1. Approach to the patient with renal disease: lab assessment and kidney biopsy

Question 1

What kind of medical history do we need?

Answer 1

Taking full medical history is crucial assessing a patient with renal disease. This should include:

• Past medical history: urinary tract problems in childhood and adulthood, past infections, hypertension, cardiovascular risk factors or disease and systemic diseases, DM, autoimmune diseases
• Local symptoms: pain, hematuria, change in color and volume of urine
• Social history
• Drug and treatment history: analgesics, NSAIDs, contraceptives, antibiotics, steroids and immunosuppressants
• Family history

Question 2

What are the lab tests and data usefull for the diagnosis of renal diseases?

Answer 2

• Estimation of GFR
  
  • Serum creatinin
  • eGFR
  • MDRD
  • Serum cystatin C
• Measurement of tubular function
  
  • Fractional excretion of sodium (FE_Na+)
  • Renal concentration capacity
  • Renal acid secretion
• Uinanalysis:
  
  • Tests
  • Proteinuria
  • Hematuria
  • Urine sediment
  • Casts
  • Crystals
• Imaging
  
  • US
  • X-ray
  • Renal CT scan
  • Renal MRI
  • Antiography, scintigraphy
• Renal biopsy

Question 3

What is the GFR and what is it useful for?

Answer 3

GFR is relatively constant in an individual and decreased GFR may result from a reduction in nephron number or a reduction in the GFR of single nephrons.

GFR is useful for:

• Providing a consistent measure of kidney function
• Monitoring progression of CKD (and response to treatment)
• Forecasting the need for dialysis and transplantation
• Determining appropriate drug dosing in renal impairment

It provides no information regarding the cause of renal insufficiency.

GFR is measured indirectly by evaluating clearance (the volume of plasma from which this substance is removed per unit time) from plasma of a (renally excreted) marker substance.

Question 4

How do we measure GFR?

Answer 4

• Serum creatinin
  
  • SCr is convenient and inexpensive ==> most commonly used indirect measure of GFR.
  • Creatinine is generated from non-enzymatic metabolism of creatine in skeletal muscle.
    
    • Production is proportional to muscle mass.
    • Decreased muscle mass (elderly, cachectic) or increased Cr production may result in overestimation of GFR.
• eGFR
  
  • eGFR equations attempt to correct for the effects of body weight, age, sex, race, and muscle mass.
  • Limitations as the calculation is still based on Cr and do not take into account tubular secretion, extrarenal elimination, or differences in production between individuals of the same age and sex, or the same individual over time.
  • Cockcroft-Gault equation:
    
    • eGFR [ml/min] = (140-age) x weight [Kg] / (0.814xCr[µM])
      
      • Multiply by 0.85 in women to correct reduced creatinin production
• MDRD (Modification of Diet in Renal Disease)
  
  • A widely used internationally and the current basis of CKD classification.
  • Takes into account SCr, BUN, age and serum albumin.
• Serum cystatin C
  
  • A 13kDa cysteine protease inhibitor produced by all nucleated cells and freely filtered at the glomerulus before tubular reabsorption and metabolism.
  • Unlike Cr, it does not undergo tubular secretion, but due to the tubular metabolism it is not suitable for measuring clearance. However, cystatin C appears to be a better predictor of adverse outcomes than either SCr or eGFR based on the SCr.

Question 5

How do we measure the tubular function?

Answer 5

Frational excretion of sodium (FE_Na):

• It is the % of Na filtered by kidney that is excreted in urine. It is measured from plasma and urine sodium.
  
  • Thus urinary and plasma concentrations of Na must be compared to get and accurate picture of renal clearance
• FE_Na = (U_Na x P_Cr) / (P_Na x U_Cr)
• Clinically, it is used for the evaluation of acute renal failure to differentiat AKI of prerenal origin (FE_Na < 0.1%) and acute tubular necrosis (FE_Na > 2-3%)

Renal concentration capacity:

• Normal morning urine specific gravity ≈ 1.022 with osmolarity > 800 mosm/L
• Measured by water deprivation test of 18-24h, where urine quantity and osmolarity are measured hourly, while serum osmolarity and Na⁺ are measured every 2h.
  
  • Urine osmolarity > 600 mosm/L ==> physiological response
  • Serum osmolarity increases, urine osmolarity is the same ==> diabetes insipidus
    
    • Central and nephrogenic DI is differentiated by administration of ADH.

Renal acid secretion:

• Diagnosis of renal tubular acidosis
• Acid loading (ammonium chloride) and measurement of urine pH every 2h
  
  • Urine pH < 5.3 and HCO3- < 18mM is physiological

Question 6

How do we measure urinanalysis?

Answer 6

Urine dipstick

• Presence or ptoeins, blood, glucose, bilirubine, urobilinogen, ketones and more in the urine
  
  • May be comprised up to 10 different chemical pads or reagents which reaction (color change) when immersed in urine.

ELFO:

• Electrophoresis for protein detection

24h urine sample:

• Electrolyte detection
• Urea, creatinine and protein detection

Microscopic examination of urine sediment:

• Cells: RBC, WBC, bacteria, fungi, …
• Casts
• Crystals

Question 7

What do we measure in urinalysis?

Answer 7

Proteinuria:

• Requires 24h collection and uses albumin:creatinin ratio (ACR) or protein:creatinin ratio (PCR) ideally in an early morning sample. ACR is preffered
  
  • Normal proteinuria < 150mg/day; normal albuminuria <30mg/day
  • Mild-moderate proteinuria 150mg-3g/day
  • Severe proteinuria >3g/day (indication of glomerular disease)
    
    • False positive: UTI, fever, CHF, sternuous exercise, uncontrolled DM and NSAID abuse

Urine sediment:

• Microscopic examination of urine sediment
• Hematuria:
  
  • Microscopic (>3 RBCs) Vs macroscopic
  • Dysmorphic RBCs (glomerular origin) Vs Regular RBC (urinary tract origin)
• Pyuria:
  
  • WBC can be found in the urine during UTIs or inflammatory parenchymal diseases (GN, TIN)
• Epithelial cells:
  
  • Renal tubular cells are present in normal urine, but increase means tubular damage (ATN or TIN)
  • Squamous epithelial cells indicate skin/vaginal contaminant
  • Urothelial cell suggest cystitis
• Microorganisms:
  
  • ​Bacteriuria
  • Fungiuria

Casts:

• They are intratubular precipitations/plugs of Tamm-Horsfall mucoproteins or cells. Produced in normal kidney, but can be clues of kidney disease
  
  • Non-cellular:
    
    • Hyaline casts: Mucoprotein alone
    • Granular casts: Aggregates of protein or cellular remnants. Non-specific, but often pathological
    • Broad or waxy casts: hylaine material of waxy appearance. Formed in dilated tubules of CKD
  • Cellular:
    
    • RBC casts (GN)
    • WBC casts (acute pyelonephritis)
    • Epithelial cell casts (non-sepcific of ATN, GN)
    • Fatty casts

Crystals:

• Detected under polarized light and are clinically irrelevant.

Question 8

What imaging techniques are used in renal disease diagnostics?

Answer 8

US:

• Diagnosis of masses, obstructions, cysts, renal size in CKD, PKD, calculi, estimation of prostate size
• Used for guided percutaneous procedures (biopsies and nephrostomy)

X-ray:

• Stones, calcifications

Renal CT:

• Renal or retroperioneal masses, ureterolithiasis, acute pyelonephritis, renal artery stenosis, localization of ectopic kidney
• Limitation: requires contrast material which is contraindicated in case of allergy or GFR <30ml/min

Renal MRI:

• Not 1st line investigation
• Indicated for non-calculous urinary tract obstruction and renal artery stenosis

Question 9

What are the indications and contraindications of renal biopsies?

Answer 9

Indications:

• Isolated 1-2g/day proteinuria with decreased GFR
• Nephrotic syndrome
• Acute GN
• RPGN (rapidly progressing GN)
• AKI (after excluding ATN)
• Renal failure of unknown origin
• Transplanted kidney dysfunction

Contraindication:

• Solitary kidney
• Multiple cysts
• Renal tumor
• Acute pyelonephritis
• Uncontrolled bleeding disorder
• Unconctrolled HTN