -cyte

++++

Excellent

< 35 year olds

Poor

Older males with disseminated disease

Non-Hodgkins Lymphoma (p.339)

Type
Small lymphocytic lymphoma Follicular lymphoma (small cleaved cell)

Occurs in

Cell type

Genetics

Comments
Like CLL with focal mass

Adults

B cells

Adults

B cells

-Difficult to t(14:18) cure bcl-2 expression -bcl-2 inhibits apoptosis - Most common - Aggressive but many are curable

Diffuse large cell lymphoma Mantle Cell Lymphoma

Usually older 80% B cells adults, but 20% T cells 20% in kids (mature)

Adults

B cells

t(11:14)

Poor prognosis CD5+

Non-Hodgkins Lymphoma (p.339)

Type Occurs in Cell type Genetics Comments
- Most common in kids, commonly with ALL and mediastinal mass - Very aggressive Tcell lymphoma t(8:14) c-myc gene moves next to heavy-chain Ig gene (14) Lymphoblastic lymphoma Most often in T cells kids (immature)

Burkitts lymphoma

Most often in B cells kids

- 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 RBCs stacked like poker chips (Rouleaux formation)

Compare to Waldenstrms 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
t(9;22) Philadelphia chromosome t(8;14) t(14;18) t(15;17) t(11;22) t(11;14)

Associated Disorder
CML (bcr-abl hybrid) Burkitts lymphoma (c-myc activation) Follicular lymphoma (bcl-2 activation) M3 type of AML (responsive to alltrans retinoic acid) Ewings sarcoma 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 WBCs)

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 leukemiamature 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)

RBCs Polycythemia Vera (PCV) WBC Platelets Philadelphia chromosome Neg --Variable Variable Neg JAK2 mutations Pos Pos (30-50%)

Essential Thrombocytosis
Myelofibrosis CML

Neg
Pos

Pos (30-50%)
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 = ECF, Interstitial vol = 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 = Bowmans 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 NSAIDs 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
Afferent arteriole constriction Efferent arteriole constriction

RPF

GFR

FF
NC

Incr plasma protein conc

Decr plasma protein conc Constriction of ureter

NC
NC NC

Clearance (p.438)

Free Water: Ability to dilute urine

CH
20

= V- Cosm
< 20

V = urine flow rate; Cosm = UosmV/Posm With ADH: CH

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.

NSAIDs can cause renal failure by

inhibiting the renal production of prostaglandins.

Hormones acting on the kidney (p. 442)

Acid/BaseVERY IMPORTANT (p.442)

pH Met acidosis Met alkalosis PCO2 [HCO3] Compensatory mech Hyperventilation Hypoventilation

Resp acidosis
Resp alkalosis

Increase renal HCO3 reabsorption

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 Winters Formula: used to check for resp. compensation when met. acid is present

4.

Is there proper compensation?

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 LM and IF-crescent moon 1. Goodpastures-type II hypersensitivity, Ab to GBM=linear IF 2. Wegeners granulomatosis 3. Microscopic polyarteritis Subendothelial DNA-anti-DNA ICs wire-looping of capillaruies IF-granular Increased synthesis of IgA. ICs deposit in mesangium

Most freq seen in children. Periph and periorbital edema. Resolves spontaneously
Male-dominant dz Hematuria/hemoptysis (lung involved)

Rapidly progressive GN (Cresentic)

c-ANCA p-ANCA Most common cause of death in SLE. SLE can present as nephrotic syndrome Often follows URI, often presents as nephrotic syndrome

Diffuse proliferative GN (due to SLE) Bergers disease

(IgA glomerulopathy)

Alports syndrome

Mutation in type IV collagen split basement membrane

Nerve disorders, ocular disoders, 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 glomerulonephritis (Diffuse membranous glomerulopathy) Minimal change disease (Lipoid nephrosis) LM-diffuse capillary and GBM thickening EM-spike dome appearance IF-granular SLE nephrotic presentation 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
LM- segmental sclerosis and hyalinosis Most common glomerular dz in HIV pts. More severe in these pts as well.

Focal segmental glomerulosclerosis

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 (Goodpastures) 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 UTIs 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, NSAIDs, 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.

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

3.

Postrenal: outflow obstruction (stones, BPH, neoplasia)

1.

Stones as cause only develops with bilateral obstruction

Acute Renal Failure (p.448)

Variable Urine osmolality Urine Na Prerenal > 500 < 10 < 1% Renal < 350 > 20 > 2% Postrenal < 350 > 40 > 4%

FENa
FENa = (UNa * PCr/ PNa * UCr) x 100

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 sxs (confusion, HTN, coma, fibrinous pericarditis, etc.)

2 forms of renal failure

Acute: often due to ATN
Chronic: MCCs 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

Fanconis syndrome (p.448)

Decreases tubule transport of AA, glucose, PO4, Uric acid, protein and electrolytes Can be acquired or congenital Causes include Wilsons Dz, glycogen storage dz, and drugs (cisplatin,
expired tetracycline)

Defect Decr PO4 reabsorption Decr HCO3 reabsorption

Complications Rickets 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 Infantile presentation in parenchyma. AR, associated with hepatic cysts and fibrosis Cortical and medullary cysts resulting from long standing dialysis Medullary cysts. U/S shows small kidneys. POOR prognosis Collecting duct cysts. GOOD prognosis Benign, incidental finding. Cortex only

ARPKD Dialysis cysts Medullary cystic dz Medullary sponge dz Simple Cysts

Electrolyte Disturbances (p.449)

Electrolyte Low serum conc Disorientation, coma, stupor Na High serum conc
Neurologic: irritability, delirium, coma

Cl
K

2/2 met alk, hypoK, hypovol, incr aldosterone

U waves in EKG, flattened T waves, arrhythmias, paralysis Tetany, neuromuscular irritability neuromuscular irritability, arrhythmias Low-mineral ion product causes bone loss, osteomalacia

2/2 NAGMA
Peaked T waves, wide QRS, arrhythmias Delirium, renal stones, abd pain, not necessary calciuria Delirium, decreased DTR, cardiopulm arrest High-mineral ion product causes renal stones, metastatic calcifications

Ca
Mg PO4

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

Thiazide (HCTZ)
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
Ototoxicity, HypoK, Dehydration, Allergy (sulfa), Nephritis, Gout OH DANG!

HTN, CHF, idiopathic hypercalciuria, nephrogenic diabetes insipidus

Hypokalemic met alk, hypoNa, hyperGlycemia, hyperLipidemia, hyperUricemia, hyperCalcemia. Sulfa allergy. hyperGLUC

Toxicity

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!