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Urine formation occurs through three steps: glomerular filtration, tubular reabsorption, tubular secretion.
Glomerular filtration:
GFR = 120–125 mL/min in a 70-kg adult.
Produces 170–180 L/day of filtrate.
Filtrate contains water + crystalloids (Na⁺, Cl⁻, glucose, amino acids, small molecules).
Cells and plasma proteins are retained.
Only 1.5 L/day is finally excreted → most of the water is reabsorbed.
Filtration barrier allows Hb (67 kDa) to pass but retains albumin (69 kDa).
Earliest sign of glomerular dysfunction = albumin in urine.
Tubules modify filtrate via reabsorption and secretion.
Proximal Convoluted Tubule (PCT):
Reabsorbs 70% water, Na⁺, Cl⁻.
Reabsorbs 100% glucose, amino acids, K⁺.
Partial reabsorption of urea, phosphate, calcium.
Loop of Henle:
Creates countercurrent multiplier.
Thick ascending limb reabsorbs Na⁺/K⁺/Cl⁻ but is water-impermeable.
Distal Convoluted Tubule (DCT):
Fine-tuning of electrolytes.
Aldosterone-dependent Na⁺ reabsorption and K⁺ secretion.
Collecting Tubule:
ADH-controlled water reabsorption.
Determines final urine concentration.
Major processes: solute reabsorption, solute secretion, water reabsorption.
Threshold substances are those whose urinary excretion depends on plasma concentration.
At normal levels → fully reabsorbed, absent in urine.
When plasma level exceeds threshold → reabsorptive capacity saturates → substance appears in urine.
Examples: glucose, amino acids, phosphate, bicarbonate.
Clinical utility:
Glycosuria in diabetes (high load).
Aminoaciduria in metabolic disorders.
Tubular disorders.
Tm = maximum reabsorptive capacity of renal tubules for a substance.
Represents saturation of transport systems.
When filtered load exceeds Tm → excess is excreted in urine.
Example: Glucose Tm ≈ 375 mg/min.
Helps distinguish overflow glycosuria (high glucose load) from renal glycosuria (low Tm due to tubular defect).
Healthy urine contains no proteins, no glucose, no ketone bodies, no bile pigments, no bile salts, and only trace urobilinogen.
Presence of abnormal substances suggests specific pathology.
Important abnormal constituents include:
Proteins → glomerular/tubular disease.
Glucose → diabetes, renal glycosuria.
Ketone bodies → ketosis, uncontrolled diabetes.
Bile salts → early obstructive jaundice.
Bile pigments (bilirubin) → obstructive or hepatocellular jaundice.
Blood → hematuria/hemoglobinuria.
Pus cells → infection.
Reducing sugars → glycosuria, galactosuria, fructosuria.
Crystals → stones, metabolic disorders.
In hemolytic jaundice → increased urobilinogen.
In hepatocellular jaundice → absent urobilinogen.
Presence of proteins in urine indicates glomerular or tubular dysfunction.
Types of proteinuria:
Glomerular proteinuria:
Due to increased permeability of glomerular basement membrane.
Albumin is the major protein lost.
Seen in nephrotic syndrome, glomerulonephritis.
Tubular proteinuria:
Tubules fail to reabsorb filtered proteins.
Smaller proteins appear in urine.
Seen in interstitial nephritis, toxins.
Overflow proteinuria:
Excess production of small proteins exceeds reabsorptive capacity.
Example: Bence-Jones proteins in multiple myeloma.
Post-renal proteinuria:
Infection or inflammation of urinary tract.
Transient proteinuria may occur with fever, exercise, dehydration.
Detecting proteinuria: heat test, sulfosalicylic acid test, dipstick.
Reducing sugars react with Benedict’s reagent and give a positive reaction.
Normal urine has no reducing sugars.
Causes:
Glucose: Diabetes mellitus, stress, renal glycosuria.
Galactose: Galactosemia (infants).
Fructose: Essential fructosuria, hereditary fructose intolerance.
Pentoses: Xylosuria after fruit ingestion.
Not all positive Benedict tests are glucose → confirm with glucose-specific dipstick.
Clearance = volume of plasma completely cleared of a substance per minute.
Used to measure glomerular filtration, tubular function, renal plasma flow.
Clearance (C) is calculated as:
C = (U × V) / P
U = urine concentration
V = urine flow rate
P = plasma concentration
Properties of an ideal filtration marker:
Freely filtered.
Not reabsorbed or secreted.
Not metabolized.
Not protein-bound.
High clinical value in assessing GFR.
Inulin is a fructose polysaccharide, not metabolized by the body.
Gold standard test for accurate GFR measurement.
Why inulin is ideal:
Freely filtered at glomerulus.
Not reabsorbed by tubules.
Not secreted by tubules.
Not synthesized or degraded in kidneys.
Not protein bound.
Procedure:
Continuous IV infusion of inulin to achieve steady plasma levels.
Collect timed urine samples and corresponding blood samples.
Apply clearance formula.
Normal value: 125 mL/min.
Limitations:
Labor-intensive, expensive.
Not used in routine clinical practice.
Creatinine clearance replaces inulin clearance in routine settings.
Creatinine is produced from creatine in muscle at a constant rate.
Freely filtered at glomerulus; not reabsorbed.
Tubular secretion occurs slightly → clearance slightly overestimates GFR.
Widely used clinically because:
Endogenous substance → no infusion needed.
Easy, inexpensive.
Stable production rate.
Formula:
C = (U × V) / P
U = urine creatinine
V = urine flow rate
P = plasma creatinine
Normal value: ~ 120 mL/min.
Interpretation:
Decreased clearance → decreased GFR → kidney dysfunction.
Useful for staging CKD.
Limitations:
Overestimates GFR due to tubular secretion.
Dependent on muscle mass (elderly, malnourished → falsely low).
Requires accurate 24-hour urine collection.
Low molecular weight protein produced by all nucleated cells at a constant rate.
Freely filtered by glomerulus.
Completely reabsorbed and metabolized by proximal tubules → not returned to blood, not excreted in urine.
Serum cystatin C rises when GFR decreases.
Advantages over creatinine:
Unaffected by muscle mass, age, sex.
More sensitive for early kidney disease.
Useful in elderly, children, malnourished, and cirrhosis patients.
Interpreted via equations like CKD-EPI cystatin C formula.
Increasingly preferred for early CKD detection.
Urea is freely filtered but 40–70% reabsorbed → not an ideal GFR marker.
Reabsorption varies with hydration status → affects accuracy.
Types of urea clearance:
Maximal urea clearance:
Performed with high urine flow rate (> 2 mL/min).
Normal: 75 mL/min.
Standard urea clearance:
When urine flow < 2 mL/min.
Normal: 54 mL/min.
Clinical significance:
Less reliable measure of GFR.
Used when creatinine testing unavailable.
Plasma urea also rises in high protein intake, dehydration, GI bleed → poor specificity.
Because of low accuracy, replaced by creatinine clearance and cystatin C.
(Assess ability of tubules to reabsorb, secrete, concentrate, and acidify urine)
Tubular function tests evaluate PCT, Loop of Henle, DCT, and Collecting duct activities.
Main tubular functions measured:
Reabsorption (glucose, amino acids, phosphate, bicarbonate, water).
Secretion (H⁺, K⁺, NH₄⁺, organic acids/bases).
Concentration of urine (ADH-dependent).
Dilution of urine.
Acidification of urine (H⁺ secretion + NH₄⁺ generation).
Concentration test
Dilution test
Specific gravity measurement
Urine osmolality
Acidification test
Fractional excretion tests (Na⁺, HCO₃⁻, phosphate)
Glucose reabsorption tests (renal threshold/Tm)
Used in clinical evaluation of acute tubular necrosis, interstitial nephritis, CKD, Fanconi syndrome, etc.
(Measures the concentration ability of kidneys)
Osmolality = number of osmotically active particles per kg of water.
Normal urine osmolality varies widely: 50 – 1200 mOsm/kg.
Reflects the kidney's ability to concentrate or dilute urine.
Determined largely by:
ADH secretion
Tubular integrity
Medullary concentration gradient
Hydration status
High urine osmolality
Dehydration
SIADH
Heart failure
Pre-renal azotemia (intact concentrating ability)
Low urine osmolality
Diabetes insipidus (central or nephrogenic)
Acute tubular necrosis
Primary polydipsia
Medullary washout states
SG depends on mass; osmolality depends on number of particles → osmolality is more accurate.
(Measures the kidney’s ability to excrete hydrogen ions and acidify urine)
Normal kidneys can acidify urine to pH < 5.5 after acid load.
Assesses distal tubular H⁺ secretion and NH₄⁺ generation.
Patient is given an acid load (e.g., ammonium chloride).
Urine pH is monitored over a few hours.
Normal kidney response: urine pH falls to ≤ 5.3.
Normal:
Urine pH drops below 5.3 → intact distal acidification.
Impaired acidification:
Urine pH remains > 5.5 despite systemic acidosis.
Indicates Distal Renal Tubular Acidosis (Type 1 RTA).
Also seen in:
Interstitial nephritis
Autoimmune diseases
Obstructive uropathy
Urinary NH₄⁺ excretion
Urinary anion gap (UAG)
Bicarbonate levels
(Assesses kidney’s ability to concentrate urine — mainly function of Loop of Henle + Collecting Duct + ADH)
Evaluates integrity of:
Countercurrent mechanism (Loop of Henle).
Medullary hypertonicity.
ADH secretion and response (Collecting duct).
Normally, kidney can concentrate urine to > 800 mOsm/kg or specific gravity > 1.022.
Water is restricted overnight (8–12 hours).
Early morning urine sample collected.
Measure specific gravity or osmolality.
Urine osmolality > 800 mOsm/kg
OR
Specific gravity > 1.022
Urine osmolality < 600 mOsm/kg after dehydration → suggests tubular or ADH-related defect.
Chronic kidney disease
Acute tubular necrosis
Nephrogenic diabetes insipidus
Central diabetes insipidus
Medullary washout (prolonged diuretics, polydipsia)
Severe electrolyte disturbances (hypokalemia, hypercalcemia)
(Assesses kidney’s ability to dilute urine — function of DCT + Collecting Duct in absence of ADH)
Checks ability to excrete free water.
Requires intact:
Glomerular filtration
Active NaCl reabsorption in thick ascending limb
Suppression of ADH
Patient drinks water load (10–20 mL/kg).
Urine samples collected over next 4 hours.
Large volume of dilute urine produced.
Urine osmolality < 100 mOsm/kg
OR
Specific gravity < 1.003
Urine remains concentrated despite water load.
SIADH
Advanced renal failure
Congestive heart failure
Cirrhosis
Hypothyroidism
Adrenal insufficiency
(Assess specific tubular transport functions — mainly PCT and DCT)
(Assesses proximal tubular reabsorption of phosphate)
Phosphate is freely filtered and partially reabsorbed in PCT.
Reabsorption is regulated by PTH.
TmP/GFR measures maximal tubular reabsorptive capacity.
Detects Fanconi syndrome (↓ phosphate reabsorption).
Diagnoses renal phosphate wasting.
Differentiates causes of hypophosphatemia.
Evaluates hyperparathyroidism (↓ reabsorption due to PTH).
Low TmP/GFR → proximal tubular defect or high PTH.
Normal/high TmP/GFR → extrarenal causes of phosphate loss.
(Assesses proximal tubular reabsorption of bicarbonate & ability to handle acid-base balance)
Normally, PCT reabsorbs 80–90% of filtered bicarbonate.
Test evaluates whether tubules can reclaim filtered HCO₃⁻.
Raise plasma bicarbonate slightly; measure:
Plasma HCO₃⁻
Urinary HCO₃⁻ excretion
Calculate fractional excretion.
Diagnoses Proximal Renal Tubular Acidosis (Type 2 RTA).
Evaluates Fanconi syndrome.
Helps differentiate:
Type 2 RTA → poor HCO₃⁻ reabsorption
Type 1 RTA → normal HCO₃⁻ reabsorption, but impaired distal acidification
High bicarbonate excretion at normal plasma HCO₃⁻ → tubular defect.
Low ability to reclaim HCO₃⁻ → Type 2 RTA.
Normally absent in urine.
Appears only in obstructive jaundice (early phase).
Indicates obstruction to bile flow → bile salts regurgitate into blood → filtered into urine.
Test:
Hay’s sulfur test becomes positive.
Clinical significance:
Early detection of obstructive jaundice even before severe rise in bilirubin.
Normal urine contains no bilirubin.
Bilirubin appears in urine in:
Obstructive jaundice.
Hepatocellular jaundice.
Not seen in hemolytic jaundice because unconjugated bilirubin is not water-soluble.
Test:
Fouchet’s test for bilirubin.
Urine becomes dark yellow or greenish.
Ketone bodies = acetoacetate, β-hydroxybutyrate, acetone.
Normally absent; appear when fat breakdown exceeds carbohydrate availability.
Causes:
Diabetic ketoacidosis (DKA)
Starvation, fasting
Prolonged vomiting, dehydration
High-fat/low-carb diets
Tests:
Rothera’s test for acetoacetate.
Ketostix dipsticks commonly used.
Presence of ketones indicates poor glucose utilization or excessive fat metabolism.
Normally present in trace amounts.
Derived from intestinal breakdown of bilirubin.
Reabsorbed urobilinogen is partly excreted into urine.
Hemolytic jaundice
Ineffective erythropoiesis
Early liver disease (reduced hepatic uptake)
Obstructive jaundice (bile cannot reach intestine)
Severe hepatocellular failure
Ehrlich test
Schlesinger’s test
(Highly exam-important: differentiate markers based on accuracy & clinical use)
Gold standard (most accurate).
Freely filtered.
Not reabsorbed, not secreted, not metabolized.
Used only in research; not practical clinically.
Most commonly used marker in clinical practice.
Freely filtered; slightly secreted → slight overestimation of GFR.
Serum creatinine rises only after significant nephron loss (> 50%).
Better approximation of GFR than serum creatinine alone.
Requires 24-hour urine.
Overestimates GFR by 10–20%.
Constant production by all nucleated cells.
Filtered and completely metabolized in tubules.
More sensitive than creatinine in early kidney disease.
Unaffected by muscle mass → useful in elderly & malnourished.
Freely filtered, but significantly reabsorbed → not reliable.
Affected by hydration, protein intake, GI bleed.
Used mainly as supportive marker (BUN).
Evaluate tubular function rather than pure GFR.
Kidney performs filtration, reabsorption, secretion, acid-base balance, electrolyte balance, vitamin D activation, erythropoietin production.
GFR = 120–125 mL/min in adults; produces 180 L/day filtrate; only 1.5 L/day becomes urine.
Earliest sign of glomerular damage = albuminuria.
PCT reabsorbs 100% glucose, amino acids, and 70% water + Na⁺ + Cl⁻.
Threshold substances (glucose, amino acids, phosphate) appear in urine when plasma levels > tubular capacity.
Tm (tubular maximum) = maximal reabsorption capacity; for glucose ≈ 375 mg/min.
In obstructive jaundice → bile salts + bilirubin appear in urine.
Ketone bodies appear in DKA, starvation, prolonged vomiting.
Urobilinogen:
↑ in hemolytic jaundice
Absent in obstructive jaundice
Best measure of GFR: Inulin clearance (gold standard).
Most used clinically: Creatinine clearance.
Cystatin C is the most sensitive marker for early CKD.
Urea clearance is unreliable due to variable reabsorption.
Concentration ability depends on ADH + medullary gradient + Loop of Henle integrity.
Dilution ability depends on suppressed ADH + intact thick ascending limb.
Inability to acidify urine (<5.5) after acid load = Distal RTA (Type 1).
Fanconi syndrome affects PCT → phosphate, bicarbonate, glucose, amino acid losses.
Specific gravity is less accurate than osmolality for assessing concentration.
Tubular function tests help diagnose tubular necrosis, interstitial nephritis, RTA, CKD.
Marker of early CKD progression = rise in cystatin C before creatinine.
Renal plasma flow estimated using PAH clearance (not discussed but high-yield conceptually).
Inulin clearance (gold standard).
Endogenous, easy to measure, inexpensive, stable production rate.
Because creatinine is slightly secreted by the tubules.
Cystatin C, because it is unaffected by muscle mass.
Albumin (microalbuminuria in early diabetic nephropathy).
Due to renal glycosuria (low Tm of glucose).
Obstructive jaundice (early phase).
Hemolytic jaundice or early hepatic disease.
Acetoacetate.
Urea is significantly reabsorbed, affected by hydration and protein intake.
Suggests Distal Renal Tubular Acidosis (Type 1).
Plasma concentration above which a substance begins to appear in urine because reabsorption is saturated.
Maximum rate at which tubules can reabsorb a substance.
Loop of Henle + Collecting ducts (ADH-dependent).
Poor concentrating ability → DI, ATN, CKD, polydipsia.
Reappearance of urobilinogen in urine.
Ketone bodies (acetoacetate with Rothera’s test).
Rough indicator of urine concentration; influenced by large molecules → less accurate than osmolality.
A. Creatinine clearance
B. Cystatin C
C. Inulin clearance
D. Urea clearance
Answer: C
A. Glucosuria
B. Albuminuria
C. Hematuria
D. Ketonuria
Answer: B
A. Plasma glucose exceeds renal threshold
B. Tubular secretion increases
C. Plasma sodium decreases
D. Urea increases
Answer: A
A. Maximum filtration capacity
B. Maximum secretion rate
C. Maximum reabsorption capacity
D. Minimum reabsorption threshold
Answer: C
A. Hemolytic jaundice
B. Obstructive jaundice
C. Gilbert syndrome
D. Neonatal jaundice
Answer: B
A. Acetone
B. Beta-hydroxybutyrate
C. Acetoacetate
D. All three ketone bodies
Answer: C
A. Obstructive jaundice
B. Hemolytic jaundice
C. Severe hepatitis (late stage)
D. Cirrhosis (end stage)
Answer: B
A. Creatinine is reabsorbed
B. Creatinine is secreted by tubules
C. Creatinine binds to proteins
D. Creatinine is unstable
Answer: B
A. GFR increases
B. GFR decreases
C. Creatinine secretion increases
D. Urine output increases
Answer: B
A. Urine pH < 5.3 after acid load
B. Urine pH remains > 5.5
C. Severe glucosuria
D. Increased bicarbonate reabsorption
Answer: B
A. Normal concentrating ability
B. Diabetes insipidus
C. Obstructive uropathy (early)
D. Dehydration
Answer: B
A. Fanconi syndrome
B. Hyperparathyroidism
C. Hypoparathyroidism
D. SIADH
Answer: A
A. Urine flow > 2 mL/min
B. Urine flow < 2 mL/min
C. Urine is alkaline
D. Plasma urea is normal
Answer: B
A. SG is affected by number of particles only
B. SG is affected by mass of particles
C. SG requires complex instruments
D. SG cannot detect proteins
Answer: B
A. Distal convoluted tubule
B. Collecting duct
C. Proximal convoluted tubule
D. Loop of Henle
Answer: C
A. Ketone bodies
B. Bile pigments
C. Bile salts
D. Urobilinogen
Answer: B
A. Urea
B. Creatinine
C. Glucose
D. PAH
Answer: C
A. Not reabsorbed significantly
B. Not secreted
C. Unaffected by muscle mass
D. More stable in plasma
Answer: A
A. Hypoparathyroidism
B. Fanconi syndrome
C. Dehydration
D. Diabetes insipidus
Answer: B
A. Hemolytic jaundice
B. Hepatocellular jaundice
C. Obstructive jaundice
D. Crigler–Najjar syndrome
Answer: C
A 32-year-old man with long-standing diabetes presents for routine checkup. Urine dipstick shows trace albumin. Blood glucose is mildly elevated.
Q: What is the earliest renal abnormality in this patient?
Answer: Early glomerular dysfunction (microalbuminuria).
Explanation: Albumin is the earliest indicator of glomerular damage in diabetic nephropathy.
A 20-year-old woman has glucose in urine, but fasting glucose is normal.
Q: What is the likely diagnosis?
Answer: Renal glycosuria (low Tm of glucose).
Explanation: Tubular defect causes glucose spill despite normal plasma levels.
A young male with vomiting and dehydration shows positive Rothera’s test.
Q: Which ketone body is detected?
Answer: Acetoacetate.
Explanation: Rothera’s test detects acetoacetate (and weakly acetone).
A patient has yellowish urine, positive Fouchet’s test, and absent urobilinogen.
Q: What does this pattern suggest?
Answer: Obstructive jaundice.
Explanation: Conjugated bilirubin and bile salts appear in urine; urobilinogen becomes absent.
A patient with dark urine shows high urobilinogen.
Q: Which jaundice does this suggest?
Answer: Hemolytic jaundice.
Explanation: Increased bilirubin turnover increases urobilinogen formation.
A 35-year-old man reports polyuria and polydipsia. After dehydration overnight, his urine osmolality remains < 300 mOsm/kg.
Q: What is the most likely cause?
Answer: Diabetes insipidus (central or nephrogenic).
Explanation: Inability to concentrate urine.
After ammonium chloride loading, a patient’s urine pH remains > 5.5.
Q: What renal tubular defect is present?
Answer: Distal Renal Tubular Acidosis (Type 1 RTA).
Explanation: Failure of distal nephron to acidify urine.
A child presents with metabolic acidosis, hypophosphatemia, glucosuria, and aminoaciduria.
Q: Which renal condition fits this picture?
Answer: Fanconi syndrome (Proximal RTA type 2).
Explanation: PCT fails to reabsorb multiple solutes.
A dehydrated patient has BUN:Cr ratio > 20:1 with low urine sodium (< 20 mEq/L).
Q: What is the likely diagnosis?
Answer: Pre-renal azotemia.
Explanation: Increased urea reabsorption due to low renal perfusion.
A 60-year-old man’s creatinine clearance = 45 mL/min.
Q: What stage of kidney function impairment does this indicate?
Answer: Moderate reduction in GFR → CKD Stage 3.
Explanation: Normal = 120 mL/min; 30–59 is moderate CKD.
After water deprivation, urine specific gravity remains 1.003.
Q: What does this indicate?
Answer: Impaired concentrating ability (e.g., CKD, DI, ATN).
Explanation: SG should rise above 1.022 with intact concentration.
A frail elderly woman has normal serum creatinine but high cystatin C.
Q: What does this suggest about kidney function?
Answer: Early decline in GFR.
Explanation: Cystatin C detects early kidney impairment even when creatinine appears normal.
A patient shows low urea clearance but normal creatinine clearance.
Q: What explains this discrepancy?
Answer: Urea is partially reabsorbed, making its clearance unreliable.
Explanation: Hydration and protein intake affect urea levels.
A patient cannot dilute urine after water load; urine osmolality stays high.
Q: Which nephron segment is likely affected?
Answer: Thick ascending limb of Loop of Henle.
Explanation: Dilution requires solute reabsorption without water.
A diabetic patient has 30–300 mg/day albumin in urine.
Q: What is this condition called?
Answer: Microalbuminuria.
Explanation: Early marker of diabetic nephropathy.
Nephron.
120–125 mL/min in adults.
170–180 liters/day.
About 1.0–1.5 liters/day.
Albumin in urine.
Glucose (most common).
Others: amino acids, phosphate.
Maximum rate at which tubules can reabsorb a substance.
Approximately 180 mg/dL.
Inulin clearance.
Endogenous, easy, cheap, good estimate of GFR.
Because creatinine is slightly secreted by tubules.
Cystatin C.
Acetoacetate.
Presence of bilirubin (bile pigments) in urine.
Obstructive jaundice.
Hemolytic jaundice.
50 – 1200 mOsm/kg.
Loop of Henle (countercurrent mechanism).
ADH (antidiuretic hormone).
Rough indicator of urine concentration.
Osmolality depends on number of particles, not weight.
Distal RTA (Type 1).
Proximal convoluted tubule (PCT).
To estimate renal plasma flow.
About 120 mL/min.
Phosphate clearance or bicarbonate reabsorption test.
Water dilution test (water load test).
Water deprivation (concentration) test.
Obstructive jaundice.
Earliest marker of diabetic nephropathy.
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