APPROACH TO proteinuriaHEMATURIA (1).pptx

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1. APPROACH TO PROTEINURIA & HEMATURIA Dr Nishan Bhurtyal

2. Basic concepts Each kidney in the human contains about 1 million nephrons Nephron is the functional unit of the kidney Each nephron contains a tuft of glomerular capillaries: glomerulus A long tubule in which the filtered fluid is converted into urine on its way to the pelvis of the kidney

3. The Glomerulus Made of a tuft of specialized capillaries supplied by an afferent arteriole, drained by an efferent arteriole, enclosed in Bowman’s capsule Entire tuft of capillaries is covered by the epithelial cells

4. Glomerular filtration barrier Filtration barrier: the endothelium of the capillary a basement membrane a layer of epithelial cells (podocytes) with the slit diaphragm Glycocalyx: Layer of negatively charged matrix over the cappilary endothelium

5. Evaluating for kidney disease GFR Urine analysis an microscopic evaluation Imaging Histology

6. Urine evaluation

7. Proteinuria Link between proteinuria and kidney disease first demonstrated by Richard Bright (1827) Prevalence of proteinuria on a routine screening of healthy subjects has been found to be as high as 4.9% Normal daily protein excretion < 150mg/dl,

8. Classification Based on amount: Nephrotic : >3.5gm/day Non- nephrotic : Microalbuminuria : 30-300mg albumin/day Macroalbuminuria : >300mg/day Based on pathophysiology Glomerular Tubular Overflow Post renal Isolated proteinuria: proteinuria without abnormalities in the urinary sediment, the absence of hypertension or diabetes. protein excretion is less than 3.5 g/day (non- nephrotic ), Orthostatic proteinuria: characterized by increased protein excretion in the upright position but normal protein excretion when the patient is supine

9. Pathophysiology Glomerular Increased glomerular capillary permeability to protein Primary or secondary glomerulopathy 2.0-4.0gm/day Tubular Decreased tubular reabsorption of proteins in glomerular filtrate Tubular or interstitial disease 0.15-2.0 Overflow Increased production of low-molecular-weight proteins Monoclonal gammopathy , leukemia Post-renal proteinuria  Inflammation in the urinary tract, UTI

10. Glomerular proteinurua Primary glomerulonephropathy Minimal change disease Idiopathic membranous glomerulonephritis Focal segmental glomerulonephritis Membranoproliferative glomerulonephritis IgA nephropathy Secondary glomerulonephropathy Diabetes mellitus Collagen vascular disorders (e.g., lupus nephritis) Amyloidosis Preeclampsia Infection (e.g., HIV, hepatitis B and C, poststreptococcal illness, syphilis, malaria and endocarditis) Gastrointestinal and lung cancers Lymphoma, chronic renal transplant rejection

11. Tubular and overflow proteinuria Tubular Hypertensive nephrosclerosis Tubulointerstitial disease due to: Uric acid nephropathy Acute hypersensitivity interstitial nephritis Fanconi syndrome Heavy metals Sickle cell disease NSAIDs, antibiotics Overflow Hemoglobinuria Myoglobinuria Light Chain disease Multiple myeloma Amyloidosis

12. Screening : The dipstick Routine test for urine analysis based on colour reactivity with tetrabromphenol blue, which is yellow in the absence of protein green in its presence. Sensitive to albumin but not other proteins

13. Interpreting the dipstick False Positives Very alkaline urine (UTI) Pigmented urine (Hematuria) Very concentrated urine (Sp.gravity>1.030) Contaminant with disinfectant pH>7 Iodinated contrast agent False negatives Not albumin (Multiple myeloma) Sp.gravity<1.003 Protein loss <300 to 500 mg/day (albumin <10–20 mg/day) Positively charged proteins : pH<4

14. Predictive value? The sensitivity, specificity and positive and negative predictive values of the dipstick test for detection of protein are 80.0%, 95.0%, 22.2% and 99.6% respectively

15. Urine microanalysis Fatty casts, free fat or oval fat bodies Nephrotic range proteinuria (> 3.5 g per 24 hours) Leukocytes, leukocyte casts with bacteria Urinary tract infection Leukocytes, leukocyte casts without bacteria Renal interstitial disease Normal-shaped erythrocytes Suggestive of lower urinary tract lesion Dysmorphic erythrocytes Suggestive of upper urinary tract lesion Erythrocyte casts Glomerular disease Waxy, granular or cellular casts Advanced chronic renal disease Eosinophiluria Suggestive of drug-induced acute interstitial nephritis Hyaline casts No renal disease; present with dehydration and with diuretic therapy

16. Transient proteinuria 8-12% of patient younger than 18 years, and 0.6-6% in an older population Due to alteration in glomerular permeability and proximal reabsorbtion . Causes: Urinary tract infection High dietary protein intake Acute febrile illness Heavy exercise within 24 hours Menstruation or vaginal discharge Drugs (especially non-steroidal anti-inflammatory drugs ) Dehydration Heat injury

17. Orthostatic proteinuria increased protein excretion in the upright position but normal protein excretion when the patient is supine common finding in adolescents, not in age >30

18. Quantification of proteinuria

19. Semi quantitative method Dipstick test Negative: 0mg/dl Trace: 15-30mg/dl 1+: 30-100mg/dl 2+:100-300mg/dl 3+:300-1000mg/dl 4+:>1000mg/dl Turbidity Precipitation of urine with sulfosalicyclic acid (SSA) Detects all types of protein Grades resultant turbidity from 0---4+

20. 24 hour urine protein Gold standard for quantifying proteinuria Is the collection adequate? – measure the 24 hour excretion of Creatinine

21. UPCR, UACR Urine protein creatinine ratio and urine albumin creatinine ratio are other methods to quantify proteinuria require a single sample for the estimation They can be very sensitive but have a wide confidence interval Influenced by muscle mass, diurnal variation

22. Interpreting UACR/UPCR UPCR is numerically the same as 24 hour urine protein That is a ratio of 0.2 is equivalent to 0.2 g of protein per day

23. RE-EVALUATION Changes occurred in the urine’s appearance Edema ? Hypertension? History of multisystem disease? Past or family history of kidney disease (including pregnancy related) present? Diabetes? Joint discomfort, a skin rash, eye symptoms, or Raynaud syndrome Any medications ? Are any other systemic symptoms, such as fever, night sweats, weight loss, or bone pain, present Does the patient have any risk factors for human immunodeficiency virus (HIV) infection or hepatitis

24. Further testing Antinuclear antibody Elevated in systemic lupus erythematosus Antistreptolysin O titer Elevated after streptococcal glomerulonephritis Complement C3 and C4 Levels are low in glomerulonephritides Erythrocyte sedimentation rate If normal, helps to rule out inflammatory and infectious causes Fasting blood glucose Elevated in diabetes mellitus Hemoglobin, hematocrit, or both Low in chronic renal failure that impairs hematopoiesis HIV, VDRL, and hepatitis serologic tests HIV, hepatitis B and C, and syphilis have been associated with glomerular proteinuria

25. Further testing Serum albumin and lipid levels Albumin level decreased and cholesterol level increased in nephrotic syndrome Serum electrolytes (Na + , K + , Cl -, HCO 3 -,  Ca 2+  and PO 4 2-) Provide a screening examination for any abnormalities following renal disease Serum and urine protein electrophoresis Results are abnormal in multiple myeloma Serum urate In addition to stones, elevated urate can cause tubulointerstitial disease Renal ultrasonography Provides evidence of structural renal disease Chest radiograph Can provide evidence of systemic disease (e.g., sarcoidosis )

26. Microalbuminuria Urine albumin 30-299mg/day Estimated by radioimmunoassay Seen In diabetic nephropathy, HTN, cardiac failure and viral illness Predicts the development of nephropathy in diabetes Correlates mortality in diabetics & hypertensives

27. Management Non specific Non pharmacological Pharmacological Disease specific

28. Complications of proteinuria Hypoalbuminemia Vitamin D deficiency Edema Hypocalcaemia Increased hepatic lipoprotein synthesis Reduces cellular immunity Atherosclerosis Tubular damage Alteration in coagulation factors

29. HEMATURIA The normal excretion rate of RBC in urine is around 1 million RBCs/24 hr, this equates to 1-3 RBCs/ hpf on microscopic examination of a urine specimen Hematuria - Presence of an abnormal quantity of red blood cells in the urine Can arise from any part of the kidneys or urogenital tract Can be a sign of serious underlying pathology of the kidneys or urinary tract Can occur due to non renal causes

30. Terminologies Gross hematuria- visible to the naked eye Microscopic hematuria- not visible to naked eye 3 or more RBCS/ hpf from 2 out of 3 properly collected urine specimen Isolated hematuria – occurs in an asymptomatic patient who has normal rate of albumin excretion, normal serum creainine , and normal blood pressure Transient/persistent hematuria Significant hematuria

31. ETIOLOGY Glomerular Hematuria IgA nephropathy Thin basement membrane disease Hereditary nephritis ( Alport's syndrome) Poststreptococcal glomerulonephritis Lupus nephritis Mesangial proliferative glomerulonephritis Hemolytic uremic syndrome Anaphylactoid purpura (HSP)

32. NON-GLOMERULAR HEMATURIA Upper urinary Tract Pyelonephritis Polycystic kidney disease Analgesic nephropathy Renal cell cancer Renal stones Renal infarction Ureteral stricture and hydroureteronephrosis Lower urinary Tract Bacterial cystitis (UTI) Benign prostatic hyperplasia Strenuous exercise Transitional cell carcinoma Instrumentation Urethral stricture

33. Systemic causes of hematuria Vasculitis Bleeding diathesis Sickle cell disease Primary malignancies Renal cell carcinoma (RCC) Transitional cell carcinoma (TCC); Prostate cancer; less commonly, squamous cell carcinoma

34. Metabolic causes of hematuria Hypercalciuria Hyperuricosuria Renal vascular causes of hematuria Arteriovenous malformation Thrombosis, embolus, dissecting aneurysm, Malignant hypertension Renal vein thrombosis

35. Drugs that can cause hematuria Analgesics- NSAIDS Anticoagulants, antiplatelets Cyclophosphamide Antibiotics- Rifampicin,Penicillins,nitrofurantoin Oral contraceptives Busulfan Quinine Vincristine

36. PATHOPHYSIOLOGY Glomerular hematuria – structural disruption in the integrity of glomerular basement membrane caused by inflammatory or immunologic processes. Extravastation of Rbc to the urinary space Chemicals may cause toxic disruptions of the renal tubules Calculi may cause mechanical erosion of mucosal surfaces in the genitourinary tract, resulting in hematuria .

37. APPROACH History Age of the patient Timing of hematuria Urinary symptoms Trauma, exercise Obstructive symptoms RFs: smoking, chemicals, radiation Drug history Family and travel history Age gender and ancestry major factors influencing work up

38. HISTORY TAKING Age- Wilms tumors common in preschool age children Acute postinfectious glomerulonephritis is more common in the school-aged population Malignancy – age >40 yrs is a much greater possibility than in younger people Gender: Premenopausal women may have pseudohematuria from menses or recent intercourse. Hematuria due to UTI more common in females Elder males may bleed from their prostate Lupus nephritis more commmon in female Men have a higher incidence of urinary tract cancer

39. HISTORY TAKING Risk Factors for Malignancy in Patients with Hematuria Age - >40 yrs Male gender History of cigarette smoking History of chemical exposure (cyclophosphamide, benzenes, aromatic amines, aniline dyes ) History of pelvic radiation Irritating voiding symptoms (urgency, frequency, dysuria) Prior urologic disease or treatment

40. Onset of associative symptoms: Patient having acute onset of dysuria and hematuria, flank pain, fever likely has an infection, stone. Patient with colicky unilateral flank pain and microscopic or macroscopic hematuria likely has a ureteral stone or a blood clot or sloughed renal papilae Preceding infection h/o recent upper respiratory or gastrointestinal infection. Onset of gross hematuria 2 to 3 days later suggests a diagnosis of IgA nephropathy, particularly In young adults. Hematuria 2 to 3 weeks after a pharyngitis suggests PSGN

41. Glomerular hematuria Early-morning periorbital puffiness, weight gain, oliguria , dark-colored urine, and edema or hypertension suggest a glomerular cause Passage of clots in urine suggests an extraglomerular cause

42. Systemic involvement Younger subjects with a purpuric rash, arthralgias , and gross or microscopic Hematuria may have HSP . Joint pains, skin rashes, and prolonged fever in adolescents and young adults suggest a collagen vascular disorder . Older patients with hematuria, proteinuria, profound constitutional symptoms, arthralgias , or respiratory symptoms may have vasculitis such as Wegener’s granulomatosis or microscopic polyangiitis

43. Lower urinary tract symptoms: Dysuria, urinary frequency, urgency, and urethral discharge points to an infectious or inflammatory process. BPH can cause hematuria and obstructive urinary symptoms such as urinary hesitancy, straining to void, dribbling and a sensation of incomplete emptying. Recent urologic interventions: Bladder catheterization, placement of an indwelling ureteral stent, or recent prostate biopsy may cause recurrent hematuria

44. Relation with micturition - Hematuria at the start of urination suggests a problem in the anterior urethra distal to the external sphincter Hematuria at the end of urination suggests a problem in the bladder neck or the prostatic urethra. Hematuria throughout urination suggests upper urinary tract or upper bladder disease Association with Pain: Hematuria alone does not cause pain unless it is associated with inflammation or acute urinary obstruction. Pyelonephritis and renal nephrolithiasis may present as flank pain. Pain from kidney stones often radiates to the groin. Bladder outlet obstruction may present as suprapubic pain or discomfort.

45. Relation with exercise Gross or microscopic hematuria can occur after strenuous exercise. Purely exercise-induced hematuria disappears within 2 to 7 days after vigorous exercise and is benign, however, it is a diagnosis of exclusion. May be due to direct trauma, shunting of blood away from the kidney to the muscles and increased glomerular permeability due to lactic acidosis

46. Family History : A personal or family history of hematuria with: deafness or ocular abnormalities with hematuria - Alport's syndrome hematuria with progressive chronic renal failure ADPKD . Urolithiasis Sickle cell disease Travel History to or Endemic area Schistosoma haematobium is a common cause of hematuria in certain endemic areas Tuberculosis

47. Drug History : Antibiotic : Rifampin ( orange urine) Analgesics (papillary necrosis) Cyclophosphamide (hemorrhagic cystitis) Anticoagulants, OCP Busulfan Quinine vincristine

48. PHYSICAL EXAMINATION BP- HTN with RCC, glomerulonephritis , ADPKD Hypotension due to acute blood loss Pulse - Atrial fibrilation Endocarditis possibility of renal embolic infarction Temperature - fever with UTI Lymphadenopathy : either supraclavicular or inguinal, may indicate a neoplastic process

49. Peripheral edema : may indicate hypoalbuminemia from glomerular or renal disease Rash, ecchymoses , or petechiae - coagulopathy Non blanching palpable purpura - vasculitis Lens abnormalities and hearing loss - Alport's syndrome Cachexia : may indicate malignancy

50. PHYSICAL EXAMINATION Tenderness of the flank or costovertebral angle: pyelonephritis Suprapubic tenderness: cystitis caused by infection, Palpable kidneys- Wilms tumor, Hydronephrosis Genital examination  : Possible sites of bleeding around the urethral meatus Look for Trauma- Foley’s Catheterisation For male, look for : BPH, prostatitis prostatic cancer, do DRE For female, look for : GYN/OBS abnormalities (vaginal bleeding)

51. INVESTIGATIONS Urinalysis BUN and serum creatinine levels Hematologic and coagulation studies Glomerulonephritis work up Urine culture for suspected UTI Imaging studies

52. URINALYSIS Urine dipstick test Highly sensitive (91-100%) but less specific (65-99%) Depends on the peroxidase activity of haeme protein Detection limit : 5-20 RBC/ microlitre Cannot differentiate between RBC, myoglobin and hemoglobin.

53. Dip stick False-positive test – May occur in upto 15% specimens myoglobinuria or hemoglobinuria , presence of semen , alkaline urine False negative- ascorbic acid, low PH, formaldehyde

54. URINALYSIS Next step after a dipstick requires spun urine sample and examination of the supernatant and the urinary sediment In case of hematuria the supernatant must be clear If supernatant is coloured Ingestion of food colours Beet root ingestion Porphyrin in urine Urates Drugs like rifampicin

55. URINALYSIS Phase-contrast microscopy 10 -20 microscopic fields examined under 400X magnification To distinguish glomerular from post glomerular hematuria . Sensitivity- 83-95%, specificity- 81-95% If more than 20% of cells are dysmorphic , this strongly suggests a glomerular origin of the bleeding espically when associated with RBC Casts Presnece of more than 5% acanthocytes specific for glomerular bleeding

56. Dysmorphic RBCand RBC casts

57. URINALYSIS Is there protein in the urine? Urinary protein excretion in the range of 1 to 1.5 g/24 hours may accompany tubulointerstitial disease Hematuria a/w nephrotic range proteinurea (> 3 or 3.5 g/24 hours or a urinary protein-to- creatinine ratio > 3 or 3.5 on a spot specimen) is typically associated with glomerular disease. The presence of nitrite or leukocyte esterase may indicate infection. Crystals in the urine indicate urolithiasis .

58. URINALYSIS Urine cytology Low sensitivity( 66-79%) high specificity( 95-100%) 3 consecutive morning first void urine- increase sensitivity. Indications Risk factors for urothelial carcinoma. Age greater than 40 years A history of smoking Occupational exposure to chemicals or dyes Previous episodes of gross hematuria A history of primarily irritative voiding symptoms RCC and prostate cancers are not detected by this test.

59. URINALYSIS If history and examination is suggestive of benign cause of hematuria (menstruation, vigorous exercise, trauma) repeat urinalysis after 48 hours after cessation of precipitataing cause If hematuria resolved then no furthur work up required.

60. Brenner The Kidney 10 th edition

61. IMAGING Asymptomatic microscopic hematuria – usually no source or cause is detected on imaging. Urinary tract imaging is not required in all patients who present with hematuria . Patients with macroscopic hematuria require complete evaluation of the upper and lower urinary tracts with upper urinary tract imaging and cystoscopy to exclude neoplasia .

62. IMAGING Intravenous pyelography   X-ray examination of the kidneys, ureters and urinary bladder that uses iodinated contrast material injected into vein Advantages Provides detailed images of the collecting structures. Is relatively inexpensive. Disadvantages low sensitivity in detecting masses smaller than 3 cm in diameter. limited use in evaluating the bladder and urethra. Requires contrast material

63. IMAGING Ultrasonography Advantages is excellent for confirming and characterizing a cyst Can detect hydronephrosis , nephrocalcinosis , tumor, urolithiasis Rapid, non invasive, readily available Can be used in patients with renal insufficiency as it does not require intravenous contrast. Choice in pregnancy Disadvantages: its accuracy is lower for detecting solid lesions smaller than 3 cm in diameter(82% sensitive for mass between 2-3cm) poor for evaluating the uroepithelium .

64. IMAGING Computed Tomography Advantages CT with contrast is the best imaging test for detecting small renal parenchymal masses, urolithiasis , and renal abscesses. as good as MRI at detecting small parenchymal masses Can detect mass <3cm missed by USG Disadvantages lacks sensitivity in detecting uroepithelial malignancies. Expensive Contrast induced nephropathy

65. IMAGING CT Urography Advantages The imaging modality of choice Provides the greatest anatomic detail and the highest sensitivities and specificities for a range of etiologies ranging from renal masses to stones to urothelial tumors. The noncontrast phase of CT can also detect renal stones with sensitivity of 94% to 98%, compared with 52% to 59% for IVU.

66. MR Urography Alternative imaging approach for patients with relative or absolute contraindications to CTU Advantages Does not require ionizing radiation. Better contrast resolution than CT Urography Use of MRI facilitates simultaneous evaluation of kidneys,ureters,renal arteries,renal veins helps in assesing tumor expansion Disadvantages Lower spatial resolution than CT urography Limited availability Long imaging time High cost Risk of nephrogenic systemic fibrosis

67. CYSTOSCOPY Indications Should be part of the evaluation of all patients with isolated hematuria over 40 years. Younger patients with risk factors for genitourinary malignancy

68. Renal biopsy Proteinuria >1 gm /day Glomerular hematuria, RBC casts Unexplained fall in GFR