Interpretation of Urine Analysis

Home , Albuminuria, Glycosuria, Hemoglobinuria, Leukocyte esterase, Microalbuminuria, Proteinuria

UNDERSTANDING URINALYSIS

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Urine Analysis

Interpretation of • Appearance or color • Specific gravity • pH Urine Analysis • Leukocyte esterase March 2015 • Nitrites • Urobilinogen • Bilirubin • Glucose • Ketones • Protein • Blood • Microscopic examination

Denise K Link, MPAS, PA-C The University of Texas Southwestern Medical Center [email protected]

Proper Specimen Collection Routine Urine Analysis Appearance Chemical tests (dipstick) • Teach every patient how to collect proper specimen • pH 1. Clean-catch midstream • Protein 2. In patients with indwelling urinary catheters, a • Glucose recently produced urine sample should be obtained • Ketones (directly from the catheter tubing) • Blood 3. Best examined when fresh. Chemical composition • Urobilinogen of urine changes with standing and formed • Bilirubin elements degenerate with time • Nitrites • Leukocyte esterase 4. Refrigerated is best when infection is suspected • Specific gravity 5. First voided morning urine is ideal when evaluating suspected glomerulonephritis Microscopic examination of spun urinary sediment

Urine Analysis with Microscopy Dipstick Methodology

• Paper tabs impregnated with chemical reagents • Reagents are chromogenic • Reagents are timed developed • Some rxns are highly specific • Other are sensitive to the presence of interfering substances or extremes of pH • Rapid, semiquantitative assessment of urinary characteristics

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Contents: Urine Analysis

• Appearance or color • Specific gravity • pH • Leukocyte esterase • Nitrites • Urobilinogen • Bilirubin • Glucose • Ketones • Protein • Blood • Microscopic examination

Urine Color Change Substances Contents: Urine Analysis White Chyle, pus, phosphate crystals Pink/Red/Brown Erythrocytes, hemoglobin, myoglobin, • porphyrins, beets, senna, cascara, Appearance or color levodopa, methyldopa, deferoxame, metronidazole, phenacetin, • Specific gravity anthraquinones, doxorubicin, • pH phenothiazines • Leukocyte esterase Yellow/Orange/Brown Bilirubin, urobilin, phenazopyridine, urinary • Nitrites analgesics, senna, cascara, mepacrine, iron • Urobilinogen compounds, nitrofurantoin, riboflavin, • Bilirubin rhubarb, sulfasalazine, rifampin, flurescein, phenytoin, metronidazole • Glucose • Ketones Brown/Black Methemoglobin, homogentisic acid, • Protein melanin, levodopa, methyldopa • Blood Blue or green/Green/Brown Biliverdin, Pseudomonas infection, dyes (methylene blue, indigo carmine), • Microscopic examination triamterene, Vitamin B complex, methocarbamol, indican, phenol, chlorophyll, propofol, amitriptyline, Purple Infection with E. Coli. Pseudomonas,

Urine Specific Gravity Increased Urine Specific Gravity: Contents: Urine Analysis • Diarrhea that causes dehydration • Heart failure • Dehydration • Appearance or color • Diarrhea/emesis • Specific gravity • Renal artery stenosis • Glycosuria • pH • Syndrome of inappropriate • Leukocyte esterase antidiuretic hormone secretion (SIADH) • Nitrites • Hepatorenal syndrome • Urobilinogen • Bilirubin Decreased Urine Specific Gravity: • Glucose • Acute tubular necrosis • Ketones • Interstitial nephritis • Protein • Diabetes insipidus • Blood • Drinking too much fluid • Microscopic examination • Kidney failure • Pyelonephritis

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Urine pH

• Physiologic urine pH ranges from 4.5 to 8 • Most accurate if done promptly • Not sufficiently accurate to be used for diagnosis of renal tubular acidosis (check ABG and urine lytes) • Changing urine pH to either acidic or alkaline may prevent development of certain types of kidney stones

Contents: Urine Analysis

• Appearance or color • Specific gravity • pH • Leukocyte esterase • Nitrites • Urobilinogen • Bilirubin Ms. Smith is a 38yo who presents • Glucose with 4 days of dysuria, frequency, • Ketones urgency and foul smelling urine. UA • Protein reveals positive nitrite and leukocyte • Blood esterase. You empirically start her on • Microscopic examination Bactrim for treatment of presumed UTI.

Leukocyte Esterase Nitrites • Screening test for bacteriuria • Detects esterase, an enzyme released by WBC • Reflects presence of >10(5)CFU of Enterobacteriaceae • Reflects presence of pyuria and may be used to per ml of urine detect > 10 leukocytes per HPF • Relies on ability of gram-negative bacteria to • False negatives can occur in the presence of convert nitrate nitrite 1. Glycosuria • False negative can occur 1. Bacteria that cannot convert nitrate nitrite: 2. High specific gravity EX: Enterococcos 3. Cephalexin or tetracycline Tx 2. Presence of ascorbate 4. Excessive oxalate excretion 3. Retention of urine in bladder <4 hours • False positives can occur with contamination of 4. Decrease in urine pH vaginal debris and trichomonas infection • False positive can occur with substances that turn urine red such as use of bladder analgesic phenazopyridine or ingestion of beets

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Bacteria, Yeast and other UTI Infectious Agents: • May discern between cocci and bacillary forms of bacteria on • Symptoms of dysuria, frequency, urgency , unstained urine sample • Individual and budding yeast and suprapubic pain and/or hematuria hyphal forms occur with Candida • Trichomonas are identified by their • Uncomplicated: healthy non-pregnant adult tear drop shape and motile women flagellum • Dipstick urine analysis without urine culture is sufficient for Dx of uncomplicated UTI • Sensitivity of 75% and specificity of 82% when positive for either leukocyte esterase or nitrite.

Contents: Urine Analysis Urobilinogen and Bilirubin

• Appearance or color • Urobilinogen produced in the gut from • Specific gravity metabolism of bilirubin. Excreted in feces • pH • Leukocyte esterase and urine. • Nitrites • In obstructive jaundice, bilirubin does not • Urobilinogen reach bowel, so urinary excretion of urobilinogen is deminished • Bilirubin • Glucose • In other forms of jaundice, urinary • Ketones urobilinogen is increased • Protein • Better tests are available to diagnose • Blood obstructive jaundice • Microscopic examination

Contents: Urine Analysis Glucose (glycosuria)

• Appearance or color • Dipstick is specific for glucose. • Specific gravity • Rely on glucose oxidase to catalyze the formation • pH of hydrogen peroxide • Leukocyte esterase • Nitrites • High concentrations of ascorbic acid can result in • Urobilinogen false-negative test • Bilirubin • Due to inability of kidney to reabsorb glucose in • Glucose PT despite normal serum glucose or urinary spillage with high serum glucose • Ketones • Normal renal function: glycosuria does not • Protein generally occur until serum glucose exceeds • Blood • Microscopic examination 180mg/dl

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Ketones Contents: Urine Analysis

• Created when body breaks down fat or fatty acids for • Appearance or color energy instead of carbohydrates or sugar • Specific gravity • Measures the presence of urine ketones • pH • False positive may occur with usage of levodopa, • Leukocyte esterase captopril (drugs containing free sulfhydryl group) • Nitrites • Ordered when patient has Type 1 DM AND diabetic • Urobilinogen ketoacidosis is suspected particularly when patient is • Bilirubin sick • Glucose • Monitored in a person… • Ketones 1. On a low-carbohydrate and/or high-fat diet 2. Not able to eat (anorexia/fasting), is vomiting and/or • Protein diarrhea • Blood 3. Pregnant woman who has DM or gestational DM • Microscopic examination

Mr. Jones is a 84yo male Proteinuria who presents with chronic and progressive generalized weakness, 20lbs weight loss and pain in back particularly induced with movement. Labs reveal: serum creatinine 2.5mg/dl serum calcium 11.0mg/dl hemoglobin 9.8g/dl UA dipstick was negative for proteinuria or hematuria 24 hour urine revealed 2.5grams of total protein

Multiple Myeloma- neoplastic proliferation of immunoglobulin- producing plasma cells. • Initial screening SPEP, 24hr urine UPEP and immunofixation • DDX: MGUS, SMM, Waldenstrom macroglobulinemia, AL amyloidosis, solitary plasmacytoma, POEMS syndrome and metastatic carcinoma

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Urine Protein Composition Proteinuria

PLASMA PROTEINS EXCRETION (mg/day) • Highly sensitive to albumin AND insensitive to other Albumin 12 urinary proteins such as globumins, hemoglobin, or Immunoglobulin G 3 light chains Immunoglobulin A 1 • Scored from trace to 4+ based on concentration Immunoglobulin M 0.3 • Quantification is influenced by urine concentration: dilute urine may give falsely low results Light Chains kappa 2.3 • Ranges from 200-3000mg/24hrour are readily gamma 1.4 detected Beta-Microglobins 0.12 • Not sensitive enough to detect for Other plasma proteins 20 MICROALBUMINURIA Nonplasma-Tamm-Horsfall protein 40 • Highly alkaline urine may produce false-positive rxns Other non-renal-derived proteins <1 • IF proteinuria other than albumin is suspected, more sensitive assays should be used (SPEP, UPEP IFE, serum free light chains) TOTAL PROTEINS 80

Quantification of Proteinuria Contents: Urine Analysis

• If presence of proteinuria is detected on • Appearance or color dipstick, confirmation is required through • Specific gravity • pH quantification of proteinuria. • Leukocyte esterase • Measurement of urinary protein • Nitrites • Urobilinogen 1. 24 hour total urinary protein • Bilirubin 2. Random protein/creatinine or • Glucose albumin/creatinine. Adjustment for urinary • Ketones concentration is made by relating the urine • Protein protein concentration to the urine • Blood creatinine concentration • Microscopic examination

Hematuria Urinary RBC vs WBC

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Hematuria

Mr. Smith is 27yo male who present to the emergency • Dipstick relies on the peroxidase activity of room after 2 days of nausea, hemoglobin to catalyze an organic peroxide with vomiting, myalgias and “kool aid” colored urine. He states subsequent oxidation of an indicator dye that he is in the police • Myoglobin is also detected because it has academy in Dallas and he intrinsic peroxidase activity started intensive “boot camp” last week during the first • Suspect myoglobinuria or hemoglobinuria with week of August. positive by dipstick but negative for urinary RBC UA was positive for blood but by microscopic examination microscopy did not reveal urinary RBC. • Confirm all positive dipsticks with microscopic examination of spun urinary sediment vs supernatant

False Positive Hematuria Mimics of Hematuria

• Presence of semen in urine may cause • Menstrual cycle: remember age and sex positive heme reaction of patient • Alkaline urine with pH>9 or • Ingestion of beets, rhubarb, certain food contamination with oxidizing agents used dyes or senna: what is your patient to clean perineum eating? • Presence of myglobinuria • Drugs: pyridium, phenytoin, rifampin, nitrofurantoin

Hematuria

• Is common, particularly young adult patients, hematuria is transient and of no consequence • Can be transient or persistent (history is very Where is the important) origin of the • Grossly visible (macroscopic) or detectable only on urine examination (microscopic) hematuria? • Pathology represents the presence of 3 or more RBC per high power field (HPF) in a spun urine sediment • Dipstick for heme detect 1 to 2 RBC per HPF • Dipsticks are at least as sensitive as urine sediment examination, but result in more false positive tests • Positive dipstick test needs to be confirmed with microscopic evaluation

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Causes of Hematuria Distinguishing Extraglomerular from Glomerular Hematuria 1. Renal: renal mass, glomerular pathologies, Extraglomerular Glomerular structural disease, pyelonephritis, Color Red or pink Red, smoky brown or coca-cola malignant HTN, renal vein thrombosis, AV (due to prolonged transit thru malformation, papillary necrosis(sickle cell) nephron and an acid urine pH may result in the formation of 2. Ureter: malignancy, stone, stricture, methemoglobin) fibroepithelial polyp Clots May be present Absent 3. Bladder: malignancy, radiation, cystitis 4. Prostate/urethra: BPH, malignancy, Proteinuria <500mg/day May be >500mg/day prostatic procedures, traumatic RBC morphology Normal Some RBC are dysmorphic with catheterizations, urethritis, urethral blebs, budding, segmental loss of diverticulum membrane resulting in marked variability of RBC shape

RBC casts Absent May be present

Urinary RBC Contents: Urine Analysis

• Appearance or color • Specific gravity • pH • Leukocyte esterase • Nitrites • Urobilinogen • Bilirubin • Glucose • Ketones • Protein • Blood • Microscopic examination

Urine Microscopy Microscopic Examination of the Spun Urine Sediment 1. Cellular elements • RBC • WBC • Renal tubular epithelial cells • Squamous cells of urethral, vaginal or cutaneous origin • Transitional epithelial cells line the renal pelvis, ureter, bladder and proximal urethra 1. Casts

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Cellular Elements Urinary Casts

• Named based upon shape and origin • Consist of a matrix of Tamm-Horsfall urinary glycoprotein in the shape of the distal tubular or collecting segment where they were formed • Matrix has a straight margin compared to clumps of cells or debris has seen in cellular elements • Formation in pronounced during low flow, concentrated salts and low pH

Urinary Casts Urinary Casts Named based upon shape and/or origin 1. Hyaline 2. Granular 3. Waxy/Broad 4. RBC 5. WBC 6. Tubular

Formed via precipitation of Tamm-Horsfall mucoprotein in the distal convoluted tubule and collecting ducts.

Hyaline Casts Waxy/Broad Casts Consists of protein alone. Consists of hyaline Difficult to see b/c of material with a much RBC Cast WBC Cast refractive index is close to that of urine. greater refractive index.

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Hyaline Cast

Granular Cast Tubular Cell Cast Consists of finely (altered serum protein) or coarsely Consists of sloughed Nonspecific, solidified Tamm-Horsfall mucoprotein. Most (degeneration of embedded epithelial tubular cells. common cast. Ex: normal individuals in dehydration or vigorous cells) granular material. exercise.

Waxy/Broad Casts Granular Cast

Form in tubules that have become dilated and atrophic Usually pathologic. Most often indicative of CKD. due to chronic parenchymal disease “Muddy brown cast” can be seen in acute tubular necrosis

Tubular Cell Cast Urinary Crystals

• Formation is dependent on degree of concentration of constituent molecules, urine pH, and the presence of inhibitors of crystallization

Characteristically seen with acute tubular necrosis (ATN) and toxic • May be present spontaneously or may ingestion, such as mercury, diethylene glycol or salicylate. But precipitate with refrigeration of urine can occur in concentrated urine

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Objectives: Urine Analysis

• To understand the basics of urine analysis both dipstick (UA) and microscopy (UA with micro) and how results related to clinical practice • Appearance or color • Specific gravity • pH • Leukocyte esterase • Nitrites • Urobilinogen • Bilirubin • Glucose • Ketones • Protein • Blood • Microscopic examination

Thank you for your time Understanding the Importance of Proteinuria Questions? National Kidney Foundation Annual Meeting Advanced Practitioner Program Gaylord, Texas April , 2015

Robert D. Toto, M.D., Professor of Medicine Medical Director, Kidney Liver Pancreas Clinic Director, Patient Oriented Research in Nephrology UT Southwestern Medical Center

Understanding the Importance of Disclosure Statement Proteinuria

• Causes and Mechanisms • Research: Ardelyx • Diagnosis and Detection • Speakers Bureau: Amgen and Merck • Clinical Relevance • Consultant: Amgen, Merck, Boehringer- • Treatment Ingelheim, Stealth Peptides, BMS, and Clegene – Primary cause – Dietary sodium restriction – RAAS blockade – Complications

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Case: part A Case: part B

• Exam: BP 160/100, 1+ ejection murmur, ascites, • A 70 y/o white male presents with a 3 4+ pitting edema. mo. History of peripheral edema. • Cr 1.4 mg/dl; Serum albumin 1.4 g/dl (nl 4-5 g/dl)

• FBG 109 mg/dl; LDL cholesterol 220 mg/dl • Does not smoke, drink or use drugs. • 24-hour urine protein 8 g; Ccr 54 ml/min/1.73 m 2 • No fever, rash, nocturia, weight loss, joint pain, hemoptysis or hematuria.

I would now do the following

• Serum protein electrophoresis Diagnosis • Urine protein electrophoresis • Serologies Nephrotic Syndrome • Renal Biopsy • All of the above • None of the above

The most likely diagnosis is Case: Diagnosis and Treatment

• Renal Biopsy: Membranous glomerulopathy • Focal segmental glomerulosclerosis • Membraneous nephropathy • Diabetic nephropathy • Multiple myeloma

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Podocyte Proteins and Glomerular Disease

New Insights into Membranous Nephropathy

Antibody to Phospholipase A2 Receptor Antibody and Disease Activity in a Patient with in Membranous Nephropathy Membranous Nephropathy

Beck LH Jr et al. N Engl J Med 2009;361:11-21. Beck LH Jr et al. N Engl J Med 2009;361:11-21.

Many diseases can Cause Case: Diagnosis and Treatment Nephrotic Syndrome • Renal Biopsy: Membranous glomerulopathy • Primary glomerular • Secondary glomerular diseases diseases – Membranous nephropathy – Diabetes • Rx: Cytoxan 100 mg/d x 1 month alternating – Focal sclerosis – SLE with prednisone 1.0 mg/kg/d x 6 months – Membranoproliferative GN – Amyloidosis – IgA nephropathy – Cancer lymphoma, solid – IgM nephropathy tumors – Fibrillary GN – Hepatitis B and C • 2 gram sodium diet – Immunotactoid nephropathy – Drugs – C1q nephropathy • NSAIDS, Gold, pamidronate – Post-infectious GN, etc. • Lisinopril 40 mg once daily – Other

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Types of Proteinuria

Type Example Glomerular Glomerulonephritis What is the Basis of Glomerular Proteinuria?

Tubular Tubulointerstitial nephritis (e.g., due to drug)

Overflow Myeloma

Podocyte Podocyte Capillary Capillary Foot Proceses Lumen Lumen

Bowman ’s Space

Capillary Lumen

Plasma Plasma Membrane Membrane Bowman ’s Normal: Glomerular Permeability to Nephrin Molecules Podocyte Foot Space Albumin is Restricted Proecesses Bowman ’s Space Filtration Slit Podocyte Podocyte Diaphragm Slit Membrane Nephrin Albumin-poor Albumin-poor Nephrin ultrafiltrate ultrafiltrate Podocytes Foot process Slit Diaphragm Glomerular Basement Membrane

Fenestrated Fenestrated Albumin Normal GBM Endothelium Endothelium Molecules hydrostatic pressure Capillary Lumen

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Endothelial Injury: Glomerular Permeability to Albumin Increased

Bowman ’s Space

Albumin-rich filtrate Albumin-rich filtrate Diagnosis and Detection of Proteinuria Podocytes Foot process Slit Diaphragm Glomerular Basement Membrane

Damaged Endothelium Albumin Increased Leak hydrostatic pressure Capillary Lumen

Microalbuminuria: Manifestation of Diffuse Proteinuria and Microalbuminuria Endothelial Cell Injury

Proteinuria Albuminuria Systemic Renal Measurement Total protein Albumin only Vasculature Vasculature Injured Endothelium Routine dipstick Yes No

Method of estimate* Protein / Creatinine Albumin /Creatinine ratio ratio Cardiovascular Risk Factors Age Abnormal level > 0.15 g Prot /g Cr > 30 mg / g creatinine Diabetes Interstitial Hypertension Renal Significance Glomerular: accelerated Marker incipient Smoking Microalbuminu Albumin leak Absent nocturnal BP dipping decline in renal function diabetic nephropathy Salt sensitivity ria Tubular: sign of TIN Left ventricular hypertrophy Dyslipidemia Increased CV Risk Yes Yes Central Obesity Insulin resistance Elevated CRP * Spot urine preferably A.M. sample Sympathetic Dysfunction Hyperuricemia

Detecting Proteinuria in Routine Common Causes of Albuminuria Urine Analysis

• Diabetes Mellitus • If persistently > trace positive (> 2 occasions) • Hypertension deserves further evaluation • Glomerular or tubular disease or both • Atherosclerotic vascular disease • Detection limit is about 300 mg/L • Smoking • Misses – Microalbuminuria, e.g. diabetes – Light chain nephropathies • Urine albumin/creatinine ratio

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Quiz The most likely diagnosis is

• 70 year old man with type 2 DM c/o • Focal segmental glomerulosclerosis fatigue and found to have Scr 1.7 mg/dl • Membraneous nephropathy • Exam: BP 130/70, unremarkable • Diabetic nephropathy • Urinalysis negative for protein negative, • Multiple myeloma no cells, casts, crystals • 24 hour urine Ccr 42 ml/min • 24 hour urine protein 4,200 mg PEARL: Dipstick does Not detect light chains

Method for Detecting Evaluation of Proteinuria Microalbuminuria

• Serologies Proteinuria detected by dipstick • ANA, C3, C4 • ANCA • First morning urine void (preferred) • Anti-GBM Confirm by random Uprot/Ucr ratio • HBSAg, Hep C Ab Or 24 hour urine • Cyroglobulin • Urine albumin concentration Deteriorating renal function Renal Function Stable e.g., doubling Scr < 3 months Non-nephrotic • Urine creatinine concentration Nephrotic range proteinuria Normal U/A Abnormal urine sediment • Calculate albumin/creatinine ratio Yes SPEP or UPEP abnormal Serologies Biopsy No SPEP and UPEP Immunofixation Observe

Clinically meaningful use of albuminuria Prognostic Significance of albuminuria

Screening Test Monitoring Disease activity

Levey AS, de Jong PE, Coresh J, et al. Kidney Int. 2011;80:17-28. BMJ 2006;332:1426

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Who Should Be Treated?

• Patients with microalbuminuria (30-299 Treatment mg/g) – Diabetes – Hypertension – Biopsy proven kidney disease

• Kidney disease with macroalbuminuria > 300 mg/g)

Rationale for Lowering Albuminuria How to Treat

• Underlying Cause whenever possible, e.g. • Increases risk immunosuppression for lupus • Dietary sodium restriction for cardiovascular – Enhances antiproteinuric effect of ACEi/ARB events – Helps lower BP in hypertensive patients • Pharmacologic lowering of blood pressure in • Accelerated hypertensives decline in kidney – RAAS Blockade – Additional antihypertensives including diuretics

function GFR • Avoid NSAIDS (salt retention) ESRD Time

How Much Does a RAAS Blocker How Much Does a RAAS Blocker Lower Proteinuria? Lower Proteinuria • Overall about 50% • Variable, depending on effect on – Systemic Blood pressure – Efferent Arteriole resistance – Glomerular Basement Membrane

Brunner Am. J. Cardiology. Volume 87, Issue 8, Supplement 1, 19 April 2001, Pages 3–9

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Effect of Salt Intake on Proteinuria in Management of Albuminuria ACEi Treated Patient

Baseline ACEi + Hi Salt • Lower BP to < 130/ 80 mmHg • Use a once-daily ACEi or ARB

ACEi + Lo Salt • Titrate ACE inhibitor to maximal recommended dose • Lower urine alb/cr ratio to < 300 mg/g

ACE inhibitors and Angiotensin Receptor Blockers Slow Progression of Kidney Disease in Hypertensive Type 2 Diabetics

Clinical Trials 2000 40% ∆ GFR IDNT Overt nephropathy 2-20:10 What about Combination Rx RENAAL 200 Microalbuminuria ∆ GFR 1-3 IRMA 2

20 Normoalbuminuria ∆ GFR BENEDICT Albuminuria Albuminuria (µg/min) 1 60% ROADMAP 2 Time (Years)

Brenner et al. New Engl J Med 2001 Sep 20;345(12):861-9, Lewis et al. N Engl J Med 2001; 345:851-860, Parving et al. New Engl J Med 2001 Sep 20;345(12):870-8, Ruggenenti et al. N Engl J Med 2004; 351:1941-1951, Haller et al. N Engl J Med 364;10

The Renin Angiotensin System: Strategies Combination Rx with Drugs that for Blockade Block RAAS Angiotensinogen Renin DRI • Greater reduction in proteinuria Ang I AT1 receptor • Small or no further reduction in BP ACE ACEi ARB Adrenal Zona Ang II Glomerulosa • No improvement in long-term outcome (ESRD and CV events) • Higher incidence of complications Kidney MRB Aldosterone

DRI: Direct Renin Inhibitor, ACEi Angiotensin Converting Enzyme Inhibitor ARB Angiotensin Receptor Blocker; MRB: Mineralocorticoid Receptor Blocker

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Suppression of urinary albumin excretion by Randomized Double-Blind combined use of Losartan or Spironolactone Placebo-Controlled Trial

Run-in Double-Blind W/O Changes in 24h BP Urinary albumin excretion

Lisinopril 80 mg daily and SBP goal <130 mm Hg Mean change ratio at 48 weeks (mmHg) (%) (vs Placebo group)

N = 81 160 Systolic BP Placebo group (n=27) 60 Losartan group -16.8% p=0.2 Type 1 and 2 diabetes Placebo daily Losartan group (n=26) 140 Spironolactone (n=27) Spironolactone group -34.0% p=0.007 N.S. 40 Two 24-hour 120 (ANCOVA) UACR > 300 mg/g 20 Losartan 100 mg daily 100 at end of run-in Diastolic BP 0 80 N.S. -20 -24.6% 60

Spironolactone 25 mg daily ratio Change Blood pressure Blood Placebo group (n=27) -40 -38.2% * 40 Losartan group (n=26) mean(95% CI) -51.6% ** Spironolactone group(n=27) 20 -60 * mean(95% CI) (ANCOVA) *p=0.001 、**p<0.0001 * * * vs before additional dose(ANCOVA) 0 - 4 -2 0 12 24 36 48 52 -80 0 24 48 (weeks) 0 24 48(weeks) Weeks * Inpatient CTRC: 24 hour ABP, creatinine clearance and urine albumin/creatinine ratio

Mehdi UF, et al. J Am Soc Nephrol . 2009;20(12):2641-2650. Modified from Mehdi, U.F. et al.: J Am Soc Nephrol 20(12): 2641, 2009

Serum Potassium Concentration Perils of Higher Dose ACEi/ARB in (mean) Treatment of Proteinuria Spironolactone vs Placebo, p < 0.001 Mean serum K Losartan vs Placebo , p = 0.03 5.0 (0.51) Spironolactone vs Losartan , p = 0.05 4.7 (0.33) 4.5 (0.38) Proteinuria

AKI K

Mehdi UF, et al. J Am Soc Nephrol . 2009;20(12):2641-2650.

Combining ACEi and ARB: Large Indications for Nephrology Referral Scale Clinical Trials • 1ALTITUDE Study: Combined ACEi or ARB with a Direct Renin Inhibitor in Type 2 • Hematuria/proteinuria unexplained diabetes: No benefit, more hyperkalemia • Estimated GFR < 80 ml/min • 2NEPHRON-D Study: Combined ACEi and • Nephrotic Syndrome ARB in type 2 diabetes: Stopped for futility, • Uncontrolled hypertension more hyperkalemia • Need for Renal Biopsy • 3ONTARGET Study: Combined ACEi and – SLE, Necrotizing vasculitis, other ARB: No benefit, more acute kidney injury, hyperkalemia, hypotension 1 N Engl J Med 2012; 367:2204-2213; 2 Clin J Am Soc Nephrol. 2009 February; 4(2): 361–368.; 3 N Engl J Med 2008; 358:1547-1559

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