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proteinuria

Defined as > 50-100 mg of protein in 24 hour urine; > 3.5 grams in 24 hour urine indicates nephrotic syndrome. Etiology: 1) most renal parenchymal disease is associated with some degree of proteinuria 2) glomerular a) minimal change disease b) membranous nephropathy c) diabetic nephropathy d) focal sclerosis e) amyloidosis f) postinfectious glomerulonephritis g) IgA nephropathy h) membranoproliferative glomerulonephropathy i) obesity, especially morbid obesity (hyperfiltration) [7] - albuminuria, no pyuria, serum creatinine normal until late [7] j) other causes: endocarditis, hepatitis, endocarditis, HIV, Wegener's granulomatosis, lymphoma, malignancy nail-patella syndrome, von Gierke's disease k) pharmacologic agents - ACE inhibitors, i.e. captopril - gold salts - penicillamine - phenindione - probenecid - NSAIDs (NSAID nephropathy) 3) tubular a) generally < 1.5 grams/24 hours b) components: - beta-2 microglobulin - Tamm-Horsfall protein c) mechanism: tubular cell damage with inability to resorb filtered proteins d) congenital disorders - Fanconi syndrome - oculo-cerebral-renal syndrome - Laurence-Moon-Biedl syndrome e) hereditary disorders - Wilson's disease - cystinosis - hyperoxaluria - medullary cystic disease f) acquired - interstitial nephritis - acute tubular necrosis - sarcoidosis - heavy metals: Cd, Hg, Pb - Balkan nephropathy - pharmacologic agents - organ rejection - vitamin D intoxication - radiation - pyelonephritis - tuberculosis - obstructive uropathy - interstitial nephritis - idiopathic low-MW proteinuria g) associated systemic conditions - diabetes mellitus - lupus nephritis - polyarteritis nodosa - Wegener's granulomatosis h) pregnancy 4) overflow a) generally consists of immunoglobulin light chains - multiple myeloma - Waldenstrom's macroglobulinemia - amyloidosis - light chain nephropathy b) secondary glomerular proteinuria may be present c) lysozyme - monocytic leukemia - myelomonocytic leukemia d) hemoglobin - inherited or acquired hemolytic disorders - microangiopathic infection, i.e. malaria e) myoglobin - McArdle's disease - crush injury - succinylcholine toxicity - prolonged seizures - hyperthermia 5) orthostatic a) associated with ambulation b) resolves during sleep (supine) c) generally self-limited 6) transient a) mechanism - stimulation of renin-angiotensin-aldosterone axis - decreased renal plasma flow b) febrile illness c) hypertension d) exercise e) major motor seizures f) generally mild & self-limited Clinical manifestations: 1) edema/anasarca 2) nephrotic syndrome a) albuminuria b) increased serum cholesterol (usually) c) thromboembolism & renal vein thrombosis are common 3) hypertension may be present 4) signs & symptoms of systemic lupus erythematosus 5) signs & symptoms of systemic multiple myeloma 6) signs & symptoms of diabetes mellitus 7) hepatosplenomegaly associated with: a) amyloidosis b) lymphoma c) hepatitis d) malignancy e) endocarditis 8) gross hematuria may be present with glomerulonephritis Laboratory: 1) urinalysis a) significant proteinuria as determined by 24 hour urine with negative or trace protein by dipstick suggests overflow proteinuria b) foamy urine appearance c) microscopy - evidence of glomerular disease: RBC, RBC casts d) proteinuria + hematuria suggests glomerular disease even in the absence of RBC casts 2) urine protein/creatinine ratio (mg/mg) (screening & monitoring) [2] a) a value < 0.1 generally corresponds to 24 hour urine protein of < 100 mg/day b) a value > 0.15 = proteinuria [2] c) a value of 1.0 corresponds to 24 hour urine protein of ~ 500-1000 mg/day d) a value of > 3.0 generally corresponds to > 3 g/day, nephrotic level proteinuria 3) 24 hour urine protein - may be collected in 2 containers, recumbent & ambulating for assessment of orthostatic proteinuria - > 150 mg/24 hour = proteinuria [2] 4) serum chemistries a) serum urea nitrogen b) serum creatinine c) serum albumin d) serum total protein e) serum cholesterol 5) serum & urine protein electrophoresis 6) serologies a) anti-nuclear antibody (ANA) b) anti-glomerular basement membrane (anti-GBM) c) complement: C3, C4, CH50 d) cryoglobulins e) anti-neutrophil cytoplasmic antibody (ANCA) f) hepatitis profile g) streptozyme & antistreptolysin O (ASO) - post streptococcal glomerulonephritis 7) renal biopsy a) relatively safe b) indications - glomerular proteinuria > 1 gram/24 hours - abnormal serologic studies - azotemia c) contraindications: - small kidneys: suggests scarring & fibrosis - tubular proteinuria: not helpful - orthostatic proteinuria: not helpful Radiology: 1) renal ultrasound a) size of kidneys b) chronicity of disease c) evaluates obstruction d) often required for biopsy 2) CT angiography for suspected renal vein thrombosis Complications: - proteinuria independently predicts progressive kidney disease, cardiovascular disease & mortality, regardless of the estimated glomerular filtration rate (GFR) [2,4] - renal vein thrombosis in patients with nephrotic syndrome, membranous glomerulonephritis Management: 1) proteinuria generally not treated a) tubular b) orthostatic c) transient 2) overflow proteinuria - amyloidosis: treated as myeloma or with colchicine 3) glomerular proteinuria a) not all patients require therapy b) immunosuppressive therapy - glucocorticoids - cyclophosphamide (Cytoxan) - azathiaprine (Imuran) - cyclosporine (Sandimmune) - chlorambucil (Leukeran) c) general measures - ACE inhibitors or angiotensin receptor antagonist - lower intraglomerular pressure - decrease proteinuria, especially in diabetics - slow progression of chronic kidney disease [2] - Ca+2 channel blockers, diltiazem & verapamil preferable to dihydropyridines [3] - NSAIDs - low dose, use with caution (nephrotoxic) - may reduce proteinuria - may reduce glomerulosclerosis - protein restriction/balance - sodium restriction - potassium restriction may be indicated - no restrictions in activity

Related

nephrotic syndrome protein in 24 hour urine uromodulin; Tamm-Horsfall urinary glycoprotein; THP (UMOD)

Specific

hypertension & proteinuria microalbuminuria nephrotic range proteinuria (NRP)

General

sign/symptom

References

  1. Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 520-521
  2. Medical Knowledge Self Assessment Program (MKSAP) 11, 16, 17, 18. American College of Physicians, Philadelphia 1998, 2012, 2015, 2018. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  3. Prescriber's Letter 11(8): 2004 Antihypertensives in Patients with Hypertension and Proteinuria Detail-Document#: 200813 (subscription needed) http://www.prescribersletter.com
  4. Hemmelgarn BR et al for the Alberta Kidney Disease Network Relation Between Kidney Function, Proteinuria, and Adverse Outcomes JAMA. 2010;303(5):423-429 PMID: 20124537 http://jama.ama-assn.org/cgi/content/full/303/5/423
  5. Naderi AS, Reilly RF. Primary care approach to proteinuria. J Am Board Fam Med. 2008 Nov-Dec;21(6):569-74 PMID: 18988725
  6. Bomback AS, Kshirsagar AV, Amamoo MA, Klemmer PJ. Change in proteinuria after adding aldosterone blockers to ACE inhibitors or angiotensin receptor blockers in CKD: a systematic review. Am J Kidney Dis. 2008 Feb;51(2):199-211 PMID: 18215698
  7. NEJM Knowledge+ Nephrology/Urology