CHEMICAL PATHOLOGY OF RENAL DISORDERS

Question 1

What is the anatomy of the kidney?

Question 2

What is the nephron?

Answer 2

• Functional unit of the kidney
• 0.6 - 1.5 million per kidney

• Composed of:
• Glomerulus
• Proximal tubule
• Loop of Henle
• Distal tubule
- Collecting duct

Question 3

What’s is the glomerulus?

Answer 3

Functions: to filter plasma to form an ultrafiltrate
Filters based on size and charge of particles

Question 4

What are some ultrafiltrates filtered by the kidneys?

Answer 4

Ions/electrolytes: Nat, K+, Cl, Caz+, PO, Mgat, SO,, HCO3, H+
• Water
• Small molecules: Glucose
• Waste products: Creatinine, urea

Question 5

What is the most metabolically active part of the nephron?

Answer 5

The PCT

Question 6

How much reabsorption occurs in the PCT?
What’s the driving force?
And what does this do to the volume of the filtrate?

Answer 6

60-80%

Driving force is active transport of Na+ (water follows Na+)

Filtrate volume decreases

Question 7

What is the loop of Henle?

Answer 7

Descending limb
• Permeable to water
• Impermeable to solutes (Na+, CI)

Ascending limb
• Impermeable to water
• Permeable to solutes (Na+, Cl)
• consist of thin and thick

Question 8

What is the function of the DCT?

Answer 8

Reabsorption of Na+
• Active transport
• Cl follows Na+
• Water

• Reabsorption of Ca2+

• Excretion of K+

Question 9

What is the function of the collecting duct?

Answer 9

Determines final concentration of
urine

Normally impermeable to water reabsorption

Responds to external signals

Question 10

What are the components of healthy urine?

Answer 10

Healthy urine:
• 0.4-2 L/day
• Clear, amber colored
• pH 5.0-6.0
• Osmolality: 50-1400 mOsms/kg
• Protein: 50-80 mg/day
• Albumin: <30 mg/day
• Glucose: <0.5 g/day

Question 11

What is the driving force for glomerular filtration?

Answer 11

The driving force for glomerular filtration is the pressure gradient from the glomerulus to the Bowman space.

Question 12

What does Glomerular pressure depends on?

Answer 12

Glomerular pressure depends on renal blood flow (RBF) which is controlled by the combined resistances of renal afferent and efferent arterioles.

Question 13

The hyperfiltration and hypertrophy of residual nephrons signifies what?

Answer 13

The hyperfiltration and hypertrophy of residual nephrons has been hypothesized to represent a major cause of progressive renal dysfunction.

Question 14

Characteristics seen in Reduced GFR with normal tubular function (in the plasma and urine?

Answer 14

Plasma
High urea and creatinine concentration
Low bicarbonate concentration, with low pH (acidosis)
Hyperkalaemia
Hyperuricaemia and hyperphosphataemia

Urine
Reduced volume (oliguria)
Low (appropriate) sodium concentration only if renal blood flow is low, stimulating aldosterone secretion
High (appropriate) urea concentration and therefore a high osmolality only if ADH secretion is stimulated.

Question 15

Characteristics seen in Reduced tubular function with normal GFR (in the plasma and urine?

Answer 15

Plasma
* Normal urea and creatinine concentrations(normal glomerular function)

• Due to proximal or distal tubular failure,
  low bicarbonate concentration and low pH, hypokalaemia
• Due to proximal tubular failure,
  hypophosphataemia, hypomagnesaemia and hypouricemia

Urine
* Due to proximal and/or distal tubular failure,
increased volume, pH inappropriately high compared with that in plasma

• Due to proximal tubular failure,
  generalized aminoaciduria, phospaturia, glycosuria, proteinuria
• Due to distal tubular failure,
  an inappropriately high sodium concentration (inability to respond to aldosterone),
  an inappropriately low urea concentration and therefore osmolality (inability of the collecting ducts to respond to ADH)

Question 16

What are the 2 categories that renal failure can be divided into?
How are they differenctiated?
Apart from the above factor, how else are they differentiated?

Answer 16

Kidney failure can be divided into two categories:

• Acute Renal Failure
• Chronic Renal Failure

The type of renal failure is differentiated by the trend in the serumcreatinine

Other factors that may help differentiate acute kidney failure from chronic kidney failure include: anemiaand the kidney size on USS(ultrasound)

Question 17

What is ACUTE RENAL FAILURE (ARF)? And what are the consequences?

Answer 17

ARF also known as Acute Kidney Injury is defined as a sudden deterioration in renal function which is usually, but not invariably reversible over a period of hours to days.

Consequences of ARF includes:
Accumulation of nitrogenous waste
Disturbance of fluid and electrolyte homeostasis
+/- reduced urinary output

Urine output less than 400-450 ml/day or 15ml/hour (in adult) with a rising blood urea (N = 1.7 - 6.7 mmoles/l)

Kidney failure occur over a period of hours or days.

ARF may be reversed and normal renal function regained

The blood urea typically rises by 5 mmoles/l/day, but in surgical, trauma, or gastro-intestinal bleeding it can rise by up to 15 mmoles/l/day.

Question 18

Why do Creatine levels depend on age and gender?

Answer 18

Age: Creatinine is produced by muscle tissue. As people age, muscle mass decreases, leading to lower creatinine levels.

Gender: Men typically have a higher percentage of muscle mass and lower percentage of body fat compared to women.
Testosterone, present in higher levels in men, promotes muscle growth and creatinine production.

Question 19

How can ARF be classified?

Answer 19

• Pre-renal 60-70%: defect before the kidney- As an adaptive response to severe volume depletion and hypotension, with structurally intact nephrons.
• Intrinsic renal 25-40%: defect in the kidney. (may be due to damage to tubules, glomerulus or interstitium)- In response to cytotoxic, ischemic, or inflammatory insults to the kidney, with structural and functional damage e.g. acute tubular necrosis (due to ischemia or toxins), glomerulonephritis (depostion of antigen-antibody complexes despositing in glomerular tissue initiating the complement system and therefore inflammation).
• Post-renal 5-10%: defect after the kidney,- From obstruction to the passage of urine e.g. prostatic enlargement (in benign prostatic hyperplasia), urolithiasis (movement of renal stones).

Question 20

Prerenal causes of ARF and ratios

Answer 20

Prerenal:
Hypotension
Hypovoleamia/Haemorrhage
Renal Artery Stenosis
Hepato-Renal syndrome (HRS is the development of renal failure in patients with advanced chronic liver disease)
Cardiac Failure
Dehydration, diarrhea and vomiting

Spot Urine Sodium (mmol/l) <20
Fractional Excretion of Sodium
{(urine sodium/plasma sodium)
X (urine creatinine/plasma creatinine)} <1
Urine: Plasma creatinine ratio >40
Urine: Plasma osmolality ratio >1.2
Urine: Plasma urea ratio >10

Question 21

Intrarenal causes of ARF

Answer 21

Intral-renal:
Acute Tubular Necrosis (ischaemic or toxic)
Vasculitis Glomerulonephritis
Sepsis
Interstitial nephritis
Intratubular obstruction (e.g uric acid crystals, calcium stones)
Nephrotoxic Drugs

Spot Urine Sodium (mmol/l) >20
Fractional Excretion of Sodium
{(urine sodium/plasma sodium)
X (urine creatinine/plasma creatinine)}>1
Urine: Plasma creatinine ratio <20
Urine: Plasma osmolality ratio <1.2
Urine: Plasma urea ratio <10

Question 22

Postrenal causes of ARF

Answer 22

Post-renal:
Bilateral ureteric obstruction
(unilateral) Urethral obstruction
Retroperitoneal fibrosis
Carcinoma of cervix or bladder

Spot Urine Sodium (mmol/l) <20
Fractional Excretion of Sodium
{(urine sodium/plasma sodium)
X (urine creatinine/plasma creatinine)}<1
Urine: Plasma creatinine ratio <20
Urine: Plasma osmolality ratio <1.2
Urine: Plasma urea ratio <10

Question 23

What is the RIFLE Classification System for ARF?

Answer 23

The Acute Dialysis Quality Initiative work group set forth a definition and classification system for acute renal failure

RISK
INJURY
FAILURE
LOSS
END STAGE
- Using the serum creatinine or urinary output

Question 24

What is the Acute Kidney Injury Network (AKIN) classification system?

Answer 24

The AKIN also developed specific criteria for the diagnosis of AKI.

The AKIN defines AKI as abrupt (within 48 hours) reduction of kidney function, manifested by anyone of the following :

• An absolute increase in serum creatinine of 0.3 mg/dL or greater (≥26.4 µmol/L)
• A percentage increase in serum creatinine of 50% or greater (1.5-fold from baseline)
• A reduction in urine output, defined as less than 0.5 mL/kg/h for more than 6 hours

Question 25

What is the Kidney Disease: Improving Global Outcome (KDIGO) classification system?

Answer 25

KDIGO system was developed by merging the RIFLE and AKIN classifications into a simplified one.
It is more sensitive for AKI detection and prognostic performance.

The KDIGO defines AKI by any of the following:
* Rise in serum creatinine of ≥0.3 mg/dL (≥26.4 µmol/L) within 48hours

• Rise in serum creatinine of ≥1.5-fold from baseline

*Urine output, defined as less than 0.5 mL/kg/h for 6 hours

Question 26

What is the MANAGEMENT OF ACUTE RENAL FAILURE when it is post-renal and pre-renal?

Answer 26

• Post-renal: Relieve the obstruction, but then watch out for subsequent polyuria as accumulated waste products are excreted.
• Pre-renal: Restore blood volume, then blood pressure and GFR will return to normal levels.

Question 27

What is the MANAGEMENT OF ACUTE RENAL FAILURE when it is Intrinsic Acute Renal Failure?

Answer 27

Water:
If blood volume is low, replace with care, since fluid overload can lead to cardiac failure.
Maintain balance with 500 ml/day for insensible loss, plus previous day’s volume of urine output.
Monitor by weighing patient daily.

Na+:
Unable to regulate.
If oliguric - restrict.
In diuretic phase - may need to supplement Na+.

K+:
If oliguric - restrict; may even have to dialyse.
In diuretic phase - administer if hypokalaemic.

H+:
If severely acidotic, may need to supplement bicarbonate, but danger of Na+ overload if too much NaHCO3 is given in oliguric phase.

Protein:
Restrict protein intake to reduce production of urea and H+ .

Question 28

What is CHRONIC RENAL FAILURE?

Answer 28

Irreversible loss of nephrons

Chronic renal failure (CRF) (defined as being of more than 3 months duration) is the progressive irreversible destruction of kidney tissue by disease which, if not treated by dialysis or transplant, will result in the death of the patient.

The aetiology of CRF encompasses the spectrum of known kidney diseases.

The end result of progressive renal damage is the same no matter what the cause of the disease may have been.

The major effects of renal failure all occur because of the loss of functioning nephrons.

It is a feature of CRF that patients may have few if any symptoms until the glomerular filtration rate falls below 15 mL/minute (i.e. to 10% of normal function), and the disease is far advanced

Question 29

What are the two main phases CRF may pass through?

Answer 29

Polyuric Phase: Initial glomerular function may maintain urea and creatinine level in plasma, as more glomeruli are damaged urea excretion falls with increase in plasma level. This causes osmotic diuresis in the few functioning nephron

Oliguric phase: As more nephron is destroyed, glomerular filtration decreases significantly and urine output decreases

Question 30

What are the Causes of CRF?

Answer 30

Diabetes mellitus
Nephrotoxic drugs
Hypertension
Chronic Glomerulonephritis
Chronic Pyelonephritis
Polycystic kidneys
Urinary tract obstruction
Progression from acute renal failure

Question 31

What are the Consequences of CRF relating to Sodium and water metabolism?

Answer 31

Sodium and water metabolism
Most CRF patients retain the ability to reabsorb sodium ions, but the renal tubules may lose their ability to reabsorb water and so concentrate urine.

Polyuria, although present, may not be excessive because the GFR is so low.

Because of their impaired ability to regulate water balance, patients in renal failure may become fluid overloaded or fluid depleted very easily.

Question 32

What are the Consequences of CRF relating to Potassium metabolism?

Answer 32

Hyperkalaemia is a feature of advanced CRF and poses a threat to life.

The ability to excrete potassium decreases as the GFR falls, but hyperkalaemia may not be a major problem in CRF until the GFR falls to very low levels.

Then, a sudden deterioration of renal function may precipitate a rapid rise in serum potassium concentration.

An unexpectedly high serum potassium concentration in an outpatient should always be investigated with urgency.

Question 33

What are the Consequences of CRF relating to Acid–base balance?

Answer 33

As CRF develops, the ability of the kidneys to regenerate bicarbonate and excrete hydrogen ions in the urine becomes impaired.

The retention of hydrogen ions causes a metabolic acidosis.

Question 34

What are the Consequences of CRF relating to Calcium and phosphate metabolism?

Answer 34

The ability of the renal cells to make 1,25-dihydroxycholecalciferol falls as the renal tubular damage progresses.

Calcium absorption is reduced and there is a tendency towards hypocalcaemia.

Phosphate retention (hyperphosphatemia) , along with low calcium, induces a rise in parathyroid hormone (PTH), and the latter may have adverse effects on bone if this is allowed to continue (renal osteodystrophy).

Question 35

What are the Consequences of CRF relating to Erythropoietin synthesis?

Answer 35

Anaemia is often associated with chronic renal disease.

The normochromic normocytic anaemia is due primarily to failure of erythropoietin production.

Biosynthesized human erythropoietin may be used to treat the anaemia of CRF.

Question 36

How is CRF managed?

Answer 36

Water intake is controlled by thirst since output is fixed.

Careful control of Na+, K+, phosphate and and protein intake.

Treatment of anaemia with erythropoietin, and hypocalcaemia with Vitamin D.

Oral bicarbonate if acidosis is severe

In end-stage CRF :
Dialysis - haemodialysis or peritoneal dialysis
Renal transplantation

Question 37

What is a bio marker ?

Answer 37

A biomarker (biologic marker) is a measurable indicator of a specific biological state, particularly one relevant to the risk for, presence of, or stage of a disease.

Biomarkers can be used to screen for, diagnose, or monitor the activity of diseases as well as guide molecularly targeted therapy or assess therapeutic response.

Question 38

What are the Characteristics of an Ideal Marker for Kidney Disease?

Answer 38

1. Changes rapidly and reliably in response to kidney disease
2. Highly sensitive and specific for AKI and/or CKD
3. Adequately correlates with degree of kidney injury
4. Provides risk stratification and prognostic information (severity of kidney disease, need for dialysis, length of hospital stay, and mortality)
5. Is site-specific (proximal, distal, interstitium, or vasculature) to detect early injury and pathologic changes in specific segments of renal tubules
6. Relevant among different races and age groups
7. Indicates the cause of kidney injury or disease (eg, ischemia, toxins, sepsis, cardiovascular disease, diabetic nephropathy, lupus, combined factors)
8. Is organ-specific and allows differentiation among intrarenal, prerenal, and extrarenal causes of kidney injury
9. Identifies the duration of kidney failure (AKI versus CKD)
10. Is amenable to repeated measurement to allow monitoring of response to therapeutic intervention
11. Provides information on the risk of complications from comorbid conditions (especially in CKD)
12. Is stable over time across different temperature and pH conditions, with clinically relevant storage conditions
13. Is noninvasively, rapidly, and easily measurable
14. Is not affected by drugs or endogenous substances

Question 39

What are the Biomarkers of Acute Kidney Injury?

Answer 39

Neutrophil gelatinase-associated lipocalin (NGAL)
Interleukin-18 (IL-18)
Kidney injury molecule 1 (KIM-1)
Liver-type fatty acid–binding protein (L-FABP)
Insulin like growth factor–binding protein 7 (IGFBP7) x tissue inhibitor of metalloproteinases–2 (TIMP-2)
Calprotectin
Urinary angiotensinogen
Urinary microRNA
Cystatin C

Question 40

What are the Biomarkers of Chronic Kidney Injury?

Answer 40

• Cystatin C
• β-trace protein (BTP)
• Neutrophil gelatinase-associated lipocalin (NGAL)
• Kidney injury molecule 1 (KIM-1)
• Liver-type fatty acid–binding protein (L-FABP)
• Asymmetric dimethylarginine (ADMA)
• Uromodulin
• MicroRNA

Question 41

What is glomerulonephritis?

Answer 41

• Glomerulonephritis is inflammation of the kidney, which is often “immune-mediated”.
• Symptoms includes the sudden appearance of oedema (initially often periorbital), haematuria, hypertension, proteinuria and hypoalbuminaemia in acute condition
• This constellation of symptoms is known as the “nephritic syndrome”.
• Severity can vary from being almost asymptomatic, to patients presenting in acute renal failure with oliguria and uraemia.
• Causes of AGN includes
• Post-streptococcal glomerulonephritis
• Infections - Bacterial endocarditis, Viral infections.
• Immune diseases- IgA nephropathy, Lupus erythematosus, Goodpasture’s syndrome
• Vasculitis-polyarteritis, Wegener’s granulomatosis
• Conditions that are likely to cause scarring of the glomeruli- High blood pressure,
Diabetic kidney disease, Focal segmental glomerulosclerosis - scattered scarring of
some of the glomeruli

Question 42

What is nephrotic syndrome?

Answer 42

Characterized by increased permeability of the glomerulus to proteins, with massive proteinuria of greater than 3g/day, hypoproteinaemia and oedema.
Hypoproteinaemia stimulates an increase in liver protein synthesis, which leads to increased high MW proteins e.g., serum lipoproteins, and hypercholesterolaemia.
Nephrotic syndrome can be primary (a disease specific to the kidneys), or secondary (a renal manifestation of a systemic general illness).
Some are responsive to steroid therapy, and some not
Causes include:
Primary causes of nephrotic syndrome :Minimal-change nephropathy, Focal glomerulosclerosis, Membranous nephropathy, Hereditary nephropathies
Secondary causes: Diabetes mellitus, Lupus erythematosus, Amyloidosis and paraproteinemias, Viral infections (e.g, hepatitis B, hepatitis C, human immunodeficiency virus [HIV] ), Preeclampsia, drugs

Question 43

What is Fanconi syndrome?

Answer 43

The Fanconi syndrome is loss (inherited or acquired) of proximal tubular functions.

It is characterized by glycosuria, amino aciduria, and phosphaturia.

May also have acidosis and polyuria.

Classic cause is cystinosis, an inherited disease of lysosomal membrane transport. Other inherited causes includes:
Galactosemia
Hereditary fructose intolerance
Wilson disease
It can also be acquired. Causes includes:
Antiviral drugs

Question 44

What is renal tubular acidosis and the types?

Answer 44

This is a group of disorders characterized by tubular dysfunction, with normal or perhaps slightly decreased glomerular function

The picture is that of a normal anion gap metabolic acidosis, in the presence of a normal or near-normal plasma creatinine.

There are four types:
TYPE 1 (DISTAL) RTA: Due to inability of distal nephron to excrete H+
TYPE 2 (PROXIMAL) RTA: Due to defective proximal bicarbonate reabsorption
TYPE 3 (MIXED) RTA: Due to mutations in carbonic anhydrase II
TYPE 4 (HYPERKALEMIC) RTA: Due to diabetic nephropathy, drugs such as NSAIDs, potassium sparing diuretics, heparin

Question 45

What are RENAL STONES (NEPHROLITHIASIS)?

Answer 45

Causes:
A high concentration of a substance in the urine due to: -
low urine volume
high excretion rate
pH changes –
Alkaline urine predisposes to Ca deposition (e.g. infection)
Acid urine predosposes to uric acid deposition.
Stagnation, usually due to obstruction
Calculi are only partly mineral; up to 60% may consist of protein, the rest being varying proportions of calcium, magnesium, ammonium, phosphate, etc.

Question 46

What are types of renal stones?

Answer 46

Types of stones (calculi):

Calcium (oxalate + phosphate)stones – due to hyperparathyroidism, renal calcium leak, hyperoxaluria
Uric acid stones - in about 10% of gouty cases. May be associated with low urinary pH of <5 due to inadequate buffer production.
Struvite stones –caused by gram negative-urease positive organisms that breaks down urea to form ammonia
Rare forms: -
Cystine: In cystinuria, a transport defect of dibasic amino acids and cysteine
Xanthine: In xanthine oxidase deficiency
2,8 dihydroxyadenine: Adenine Phosphoribosyl Transferase (APRT) deficiency

Question 47

Indications for Dialysis in ARF: Uremia

Answer 47

Blood urea greater than 50mmol/L and rising
Obtundation, asterixis, seizures, nausea and vomiting, pericarditis

Question 48

Indications for Dialysis in ARF: Hyperkalemia

Answer 48

K+ > 6.5mmol/l
K+ > 5.5mmol/l if ECG changes

Question 49

Indications for Dialysis in ARF: Fluid Overload

Answer 49

Resistant to diuretics, especially pulmonary edema

Question 50

Indications for Dialysis in ARF: Metabolic acidosis

Answer 50

Bicarbonate < 10mmol/L
pH < 7.2 desire sodium bicarbonate therapy
Sodium therapy not tolerated because of fluid overload

Question 51

What are the ideal characteristic markers for GFR?
Examples of endogenous and exogenous markers?

Answer 51

1. Freely filtered at the glomerulus
2. No tubular secretion or reabsorption
3. No renal/ tubular metabolism

Endogenous: normally present in the body - creatinine
Exogenous: not normally present in the body - Inulin

Radiolabeled and non-radiolabeled