Glomerulopathies and Tubular disorders 1 Jeffrey T. Reisert, DO University of New England Physician Assistant Program 28 JAN 2010

Glomerulopathies and Tubular disorders1

Glomerulopathies and Tubular Glomerulopathies and Tubular disordersdisorders

Jeffrey T. Reisert, DOUniversity of New EnglandPhysician Assistant Program28 JAN 2010


Contact InformationContact Information

Jeffrey T. Reisert, DO103 Boulder Point Rd., Suite 3

Plymouth, NH 03264

603-536-6355603-536-6356 (fax)

[email protected]


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)


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


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


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


1) Acute nephritic syndrome1) Acute nephritic syndrome

AcuteOliguricResultant decreased glomerular filtration

rate (GFR)Focal or diffuse in kidney


2) RPGN2) RPGN

SubacuteOften used interchangeably with term

“crescentic GN”– Moon shaped lesions in Bowman’s space


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)


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)


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


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)


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 +


D) Idiopathic crescentic GND) Idiopathic crescentic GN

Middle aged menCrescent involvement in kidneysTx: Steroids


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


3) Nephrotic syndrome3) Nephrotic syndrome

>3.5g of proteinuria per 24 hoursGBM leaks protein that overwhelms

ability to resorbCharacteristic features


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)


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)


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


Treatment of proteinuriaTreatment of proteinuria

Dietary protein restrictionACE-InhibitorNSAID’s may alter glomerular dynamics


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


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®)


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


4) Abnormalities of urine sediment4) Abnormalities of urine sediment

Covered in prior lectureTwo worth mention


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


5) Chronic glomerulonephritis5) Chronic glomerulonephritis

Slow progressive development of CRFNot falling into other syndromesHematuria or proteinuria


Systemic nephropathiesSystemic nephropathies

Diabetic nephropathySystemic immune diseasesDeposition diseasesInherited disorders


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


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


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)


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


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)


Systemic immune diseasesSystemic immune diseases

Arteritis– Polyarteritis nodosa (PAN)– ANCA + arteritises– Lupus

Others


Polyarteritis nodosa (PAN)Polyarteritis nodosa (PAN)

Classic PAN is a systemic disorderFeatures

– HTN– Urine sediment– Renal insufficiency– Negative ANCA

Tx: Glucocorticoids, chemo agents


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)


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


Other systemic immune diseaseOther systemic immune disease

Rheumatoid arthritisSjögren'sMixed connective tissue disorderPolymyositis, dermatomyositis


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


Drug induced nephropathiesDrug induced nephropathies

NSAID’sGoldPenicillamine (Used in Rheumatoid

arthritis, primary biliary cirrhosis, other)IV heroinOthers


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)


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)


Infectious causes of glomerular Infectious causes of glomerular diseasediseaseViral

– Hepatitis B and C– HIV

Bacterial– Endocarditis– Endovascular infections (infected catheters)– Abscesses– Syphilis, leprosy, others


NeoplasiaNeoplasia

Malignancy can lead to renal failureSolid tumors

– Lung, breast, GI, kidney, ovarianLymphoproliferative disorders

– Hodgkin’s– Not typically seen in leukemia


Renal Cell CancerRenal Cell Cancer

Will cover here for completeness, though not a cause of primary renal insufficiency


Renal Cell CancerRenal Cell Cancer

Primary kidney cancer36,000 cases per year in USAMen>WomenAges 50-70Associations

– Smoking– Obesity


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


Renal cell cancer-EvaluationRenal cell cancer-Evaluation

CT of abdomen/pelvisChest x-ray (?mets)UrinalysisUrine cytology


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


…………moremore

Back to non cancerous renal diseases


Tubular disordersTubular disorders

Polycystic kidney disease (PKD)Medullary sponge kidneyRenal tubular acidosis


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


PKD symptomsPKD symptoms

Flank pain (mass effect)Infections risk higherStones in 15-20% pts

– Calcium oxalate– Uric acid

HTNProgressive RF


PKD-Diagnosis/TreatmentPKD-Diagnosis/Treatment

UltrasoundFamily treeControl HTNTreat UTI’s aggressivelyMay need dialysis eventually.


Medullary sponge kidneyMedullary sponge kidney

Sporadic or heritableCystic dilation of collecting ductsKidney stones, infections, hematuria


Renal tubular acidosis (RTA)Renal tubular acidosis (RTA)

Inherited or acquiredMetabolic acidosis develops (serum pH

falls)Non-anion gap (no unmeasured anions)Hyperchloremic


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


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


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


Type IV RTA-TreatmentType IV RTA-Treatment

Low K+ dietStop any offending meds

– K+ sparing diuretics such as spironolactone, amiloride, and triamterene

Mineralocorticoids


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


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

Documents

Glomerulopathies and Tubular disorders 1 Jeffrey T. Reisert, DO University of New England Physician Assistant Program 28 JAN 2010