Updates 18th Edition Final

UPDATES IN HARRISON 18TH EDITIONUPDATES IN NEPHROLOGY

Table 277-1 Inherited Disorders Affecting Renal Tubular Ion and Solute Transport

Disease or Syndrome Gene OMIM*

Disorders Involving the Proximal Tubule

Proximal renal tubular acidosis Sodium bicarbonate cotransporter

(SLC4A4, 4q21)

604278

Fanconi-Bickel syndrome Glucose transporter, GLUT2

(SLC2A2, 3q26.2)

227810

Isolated renal glycosuria Sodium glucose cotransporter

(SLC5A2, 16p11.2)

233100

Cystinuria

Type I Cystine, dibasic and neutral amino acid transporter

(SLC3A1, 2p16.3)

220100

Nontype I Amino acid transporter, light subunit

(SLC7A9, 19q13.1)

600918

Lysinuric protein intolerance Amino acid transporter (SLC7A7, 4q11.2)

222700

Hartnup disorder Neutral amino acid transporter

(SLC6A19, 5p15.33)

34500

Hereditary hypophosphatemic rickets with hypercalcemia

Sodium phosphate cotransporter

(SLC34A3, 9q34)

241530

Renal hypouricemia

Type 1 Urate-anion exchanger

(SLC22A12, 11q13)

220150

Type 2 Urate transporter, GLUT9

(SLC2A9, 4p16.1)

612076

SPEED 1


Dent's disease Chloride channel, ClC-5

(CLCN5, Xp11.22)

300009

X-linked recessive nephrolithiasis with renal failure

Chloride channel, ClC-5

(CLCN5, Xp11.22)

310468

X-linked recessive hypophosphatemic rickets Chloride channel, ClC-5

(CLCN5, Xp11.22)

307800

Disorders Involving the Loop of Henle

Bartter's syndrome

Type 1 Sodium, potassium chloride cotransporter

(SLC12A1, 15q21.1)

241200

Type 2 Potassium channel, ROMK

(KCNJ1, 11q24)

601678

Type 3 Chloride channel, ClC-Kb

(CLCNKB, 1p36)

602023

with sensorineural deafness Chloride channel accessory subunit, Barttin

(BSND, 1p31)

602522

Autosomal dominant hypocalcemia with Bartter-like syndrome

Calcium-sensing receptor

(CASR, 3q13.33))

601199

Familial hypocalciuric hypercalcemia Calcium-sensing receptor

(CASR, 3q13.33)

145980

Primary hypomagnesemia Claudin-16 or paracellin-1

(CLDN16 or PCLN1, 3q27)

248250

Isolated renal magnesium loss Sodium potassium ATPase, 1-subunit

(ATP1G1, 11q23)

154020

Disorders Involving the Distal Tubule and Collecting Duct

Gitelman's syndrome Sodium chloride cotransporter

(SLC12A3, 16q13)

263800

Primary hypomagnesemia with secondary hypocalcemia

Melastatin-related transient receptor potential cation channel 6

(TRPM6, 9q22)

602014

SPEED 2


Pseudoaldosteronism (Liddle's syndrome) Epithelial sodium channel and subunits

(SCNN1B, SCNN1G, 16p12.1)

177200

Recessive pseudohypoaldosteronism Type 1 Epithelial sodium channel, , , and subunits

(SCNN1A, 12p13; SCNN1B, SCNN1G, 16pp12.1)

264350

Pseudohypoaldosteronism Type 2 (Gordon's hyperkalemia-hypertension syndrome)

Kinases WNK-1, WNK-4

(WNK1, 12p13; WNK4, 17q21.31)

145260

X-linked nephrogenic diabetes insipidus Vasopressin V2 receptor (AVPR2, Xq28)

304800

Nephrogenic diabetes insipidus (autosomal) Water channel, aquaporin-2

(AQP2, 12q13)

125800

Distal renal tubular acidosis

autosomal dominant Anion exchanger-1

(SLC4A1, 17q21.31)

179800

autosomal recessive Anion exchanger-1

(SLC4A1, 17q21.31)

602722

with neural deafness Proton ATPase, 1 subunit

(ATP6V1B1, 2p13.3)

192132

with normal hearing Proton ATPase, 116-kD subunit

(ATP6V0A4, 7q34)

602722

*Online Mendelian Inheritance in Man database (http://www.ncbi.nlm.nih.gov/Omim).

Table 279-2 Biomarkers of Acute Kidney Injury

SPEED 3

Biomarker Comments Detection Species

Alanine aminopeptidase (AAP)

1. Proximal tubule brush border enzyme

2. Instability may limit clinical utility

Colorimetry Rat, dog, human

Alkaline phosphatase (AP)

1. Proximal tubule brush border enzyme. Human intestinal alkaline phosphatase is specific for proximal tubular S3 segment; human tissue nonspecific alkaline phosphatase is specific for S1 and S2 segments

2. Levels may not correlate with extent of functional injury

3. Instability may limit clinical utility

Colorimetry Rat, human

Alpha -Glutathione-S-transferase (alpha-GST)

1. Proximal tubule cytosolic enzyme

2. Requires stabilization buffer for specimen storage and processing

3. Upregulated in AKI and renal cell carcinoma

ELISA Mouse, rat, human

Gamma -Glutamyl transpeptidase ( gamma GT)

1. Proximal tubule brush border enzyme

2. Instability requires samples to be analyzed quickly after collection, limiting clinical utility

Colorimetry Rat, human

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.)

Colorimetry Mouse, rat, human

SPEED 4


4. Endogenous urea may inhibit activity

Beta 2-Microglobulin

1. Light chain of the MHC I molecule expressed on the cell surface of all nucleated cells

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

ELISA

Nephelometry

Mouse, rat, human

Alpha 1-Microglobulin

1. Synthesized by the liver

2. Filtered by the glomerulus and reabsorbed by proximal tubule cells

3. Early marker of tubular dysfunction; high levels may predict poorer outcome

4. Stable across physiologic urinary pH

ELISA

Nephelometry

Mouse, rat, human

Retinol-binding protein

1. Synthesized by liver, involved in vitamin A transport

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 2-microglobulin

ELISA

Nephelometry

Mouse, rat, human

Cystatin C 1. Important extracellular inhibitor of cysteineproteases

2. Filtered by the glomerulus and reabsorbed by proximal tubule

ELISA

Nephelometry

Mouse, rat, human

SPEED 5


cells

3. Elevated urinary levels reflect tubular dysfunction; high levels may predict poorer outcome

Microalbumin 1. Established marker for monitoring progression of chronic kidney disease

2. Elevated urinary levels may be indicative of proximal tubular damage

3. Lack of specificity for AKI may limit its utility

ELISA

Immunoturbidimetry

Mouse, rat, dog, monkey, human

Kidney injury molecule-1 (KIM-1)

1. Type-1 cell membrane glycoprotein upregulated in dedifferentiated proximal tubule epithelial cells

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

ELISA, Luminex®-based assay

Zebrafish, mouse, rat, dog, monkey, human

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

ELISA Mouse, rat, dog, monkey, human

SPEED 6


4. No clinical study demonstrating its use

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

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

ELISA

Luminex®-based assay

Mouse, rat, human

Interleukin-18 (IL-18)

1. Cytokine with broad immunomodulatory properties, particularly in setting of ischemic injury

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

ELISA

Luminex®-based assay

Mouse, rat, human

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

2. Urinary levels decrease rapidly in spite of progression of injury indicating stability issue


Western blot Mouse, rat, human

SPEED 7


4. No quantitative method established

Osteopontin 1. Upregulated in various rodent models of AKI

2. The induction correlates with inflammation and tubulointerstitial fibrosis


ELISA Mouse, rat, monkey, human

Liver fatty acid–binding protein (L-FABP)

1. Expressed in proximal tubule epithelial cells

2. Current evidence suggests clinical utility as a biomarker in CKD and diabetic nephropathy

3. Additional studies necessary to determine utility in setting of preclinical and clinical AKI

ELISA Mouse, rat, human

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

Immunoblotting Mouse, rat, human

Exosomal fetuin-A 1. Acute phase protein synthesized in the liver and secreted into the circulation2. Levels in proximal tubule cell cytoplasm correspond to degree of injury3. Urinary levels found to be much higher in ICU patients with AKI compared to ICU patients without AKI and healthy volunteers4. Samples require considerable processing, limiting assay throughput5. Additional studies necessary to determine utility in setting of

Immunoblotting Rat, human

SPEED 8


preclinical and clinical AKIAbbreviations: AKI, acute kidney injury; ELISA, enzyme-linked immunosorbent assay; ICU, intensive care unit; RCC, renal cell carcinoma.

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 patientaKidneys 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.

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

SPEED 9

Peritransplant (<1 month)

Wound infections

Herpesvirus

Oral candidiasis

Urinary tract infection

Early (1–6 months)

Pneumocystis carinii

Cytomegalovirus

Legionella Listeria

Hepatitis B

Hepatitis C

Late (>6 months)

Aspergillus Nocardia

BK virus (polyoma)

Herpes zoster

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:

SPEED 10

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.

SPEED 11

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 renovascularhypertension

Multiple limitations in patients with advanced atherosclerosis or creatinine >;2.0

mg/dL (177 mol/L)

Nuclear imaging with technetium mertiatide or technetium-labeled pentetic acid (DTPA) to estimate fractional flow to each kidney

Estimates fractional flow to each kidney

Allows calculation of single-kidney glomerular filtration rate

Results may be influenced by other conditions, e.g., obstructive uropathy

Vascular Studies to Evaluate the Renal Arteries

Duplex ultrasonography

Shows the renal arteries and measures flow velocity as a means of assessing the severity of stenosis

Inexpensive; widely available Heavily dependent on operator's experience; less useful than invasive angiography for the diagnosis of fibromuscular dysplasia and abnormalities in accessory renal arteries

Magnetic resonance angiography

Shows the renal arteries and perirenal aorta

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 renal arteries and perirenal aorta

Provides excellent images; stents do not cause artifacts

Expensive, moderate volume of contrast required, potentially nephrotoxic

Intra-arterial Shows Considered "gold standard" for Expensive,

SPEED 12

angiography location and severity of vascular lesion

diagnosis of large vessel disease, usually performed simultaneous with planned intervention

associated hazard of atheroemboli, contrast toxicity, procedure-related 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)

SPEED 13

Abbreviations: ACE, angiotensin-converting enzyme; ARBs, angiotensin receptor blockers; GFR, glomerular filtration rate.

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

SPEED 14

International Working Group Blood and Marrow Transplant Clinical Trials Network Toxicity Committee

A sudden and persistent increase in LDH Negative direct and indirect Coombs test

Decrease in hemoglobin or increased RBC transfusion requirement

Concurrent renal and/or neurologic dysfunction 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

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.

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

SPEED 15

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

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

SPEED 16

Manifestation %

Hematologic Manifestations

Thrombocytopenia 30

Autoimmune hemolytic anemia 10Source: Adapted from R Cervera et al.

3. KNOW THE LATEST CRITERIA FOR RHEUMATOID ARTHRITIS

NEW 2010 ACR-EULAR CRITERIA

Table 321-1 Classification Criteria for Rheumatoid Arthritis

Score

Joint involvement 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

Serology Negative RF and negative ACPA 0

Low-positive RF or low-positive anti-CCP antibodies ( 3 times ULN)

2

High-positive RF or high-positive anti-CCP antibodies (>3 times ULN)

3

Acute-phase reactants

Normal CRP and normal ESR 0

Abnormal CRP or abnormal ESR 1

Duration of symptoms

<6 weeks 0

6 weeks

1

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.

SPEED 17

Source: Neogi et al: Arthritis Rheum 62:2569, 2010.

LATEST TNF ALPHA INHIBITORS:

Drug Dosage Serious Toxicities

Other Common Side Effects

Initial Evaluation Monitoring

Adalimumab: 40 mg SQ every other week

Risk of bacterial, fungal infections

Reactivation of latent TB

Lymphoma risk (controversial)

Drug-induced lupus

Neurologic deficits

PPD skin test Monitor for injection site reactions

Golimumab: 50 mg SQ monthly

PPD skin test Monitor for injection site reactions

SPEED 18

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 1

Swollen joint count 1

C-reactive protein 1 mg/dL

Patient global assessment 1 (on a 0–10 scale)ORAt any time point, patient must have a Simplified Disease Activity Index score of less than 3.3Source: Adapted from Felson et al.

SPONDYLOARTHROPATHIES

ASAS CRITERIA FOR CLASSIFICATION OF AXIAL SPONDYLOARTHRITIS. New York criteria is no longer used at present.

SPEED 19

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

and/or--Definite radiographic sacroiliitis according to modified New York criteriac

Inflammatory back paind

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

aSensitivity 83%, specificity 84%. The imaging arm (sacroiliitis) alone has a sensitivity of 66% and a specificity of 97%.

bBone marrow edema and/or osteitis on short tau inversion recovery (STIR) or gadolinium-enhanced T1 image.

cBilateral grade =2 or unilateral grade 3 or 4.

d See text for criteria.

ePast or present, diagnosed by a physician.

f Past or present pain or tenderness on examination at calcaneus insertion of Achilles tendon

SPEED 20

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, C-reactive protein; NSAIDs, nonsteroidal anti-inflammatorydrugs; SpA, spondyloarthritis.

Source: From M Rudwaleit et al: Ann Rheum Dis 68:777, 2009. Copyright 2009, with 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 footaSpecificity of 99% and sensitivity of 91%.

bCurrent 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.

SPEED 21

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.

SPEED 22

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

aRandom 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 cotransporter 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.

SPEED 23

The bile acid–binding resin colesevelam has been approved for the treatment of type 2 diabetes (already approved for treatment of hypercholesterolemia).

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).

CARDIOLOGYKNOW 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)

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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

aGamma-2 regulatory subunit of the AMP-activated protein kinase important for glucose metabolism.

Drug Class Examples Usual Total Daily Dose* (Dosing Frequency/Day)

Other Indications

Contraindications/Cautions

Renin inhibitors

Aliskiren 150–300 mg (1) Diabetic nephropathy

Pregnancy

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

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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 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

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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 TRANSPLANTATION-

Table 266-1 Disease-Specific Guidelines for Referral and Transplantation

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Chronic Obstructive Pulmonary Disease

Referral

BODE index >5

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

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Right atrial pressure >15 mmHgAbbreviations: 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 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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