THE CLINICAL BIOCHEMISTRY OF KIDNEY FUNCTIONS Dr Boldizsár CZÉH
The kidneys are vital organs Functional unit: Nephron
RENAL FUNCTIONS Electrolyte & Fluid Balances Acid-Base Balances Elimination of Metabolic Wastes Blood Pressure Regulation Endocrine functions: Vitamin D Synthesis, EPO, RAA system Red Blood Cell Production Prostaglandins Synthesis
Why do we test renal functions? To identify renal dysfunction. To diagnose renal disease. To monitor disease progress. To monitor response to treatment. To assess changes in function that may impact on therapy (e.g. Digoxin, chemotherapy).
Urinalysis Liquid biopsy of the urinary tract. Painless, non-invasive, inexpensive. Yields much information quickly.
The 3 stages of urine analysis FRESH SAMPLE!!
Urine in different colors
Gross appearance Amount 800 1800 ml / die Polyuria > 2.5 L / die Oliguria < 400 ml / die, Anuria 100 ml / die Pollakisuria: frequent, but small amount, becasue of tumor or infection Color Normally yellowish Food, drugs Blood, myoglobin Transparency Infection, blood, bacteria, fungi Odor typical urine smell sweet: sugar ammoniac
Urine sediment: microscopic examination from freshly passed urine Looking for cells, casts (Tamm-Horsfall protein), fat droplets Red Cell casts : haematuria = glomerular disease White cell cast : polymorphs + bacteruria = pylonephritis Lower UTI: polymorphs, but no casts Acute glomerulonephritis = haematuria, cells, casts Chronic glomerulonephritis = less sediment Erythrocyte cylinder Leucocyte cylinder
Biochemical Tests of Renal Function Specific gravity and osmolality ph: normal ph 4.8 7.5 Glucose Protein Bilirubin Keton bodies
Biochemical Tests of Renal Function Glucose Increased blood glucose Low renal threshold or other tubular disorders Proteinuria Normal < 200 mg / 24h. Urine sticks = > 300mg/L Causes: - overflow (raised plasma Low MW Proteins, Bence Jones, myoglobin) glomerular leak decreased tubular reabsorption of protein protein with renal origin
Functional tests
Glomerular Function = GFR
Measurement of Glomerular Filtration Rate: determination of clearance GFR is essential to renal function Most frequently performed test of renal function. Measurement is based on concept of clearance: clearance is a pharmacokinetic measurement of the volume of plasma from which a substance is completely removed per unit time; the usual units are ml/min
Measurement of Glomerular Filtration Rate: determination of clearance Clearance = (U x V) / P where U = is the urinary concentration of a given substance V = is the volume of urine produced (ml/min) P = is the plasma concentration of the given substance Unit = volume / time (ml/min) If clearance = GFR then: freely filtered by glomerulus glomerulus = sole route of excretion from the body (no tubular secretion or reabsorption) Non-toxic and easily measurable
Creatinine Clearance 1-2 % / day of muscle creatine converted to creatinine. Amount produced relates to muscle mass. Freely filtered at the glomerulus. Some tubular excretion.
Creatinine Clearance Timed urine collection for creatinine measurement (usually 24h) Blood sample taken within the period of collection. Problems: Practical problems of accurate urine collection and volume measurement. Within subject variability = 11% Interference in creatinine measurement In vitro interference: acetoacetate, ascorbic acid, fructose, pyruvate, cephalosporins, creatine, proline, chronic lidocaine administration, bilirubin. In vivo inhibition of creatinine secretion occurs with cimetidine or trimethoprim.
Estimated GFR (egfr) Plasma Creatinine Concentration
Estimated GFR (egfr) Plasma Creatinine Concentration Difficulties: Concentration depends on balance between input and output. Production determined by muscle mass which is related to age, sex and weight. High between subject variability but low within subject. Concentration inversely related to GFR. Small changes in creatinine within and around the reference limits = large changes in GFR. Reference limits can be misleading Plasma creatinine can increase following protein loads. Goulash effect. 80% rise in creatinine after 300g of cooked beef. Less variability in early morning creatinine Strenuous exercise may increase creatinine by 14% Muscle mass more difficult to predict in oedematous patients and late pregnancy Patients with muscle wasting Patients with liver disease Drugs inhibiting tubular secretion can raise creatinine conc.
Effect of Muscle Mass on Serum Creatinine Creatinine Input Normal Muscle Mass Normal Muscle Mass Increased Muscle Mass Reduced Muscle Mass Plasma Pool Content Output Kidney Normal Kidneys Diseased Kidneys Normal Kidneys Diseased Kidneys
Cystatin-C Cysteine proteinase inhibitor C (MW13 000) Small size = freely filtered at glomerulus Constant production rate by all nucleated cells No known extra-renal excretion routes Not influenced by muscle mass, diet or sex Estimation of GFR for/in: Early detection of kidney disease Acute and chronic renal disease Renal transplantation and haemodialysis Diseases associated with kidneys, e.g. diabetes mellitus, hypertension Patients receiving nephrotoxic drugs Liver failure Paediatrics and elderly
Tubular Functions
Tests of Tubular Functions Proximal Tubular Function Phosphate reabsorption Aminoaciduria Glycosuria Fractional HCO 3 - excretion. Distal Tubular Function Acidification Concentration Concentrating capacity of the kidneys
Renal failure: laboratory studies
Serum Studies BUN = blood urea nitrogen (2.5-6.4 mmol/l) Creatinine (70-124 umol/l) Hematocrit Albumin Electrolytes (K +, Na +, Ca 2+, Mg ++ & Phosphate) Urine Studies Urine Analysis (UA) Color, appearance, ph, specific gravity, glucose, protein, WBC, RBC and casts. Culture & Sensitivity (C&S): Bacteria Urinary Collection: 24 Hour Urine: i.e. creatinine or electrolytes Spot / Random Urine: first a.m. void preferred Combination Studies Creatinine Clearance (110-120 ml/min) 24 hour urine and a serum sample
Acute Renal Failure (ARF) Sudden loss of kidney function over a period of hours or days Characterized by: A rapid GFR Retention of metabolic waste A progressive BUN and Creatinine (Azotemia) Associated with: Classic finding of Oliguria (UO < 400ml/day) Fluid, electrolyte and acid-base imbalances Usually reversible with prompt treatment
Classification of ARF: according to the location of the insult Prerenal Blood flow to kidneys Occurs in about 50-70% of all ARF cases Intrarenal actual damage to kidneys Occurs in about 20-30% of all ARF cases Postrenal obstruction of urinary excretion Occurs in about 1-10% of all ARF cases
Pre-Renal ARF Renal blood flow is decreased before reaching the kidney. Renal Perfusion = GFR leading to Oliguria Most common type of ARF Common Causes: Hypotension (severe and abrupt) Hypovolemia Low Cardiac Output States Treatment to correct cause, if not corrected it may cause intrarenal failure i.e. acute tubular necrosis (ATN)
Intrarenal ARF: a condition that leads to actual damage of the renal tissue (parenchyma) resulting in malfunction of nephrons. Acute Tubular Necrosis (ATN) Damage to the renal tubules caused by ischemia or toxins Characterized by varying degrees of cellular damage or death. Ischemic: trauma to kidneys, massive hemorrhage or postsurgery Nephrotoxic: I.V. contrast dyes, heavy metals or antibiotics (aminoglyclosides)
Pre-renal versus renal ARF TEST RESULT Pre-renal Renal Urea & Creatinine Urea Both in serum Creatinine Protein in the urine - +
Pre-renal versus renal ARF TEST Pre-renal RESULT Renal Urine Na + (mmol / L) < 20 > 40 Urine / Plasma Osmolality > 1.5 : 1 < 1.1 : 1 Urine urea cc / Plasma urea cc > 10 < 5
Postrenal ARF: conditions that block urine flow distal to kidneys Caused by an obstruction below the kidneys in the urinary tract Calculi (stones) Tumors or masses Blood clots Benign prostate hypertrophy (BPH) Urine Output common; Oliguria or anuria (UO < 50 ml/day) Causes urine to back up into the kidneys; eventually increases pressures leading to a GFR
Chronic Renal Failure A progressive and irreversible loss of renal function over a period of months to years The kidneys can loose up to 80% of all nephrons with relatively few overt changes in functioning of the body Nephrons are destroyed and replaced with scar tissue; remaining nephrons become hypertrophied and do not function as well. Resulting in systemic disease involving all of the body s organs (Uremic syndrome of CRF)
Chronic Renal Failure Diabetes Mellitus Hypertension Vascular disorders Infections Nephrotoxic medications Toxic agent exposure Sickle cell anemia Systemic lupus erythematosus Chronic glomerulonephritis Pyelonephritis Obstructions of the urinary tract Polycystic kidney disease
Three Stages of CRF Stage 1 Reduced renal reserve Characterized by a 40-75% loss of nephron function Usually asymptomatic; normal BUN & Creatinine Stage 2 Renal Insufficiency Characterized by a 75-90% loss of nephron function BUN and Creatinine Kidneys loose ability to concentrate urine; client may report polyuria or/and nocturia; Anemia develops Stage 3 End-stage renal disease (ESRD) Final Stage Characterized by a >90% loss of nephron function Characterized by BUN Creatinine and electrolyte imbalances Uremic symptoms Requires Lifelong Dialysis
Nephrotic syndrome
Most common syndromes associated with glomerular disease Acute Glomerulonephritis Rapidly Progressive Glomerulonephritis Chronic Glomerulonephritis Nephrotic Syndrome
Pathophysiology of nephrotic syndrome Increased glomerular capillary permeability Heavy proteinuria Hypogammaglobulinemia Hypoalbuminemia Loss of antithrombin-3 Susceptibility to infection Edema Compensatory Increase in lipoprotein synthesis Hyperlipemia Hypercoagulability
Systemic biochemical manifestations, complications Anemia Inadequate erythropoietin production Decreased life span of RBC Nutritional deficits S/SX: fatigue, shortness of breath and even angina Renal Osteodystrophy A syndrome of skeletal changes found in CRF from alterations in calcium & phosphate metabolism and elevated PTH levels: PTH reabsorbs calcium & phosphorous from bone stores in an attempt to increase serum calcium levels. Long term effects: bone deformity and weakness Increased triglyceride levels Occurs in 30-70% in CFR Increased blood sugars Usually moderate; alterations cellular use of glucose Increased tendency to bleed Altered platelet function and coagulation factors Increased risk of Infection Impaired leukocyte function and immune responses Reproductive Dysfunction Infertility and decreased libido
Biochemical manifestations: electrolyte imbalances Hyperkalemia Kidney s can t excrete 80-90% of body s potassium like normal Irritability, restlessness, weakness, diarrhea and abdominal pain/cramping Hyperphosphatemia Primarily excreted by kidneys; UO = decreased excretion Hypocalcemia The active form of Vitamin D is required for Ca 2+ to be absorbed; only functioning kidneys can activate Vitamin D Hypermagnesemia Usually normal or slightly elevated Hyponatremia Sodium levels maybe decreased due to hemodilution from fluid overload.
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