August 2019

Approach to glomerular diseases

Abdallah S. Geara, MD

Assistant Professor of Clinical Medicine

Renal, Electrolyte and Hypertension

University of Pennsylvania

Abdallah.geara@uphs.upenn.edu

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Approach to proteinuria:

• Dipstick, quantification

Isolated glomerular hematuria:

• Collagen IV nephropathies

Nephrotic syndromes

Rapidly progressive glomerulonephritis

Nephritic syndromes

Acute/inpatient management of nephrotic and nephritic syndromes

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Proteinuria

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Different types of proteinuria

Glomerular:

• Mainly albuminuria

• Can be heavy

Tubular:

• Less than 3 g/d, the dipstick can be negative

• LMW (<25 KDa) proteinuria (α1-microglobulin, retinol-binding protein and in the β2-microglobulin

region)

Overflow:

• Albumin infusion

• Immunoglobulin (MM), Myoglobin (rhabdo), hemoglobin (intravascular hemolysis), Lysozyme

(AML)

Post-renal:

• Less than 1g

• UTIs, stones, tumors

Others:

• Transient: Acute illness, heavy exercise (mild <1g/d)

• Orthostatic: 2-5% of adolescents, (1-2 g/d), split urine collection, benign

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Proteinuria

Normal protein excretion is 80 mg/day (up to 150mg/d is considered normal)J Clin Invest, 1969, vol. 48 (pg. 1189 -1198

Isolated proteinuria:

• NO AKI, NO hematuria, NORMAL sediment

Direct measurement of albuminuria with traditional immunology-based laboratory methods,

such as immunonephelometry, immunoturbidimetry, and radioimmunoassay, can produce

results that vary considerably

Estimated albumin excretion rate (or eAER) can be calculated by multiplying the

spot UACR by the expected 24-hour creatinine generation

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The value of simultaneous measurements of urinary

albumin and total protein in proteinuric patients

Nephrol Dial Transplant. 2012 Apr;27(4):1534-41.

a) ROC curves for uAPR, uACR and uPCR

demonstrating the superiority of uAPR over

uACR in discriminating between tubular

pattern and non-tubular proteinuria pattern

on uPEI (n =1011).

b) (b) ROC curves for uAPR and the specific

tubular markers uNCR and

uβ₂CR demonstrating non-

inferiority of the uAPR for detecting tubular

proteinuria patterns on uPEI in the renal

outpatient subgroup (n = 248)

UAPR < 0.4 in tubular or overflow proteinuria

UAPR > 0.4 in glomerular proteinuria.

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Measurement of proteinuria

Urine dipstick:

• Detects albumin (sulfosalicylic acid test for tubular)

• False positive:

– IV contrast (iodinated)

– Alkaline urine (pH>8)

– Gross hematuria

– Antiseptics (chlorhexidine)

24h-urine protein:

• Limited by the amount of daily creatinine excretion

UPCR (first or second morning urine) correlated well with 24 hours); it assume 1g/d

of creat excretion

• UPCR depends on the muscle mass

• underestimate 24-hour proteinuria in blacks, in Hispanics, and in men,

• overestimate proteinuria in whites and in women.

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Glomerular structure

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Spectrum of Glomerular diseases

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Isolated hematuria

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Isolated hematuria

Transient hematuria is a relatively common finding over time in adults

Etiologies:

• IgA nephropathy: episodic gross hematuria

• hereditary nephritis (Alport’s syndrome): + family history

• Thin basement membrane nephropathy: + family history

Renal biopsy does not lead to a change in management (1 of 36 patients)

• 24/28 (86%) of cases of nephrotic range proteinuria

• 22/31 (71%) of cases of acute renal failure

• 58/128 (45%) of cases of chronic renal failure

• 9/28 (32%) of cases with hematuria and proteinuria

• 3/25 (12%) of cases with non-nephrotic proteinuria alone

• 1/36 (3%) of cases with hematuria alone.

Nephrol Dial Transplant. 1994;9(9):1255.

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Type IV collagen associated nephropathies

3 triple helical protomers:

• alpha-1-1-2

• alpha-3-4-5 (GBM)

• alpha-5-5-6

GBM is a meshwork of laminins, type IV

collagen and others.

GBM measures 300 to 350nm

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Thin basement membrane disease

(benign familial hematuria) or (AD Alport’s syndrome)

Epidemiology:

• Family history in 30-50%

• 5-9% of the general population

heterozygous mutations in either COL4A3 (α3) or COL4A4 (α4)

Biopsy:

• EM: diffuse thinning of the glomerular basement membranes (GBM)

• Immunostaining for alpha 3,4 and 5 is normal

• Some patients can have an FSGS lesion

Some of the patients develops proteinuria

No ocular or hearing loss

Prognosis is good:

CKD preventive approach

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Alport’s Syndrome

(hereditary nephritis)

often associated with sensorineural hearing loss and ocular abnormalities

Mutations in the α3 (ch 2), α4 (ch 2) and α5 (ch X) chains of type IV collagen

80% are X-lined, 15% AR, 5% AD

Clinically (genetic abnormality influence the phenotype):• Glomerular hematuria• Ocular abnormalities and progressive

sensorineural hearing loss • X linked: Male ➔ ESRD; female ➔ CKD

and proteinuria• 3% have post transplant anti-GBM disease

Biopsy:

Lamellated GBM or

abnormal deposition

of α3α4α5(IV) on

immunostaining

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Thin basement membrane

Patients with thin GBMs may have episodic macroscopic hematuria throughout life and

are at risk of developing proteinuria and progressive CKD.

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Nephrotic syndromes

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Definition of nephrotic syndrome

Nephrotic syndrome (clinical + lab features)

Proteinuria > 3.5g/24h Alb< 3.0 Edema

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Etiologies of nephrotic syndromes

Renal Sd: Systemic diseases

Minimal change disease (MCD)

(some are genetic: nephrin, podocin, alpha-

actinin-4)

SLE

Focal Segmental GlomeruloSclerosis (FSGS) DM

Membranous Nephropathy (MN) Amyloidosis (AL, AA, familial, senile, others)

Sec FSGS

Sec MCD

(NSAIDs, Hodgkin)

Sec MN

HepB, autoimmune diseases, thyroiditis,

carcinoma, meds (NSAIDs, penicillamine, gold,

and captopril).

Postinfectious and infection-associated glomerulonephritis, membranoproliferative

glomerulonephritis, and IgA nephropathy

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Associated findings with nephrotic syndrome

Nephrotic range proteinuria without nephrotic syndrome

Hypoalbuminemia:

• Urinary loss (?other factors)

Hyperlipidemia:

• Hyperchol, hypertrig

• Low oncotic pressure => ↑ lipoprotein secretion

Edema:

• Hypoalbuminemia => ↓ oncotic pressure

• Primary renal sodium retention

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Minimal Change Disease

90% of Nephrotic syndromes in children < 10yo

Biopsy:

• EM: diffuse effacement of the epithelial cell foot processes

Pt can show signs of hypovolemia (Low BP)

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Focal Segmental GlomeruloSclerosis (FSGS)

Most common primary etiology for nephrotic

syndrome (35%; up to 50% in blacks)

Secondary FSGS:

HIV Reflux nephropathy Previous

glomerular injury (hyperfiltration) Obesity

Meds (bisphosphonate; pamidronate; IFN therapy)

Histology:

• Focal vs diffuse to all the glomeruli

• Segmental vs global to the glomeruli

Primary podocytopathy:

• More acute onset, lower albumin, higher proteinuria, full

nephrotic syndrome

Collapsing FSGS: HIV and bisphosphonate

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Membranous nephropathy

Thickening of the BM with ED deposits without a proliferative lesion

Primary: Anti-Phospholipase A2 receptor (anti-PLA2R Ab)

Secondary: Hep B, autoimmune diseases, thyroiditis, carcinoma, and drugs (gold,

penicillamine, captopril, and NSAIDs)

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Amyloidosis

AA, AL, hereditary/familial or age-related

Localized vs systemic

Amyloid fibrils are insoluble polymers comprised of

low molecular weight subunit proteins

Co-deposition of other non-fibrillar substances:

GAGs, serum amyloid P-component (SAP, a

member) and specific apolipoproteins (E and J)

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Proteinuria

Hypoalbuminemia: due to loss in the urine

• ?hypoalb is out of proportion to the loss

• ?albumin level can be different for the same degree of proteinuria

• Hypoalbuminemia is more severe than PD patients with similar protein loss

Edema:

• Underfilling: decrease oncotic pressure

• Overfilling: primary salt/water retention in the collecting tubules (ANP)

• Less responsive to loops diuretics

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Hyperlipidemia

1. The low oncotic pressure ➔ it increases hepatic lipoprotein synthesis ➔

hyperlipidemia.

2. Decrease clearance ➔ hyperTrig

hyperChol and hyperTrig and lipiduria

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Thromboembolism

Pathogenesis:

• Urinary loss of antithrombin and plasminogen

• Increase plts activation

• Hyperfibrinogenemia

Usually Renal vein thrombosis are chronic (acute RVT causes infarction)

• It was never shown that chronic RVT increases the proteinuria or causes AKI

Therapy:

• No guidelines

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Main clinical consequences

AKI: less in children

Thromboembolism:

• venous, mainly membranous (>10g), renal venous thrombosis (asymptomatic, flank pain + AKI)

• Membranous: Occurs early in the disease, alb ≤ 2.8 increases the risk by 2.5x, doubles for every 1g/dL decrease.

• Other disease: alb <2g/dL; the risk doubles for every 1g/dL decrease of albumin

• ? decreased levels of antithrombin and plasminogen (due to urinary losses)

Infections: low IgG levels (due to urinary loss)

Proximal tubular dysfunction

• glycosuria, aminoaciduria, phosphaturia, bicarbonaturia, and vitamin D deficiency

Anemia

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Therapy

The approach is histology driven (steroids, CNI, anti-CD20, Cytoxan…)

Proteinuria:

• ACEI/ARBs (caution if the BP is low e.g. MCD)

Edema: low salt diet, diuretics (less delivery due to hypoalbuminemia , urinary prot

binding due to albuminuria)

Hyperlipidemia: reversible, statin

Hypercoag: prophylactic anticoagulation

• 2-3 => aspirin

• <2 => LMWH, warfarin

Most nephrotic syndromes are not an imminent risk of ESRD and the initial therapy

should address the symptoms and prevention of complications

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Nephritic disease

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Definition of nephritic syndrome

Rapidly progressive glomerulonephritis (RPGN):

• clinical syndrome

• + urine sediments + AKI (days, weeks or months).

Crescentic GNItis:

• Extensive crescent formation

Crescents:

• Cellular/fibrocellular/fibrous

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Mild nephritic: nephritic sediment, mild proteinuria (usually less than 1.5 g/day).

(No heavy proteinuria, edema, hypertension, and renal insufficiency)

Severe nephritic (RPGN) diffuse glomerulonephritis, heavy proteinuria (may be in the nephrotic range),

edema, hypertension, and/or renal insufficiency. Diffuse glomerulonephritis affects most or all of the glomeruli.

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Pathogenic classification

Immune complex:

• IgA nephropathy: mesangial IgA

• Post-infectious: subepithelial humps

• Lupus: Full house (IgG, IgA, IgM, C3 and C1q), mesangial+ subendothelial

• Cryoglobulin: pseudothrombi (intraluminal)

Pauci-Immune:

• Necrotising GN

• No immune deposits

• ANCA +; GPA or MPA

• ANCA – (5-10%); lysosome-associated membrane protein 2 (LAMP-2)

• Medication induced:

– Propylthiouracil, hydralazine, allopurinol, penicillamine, minocycline.

– MPO-ANCA positive, but some are both high-titer MPO and PR3 (hydralazine).

Anti-GBM

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Anti-GBM (Goodpasture’s disease)

Ab ((IgG 1 and 3) against an antigen intrinsic (GBM)

anti-GBM antibodies (which are typically immunoglobulin G but sometimes IgA or IgM) is

the NC1 domain of the alpha-3 chain of type IV collagen (alpha-3(IV) chain)

No systemic complaints

Biopsy:

• Linear deposits of IgG or IgA (no clonality)

• (diabetic nephropathy and fibrillary can cause linear deposits)

The Ab is short lived and relapses are rare

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Lupus nephritis

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IgA nephropathy

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Poststreptococcal or infection-related GNitis

The IC formation is likely in situ process

Antigen is a Nephritis-associated plasmin receptor (NAPlr)

Pathology:

• Diffuse proliferative, endocapillary proliferation, subepithelial humps

• Crescent is uncommon

• IF: C3 and IgG

• EM: subepithelial and subendothelial deposits

C3 and CH50 are depressed (C4 usually normal)

Infective endocarditis/Shunt nephritis:

• C3 can be depressed, ANCA can be positive, Crescentic GN is more frequent

• Some patients have a pauci-immune biopsy

Staph-associated GNitis:

• Middle-aged to older adults with concurrent infection, some have cutaneous vasculitis

• Low C3, kidney biopsy is similar to post-infectious

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Cryoglobulinemic

Cryoglobulins are Igs or a mixture of Igs + Complement components.

Clinical:

• Arthralgia, purpura, skin ulcers, glomerulonephritis, and peripheral neuropathy

Classification:

• Type I: Monoclonal Ig (IgG or IgM)

– Ischemic symptoms (skin, kidney…); thrombotic changes in the kidney

• Mixed cryoglobulin: (MPGN kidney changes)

– type II: monoclonal IgM (RF) + polyclonal IgG (HepC/B, HIV, autoimmune,

lymphoproliferative))

– type III: Polyclonal Igg and IgM

Lab:

• Normal C’ in type I; -RF

• Low C4 in type II; +RF

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General therapy

Pulse methylprednisolone (500 to 1000 mg/day) for 3 days

Consider plasmapheresis (especially with pulmonary involvement)

Prepare for kidney biopsy

Anticipate long term immunosuppression with infection prevention:

• Tb, hepatitis screening

• Immunization (influenza, pneumonia, Varicella)

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ANCA-associated Vasculitis

Testing for ANCA:

• ELISA

• Indirect IF

Drug-induced ANCA-associated vasculitis:

• (Mostly MPO), including hydralazine,

propylthiouracil, methimazole, carbimazole, and

minocycline.

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Plasma-cell associated disorder

Blood. 2012 Nov 22;120(22):4292-5

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Thank you