อายุรศาสตร์โรคไต

Transcription

อายุรศาสตร์โรคไต

อายุรศาสตร์โรคไต
Nephrology
GLOMERULAR
DISEASES
APPROACH TO THE
PATIENTS WITH
SUSPECTED OF
GLOMERULAR DISEASES
2
Clinical presentations of
glomerular diseases
Differentiate between glomerular syndromes
• Nephritic syndrome versus nephrotic syndrome
• Proteinuria: varying in degree
of proteinuria, more specific in
proteinuria > 2 g/day
Nephritic syndrome
• Glomerular hematuria
• Decreased GFR: oliguria,
anuria, uremic symptoms
• Salt and water retention:
edema, hypertension
Decreased of GFR: edema, oliguria,
hypertension, azotemia
Active urine sediments: dysmorphic RBC, RBC
cast
Subnephrotic-ranged proteinuria
Nephrotic-ranged proteinuria
Hyperlipidemia
Nephrotic syndrome Hypoalbuminemia
Edema
Lipiduria: oval fat body, fatty cast
• Asymptomatic versus symptomatic
• Define onset of disease: history of urine volume and characters
change, nocturia, edema, broad cast in urine (subacute to chronic onset), ultrasound kidney
‣ Acute onset: days to week
‣ Subacute onset: weeks to month
‣ Chronic onset: ≥ 3 months
3
Isomorphic RBC from light microscope
Broad cast
4
Classify glomerular syndromes
Evaluation of secondary causes of glomerular disease
• Predict pathological findings by clinical manifestations
• Asymptomatic urinary abnormalities
‣ Asymptomatic proteinuria
Nephrotic
features
Nephritic
features
Minimal change disease (MCD)
++++
-
Membranous nephropathy (MN)
++++
+
Focal segmental glomerulosclerosis (FSGS)
+++
++
Fibrillary glomerulonephritis
+++
++
Mesangioproliferative glomerulonephritis
++
++
Membranoproliferative glomerunephritis
(MPGN)
++
+++
Proliferative glomerulonephritis
++
+++
Acute diffuse proliferative glomerulonephritis
+
++++
Crescentic glomerulonephritis
+
++++
‣ Asymptomatic hematuria
• Nephrotic syndrome
• Acute glomerulonephritis
(AGN): acute onset
• Rapidly progressive glomerulonephritis (RPGN): subacute
onset
• Chronic glomerunephritis
(CGN): chronic onset • Evaluation of secondary causes according to predicted pathological
findings
5
Renal biopsy
• Indication
‣ Significant proteinuria: urine protein > 1 g/day
(or equivalent)
‣ Glomerular hematuria
‣ Unexplained renal impairment
‣ Renal manifestation of systemic disease
• Contraindication
Absolute
contraindication
Relative
contraindication
• Complication: incidence 3-9% (majority are minor complication), <7% of bleeding required intervention, > 90% occurs in 24 hours
‣ Gross hematuria
‣ Perinephric hematoma
‣ Arteriovenous fistula
‣ Sepsis
Uncontrolled hypertension
Bleeding diathesis
Widespread cystic disease
Renal malignancy
Hydronephrosis
Uncooperative patient
Renal vein thrombosis
Single kidney
Antiplatelet or anticoagulant therapy
Anatomic abnormalities
Small kidneys
Active urinary or skin sepsis
Obesity
‣ Death: due to undiagnosed hematoma
0.2%
• Prepare the patients for treatment: evaluation of
occult infection (chest x-ray, dental examination, stool concentrate for parasite)
• Select the treatment regimen according to type
of glomerular disease
6
References
• Emmett M, Fenves AZ, and Schwartz JC. Approach to the patient with kidney disease. In: Taal MW, et al.
editor. Brenner & Rector’s The Kidney. 9th ed. Philadephia: Elsevier Saunders; 2012. p 844-867.
• Salama AD, and Cook HT. The renal biopsy. In: Taal MW, et al. editor. Brenner & Rector’s The Kidney. 9th
ed. Philadephia: Elsevier Saunders; 2012. P 1006-1016.
7
ASYMPTOMATIC
PROTEINURIA
8
DEFINITION
• Total protein excretion
‣ Normal
< 150 mg/day
‣ Proteinuria
≥ 150 mg/day
‣ Nephrotic-ranged proteinuria
mg/day
> 3,500
• Albumin excretion
‣ Normal
2 – 30 mg/day
‣ Microalbuminuria
30 – 300 mg/day
9
Pathogenesis and etiologies
• Overflow proteinuria
‣ Large amount of small molecular weight protein filter through normal glomerulus and exceeds the capacity of normal tubular cells for
complete reabsorption
‣ Causes: monoclonal gammopthies (e.g. multiple myeloma), intravascular hemolysis (hemoglobinuria), rhabdomyolysis (myoglobinuria)
• Tubular proteinuria
‣ Tubular cells injury results in increase secretion of Tamm-Horsfall protein, increase secretion of other brush border components, and
decrease reabsorption of small molecular
weight protein in urine
- Infections: pyeolonephritis, tuberculosis
- Metabolic: DM, hyperuricemia, uricosuria, hypercalcemia, hypercalciuria, hypokalemia, oxalosis, cystinosis
- Immunologic: SjÖgrens’s syndrome, renal transplant rejection, drug hypersensitivity, sarcoidosis
- Toxic: analgesic abuse, radiation nephritis, lithium, heavy metals (lead, cadmium, mercury), Balkan nephropathy, cyclosporine, cisplatin, aminoglycoside
- Anatomic: obstruction, ureterovesical reflux, medullary sponge kidney
- Miscellaneous: multiple myeloma, amyloidosis, sickle cell disease, medullary
sponge kidney
‣ Urine protein usually < 2 g/day
‣ Urine albumin : β2 microglobulin ratio 10:1
‣ Causes
- Hereditary: polycystic kidney disease,
medullary cystic disease
10
• Glomerular proteinuria
‣ Glomerular injuries result in loss charge- and/
or size-selectivity properties of glomerular
basement membrane, and subsequently abnormally increase in clearance of urine protein
‣ Urine protein usually < 2 g/day
‣ Urine albumin : β2 microglobulin ratio >
1,000:1
‣ Causes: primary and secondary glomerulonephritis and nephrotic syndrome (see in
“Etiologies of nephrotic syndrome”), hereditary nephritis (Alport’s syndrome, thin basement membrane disease)
• Benign orthostatic proteinuria
‣ Commonly found in tall adolescents
‣ Protenuria occurs only in the morning after
ambulation, but not in the nighttime
‣ Urine protein < 1 g/day, and no any abnormal
urine sediment
‣ Half of patients spontaneous recovery in 10
years, but small number progress to overt renal disease
‣ Functional and transient proteinuria
‣ Proteinuria which occurs associated with
non-renal cause and disappear after resolution of disease process
‣ Heart failure, fever, or heavy exercise
11
Approach to the patients with asymptomatic proteinuria
12
Indications for renal biopsy
• Urine protein > 2 g/day
• Urine protein < 2 g/day with any of the followings: microscopic hematuria, hypertension, low serum complement, or family history of hereditary nephritis
References
• Kashif W, et al. Proteinuria: How to evaluate an important finding. Cleve Clin J Med 2003;70:535-547.
• Adler SG and Kairley K. The patient with hematuria, proteinuria, or both, and abnormal findings on urinary microscopy. In: Schrier RW. editor. Manual of nephrology. 7th ed. Phiadephia: Lippincott Williams & Wilkins;
2009. P 122-139.
13
ASYMPTOMATIC
HEMATURIA
14
DEFINITION AND
ETIOLOGIES
• Bed rest
• Analgesics
• Hydration: to increase urine flow rate to 2 – 3 L/
day
• Avoid sports which at a risk of abdominal
trauma: such as rugby, boxing
15
APPROACH TO THE
PATIENTS WITH
ASYMPTOMATIC
HEMATURIA
16
17
Indications for renal biopsy
• Impaired renal function
• Urine protein > 2 g/day
• Any of the followings: hypertension, low serum complement, or family history of hereditary nephritis
References
• Adler SG and Kairley K. The patient with hematuria, proteinuria, or both, and abnormal findings on urinary microscopy. In: Schrier RW. editor. Manual of nephrology. 7th ed. Phiadephia: Lippincott Williams & Wilkins;
2009. P 122-139.
• Emmett M, Fenves AZ, and Schwartz JC. Approach to the patient with kidney disease. In: Taal MW, et al. editor. Brenner & Rector’s The Kidney. 9th ed. Philadephia: Elsevier Saunders; 2012. p 844-867.
18
NEPHRITIC SYNDROMES
19
DEFINITION
• Inflammatory process occurred in glomeruli
20
ETIOLOGIES
21
Immune complex glomerulonephritis
• Lupus nephritis (LN)
• Post-infectious glomerulonephritis (PIGN)
• IgA nephropathy (IgAN) and Henoch-SchÖnlein
purpura (HSP)
• Subacute bacterial endocarditis
• Membranoproliferative glomerulonephritis
(MPGN)
• Cryoglobulinemia
Anti-glomerular basement membrane
Pauci-immune glomerulonephritis
• ANCA-associated glomerulonephritis
‣ Granulomatosis with polyangitis (GPA) or
Wegner’s granulomatosis
‣ Eosinophilic granulomatosis with polyangitis
(EGPA) or Churg-Strauss syndrome
‣ Microscopic polyangiitis (MPA)
‣ Renal limited pauci-immune glomerulonephritis
• Double positive disease
(GBM)
• Anti-GBM disease
• Goodpasture’s syndrome
22
CLASSIFICATION
• By onset of disease
‣ Acute glomerulonephritis (AGN)
‣ Rapidly progressive glomerulonephritis
(RPGN) or crescentic glomerulonephritis
‣ Chronic glomerulonephritis (CGN)
• By etiologies: see “Etiologies”
23
CLINICAL
MANIFESTATIONS
• Active urine sediment: dysmorphic RBCs, RBC
casts, and often WBCs and WBC casts
• Hematuria
‣ Sporadic, intermittent, or persistent hematuria
‣ Microscopic, or gross hematuria
• Reduced GFR
• Subnephrotic-ranged to nephrotic-ranged proteinuria
• Variable degree of hypertension, oliguria, and
edema
24
APPROACH TO THE
PATIENTS WITH NEPHRITIC
SYNDROME
• Differentiate onset of disease
‣ AGN: most common and prototype is postinfectious GN
‣ RPGN: can caused by any disease in all three
groups (immune complex GN, anti-GBM, and
pauci-immune GN)
‣ CGN: can result from any diseases that causes
nephritic or nephrotic syndrome
• Differential diagnosis by using data from history taking and physical examination
• (See “Approach to the patients suspected glomerular diseases”)
• Investigations: depend on the differential diagnosis
e.g. serum complement, ANA, ANCA, anti-GBM,
HBsAg, anti-HCV, and renal biopsy
25
References
26
NEPHROTIC SYNDROME
(NS)
27
DEFINITION
• Nephrotic-ranged proteinuria: urine protein
> 3 – 3.5 g/day or equivalent
• Hypoalbuminemia
• Edema
• Hperlipidemia
28
ETIOLOGIES
29
Secondary NS
• Infections: HBV, HCV, HIV, tuberculosis, infective
endocarditis, visceral abscess, shunt nephritis
Secondary causes of NS
MCD
Hodgkin’s lymphoma, NSAIDs
FSGS
HIV, nephron loss, familial, obesity,
hypertension, reflux nephropathy,
heroin, analgesic nephropathy
MN
HBV, HCV, solid tumors, Dpenicillamine, NSAIDs, gold, SLE,
non-Hodgkin’s lymphoma,
amyloidosis
MPGN
Chronic infection (infective
endocarditis, tuberculosis, HCV,
HBV, visceral abscess, shunt
nephritis), chronic inflammation
(rheumatoid arthritis, SLE), light
chain disease
• Autoimmune diseases: SLE, rheumatoid arthritis,
SjÖgren syndrome
• Medications: NSAIDs, gold, D-penicillamine, heroin
• Malignancies: hematologic malignancy (Hodgkon’s and non Hodgkin’s lymphoma, plasma cell
dyscrasia), solid tumors
• Metabolic abnormalities: DM, hypertension, obesity
• Miscellaneous diseases: reflux nephropathy, analgesic, nephron loss, amyloidosis
30
Primary NS
• Primary NS: diagnosis can be made after exclude secondary causes
‣ Minimal change disease (MCD)
‣ Focal segmental glomerulonephritis (FSGS)
‣ Membranous nephropathy (MN)
‣ Membranoproliferative glomerulonephritis (MPGN)
‣ IgM nephropathy (IgMN)
31
CLINICAL
MANIFESTATIONS
• Severity of diseases in primary NS are more severe than in secondary NS
32
Clinical manifestation of primary nephrotic syndrome
Age
Hypertension
Hematuria
Response to steroid
therapy
MCD
Very young
-
-
Good
FSGS
Young
1/3 of patients
2/3 of patients
1/3 response
MN
Aging
1/3 of patients
2/3 of patients
None, but 1/3 of patients
have spontaneous
remission
MPGN
Young
1/3 of patients
80% of patients
Poor
IgMN
Middle age
10% of patients
<5% of patients
80% response
33
References
34
COMMON
GLOMERULAR DISEASES
35
LUPUS NEPHRITIS
36
Epidemiology
• Incidence 1.8 – 7.6 cases / 100,000 people, prevalence 40 – 200 cases / 100,000 people
• Age of onset: peak 15 – 45 years, 85% are younger than 55 years
• Female:male ratio 10:1
• More than 60% of adults with SLE have renal involvement
• 50% of adults with SLE have renal involvement at presentation
• Same incidence of renal involvement in male and female
Pathogenesis
• Genetic, environmental, immunoregulatory, hormonal, and epigenetic factors contribute sequentially or simultaneously on the immune system result in loss of self-tolerance and generation of autoantibodies, immune complexes, autoreactive or inflammatory T cells and cytokines which damage to various organ, including kidneys.
37
Classification
International society of nephrology/renal pathology society (ISN/RPS) 2003 classification of LN
Class I
Minimal mesangial lupus nephritis
Normal glomeruli by light microscopy, but mesangial immune deposits by immunofluorescence
Class II
Mesangial proliferative lupus nephritis
Purely mesangial hypercellularity of any degree or mesangial matrix expansion by light
microscopy, with mesangial immune deposits
May be a few isolated subepithelial or subendothelial deposits visible by immunofluorescence or
electron microscopy, but not by light microscopy
Class III
Focal lupus nephritisa
Active or inactive focal, segmental or global endo- or extracapillary glomerulonephritis involving
<50% of all glomeruli, typically with focal subendothelial immune deposits, with or without
mesangial alterations
Active lesions: focal proliferative lupus nephritis
Class III (A)
Active and chronic lesions: focal proliferative and sclerosing lupus nephritis
Class III (A/C)
Chronic inactive lesions with glomerular scars: focal sclerosing lupus nephritis
Class III (C)
Class IV
Diffuse lupus nephritisb
Active or inactive diffuse, segmental or global endo- or extracapillary glomerulonephritis
involving >50% of all glomeruli, typically with diffuse subendothelial immune deposits, with or
without mesangial alterations. This class is divided into diffuse segmental(IV-S) lupus nephritis
when > 50% of the involved glomeruli have segmental lesions, and diffuse global (IV-G) lupus
nephritis when >50% of the involved glomeruli have golbal lesions. Segmental is defined as a
glomerular lesion that involves less than half of the glomerular tuft. This class includes cases
with diffuse wire loop deposits but with little or no glomerular proliferation
38
Class IV-S (A)
Class IV-G (A)
Class IV-S (A/C)
Class IV-S (C)
Class IV-G (C)
Class V
Class VI
Active lesions: diffuse segmental proliferative lupus nephritis
Active lesions: diffuse global proliferative lupus nephritis
Active and chronic lesions: diffuse segmental proliferative and sclerosing lupus nephritis
Active and chronic lesions: diffuse global proliferative and sclerosing lupus nephritis
Chronic inactive lesions with scars: diffuse segmental sclerosing lupus nephritis
Chronic inactive lesions with scars: diffuse global sclerosing lupus nephritis
Membranous lupus nephritis
Global or segmental subepithelial immune deposits or their morphologic sequelae by light
microscopy and by immunofluorescence or electron microscopy, with or without mesangial
alterations
Class V lupus nephritis may occur in combination with class III or IV in which case both will be
diagnosed
Class V lupus nephritis show advanced sclerosis
Advanced sclerosis lupus nephritis
>90% of glomeruli globally sclerosed without residual activity
aIndicate
the proportion of glomeruli with active and with sclerotic lesions.
bIndicate the proportion of glomeruli with fibrinoid necrosis and/or cellular crescents.
Indicate and grade (mild, moderate, severe) tubular atrophy, interstitial inflammation and fibrosis,
severity of arteriosclerosis or other vascular lesions.
39
Abbreviated international society of
nephrology/renal pathology society
(ISN/RPS) 2003 classification of LN
Class I
Minimal mesangial lupus nephritis
a
Class II
Mesangial proliferative lupus nephritis
Indicate the proportion of glomeruli with active and
with sclerotic lesions
b Indicate
Class III
Focal lupus nephritisa
the proportion of glomeruli with fibrinoid necrosis and cellular crescents
c Class
Class IV
Class V
Diffuse segmental (IV-S) or global (IV-G)
lupus nephritisb
Membranous lupus nephritisc
V may occur in combination with class III or IV
in which case both will be diagnosed
Indicate and grade (mild, moderate, severe) tubular atrophy, interstitial inflammation and fibrosis, severity of
arteriosclerosis or other vascular lesions
Class VI Advanced sclerosing lupus nephritis
40
Clinical manifestations
Class I
No clinical renal manifestation
Class II
Proteinuria: usually < 1 g/day,
no hematuria, normal blood pressure,
normal renal function
Class III
Hematuria,
subnephrotic-ranged proteinuria,
mild renal impairment,
mild hypertension
Class IV
Hematuria,
subnephrotic-ranged to nephrotic-ranged proteinuria, mild to severe renal
impairment,
mild to severe hypertension
Class V
Nephrotic syndrome,
no hematuria,
usually normal blood pressure, normal renal function
Class VI
Chronic kidney disease, depend of severity of disease
41
Investigations
• Low complement in class IV, but variable in
class V
• Extra-renal manifestations as in the criteria for diagnosis
Renal pathology
Light microscope
• see in classification
Immunofluoresence
• Immunofluoresence: positive staining in glomeruli, tubules, interstitium, and blood vessels
‣ Predominant IgG, with co-deposits of IgM and
IgA in most specimens
‣ Presence of fibrin, fibrinogen, C3 and C1q
staining are common
Electron microscope
• Class I and II: mesangial EDD
• Class III, IV and V: subendothelial and subepithelial EDD
• Tubulorecticular inclusions (TRIs): intracellular
branching tubular structures, 24 nm in diameter
located within dilated cisternae of the endoplasmic reticulum of glomerular nad vascular endothelial cells, can be found in patients with HIV infection, other viral infections, and who receive
INF-α
Diagnosis
• Definite diagnostic tool for LN is renal biopsy
• Presumptive diagnosis of LN can be done in the
patients with renal manifestations who meet the
criteria for diagnosis of SLE
‣ Full house staining: presence of IgG, IgM,
IgA, C3 and C1q staining, highly suggestive
of LN
42
Criteria for diagnosis SLE
•SLICC
‣ SLICC (systemic lupus international collaborating clinics) criteria (2012)
➡ Diagnosis can be made if
➡ Presence of at least 4 of the followings, including at least one clinical criterion and one
immunologic criterion, or
➡ Presence of biopsy-proven nephritis compatible with SLE, and presence of ANAs or antidsDNA antibodies
Clinical criteria
1. Acute cutaneous lupus, including:
• Lupus malar rash (do not count if malar
discoid)
• Bullous lupus
• Toxic epidermal necrolysis variant of SLE
• Maculopapular lupus rash
• Photosensitivity lupus rash
In the absence of dermatomyositis
OR
• subacute cutaneous lupus (nonindurated
psoriaform and/or annular polycyclic lesions
that resolve without scarring, although
occasionally with postinflammatory
dyspigmentation or telangiectasias)
2. Chronic cutaneous lupus, including:
• Classic discoid rash
‣ Localized (above the neck)
‣ Generalized (above and below the neck)
• Hypertrophic (verrucous) lupus
• Lupus panniculitis (profundus)
• Mucosal lupus
• Lupus erythematosus tumidus
• Chillblains lupus
• Discoid lupus/lichen plannus overlap
43
Clinical criteria
Clinical criteria
3. Oral ulcers
• Palate
‣ Buccal
‣ Tongue
OR
• Nalsal ulcers
• in the absence of other causes, such as
vasculitis, Behḉet’s disease, infection
(herpesvirus), inflammatory bowel disease,
reactive arthritis, and acidic foods
6. Serositis
• Typical pleurisy for more than 1 day OR pleural
effusion OR pleural rub
• Typical pericardial pain (pain with recumbency
improved by sitting forward) for more than 1
day OR pericardial effusion OR pericardial rub
OR pericarditis by EKG in the absence of other
causes, such as infection, uremia, and
Dressler’s pericarditis
4. Nonscarring alopecia (diffuse thinning or hair
fragility with visible broken hairs) in the absence of
other causes such as alopecia areata, drugs, iron
deficiency, and androgenic alopecia
7. Renal
Urine protein-to-creatinine ratio (or 24-hour urine
protein) representing 500 mg protein/24 horurs OR red
blood cell casts
5. Synovitis involving 2 or more joints, characterized by
swelling or effusion
OR tenderness in 2 or more joints and at least 30
minutes of morning stiffness
44
Clinical criteria
8. Neurologic
• Seizures
• Psychosis
• Mononeuritis multiplex
in the absence of other known causes such as
primary vasculitis
• Peripheral or cranial neuropathy
primary vasculitis, infection, and diabetes
mellitus
• Acute confusional state in the absence of other
causes, including toxic/metabolic, uremia,
drugs
9. Hemolytic anemia
Clinical criteria
10. Leukopemia (< 4,000/mm3 at least once)
in the absence of other known causes such as Felty’s
syndrome, drugs, and portal hypertension
OR
Lymphopenia (< 1,000/mm3 at least once)
corticosteroids, drugs, and infection
11. Thrombocytopenia (< 100,000/mm3 at least once)
in the absence of other known causes such as drugs,
portal hypertension, and thrombotic thrombocytopenic
purpura
45
Immunologic criteria
Immunologic criteria
1. Immunologic criteria
5. Low complement
• Low C3
• Low C4
• Low CH50
2. Anti-dsDNA antibody level above laboratory
reference range (or > 2-fold the reference range if
tested by ELISA)
3. Anti-Sm: presence of antibody to Sm nuclear
antigen
6. Direct Coombs’ test in the absence of hemolytic
anemia
4. Antiphospholipid antibody positivity as determined
by any of the following:
• Positive test result for lupus anticoagulant
• False-positive test result for rapid plasma
regain
• Medium- or high-titer anticardiolipin antibody
level (IgA, IgG, or IgM)
• Positive test result for anti-β2-glycoprotein I
(IgA, IgG, or IgM)
46
ACR (American college of rheumatology)
criteria (1997)
4 of the 11 criteria are needed for the diagnosis
Criterion
Definition
Malar rash
Fixed erythema, flat or raised,
over the malar eminences,
tending to spare the nasolabial
folds
Discoid rash
Erythematous raised patches with
adherent keratotic scaling and
follicular plugging; atrophic
scarring may occur in older
lesions
Skin rash as a result of unusual
Photosensitivity reaction to sunlight, by patient
history or physician observation
Oral ulcers
Oral or nasopharyngeal
ulceration, usually painless,
observed by physician
Nonerosive
arthritis
Involving 2 or more peripheral
joints, characterized by
tenderness, swelling, or effusion
Criterion
Definition
Pleuritis or
pericarditis
1. Pleuritis – convincing history of
pleuritic pain or rubbing heard by
physician or evidence of pleural
effusion, or
2. Pericarditis – documented by
EKG or rub or evidence of
pericardial effusion
Renal disorder
1. Persistent proteinuria > 0.5 g/
day or more than 3+ if quantitation
not performed, or
2. Cellular casts – may be red
cell, hemoglobin, granular,
tubular, or mixed
47
Criterion
Definition
Neurologic
disorder
1. Seizures – in the absence of
offending drugs or known
metabolic derangements; e.g.,
uremia, ketoacidosis, or
electrolyte imbalance, or
2. Psychosis – in the absence of
offending drugs or known
metabolic derangements, e.g.,
uremia, ketoacidosis, or
electrolyte imbalance
Hematologic
disorder
1. Hemolytic anemia – with
recticulocytosis, or
2. Leukepenia < 4,000/mm3 on ≥2
occasions, or
3. Lymphopenia <1,500/mm3 on
≥2 occasions, or
4. Thrombocytopenia <100,000/
mm3 in the absence of offending
drugs
Criterion
Definition
1. Anti-DNA: antibody to native DNA in
abnormal titer, or
2. Anti-Sm: presence of antibody to Sm
nuclear antigen, or
3. Positive finding of antiphospholipid
antibodies on:
3.1 an abnormal serum level of IgG
Immunologic
or IgM anticardiolipin antibodies,
disorder
3.2 a positive test result for lupus
anticoagulant using a standard method,
or
3.3 a false positive test result for at
least 6 months confirmed by Treponema
pallidum immobilization or fluorescent
treponemal antibody absorption test
Antinuclear
antibodies
An abnormal titer of antinuclear
antibody by immunofluoresence or an
equivalent assay at any point in time
and in the absence of drugs
48
Treatment
Specific treatment
• Specific treatment
• Class I: treat extrarenal manifestations
• Class II: treat extrarenal manifestations
‣ In case of proteinuria > 3 g/day, treat as MCD
• Class III and IV
‣ Initial therapy
- Calcineurin inhibitors (CNIs): alternative therapy for patients who intolerance to azathioprine or MMF
• Class V
‣ In case of persistent nephrotic-ranged proteinuria: corticosteroid plus cyclophosphamide, or
CNIs, or MMF, or azathioprine
• Class VI: treat extrarenal manifestations
• Hydroxychloroquine: maximum dosage 6 – 6.5
mg/kg/day, in all LN patients unless contraindicate
- Corticosteroid plus cyclophosphamide or
MMF
- In case of worsening LN during first 3
months of treatment, change to alternative
treatment, or repeat renal biopsy to guide the
treatment
‣ Maintenance therapy: continue after complete
remission for at least 1 year before tapering the
dosage
- Corticosteroid ≤ 10 mg/d plus azathioprine
1.5 -2.5 mg/kg/day or MMF 1 – 2 g/day
49
Other circumstances
• Relapse disease
‣ Resume the effective initial therapy, or
‣ High cumulative dosage of cyclophosphamide, change to non-cyclophosphamidebased regimen
‣ In case of antiphospholipid antibody syndrome (APS) involve kidney, treat the patients
with anticoagulants with target INR 2 – 3
‣ In case of thrombotic thrombocytopenic purpura (TTP), treat the patients with plasma exchange
• Pregnancy
‣ In case of possible histologic class of LN has
changed, repeat renal biopsy
‣ Delay pregnancy until achieve complete remission
‣ Evaluation for the precipitating factors: poor
drug compliance, infections, pregnancy, or
drugs (estrogen-containing oral contraceptive pills)
‣ Mode of contraception: condom
• Resistant disease
‣ Repeat renal biopsy to distinguish active disease from scarring
‣ In case of active disease, treat the patients
with alternative regimen
‣ In case of failed treatment ≥ 2 initial regimens, consider treatment with rituximab, or IV
immunoglobulin (IVIG), or CNIs
• SLE with thrombotic microangiopathy (TMA)
‣ Administration of low-dose aspirin during
pregnancy to decrease risk of fetal loss
‣ Do not use cyclophosphamide, MMF, ACEI
and ARB
‣ Switch MMF to azathioprine during the pregnancy
‣ In case of relapse disease during pregnancy,
treat the patients with corticosteroid and/or
azathioprine depend on disease severity
‣ In case of receiving corticosteroid and
azathioprine, continue same dosage for at
least 3 months after delivery
50
Side effect of treatment
• Corticosteroid
‣ Hyperglycemia, hypertension, hyperlipidemia, atherosclerosis, adrenal insufficiency
‣ Cushingoid appearance, abnormal hair
growth, weigt gain, growth retardation
‣ Peptic ulcer, pancreatitis
‣ Posterior subcapsular cataract, glaucoma
‣ Psychosis, sleeplessness, pseudotumor
cerebri
‣ Proximal muscle weakness, osteoporosis,
AVN
‣ Infections, panniculitis, spontaneous tendon rupture
‣ Birth defect: 1/1,000 of cleft lip/palate
‣ Increase risk of infertility if cumulative dosage ≥ 250 mg/kg (if BW 50 kg = 12.5 g)
‣ Hemorrhagic cystitis
• Azathioprine
‣ Bone marrow suppression
‣ Hepatitis
‣ DO NOT concomitantly use with allopurinol, unless severe bone marrow suppression
‣ Increase risk of malignancy if cumulative
dosage > 600 g
• MMF
‣ Bone marrow suppression
‣ GI side effect: nausea, vomiting, diarrhea
‣ Pneuonitis
• Cyclophosphamide
‣ Bone marrow suppression: nadir at 2
weeks
‣ Increase risk of malignancy if cumulative
dosage ≥ 36 g
51
Prognosis
• Progress to ESRD 5 - 50%
• Class I and II: excellent prognosis
• Class IV: least favorable prognosis
‣ Patient survival: 10 years – 100%, 20 years – 85%
‣ No doubling serum creatinine: 10 years – 85%, 20 years – 72%
• Class V: natural history is less clear
52
References
• Appel GB, Radhakrishnan J, and D’Agati VD. Secondary glomerular disease. In: Taal MW, et al. editor.
Brenner & Rector’s The Kidney. 9th ed. Philadephia: Elsevier Saunders; 2012. p 1192-1277.
• Weening JJ, et al. The classification of glomerunephritis in systemic lupus erythematosus revisited. J Am
Soc Neprhol 2004;15:241-250.
• Petri M, et al. Derivation and validation of the systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012;64:2677-2686.
• Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of
systemic lupus erythematosus [letter]. Arthritis Rheum 1997;40:1725.
• Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO Clinical
Practice Guideline for Glomerulonephritis. Kidney Inter., Suppl. 2012;2:139-274.
• Ponticell C. Glucocorticoids and immunomodulating agents. In: Ponticelli C, and Glassock RJ. Editor.
Treatment of Primary Glomerulonephritis. 2nd ed. New York: Oxford University Press Inc.; 2009. P 47-126.
53
POST-INFECTIOUS
GLOMERULONEPHRITIS
(PIGN)
54
Definition
• An immunologic response of the kidney that
occurs following a non-renal infection
Related terms
• Bright disease
• Streptococcus-related glomerulonephritis
• Post-streptococcal glomerulonephritis
Epidemiology
• Incidence and prevalence are lower
in developed countries
• Incidence 0.6 – 39.24 and prevalence 0.02 – 10.14 cases / 100,000
population
• Median age of onset 36 – 58 years
• High prevalence in DM, alcoholism
• 30 – 50% associated with gram negative bacilli infection
55
Pathogenesis
• Remains unknown, believed to be the deposition of
immune complex within glomerular tuft
• Nephritogenic antigens
‣ SpeB (Streptococcal cationic proteinase exotoxin
B) or NSAP (neprhitis-strain-associated protein) or
NPBP (nephritis plasmin-binding protein)
‣ GADPH (Streptococcal gluceraldehyde phosphate
dehydrogenase) or NAPIr (nephritis-associated
plasmin receptor)
The nephritogenic antigens are normally unable to penetrate
through the GBM because of having similar negative charge.
These antigens interact with plasmin and activate procollagenase
and matrix metalloproteinase (MMP) result in degradation and
reducing the negative charge of the GBM. These antigens and immune complexes are now able to pass through the GBM and deposit at subepithelial area to form hump-liked EDD result in foot
processes effacement and proteinuria.
56
Infections associated with PIGN
• Infectious syndromes
‣ Skin and throat infections (S. pyogenes, S.
equi, S. constellatus)
‣ Bacterial endocarditis (S. aureus, S. viridans)
‣ Pneumonia (S. pneumoniae, M. pneumoniae)
‣ Visceral abscesses (dental abscess, deepseated abscesses, osteomyelitis)
‣ Shunt nephritis (S. epidermidis, Propionivacterium)
• Specific bacterial diseases
‣ Gram positive bacteria: streptococci, staphylococci, pneumococci, enterococci, L. monocytogenes
• Fungal infections
‣ C. albicans, H. capsulatum, C. immitis
• Viruses
‣ DNA viruses: HBV, VZV, EBV, cytomegalovirus, parvovirus B19, adenovirus
‣ RNA viruses: HIV, coxsackievirus, echovirus,
HAV, dengue virus, HCV, mumps virus, measles virus, hantavirus, rotavirus
• Parasitic infections
‣ P. falciparum, P. malariae
‣ S. hematobium, S. mansoni
‣ T. gondii, W. bancrofti, T. spiralis, E. granulosus, E. histolytica
• Others
‣ Gram negative cocci: Meningococcus, N.
gonorrhea
‣ oTuberculosis and nontuberculous mycobacterium
‣ Gram negative coccobacilli: Hemophilus
‣ T. pallidum, L. interrogans, C. burnetii, M.
pneumonia, C. pneumoniae
‣ Gram negative bacilli: Salmonella Klebsiella,
Seratia, Yersinia, Proteus, Pseudomonas
‣ Others: Legionellosis, brucellosis, bartonellosis
57
• There are 3 major patterns of clinical manifestations
‣ Acute nephritc syndrome
- Prototype of PIGN
- Common after Streptococcal infection
- Some patients had anuria and
nephrotic-range proteinuria
‣ Rapidly progressive glomerulonephritis
- Rare
- Crescent formation in glomeruli
- Associated with aging, S. aureus, gram
negative bacilli, Mycoplasma and M. leprae infection
- Subclinical disease was 4 – 19 times
more common than classic PIGN
• Gross hematuria is possible
• Hypertension: 75% of patients
• Edema: 90% of patients
• Prior infection before onset of disease: pharyngitis 10 days (7 – 21 days), skin infection
14 – 21 days
• Site of infection: upper respiratory tract 0 –
67%, skin 6 – 28%, teeth and oral mucosa 0 –
23%, heart 0 – 20%, urinary tract 0 – 15%, osteomyelitis 0 – 10%
• Some different manifestations between age
group
- In case of crescent formation less than
50%, recovery of renal function are likely
‣ Subclinical glomerulonephritis
- Low-graded proteinuria (< 1 g/day),
pyuria, microscopic hematuria
58
GBM
Fibrocellular
Cresent
Parietal
Epithelial
Cell
Endothelial
Cell
Bowman
Capsule
Podocyte
Mesangial
Cell
Crescent formation
Bowman
Space
Normal glomerulus
59
Investigations
• Hematuria: 2/3 had microscopic hematuria, gross hematuria is possible
• Proteinuria: 80% had subnephrotic-ranged proteinuria, 20% had nephrotic-ranged proteinuria
Children
Adult
Elderly
Hematuria
97- 100%
86%
100%
Gross hematuria
30%
NA
NA
Proteinuria
47 – 80%
56 – 99%
92%
Nephrotic syndrome
4%
20 – 32%
20%
Renal failure
25 – 40%
38 – 51%
72 – 83%
Hypertension
50 – 60%
63 – 89%
81 – 86%
Heart failure
< 5%
46%
43%
• Declined GFR in 60% of patients age of 55 years or more
• Throat swab culture: can be found ¼ of group A Streptococci infected patients
• Transient RTA type 4
• Antibodies for detection of recent Streptococcal infection
60
‣ ASO (Anti-streptolysis O): found in 2/3 in patients with URI, and 1/3 in patients with impetigo
‣ Antideoxyribonuclease B (anti-DNaseB), antihyaluronidase (anti-Hase): associated with impetigo
‣ Antistreptokinase, anti-nicotinamide adenine dinucleotidase
‣ Streptozyme test combines several antistreptococcal antibody assays: screening test
• Low C3 and CH50, but normal C4 level
61
Renal pathology
Light microscope:
diffuse endocapillary prolifGarland
Starry sky
Mesangial
pattern
pattern
pattern
(Capillary
(diffuse
wall pattern) pattern)
eration, mesangial hypercellularity, PMN infiltration,
some had crescent formation
Immunofluoresence
• Positive IgG, C3 staining, occasionally IgM
and rare for IgA
• 3 patterns of staining which associated with
clinical manifestation patterns
Electron microscope:
Acute
nephritic
syndrome
X
RPGN
electron dense deposit
(EDD) at subepithelial area (subepithelial hump),
some had EDD at subendothelial and intramembranous area
Subclinical
GN
X
X
X
X
62
Treatment
• Specific treatment
‣ None for glomerulonephritis
‣ Treatment of underlying infectious diseases
‣ Steroid therapy is controversial
- RPGN and/or high percentage of crescent and severe interstitial lesion: short
course of high-dose intravenous steroid,
follows by 1 - 2 months with prednisolone
- In patients with S. aureus, Brucellosis
and Schistosomiasis infection, glomerulonephritis can progress in spite of eradicate of the organism. Treatment with corticosteroids or cytotoxic agents might
have a role in this circumstance.
• Supportive treatment
‣ BP control
‣ Restrict protein intake
‣ Correct electrolytes and acid-base disturbances
‣ RRT if indicated
Prognosis
• Resolve of clinical manifestations
‣ Edema and hypertension in 1 – 2 weeks:
occurs after dieresis
‣ Normal complement level in 8 weeks
‣ No hematuria and proteinuria in months to
year
• Complete remission: children almost 100%,
adults about 60%
• Hypertesion with urinary abnormalities 5 –
60%, CKD 0 – 49%, ESRD 4 – 34%
• Mortality 0 – 36%
• More unfavorable prognosis in aging patients
‣ Volume control: diuretic
‣ Restrict salt intake
63
References
• Nasr SH, Radhakrishnan J and D’Agati VD. Bacterial infection-related glomerulonephritis in adults. Kidney
Int 2013;83:792-803.
• Kanjanabuch T, Kittikowit W and Eiam-ong S. An update on acute postinfectious glomerulonephritis worldwide. Nat Rev Nephrol 2009;5:259-69.
• Ponticell C, and Moroni G. Acute post-infectious glomerulonephritis. In: Ponticelli C, and Glassock RJ. Editor. Treatment of Primary Glomerulonephritis. 2nd ed. New York: Oxford University Press Inc.; 2009. P 153178.
• Nachman PH, Jennete C, and Falk RJ. Primary glomerular disease. In: Taal MW, et al. editor. Brenner &
Rector’s The Kidney. 9th ed. Philadephia: Elsevier Saunders; 2012. p 1100-1191.
64
IgA NEPHROPATHY
(IgAN)
65
Definition
• Predominance of IgA deposits, either alone
or with IgG, IgM, or both in the glomerular mesangium
Epidemiology
• Most common primary glomerular disease
‣ Hit 3: Formation of pathogenic circulating immune complexes from autoantigen
(galactose-deficient IgA) and O-glycanspecific antibodies
‣ Hit 4: Deposition of pathogenic immune
complexes in the mesangium, activation
of mesangial cells, and induction of glomerular injury
• Occurs in all age groups
• Most common at age of 10 – 20 years, 80%
of patients are age of 16 – 35 years at the
time of biopsy
• More common in males than females: male /
female ratio 2:1 to 6:1
Pathogenesis
• Multi-hit mechanism
‣ Hit 1: Increased circulating galactosedeficient (at hinge region of heavy chain)
IgA1
‣ Hit 2: Production of anti-glycan antibodies that recognize galactose deficient
IgA1
66
Etiologies
• Primary IgAN
• Secondary IgAN: associate with
‣ Rheumatologic disorders: HenochSchÖnlein purpura, seronegative spondyloarthropathy, ankylosing spondylitis, Reiter’s syndrome, Berger’s disease
Classification
• Oxford classification: is a pathological classification using 4 scoring system
‣ M: mesangial score; ≤ 0.5 (M0) or > 0.5
(M1)
‣ E: Endocapillary hypercellularity; absent
(E0) or present (E1)
‣ Infections: HIV infection, toxoplasmosis,
leprosy
‣ S: segmental glomerulosclerosis; absent
(S0) or present (S1)
‣ GI disorders: liver disease, alcoholic cirrhosis, celiac disease, Crohn’s disease,
gluten-sensitive enteropathy
‣ T: Tubular atrophy; atrophy/interstitial fibrosis ≤25% (T0), 26 – 50% (T1) or
>50% (T2)
‣ Neoplasm: mycosis fungoides, lung cancer, mucin-secreting carcinoma
‣ Hematologic disorders: cyclic neurtopenia,
immunothrombocytopenia (ITP),
‣ Others: scleritis, Sicca syndrome, mastitis,
pulmonary hermosiderosis, dermatitis herpitiformis
• Familial IgAN
67
There are 4 patterns of clinical manifestations
• Asymptomatic hematuria and/or proteinuria:
50 – 61%
• Nephrotic syndrome : 0 – 13%, found in 2 patterns of renal pathology
‣ Mesangial IgA deposit with extensive foot
process effacement (coexisting IgAN and
MCD)
‣ Isolated microscopic hematuria 27 – 36%
- Hematuria: may presence or absence
‣ Microscopic hematuria with proteinuria 16
– 17%
- Good response to steroid as in MCD,
and excellent prognosis
• AKI or RPGN: 25 – 29%
‣ AKI: ATN
- Occured after gross hematuria, due to
obstruction of RBC casts or Hb degradation product toxicity
- Duration 5 – 7 days
- Could be spontaneous recovery to need
RRT
‣ RPGN or crescentic IgAN
- Turn to ESRD 50% and 80% at 1 and 5
years, respectively
- In case of there are cellular crescent >
10 – 20%, immunosuppressive may be
beneficial
‣ Mesangial expansion
- Microscopic hematuria
- Progress to CKD
• CKD or ESRD
Hematuria: could be asymptomatic hematuria to
gross hematuria
• 40 -50% had gross hematuria without dysuria, and tend to occur close to upper respiratory tract infection, so called “synpharyngitis” or “synpharyngitic nephritis”
• 30 – 40% had microscopic hematuria
• Intermittent macroscopic hematuria occurred
in 25% of patients
68
Proteinuria: could be asymptomatic proteinuria to
nephrotic-ranged proteinuria
• Most common: subnephrotic-ranged proteinuria
Edema, hypertension
Renal pathology
• Light microscope: focal or diffuse mesangial
matrix expansion and hypercellularity, focal
glomerular sclerosis
Azotemia: could be AKI, RPGN, CKD, ESRD
‣ Crescent formation may be found in severe
IgA nephropathy
Systemic symptoms: some had abdominal pain or
flank pain
‣ Some patients had endocapillary proliferation
Investigations
• UA: dysmorphic RBC, proteinuria
• Normal complement level
• Serum galactose-deficient IgA1 level, IgG
specific for galactose-deficient IgA, urine immune complex with galactose-deficient IgA1
• Immunofluoresence: positive stain dominant
IgA or codominant for IgA with IgG and IgM,
positive stain for C3, rare for C1q
• Electromicrocope: mesangial electron dense
deposit (EDD), minority subendothelial and/or
subepithelial EDD, foot process effacement
• IgA / C3 level > 4 – 4.5
69
Treatment
Specific treatment
• Corticosteroid therapy:
‣ Use in patients with GFR > 50 ml/min/1.73
m2 who had persistent proteinuria ≥ 1 g/day,
despite 3 – 6 months of optimized supportive
care
- Prednisolone: 6-month course
➡ 1.0 mg/kg/d x 2 months, then
➡ 0.8 mg/kg/d x 1 month, then
‣ Similar regimen to the treatment of ANCAassociated GN (see “ANCA-associated glomerulonephritis (ANCA-associated GN)”)
• Fish oil therapy
‣ Use in patients with GFR > 50 ml/min/1.73
m2 who had persistent proteinuria ≥ 1 g/day,
despite 3 – 6 months of optimized supportive
care
- Fish-oil supplement 6 g oral bid (1.87 g
of eicosapentaenoic acid and 1.36 g of
docosahexaenoic acid) x 2 years
• Mycophenolate mofetil (MMF), antiplatelet therapy, and tosillectomy: not recommend
➡ 0.2 mg/kg/d x 1 month, then off
‣ Use in patients with coexisting IgAN and
MCD
- Similar regimen to the treatment of MCD
(see “Minimal change disease (MCD)”)
• Cyclophosphamide and azathioprine therapy:
‣ Use in patients with crescentic IgAN (crescent > 50% of glomeruli) and RPGN
70
71
Supportive treatment
• Control BP: target BP depend on degree of
proteinuria
‣ Proteinuria < 1 g/day: < 130/80 mmHg
‣ Proteinuria > 1 g/day: < 125/75 mmHg
• ACEI and/or ARB therapy in patients with proteinuria ≥ 0.5 g/d, with up-titrating as far as
tolerated to achieve proteinuria < 1 g/day
• Avoid dihydropyridine calcium channel blockers if possible
• As in general CKD treatment (see “Chronic
kidney disease (CKD)”)
Prognosis
• Poor prognostic factors
‣ Clinical factors: severe proteinuria, hypertension, elevated serum creatinine, male,
absence of any history of recurrent macroscopic hematuria, older age at presentation, marked erythrocyturia
‣ Histologic factors: widespread global and/
or segmental glomerulosclerosis, marked
tubulointerstitial fibrosis, marked extracapillary proliferation, marked arteriolar hyalinosis, extension of IgA deposits into the walls
of peripheral capillary loops
• Serum creatinine
‣ 1.7 mg/dL
- Proteinuria <1 g/day: turn to ESRD
13.4% at 7 years
- Proteinuria ≥1 g/day: turn to ESRD
78.7% at 7 years
‣ > 3 mg/dL: all patients turn to ESRD, so
called “point of no return”
72
References
• Nachman PH, Jennete C, and Falk RJ. Primary glomerular disease. In: Taal MW, et al.
editor. Brenner & Rector’s The Kidney. 9th ed.
Philadephia: Elsevier Saunders; 2012. p
1100-1191.
• Wyatt RJ, and Julian BA. IgA nephropathy. N
Engl J Med 2013;368:2402-2414.
• Suzuki H, et al. The pathophysiology of IgA
nephropathy. J Am Soc Nephrol
2011;22:1795-1803.
• Kang SH, et al. The Oxford classification as a
predictor of prognosis in patients with IgA
nephropathy. Nephrol Dial Transplant
2011;0:1-7.
• Ishiguro C, et al. Serum IgA/C3 ratio may predict diagnosis and prognostic grading in patients with IgA nephropathy. Nephron
2002;91:755-758.
erulonephritis. Kidney Inter., Suppl.
2012;2:139-274.
• Floege J, and Eitner F. Current therapy for
IgA nephropathy. J Am Soc Nephrol
2011;22:1785-1794.
• Manno C, et al. Randomized controlled clinical trial of corticosteroid plus ACE-inhibitors
with long-term follow-up in proteinuric IgA
nephropathy. Nephrol Dial Transplant
2009;24:3694-3701.
• Donadio JV, et al. A controlled trial of fish oil
in IgA nephropathy. N Engl J Med
1994;331:1194-1199.
• D’Amico G. Natural history of idiopathic IgA
nephropathy and factors predictive of disease outcome. Semin Neprhol
2004;24:179-196.
• Kidney Disease: Improving Global Outcomes
(KDIGO) Glomerulonephritis Work Group.
KDIGO Clinical Practice Guideline for Glom-
73
ANCA-ASSOCIATED
GLOMERULONEPHRITIS
(ANCA-ASSOCIATED GN)
74
Definition
• Necrotizing vasculitis, with few or no immune
deposits, predominantly affecting small vessels (i.e., capillaries, venules, arterioles, and
small arteries), associated with myeloperoxidase (MPO) ANCA (anti-neutrophil cytoplasmic antibodies) or proteinase 3 (PR3) ANCA.
Not all patients have ANCA
Related terms
• Pauci-immune glomerulonephritis
Epidemiology
• Incidence 3.9 cases / 1,000,000 people
• Renal-limited ANCA-associated vasculitis 23
– 25%
• ANCA-negative pauci-immune GN 27 – 38%
75
Pathogenesis
• Anti-anti-complementary PR3
‣ The sense strand of PR3 gene encodes
sense PR3, and the anti-sense strand encodes complementary PR3 (cPR3).
‣ Subsequently, the immune system responses against cPR3 by developing anticPR3 antibody.
‣ The immune system, again, responses
against anti-cPR3 antibody and develops
anti-anti-cPR3, which is PR3-ANCA because the epitope of anti-cPR3 was resembled to sense PR3.
• ANCAs bind to endothelial cells and
membrane-bound PR3/MPO on neutrophils,
results in inflammation of vascular endothelial
cells, called vasculitis.
• Dysregulation of immune system result in further worsening inflammatory response.
76
77
Etiologies
• Genetics factors
‣ GPA: HLA-DPB1*0401, SERPINA1, PRTN3
‣ MPA: HLA-DQ
‣ Others: PTPN22, CTLA4
• Environment factors
‣ Air pollutants: silica
‣ Infection: S. aureus, E. coli
‣ Medications: propylthiouracil, cocaine
Classification
• 4 types of ANCA-associated vasculitis (AAV)
‣ Granulomatous with polyangiitis (GPA) or
Wegener’s granulomatosis
‣ Eosinophilic granulomatosis with polyangiitis (EGPA) or Churg-Strauss syndrome
‣ Renal limited AAV or idiopathic necrotizing crescentic GN or renal-limited pauciimmune GN
• Renal manifestations: RPGN
• Extra-renal manifestations: can be found in
others, not renal-limited ANCA-vasculitis
Criteria for diagnosis
At least 2 of the 4 criteria, as followings
• Nasal or oral inflammation (oral ulcers
or bloody nasal drainage)
Granulomatous
• Abnormal chest radiograph (nodules,
with
fixed infiltrates, cavities)
polyangiitis
• Urinary sediment (> 5 RBC/HPF or
(GPA) or
RBC casts)
Wegener’s
granulomatosis • Granulomatous inflammation on
biopsy (in wall of artery or arteriole,
perivascular, or extravascular)
Eosinophilic
granulomatosis
with
polyangiitis
(EGPA) or
Churg-Strauss
syndrome
At least 4 of the 6 criteria, as followings
• Asthma
• Eosinophilia >10%
• Neuropathy, mono or poly
• Pulmonary infiltrates, non-fixed
• Paranasal abnormality
• Extravascular eosinophils
78
Investigations
• Urinalysis: telescopic urine sediments (can
be found in other causes of RPGN) which
composed of
‣ Dysmorphic RBCs or RBC cast
‣ Oval fat bodies
‣ Broad casts
• Normal complement level
• P-ANCA (anti-MPO antibodies) and C-ANCA
(anti-PR3 antibodies): positive 62 – 73%
• HNE-ANCA (Human neutrophil elastaseANCA): associated with drug-induced AAV
• Anti-LAMP-2 antibody (anti-lysosomal membrane protein-2 antibody): controversial
79
Renal pathology
Treatment
Light microscope: crescent formation, fibrinoid necrosis, karryorhectic nuclei
• 2 phases of treatment
• EGPA: presence of eosinophils in interstitium,
tubule
• Unable to differentiate between GPA and
MPA
Immunofloresence: no staining, or minimal of IgG
or IgM
Electromicroscope: no EDD, or minimal EDD
‣ Initial treatment
๏ Cyclophosphamide
- Intravenous 15 mg/kg every 2 weeks for
two cycles the every 3 weeks till remission for 3 months, or
- Oral 2 mg/kg/day till remission, then 1.5
mg/kg/day for 3 months
Plus
prednisolone 1 mg/kg/day, and decrease
dosage to 10 mg/day
๏ Rituximab and corticosteroid: alternative
treatment in
- Patients without severe disease
- Contraindicated to cyclophosphamide
๏ Plasmapheresis: additional treatment in patients with
- Dialysis dependent
- Rapidly increasing serum creatinine
80
- Diffuse pulmonary hemorrhage
- Overlap with anti-GBM (glomerular
basement membrane) GN
๏ Discontinue cyclophosphamide therapy who
require dialysis after 3 months of treatment
and do not have extra-renal manifestation of
disease
‣ Maintenance therapy: in patients who achieved
remission, continue treatment for at least 18
months with prednisolone 10 mg/d with
๏ Azathioprine 1 – 2 mg/kg/day oral
๏ MMF up to 1 g po bid: alternative in patients
who
- Allergic to azathioprine
๏ Etanercept: not use
• Relapse disease
‣ In severe case, use similar regimen to initial
treatment
‣ In non-severe case, increasing dose, or reinstituting, or add other immunosuppressive drugs
• Resistant disease
‣ Addition of rituximab
‣ Immunoglobulin iv (IVIG) or plasmapheresis: alternative treatment
• Transplantation
• After complete extra-renal remission for 12
months, not including positive ANCA
- Intolerance to azathioprine
๏ Methotrexate 0.3 mg/kg/week, up to 25 mg/
week: alternative in patients who intolerance
to azathioprine and MMF, and have eGFR ≥
60 ml/min/1.73m2
๏ Trimethoprim-sulfamethoxazole: adjunctive
treatment in patients with upper respiratory
tract disease
81
Prognosis
• Histopathological classification of ANCAassociated GN
Class
• Renal survival (no development of ESRD) rate according to histopathological classification
Inclusion criteria
Class
Focal
≥ 50% normal glomeruli
Crescentic
≥ 50% glomeruli with cellular
crescents
Mixed
Sclerotic
< 50% normal, < 50% crescentic,
<50% globally sclerotic glomeruli
≥ 50% globally sclerotic glomeruli
1-year renal 5-year renal 7-year renal
survival
survival
survival
Focal
93%
93%
≈ 93%
Crescentic
84%
76%
≈ 70%
Mixed
69%
61%
≈ 50%
Sclerotic
50%
50%
25%
•
82
References
• Jennette JC, et al. 2012 Revised international Chapel Hill consensus conference nomenclature of vasculitides. Arthritis Rheum 2013;65:pp 1-11.
• Wilde B, et al. New pathophysiological insights and treatment of ANCA-associated vasculitis. Kidney Int
2011;79:599-612.
• Furuta S, and Jayne DRW. Antineutrophil cytoplasm antibody-associated vasculitis: recent developments.
Kidney Int 2013;84:224-249.
• Appel GB, Radhakrishnan J, and D’Agati VD. Secondary glomerular disease. In: Taal MW, et al. editor.
Brenner & Rector’s The Kidney. 9th ed. Philadephia: Elsevier Saunders; 2012. p 1192-1277.
• Leavitt RY, et al. The American college of the rheumatology 1990 criteria for the classification of Wegener’s granulomatosis. Arthritis Rheum 1990;33:1101-1107.
• Masi AT, et al. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss
syndrome (allergic granulomatosis and angiitis). Arthritis Rheum 1990;33:1094-1100.
• Kain R, et al. Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis. Nat Med
2008;14:1088-1096.
• Roth AJ, et al. Anti-LAMP-2 antibodies are not prevalent in patients with antineutrophil cytoplasmic autoantibody glomerulonephritis. J Am Soc Nephrol 2012;23:545-555.
• Kain R, et al. High prevalence of autoantibodies to hLAMP-2 in anti-neutrophil cytoplasmic antibodyassociated vasculitis. J Am Soc Nephrol 2012;23:556-566.
• Slot MC, et al. Occurrence of antineutrophil cytoplasmic antibodies and associated vasculitis in patients
with hyperthyroidism treated with antithyroid drugs: A long-term followup study. Arthritis Rheum
2005;53:108-113.
83
• Berden AE, et al. Histopathological classification of ANCA-associated glomerulonephritis. J Am Soc Nephrol 2010;21:1-9.
84
MINIMAL CHANGE
DISEASE
(MCD)
85
Related terms
• Lipoid nephrosis
• Minimal change glomerulopathy
Epidemiology
‣ Drugs: NSAIDs, gold, lithium, interferon,
ampicillin, rifampin, trimethadione, tiopronin
‣ Tumors: Hodgkin’s disease, lymphoma, leukemia, solid tumors
• 10 – 15% of primary glomerular syndrome in
adults
‣ Allergies: food, dust, bee stings, pollen,
poison ivy, poison oak, dermatitis herpitiformis
• 70 - 90% of nephrotic syndrome in children
under age of 10 year, and 50% of older children
‣ Others: SLE, following hematopoietic cell
transplantation
• Male : female ratio 2:1 – 3:1
Pathogenesis
• Remains unclear
• Most likely a consequence of abnormal regulation of T cells
Etiologies and classification
• Primary MCD
• Abrupt onset of nephrotic syndrome
• Hematuria is distinctive unusual
• Hypertension is uncommon, but can be
found in aging patient
• AKI can be found in adults with MCD, but the
true cause remains uncertain and probably
multifactorial
• Secondary MCD
‣ Infections: virus, parasite
86
Investigations
• Severe proteinuria
• 15% of patients have microscopic hematuria
• Serum albumin concentration is generally
less than 2 g/dL
• Renal function is usually preserved, but can
deteriorate in some adult patients
The diagrams show A) normal glomerular capillary loop and
Renal pathology
Light microscope: normal, or minimal focal segmental mesangial prominence
Immunofloresence: no staining, or low level of mesangial staining of IgM, or C3
Electromicroscope: podocyte foot process effacement, microvillous transformation
B) capillary loop in MCD. The latter shows epithelial (podocyte) foot process effacement (arrow),
and microvillous transformation.
87
Treatment
• Frequent relapse and steroid-dependent MCD
• Initial episode
‣ Corticosteroid:
๏ Prednisolone
- 1 mg/kg/day (maximum 80 mg/day),
or
- 2 mg/kg every other days (maximum
120 mg/day)
๏ Maintain high-dose of prednisolone for
- Minimum for 4 weeks, if achieve
complete remission
‣ Then, tapered slowly over 6
months
- Maximum for 16 weeks, if not
achieve complete remission
‣ Cyclophosphamide oral: in case of intolerate,
or contraindicate to corticosteroid
‣ Calcineurin inhibitor: in case of intolerate, or
contraindicate to corticosteroid
• Infrequent relapse disease: similar regimen to the
treatment of initial episode
‣ Cyclophosphamide 2 – 2.5 mg/kg/day oral
for 8 weeks
‣ Cyclosporine 3 – 5 mg/kg/day or tacrolimus
0.05 – 0.1 mg/kg/day oral for 1 – 2 years: in
patients who
๏ Relapse during cyclocphosphamide
therpy, or
๏ Wish to preserve their fertility
‣ MMF 500 – 1,000 mg twice daily for 1 – 2
years: in patients who intolerant to corticosteroid, cyclophosphamide, and calcineurin inhibitors (cyclosporine, or tacrolimus)
• Steroid-resistant MCD
‣ Re-evaluate other causes of nephrotic syndrome, especially FSGS
• Statin: not be used in initial episode of MCD
• ACEI or ARB: not be used in normotensive patients
Prognosis
• Good long-term prognosis
88
References
89
FOCAL SEGMENTAL
GLOMERULOSCLEROSIS
(FSGS)
90
Definition
• Histological pattern of glomerular injuries,
segmental obliteration of glomerular capillaries by extracellular matrix
Related terms
• Progressive lipoid nephrosis
• Focal glomerular scleroses
• Epidemiology
• Epidemiology Incidence 0.84 – 21 cases /
1,000,000 people
• 0 – 67% of primary glomerular diseases
causing ESRD in US
Pathogenesis
• Circulating permeability factors: alters the podocytes’ structure and increase proteinuria
‣ Serum soluble urokinase receptor (suPAR):
found 2/3 of patients with primary FSGS
‣ Cardiotrophin-like cytokine 1 (CLC-1)
‣ |Integrin-linked kinase (ILK)
Etiologies
Primary FSGS
Secondary FSGS
• Familial or genetic: mutation in specific genes
‣ Slit diaphragm protein: nephrin (NPHS1), podocin (NPHS2), CD2-associated protein
(CD2AP)
‣ Cell membrane-associated proteins: transient
receptor potential cation channel 6 (TRPC6),
protein tyrosine phosphatase receptor type O
(PTPRO), laminin-β2 (LAMB2), β4-integrin
(ITGB4), tetraspanin CD151 (CD151)
‣ Cytosolic or cytoskeletal proteins: α-actinin-4
(ACTN4), phospholipase Cε1 (PLCE1), my91
osin heavy chain 9 (MYH9), inverted formin 2
(INF2), myosin 1E (MYO1E)
‣ Nuclear proteins: wilms tumor 1 (WT1),
SMARCA-like protein (SMARCAL1)
‣ Mitochondrial components: tRNAleu (mtDNAA3243G), parahydroxybenzoatepolyprenyltransferase (COQ2), coenzyme
Q10 biosynthesis monooxygenase 6 (COQ6)
‣ Lysosomal protein: lysosomal integral membrane protein type 2 (SCARB2)
‣ Unknown cellular location: apolipoprotein L1
(APOL1)
• Viral-associated: HIV type 1, parvovirus B19, simian virus 40, cytomegalovirus, EBV
• Drug-induced: heroin, IFN-α, IFN-β, IFN-γ, lithium,
pamidronate, sirolimus, calcineurin-inhibitor nephrotoxicity, anabolic steroids
vanced renal disease with reduced functioning nephrons
‣ Initially normal renal mass: hypertension,
acute or chronic vaso-occlusive processes
(atheroembolization, thrombotic microangiopathy, renal artery stenosis), elevated bodymass index (obesity, increased lean body
mass [e.g. bodybuilding]), cyanotic heart disease, sickle cell anemia
Classification
• Not otherwise specified (NOS)
• Perihilar
• Cellular
• Tip
• Collapse
• Adaptive
‣ Reduced renal mass: oligomeganephronia,
very low birth weight, unilateral renal agenesis, renal dysplasia, reflux nephropathy, sequel to cortical necrosis, surgical renal ablation, renal allograft, aging kidney, any ad92
Histological variants of FSGS
Subtypes
Defining features
Associations
NOS
≥ 1 glomerulus with segmental increases
in matrix obliteraign the capillary lumina
There may be segmental glomerular
capillary wall collapse without overlying
podocyte hyperplasia
Exclude perihilar, cellular, tip, and
collapsing variants
Most common subtype
Primary or secondary
(including genetic forms and
other diverse secondary
causes)
Other variants can evolve
into FSGS (NOS) over time
May present with the
nephrotic syndrome or
subnephrotic-ranged
proteinuria
Common in adaptive FSGS
Predisposition for vascular
≥ 1 glomerulus with perihilar hyalinosis, pole is probably due to
with or without sclerosis
normally increased filtration
> 50% of glomeruli with segmental
pressures at the proximal
lesions must have perihilar sclerosis and/ afferent end of glomerular
or hyalinosis
capillary bed, which are
Exclude cellular, tip, and collapsing
heightened under conditions
variants
of compensatory demand
and vasodilatation of the
afferent arteriole
In adaptive FSGS,
patients are more likely
to present with
subnephrotic-ranged
proteinuria and normal
serum albumin level
Perihilar
Clinical features
93
Subtypes
Cellular
Tip
Defining features
Associations
≥ 1 glomerulus with segmental
endocapillary hypercellularity occluding Usually primary, but also
lumina, with or without foam cells and
seen in secondary FSGS
karyorrhexis
Least common variant
Exclude tip, and collapsing variants
≥ 1 segmental lesion involving the tip
domain (outer 25% of tuft next to origin of
proximal tubule)
The tubular pole must be indentified in
the defining lesion
The lesion must have either and
adhesion or confluence of podocytes
with parietal or tubular cells at the tubular
lumen or neck
The tip lesion may be cellular or sclerosis
Exclude collapsing, and perihilar variants
Clinical features
Usually present with
nephrotic syndrome
Usually presents with
Usually primary
abrupt onset of
Probably mediated by
nephrotic syndrome
physicl stresses on the
More common in white
paratubular segment owing
race
to the convergence of
Best prognosis, high
protein-rich filtrate on the
rate response to
tubular pole, causing shear
gllucocorticoid
stress and possible
Lowest risk of
prolapse
progression
94
Subtypes
Defining features
Associations
Primary or secondary to
Viruses: HIV-1, parvovirus
B19, simian virus 40, EBV,
CMV, hemophagocytic
syndrome
≥ 1 glomerulus with segmental or global
Drugs: pamidronate and
Collapsing collapse and overlying podocyte
interferon
hypertrophy and hyperplasia
Vaso-occlusive disease:
atheroemboli, calcineurin
inhibitor nephrotoxicity, and
chronic allograft
nephropathy
Clinical features
Most aggressive variant
Severe nephrotic
syndrome
More common in black
race
Worst prognosis, poor
response to
glucocorticoid
Rapid course tot renal
failure
95
• Depend on histopathological variants (see
“Histological variants of FSGS”)
Renal pathology
Adequate sampling: ≥ 25 glomeruli, and include
juxtamedullary glomeruli
‣ Proteinuria: subnephrotic-ranged proteinuria to nephrotic-ranged proteinuria
Light microscope: depend on histopathological
variants (see “Histological variants of FSGS”)
‣ Normal renal function to rapid declined of
renal function
Immunofloresence: IgM, C3, granular pattern
Investigations
Electromicroscope: tubulorecticular inclusion (TRI)
in HIV-associated nephropathy (HIVAN)
• Evaluation of the secondary causes
96
Treatment
• Corticosteroid: in primary nephrotic syndrome
‣ Prednisolone 1 mg/kg/day (maximum 80 mg) or 2 mg/kg/day every other days (maximum 120 mg)
๏ Duration of high-dose corticosteroid
- Minimum 4 weeks
- Maximum: up to 16 weeks, or as tolerated, or until complete remission, whichever earlier
๏ After complete remission, slowly tapered off in 6 months
• Calcineurin inhibitors (CNI): alternative for patients intolerance to, or contraindicated to high-dose corticosteroid
• Relapse disease: treat as relapse MCD
• Steroid-resistant FSGS
‣ Cyclosporine 3 -5 mg/mg/day bid for at least 4 – 6 months
๏ In case of partial or complete remission, continue cyclosporine treatment for at least 12 months, followed by slowly taper off
‣ Combination of MMF with high-dose dexamethasone, in patients who intolerate to cyclosporine
97
Prognosis
Variants
1-year renal survival
3-year renal survival
Tip
88%
76%
Perihilar
89%
75%
NOS
86%
65%
Cellular
83%
NA
Collapsing
74%
33%
Overall
86%
67%
98
References
• Wei C, et al. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat Med
2011;17:952-960.
• McCarthy ET, et al. Circulating permeability factors in idiopathic nephrotic syndrome and focal segmental
glomerulosclerosis. Clin J Am Soc Nephrol 2010;5:2115-2121.
• Hattori M, et al. Increase of integrin-linked kinase activity in cultured podocytes upon stimulation with
plasma form patients with recurrecnt FSGS. Am J transplant 2008;8:1550-1556.
• D’Agati, et al. Focal segmental glomerulosclerosis. N Engl J Med 2011;365:2398-2411.
• D’Agati, et al. Pathological classification of focal segmental glomerulosclerosis: a working proposal. Am J
Kidney Dis 2004;43:368-382.
• Thomas DB, et al. Clinical and pathological characteristics of focal segmental glomerulosclerosis pathologic variants. Kidney Int 2006;69:920-926.
99
MEMBRANOUS
NEPHROPATHY (MN)
100
Related terms
• Membranous glomerulopathy
Epidemiology
• 25% of nephrotic syndrome in adults, most
common
• Male : female ratio 2:1
Pathogenesis of primary MN
• Possible from circulating anti-M-type phospholipase A2 receptor (PLA2R) autoantibodies which most are IgG4 subclass
‣ Sensitivity 75%, and specificity 100%
• Primary MN
• Secondary MN
‣ Autoimmune disease: SLE, autoimmune
thyroiditis
‣ Infections: HBV, HCV, malaria
‣ Drugs: D-penicillamine, gold
‣ Malignancies: colon cancer, lung cancer,
prostate cancer
• Malignancy in MN
‣ 25% of patients have negative test on
anti-PLA2R, might be possibly caused
by unknown antigens
‣ In patients older than 60 years, MN associate with malignancy in 20 – 30% of patients
‣ PLA2R-Ag-Ab immune complexes deposit at subepithelial area, subsequently
complement pathway is activated, results in podocyte injuries and proteinuria
‣ Usually asymptomatic
‣ Median time from diagnosis of MN to diagnosis of cancer is 60 months
‣ Risk factors: older age, and smoking
‣ Remission of malignancy is associated
with reduction in proteinuria
101
Investigations
• Proteinuria: most nephrotic-ranged proteinuria, 10 – 20% subnephrotic-ranged proteinuria
• Microscopic hematuria: 1/3 of patients
• Hypertension: 2/3 of patients
Renal pathology
• Light microscope:
• Immunofloresence: positive staining of IgG
and C3 in granular pattern
• Electromicroscope: subepitheial immune complex deposits, podocyte foot process effacement, microvillous transformation
102
Pathological staging
• Stage I: small EDD at subepithelial area
• Stage II: projections of basement membrane material around the subepithelial deposits, appears as a
“spike formation”
• Stage III: new basement membrane material surrounds the EDD, appears as intramembranous EDD
• Stage IV: loss of EDD, results in irregular electro-lucent zones within irregularly thickened basement membrane
Stage I
Stage II
Stage III
Stage IV
103
Treatment of primary MN
• Evaluation for secondary causes of MN
• Immunosuppressive therapy should be started only in patients with NS with one of the followings
‣ Urine protein > 4 g/day, and remains over 50% of the baseline value, and does not progressive decline during antihypertensive and antiproteinuria therapy during an observation period of at least 6
months
‣ Presence of severe, disabling, or life-threatening symptoms related with NS
‣ Rising of serum creatinine ≥ 30% within 6 – 12 months from the time of diagnosis and eGFR > 25 – 30
ml/min/1.73 m2 and this change is not explained by superimposed complications
• Initial therapy
‣ 6-month course of alternating monthly cycles of
๏ Corticosteroids IV and oral
Plus
Alkylating agents oral
- Prefer cyclophosphamide rather than chlorambucil
๏ In case of unable to achieve complete remission after completion of this regimen, considered as
a treatment failure if
- Presence of deterioration of kidney function, severe, disabling, or potentially life-threatening
symptoms related to NS
- Unless, after conservative treatment for at least 6 months
104
- Repeat kidney biopsy if the patients have rapid deteriorate of kidney function (double of serum creatinine over 1 – 2 months) without massive proteinuria (> 15 g/day)
‣ Continuous daily (noncyclical) use of oral alkylating agents may also effective, but my be at a greater
risk of toxicity, particularly when administered for > 6 months
‣ Not use monotherapy regimen with neither corticosteroid nor MMF
• Alternative therapy
‣ Cyclosporine or tacrolimus for 6 months, if the patients are contraindicated, or choose to not use cyclical regimen
๏ Monitor drug level during the initial treatment, and whenever unexplained rising in serum creatinine > 20% during the treatment
๏ Gradually decrease the dosage of CNIs every 1 – 2 months to 50% of initial dosage, and continue for at least 12 months
๏ Discontinue, if unable to achieve complete or partial remission after 6 months of treatment
• Resistant to initial therapy
‣ Patients who resistant to cyclical regimen, should switch to CNI-based regimen
‣ Patients who resistant to CNI-based regimen, should switch to cyclical regimen
• Relapse disease
‣ Reinstitution of the same therapy that results in initial remission
๏ Cyclical regimen can be repeat only once
105
• Prophylactic anticoagulant (warfarin) should be considered in patients with MN and nephrotic syndrome
with serum albumin < 2.5 g/dL and additional risks for thrombosis
Prognosis
• Complete spontaneous remission: 25 - 50% at 5 years
• Progressive renal impairment: 30% at 8 years, and 62% in patients who had nephrotic-ranged proteinuria
at presentation
• Renal survival: 86% at 5 years, 65% at 10 years, and 59% at 15 years
• ESRD: 35% at 10 years
106
References
• Beck LH, and Salant DJ. Membranous nephropathy: recent travels and new road ahead. Kidney int
2010;77:765-770.
Practice Guideline for Glomerulonephritis. Kidney Inter., Suppl. 2012;2:139-274
107
ACUTE KIDNEY INJURY
(AKI)
DEFINITION
• Increase in serum creatinine ≥ 0.3 mg/
dL within 48 hours; or
• Increase in serum creatinine ≥ 1.5
times baseline, which is known or presumed to have occurred within the prior
7 days; or
• Urine volume < 0.5 ml/kg/hour for 6
hours
109
STAGING
Stage
Serum creatinine
Urine output
1
1.5 – 1.9 times baseline; or
≥ 0.3 mg/dL increase
< 0.5 ml/hg/hour for 6-12 hours
2
2.0 – 2.9 times baseline
< 0.5 ml/hg/hour for ≥ 12 hours
3
3.0 times baseline; or
Increase in serum creatinine to ≥4.0 mg/dL; or
Initiation or renal replacement therapy; or
In patients < 1 years, decrease in eGFR to
< 35 ml/min/1.73 m2
< 0.5 ml/hg/hour for ≥ 24 hours; or
Anuria for ≥ 12 hours
110
ETIOLOGIES
111
Pre-renal AKI
Pre-renal AKI: decreased renal blood flow
• Decrease intravascular fluid volume
‣ Renal loss: diuretic, renal salt wasting, primary adrenal insufficiency
‣ Extra-renal loss
- GI loss: vomiting, diarrhea, fistula, GI bleeding, NG suction
- Peritoneal cavity: ascites in cirrhosis, pancreatitis, peritonitis
- Insensible loss: burn, sweating
- Fluid leakage: hypoalbuminemia (serum albumin <2 g/dL), cirrhosis, nephrotic syndrome
- Others: external or occult bleeding, shock
• Heart failure
• Peripheral vasodilatation: sepsis, adrenal insufficiency, vasodilators, hypoxia, hypercarbia
• Obstruction of renal artery
‣ Mechanical obstruction: stenosis, thrombosis, emboli, surgery
‣ Vasculitis: Polyarteritis nodosa, Takayasu arteritis
‣ Vasoconstriction: sepsis, NSAIDs, hepatorenal syndrome
112
Intrinsic renal AKI
• Vascular causes: malignant hypertension, TTP,
HUS, DIC, sclerodermal renal crisis
• Glomerular causes (acute glomerulonephritis;
AGN): post-infectious glomerulonephritis, IgA
nephropathy
• Interstitial causes (acute interstitial nephritis; AIN)
‣ Drugs
- Common causes: penicillin, NSAIDs use
Post-renal AKI
• Occurs in
‣ Lower urinary tract obstruction
‣ Upper urinary tract obstruction: bilateral obstruction, unilateral obstruction in solitary
functioning kidney
• Nephrolithiasis, retroperitoneal fibrosis, CA bladder, CA cervix, neurogenic bladder, urethral stenosis, urethral stone, obstructed Foley catheter
- Uncommon causes: quinolone, leukemia, lymphoma, sarcoidosis
‣ Infections: various organisms
• Tubular causes (acute tubular necrosis; ATN)
‣ Ischemic ATN: prolong pre-renal AKI
‣ Nephrotoxic ATN: aminoglycosides, colistin,
vancomycin, NSAIDs, radiocontrast agents
‣ Intratubular obstruction: tumor lysis syndrome, cast nephropathy, rhabdomyolysis,
crystals (methotrexate, acyclovir, indinavir)
113
APPROACH TO THE
PATIENTS WITH AKI
114
Differentiate between AKI and progression of CKD
• Differentiate between AKI and progression of
CKD: onset of renal disease
‣ History of nocturia, history of intermittent
edema, change of urine volume
‣ Investigations: small size kidneys (< 9 cm in
length), anemia of renal disease
Using data from history taking and physical examination to determine the most
possible causes of AKI
• Using data from history taking and physical examination to determine the most possible causes of
AKI
‣ Pre-renal AKI: vomiting, diarrhea, bleeding,
diuretic, vasodilator use, underlying diseases
(nephrotic syndrome, cirrhosis), hypotension,
orthostatic hypotension, low JVP
- In patients with heart failure: orthopnea, PND,
chest pain, edema, high JVP
‣ Post-renal AKI: passing stone, underlying diseases (CA bladder, CA prostate, CA cervix, BPH,
neurogenic bladder), positive bimanual palpation
and/or full bladder
‣ Intrinsic AKI; vascular causes: severe hypertension, diarrhea, fever, alteration of consciousness,
underlying disease (scleroderma, atrial fibrillation,
hypercoagulable state)
‣ AGN: hematuria, history of infection (see Postinfectious glomerulonephritis (PIGN) and IgA nephropathy (IgAN), hypertension, edema, high JVP
‣ AIN: penicillin, NSAIDs, quinolone use, leukemia,
lymphoma, sarcoidosis, infection, arthralgia, rash
‣ ATN: prolong pre-renal AKI, red-brown urine (rhabdomyolysis), hematologic malignancy, aminoglycosides, colistin, vancomycin, NSAIDs, radiocontrast agents, methotrexate, acyclovir, indinavir
115
Urine examination
• Urinary indices to differentiate
between pre-renal AKI and intrinsic AKI
‣ AIN: presence of WBC in
urine, without bacteriuria,
eosinophiluria by Hansel
stain
‣ ATN: muddy brown cast
‣ AGN: dysmorphic RBCs,
RBC cast, glomerular proteinuria
Ultrasound
Urinary indices
Parameters
Pre-renal Intrinsic renal
AKI
AKI
uNa (mEq/L)
<20
> 40
Urine specific gravity
> 1.020
≤ 1.010
Urine osmolality (mOsm/kgH₂O)
> 500
< 350
sUrea / sCr
> 20
10 - 15
Fractional excretion of Na (FE Na)
[ (uNa/sNa) / (uCr/sCr) ] x 100%
< 1%
>2%
Fractional excretion of urea (FE urea)
[ (uUrea/sUrea) / (uCr/sCr) ] x 100%
< 30%
> 50%
• Post-renal AKI: bilateral hydronephrosis, hydroureter
Renal biopsy
sCr: serum creatinine, sNa: serum sodium, sUrea: serum urea or BUN,
uCr: urine creatinine, uNa: urine sodium, uUrea: urine urea
116
Limitation in interpretation of urinary indices
• Urine specific gravity: false high in proteinuria, glucosuria, mannitol, colloidal fluid use
• sUrea/sCr: false low in rhabdomyolysis, malnutrition
• uNa and FE Na: false high in diuretic use, CKD, non-reabsorbable solute excretion (bicarbonate, glucose,
mannitol)
• FE Na and FE urea: false low in contrast-induced nephropathy, acute myeloma kidney,
acute urate nephropathy, hepatorenal syndrome, NSAIDs, sclerodermal renal crisis,
TTP, sepsis, acute glomerulonephritis, early obstructive nephropathy, 10-15% of
non-oliguric ATN
117
TREATMENT
118
Treatment
Specific treatment
• Correct the causes of AKI
• Diet requirement
‣ Fluid requirement (in case of patients in euvolemic status) = urine output + insensible loss
(in general 500 – 800 ml/d)
• Discontinue all nephrotoxic agent when possible
‣ Energy requirement 20 – 30 kcal/kg/day
• Avoid all nephrotoxic agent if possible. In case of
therapeutic alternatives are not available
‣ Protein
‣ Aminoglycoside: prefer single dose daily,
rather than multiple-dose daily treatment and
monitor drug level if possible
‣ Amphotericin B: prefer lipid formulation,
rather than conventional formulation
• Ensure volume status and perfusion pressure
• Avoid hyperglycemia: keep plasma glucose 110149 mg/dL in critically ill patients
- Noncatabolic AKI without dialysis: 0.8 –
1.0 g/kg/day
- AKI with dialysis: 1.0 – 1.5 g/kg/day, and
up to maximum of 1.7 g/kg/day in patients on CRRT (continuous renal replacement therapy) and in hypercatabolic patients
‣ Sodium restriction in case of hypervolemia
‣ Potassium restriction for prevention of hyperkalemia
119
• Furosemide may be beneficial in switch the hypervolemic patients with oliguric AKI and to non-oliguric
AKI, but not enhancing kidney function recovery
Indications for initiate renal replacement
therapy
• Adjust the drug dosage: eGFR of the patients with
AKI are presumed to be less than 10 ml/min/1.73 m2
• Not using dopamine, fenoldopam, atrial natriuretic
peptide (ANP), and recombinant human IGF-1 (rh
IGF-1) to treat AKI
• Monitor serum creatinine, urine output
Biochemical
indications
• Correct electrolytes and acid-base abnormalities: hyperkalemia, metabolic acidosis, hypocalcemia
• If indicated, initiate renal replacement therapy
(RRT)
‣ Modalities of RRT: intermittent hemodialysis
(IHD), SLEDD (sustained low efficacy daily
dialysis), CRRT (continuous renal replacement therapy), PD (peritoneal dialysis)
‣ Adjust the drug dosage according to modalities of RRT
Clinical
indications
Refractory hyperkalemia > 6.5 mEq/L
Refractory metabolic acidosis pH < 7.15
Refractory other electrolyte abnormalities:
hyponatremia, hypernatremia, or
hypercalcemia
BUN > 80 mg/dL
Tumor lysis syndrome with hyperuricemia and
hyperphosphatemia
Refractory volume overload
End organ involvement: pericarditis,
encephalopathy, neuropathy, myopathy,
uremic bleeding
Severe poisoning or drug overdose
Creation of intravascular space for plasma
and other blood product infusions and
nutrition
AKI with multiple organ failure
Severe hypothermia or hyperthermia
• Discontinue RRT when it is no longer required
120
Advantages and disadvantages of different RRT modalities in AKI
Modality
Use in
hemodynamically
unstable patients
Solute clearance
Volume control
Anticoagulant
PD
Yes
Moderate
Moderate
No
IHD
No
High
Moderate
Possible without
SLEDD
Possible
High
Good
Possible without
CRRT
Yes
Moderate / High
Good
Possible without
CRRT: continuous renal replacement therapy, IHD: intermittent hemodialysis, PD: peritoneal dialysis, SLEDD: sustained low efficacy daily dialysis
121
The video was taken on the 81-year-old male with AKI due to septic shock. His serum BUN was more
than 100 mg/dL and he became uremic encephalopathy. The physical examination showed positive
frog legs sign. He was resuscitated and underwent hemodialysis.
122
The video was taken on the 81-year-old male with AKI due to septic shock. The video was taken
8 days later when his serum BUN was 94 mg/dL. The physical examination showed positive
flapping tremor sign.
123
CHRONIC KIDNEY DISEASE
(CKD)
DEFINITION
Either of the following present for > 3 months
• Markers of kidney damage (one or more)
‣ Albuminuria ≥ 30 mg/day, or albumin-tocreatinine ratio ≥ 30 g/ g creatinine
‣ Urine sediment abnormalities
‣ Electrolyte and other abnormalities due
to tubular disorders
‣ Abnormalities detected by histology
‣ Structural abnormalities detected by imaging
‣ History of kidney transplantation
Decreased GFR: < 60 ml/min/1.73 m2
125
STAGING
Green: low risk (if no other markers of kidney disease, no CKD);
Yellow: moderately increased risk; Orange: high risk; Red, very high risk.
126
APPROACH TO THE
PATIENT WITH CKD
Determine the duration of kidney disease
• If > 3 months, CKD is confirmed
• If not > 3 months or unclear, CKD is not confirmed. Patients may have CKD or AKI or AKI
on top CKD, thus the test should be repeated
accordingly.
127
Evaluation of causes: using data from history taking,
physical examination, laboratory measures, imaging and
renal biopsy
Evaluation of GFR
• Initial assessment: using serum creatinine and
GFR estimating equation
• More accurate ascertainment: using exogenous
filtration marker
Evaluation of albuminuria
• Initial assessment: spot urine sample (prefer early
morning urine sample) for reagent strip urinalysis
(UA)
• Confirmatory tests for quantitative measurement
‣ Spot urine sample (prefer early morning urine
sample) for albumin-to-creatinine ratio (ACR)
, urine protein-to-creatinine ratio (PCR)
‣ Timed urine sample for albumin excretion
rate (AER) or total protein excretion rate
128
TREATMENT
129
Prevention of CKD progression
Blood pressure control
• BP target
‣ Individualize BP targets and agents according to age, underlying diseases, risk of CKD progression,
and tolerance of treatment
‣ In patients with urine AER
- < 30 mg/day (or equivalent): ≤ 140/90 mmHg
- ≥ 30 mg/day (or equivalent): ≤ 130/80 mmHg
• ACEI or ARB are recommended in patients with urine AER > 30 mg/day (or equivalent)
• Kidney transplant recipients
‣ Target BP ≤ 130/80 mmHg
‣ BP-lowering agents depend on timing after transplantation, use of calcineurin inhibitor,degree of albuminuria, and other comorbidities
• Insufficient evidence for combining ACEI and ARB therapy for prevent progression of CKD
130
Glycemic control
• Glycemic control: target HbA1c about 7.0 %
‣ > 7.0% in individuals with comorbidities or limited life expectancy and risk of hypoglycemia
‣ Avoid <7.0% in patients at risk of hypoglycemia
Lipid control
• Lipid control: treatment depend on age of patients and other comorbidities
‣ Cholesterol-lowering Treatment
๏ Non-dialysis-dependent or kidney transplantat recipients
➡ Age 18 – 49 years: statin if presence one or more of the followings: known coronary disease, DM,
prior ischemic stroke, estimated 10-year incidence of coronary death or non-fatal MI > 10%
➡ Age ≥ 50 years
- eGFR ≥ 60 ml/min/1.73m2: statin
- eGFR < 60 ml/min/1.73m2: statin or statin with ezetimibe
๏ Dialysis-dependent patients
➡ Not initiate statin or statin with ezetimibe
➡ If patients already receiving statin or statin with ezetimibe at time of initiation RRT: continue these
agents
131
๏ Kidney transplant recipients: statin
‣ Triglyceride lowering treatment: therapeutic
lifestyle changes
‣ Target lipid: LDL-C < 70, HDL-C > 40, nonHDL-C <100, and TG <150 mg/dL
Diet
• Protein intake
‣0.8 g/kg/day in diabetic patients or eGFR <
30 ml/min/1.73 m2
‣Avoid high protein intake > 1.3 g/kg/day
• Sodium intake < 2 g/day (corresponding to 90
mEq/d of sodium or 5 g/d of sodium chloride), unless contraindicated
• Potassium restriction: in case of hyperkalemia
• Phosphate restriction: in case of hyperphosphatemia
Lifestyle modification
• Exercise: ≥ 30 minutes 5 times/week
• Target BMI 20 – 25 kg/m2
• Stop smoking
• Limiting alcohol intake: ≤ 2 standard drinks/day
for male, and ≤ 1 standard drinks/day for female
132
Management of complications of CKD
Anemia
• Evaluation: annually in CKD stage 3, twice a year in CKD stage 4 or 5, and every 3 months in dialysis patients
• Definition: Hb < 13.0 g/dL in male and < 12.0 g/dL in female
• Evaluation causes of anemia: CBC, absolute recticulocyte count, iron study, B12 and folate level
• Treatment
‣ Iron therapy in TSAT (transferring saturation) ≤ 30%, and serum ferritin ≤ 500 ng/ml
‣ ESA (erythrocyte stimulating agent) therapy
๏ Use with caution in patients with active or history of malignancy and history of stroke
๏ Address all correctable causes of anemia prior to initiation
๏ Initiation of ESA therapy: individualize
➡ In general, patients with Hb < 10.0 g/dL
‣ Target Hb: individualize
๏ In general, 10.0 – 11.5 g/dL, not intentionally increase > 13.0 g/dL
133
Metabolic bone disease
• Evaluation of serum calcium, phosphate, PTH
and alkaline phosphatase in eGFR < 45-60
ml/min/1.73 m2
• Target:
‣ Calcium and phosphate level in normal
range
‣ Intact PTH (iPTH)
๏ Non-dialysis patients: no known optimal
level, in case of iPTH level above normal limit: evaluate for hyperphosphatemia, hypocalcemia, and vitamin D
deficiency
๏ Dialysis patients: 2 – 9 times of upper
normal limit
• Treatment
‣ Hyperphosphatemia: phosphate binders
๏ Available agents: calcium carbonate,
calcium acetate, savelamer, lanthanum,
aluminium hydroxide
๏ Calcium-based phosphate binders: restricting dose in patients with hypercalcemia, arterial calcification and/or adynamic bone
๏ Aluminum-containing phosphate
binder: avoid long-term use
‣ High iPTH level
๏ Non-dialysis patients: calcitriol or vitamin D analogue
๏ Dialysis patients: : calcitriol or vitamin D
analogue or combination with calcimimetic drug
๏ Severe hyperparathyroidism with fail to
medical treatment: parathyroidectomy
Metabolic acidosis
• Target: normal range of serum bicarbonate level
• Treatment: oral sodium bicarbonate in case of
serum bicarbonate level < 22 mEq/L
134
Management of other aspects of CKD
Cardiovascular disease (CVD)
• Cardiovascular disease (CVD): considered at increased risk of CVD
Peripheral arterial disease (PAD)
• Medications
‣ Adjust drug dosage according to eGFR
‣ Avoid herbal remedies
Imaging studies
• Balance risk of contrast-induced AKI against diagnostic value and therapeutic implication of the investigation
• Radiocontrast
‣ Avoid high osmolar agents
‣ Use of lowest possible radiocontrast dose
‣ Withdrawal of potentially nephrotoxic drugs before and after the procedure
‣ Adequate hydration with saline before, during and after the procedure
‣ Measurement of eGFR 48 – 96 hours after the procedure
• Gadolinium-based contrast media
135
‣ Not use in patients with CKD stage 5, unless there is no alternative test
‣ In patients with CKD stage 4-5 who require gadolinium-based contrast media, prefer use of macrocyclic
chelate preparation
• Bowel preparation
‣ Not use oral phosphate-containing bowel preparation
Vaccination
• Hepatitis B vaccine
• Influenza vaccine: annually
• Pneumococcal vaccine: every 5 years in CKD stage 4-5, nephrotic syndrome, DM, or those receiving immunosuppression
136
Renal replacement therapy (RRT)
• Referral to nephrologists for plan of RRT in patients with eGFR < 30 ml/min/1.73 m2
• Topics for counselling with the patients:
‣ Indications for RRT
‣ Available modalities of treatment: hemodialysis, peritoneal dialysis, kidney transplantation and conservative treatment
‣ Advantages and disadvantages
‣ Complications
‣ Preparations
‣ Financial issues
• Prepare the patients for RRT: vascular access, or Tenckhoff catheter implantation
• Indications for RRT
‣ Presence of symptoms and signs attributable to CKD: serositis, acid-base or electrolytes disturbances,
pruritus, inability to control volume status or blood pressure, malnutrition, cognitive impairment, encephalopathy
‣ eGFR < 7 ml/min/1.73 m2
‣ Preemptive kidney transplantation in patients with irreversible CKD over 6-12 months with eGFR <20
ml/min/1.73 m2
137
แสดงการเปรียบเทียบการบำบัดทดแทนไตวิธีต่าง
การฟอกเลือดด้วยเครื่องไตเทียม
หลักการการ
รักษา
• ขจัดของเสียในเลือดด้วยการกรองผ่าน
ตัวกรองเลือดโดยใช้เครื่องไตเทียม
• ต้องมีการผ่าตัดต่อเส้นเลือดหรือใส่ท่อ
ลักษณะและ
สถานที่การ
บำบัดทดแทน
ไต
พลาสติกในหลอดเลือดเพื่อใช้เป็นทาง
สำหรับนำเลือดออกมาฟอก
• ทำ 2-3 ครั้ง/สัปดาห์ ครั้งละ 4-5 ชม.
และทำต่อเนื่องไปตลอด
• พยาบาลเป็นผู้ทำให้
• ทำที่โรงพยาบาล / ศูนย์ไตเทียม
การล้างไตทางช่องท้อง
• ขจัดของเสียในเลือดโดยกรองผ่านเยื่อ
บุช่องท้องเข้ามาอยู่ในน้ำยาที่ใส่
เข้าไปในช่องท้อง
• ต้องมีการผ่าตัดต่อใส่ท่อพลาสติกฝัง
ไว้ที่หน้าท้อง
• ทำทุกวันโดยใส่และปล่อยน้ำยา 4-5
ครั้ง/วัน ทำต่อเนื่องไปตลอด
• ผู้ป่วยหรือผู้ดูแลเป็นผู้ทำการล้างไต
การปลูกถ่ายไต
• ไตที่ปลูกถ่ายสามารถทำ
หน้าที่ขับของเสียในเลือด
ได้เหมือนหรือใกล้เคียงไต
ปกติ
• ต้องได้รับบริจาคจากญาติ
สายตรง คู่สมรสหรือจากผู้
ป่วยที่เสียชีวิต
• ทำการผ่าตัดปลูกถ่ายไตที่
โรงพยาบาลโดยแพทย์
ทางช่องท้องหลังจากได้รับการสอนวิธี • มาตรวจตามแพทย์นัด
การทำ
• ทำที่บ้านหรือที่ทำงาน
• ต้องรับประทานยากด
ภูมิคุ้มกันไปตลอด
138
• มีการจำกัดชนิดอาหาร ผลไม้ และน้ำ
มากกว่า
• ไม่อิสระ ต้องเสียเวลามาห้องไตเทียม
ข้อจำกัดใน
การรับ
ประทาน ความ
สะดวก/อิสระ
• มีการจำกัดผลไม้และน้ำน้อยกว่า
โดยเฉพาะถ้าผู้ป่วยอยู่ไกลและไม่มีที่
• ไม่ต้องเสียเวลามาห้องไตเทียม
ฟอกเลือดใกล้บ้าน
• มาตรวจเฉพาะวันนัดหรือมีปัญหา
• ถ้าจะไปท่องเที่ยวหลายวัน ต้องติดต่อกับ • ในการไปท่องเที่ยว ต้องนำถุงน้ำยาไป
ห้องไตเทียมที่จะเดินทางไปล่วงหน้าซึ่ง
ค่อนข้างยุ่งยาก
• เนื่องจากการฟอกเลือดทำโดยพยาบาล
ด้วย
• เกิดความสะดวกแก่ญาติมากกว่า ถ้า
ได้ดูแลผู้ป่วยที่บ้าน โดยเฉพาะอย่าง
ผู้ป่วยที่มีความพิการทางร่างกายหรือ
ยิ่งผู้ป่วยที่มีความพิการทางร่างกาย
สมองก็สามารถทำได้ แต่อาจเกิดความ
หรือสมอง
• กินอาหารได้ใกล้เคียงปกติ
• ดำรงชีวิตได้ใกล้เคียงคน
ปกติ ต้องยินยาสม่ำเสมอ
และตรงเวลา
• มาตรวจตามแพทย์นัดหรือ
เมื่อมีอาการผิดปกติ
• ไปท่องเที่ยวที่ต่างๆ ได้
ปกติ
ไม่สะดวกแก่ญาติ ถ้าต้องรับส่งผู้ป่วยใน
เวลาที่ตัวเองทำงาน
ภาวะ
• ที่พบบ่อยคือการติดเชื้อในผู้ป่วยที่ใส่ท่อ
แทรกซ้อนจาก
พลาสติกไว้ในหลอดเลือดดำ ซึ่งอาจ
การติดเชื้อ
ทำให้เกิดภาวะติดเชื้อในกระแสเลือดได้
• ที่พบบ่อยคือการติดเชื้อบริเวณหน้า
ท้องที่ใส่ท่อพลาสติก และสามารถ
ลุกลามจนเกิดการติดเชื้อในช่องท้อง
ได้
• ต้องระมัด ระวังอย่างมาก
โดยเฉพาะในระยะแรกๆ ที่
ผู้ป่วยได้รับยากดภูมิคุ้มกัน
ขนาดสูง ซึ่งอาจติดเชื้อ
รุนแรงถึงชีวิตได้
139
• มักไม่มีปัญหาระหว่าง
ผ่าตัดเนื่องจากได้รับการ
• เสี่ยงต่อภาวะความดันโลหิตต่ำ หัวใจ
ภาวะ
แทรกซ้อนทาง
หัวใจและ
หลอดเลือด
เต้นผิดจังหวะหรือกล้ามเนื้อหัวใจขาด
• มีความปลอดภัยต่อผู้ป่วยที่มีโรค
เลือดกำเริบ ถ้าผู้ป่วยมีการทำงานของ
หัวใจหรือหลอดเลือดสมองมากกว่า
หัวใจไม่ดี โดยเฉพาะอย่างยิ่งในรายที่
การฟอกเลือด
ต้องดึงน้ำออกในปริมาณมาก
• บางรายอาจมีความดันโลหิตสูงถ้ารับ
• บางรายอาจมีความดันโลหิตสูง ถ้ารับ
ประทานอาหารรสเค็ม
ประทานอาหารรสเค็ม
ประเมินและแก้ไขก่อนการ
ปลูกถ่ายไต
• เนื่องจากยากดภูมิคุ้มกันมี
ผลเกี่ยวข้องกับปัจจัยเสี่ยง
เช่น ความดันโลหิตสูง ไข
มันสูง ทำให้มีผลต่อการ
เกิดโรคหลอดเลือดและ
หัวใจในระยะยาว
อัตราการรอด • โดยรวมแล้วใกล้เคียงกับการล้างไตทาง • โดยรวมแล้วใกล้เคียงกับการฟอก
ชีวิต
ช่องท้อง
เลือดด้วยเครื่องไตเทียม
• ดีกว่ามากโดยเฉพาะหลัง
จากปลูกถ่ายไตไปแล้ว 3
เดือน
• ค่าผ่าตัด
150,000-250,000 บาท
ค่าใช้จ่าย/
เดือน (บาท)
• ค่าฟอกเลือด (2-3 ครั้งต่อสัปดาห์)
12,000-25,000 (ไม่รวมค่ายาอื่นๆ)
• ค่าล้างไตทางช่องท้อง
15,000-25,000
• (ไม่รวมค่ายาอื่น)
(ทำในโรงพยาบาลรัฐ)
หลังจากนั้นค่ายากด
ภูมิคุ้มกัน ~ 20,000 (3-6
เดือนแรก)
- 15,000
(6-12 เดือนถัดมา)
-10,000 (หลัง 1 ปี)
140
• ข้าราชการสามารถเบิกได้
• ข้าราชการสามารถเบิกได้ 2,000 บาท
ต่อการฟอกเลือด 1 ครั้ง และไม่จำกัด
สิทธิการรักษา
จำนวนครั้ง เบิกได้ทั้งในโรงพยาบาลรัฐ
การบำบัด
และเอกชนที่เข้าร่วม
ทดแทนได้ที่
ใช้ได้
• ผู้ที่มีประกันสังคมยื่นขอสิทธิกับสำนักงาน
ประกันสังคมเมื่ออนุมัติแล้วเบิกได้
1,000-1,500 บาทต่อการฟอกเลือด 1
เมื่อรักษาในโรงพยาบาล
• ข้าราชการสามารถเบิกได้ทั้งหมดเมื่อ
รักษาในโรงพยาบาลรัฐ
• ผู้ที่มีประกันสังคมยื่นขอสิทธิกับ
รัฐ
• ผู้ที่มีประกันสังคมยื่นเรื่อง
ขอปลูกถ่ายไตกับ
สำนักงานประกันสังคมเมื่ออนุมัติแล้ว
สำนักงานประกันสังคมเมื่อ
เบิกได้ไม่เกิน 20,000 บาทต่อเดือน
อนุมัติจึงเบิกได้ตามข้อ
กำหนดสำนักงานประกัน
ครั้ง และไม่เกิน 3 ครั้งต่อสัปดาห์
สังคม
• สิทธิบัตรทอง (ประกัน
• สิทธิบัตรทอง (สปสช) ผู้ป่วยที่เริ่มฟอก
สิทธิการรักษา
เลือดหลัง 1 ตค. 2551 เบิกไม่ได้ ยกเว้น
การบำบัด
ถ้าผู้ป่วยมีข้อห้ามทางการแพทย์ต่อการ
ทดแทนได้ที่
ล้างไตทางช่องท้องจึงจะเบิกได้ 1,500
ใช้ได้
บาทต่อการฟอกเลือด 1 ครั้ง และ ไม่
สุขภาพแห่งชาติ) ต้องไป
• สิทธิบัตรทอง (ประกันสุขภาพแห่ง
ชาติ) เบิกได้ทุกราย ในสถานพยาบาล
ที่เข้าร่วม
จำกัดจำนวนครั้ง
สมัครเพื่อรอการปลูกถ่าย
ไตกับโรงพยาบาลรัฐและ
เอกชนที่เข้าร่วมเมื่ออนุมัติ
จึงเบิกได้ตามข้อกำหนด
ของสำนักงานสุขภาพแห่ง
ชาติ
การเตรียม
ความพร้อม
อื่นๆ
• ต้องมีการผ่าตัดต่อเส้นเลือดล่วงหน้า
อย่างน้อย 4 เดือน
• ต้องมีการผ่าตัดต่อใส่ท่อพลาสติกฝัง
ไว้ที่หน้าท้องล่วงหน้าอย่างน้อย 2
สัปดาห์
• ควรหลีกเลี่ยงการได้รับ
เลือด
141
Hemodialysis
142
Peritoneal dialysis
143
Kidney transplantation
144
REFERENCES
• Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Inter., Suppl. 2013;3:1-150.
• Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney Inter., Suppl. 2012;2:279-335.
• Kidney Disease: Improving Global Outcomes (KDIGO) Lipid Work Group. KDIGO Clinical Practice Guideline
for Lipid Management in Chronic Kidney Disease. Kidney Inter., Suppl. 2013;3:259-305.
• Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO Clinical Practice
Guideline for the Management of Blood Pressure in Chronic Kidney Disease. Kidney Inter., Suppl.
2012;2:337-414.
• Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and the Treatment of Chronic Kidney Disease-Mineral and Bone
disorder (CKD-MBD). Kidney Inter., 2009;76(Suppl 113): S1-S130.
• Jellinger PS, et al. American Association of Clinical Endocrinologists’ Guidelines for Management of Dyslipidemia and Prevention of Atherosclerosis. Endocr Pract. 2012;18(Suppl 1):1-78.
• กลวิชย์ ตรองตระกูล และ ไพฑูรย์ ขจรวัชรา. การป้องกันภาวะแทรกซ้อนและเตรียมการบำบัดทดแทนไต. ใน วรวรรณ ลิมปมน
ตรี, บรรณาธิการ. คู่มือการจัดการดูแลผู้ป่วยโรคไตระยะเริ่มต้น.91-99. กรุงเทพมหานคร : บริษัท ยูเนียนอุลตร้าไวโอเลต
จำกัด, 2555. ISBN 978616723671.
145
COMMON GENETICS
KIDNEY DISEASES
AUTOSOMAL
DOMINANT POLYCYSTIC
KIDNEY DISEASE
147
Epidemiology
• Most common form of polycystic kidney diseases
• Affected 1 in 800 live births, and 4 – 6 million worldwide
• Autosomal dominant penetrance, but 5% of patients have spontaneous mutation
Classification
• Type I: caused by mutation in PKD1 gene
• Type II: caused by mutation in PKD2 gene
148
Pathogenesis
• Numerous site of PKD1 and PKD2 gene point mutations caused reduction in functional polycystin-1 and
polycystin-2, their encoded proteins.
• A “two-hit” mechanism: germ-line mutation of PKD1 and PKD2 with additional somatic mutation in wild-type
gene to initiate the cysts formation
Chromosomal
Length of
Abberant gene
location
transcript (kb)
Protein
encoded
Molecular
mass
(kD)
Type
Frequency
Type I
85 – 90%
PKD1
16q13.3
14.5
Polycystin-1
462
Type II
10 – 15%
PKD2
4q21
5.6
Polycystin-2
110
• Polycystin-1 is membrane receptor capable of interacting with extracellular substances as a sensors and signaling through phosphorylation pathways to activate the intracellular response.
• Polycystin-2 is a calcium channel.
• Polycystin-1 interacts with polycystin-2 and other proteins to form the complexes which can be found at the
cell-matrix interface, cell-cell contacts and luminal cilium. Stimulation on these complexes cause calcium influx, which act as a intracellular second messenger, subsequently effect several signal-transduction cascades
149
and regulate cell proliferation, apoptosis, epithelial cell differentiation, polarity, adhesion, migration, cell shape,
and tubular diameter.
• The reduction in functional polycystin causes reduction in intracellular calcium and subsequently over activation of adenylate cyclase, increasing number of cyclic AMP, and lessening intracellular signal-transduction cascades results in
‣ Increase cell proliferation
‣ Increase fluid accumulation
‣ Alter cell polarity
‣ Matrix remodeling
• All of these consequences lead to cyst formation in ADPKD patients.
150
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151
Defects in the noncanoical Wnt/PCP pathway leading to renal cysts
152
Defects in the noncanoical Wnt/PCP pathway leading to renal cysts
153
• Two types of ADPKD have similar pathological and physiological features, but type II disease has a later onset
of symptoms, thus patients with type II disease have
‣ Older mean age of ESRD: 54 years in type I and 74 years in type II
‣ Longer life expectancy: 53 years in type I and 69 years in type II
• Progressive enlarge of kidney: mean increase in total kidney volume is 5.3%/year
• Renal failure: patients with kidney volume > 1,500 ml have mean decreased in GFR 4.3 ml/min/year
• Renal pain: found in 60% of patients, located at flank or abdomen
‣ Causes: renal infection, cyst hemorrhage, renal stone, or ADPKD itself
• Hypertension: 50% of patients and increase to nearly 100% of patients with ESRD
• Hematuria
‣ Imaging: to identify intraparenchymal or external hemorrhage, bleeding into the collecting system, solid
tumors
‣ Renal colic: in some patients with hematuria
‣ Usually recovery in few days
• Urinary tract infection
• Renal stones: 20% of patients
154
‣ Usually composed of uric acid and calcium oxalate
‣ Investigation of choice: CT scan of kidneys
• Renal cell carcinoma: not frequent than in the normal population
• Anemia: less frequent than in other renal diseases because of enhanced production of erythropoietin by
polycystic kidneys
• Extra-renal manifestations
‣ Polycystic liver disease:
๏ Most common extrarenal manifestations: 80% of patients
๏ Usually asymptomatic
๏ Associated with estrogen exposure: female, exogenous estrogen use, and repeated pregnancy
๏ Complications: cyst hemorrhage, infections, and rarely torsion or rupture
‣ Cyst in other organs: 5% in pancreas, 8% in arachnoid, and 40% in seminal vesicles
‣ Intracranial aneurysm: found in 16% and 6% of patients with and without family history of aneurysm
๏ Most often asymptomatic
๏ Ruptured: 35 – 55% risk of combined severe morbidity and mortality
๏ Screening for intracranial aneurysm
➡ Diagnostic tools: MR angiography (MRA) or CT angiography (CTA)
➡ Indications
155
- Family history of aneurysm or stroke
- New onset of headache
- Central nervous system symptoms or signs
➡ Management
- Negative: repeat imaging every 5 – 10 years
- < 7 mm-aneurysm: repeat imaging every ½ - 1 year
- ≥ 7 mm-aneurysm: surgical treatment
‣ Other vascular malformation: dolichoectasias, thoracic aortic and cervicocephalic artery dissections, and
coronary artery aneurysm
‣ Cardiac manifestations: mitral valve prolapsed 25% of patients, aortic insufficiency
‣ Colonic diverticulosis and diverticulitis
‣ Bronchiectasis
156
Diagnosis
• Use radiologic imaging to demonstrate the number of cyst in kidney
Criteria for diagnosis ADPKD type 1
Age
Criteria
15 – 29 years
2 cysts, unilateral or bilateral
30 – 59 years
2 cysts in each kidney
≥ 60 years
Revised criteria for diagnosis ADPKD type 1 and type 2
Age
Criteria
15 – 29 years
3 cysts, unilateral or
bilateral
30 – 39 years
3 cysts, unilateral or
bilateral
40 – 59 years
≥ 60 years
Revised criteria for exclusion of ADPKD type 1 and type 2
Age
Criteria
15 – 29 years
1 cyst
157
CT scan of the patient with ADPKD coronal view
158
Treatment
Specific treatment
• No any agents are able to reduce the kidney volume in patients with ADPKD
Summary of the results from landmark randomized control studies in patients with ADPKD
Decrease
kidney volume
Slowed increase in kidney
volume
Slowed decline in
renal function
Sirolimus
No
No
No
Everolimus
No
Yes
No
Somatostain
No
Yes
No
Tolvaptan
No
Yes
Yes
159
• BP Control
‣ Target BP ≤ 130/80 mmHg
‣ ACEI or ARB: drug of choice
‣ Salt restriction: NaCl < 6 g/day
‣ Diuretics: in case of fail to lower BP with 2
strategies above
• Smoking cessation
• Hematuria
‣ Bed rest
‣ Analgesics
‣ Hydration: to increase urine flow rate to 2 –
3 L/day
‣ Avoid sports which at a risk of abdominal
trauma: such as rugby, boxing
• Urinary tract infection
‣ Lower tract: treat as in general population
‣ Upper tract
๏ Acute pyelonephritis, or symptomatic
cyst infection
๏ Required hospitalization
๏ Drug of choice: fluoroquinolone
‣ In men: radiologic and urologic evaluation is
indicated
• Renal stones: treat as in general population
• ESRD:
‣ RRT
๏ Peritoneal dialysis or hemodialysis may
be used
๏ Kidney transplantation
- Similar outcome to non-AKPKD patients
- Identification of ADPKD in related
living donors are requied: MRI
KUB and/or genetic testing
• Renal pain: analgesics, transcutaneous stimulation, local injections of anesthetics, laparoscopic
160
or opened surgical unroofing of cysts, or laparoscopic renal denervation
• Liver cysts
‣ Avoid exposure to estrogens, or least as possible
‣ Partial hepatectomy: in severe liver enlargement
• Pregnancy
‣ Generally uncomplicatied in case of normal
BP and renal function
‣ Increase risk of severe hypertension and
preeclampsia, particularly in patients who
have hypertension and renal impairment before conception
161
References
• Torres VE, and Grantham JJ. Cystic diseases of the kidney. In: Taal MW, et al. editor. Brenner & Rector’s The Kidney. 9th ed. Philadephia: Elsevier Saunders; 2012. p 1626-1669.
• Granthham JJ. Autosomal dominant kidney disease. N Engl J Med 2008;359:1477-85.
• Wilson PD. Polycystic kidney disease. N Engl J Med 2004;350:151-164.
• Hildebrant F, et al. Ciliopathies. N Engl J Med 2011;364:1533-1543.
• Grantham JJ, et al. Volume progression in polycystic kidney disease. N Engl J Med 2006;354:2122-2130.
• Ravine D, et al. Evaluation of ultrasonographic diagnostic criteria for autosomal dominant polycystic kidney disease 1. Lancet 1994;343:824-27.
• Pei Y, et al. Unified criteria for ultrasonographic diagnosis of ADPKD. J Am So Nephrol 2009;20:205-212.
• Perico N, et al. Sirolimus therapy to halt the progression of ADPKD. J Am Soc Nephrol 2010;21:1031-1040.
• Serra AL, et al. Sirolimus and kidney growth in autosomal dominant polycystic kidney disase. N Engl J Med
2010;363:820-829.
• Walz G, et al. Everolimus in patients with autosomal dominant polycystic kidney disease. N Engl J Med
2010;363:830-840.
• Hogan MC, et al. Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney
and liver disease. J Am Soc Nephrol 2010;21:1052-1061.
• Torres VE, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med
2012;367:2407-2418.
162
ALPORT’S SYNDROME
163
Epidemiology
• Accounts for 0.4% of adults with ESRD in United States
Pathogenesis
• Type IV collagen composed of 6 genetically distinct α chains, α1(IV)- α6(IV) monomer, which are encoded
from COL4A1 - COL4A6, respectively.
• Three of α chain monomers form into only 3 sets of protomers which are designated as α1.α1.α2(IV),
α3.α4.α5(IV) and α5.α5.α6(IV).
Triple helical organization of the type IV collagen family
164
• These protomers pair into 3 canonical set of hexamers to from networks, which are α1.α1.α2(IV)-α1.α1.α2(IV),
α3.α4.α5(IV)-α5.α5.α6(IV) and α1.α1.α2(IV)-α5.α5.α6(IV).
Assembly and network organization of collagen IV protomers
165
• During the embryonic development, component of GBM structure is change from α1.α1.α2(IV)-α1.α1.α2(IV)
network to α3.α4.α5(IV)-α5.α5.α6(IV) network to form a mature GBM.
Normal glomerular development and the change of networks component of GBM structure
166
• Mutations in the COL4A3, COL4A4, COL4A5 genes which encode α3, α4 and α5 chain collagen type IV, a
component of glomerular basement membrane (GBM), results in arrest of switching of GBM network. The
GBM in the patients with Alport’s syndrome become persistence of α1.α1.α2(IV)-α1.α1.α2(IV) network results
in dysconfiguration of GBM.
Glomerular development and the abnormal switching of networks component of GBM structure in the patients
with Alport’s syndrome
167
Genetics
• X-linked inheritance
‣ 85% of patients
‣ Mutations in COL4A5 gene encoding α5(IV)
collagen chain
‣ Located on chromosome Xq26-48
COL4A3 and COL4A4 gene encoding α3(IV)
and α4(IV) collagen chain
‣ Located on chromosome 2q35-37
‣ Severity similar to X-linked inheritance
• Autosomal dominant
‣ Rare
‣ Male predominate: ESRD at age of 30 – 40
years, deafness
‣ Missense mutations in COL4A3 and COL4A4
gene encoding α3(IV) and α4(IV) collagen
chain
‣ Female: varying in severity, but less severe
than in male patients
‣ Less severity; benign familial hematuria or
thin basement membrane disease
‣ Concomitant deletion mutations in COL4A6
gene encoding α3(VI) chain are associated
with leiomyomatosis
• Autosomal recessive
‣ 15% of patients
‣ Homozygous or compound heterozygous nonsense mutations, missense mutations, frame
shifts, small deletions, or splice variants in
168
• Hematuria: often the presenting sign
• Severity of disease depend on the mutations
• High-tone sensorineural hearing loss: 80% of patients
• Ocular defects: 40% of patients
‣ Anterior lenticonus: 25% of patients
‣ Perimacular dots and flecks
‣ Posterior polymorphous dystrophy (PPMD)
‣ Microcornea, arcus cornealis, iris atrophy, cataracts,
• Family history of deafness and renal failure
169
Diagnosis
• Electron microscopic findings in renal biopsy
• Immunostaining of α3(IV) and α5(IV) collagen from skin or renal tissue
[ Skin collagen networks composed of α1.α1.α2(IV)-α5.α5.α6(IV) ]
α5(IV)
X-linked
Normal
Male
Female
α3(IV)
Autosomal
recessive
X-linked
Autosomal
recessive
Normal
Male
Female
GBM
+
-
Mosaic
-
+
-
Mosaic
-
Skin
basement
membrane
+
-
Mosaic
+
+
-
-
-
170
Renal pathology
• Light microscope: nonspecific, normal or nearly
normal, segmental to diffuse mesangial cell proliferation, matrix increase, and thickening of the
glomerular capillary wall
Treatment
• No proven therapy
• Control hypertension with ACEI
• Light microscope: nonspecific, normal or nearly
normal, segmental to diffuse mesangial cell proliferation, matrix increase, and thickening of the
glomerular capillary wall
• Electron microscope: thin GBM thicken over time
into multilamellations and lucent spaces results in
split appearance of the basement membrane;
“basket weaving appearance”
171
References
• Appel GB, Radhakrishnan J, and D’Agati VD. Secondary glomerular disease. In: Taal MW, et al. editor. Brenner & Rector’s The Kidney. 9th ed. Philadephia: Elsevier Saunders; 2012. p 1192-1277.
• Hudson BG, et al. Alport’s syndrome, Goodpasture’s syndrome, and type IV collagen. N Engl J Med
2003;348:2543-2556.
172
APPROACH TO COMMON
SYMPTOMS IN NEPHROLOGY
EDEMA
174
Localized edema
• Vascular abnormalities
‣ Increased venous pressure
๏ Deep vein thrombosis
๏ Venous insufficiency
๏ Vena cava obstruction
‣ Decreased arteriolar resistance
๏ Calcium channel blocker (CCB)
• Lymphatic obstruction
‣ Malignancy
‣ Infection
‣ Hypothyroidism
‣ Congenital anomalies of lymphatic system
ETIOLOGIES
• Increased capillary permeability
‣ Inflammation
‣ Angioedema
175
Generalized edema
- Anti-GBM
• Liver diseases: cirrhosis
- Immune complex disease
• Heart diseases: congestive heart failure
- Pauci-immune glomerulonephritis
‣ Mechanical abnormalities
• Other causes of hypoalbuminemia
๏ Pericardial disease
‣ Protein-losing enteropathy
๏ Myocardial disease
‣ Malnutrition
๏ Endocardial disease
‣ Electrical abnormalities
๏ Bradyarrhythmia
๏ Tachyarrhythmia
• Kidney diseases
‣ AKI, AKI on top CKD, CKD
‣ Glomerular diseases
๏ Nephrotic syndrome
- Primary causes
- Secondary causes
๏ Nephritic syndrome (NS)
176
APPROACH TO
THE PATIENTS
177
History taking
General appearance
Body weight change, prolong fever
HEENT
Dry eyes, dry mouth, sinusitis
CVS
history of heart disease, cardiovascular risk factors (DM, hypertension, dyslipidemia,
smoking), orthopnea, paroxysmal nocturnal dyspnea (PND), chest pain
RS
History of smoking, hemoptysis
GI
Jaundice, alcohol drinking, family history of liver disease, viral hepatitis (blood transfusion,
unsafe sex, IVDU, tattoo) , constipation, palpable intraabdominal lymph nodes
KUB
Edema (location, duration, onset, intermittent edema), urine (volume, foamy urine,
hematuria, nocturia, passing stone), polyuria
GU
Bleeding per vagina, palpable breast mass, abnormal nipple discharge
NS
Seizure, psychosis, polyneuritis multiplex
Dermatology
Rash, photosensitivity, hair loss, oral ulcer
Rheumatology
Arthritis
Hematology
Palpable lymph nodes, fever, night sweat, anemia, abnormal systemic bleeding, bone pain
Infections
Respiratory tract, skin and soft tissue infection with lag period, synpharyngitis, chronic
infection
Medications
CCB, drug allery, antibiotics (penicillin, quinolone, vancomycin, colistin, aminoglycoside),
contrast exposure, NSAIDs, D-penicillamine, PTU, gold, hydralazine, heroine
Family history
Sensorineural hearing loss, eye disease, chronic kidney disease
178
Physical examination
Vital signs
Body temperature, BP, pulsus paradoxus
General
appearance
Body weight, sign of chronic liver disease
HEENT
Anemia, jaundice, cervical lymphadenopathy, oral ulcer, thyroid examination,
exophthalmos, lid lag/retraction, keratoconjunctivitis sicca, xerostomia, parotid gland
enlargement, Schirmer test, tender on sinus, saddle nose deformity, pinch purpura,
raccoon eye, tongue indentation, anterior lenticonus
CVS
JVP, Kussmaul sign, PMI, heaving, thrill, murmur, pericardial rub, peripheral bruit
(carotid, subclavian, abdominal)
RS
Tracheal deviation, decreased breath sound, consolidation sign, wheezing
Abdomen
Liver and spleen examination, shifting dullness, fluid thrill, bimanual palpation, full
bladder
Extremities
Edema, should pad sign, nail dystrophy, absent of patella
GU
Breast mass, abnormal nipple discharge, PV examination
NS
Polyneuritis multiplex, flapping tremor, visual acuity, Tinel and phalen test, whispering
sound
Skin
Tattoo, malar and discoid rash, photosensitivity, hair loss, peau d’orange skin,
vasculitis lesion, dark, pigmented skin and ulcer at medial malleolus area
179
Key to differential diagnosis
• Localized edema
• Generalized edema
‣ Liver diseases: cirrhosis
‣ Heart diseases: mechanical abnormalities,
electrical abnormalities
‣ Renal diseases: AKI, AKI on top CKD, RPGN,
CKD and NS, nephritic syndrome
‣ Hypoalbuminemia of other
causes
180
COMMON
CAUSES
181
Causes
Symptoms and signs
Investigations
CCBinduced
edema
Dihydropyridine CCB, 1st 6 months of initiation, high dose
Stable BW
-
Cirrhosis
Jaundice, alcohol drinking, family history of liver disease, viral
hepatitis (blood transfusion, unsafe sex, IVDU, tattoo)
Jaundice, liver and spleen examination, shifting dullness, fluid thrill,
tattoo marks
LFT, USG upper abdomen
Heart
disease
CV risk factors, orthopnea, PND, chest pain, palpitation
Arrthythmia, JVP, Kussmaul sign, PMI, heaving, thrill, murmur,
pericardial rub, peripheral bruit
EKG, cardiac markers, CXR
Foamy urine, edema
UA, UPCI, 24-hr urine protein, Cr,
MN solid tumor
albumin, lipid, HBsAg, Anti-HCV,
FSGS heroine, obesity, HBV/HCV/HIV infection,
Anti-HIV, ANA, Anti-dsDNA, CXR,
Nephrotic
MPGN chronic infection, HCV
EKG, calcium, CBC, SPEP, serum
syndrome LN malar rash, discoid rash, oral ulcer, arthritis, alopecia, vasculitis
free light chain, FBS, CA screening
lesion
(CXR, FOBT, PV, mammogram,
Amyloidosis polyuria, constipation, anemia, bone pain, raccoon
USG abdomen)
eye, pinch purpura, Tinel and Phalen test
182
Causes
Nephritic
syndrome
Symptoms and signs
Investigations
Hematuria, hypertension, edema
IgAN synpharyngitis
UA, UPCI, 24-hr urine protein,
PIGN lag period after URI or skin infection
Cr, complement, Anti-HCV,
MPGN chronic inflammation, HCV, palpable purpura
ANA, Anti-dsDNA, ANCA,
LN malar rash, discoid rash, oral ulcer, arthritis, alopecia, vasculitis
lesion
CXR, EKG, Rheumatoid factor
ANCA-associated disease hemoptysis, sinusitis, saddle nose
deformity, wheezing, mononeuritis multiplex (numbness, weakness)
Protein-losing
enteropathy
Edema
Albumin, cholesterol, stool α1
anti-trypsin
ADPKD
Abdominal distension, bimanual palpation
USG KUB
Alport’s
syndrome
More common in male, sensorineural hearing loss, anterior
lenticonus
Skin and/or renal biopsy
CCB: calcium channel blocker, CV: cardiovascular, CXR: chest x-ray, FOBT: fecal occult blood test, IVDU: intravenous
drug abuse, USG: ultrasound
183
OLIGURIA AND ANURIA
184
DEFINITION
• Oliguria: urine output <400 ml/day
• Anuria: urine output <100 ml/day
185
ETIOLOGIES
• AKI, AKI on top CKD,
CKD
• Nephritic syndrome:
AGN, RPGN, CGN
186
APPROACH TO THE
PATIENTS
• Nocturia, history of intermittent
edema: onset of renal disease
‣ Days to week: acute onset, suggests AKI
‣ Weeks to months: subacute onset, suggests RPGN
‣ More than 3 months: late onset,
suggests CKD
‣ Hematuria (see in “Hematuria”)
187
POLYURIA AND POLYDIPSIA
188
DEFINITION
• Urine output >3 L/day
189
ETIOLOGIES
Solute dieresis
Water diuresis
• Non-electrolytes diuresis
• Primary polydipsia (PP)
‣ Hyperglycemia
• Diabetes insipidus (DI)
‣ High protein intake
‣ Osmotic diuretic: mannitol, sorbitol
• Electrolytes diuresis
‣ Diuretics
‣ Intravenous fluid
‣ Central DI (CDI)
๏ Pituitary disease: post pituitary surgery, craniopharyngioma,
intracerebral hemorrhage, intracranial tumor (primary, metastasis), Sheehan’s syndrome, sarcoidosis, histiocytosis X, tuberculosis
๏ Pregnancy: diabetes insipidus of pregnancy (vasopressinase), lymphocytic hypophysitis
๏ Familial CDI
‣ Nephrogenic DI (NDI)
๏ Electrolytes abnormalities: hypercalcemia, hypokalemia
๏ Drug-induced nephrogenic DI: lithium, cisplatin, foscanet, amphotericin B, demeclocycline, methoxyflurane, foscanet
๏ Miscellaneous: obstructive uropathy, interstitial renal disease,
sickle cell disease, amyloidosis
๏ Congenital NDI
190
APPROACH TO
THE PATIENTS
191
History taking
General appearance
Fever, night sweat, weight loss
HEENT
Surgical scar at head, tinnitus
CVS
-
RS
Chronic cough, hemoptysis
GI
Dysphagia, bowel habit change, anorexia,
KUB
Urine volume, frequency (day:night), nocturia, onset of polyuria
GU
Postpartum hemorrhage, bleeding per vagina, LMP
NS
Blur vision (diabetic retinopathy), bitemporal hemianopia, psychiatric disease
Endocrinology
DM and control, steroid use
Dermatology
-
Rheumatology
-
Hematology
Anemia, bone pain, abnormal bleeding
Infections
Contact to tuberculosis patient
Medications
lithium, cisplatin, foscanet, amphotericin B, demeclocycline, methoxyflurane,
foscanet, mannitol, diuretics, TPN, protein intake
Family history
DM
192
Vital signs
BP, PR
General appearance
Body weight
HEENT
Anemia, jaundice, cervical lymphadenopathy
CVS
JVP
RS
Treacheal deviation, sign of consolidation, pleural effusion
Abdomen
Liver and spleen examination, fundal height
Extremities
Skin turgor
GU
NS
Visual field, fundoscopic examination (DR), general neurological examination and
screening for psychiatric disorders
Skin
Shin spot
193
Common causes
Causes
Symptoms and signs
Investigations
Medication mannitol administration, high protein intake
include TPN, diuretic use
Hyperglycemia history or family history of DM, poor
FPG, HbA1c, BUN, Cr, urine Sp.gr., uOsm
Solute diuresis
control DM, steroid use, recurrent infection, diabetic
retinopathy, shin spot
Primary
polydipsia
DI
Psychiatric disease, more polyuria in daytime
Urine Sp.gr., uOsm, water deprivation test,
low to normal serum sodium
Nocturia, weight loss
Central DI head trauma, neurosurgery, postpartum
Urine Sp.gr., uOsm, water deprivation test,
hemorrhage, prefer cool drinks, sudden onset,
normal to high serum sodium, electrolyte,
nocturia, pregnancy, malignancy (weight loss,
anorexia, bowel habit change, dysphagia, bleeding per calcium, albumin, phosphate, CBC, bone
vagina, fever night sweat, tinitus), abnormal palpable
survey, CT brain, MRI pituitary protocol
mass, bitemporal hemianopia, PV
(posterior pituitary bright spot in MRI
Nephrogenic DI medication (lithium, cisplatin, foscanet,
pituitary presence in 95% of patients
amphotericin B, demeclocycline, methoxyflurane,
without CDI, absence in 20% of normal
foscanet), multiple myeloma (bone pain, anemia),
aging)
malignancy (constitutional symptoms, localized
symptoms), tuberculosis, gradual onset
194
• Solute dieresis: uOsm >300 mOsm/kgH2O, uOsm / sOsm >
0.9
‣ Electrolyte
‣ Non-electrolyte
• Water dieresis: uOsm <250 mOsm/kgH2O, uOsm / sOsm < 0.9
‣ Primary polydipsia
‣ DI
๏ Central
๏ Nephrogenic
195
Water deprivation test
• Procedure
‣ NPO: initiation of test depends on the severity of DI
๏ Routine case: after dinner of the day before the test
๏ More severe case: early in the morning of the test
‣ At the start of the test: obtain sOsm, uOsm, serum electrolyte, plasma AVP
‣ Hourly: measure of urine volume, uOsm, body weight, blood pressure
‣ Endpoint: any of the followings
๏ Body weight decreases by ≥3%
๏ Presence of orthostatic hypotension
๏ uOsm change <10% over 2 consecutive measurements
๏ Serum sodium > 145 mEq/L
‣ At the endpoint
๏ Obtain sOsm, uOsm, serum electrolyte, plasma AVP
๏ Administer of AVP 5 U or DDAVP 1 µg subcutaneously
‣ Hourly: measure of uOsm, urine volume for 2 hours
• Interpretation
196
‣ After water restriction
๏ uOsm >600 mOsm/kgH2O suggests primary polydipsia
๏ uOsm <600 mOsm/kgH2O suggests DI and minority of primary polydipsia
‣ After AVP/DDAVP administration
๏ Unequivocal uOsm
➡ < 10% increase: NDI, primary polydipsia
➡ > 50% increase: CDI
๏ Equivocal uOsm
➡ 10-50% increase
- Non-diagnostic result
- Need correlation between sOsm and plasma AVP level
197
HEMATURIA
198
DEFINITION
• Presence of RBCs > 3 cells/HPF
• Gross hematuria: presence of RBCs in
urine enough to turn it in red or brown
• Microscopic hematuria: detectable
RBCs only in microscopic examination
199
ETIOLOGIES
Negative heme in urine
Porphyrins prophyria, lead poisoning, pellagra
Drugs adriamycin, chloroquine, desferoxamine, levodopa, methyldopa,
metronidazole, nitrofurantoin, phenazopyridine, phebolphthalein,
phenytoin, prochlorperazine, quinine, rifampicin, sulfonamide
Foods artificial food coloring, beets, blackberries, blueberries, fava beans,
paprika, rhubarb
Positive heme in urine
Hemoglobinuria (hemolysis)
Myoglobinuria (rhabdomyolysis)
Nonhematuria
Hematuria
Upper tract pyelonephritis, nephrolithiasis, hypercalciuria, hyperuricosuria,
trauma, papillary necrosis, ureteral stricture, sickle cell disease, renal
infarction, arteriovenous malformation, renal tuberculosis, ADPKD, renal
cell carcinoma, transitional cell carcinoma of renal pelvis or ureter
Non-glomerular in origin
Lower tract cystitis, urethritis, prostatitis, bladder polyp, Schistosoma
haematobium infection
Uncertain Exercise hematuria, benign hematuria, over-anticoagulation,
factitious hematuria
Glomerular in origin
Gross hematuria IgAN, PIGN, pauci-immune GN, LN, MPGN
Microscopic hematuria Immune complex diseases (IgAN, PIGN, LN,
MPGN), pauci-immune GN, anti-GBM (anti-GBM disease, Goodpasture’s
syndrome), Hereditary nephritis (Alport’s syndrome, thin basement
membrane disease), other glomerular diseases (FSGS, MN)
200
APPROACH TO
THE PATIENTS
201
History taking
General
appearance
Body weight change, fever
HEENT
sinusitis
CVS
Orthopnea, paroxysmal nocturnal dyspnea (PND)
RS
Wheezing, hemoptysis
GI
Jaundice, alcohol drinking, family history of liver disease, viral hepatitis (blood transfusion,
unsafe sex, IVDU, tattoo) , constipation, palpable intraabdominal lymph nodes
KUB
Urine (volume, foamy urine, hematuria, nocturia, passing stone)
GU
Bleeding per vagina, palpable breast mass, abnormal nipple discharge
NS
Seizure, psychosis, polyneuritis multiplex, subarachnoid hemorrhage
Dermatology
Rash, photosensitivity, hair loss, oral ulcer
Rheumatology
Arthritis
Hematology
Palpable lymph nodes, fever, night sweat, anemia, abnormal systemic bleeding, bone pain
Infections
Respiratory tract, skin and soft tissue infection with lag period, synpharyngitis, chronic infection
Medications
NSAIDs, PTU, hydralazine, anti-TNF, minocycline, methydopa, INH, chlorpromazine,
pyrazinamide, D-penicillamine, heroine
Family history
Sensorineural hearing loss, eye disease, chronic kidney disease
202
Vital signs
Body temperature, BP
General
appearance
Body weight, sign of chronic liver disease
HEENT
Anemia, jaundice, cervical lymphadenopathy, oral ulcer, thyroid examination, exophthalmos, lid lag/
retraction, tender on sinus, saddle nose deformity, anterior lenticonus
CVS
JVP, PMI, murmur
RS
Tracheal deviation, decreased breath sound, consolidation sign, wheezing, creptiation
Abdomen
Liver and spleen examination, shifting dullness, fluid thrill, bimanual palpation
Extremities
Edema, should pad sign, nail dystrophy, absent of patella
GU
NS
Polyneuritis multiplex, flapping tremor, visual acuity, Tinel and phalen test, whispering sound
Skin
Tattoo, malar and discoid rash, photosensitivity, hair loss, vasculitis lesion
203
red-brown urine
Non-hematuria
• Negative heme in urine: drugs, food, porphyrins
• Positive heme without RBC in urine
‣ Hemoglobinuria (hemolysis): low serum haptoglobin, indirect hemolytic evidences
‣ Myoglobinuria (rhabdomyolysis)
Picture A
The pictures show urine of the patient with rhabdomyolysis from
electrical injury on A) 1st day (comparing with black plastic
board on the right)
204
Hematuria
Hematuria: RBC >3 /HPF in urine
• Only in gross hematuria: 3 glass test
‣ Initial hematuria: bleeding from urethra
‣ Terminal hematuria: bleeding from bladder
‣ Total hematuria: bleeding from kidney or ureter
• Microscopic hematuria
‣ Non-glomerular hematuria
๏ Urinary tract infection (UTI)
๏ No UTI
➡ Imaging: plain KUB, IVP, ultrasound, CT scan
➡ Cystoscopy: in age >40 years old or high index of suspicious
➡ Cytology: in age <40 years old or low index of suspicious
‣ Glomerular hematuria: blood test and renal biopsy
205
Differentiate glomerular versus non-glomerular hematuria
Glomerular hematuria
Non-glomerular hematuria
Urine color
Dark red, brown, cola colored,
smoky
Bright red
Clots
-
+
Proteinuria >500 mg/d
+
-
RBC morphology
Dysmorphic
Isomorphic
Hypertension
+
-
Edema
+
-
Urinary voiding symptoms
-
+
Back or flank pain
+
+
Renal function
Reduced
Normal
Family history
+
+
Trauma
-
+
Upper respiratory tract infection
+
-
Fever, rash
+
-
206
Complement levels in acute glomerulonephritis
Low C3 and C4
Lupus nephritis
Cryoglobulinemia
Bacterial endocarditis
Shunt nephritis
MPGN type 1
Low C3 and normal C4
Normal C3 and C4
Post-infectious GN
MPGN type II (dense deposition
disease)
Polyarteritis nodosa
ANCA-associated GN
Hypersensitivity vasculitis
Henoch-Scholein purpura
Anti-GBM disease
Goodpasture’s syndrome
IgA nephropathy
207
PROXIMAL MUSCLE
WEAKNESS
208
ETIOLOGIES
• Myopathy
‣ Inflammatory myopathy
๏ Dermatomyositis
๏ Polymyositis
๏ Inclusion-body myositis
๏ Infections: HIV, influenza, coxackie virus,
Trichinella spiralis
‣ Non-inflammatory myopathy
๏ Electrolyte imbalances: hypokalemia, hyperkalemia, hypophosphatemia, hypermagnesemia, hypocalcemia, hypercalcemia
๏ Endocrinopathies: hyperthyroidism,
Cushing syndrome, DM
๏ Metabolic causes: glycogen storage diseases, lipid storage myopathy, mitochondrial disease
๏ Muscular dystrophy (MD): Duchene MD,
Becker MD, fascioscapulohumeral MD,
limb-girdle MD, scapuloperoneal syndrome
๏ Congenital myopathies: central core disease, Nemalin myopathy, centronuclear
myopathy
• Neuromuscular junction (NMJ) disease
‣ Presynaptic defect: Lambert-Eaton myasthenic syndrome, Botulism, neurotoxin snake
venom
‣ Postsynaptic defect: myasthenia gravis
• Polyneuropathy: Guillain-Barre syndrome (GBS),
chronic inflammatory demyelinating polyneuropathy (CIDP), porphyria
๏ Drugs: corticosteroid, statin, colchicines,
chloroquine, alcohol, zidovudine
209
APPROACH TO THE PATIENTS
Differentiate site of lesions of muscle weakness
• Upper motor neuron: long tract signs
• Lower motor neuron
‣ Distal muscle weakness
‣ Proximal muscle weakness
๏ Anterior horn cell diseases: history of lead exposure, poliomyelitis, familial spinal atrophy
๏ Peripheral neuropathy: loss of sensation
๏ NMJ diseases: fluctuation of symptoms
๏ Myopathies: no loss of sensation, no fasciculation, normoreflexia
➡ Family history of muscle weakness, specific sites of muscle weakness, hepatosplenomegaly
➡ History of infections, muscle pain, malignancy
➡ Skin lesions: V sign, shawl sign, guttron papules
➡ Medications
➡ Check electrolytes, phosphate, magnesium, calcium
➡ Check plasma glucose, morning cortisol, thyroid function
➡ Check CPK
210
HYPERTENSION IN THE
YOUNG
211
DEFINITION
• Hypertension at the age of onset <20 years
212
ETIOLOGIES
• Renal diseases
‣ Renovascular diseases: renal artery stenosis (fibromuscular dysplasia, atherosclerosis), polyarteritis nodosa
‣ Renal parenchymal diseases: nephritic syndrome, chronic kidney disease
• Endocrinopathies: hypothyroidism, hyperthyroidism, acromegaly, pheochromocytoma, Cushing syndrome, hyperaldosteronism, congenital adrenal hyperplasia
• Cardiovascular diseases: coarctation of aorta, Takayasu’s arteritis
• Lung diseases: obstructive sleep apnea
• Drugs: estrogen, herbs, amphetamine, cocaine, NSAIDs, corticosteroid, decongestants, diet pills, psychiatric
drugs (buspirone, carbamazepine, clozapine, fluoxetine, lithium, tricyclic antidepressant, cyclosporine)
• Pregnancy-induced hypertension: preeclampsia, eclampsia
• Neurological diseases: dysautonomia, increased intracranial pressure
213
APPROACH TO
THE PATIENTS
214
History taking
• Medications, last menopausal period, history of
claudication, snoring, endocrinopathies
• Coarctation of aorta: BP 4 extremities, delayed radiofemoral pulses, associated diseases (Turner
syndrome)
• Family history of DM, hypertension: suggests essential hypertension
• HEENT: lid lag, lid retraction, thyroid examination,
cushingoid appearances, enlarged tongue, cutis
verticis gyrata
• CVS: unequal pulses, bruits (abdominal, renal,
subclavian)
• Extremities: spade hands
• Genitalia: ambiguous genitalia
• NS: bilateral hemianopia, fundus examination (silver wire, copper wire appearance, A:V ratio, AV
nicking)
215
Investigations
• Serum electrolytes, urine electrolytes, sOsm, uOsm
• BUN, creatinine, UA
• Doppler renal ultrasound, renal artery MRA, renal angiogram
• EKG: LVH
• CXR: rib notching, reverse three sign
• Aldosterone-renin ratio (ARR) ≥20 ng/dL per ng/mL/hour: plasma aldosterone concentration (PAC) ≥15 ng/dL,
plasma renin activity (PRA) <1.0 ng/mL/hour
• Urine VMA, urine metanephrine, plasma metanephrine, imaging, MIBG scan
• Thyroid function test
• 1-mg overnight dexamethasone suppression test
• Serum IGF-1
216
ANCA-ASSOCIATED GLOMERULONEPHRITIS
(ANCA-ASSOCIATED GN)
Definition
• Necrotizing vasculitis, with few or no immune deposits, predominantly affecting small vessels (i.e., capillaries, venules, arterioles,
and small arteries), associated with myeloperoxidase (MPO) ANCA
(anti-neutrophil cytoplasmic antibodies) or proteinase 3 (PR3) ANCA.
Not all patients have ANCA
Related terms
• Pauci-immune glomerulonephritis
Epidemiology
• Incidence 3.9 cases / 1,000,000 people
• Renal-limited ANCA-associated vasculitis 23 – 25%
• ANCA-negative pauci-immune GN 27 – 38%
Related Glossary Terms
Drag related terms here
Index
Find Term
Chapter 1 - Common glomerular diseases
APPROACH TO THE PATIENTS SUSPECTED
GLOMERULAR DISEASES
Clinical presentations of glomerular diseases
• Proteinuria: varying in degree of proteinuria, more specific in proteinuria > 2 g/day
• Glomerular hematuria
• Decreased GFR: oliguria, anuria, uremic symptoms
• Salt and water retention: edema, hypertension
Differentiate between glomerular syndromes
• Nephritic syndrome versus nephrotic syndrome
Nephritic syndrome
Decreased of GFR: edema, oliguria,
hypertension, azotemia
Active urine sediments: dysmorphic RBC, RBC
cast
Subnephrotic-ranged proteinuria
Nephrotic-ranged proteinuria
Hyperlipidemia
Nephrotic syndrome Hypoalbuminemia
Edema
Lipiduria: oval fat body, fatty cast
• Asymptomatic versus symptomatic
• Define onset of disease: history of urine volume and characters
change, nocturia, edema, broad cast in urine (subacute to chronic
onset), ultrasound kidney
‣ Acute onset: days to week
‣ Subacute onset: weeks to month
Index
Find Term
Chapter 1 - Nephritic syndromes
CHRONIC KIDNEY DISEASE (CKD)
Definition
Either of the following present for > 3 months
• Markers of kidney damage (one or more)
‣ Albuminuria ≥ 30 mg/day, or albumin-to-creatinine ratio ≥ 30 g/ g
creatinine
‣ Urine sediment abnormalities
‣ Electrolyte and other abnormalities due to tubular disorders
‣ Abnormalities detected by histology
‣ Structural abnormalities detected by imaging
‣ History of kidney transplantation
• Decreased GFR: < 60 ml/min/1.73 m2
Index
Find Term
ETIOLOGIES OF NEPHROTIC SYNDROME
(NS)
Secondary NS
• Infections: HBV, HCV, HIV, tuberculosis, infective endocarditis, visceral abscess, shunt nephritis
• Autoimmune diseases: SLE, rheumatoid arthritis, SjÖgren syndrome
• Medications: NSAIDs, gold, D-penicillamine, heroin
• Malignancies: hematologic malignancy (Hodgkon’s and non Hodgkin’s lymphoma, plasma cell dyscrasia), solid tumors
• Metabolic abnormalities: DM, hypertension, obesity
• Miscellaneous diseases: reflux nephropathy, analgesic, nephron loss,
amyloidosis
Index
Find Term
Chapter 1 - Asymptomatic proteinuria
GLOMERULAR HEMATURIA
Hematuria
• Bed rest
• Analgesics
• Hydration: to increase urine flow rate to 2 – 3 L/day
• Avoid sports which at a risk of abdominal trauma: such as rugby, boxing
Index
Find Term
Chapter 1 - Approach to the patients with suspected of glomerular diseases
HEMATURIA
Definition
• Presence of RBCs > 3 cells/HPF
• Gross hematuria: presence of RBCs in urine enough to turn it in red
or brown
• Microscopic hematuria: detectable RBCs only in microscopic examination
Index
Find Term
Chapter 5 - Oliguria and anuria
IGA NEPHROPATHY (IGAN)
Definition
• Predominance of IgA deposits, either alone or with IgG, IgM, or both
in the glomerular mesangium
Epidemiology
• Occurs in all age groups
• Most common at age of 10 – 20 years, 80% of patients are age of 16
– 35 years at the time of biopsy
• More common in males than females: male / female ratio 2:1 to 6:1
Pathogenesis
• Multi-hit mechanism
‣ Hit 1: Increased circulating galactose-deficient (at hinge region
of heavy chain) IgA1
‣ Hit 2: Production of anti-glycan antibodies that recognize galactose deficient IgA1
‣ Hit 3: Formation of pathogenic circulating immune complexes
from autoantigen (galactose-deficient IgA) and O-glycanspecific antibodies
‣ Hit 4: Deposition of pathogenic immune complexes in the mesangium, activation of mesangial cells, and induction of glomerular
injury
Index
Find Term
Chapter 2 - Approach to the patients with AKI
MINIMAL CHANGE DISEASE (MCD)
Related terms
• Lipoid nephrosis
• Minimal change glomerulopathy
Epidemiology
• 10 – 15% of primary glomerular syndrome in adults
• 70 - 90% of nephrotic syndrome in children under age of 10 year,
and 50% of older children
• Male : female ratio 2:1 – 3:1
Pathogenesis
• Remains unclear
• Most likely a consequence of abnormal regulation of T cells
• Primary MCD
• Secondary MCD
‣ Infections: virus, parasite
‣ Drugs: NSAIDs, gold, lithium, interferon, ampicillin, rifampin, trimethadione, tiopronin
‣ Tumors: Hodgkin’s disease, lymphoma, leukemia, solid tumors
‣ Allergies: food, dust, bee stings, pollen, poison ivy, poison oak,
dermatitis herpitiformis
‣ Others: SLE, following hematopoietic cell transplantation
Index
Find Term
NEPHRITIC SYNDROMES ETIOLOGY
Immune complex glomerulonephritis
• Lupus nephritis (LN)
• Post-infectious glomerulonephritis (PIGN)
• IgA nephropathy (IgAN) and Henoch-SchÖnlein purpura (HSP)
• Subacute bacterial endocarditis
• Membranoproliferative glomerulonephritis (MPGN)
• Cryoglobulinemia
Anti-glomerular basement membrane (GBM)
• Anti-GBM disease
• Goodpasture’s syndrome
Pauci-immune glomerulonephritis
• ANCA-associated glomerulonephritis
‣ Granulomatosis with polyangitis (GPA) or Wegner’s granulomatosis
‣ Eosinophilic granulomatosis with polyangitis (EGPA) or ChurgStrauss syndrome
‣ Renal limited pauci-immune glomerulonephritis
• Double positive disease
Index
Find Term
Chapter 1 - Nephritic syndromes
POST-INFECTIOUS GLOMERULONEPHRITIS
(PIGN)
Definition
• An immunologic response of the kidney that occurs following a nonrenal infection
Related terms
• Bright disease
• Streptococcus-related glomerulonephritis
• Post-streptococcal glomerulonephritis
Epidemiology
• Incidence and prevalence are lower in developed countries
• Incidence 0.6 – 39.24 and prevalence 0.02 – 10.14 cases / 100,000
population
• Median age of onset 36 – 58 years
• High prevalence in DM, alcoholism
• 30 – 50% associated with gram negative bacilli infection
Index
Find Term
Chapter 2 - Approach to the patients with AKI

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