Renal Investigations

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    Clinical Evaluation of Kidney Function

    GFR

    • Estimation of GFR - using serum indicators of kindey function.
    • Creatinine
      • Women should never have creat >1mg/dL (88 umol/L)
      • GFR and creatinine is a non-linear relationship.
        • At Low Creatinine levels --> Doubling of Creatinine = half of GFR
        • When creatinine gets high, large changes in creat = small GFR changes
        • Black persons have higher creatinine
      • serumCreatGFR.png(Source: National Institute of Health)
      • Some medications can block tubular creatinine excretion (make GFR look low)
        • Dronedarone
        • Cimetidine
        • Trimethoprim
        • Stribild (HIV med) can block creatinine
      • Some medications can interfere creatinine colorimetric assay
        • Cefoxitin, flucytosine, acetoacetate (falsely elevate creatinine)
        • High Bilirubin (falsely lower creatinine)
    • Serum Cystatin C
      • Another marker of GFR --> not well validated
        • Less influenced by age, gender, body weight, muscle weight etc...
    • Blood urea nitrogen (BUN)
      • No formulas that translate BUN to kidney function.
      • BUN elevated out of proportion to creatinine in AKI (BUN 20:1, Urea 100:1) --> concern for pre-renal azotemia. 
      • BUN goes up with:
        • High protein meal, corticosteroids, pre-renal azotemia (Urea filtered and reabsorbed proximally)
      • BUN down with:
        • Muscle wasting, protein malnutrition, cirrhosis
    • Estimating Kidney Function
      • Formulas all validated in steady state (stable creat 24-48hrs), no role in AKI really
        • Pregnant women, reduced muscle mass, amputations... less accurate
      • MDRD Equation (Modification of Diet in Renal Disease)
        • Most popular
        • Not useful if GFR > 60 (or when close to normal)
      • Cockcroft-Gault Equation
        • Easy to calculate (simple)
        • Good for age <65yo, POOR in obesity, POOR if GFR > 60
      • CKD-EPI Equation (Epidemiology Collaboration Study)
        • More accurate in elderly population
        • Superior to CGE, and MDRD
      • Others:
        • Creatinine Clearance (using 24-hour urine creatinine)
        • Cystatin C
        • Radionuclide Kidney Clearance Screening (most precise and expensive)

     

    Urinalysis

    • Findings on Urinalysis

       

       

      Normal

      Comments

      Dipstick

      Specific gravity

      1.005-1.030

      Low with dilute urine; (1.000 = tap water)

      high with concentrated urine or hypertonic product excretion such as contrast dye

      pH

      5.0-6.5

      Elevated with low acid ingestion, inability to excrete acid load (renal tubular acidosis)

      - Strict vegetarians --> alkaline urine  (protien cause acid)

      - dRTA --> Alkaline urine (cannot acidify)

      - Proteus + pseudomonas can split urea --> high pH

      Blood

      None

      Very sensitive;  False positives with myoglobin or intravascular hemolysis

      - if red urine, but negative blood --> other cause (like beets)

      - Detects RBCs, myoglobin, and free hemoglobin.

      - False positives: Rifampin, chloroquine, iodone, bacterial peroxidase, myoglobin

      Protein (only measurs albumin)

      None to trace

      Most dipsticks detect primarily albumin (not other proteins); trace positive can be normal if urine is concentrated

      - Varies by concentration of urine (often need to normalize to creatinine)

      - False positive if high urine pH (alkaline) - confirm with ACR/PCR

      Glucose

      None

      Positive when plasma glucose > 180 mg/dL (10.0 mmol/L) "renal threshold"

      - pRTA (Type II) - can cause glycosuria

      Ketones

      None

      Positive for acetoacetic acid, not acetone or β-hydroxybutyrate

      - Starvation ketosis, DKA, ASA toxicity, isopropyl alcohol intoxication, alcohol ketoacidosis

      - Alcohol ketoacidosis (starvation + EtOH metabolically chronically can cause ketosis)

      - Drugs: captopril, levodopa (sulfhydril groups --> false positives)

      Nitrites

      None

      Detects nitrite converted from dietary nitrate by bacteria; normally, no nitrites are present in urine

      Leukocyte esterase

      None

      Detects the presence of leukocytes in the urine; positive test if > 3 leukocytes/hpf

      Microscopy

      Erythrocytes

      0-3/hpf

      Urine microscopy should be performed to evaluate erythrocyte morphology

      Leukocytes

      0-3/hpf

      The presence of any leukocytes may be abnormal depending on clinical circumstances

      Casts

      None or hyaline

      Hyaline casts are indicative of poor kidney perfusion but can be benign or reversible; other casts are indicative of intrinsic injury

      Crystals

      None

      Most common include calcium oxalate, calcium phosphate, uric acid, and struvite; occur when urine is supersaturated with a specific substance

    • Source: Most information in this table is from MKSAP 16

     

    Urine Microscopy

    • Assessment of a urinary sediment indicated for:
      • Abnormal dip stick
      • AKI
      • Suspicion for Glomerulonephritis
      • Newly diagnosted CKD
    • Done to determine why urine dipstick is abnormal, esp if suspect:
      • AKI, Glomerular Insulin (nephrotic, nephritic), newly recognized CKD.
      • Crystals, Casts, Cells
    • Leukocytes (aka Pyurea)
      • if >4 counts/HPF - most common UTI.
      • "Sterile Pyurea" - seen with TB, interstitial nephritis (abx, nsaids, ppis, etc..).
        • Also: Kidney stones, transplant rejection.
    • Eosinophils
      • Cannot be visualized -- use Wright's/Hansel stains.
        • Allergic (AIN), atheroembolic disease, RPGN, small-vessel vasculitis, UTI, prostatic, parasitic inf.
    • Erythrocytes
      • Can originate anywhere (glomerulus to urethra).  Look at morphology:
      • Acanthocytes - dysmorphic RBCs (with "Mickey Mouse" ears)
        • Very suggestive of glomerulonephritis (not as pathognomonic like RBC casts)
          • Also seen in ATN and Interstitial Nephritis
        • Like budding yeast
        • Microscopic hematuria = >2 RBC/HPF
          • acanthocytes2.jpg
          • Photo: UpToDate

    Casts

    • Most common: Hyaline Casts (cast matrix comprised of Tamm-Horsfall mucoprotein)
      • Tamm-Horsfall is only in urine (not in blood)
    • Granular Casts: Nephron insult
      • Debris from tubular cells that died
    • RBC Casts: Glomerulonephritis
    • WBC Cases: Glomerulonephritis (not pathognomonic), also seen in AIN, rarely Pyelonephritis

     

    Crystals

    • Urine Crystals

       

      Type

      Morphology/Shape

      Associated Conditions

      Calcium oxalate

      Envelope; dumbbell; needle

      - MOST COMMON

      Hypercalciuria; hyperoxaluria; calcium oxalate stones; ethylene glycol poisoning

      Calcium phosphate

      Prism; needle; star-like clumps

      - Mostly seen in acid (very alkaline soluble), to treat, alkalanize urine

      Distal renal tubular acidosis; urine pH above 6.5; tumor lysis syndrome; acute phosphate nephropathy

      Uric acid

      Rhomboid; needle; rosette

      Diabetes mellitus; obesity; gout; hyperuricemia; tumor lysis syndrome; urine pH below 6.0

      Magnesium ammonium phosphate (struvite)

      Coffin-lid

      Chronic urinary tract infection with urease-producing organisms

      Cystine

      Hexagonal

      Cystinuria

      Drugs  

      Sulfa drugs, Calcium Carbonate, IV acyclovir, indinavir


       

    ​Albumin / Protein Excretion

    • National Kidney Foundation
    • Measuring Proteinuria:
      • 24-Hour Excretion (normal < 150mg/24hrs)
        • Protien /24h Protein:Creat Ratio  
          < 0.2 g/day < 0.2 Normal
          0.2-3.5 g/day   Proteinuria
          >3.5 g/day > 3.5 Nephrotic Range Proteinuria
        • Compare expected creatinine excretion to find the accuracy of sample:
          • Men: 20 to 25 mg/kg/24 h (177-221 mmol/kg/24 h)
          • Women: 15 to 20 mg/kg/24 h (133-177 mmol/kg/24 h)
      • Spot urine dipstick 
      • Spot Protien-Creatinine ratio - < 0.2mg/mg (All proteins including Bence-Jones, cheap)
        • Approximates protein in one day (i.e. if PCR is 4, then suggests 4g/day 24hr urine excretion).
        • If small muscle mass, denominator can be smaller.
    • Measuring Albuminuria
      • Spot Albumin:Creatinine Ratio: 
        • If wish to detect albuminuria (i.e. if dipstick negative)
        • Immunoassay, now very cheap.
        • Validated only in diabetes
    • Term

      24 hour Protein

      g/24hr

      Albumin or Protein

      To Creat Ratio

      Dipstick

      - only detects high

      protein/albumin levels

      Normal < 0.2 < 0.2 < 30 mg/dL?
      Proteinuria 0.2 - 3.5 0.2 - 3.5 < 30 mg/dL?
      Nephrotic Range Proteinuria > 3.5 > 3.5  > 30 mg/dL?
      Normal Albumin < 30 < 30 mg/g ---
      Microalbuminuria  30-300 30 -300 mg/g ---
      Macroalbuminuria > 300 > 300 mg/g Threshold for distick
    • National Kidney Foundation Kidney Disease Outcomes Quality Initiative Definitions of Proteinuria and Albuminuria
    • (MKSAP 16 and American Journal of Kidney Diseases. 39(2 Suppl 1). K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Part 4: Definition and classification of stages of chronic kidney disease. S46-S75. PMID: 11904577)

     

    • Measuring Monoclonal Protein (Bence-Jones Protein)
      • Will NOT be detected by albumin to creatinine ratio or urinary dipstick.
      • WILL BE detected by Urine Protein-to-Creatinine ratio
        • No Albumin, but Lots of Protein in prot-to-creat is a hint that Bence-Jones protein is present
      • Best Test: Urinary immunofixation (urine for light chains)
    • Transient Proteinuria
      • Cold, fever, heart failure, after marathon etc...
      • Usually transient, and mild... should never be close to nephrotic range (< 1gram/24hr)
    • Orthostatic Proteinuria
      • Proteinuria happens during day, but disappears at night (when recumbent).
      • Bening.. resolves by itself by age 30.
      • "Split" urine collection, one jug in daytime, and one nighttime. 

    Hematuria Evaluation

    • Confirm blood (dipstick)
    • Determine if free heme or RBCs or myoglobin
    • Most common: Kidney stones and UTI
    • Isomorphic (normal size/shape) erythrocytes usually arise from primary urologic process (tumor/infection etc.)
    • Look for glomerular bleeding, R/O trauma, menstruation, exercise, if normal (isomorphic erythrocytes)-->
      • --> Asse upper tract (CT/US, if no answer then MRI), then urology referral for lower urinary tract.
      • Urine Cytology (not very sensitive), good for large lesions
      • Urologic malignancy: Risk Factors:
        • Age > 40, smoking, gross hematuria, voiding symptoms, urologic disorders, pelvic rads, exposures (benzene, aromatic amines, cyclophosphamide, etc.)
      • Aristolochic Acid --> chinese herb nephropathy (weight-loss agents).
    • Screening urinalysis NOT recommended.

     

    Imaging Kidneys: 

    • CT urography - very sensitive/specific.  Picks up kidney stones.
      • High radiation dose (2x renal pyelogram)
      • Best for high-risk, well preserved GFR
    • MRI urography - uses gadolinium (contraindicated for GFR < 30).  Less sensitive for very small stones/cancers.
      • Best for GFR 30-60
      • Can find mass lesions and cyst.
      • Avoid gadolinium in Stage 4-5 CKD (GFR < 30), AKI, transplant
        • Gadolinium carries risk of nephrogenic systemic fibrosis
        • Renally excreted, if not excreted can cause debilitating skin disease
      • Gadolinium enhancement used for:
        • If mass lesion has malignant features.
        • MR Angiography for Renal Artery Stenosis
    • Ultrasound - Cannot see stones in ureter, but excellent modality.
      • <40yo, no risk factors for urologic malignancy
      • Often the first imaging study for structures of upper-urinary tract.
    • IV Pyelogram (IVP) - may not get periphery of kidney.  Cannot see if cystic/solid etc..
      • Rarely done
    • Radionuclide Kidney Clearance Scanning
      • Gold standard in quantifying GFR + renal plasma flow.
      • Very accurate for functional studies!
      • Used in transplanted kidneys, renovascular disease, pre-surgical assessment before nephrectomy (even partial nephrectomy).

    Renal Biopsy

    • Indications:
      • Suspected glomerular pathology (GN or Nephrotic Syndrome)
      • AKI of unknown cause
      • Renal Transplant Dysfunction
    • Contraindications:
      • Bleeding diathesis
      • Low platelet count
      • Uncontrolled HTN
      • Active urinary infection
      • Atrophic kidneys
      • Hydronephrosis.
    • Risks:
      • Aim: 8-10 glomeruli 
      • Can bleed - common.  (massive bleed uncommon)
        • Hematuria post-bx.
        • In rare cases transfusion is needed, and <0.3% risk of nephrectomy, and <0.1% risk of death
      • 0.3% require nephrectomy due to significant bleeding, 0.1% death.

     

    Urine Protein

    • Can be measured by:
      • Urine 24-hr protein (with albumin to ensure adequacy of collection)
      • Albumin-Creatinine ratio (spot) (estimation)
      • Urine dipstick (estimation)
    • Generally:
      • Albumin - used for diabetics (studies validated using albumin)
      • Protein - used for pregnancy (studies done this way)
    • Measure

      A1

      (normal to mild)

      A2

      (moderate)

      Pre-Eclampsia

      threshold

      A3 

      (Severe)

      Nephrotic Range
      ACR (mg/g) < 30 30 - 300   > 300 > 2200
      24-hr Albumin (mg/24h) < 30 30 - 300   > 300  
      PCR (mg/g) < 150 150 - 500 300 > 500  
      24-hr Protein (mg/24h) < 150 150 - 500 300 > 500 > 3500
      Dip Stick Normal or trace +   ++, +++  
    • To convert protein or albumin ratios mg/g to mg/mmol (divide by 10)
      (For an exact conversion from mg/g of creatinine to mg/mmol of creatinine, multiply by 0.113)
      • For Example: normal ACR is < 3 mg/mmol
    • ACR * 10 = 24hr Urine 
    • ACR * 15?? = 24hr Urine
    • PCR * 10
    • ACR 2-20
    •  
    • NOTE: Proteinuria in pregnancy defined as: (> 300mg/24hrs) , and if CKD III/IV its > 500mg/24h
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