Clinical biochemistry (Bushra) - sec A

Describe the structure and function of the kidney

Highly vascular, bean shaped organs enclosed by a fibrous capsule. Functions:

• filtration of blood

• removal of waste products

• regulation of fluid / electrolyte balance

What do kidneys consist of?

• approx a million nephrons (microscopic functional unit of the kidney)

Each nephron consists of:

• glomerus

• Renal tubule

• collecting duct

What is the glomerus and its function?

The glomerus is a network of capillaries located in the renal cortex.

Functions:

• filtration of the blood

• removal of excess water

• removal of metabolic waste

• formation of glomerular filtrate

The glomerus is surrounded by Bowmans capsule, forming the renal corpuscle.

What are the two types of nephrons?

• cortical nephrons (in cortex)

• Juxtamedullary nephrons (located near corticomedullary junction)

What waste products are normally excreted by the kidneys?

• Urea

• Ammonia

• Creatine

• Uric acid

What hormones are produced by the kidney?

• Erythropoietin (EPO)

• Renin

• Calcitriol (active vitamin D)

• Prostaglandins

What is the functional unit of the kidney?

• The nephron

What is the function of the glomerulus?

Filtration of plasma to produce ultrafiltrate.

What is the function of the Loop of Henle?

Creates the medullary osmotic gradient required for concentrated urine.

What is the function of the juxtaglomerular apparatus?

Releases renin and regulates blood pressure via the RAAS system.

What normally passes through the glomerular filtration barrier?

• Water

• Electrolytes

• Urea

• Creatinine

• Glucose

What is normally retained by the filtration barrier?

• Albumin

• Plasma proteins

• Blood cells

Why is albumin normally absent from urine?

The glomerular filtration barrier prevents filtration of large negatively charged proteins.

what is eGFR?

measures how well kidney filters blood

what does high creatine levels and low GFR show

kidney function failure

What happens to GFR as kidney function declines?

GFR decreases

What happens to creatinine when GFR falls?

Creatine increase due to reduced clearance

Describe the relationship between creatinine and GFR.

inverse relationship

• GFR ↓ → Creatinine ↑

• GFR ↑ → Creatinine ↓

Why is eGFR used rather than measured GFR?

Direct GFR measurement is impractical and expensive.

What is creatinine?

A breakdown product of muscle creatine metabolism.

Why is creatinine useful as a renal biomarker?

It is produced relatively constantly and is freely filtered by the glomerulus.

Why can creatinine be misleading?

depends on muscle mass, age and diet

Where is urea produced?

In the liver via the urea cycle.

What factors increase urea?

• High protein diet

• Dehydration

• Tissue breakdown

(these make it an unreliable marker)

What is proteinuria?

Excess protein in urine due to renal pathology.

What is albuminuria?

Presence of albumin in urine due to glomerular damage.

What is microalbuminuria?

Small amounts of albumin in urine below dipstick detection.

Why is microalbuminuria clinically important?

earliest marker of diabetic nephropathy.

What causes albuminuria?

Increased permeability of the glomerular filtration barrier.

what is ACR?

Albumin-to-creatine ratio (ACR)= test to detect kidney damadge, tests for microalbumuria (high protein/albumin in urine)

What does an elevated ACR indicate?

Glomerular damage and increased risk of CKD progression.

What is AKI?

Acute kidney injury = sudden loss of kidney function (eg. dehydration)

What biochemical changes occur in AKI?

• Creatinine ↑

• Urea ↑

• eGFR ↓

What are the three categories of AKI?

• Pre-renal

• Intrinsic renal

• Post-renal

What causes pre-renal AKI?

Reduced renal blood flow. (eg. dehydration / heart failure)

Explain the mechanism of pre-renal AKI.

Reduced renal perfusion

• Reduced glomerular pressure

• Reduced GFR

• Creatinine accumulation

What causes intrinsic renal AKI?

direct damadge to kidney tissue

Explain the mechanism of intrinsic renal AKI.

Nephron injury
→ Reduced filtration capacity
→ Reduced GFR
→ Creatinine retention

What causes post renal AKI?

Functional kidney but obstruction in urinary tract

Examples of post-renal AKI?

• Kidney stones

• Enlarged prostate

• Tumours

Explain the mechanism of post-renal AKI.

Urinary obstruction
→ Increased hydrostatic pressure in Bowman's space
→ Reduced net filtration pressure
→ Reduced GFR
→ Creatinine accumulation

define CKD?

Chronic kidney disease = long term kidney damage (3+ months)

What eGFR defines CKD?

An eGFR of less than 60 ML/min/ 1.73m² (considered Chronic Kidney Disease)

What are the two major causes of CKD?

1. Diabetes mellitus

2. Hypertension

What is the endocrine system?

network of glands that produce and secrete hormones into bloodstream

What are hormones function?

chemical messangers that can only trigger reactions in target cells (specific receptors on these). This response can be stimulatory ( growth hormone) or inhibitory (e.g., gonadotropin-inhibitory hormone).

Why is hormone production so tightly regulated? how is it tightly regulated?

to maintain homeostasis. Regulation occurs through feedback mechanisms.

What are the hormone feedback mechanisms and define each

• Negative feedback = self regulatory process that triggers signal to pituitary gland to stop releasing stimulatory hormone (eg. regulation of reproductive hormones)

• Positive feedback = process initiated by a receptor on a target organ and amplifies response until stimulus is removed (eg. ovulation / childbirth)

*Explain the hypothalamic-pituitary axis and its importance in endocrine regulation.

Definition

The hypothalamic-pituitary axis is a hierarchical endocrine control system that regulates hormone production and maintains homeostasis.

Explanation

The hypothalamus acts as the control centre and releases regulatory hormones that stimulate or inhibit the pituitary gland.

pituitary gland releases trophic hormones which stimulate peripheral endocrine glands (thyroid gland, adrenal glands and gonads).

These glands produce end hormones that exert physiological effects throughout the body.

Clinical Significance

The axis allows communication between the nervous system and endocrine system and ensures hormone production is tightly regulated.

Disruption of this axis can lead to endocrine disorders such as hyperthyroidism, adrenal insufficiency and Cushing's disease.

hypothalamic-pituitary axis definition

HPA axis is the endocrine control system that regulates hormone production and maintains homeostasis

What does the HPA axis do?

1. releases regulatory hormones that stimulate OR inhibit the pituitary gland (master gland)

2. The pituitary gland releases trophic hormones = stimulate peripheral endocrine glands (thyroid gland, adrenal glands and gonads).

3. Producing end hormones (send pysiological effects through body)

How does endocrine disorders arise?

either the overproduction (hypersecretion) or underproduction (hyposecretion) of hormones, or from defective hormone responses.

What is ACTH

hormone released by the anterior pituitary gland, stimulating the adrenal cortex to produce cortisol.

what is Cushings syndrone

condition caused by an excess (too much) of cortisol hormone

What causes Cushings syndrone

• Adrenal gland tumours = adrenal glands produce excess cortisol, independent of ACTH

• long term steriod use

• pituitary glands produce excess ACTH, stimulating adrenal glands to overproduce cortisol

What are the clinical symptoms of cushings syndrone

• moon face

• thin skin, easily bruised

• Muscle weakness

Diagnostic testing methods of Cushings syndrone

• Overnight dexamethasone suppression test = measure plasma cortisol after a dose of dexamethasone. High cortisol = cushing’s syndrone

• 24 hour urine free cortisol (UFC) = measures amount of cortisol excreted in the 24 hours. High urine free cortisol = Cushing’s syndrone

What is diabetes mellitus

chronic metabolic condition, where the body cant produce enough insulin or cant effectively use the insulin it has produced

Diagnosis strategies for diabetes mellitus

• Random plasma glucose: over 11.1 mmol/L = diabetes

• Fasting plasma glucose: over 7mmol/L = diabetes

• Oral glucose tolerance test = tests how well body clears sugar from blood over set period of time

• HbA1C= measures average blood glucose over 2 / 3 months

Long term complications of diabetes?

• Macrovascular disese: heart attack, stroke

• Microvascular disease: kidney damage, eye damage, nerve damage

Describe the oral glucose tolerance test

• normal carb intake 3 days prior

• fasting for minimum 8 hrs

• patient drinks 75g glucose in 200ml water within 5 mins

Describe the HbA1C test

• reflects lifespan of red blood cells

Weakness: not recommended to patients who are pregnent of have anemia due to interference

What is the thyroid gland

The thyroid gland is an endocrine gland in the neck. It regulates metabolism and produces T3 and T4

What is the clinical significance of the thyroid gland?

Abnormal thyroid function causes hyperthyroidism or hypothyroidism (one has an e and the other has an o)

What is hyperthyroidism

excessive thyroid hormone production

High thyroid hormone suppresses TSH through negative feedback (overproduction control):

• High T3 and T4

• Low TSH

Graves disease can cause this: autoimmune condition

Could also be caused by thyroiditis = release of preformed hormone

what is Graves disease

autoimmune cause of hyperthyroidism

effects tissues around the eyes (bulding eyes)

what is hypothyroidism

reduced thyroid hormone production

Low T3 / T4, so it compensates by increasing TSH production:

• low T3/T4

• High TSH

what is TSH (thyroid stimulating hormone)

stimulates the thyroid gland to release T3 and T4

what causes weight gain?

Reduced metabolism lowers energy. Hypothyroidism slows bodies metabolism and reduces your resting metabolic rate

what causes weight loss?

Increased metabolism , breaks down fat and muscle for energy. Hyperthyroidism = high metabolic state. Diabetes mellitus = burns fat and muscle because not enough insulin

What causes fatigue?

Reduced metabolism decreases energy production = hypothyroidism. Waste products also accumulate in the blood = CKD (function failure) , addinsons disease (low blood pressure)

What causes sweating / heat intolerance

increased metabolism produces excess body heat. hyperthyroidism = increases metabolism

what causes cold intolerance

less heat is produced due to reduced metabolic activity. seen in hypothyroidism

what causes tachycardia (fast heart rate)

thyroid hormone increases heart sensitivety to adrenaline, heart beats faster. seen in hyperthyroidism

What causes palpitations

Increased thyroid hormone overstimulates cardiovascular system, causing awareness of heartbeat.

seen in hyperthyroidism

what causes tremor

increased thyroid hormone increases sympathetic nervous system activity, causing shaking. seen in hyperthyroidism

what causes dry skin

reduced metabolism slows skin turnover and gland activity. seen in hyporthyroidism

what causes constipation

reduced metabolism slows gut mobility. seen in hypothyroidism

what causes hypertension?

Hormonal effects increase blood pressure (too high). seen in CDK, Cushings syndrone

what causes hypotension?

Reduced cortisol or dehydration lowers blood pressure. seen in pre-renal AKI, Addisons disease

what causes polyuria (frequent urination)

Excess glucose enters urine = excess urine. seen in diabetes mellitus

what causes thirst

excessive urination causes dehydration, leading to thirst. seen in diabetes mellitus

what causes swelling

kidneys fail to remove excess fluid = fluids builds up in tissues. seen in CKD

what causes proteinuria / albuminuria

protein leaks through glomerus filtration barrier. seen in CDK, diabetic nephropathy

what casues reduced urination

reduced kidney filtration = less urine production. seen in AKI, CDK, post-renal AKI

what causes dizziness

low blood pressure reduces blood flow to the brain. seen in addinsons disease, dehydration

what causes muscle weakness

excess cortisol causes muscle protein breakdown. seen in cushings syndrone

what test do we use to diagnose hyper / hypothyroidism

T4 test = used alongside TSH to measure amount of thyroid hormone in your blood

What test do we use to diagnose Graves disease

thyroid antibody test= measures antibodies that mistakenly attack healthy thyroid cells

what test can we use to diagnose cushings syndrone and/or addinsons disease

Cortisol blood test = measure cortisol levels

what test can we use to diagnose cushings

Dexamethasone suppresion test (DST)= measures adrenal glands response to hormone dexamethasone, to see if cortisol can be supressed

What 2 tests can we use to detect kidney damage?

ACR test= measures albumin to creatine ratio in urine

eGFR test = blood test that measures how efficiently your kidneys filter waste from your blood

what 2 tests can we use to diagnose diabetes mellitus

HbA1c test= measures average blood glucose over 2-3 months

Oral glucose tolerance test = asseses how your body processes glucose.

what are symptoms of hypertension (high metabolic rate)

• weight loss

• sweaty

• tremors

• anxiety

• confusion

• palpitations

• fast heart rate

• hypertension

• heat intolerance

what are symptoms of hypotension (low metabolic rate)

• weight gain

• fatigue

• dry skin

• cold intolerance

• constipation

what diseases casues hyperthyroidism

• graves disease= autoimmune disease that attacks healthy thyroid cells

• thyroiditis= inflammation of thyroid gland

What is the difference between diabetes mellitus and diabetic nephropathy

Diabetes mellitus occurs in pancreas

Over time it gets worse and diabetic nephropathy occurs in the kidneys due to nerve damage and unregulated diabetes mellitus