UPDATES IN HARRISON 18TH EDITION
UPDATES IN NEPHROLOGY
Table 277-1 Inherited Disorders Affecting Renal Tubular Ion and Solute Transport
Disease or Syndrome
Gene
OMIM*
Sodium bicarbonate
cotransporter
604278
Disorders Involving the Proximal Tubule
Proximal renal tubular acidosis
(SLC4A4, 4q21)
Fanconi-Bickel syndrome
Glucose transporter, GLUT2
227810
(SLC2A2, 3q26.2)
Isolated renal glycosuria
Sodium glucose cotransporter
233100
(SLC5A2, 16p11.2)
Cystinuria
Type I
Cystine, dibasic and neutral
amino acid transporter
220100
(SLC3A1, 2p16.3)
Nontype I
Amino acid transporter, light
subunit
600918
(SLC7A9, 19q13.1)
Lysinuric protein intolerance
Amino acid transporter
(SLC7A7, 4q11.2)
222700
Hartnup disorder
Neutral amino acid transporter
34500
(SLC6A19, 5p15.33)
Hereditary hypophosphatemic rickets with
hypercalcemia
Sodium phosphate cotransporter 241530
(SLC34A3, 9q34)
Renal hypouricemia
Type 1
Urate-anion exchanger
220150
(SLC22A12, 11q13)
Type 2
Urate transporter, GLUT9
612076
(SLC2A9, 4p16.1)
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Dent's disease
Chloride channel, ClC-5
300009
(CLCN5, Xp11.22)
X-linked recessive nephrolithiasis with renal
failure
Chloride channel, ClC-5
310468
(CLCN5, Xp11.22)
X-linked recessive hypophosphatemic rickets
Chloride channel, ClC-5
307800
(CLCN5, Xp11.22)
Disorders Involving the Loop of Henle
Bartter's syndrome
Type 1
Sodium, potassium chloride
cotransporter
241200
(SLC12A1, 15q21.1)
Type 2
Potassium channel, ROMK
601678
(KCNJ1, 11q24)
Type 3
Chloride channel, ClC-Kb
602023
(CLCNKB, 1p36)
with sensorineural deafness
Chloride channel accessory
subunit, Barttin
602522
(BSND, 1p31)
Autosomal dominant hypocalcemia with Bartter- Calcium-sensing receptor
like syndrome
(CASR, 3q13.33))
601199
Familial hypocalciuric hypercalcemia
145980
Calcium-sensing receptor
(CASR, 3q13.33)
Primary hypomagnesemia
Claudin-16 or paracellin-1
248250
(CLDN16 or PCLN1, 3q27)
Isolated renal magnesium loss
Sodium potassium ATPase, 1subunit
154020
(ATP1G1, 11q23)
Disorders Involving the Distal Tubule and Collecting Duct
Gitelman's syndrome
Sodium chloride cotransporter
263800
(SLC12A3, 16q13)
Primary hypomagnesemia with secondary
hypocalcemia
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Melastatin-related transient
602014
receptor potential cation channel
2
6
(TRPM6, 9q22)
Pseudoaldosteronism (Liddle's syndrome)
Epithelial sodium channel and
subunits
177200
(SCNN1B, SCNN1G, 16p12.1)
Recessive pseudohypoaldosteronism Type 1
Epithelial sodium channel, , ,
and subunits
264350
(SCNN1A, 12p13; SCNN1B,
SCNN1G, 16pp12.1)
Pseudohypoaldosteronism Type 2 (Gordon's
hyperkalemia-hypertension syndrome)
Kinases WNK-1, WNK-4
145260
(WNK1, 12p13; WNK4,
17q21.31)
X-linked nephrogenic diabetes insipidus
Vasopressin V2 receptor
(AVPR2, Xq28)
304800
Nephrogenic diabetes insipidus (autosomal)
Water channel, aquaporin-2
125800
(AQP2, 12q13)
Distal renal tubular acidosis
autosomal dominant
Anion exchanger-1
179800
(SLC4A1, 17q21.31)
autosomal recessive
Anion exchanger-1
602722
(SLC4A1, 17q21.31)
with neural deafness
Proton ATPase, 1 subunit
192132
(ATP6V1B1, 2p13.3)
with normal hearing
Proton ATPase, 116-kD subunit 602722
(ATP6V0A4, 7q34)
Online Mendelian Inheritance in Man database (http://www.ncbi.nlm.nih.gov/Omim).
*
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Table 279-2 Biomarkers of Acute Kidney Injury
Biomarker
Comments
Detection
Species
Alanine
aminopeptidase
(AAP)
1. Proximal tubule brush border
enzyme
Colorimetry
Rat, dog,
human
2. Instability may limit clinical
utility
Alkaline
phosphatase (AP)
1. Proximal tubule brush border
Colorimetry
enzyme. Human intestinal
alkaline phosphatase is specific
for proximal tubular S3 segment;
human tissue nonspecific alkaline
phosphatase is specific for S1 and
S2 segments
Rat, human
2. Levels may not correlate with
extent of functional injury
3. Instability may limit clinical
utility
Alpha -Glutathione- 1. Proximal tubule cytosolic
ELISA
S-transferase
enzyme
(alpha-GST)
2. Requires stabilization buffer for
specimen storage and processing
Mouse, rat,
human
3. Upregulated in AKI and renal
cell carcinoma
Gamma -Glutamyl
transpeptidase (
gamma GT)
1. Proximal tubule brush border
enzyme
Colorimetry
Rat, human
Colorimetry
Mouse, rat,
human
2. Instability requires samples to
be analyzed quickly after
collection, limiting clinical utility
N-Acetyl-beta -(D)
glucosaminidase
(NAG)
1. Proximal tubule lysosomal
enzyme
2. More stable than other urinary
enzymes
3. Extensive preclinical and
clinical data in a variety of
conditions (nephrotoxicant
exposure, cardiopulmonary
bypass, delayed renal allograft
function, etc.)
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4. Endogenous urea may inhibit
activity
Beta 2Microglobulin
1. Light chain of the MHC I
molecule expressed on the cell
surface of all nucleated cells
ELISA
Mouse, rat,
human
Nephelometry
2. Monomeric form is filtered by
the glomerulus and reabsorbed by
the proximal tubule cells
3. Early marker of tubular
dysfunction in a variety of
conditions
4. Instability in acidic urine limits
clinical utility
Alpha 1Microglobulin
1. Synthesized by the liver
ELISA
2. Filtered by the glomerulus and
reabsorbed by proximal tubule
cells
Nephelometry
Mouse, rat,
human
3. Early marker of tubular
dysfunction; high levels may
predict poorer outcome
4. Stable across physiologic
urinary pH
Retinol-binding
protein
1. Synthesized by liver, involved
in vitamin A transport
ELISA
Mouse, rat,
human
Nephelometry
2. Filtered by glomerulus and
reabsorbed by proximal tubule
cells
3. Early marker of tubular
dysfunction
4. Increased stability in acidic
urine when compared to
microglobulin
Cystatin C
2-
1. Important extracellular
inhibitor of cysteineproteases
ELISA
Mouse, rat,
human
Nephelometry
2. Filtered by the glomerulus and
reabsorbed by proximal tubule
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cells
3. Elevated urinary levels reflect
tubular dysfunction; high levels
may predict poorer outcome
Microalbumin
1. Established marker for
ELISA
Mouse, rat,
monitoring progression of chronic
dog,
kidney disease
Immunoturbidimetry monkey,
human
2. Elevated urinary levels may be
indicative of proximal tubular
damage
3. Lack of specificity for AKI
may limit its utility
Kidney injury
1. Type-1 cell membrane
molecule-1 (KIM-1) glycoprotein upregulated in
dedifferentiated proximal tubule
epithelial cells
ELISA, Luminex®based assay
Zebrafish,
mouse, rat,
dog,
monkey,
human
ELISA
Mouse, rat,
dog,
monkey,
human
2. Ectodomain is shed and can be
quantitated in urine following
AKI in preclinical and clinical
studies
3. Elevated urinary levels are
highly sensitive and specific for
AKI
4. Upregulated following various
models of preclinical and clinical
AKI, fibrosis, renal cell
carcinoma, and polycystic kidney
disease
Clusterin
1. Expressed on dedifferentiated
proximal tubular epithelial cells
2. Elevated kidney and urinary
levels are very sensitive for AKI
in preclinical models
3. Upregulated in various rodent
models of AKI, fibrosis, renal cell
carcinoma, and polycystic kidney
disease
4. No clinical study demonstrating
its use
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Neutrophil
gelatinase
associated lipocalin
(NGAL)
1. Initially identified bound to
gelatinase in specific granules of
the neutrophils, but also may be
induced in epithelial cells in the
setting of inflammation or
malignancy
ELISA
Mouse, rat,
human
Luminex®-based
assay
2. Expression upregulated in
kidney proximal tubule cells and
urine following ischemic or
cisplatin induced renal injury
3. Found to be an early indicator
of AKI following
cardiopulmonary bypass
4. Specificity for AKI in setting of
sepsis and pyuria need to be
further established
Interleukin-18 (IL18)
1. Cytokine with broad
ELISA
immunomodulatory properties,
particularly in setting of ischemic Luminex®-based
injury
assay
Mouse, rat,
human
2. Constitutively expressed in
distal tubules; strong
immunoreactivity in proximal
tubules with transplant rejection
3. Elevated urinary levels found to
be early marker of AKI and
independent predictor of mortality
in critically ill patients
Cysteine-rich
protein (CYR-61)
1. Induced in proximal straight
tubules of kidney and secreted in
the urine within 3–6 h following
ischemic kidney injury
Western blot
Mouse, rat,
human
ELISA
Mouse, rat,
2. Urinary levels decrease rapidly
in spite of progression of injury
indicating stability issue
3. No clinical study demonstrating
its use
4. No quantitative method
established
Osteopontin
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1. Upregulated in various rodent
7
models of AKI
monkey,
human
2. The induction correlates with
inflammation and
tubulointerstitial fibrosis
3. No clinical study demonstrating
its use
Liver fatty acid–
1. Expressed in proximal tubule
binding protein (L- epithelial cells
FABP)
2. Current evidence suggests
clinical utility as a biomarker in
CKD and diabetic nephropathy
ELISA
Mouse, rat,
human
Immunoblotting
Mouse, rat,
human
3. Additional studies necessary to
determine utility in setting of
preclinical and clinical AKI
Sodium/hydrogen
exchanger isoform
(NHE3)
1. Most abundant sodium
transporter in the renal tubule
2. Urinary levels found to
discriminate between prerenal
azotemia and AKI in ICU patients
3. Samples require considerable
processing, limiting assay
throughput
Exosomal fetuin-A
1. Acute phase protein
Immunoblotting
Rat, human
synthesized in the liver and
secreted into the circulation
2. Levels in proximal tubule cell
cytoplasm correspond to degree of
injury
3. Urinary levels found to be
much higher in ICU patients with
AKI compared to ICU patients
without AKI and healthy
volunteers
4. Samples require considerable
processing, limiting assay
throughput
5. Additional studies necessary to
determine utility in setting of
preclinical and clinical AKI
Abbreviations: AKI, acute kidney injury; ELISA, enzyme-linked immunosorbent assay; ICU,
intensive care unit; RCC, renal cell carcinoma.
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3.ALSO KNOW THE EXPANDED DONOR CRITERIA UPDATED IN 18TH EDITION HARRISON
Table 282-1 Definition of an Expanded Criteria Donor (ECD) and a Non-Heart-Beating
Donor [Donation after Cardiac Death (DCD)]
Expanded Criteria Donor (ECD)
Deceased donor >60 years
Deceased donor >50 years and hypertension and creatinine >1.5 mg/dL
Deceased donor >50 years and hypertension and death caused by cerebrovascular accident
(CVA)
Deceased donor >50 years and death caused by CVA and creatinine >1.5 mg/dL
Donation after Cardiac Deatha (DCD)
I Brought in dead
II Unsuccessful resuscitation
III Awaiting cardiac arrest
IV Cardiac arrest after brainstem death
V Cardiac arrest in a hospital patient
Kidneys can be used for transplantation from categories II–V but are commonly only used
from categories III and IV. The survival of these kidneys has not been shown to be inferior to
that of deceased-donor kidneys.
a
Note: Kidneys can be bought ECD and DCD. ECD kidneys have been shown to have a poorer
survival, and there is a separate shorter waiting list for ECD kidneys. They are generally
utilized for patients for whom the benefits of being transplanted earlier outweigh the
associated risks of using an ECD kidney.
4. ALSO KNOW THE INFECTIONS IN RENAL TRANSPLANT RECIEPIENTS
Table 282-5 The Most Common Opportunistic Infections in Renal Transplant Recipients
Peritransplant (<1 month)
Late (>6 months)
Wound infections
Aspergillus Nocardia
Herpesvirus
BK virus (polyoma)
Oral candidiasis
Herpes zoster
Urinary tract infection
Hepatitis B
Early (1–6 months)
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Hepatitis C
9
Pneumocystis carinii
Cytomegalovirus
Legionella Listeria
Hepatitis B
Hepatitis C
5. INDICATIONS FOR IMMUNOSUPRESSIVES HAVE BEEN ADDED IN THE 18TH EDITION.JUST GO
THROUGH IT QUICKLY.
Table 285-2 Indications for Corticosteroids and Immunosuppressives in Interstitial Nephritis
Absolute Indications
Sjögren's syndrome
Sarcoidosis
SLE interstitial nephritis
Adults with TINU
Idiopathic and other granulomatous interstitial nephritis
Relative Indications
Drug-induced or idiopathic AIN with:
Rapid progression of renal failure
emsp; Diffuse infiltrates on biopsy
emsp; Impending need for dialysis
emsp; Delayed recovery
Children with TINU
Postinfectious AIN with delayed recovery (?)
Abbreviations: AIN, acute interstitial nephritis; SLE, systemic lupus erythematosus; TINU,
tubulointerstitial nephritis with uveitis.
Source: Modified from S Reddy, DJ Salant: Ren Fail 20:829, 1998.
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6.RENAL ARTERY STENOSIS EVALUATION
Table 286-1 Summary of Imaging Modalities for Evaluating the Kidney Vasculature
Perfusion Studies to Assess Differential Renal Blood Flow
Captopril
renography with
technetium 99mTc
mertiatide (99mTc
MAG3)
Captopril-mediated
fall in filtration
pressure amplifies
differences in renal
perfusion
Normal study excludes
Multiple limitations
renovascularhypertension in patients with
advanced
atherosclerosis or
creatinine >;2.0
mg/dL (177
mol/L)
Nuclear imaging
Estimates fractional
with technetium
flow to each kidney
mertiatide or
technetium-labeled
pentetic acid
(DTPA) to estimate
fractional flow to
each kidney
Allows calculation of
Results may be
single-kidney glomerular influenced by other
filtration rate
conditions, e.g.,
obstructive uropathy
Vascular Studies to Evaluate the Renal Arteries
Duplex
ultrasonography
Shows the Inexpensive; widely available
renal
arteries and
measures
flow
velocity as
a means of
assessing
the severity
of stenosis
Magnetic resonance Shows the
angiography
renal
arteries and
perirenal
aorta
Heavily dependent
on operator's
experience; less
useful than invasive
angiography for the
diagnosis of
fibromuscular
dysplasia and
abnormalities in
accessory renal
arteries
Not nephrotoxic, but concerns for
gadolinium toxicity exclude use in
GFR <30 mL/min/1.73 m2; provides
excellent images
Expensive;
gadolinium excluded
in renal failure,
unable to visualize
stented vessels
Computed
tomographic
angiography
Shows the Provides excellent images; stents do
renal
not cause artifacts
arteries and
perirenal
aorta
Expensive, moderate
volume of contrast
required, potentially
nephrotoxic
Intra-arterial
angiography
Shows
location
and
severity of
vascular
Expensive,
associated hazard of
atheroemboli,
contrast toxicity,
procedure-related
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Considered "gold standard" for
diagnosis of large vessel disease,
usually performed simultaneous
with planned intervention
11
lesion
complications, e.g.,
dissection
Abbrevations: DTPA, diethylenetriamine pentaacetic acid (pentetic acid); GFR, glomerular
filtration rate.
Table 286-2 Clinical Factors Favoring Medical Therapy and Revascularization or
Surveillance for Renal Artery Stenosis
Factors Favoring Medical Therapy and Revascularization for Renal Artery Stenosis
Progressive decline in GFR during treatment of systemic hypertension
Failure to achieve adequate blood pressure control with optimal medical therapy
(medical failure)
Rapid or recurrent decline in the GFR in association with a reduction in systemic
pressure
Decline in the GFR during therapy with ACE inhibitors or ARBs
Recurrent congestive heart failure in a patient in whom the adequacy of left ventricular
function does not explain a cause
Factors Favoring Medical Therapy and Surveillance of Renal Artery Disease
Controlled blood pressure with stable renal function (e.g., stable renal insufficiency)
Stable renal artery stenosis without progression on surveillance studies (e.g., serial
duplex ultrasound)
Very advanced age and/or limited life expectancy
Extensive comorbidity that make revascularization too risky
High risk for or previous experience with atheroembolic disease
Other concomitant renal parenchymal diseases that cause progressive renal dysfunction
(e.g., interstitial nephritis, diabetic nephropathy)
Abbreviations: ACE, angiotensin-converting enzyme; ARBs, angiotensin receptor blockers;
GFR, glomerular filtration rate.
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7. TRANSPLANTATION-ASSOCIATED
THROMBOTIC MICROANGIOPATHY (TA-TMA).







TA-TMA can develop after hematopoietic stem cell transplantation (HSCT) with an
incidence of 8.2%.
Etiologic factors include conditioning regimens, immunosuppression, infections, and
graft-versus-host disease. Other risk factors include female sex, age, and human
leukocyte antigen (HLA)-mismatched donor grafts.
TA-TMA usually occurs within the first 100 days after HSCT.
A firm diagnosis may be difficult because thrombocytopenia, anemia, and renal
insufficiency are common in the posttransplant period.
TA-TMA carries a high mortality rate (75% within 3 months).
Plasma exchange is beneficial in less than 50% of patients, most of whom have more
than 5% ADAMTS13 activity.
Calciuria inhibitors should be discontinued, and substitution with daclizumab
[antibody to the interleukin 2 (IL-2) receptor] is recommended. Treatment with
rituximab and defibrotide may also be helpful.
Microangiopathic Kidney Injury Can Be Associated With Hematopoietic Stem Cell Transplantation.
IF POSSIBLE KNOW THE CRITERIA FOR IT.
Table 286-3 Criteria for Establishing Microangiopathic Kidney Injury Associated with
Hematopoietic Stem Cell Transplantation
International Working Group
Blood and Marrow Transplant Clinical
Trials Network Toxicity Committee
>;4% schistocytes in the blood
RBC fragmentation and at least 2 schistocytes
per high-power field
De novo, prolonged, or progressive
thrombocytopenia
Concurrent increase in LDH above baseline
A sudden and persistent increase in LDH
Negative direct and indirect Coombs test
Decrease in hemoglobin or increased RBC Concurrent renal and/or neurologic dysfunction
transfusion requirement
without other explanations
Decrease in haptoglobin concentration
Note: These features underscore the need to identify pathways of hemolysis and
thrombocytopenia that accompany deterioration of kidney function.
Abbreviations: LDH, lactate dehydrogenase; RBC, red blood cell.
HIV-RELATED TMA

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TMA is mainly a complication encountered before widespread use of highly active
retroviral therapy for HIV.
It is seen in patients with advanced AIDS and low CD4 count, although it
occasionally can be the first manifestation of HIV infection.
13




The presence of MAHA thrombocytopenia and renal failure are suggestive, but renal
biopsy is required to establish the diagnosis since HIV is associated with several other
renal diseases.
The median platelet count is 77,000/L with a range of 10,000 to 160,000/L, which
may prohibit a renal biopsy in some patients.
Cytomegalovirus (CMV) coinfection may also be a risk factor. The mechanism of
injury is unclear, but HIV may induce apoptosis in endothelial cells.
Plasma exchange is effective and is recommended in conjunction with antiviral
therapy.
UPDATES IN RHEUMATOLOGY
1.BELIMUMAB IN SLE:


Recent trials of anti-BLyS (belimumab, directed against the ligand of the BLyS/BAFF
receptor on B cells that promotes B cell survival and differentiation to plasmablasts)
showed a small, but statistically significant, better suppression of disease activity in
comparison to placebo, when added to standard combhnation therapies.
The US FDA has approved belimumab for treatment of SLE: it has not been studied
in active nephritis or central nervous system lupus.
2.CLINICAL FEATURES OF ANTIPHOSPHOLIPID ANTIBODY SYNDROME
Table 320-2 Clinical Features of Antiphospholipid Antibody Syndrome
Manifestation
%
Venous Thrombosis and Related Consequences
Deep vein thrombosis
39
Livedo reticularis
24
Pulmonary embolism
14
Superficial thrombophlebitis
12
Thrombosis in various other sites
11
Arterial Thrombosis and Related Consequences
Stroke
20
Cardiac valve thickening/dysfunction and/or Libman-Sacks vegetations
14
Transient ischemic attack
11
Myocardial ischemia (infarction or angina) and coronary bypass thrombosis
10
Leg ulcers and/or digital gangrene
9
Arterial thrombosis in the extremities
7
Retinal artery thrombosis/amaurosis fugax
7
Ischemia of visceral organs or avascular necrosis of bone
6
Multi-infarct dementia
3
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14
Neurologic Manifestations of Uncertain Etiology
Migraine
20
Epilepsy
7
Chorea
1
Cerebellar ataxia
1
Transverse myelopathy
0.5
Renal Manifestations Due to Various Reasons (Renal Artery/Renal
Vein/Glomerular Thrombosis, Fibrous Intima Hyperplasia)
3
Osteoarticular Manifestations
Arthralgia
39
Arthritis
27
Obstetric Manifestations (Referred to the Number of Pregnancies)
Preeclampsia
10
Eclampsia
4
Fetal Manifestations (Referred to the Number of Pregnancies)
Early fetal loss (<10 weeks)
35
Late fetal loss (10 weeks)
17
Premature birth among the live births
11
Hematologic Manifestations
Thrombocytopenia
30
Autoimmune hemolytic anemia
Source: Adapted from R Cervera et al.
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3. KNOW THE LATEST CRITERIA FOR RHEUMATOID ARTHRITIS
NEW 2010 ACR-EULAR CRITERIA
Table 321-1 Classification Criteria for Rheumatoid Arthritis
Score
Joint involvement
Serology
1 large joint (shoulder, elbow, hip, knee, ankle)
0
2–10 large joints
1
1–3 small joints (MCP, PIP, Thumb IP, MTP, wrists)
2
4–10 small joints
3
>10 joints (at least 1 small joint)
5
Negative RF and negative ACPA
0
2
Low-positive RF or low-positive anti-CCP antibodies (
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3
15
times ULN)
Acute-phase
reactants
Duration of
symptoms
High-positive RF or high-positive anti-CCP antibodies (>3
times ULN)
3
Normal CRP and normal ESR
0
Abnormal CRP or abnormal ESR
1
<6 weeks
0
1
6 weeks
Note: These criteria are aimed at classification of newly presenting patients who have at least
1 joint with definite clinical synovitis that is not better explained by another disease.
Abbreviations: CCP, cyclic citrullinated peptides; CRP, C-reactive protein; ESR, erythrocyte
sedimentation rate; IP, interphalangeal joint; MCP, metacarpophalangeal joint; MTP,
metatarsophalangeal joint; PIP, proximal interphalangeal joint; RF, rheumatoid factor; ULN,
upper limit of normal.
Source: Neogi et al: Arthritis Rheum 62:2569, 2010.
LATEST TNF ALPHA INHIBITORS:
Drug Dosage Serious
Toxicities
Other Common Side
Effects
Adalimumab: 40 mg SQ every Risk of bacterial,
other week
fungal infections
Initial Evaluation
Monitoring
PPD skin test
Monitor
for
injection
site
reactions
PPD skin test
Monitor
for
injection
site
reactions
Reactivation of latent
TB
Lymphoma risk
(controversial)
Golimumab: 50 mg SQ
monthly
Drug-induced lupus
Neurologic deficits
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TOCILIZUMAB






Tocilizumab is a humanized monoclonal antibody directed against the membrane and
soluble forms of the IL-6 receptor.
IL-6 is a proinflammatory cytokine implicated in the pathogenesis of RA, with
detrimental effects on both joint inflammation and damage.
IL-6 binding to its receptor activates intracellular signaling pathways that affect the
acute-phase response, cytokine production, and osteoclast activation.
Clinical trials have attested to the clinical efficacy of tocilizumab therapy for RA,
both as monotherapy and in combination with methotrexate and other DMARDs.
Tocilizumab has been associated with an increased risk of infection, neutropenia, and
thrombocytopenia; however, the hematologic abnormalities appear to be reversible
upon stopping the drug.
In addition, this agent has been shown to increase LDL cholesterol; however, it is not
known as yet if this effect on lipid levels increases the risk for development of
atherosclerotic disease.
Also know the criteria for remission
Table 321-3 Acr/Eular Provisional Definition of Remission in Rheumatoid Arthritis
At any time point, patient must satisfy all of the following:
Tender joint count
Swollen joint count
C-reactive protein
1
1
1 mg/dL
Patient global assessment
1 (on a 0–10 scale)
OR
At any time point, patient must have a Simplified Disease Activity Index score of less than
3.3
Source: Adapted from Felson et al.
SPONDYLOARTHROPATHIES
ASAS CRITERIA FOR CLASSIFICATION OF AXIAL SPONDYLOARTHRITIS.
New York criteria is no longer used at present.
Table 325-1 Asas Criteria for Classification of Axial Spondyloarthritis (to Be Applied for
Patients with Back Pain
3 Months and Age of Onset <45 Years)a
Sacroiliitis on imaging plus > 1 SpA feature
or HLA-B27 plus >2 other
SpA features
Sacroiliitis on imaging
SpA features
--Active (acute) inflammation on MRI highly suggestive of
SpA-associated sacroiliitisb
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Inflammatory back paind
17
and/or
--Definite radiographic sacroiliitis according to modified
New York criteriac
Arthritise
Enthesitis (heel)f
Anterior uveitisg
Dactylitise
Psoriasise
Crohn's disease or
ulcerative colitise
Good response to
NSAIDsh
Family history of SpAi
HLA-B27
Elevated CRPj
a
Sensitivity 83%, specificity 84%. The imaging arm (sacroiliitis) alone has a sensitivity of
66% and a specificity of 97%.
b
Bone marrow edema and/or osteitis on short tau inversion recovery (STIR) or gadoliniumenhanced T1 image.
c
Bilateral grade =2 or unilateral grade 3 or 4.
d
e
See text for criteria.
Past or present, diagnosed by a physician.
f
Past or present pain or tenderness on examination at calcaneus insertion of Achilles tendon
or plantar fascia.
g
Past or present, confirmed by an ophthalmologist.
h
Substantial relief of back pain at 24–48 h after a full dose of NSAID.
i
First- or second-degree relatives with ankylosing spondylitis (AS), psoriasis, uveitis, reactive
arthritis (ReA), or inflammatory bowel disease (IBD).
j
After exclusion of other causes of elevated CRP.
Abbreviations: ASAS, Assessment of Spondyloarthritis International Society; CRP, Creactive protein; NSAIDs, nonsteroidal anti-inflammatorydrugs; SpA, spondyloarthritis.
Source: From M Rudwaleit et al: Ann Rheum Dis 68:777, 2009. Copyright 2009, with
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permission from BMJ Publishing Group Ltd.
Also know the caspar criteria for psoriatic arthritis.
Table 325-2 The Caspar (C Lassification Criteria for Psoriatic Arthritis) Criteriaa
To meet the CASPAR criteria, a patient must have inflammatory articular disease
(joint, spine, or entheseal) with
3 points from any of the following five categories:
1. Evidence of current psoriasis,b, c a personal history of psoriasis, or a family history of
psoriasisd
2. Typical psoriatic nail dystrophye observed on current physical examination
3. A negative test result for rheumatoid factor
4. Either current dactylitisf or a history of dactylitis recorded by a rheumatologist
5. Radiographic evidence of juxtaarticular new bone formationg in the hand or foot
a
Specificity of 99% and sensitivity of 91%.
b
Current psoriasis is assigned 2 points; all other features are assigned 1 point.
c
Psoriatic skin or scalp disease present at the time of examination, as judged by a
rheumatologist or dermatologist.
d
History of psoriasis in a first- or second-degree relative.
e
Onycholysis, pitting, or hyperkeratosis.
f
Swelling of an entire digit.
g
Ill-defined ossification near joint margins, excluding osteophyte formation.
Source: From W Taylor et al.
GRANULOMATOSIS WITH POLYANGIITIS IS THE NEWER NAME FOR WEGENER’S
GRANULOMATOSIS.
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ENDOCRINOLOGY
1. CRITERIA FOR DIAGNOSIS OF DIABETES MELLITUS
Table 344-2 Criteria for the Diagnosis of Diabetes Mellitus
Symptoms of diabetes plus random blood glucose concentration 11.1 mmol/L (200
mg/dL)aor
Fasting plasma glucose 7.0 mmol/L (126 mg/dL)bor
A1C > 6.5%cor
Two-hour plasma glucose 11.1 mmol/L (200 mg/dL) during an oral glucose tolerance testd
a
Random is defined as without regard to time since the last meal. bFasting is defined as no
caloric intake for at least 8 h. cThe test should be performed in laboratory certified according
to A1C standards of the Diabetes Control and Complications Trial. dThe test should be
performed using a glucose load containing the equivalent of 75 g anhydrous glucose
dissolved in water, not recommended for routine clinical use. Note: In the absence of
unequivocal hyperglycemia and acute metabolic decompensation, these criteria should be
confirmed by repeat testing on a different day. Source: American Diabetes Association, 2011.
2. New therapies under development for type 2 diabetes include
 Inhibitor of the sodium-glucose co- transporter in the kidney,
 Activators of glucokinase,
 An inhibitor of 11 -hydroxysteroid dehydrogenase-1
 Salsalate.
 Liraglutide – GLP-1 AGONIST
 Saxagliptin, Vildagliptin -- Dipeptidyl Peptidase-4 Inhibitors
 PANCREATIC ISLET TRANSPLANTATION:
Pancreatic islet transplantation has been plagued by limitations in
 pancreatic islet supply and
 graft survival.
Other Therapies for Type 2 Diabetes:
BILE ACID–BINDING RESINS.
 Bile acid metabolism is abnormal type 2 diabetes.

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The bile acid–binding resin colesevelam has been approved for the
treatment of type 2 diabetes (already approved for treatment of
hypercholesterolemia).
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Emerging evidence indicates that bile acids, by signaling through nuclear receptors,
may have a role in metabolism.
COLESEVELAM
 Colesevelam (available as a powder for oral solution and as 625-mg tablets) is
prescribed as 3–6 tablets prior to meals.
 The most common side effects are gastrointestinal (constipation, abdominal pain, and
nausea).
 Bile acid–binding resins can increase plasma triglycerides and should be used
cautiously in patients with a tendency to hypertriglyceridemia.
Bromocriptine.
 A formulation of the dopamine receptor agonist bromocriptine (Cycloset), has been
approved by the FDA for the treatment of type 2 diabetes (approved in 2009).
CARDIOLOGY
KNOW THE CARDIOMYOPATHIES ASSOCIATED WITH VARIOUS METABOLIC
PATHWAY ABNORMALITIES.
Table 238-4 Examples of Inherited Defects in Metabolic Pathways Associated With
Cardiomyopathy, Usually Restrictive or Pseudohypertrophic Phenotype
Glycogen Storage Diseases
II—Pompe's (alpha 1,4 glucosidase)
III—Forbes: de-branching enzyme (amylo 1,6 glucosidase)
Glucose Metabolism (Defective PRKAG2a)
Fatty acid metabolism
Carnitine transport defect
Medium chain Acyl-CoA dehydrogenase
Long chain Acyl-CoA dehydrogenase
Sphingolipidoses
Fabry's disease (alpha galactosidase A)
Gaucher disease (beta-glucocerebroside)
Disorders of lysosomal function
Danon's disease—(lysosome-associated membrane protein, LAMP2)
Miscellaneous
Hemochromatosis—Fe metabolism
Familial amyloidosis—abnormal transthyretin
Barth syndrome—tafazzin defect affecting cardiolipin
Friedreich's ataxia—frataxin
a
Gamma-2 regulatory subunit of the AMP-activated protein kinase important for glucose
metabolism.
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Drug Class Examples Usual Total Daily Dose* Other
(Dosing Frequency/Day) Indications
Contraindications/Cautions
Renin
inhibitors
Pregnancy
Aliskiren 150–300 mg (1)
Diabetic
nephropathy
ENDOTHELIN RECEPTOR ANTAGONISTS
 The endothelin receptor antagonists bosentan and ambrisentan are approved treatments
of PAH.
 In randomized clinical trials, both improved exercise tolerance as measured by an increase
in 6-min walking distance.
 Therapy with bosentan is initiated at 62.5 mg bid for the first month and increased to 125
mg bid thereafter. Ambrisentan is initiated as 5 mg once daily and can be increased to 10
mg daily.
 Because of the high frequency of abnormal hepatic function tests associated with these
drugs, primarily an increase in transaminases, it is recommended that liver function be
monitored monthly throughout the duration of use.
 Bosentan is contraindicated in patients who are on cyclosporine or glyburide concurrently.
UPDATES:
Respiratory system
FUTURE THERAPIES IN ASTHMA
There is a need for the development of new therapies for patients with refractory asthma who
have side effects with systemic corticosteroids.
Antagonists of specific mediators have little or no benefit in asthma, apart from
antileukotrienes, which have rather weak effects, presumably reflecting the fact that multiple
mediators are involved.
Blocking antibodies against IL-5 mepolizumab, reslizumab may reduce exacerbations in
highly selected patients who have sputum eosinophils despite high doses of corticosteroids.
anti-TNF-alpha antibodies are not effective in severe asthma.
Novel anti-inflammatory treatments that are in clinical development include inhibitors of
phosphodiesterase-4, NF-kappa B and p38 MAP kinase.
However, these drugs, which act on signal transduction pathways common to many cells, are
likely to have troublesome side effects, necessitating their delivery by inhalation. Safer and
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more effective immunotherapy using T-cell peptide fragments of allergens or DNA
vaccination are also being investigated.
Bacterial products, such as CpG oligonucleotides that stimulate TH1 immunity or regulatory
T cells, are also currently under evaluation.
DEEP VEIN THROMBOSIS:
Table 262-1 Clinical Decision Rules
Low Clinical Likelihood of DVT if Point Score Is Zero or Less; Moderate-Likelihood
Score Is 1 to 2; High-Likelihood Score Is 3 or Greater
Clinical Variable
Score
Active cancer
1
Paralysis, paresis, or recent cast
1
Bedridden for >3 days; major surgery <12 weeks
1
Tenderness along distribution of deep veins
1
Entire leg swelling
1
Unilateral calf swelling >3 cm
1
Pitting edema
1
Collateral superficial nonvaricose veins
1
Alternative diagnosis at least as likely as DVT
–2
High Clinical Likelihood of PE if Point Score Exceeds 4
Clinical Variable
Score
Signs and symptoms of DVT
3.0
Alternative diagnosis less likely than PE
3.0
Heart rate >100/min
1.5
Immobilization >3 days; surgery within 4 weeks
1.5
Prior PE or DVT
1.5
Hemoptysis
1.0
Cancer
1.0
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- POINT SCORE METHOD FOR D.V.T.
USG of deep leg veins:
Table 262-3 Ultrasonography of the Deep Leg Veins
Criteria for Establishing the Diagnosis of Acute DVT
Lack of vein compressibility (principal criterion)
Vein does not "wink" when gently compressed in cross-section
Failure to appose walls of vein due to passive distention
Direct Visualization of Thrombus
Homogeneous
Low echogenicity
Abnormal Doppler Flow Dynamics
Normal response: calf compression augments Doppler flow signal and confirms vein
patency proximal and distal to Doppler
Abnormal response: flow blunted rather than augmented with calf compression
Warfarin dosing in pulmonary embolism:
CYP2C9 variant alleles impair the hydroxylation of S-warfarin, thereby lowering the dose
requirement. Variants in the gene encoding the vitamin K epoxide reductase complex 1 (VKORC1)
can predict whether patients require low, moderate, or high warfarin doses.
NOVEL ANTICOAGULANTS:
Rivaroxaban, a factor Xa inhibitor, and dabigatran, a direct thrombin inhibitor, are approved in
Canada and Europe for prevention of VTE after total hip and total knee replacement. In a large-scale
trial of acute VTE treatment, dabigatran was as effective as warfarin and had less nonmajor
bleeding. Because of these drugs' rapid onset of action and relatively short half-life compared with
warfarin, "bridging" with a parenteral anticoagulant is not required.
DISEASE-SPECIFIC GUIDELINES FOR REFERRAL AND TRANSPLANTATIONTable 266-1 Disease-Specific Guidelines for Referral and Transplantation
Chronic Obstructive Pulmonary Disease
Referral
BODE index >5
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Transplantation
BODE index 7–10
or
any of the following criteria:
Hospitalization for exacerbation, with PaCO2 >50 mmHg
Pulmonary hypertension or cor pulmonale despite oxygen therapy
FEV1<20% with either DLCO <20% or diffuse emphysema
Cystic Fibrosis/Bronchiectasis
Referral
FEV1<30% or rapidly declining FEV1
Hospitalization in ICU for exacerbation
Increasing frequency of exacerbations
Refractory or recurrent pneumothorax
Recurrent hemoptysis not controlled by bronchial artery embolization
Transplantation
Oxygen-dependent respiratory failure
Hypercapnia
Pulmonary hypertension
Idiopathic Pulmonary Fibrosis
Referral
Pathologic or radiographic evidence of UIP regardless of vital capacity
Transplantation
Pathologic or radiographic evidence of UIP
and
any of the following criteria
DLCO <39%
Decrement in FVC
10% during 6 months of follow-up
Decrease in SpO2 below 88% during a 6-min walk test
Honeycombing on HRCT (fibrosis score >2)
Idiopathic Pulmonary Arterial Hypertension
Referral
NYHA functional class III or IV regardless of therapy
Rapidly progressive disease
Transplantation
Failing therapy with intravenous epoprostenol (or equivalent drug)
Persistent NYHA functional class III or IV on maximal medical therapy
Low (<350 m) or declining 6-min walk test
Cardiac index <2 L/min/m2
Right atrial pressure >15 mmHg
Abbreviations: BODE, body-mass index (B), airflow obstruction (O), dyspnea (D), exercise
capacity (E); FVC, forced vital capacity; FEV1, forced expiratory volume in 1 s; DLCO,
diffusing capacity for carbon monoxide; PaCO2, partial pressure of carbon dioxide in arterial
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blood; SpO2, arterial oxygen saturation by pulse oximetry; ICU, intensive care unit; UIP,
usual interstitial pneumonitis; HRCT, high-resolution computed tomography; NYHA, New
York Heart Association.
Source: Summarized from Orens et al. For BODE index, BR Celli et al: N Engl J Med
350:1005, 2004.
Dear students,
Since it is already December, keep revising the same material again & again.
Go via the updates quickly. Don’t take very long time for going via the
updates.
ALL THE BEST WISHES.
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