glomerulopathies and tubular disorders 1 jeffrey t. reisert, do university of new england physician...
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Glomerulopathies and Tubular disorders1
Glomerulopathies and Tubular Glomerulopathies and Tubular disordersdisorders
Jeffrey T. Reisert, DOUniversity of New EnglandPhysician Assistant Program28 JAN 2010
Glomerulopathies and Tubular disorders2
Contact InformationContact Information
Jeffrey T. Reisert, DO103 Boulder Point Rd., Suite 3
Plymouth, NH 03264
603-536-6355603-536-6356 (fax)
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Introduction Introduction
Two Classifications of Glomerular Diseases– Primary (Primarily affect kidney)– Secondary (Diffuse or systemic diseases that
effect glomerulus in addition to other organ systems)
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AgendaAgenda
Primary Diseases causing glomerular disease– 1) Acute nephritic syndrome/Nephritis
– 2) Rapidly progressing glomerulonephritis (RPGN)
– 3) Nephrotic syndrome
– 4) Abnormalities of urine sediment
– 5) Chronic glomerulonephritis. Secondary Diseases glomerular disease
– Systemic diseases (several common) Tubular disorders
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General featuresGeneral features
Cause either:– Acute renal failure (days to weeks) or
– Chronic renal failure (months to years) Typical features:
– Oliguria (less than 400 cc/24 hours)
– and progressive azotemia Overlap exists between syndromes and
etiologies, with some presentations being more classic and some less common
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1) Acute nephritis and 2) RPGN1) Acute nephritis and 2) RPGN
Share similar features– Inflammation
– HTN
– Edema
– Casts (Red blood cell, others)
– Hematuria
– Sub nephrotic range proteinuria (less than 3.5g/24 hours)
Immune mediated
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1) Acute nephritic syndrome1) Acute nephritic syndrome
AcuteOliguricResultant decreased glomerular filtration
rate (GFR)Focal or diffuse in kidney
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2) RPGN2) RPGN
SubacuteOften used interchangeably with term
“crescentic GN”– Moon shaped lesions in Bowman’s space
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1) Nephritis and 2) RPGN 1) Nephritis and 2) RPGN EtiologiesEtiologiesIdiopathicReactive to known stimulus (IE: due to
infections)– A) Immune complex nephropathies (MC)– B) Anti-glomerular basement membrane
disease (Anti GBM) (Least common)– C) Pauci immune GN– D) Idiopathic crescentic GN
Multisystemic (due to lupus, others)
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A) Immune complex nephropathiesA) Immune complex nephropathies
Post streptococcal GN is most common (MC)– 10d after strep throat or 2w after skin infection
(impetigo)– Sporadic or epidemic (children)– Nephritis, hematuria, headache, nausea/vomiting
(N/V), back pain– Urine sediment, low complement levels (though C4
usually normal)– Circulating levels of antistreptolysin antibodies (MC
is ASO)– Treatment is supportive (Treat infection, control HTN,
diuretics if edema)
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B) Anti-GBM diseaseB) Anti-GBM disease
Antibodies against type IV collagenUsually causes RPGN not acute nephritisYoung menHave circulating levels of anti GBM
antibodiesRenal bx to DX shows IgG along GBMTx: Immunosuppressants
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ImmunosuppressantsImmunosuppressants
Used to treat many renal and other disorders Glucocorticoids most commonly used initially
– A wealth of side effects, though may be life saving or prevent ESRD
Chemotherapeutic agents– Cyclophosphamide (Cytoxan®)
– Many side effects (Immune suppression, cytopenia, others)
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C) Pauci Immune GNC) Pauci Immune GN
Glomerulonephritis without IG present3 types
– Idiopathic renal limited crescentic GN– Microscopic polyarteritis nodosa (PAN)– Wegener’s Granulomatosis
ANCA +
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D) Idiopathic crescentic GND) Idiopathic crescentic GN
Middle aged menCrescent involvement in kidneysTx: Steroids
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Nephritis and RPGN EvaluationNephritis and RPGN Evaluation
Biopsy often required– Immunofluorescence
Serum testing (May help alleviate need for biopsy)– C3 (Complement) levels
– Anti glomerular basement antibodies (anti GBM)
– Antineutrophilic cytoplasmic antibodies (ANCA)
– See figure 264-2
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3) Nephrotic syndrome3) Nephrotic syndrome
>3.5g of proteinuria per 24 hoursGBM leaks protein that overwhelms
ability to resorbCharacteristic features
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3) Nephrotic syndrome features3) Nephrotic syndrome features
Low serum albumen (leak/loss, or decreased hepatic synthesis)
Edema (etiology unclear)High cholesterol (increased hepatic
synthesis due to low oncotic pressure)LipiduriaHypercoagulability (possibly due to
altered Anti-Thrombin III, Proteins C or S)
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3) Nephrotic syndrome-Etiologies3) Nephrotic syndrome-Etiologies
Minimal change disease (often in children, light microscopy normal)
Focal and segmental glomerulosclerosis (etiology unclear, may not recover)
Membranous glomerulopathy (MC in adults 30-40% of cases. Thick GBM without inflammation)
Membranoproliferative GN (Thick GBM associated with infection, inflammation, or malignancy)
Diabetes mellitus nephropathy (later) Amyloidosis (later)
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3) Nephrotic syndrome treatment3) Nephrotic syndrome treatment
Treat precipitant, if knownPrevent complications of disease
– Treat edema with diuretics and salt restriction– Lipid lowering rx– Anticoagulation if appropriate
Decrease proteinuria– Next slide
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Treatment of proteinuriaTreatment of proteinuria
Dietary protein restrictionACE-InhibitorNSAID’s may alter glomerular dynamics
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ACE-Inhibitors-HistoryACE-Inhibitors-History
Inhibit formation of angiotensin converting enzyme II, a potent vasoconstrictor
Originally used to treat HTN aloneLater found to have other benefits (next
slide)Cough common
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ACE-InhibitorsACE-Inhibitors
Many on market– Captopril (Capoten®)– Enalapril (Vasotec®)– Many others
Now Angiotensin II Receptor blockers (no cough) (aka ARB’s)– Losartan (Cozaar®)– Irbesartan (Avapro®)
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ACE-I usesACE-I uses
HTN Retards progression of congestive heart failure Ischemic heart disease
– Acute MI– Decreases mortality– Decrease afterload– Help remodeling
Renal protective– Prevent progression to ESRD by perhaps decreasing glomerular
pressure– Decrease proteinuria– “All diabetics” with HTN or microalbuminuria
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4) Abnormalities of urine sediment4) Abnormalities of urine sediment
Covered in prior lectureTwo worth mention
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Hematuria-Two diseasesHematuria-Two diseases IgA nephropathy (Berger’s disease)
– Thin GBM disease– Common cause of benign hematuria– MC glomerulopathy worldwide– Typically gross hematuria after infection– Biopsy (IgA on immunofluorescence)– Treatment-supportive
Alport’s syndrome– Hereditary nephritis (covered preciously under
hematuria)– Associations include deafness, eye problems
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5) Chronic glomerulonephritis5) Chronic glomerulonephritis
Slow progressive development of CRFNot falling into other syndromesHematuria or proteinuria
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Systemic nephropathiesSystemic nephropathies
Diabetic nephropathySystemic immune diseasesDeposition diseasesInherited disorders
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DM nephropathy-OverviewDM nephropathy-Overview
MC etiol of ESRD30% of DM I20% of DM IIMechanisms may include hyperglycemia,
intraglomerular HTN, and glomerular hypertrophy
Effects– HTN, ESRD in 15 years
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DM nephropathy diagnosisDM nephropathy diagnosis
Mechanism– Injured filtration barrier with thickened GBM
Pores biggerElectrical charge barrier favors passage of proteinAfter present, 10-20% of nephropathy in 10 years
Screen DM every year– All DM type II– and after 5 years of DM type I
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Proteinuria-vs-MicroalbumenProteinuria-vs-Microalbumen
Normal protein– <150 mg per day (though most are <100)
Standard urine dipstick– 300-500 mg/d positive (“Overt proteinuria” or
merely “Proteinuria)Microalbumen is specialized test to
identify persistent protein excretion between 30-300 mg/d)
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Albumen to creatinine ratioAlbumen to creatinine ratio
Another measure of proteinuriaTakes into account the urine volume
producedNormally <30 mg/g (or <0.03 mcg/mg)If >30mg/d microalbumenuria, then this
measure is 100% sensitive for identifying microalbumenuria
Reported automatically now with microalbumen in some labs
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DM nephropathy treatmentDM nephropathy treatment
Treatment– Control DM and HTN (goal <130/80)– Weight loss– Treat other CV risk factors (lipids)– ?Protein restriction– ACE inhibitors– Angiotensin 2 Receptor blockers (ARB’s)
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Systemic immune diseasesSystemic immune diseases
Arteritis– Polyarteritis nodosa (PAN)– ANCA + arteritises– Lupus
Others
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Polyarteritis nodosa (PAN)Polyarteritis nodosa (PAN)
Classic PAN is a systemic disorderFeatures
– HTN– Urine sediment– Renal insufficiency– Negative ANCA
Tx: Glucocorticoids, chemo agents
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ANCA + ArteritisANCA + Arteritis
ANCA=Antinuclear cytoplasmic antibody Wegener's Granulomatosis Churg Strauss
– Seen in pulmonary patients
– Nephritic urine Henoch Schönlein Purpura
– No proven tx Systemic lupus erythematosus (SLE, Lupus)
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LupusLupus
ANA +Renal disease can range from nephritis to
nephrotic syndrome to CRF/ESRDGlomerular immune complex depositionWHO has VI classes of nephritisAlso have low complement levels, and
elevated anti-double stranded DNATreatment: Glucocorticoids, chemo
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Other systemic immune diseaseOther systemic immune disease
Rheumatoid arthritisSjögren'sMixed connective tissue disorderPolymyositis, dermatomyositis
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Deposition diseasesDeposition diseases
Amyloidosis– Abnormal protein in glomerulus– Biopsy shows apple green birefringence under
polarized light using Congo Red stain– Treatment largely unsuccessful
Others– Light chain deposition disease– Waldenström's macroglobinemia
Due to IgM secreting plasma cell clone
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Drug induced nephropathiesDrug induced nephropathies
NSAID’sGoldPenicillamine (Used in Rheumatoid
arthritis, primary biliary cirrhosis, other)IV heroinOthers
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Inherited glomerular diseasesInherited glomerular diseases
Alport’s syndrome– Hereditary nephritis– X-linked dominant transmission– Hematuria, proteinuria, progressive renal
failureSickle cell anemiaFabry’s disease (next slide)
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Inherited glomerulopathies-Fabry’s Inherited glomerulopathies-Fabry’s diseasedisease Lysosomal storage disorder X-Linked Accumulation of globotriaosylceramide (Gb3) Non-specific abnormalities
– ESRD in 50% of pts– Neurological (Neuropathies, TIA’s, Strokes)– Telegenctasias– Skin deposits– Corneal lesions (verticillata)-Don’t limit vision– Cardiac (Left ventricular hypertrophy, CAD, valvular
disease)
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Infectious causes of glomerular Infectious causes of glomerular diseasediseaseViral
– Hepatitis B and C– HIV
Bacterial– Endocarditis– Endovascular infections (infected catheters)– Abscesses– Syphilis, leprosy, others
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NeoplasiaNeoplasia
Malignancy can lead to renal failureSolid tumors
– Lung, breast, GI, kidney, ovarianLymphoproliferative disorders
– Hodgkin’s– Not typically seen in leukemia
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Renal Cell CancerRenal Cell Cancer
Will cover here for completeness, though not a cause of primary renal insufficiency
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Renal Cell CancerRenal Cell Cancer
Primary kidney cancer36,000 cases per year in USAMen>WomenAges 50-70Associations
– Smoking– Obesity
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Renal Cell Cancer-PresentationRenal Cell Cancer-Presentation
Hematuria Abdominal pain Mass May be found incidentally on CT, ultrasound, or
MRI for example looking for something else Others
– Fever
– Weight loss
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Renal cell cancer-EvaluationRenal cell cancer-Evaluation
CT of abdomen/pelvisChest x-ray (?mets)UrinalysisUrine cytology
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Renal cell cancer-TreatmentRenal cell cancer-Treatment
Nephrectomy for local diseaseResponsive to immune modulators (more
so than chemotherapies)– Interferon– Others
Death rates high/Hard to treat if disseminated disease
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…………moremore
Back to non cancerous renal diseases
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Tubular disordersTubular disorders
Polycystic kidney disease (PKD)Medullary sponge kidneyRenal tubular acidosis
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PKDPKD
Autosomal dominant (1:300) form more common than recessive form (1:10,000 or greater, presents as infant)
10% of ESRD in USALarge fluid filled kidneys, may
hemorrhage3rd-4th decadeAssociations: Liver cysts, aneurysms,
mitral valve prolapse
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PKD symptomsPKD symptoms
Flank pain (mass effect)Infections risk higherStones in 15-20% pts
– Calcium oxalate– Uric acid
HTNProgressive RF
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PKD-Diagnosis/TreatmentPKD-Diagnosis/Treatment
UltrasoundFamily treeControl HTNTreat UTI’s aggressivelyMay need dialysis eventually.
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Medullary sponge kidneyMedullary sponge kidney
Sporadic or heritableCystic dilation of collecting ductsKidney stones, infections, hematuria
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Renal tubular acidosis (RTA)Renal tubular acidosis (RTA)
Inherited or acquiredMetabolic acidosis develops (serum pH
falls)Non-anion gap (no unmeasured anions)Hyperchloremic
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RTA-typesRTA-types
Type 1-Distal– Alteration in H+ transport
– Urine pH high (>5.5)
– Hypercalcuria with higher risk for kidney stone formation
– Hypokalemic, hyperchloremic non-anion gap metabolic acidosis
– Associated with systemic disorders, such as lupus
– Treatment: Alkalinize urine-NaHCO3
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RTA types cont.RTA types cont.
Type 2-Proximal– Defective bicarbonate reabsorption
– Urine pH<5.5
– Hypokalemic, hyperchloremic non-anion gap metabolic acidosis
Type 3-Classification no longer used– Probably a combination of Types I and II
– Deficiency of carbonic anhydrase II
– May be result of rare autosomal recessive trait
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Type 4 RTAType 4 RTA
“Hyperchloremic distal RTA” Hyperchloremic, hyperkalemic acidosis Abnormal tubular secretion of K+ and H+ Acidic urine Insufficient aldosterone production or
aldosterone resistance Can be induced by NSAID’s, ACE-I, other meds Also seen in renal diseases, i.e.: DM
nephropathy
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Type IV RTA-TreatmentType IV RTA-Treatment
Low K+ dietStop any offending meds
– K+ sparing diuretics such as spironolactone, amiloride, and triamterene
Mineralocorticoids
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SummarySummary
Glomerulopathies can be due to both primary renal disorders and systemic diseases that affect kidneys secondarily
Early recognition may or may not prevent progression to ESRD
Biopsies may guide treatment
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Where to Get More InformationWhere to Get More Information
Harrison’s or Cecil’s Textbooks of Internal Medicine
Bakerman’s ABC’s of Interpretive Laboratory Data
A Handbook of Routine Urinalysis, Sister Mary Laurine Graff (may be out of print, but excellent pictures!)
The diagnosis of glomerular diseases, Arch of Internal Med 161, Jan 8, 2001, pg 25-34
Clinical Hypertension by Norman M. Kaplan