Proteinuria A common problem

byDr/ khalid s ramadan

Internist Zagazig University Hospitals , EgyptMouwasat Hospital Dammam, KSA

TAKE HOME MESSAGE

DON’T LET DON’T LET PERSISTENT PERSISTENT PROTEINURIA GO PROTEINURIA GO UNQUANTIFIED OR UNQUANTIFIED OR UNEVALUATED!UNEVALUATED!

DefinitionProteinuria is defined as excess serum protein excreted in

the urine. Normal protein excretion

< 150 mg total protein/d and ~30 mg albumin/d Microalbuminuria

30–300 mg albumin/dAlso defined as 30–300 μg albumin/mg creatinine It is not detectable by dipstick analysis.

Albuminuria and moderate proteinuria 300–3500 mg albumin/d

Nephrotic-range proteinuria >3500 mg albumin/d

Isolated proteinuria Proteinuria in the presence of an otherwise normal

urinary sediment, a radiologically normal urinary tract, and absence of known renal disease

Physiology/Pathophysiology• Protein flow through renal arteries =

121,000 g/day• Protein filtered through glomerulus = 1-2

g/day (< 0.001%)• Protein excreted in urine < 150 mg/day

(<1% of filtered)• Composition of normal urine: Tamm-

Horsfall protein 60-80%, albumin 10-20%.

Magnitude of proteinuria and protein composition depends on the mechanism of renal injury

Glomerular proteinuria results from glomerular disorders, which typically involve increased glomerular permeability; this permeability allows increased amounts of plasma proteins (sometimes very large amounts) to pass into the filtrate.

EXAMPLES Primary glomerular disorders (eg, membranous

nephropathy, minimal change disease, focal segmental glomerulosclerosis)

Secondary glomerular disorders (eg, diabetic nephropathy, preeclampsia, postinfectious glomerulonephritis, lupus nephritis, amyloidosis)

Tubular proteinuria results from renal tubulointerstitial disorders that impair reabsorption of protein by the proximal tubule, causing proteinuria (mostly from smaller proteins such as immunoglobulin light chains rather than albumin). Causative disorders are often accompanied by other defects of tubular function (eg, HCO3 wasting, glycosuria, aminoaciduria) and sometimes by glomerular pathology (which also contributes to the proteinuria).

EXAMPLESFanconi syndromeAcute tubular necrosisTubulointerstitial nephritisPolycystic kidney disease

Overflow proteinuria occurs when excessive amounts of small plasma proteins (eg, immunoglobulin light chains produced in multiple myeloma) exceed the reabsorptive capacity of the proximal tubules.

EXAMPLESAcute monocytic leukemia with

lysozymuriaMonoclonal gammopathyMultiple myelomaMyelodysplastic syndromes

Functional proteinuria occurs when increased renal blood flow (eg, due to exercise, fever, high-output heart failure) delivers increased amounts of protein to the nephron, resulting in increased protein in the urine (usually < 1 g/day). Functional proteinuria reverses when renal blood flow returns to normal.

EXAMPLESFeverHeart failureIntense exercise or activitysizures

• Orthostatic proteinuria is a benign condition that most commonly occurs in children and adolescents in which proteinuria occurs mainly when the patient is upright. Thus, urine typically contains more protein during waking hours (when people are more often upright) than during sleep. It has a very good prognosis and requires no special intervention

Subnephrotic Proteinuria

• Transient or orthostatic proteinuria• Hypertensive nephrosclerosis• Ischemic renal disease/renal artery

stenosis• Interstitial nephritis• All causes of nephrotic-range

proteinuria

Nephrotic Syndrome

• Def: nephrotic-range proteinuria, lipiduria, edema, hypoalbuminemia, hyperlipidemia.

• Implies glomerular origin of proteinuria.

• Clinical manifestations: edema, hypercoagulability, immunosuppression, malnutrition, +/− hypertension, +/− renal failure.

Nephrotic Syndrome (cont.)

• 75% have primary glomerular disease• 25% have secondary glomerular disease

• Medications: NSAIDs, heavy metals, “street” heroin, lithium, penicillamine, α-INF

• Infections: post-strep, HIV, hepatitis B/C, malaria, schistosomiasis

• Neoplasms: solid tumors, leukemias, lymphomas, multiple myeloma

• Systemic diseases: diabetes mellitus, SLE, amyloidosis

Diabetic Nephropathy

• #1 cause of ESRD in the U.S. (~35% of all ESRD).

• ~ 40% of all diabetics (type I and II) will develop nephropathy.

• Microalbuminuria (> 30 mg/day) develops after ~ 5 years. Proteinuria after 11-20 years. Progression to ESRD ~15-30 years.

EVALUATION OF THE PATIENT WITH PROTEINURIA

Clinical EvaluationHistory

• Diabetic history if applicable, esp. h/o retinopathy/neuropathy

• Known renal disorders• recent serious illness

(particularly with fever)• intense physical activity .• pregnancy

Clinical EvaluationHistory (cont.)

• sickle cell disease • cancer (particularly myeloma and

related disorders). • Medications and toxins• SLE • red or brown urine

(glomerulonephritis) • bone pain (myeloma).

Clinical EvaluationPhysical Examination

• BP and weight• Fundoscopic exam• Cardiopulmonary exam• Rashes• Edema

Clinical EvaluationUrine dipstick• Urine dipstick primarily detects albumin • positive urine dipstick test usually

suggests overt proteinuria. • Dipstick testing is also unlikely to detect

excretion of smaller proteins characteristic of tubular and overflow proteinuria

• Persistent proteinuria is a sign of a glomerular disorder and requires further testing

Clinical EvaluationSulfosalicylic Acid (SSA) Assay

• Turbidimetric assay based on precipitation of proteins.

• Measures all proteins.

Test sample

Clinical EvaluationUrine Sediment

• Red cell casts or dysmorphic RBCs suggest glomerulonephritis.

• WBCs suggest interstitial nephritis or infection.

• Lipid bodies suggest hyperlipidemia and possible nephrotic syndrome.

Clinical EvaluationQuantitation of Proteinuria

• 24-hr urine is gold standard, however is often not easily obtained.

• Spot urine protein/creatinine ratio is easier to get, nearly as accurate.

• ALWAYS GET A CREATININE WITH ANY QUANTITATIVE MEASURE OF URINE!

Clinical Evaluationother tests

• ultrasonography or CT to detect size of kidneys.

• lipid profile .• complement levels .• cryoglobulins • hepatitis B and C serology • antinuclear antibody testing • urine and serum protein electrophoresis • renal biopsy

Clinical EvaluationWho To Biopsy

• Non-diabetic nephrotic syndrome• SLE for classification• Planned use of immunosuppressive agents

in primary GNs (renal insufficiency, severe edema, hypertension)

• Diagnosis of plasma cell dyscrasias• < 2 gms proteinuria without other signs:

conservative therapy (biopsy resulted in management change in only 3/24 patients in prospective trial)

E v a l u a t i o n o f P r o t e i n u r i a

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MANAGEMENT OF PROTEINURIA

Managementbroad lines• Blood pressure control• Diabetic control• ACEI ,, calcium channel

blockers• Lipid control• Dietary protein restriction

ManagementACE Inhibitors

• Have benefit over and above blood pressure control.

• Type I Diabetes: Captopril use associated with slower progression, less proteinuria with or without co-existing HTN (Lewis et al, 1993, Viberti et al, 1994)

• Type II Diabetes: Enalapril use associated with slower progression, less proteinuria. (Ravid et al, 1993, 1996).

ManagementACE Inhibitors

• Nondiabetic disease: use of benazepril vs. placebo reduced by 38% the 3-yr progression of renal failure in various diseases. Reduction greater with higher proteinuria (Maschio et al, 1996).

• Similar data emerging for angiotensin II receptor antagonists.

Screening of proteinuria in diabetic patient

Prognosis

• Diabetic nephropathy: progression to ESRD over 10-20 years after onset of proteinuria.

• Isolated non-nephrotic proteinuria: 20-yr follow-up shows incidence ~40% renal insufficiency, ~50% HTN.

• Nephrotic syndrome: variable but poorer overall prognosis.

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