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Steven Katz, MSIV. USMLE STEP I Review Week 6: Renal and Hematology Physiology. 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. - PowerPoint PPT Presentation
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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!
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