Understand 2nd year medicine

Made by a student for students!

AddThis Social Bookmark Button

Content

Genetics

 



Mutations


  • Silent: Altered DNA codes but still the SAME AMINO ACID (synonymous change)
    • Most common
      • point mutation:  one base change (but same amino acid)
        • last base redundancy: AGT and AGG both codes for serine
  • Missense: Altered DNA codes for DIFFERENT AMINO ACID
    • e.g. SICKle cell anemia: SUBstitution of SICKth amino acid of B-globin chain (Base change: Adenine -> Thymidine thus Amino acid change: glutamic acid to valine)
  • Nonsense: Altered DNA codes for Stop codon, causing premature termination of protein synthesis
    • e.g. B-thalassemia major (no synthesis of Hemoglobin A!)


Frameshift mutation
  • Insertion/deleted nucleotide(s) causing the reading frame to shift!
    • DMD
    • Taysacch’s


Translocation
  • Burkitts lymphoma t(8,14) and B cell leukemia t(14,18)

B Cell Leukemia - BCl2 (antiapoptic vs Bax!)


Burkitts lymphoma - c-myc (TF)

Genes coding for antibodies on Chromosome 2 (kappa light chains), 22 (lambda light chains) and 14 (heavy chains).The genes are expressed only in B lympphocytes because only they have the relevant TF transcription factor for promoters and enhancers.

Other cancers involving translocation of heavy chain gene on chromosome 14 - multiple myeloma.


Trinucleotide repeat disorder
  • Error in DNA replication causing amplified 3 nucleotide sequence (CAG)
  • Anticipation: Additional trinucleotide repeats increase disease severity for future generation


Nonsdisjunction

failure of chromosome pairs to separate properly during meiosis stage 1 or stage 2. This could arise from a failure of homologous chromosomes to separate in meiosis I, or the failure of sister chromatids to separate during meiosis II or mitosis. → aneuploid
If frequency of allele A is P and allele a is p and  p+q = 1
GenotypeFrequency
AAp2
Aa2pq
aaq2


Examples
  1. Carrier rate of CF is 1/25
    To find the prevalence: Chance of two couples being carriers (1/25 x 1/25) multiplied by chance of having a child with CF (1/4). Prevalence = 1/2500.  
  2. Frequency who have CF 1/2500 (i.e. pp)
    To find the carrier frequency
    1. Thus p is square root 1/2500 = 1/50
    2. P is therefore 1-1/50 = 49/50 (basically 1...)
    3. Thus carrier frequency is 2(1)q = 2/50
  3. Husband has cystic fibrosis, mother's sister has cystic fibrosis..chances that child will have the disease
    1. a and b must be Aa
    2. c is aa
    3. Probability that mom is a carrier: ⅔ as she is not affected - AA or 2Aa
      1. For the child to have the disease
        1. c definitely gives out a
        2. for d to give out a: ⅔ x ½
      2. Thus answer is ⅔ x ½ = 2/6 = ⅓
  4. For an autosomal recessive disease: Chance of being a carrier = ½ x Mom as carrier x ½ x Dad as carrier (chance of baby being carrier = prob that dad is carrier x 1/2 (i.e. passes on either A or a) x probab that mom is carrier x 1/2 (i.e. the complement one))
  1. Since e has is pp, thus a and b must be Pp.
  2. c is not affected but the chance that he’s a carrier is ⅔! NOT 2/4 as definitely not aa
  3. Probably that d is a carrier...
    1. 1/2500 is p2 thus p is 1/50
    2. q is 49/50 … assume 1!
    3. 2pq is 2 x 1/50 x 1 = 2/50
  4. Thus probability that f is carrier: ½ x 2/50 x ½ x ⅔



Inheritance of information not maintained at the level of DNA sequence is called epigenetic inheritance

Gene silencing

Chromosome → Chromatin (many nucleosomes) → Nucleosome (146 base pairs wrapped around 8 histones)

X chromosome inactivation occur due to:
  • provides proliferative advantage to cells: e.g. X-linked TSG → cancer
  • genetic predisposition
  • protective mechanism to reduce expression of detrimental X-linked alleles

Y chromosome carries very few genes.
X chromosome carries MANY...
Male: yX, Female: inactivated X and active X .. so same amount of genes translated!

End point: Just 1 X inactivated
YXX: extra X inactivated
XXX: 2 X inactivated

X chromosome inactivation occurs randomly early in embryogenesis

In all subsequent progeny from this cell – the same X-chromosome is inactivated.

men always express the maternally-inherited X-chromosome

Girl: 2 X chromosomes
  1. Barr body - Condensed and inactivated X chromosome (Xi)
  2. Xa (activated)

women are a mosaic of expression of both paternal and maternal inherited X-chromosome: usually 50/50 (except when  skewed X inactivation, in which the same X chromosome is silenced in most cells of course!)


Hetrochroma
  • 1eye: Father
  • 1eye: mother!

Stages of Gene silencing

1. Xist coating
  • Both X chromosomes weakly express Xist RNA from the Xist gene
  • During inactivation, the future Xa ceases to express Xist, whereas the future Xi dramatically increases Xist RNA production. the Xist RNA progressively coats Xi, spreading out from the XIC (X inactivation center)

2. Blocking factor binds to XIC on X chromosome

3. Histone, DNA hypermethylation






4 types of histones: h2a, h2b, h3, h4

Histone modification
  • Acetylation of histone by HAT (histone acetyltransferase) → Uncoil → Genes accessible to TF → Gene expressed (euchromatin)
  • Deacetylation of histone by HDAT (histone deacetyltase) or histone methylation → Coiled → Genes inacccessible to TF → Gene not expressed (heterochromatin e.g. Barr body)

euchromatin (euuuu disgusting!.... separate) - less compact!

heterochromatin - stains dark because compact - protect the genes when not in use!

Cancer cells and p53: Excess HDAT and little HAT → Silence TP53 → No p53 made!

End result: Xi: histones and DNA hypermethylation, macroH2A


Dystrophin: a cytoskeleton found beneath plasma membrane that links actin to dystroglycan (glycoprotein spanning sarcolemma), where the dystroglycan is bound to laminin in muscle cell basement membrane - link between the contractile cytoskeleton (myofibril) and the cell membrane.

When dystrophin is deficient, the sarcollema, the contractile elements (actin and myosin), and the cell membrane are no longer functioning in conjunction with each other. Contractions allows the sarcollema to become susceptible to stress-induced fracture because the elements are no longer sliding smoothly over each other. Tiny breaks develop in the membrane, permitting influx of calcium ions that trigger segmental hypercontraction and activates proteases leading to muscle fiber necrosis


DMD (duchenne muscular dystrophy) is the largest gene
  • Dystrophin is a very large protein so genes coding it has a very high mutation rate.


Mutation rate = no. affected individuals from non-carrier parents / 2X total number of births
Muscular dystrophy is a genetic disease that causes progressive skeletal muscle weakness and death of the muscle.

DMD and BMD becker muscular dystrophy are both types of MD.

Mechanism of mutation in Xp21
  • Deletion: Frame shift mutation → DMD, Inframe mutation → BMD
    • Frameshift mutation may cause premature termination codon: STOP codon before normal end of message
    • Exon 50 deletion which causes Exon 49 can not join up with exon 51, which prevents the rest of the exons being assembled. For the dystrophin protein to work it must have both ends of the protein.
  • Point mutation
Expresivity: Extent a genotype is expressed in individual
Penetrance: Extent a genotype is expressed in a population

Cause
  • One third arise from mothers who are NOT carriers (spontaneous mutations)
  • Carrier mother (Xx) x Unaffected father (XY) → XX, XY, Xx, xY (50% chance for a male to be affected)

Women carrier may still show DMD
duchenne muscular dystrophy symptoms - manifesting symptoms

Why Women with DMD
  • Carries two deleterious copies of DMD gene (rare)
  • Turner syndrome (monosomy X): Their only X chromosome is mutated!!!
  • Skewed (Non-random) X- chromosome inactivation
    • majority of a woman's normal X chromosomes become preferentially inactivated - not enough healthy X chromosomes to compensate for the defect (i.e. if skewed inactivation of mutant → no symptoms, but if skewed inactivation of normal, symptoms!)
Douchenne’s Muscular Dystrophy
  • X-linked recessive
    • DMD gene is in short arm (p) of X chromosome at position 21 (i.e. Xp21)
    • 1/3500 Male - most common MD
  • Absence of dystrophin
    • Allow excess calcium to enter sarcolemma → necrosis and replaced by fat and connective tissue
  • Symptom
    • SYMMETRICAL Muscle weakness
      • Calf muscle pseudohypertrophy: Enlarged calves but weak due to fibrous tissue (rubbery feel!) The muscle initially is edematous and then rapidly becomes atrophic.
      • Muscle contracture of achilles tendon: Fibrosis and walk on toes!
        • Compensate by lordosis (as in pregnant women, obese people with weak back)  to maintain center of gravity
      • Waddling gait: Weak abductor (gluteus medius and minimus) allows pelvis to tilt down (+tight iliopsoas - hip flexor ) on the opposite side → Compensate the tilt by lurching to weakened side to maintain a level pelvis
      • Proximal muscle weakness
        • Gower’s sign: Use arm to raise from floor
        • Very difficult climbing stairs
      • Myocardium pathology: Cardiomyopathy (heart weakens and enlarge)
      • Scoliosis: Unequal weakning of paravertebral muscle
    • Mentally retarded
    • Begin at 5 (delayed motor milestones!) - wheelchair by 10, death by 20
      • due to respiratory insufficiency (weak/fibrosed  diaphragm and intercostal muscle)
  • Diagnosis
    • High serum CK creatinine kinase (normal CK: 100 IU) due to muscle damage
    • Muscle biopsy
      • variable size muscle fiber
      • massive muscle group atrophy
      • connective tissue (CT)
      • Nuclei centralized
      • Absent dystrophin
      • early: necrosis, macrophage etc.
      • late: endomyseal fibrosis
    • EMG: Destroyed muscle tissue (not damaged nerves)
      • Myopathic
        • Low amplitude
        • Short duration
        • Polyphasic
      • Neuropathic
        • High amplitude
        • Long duration
        • Polyphasic
    • DNA: Multiplex PCR
  • Treatment
    • Prevent contracture (e.g. achilles) by stretching
    • Steroid: Reduce inflammation!

Immune label for dystrophin
DMD: Complete absence
Carrier: Variable stain

Muscle death: No satellite cells to replace the fiber

Becker’s muscular dystrophy
  • Milder form of DMD: Unlike DMD until 20, survive until 30
  • Abnormal/less dystrophin produced (DMD: NO dystrophin made)

Regeneration
  • Reserve cells ("satellite cells" in the endomysium → myoblasts)
  • Mitosis
  • Basophilic cytoplasm, central nuclei , obvious nucleoli (busy)

Neurogenic or Myopathic?
  • Shape of small muscle fibers
    • Round: Myopathic
    • Angular: Neurogenic
  • Distribution of atrophic fibers
    • Grouped: Denervation; Dystrophinopathies
    • Scattered: Acute neuropathy or myopathy
Acute or Chronic?
  • Acute
    • Myopathy: Muscle fiber degeneration & regeneration
    • Neuropathy: Small angular muscle fibers
  • Chronic
distribution of the pathology?
Aneuploidy: Abnormal no. of chromosomes
  • Turner syndrome: 45, X
  • Down: Trisomy 21
  • Edward: Trisomy 18
  • Patau: Trisomy 13
  • Klinefelter’s: XXY

Turner’s syndrome: 45, X (monopsony - lost 1 chromosome due to non-disjunction)
Turner Syndrome Patients look like CLOWNS (only to remember its features):

C - Cardiac anomalies (most common - coarctation of aorta)
L - Lymphoedema, low thyroid
O - Ovaries under developed (streak ovaries)
W - Webbed neck
N - Nipples widely placed
S - Short stature, Sensoneural hearing loss, Short 4th metacarpal

*for more add ABC
A - primary Amenorrhea
B - absent Barr body
C - Cystic fibrosis


Down’s syndrome

My CHILD HAS PROBLEMS
  • Congenital heart disease / Cataracts
  • Hypotonia / Hyperthyroidism
  • Incure 5th finger / Increased gap between 1st and 2nd toes
  • Leukaemia (risk x2) / Lung problems
  • Duodenal atresia / Delayed development
  • Hirshsprung’s disease / Hearing loss
  • Alzheimer’s disease / Alantoaxial instability
  • Short neck / Squint
  • Protruding tongue / Palmar crease
  • Roung face / Rolling eye (nystagmus)
  • Oblique eye fissure / Occiput flat
  • Low nasal bridge / Language problem
  • Epicanthic fold / Ear folded
  • Mental retardation / Myoclonus


Klinefelt’ers Syndrome: XXY
  • Extra X chromosome
  • Male, small penis/scrotum/testes, infertile due to blocked genital duct, tall, eunuchoid (lack sexual differentiation)

Marfan’s syndrome
  • Autosomal dominant: Mutated FBN1 gene - codes for fibrin
    • 1 normal + 1 mutant allele → can’t produce enough CT → Joint and BV Problem
  • Mitral valve prolpase
  • AA
  • Retinal detachment
  • Fibrillation
  • Arachnoidactyly
  • Negative nitroprusside test

DiGeorge syndrome: CATCH 22
  • cardiac abnormality
  • abnormal face
  • thmoplasia
  • cleft palate
  • hypocalcemia
  • 22q11 deletion

Fragile X syndrome
  • X linked recessive
  • Abnormal CGG repeats on long arm of chromosome →  FMRI gene expression → Less brain function
  • Clinical picture
    • Big testicle, ears, jaw
    • Mentally retarded

Phenylketonuria
  • Autosomal recessive
  • Absent phenylalanine hydroxylase (phenylalanine → tyrosine)
  • Clinical picture
    • less melanin synthesis → fair skin and blue eyes
    • Accumulate acetate and phenylpyruvate → mental retard
  • diagnosis
    • high urine acetate and phenylpyruvate
    • high serum phenylalanine
  • treatment
    • diet restriction of phenylalanine
    • diet restriction of aspartame (release phenylalanine when digested)

Cystic fibrosis

CFTR
  • cAMP-activated anion channel (Cl- diffusion!)
  • cAMP PKA Activate CFTR

Normal epithelium (lung/pancreas): Cl- diffuse out


Normal

Cl- efflux draws Na+ and water, thus, increasing volume of pancreatic juice/lessen viscosity of lung mucus. If too much juice, basolateral Na+ pumps pump Na+ to draw back Cl- and water.

Abnormal

Cl- trapped in cells, no sodium and water moves out to pancreatic juice/lung mucus → increased viscosity

In sweat: Cl- diffuse in



Abnormal

High chloride content in sweat → draws sodium and water → + sweat chloride test and increased volume loss


Abnormal CFTR (cystic fibrosis transmembrane regulator)
  • Autosomal recessive
  • 70% of CF cases due to ΔF508 (~5678)
    • 3x nucleotides deletion coding for phenylalanine at position 508 of the protein in long arm of chromosome 7
  • Clinical picture
    • malabsorption, steatorrhea: deficient vitamin ADEK (pancreatic juice)
    • recurrent resp. infection: Pseudomonas, Hemophilus influenzae, Staph aureus
    • Staph.
    • Clubbing
    • Infertile and meconium ileus
      • meconium (infant early poo) thickened and congested in the ileum
  • diagnosis
    • high sweat chloride test
    • treatment: antibiotic, chest physio


Huntington Disease
  • Autosomal dominant
  • Gene in 4p16.3
  • Expansion of CAG repeat in Huntington gene
  • Slow progressive with onset in midlife (40)
  • Clinical picture
    • retard
    • choreiform movement (involuntary and jerky → basal ganglia disorder)
    • life expectancy - 60 years
  • Diagnosis
    • MRI/CT: Atrophic caudate nucleus and putamen
    • MOlecular: Expanded CAG repeat  

Blood Group co-dominance: Both IA and IB
Recessive allele: i

Blood Type
O - 45%
A - 40%
B - 10%
AB - 5%

Rh+ - 85%
Rh- - 15%

 

Kidney



Always remember higher [ca] outside than intracellular (otherwise tetany!!)

PTH:  stimulates na/ca exchange in dct but inhibits hpo4-/na+ in pct
Aldosterone: Increase Na/K+ and H+ ATPase
AT2: Activate Na/H exchange
Insulin activates Na/K pump → K+ influx!!!

Ammonia buffering system is in PCT


Metabolism of glutamine generates alpha-KG (to generate bicarb) and NH4+ which dissociates eto form NH3 (ammonia) which diffuses out to lumen and binds with H+ in lumen to reform NH4+ (ammonium ion)

The bicarb is transported to blood via naxhco3 cotransporter.
PCT proximal convoluted tubuleDCT distal convoluted tubule
Apical brush border → Less lumen
Eosinophilic (enzymes.. protein!)
Hard to see nuclei
No brush border
Less eosinophilic
Easy to see nuclei
*
2 is PCT, 3 is DCT

PCT
  • Isotonic
  • 100% glucose and a’a’ absorbed via SGLT
  • Most bicarbonate, Na+, HCO reabsorbed
  • Secrete NH3 as urine buffer
  • PTH (inhibit Na/HPO4- cotransporter)
  • AT2 (Stimulate Na+/H+ exchange)
Thin descending (concentrating segment)
  • Ion impermeable
  • Water peamable → Passive H2o absorption
Thick ascending (diluting segment)
  • Active Na,K,2Cl reabsorption (loop diuretic inhibit this!)
  • Water impermeable
Early DCT
  • PTH ParaThyroid Hormone (stimulate Na/Ca exchange) → increase calcium reabsorption
  • Thiazide: Inhibit Na/Cl cotransporter
Collecting tubule
  • Aldosterone
  • ADH antidiuretic hormone



Glomerular filtration barrier
  • Size: Fenestrated glomerular endothelium
  • Charge: Fused basement membrane (heparan sulfate - negative charge!!!)
    • Nephrotic syndrome: Lose the char ge barrier → Albuminuria, proteinuria, edema
  • Visceral layer of podocyte pedicles

Filtration fraction = GFR (glomerular filtrate rate - passes into renal tubule) / RPF (renal plasma flow - passes into kidney) = 125 / 625 = 20%


GFRRPFFF

Afferent arteriole constrict e.g. Prostaglandin

-

-

same

Efferent arteriole constrict e.g. AT2

+

-

+

Increased plasma protein

-

same

-

Decreased plasma protein

+

same

+

Ureter constrict

-

same

fall





Factors increasing GFR glomerular filtraion rate

1. Dilate afferent arteriole

  • Prostaglandins (PGE2)
    • Released in response to symp and AT2 (angiotensin 2)
    • Blocked by NSAID
  • Bradykinin (BK): B1/B2 receptors causing local vasodilation.
  • Dopamine (low dose):
    • low concentrations, binds to DA1 receptors → AC → cAMP → Vasodilate
    • high concentrations cause vasoconstriction
  • Endothelial derived Nitric oxide (NO)
  • Atrial Natriuretic Peptide (ANP)

2. Constrict efferent
AT2 increases GFR and decrease RPF (due to it being a potent vasoconstrictor)
  • Preferentially constricts efferent arteriole -> Glomerular hydrostatic pressure + → +GFR
  • e.g. if volume depletion → less GFR → slow transit time → more absorption → less Na+ sensed by macula → autoregulation → renin release → AT2 to increase GFR
  • Constricted efferent → decreased flow through peritubular capillary to increase absorption
  • efferent arteriole has a smaller diameter thus constriction here will cause a much greater increase in resistance than at the afferent arteriole
  • AT2 stimulates release of NO from afferent → minimize afferent vasoconstriction
  • ACE inhibitors or AT2 inhibits abolishes the constriction of efferent arteriole → Glomerular hydrostatic pressure falls → GFR falls
  • FF (Fraction of substance that enters the kidney that is filtered) = GFR/RPF → FF increases
    • if GFR increases e.g. AT2, FF increases


Factors decreasing GFR
  • AT2 contract mesangial cells (decreasing surface area S), thus Kf reduced, thus GFR (GFR = Kf x NFP) reduced
  • Vasoconstriction of systemic (both afferent and efferent)
  • Angiotensin II (High dose)
    • binds to AT1 receptors
  • Antidiuretic hormone (ADH)
    • Vasoconstrictor at V1 receptors
    • Anti-diuretic action at V2 receptors
  • Endothelin (released by damaged endothelium - hemostasis...)
    • Binds to ET receptors → Ca2+ influx  
  • Sympathetic (renal is innervated by SYMPATHETIC ONLY!) – Noradrenaline release and binds to alpha1 - Gq → Ca+!

NE norephinephrine from sympathetic
E epinephrine from adrenal gland
3 things that stimulate renin release: Low BP, Sympathetic, low NaCl sensed by macula

Autoregulation of bloodflow - keeping GFR and RPF relatively constant
  • Vasoconstrictor reflexes in response to blood pressure
    • Afferent tone protects perfusion pressure at high BP, whilst Efferent tone maintains at low BP
    • If low BP →  Baroroflex of carotid body and aortic sinus →  Sympathetic →  AT2 → Stimulate efferent constriction over afferent  →  Preserve GFR
  • Myogenic reflex
    • SM of BV reacts to stretched thus opened ion channels ECF Ca influx → Depolarize → Muscle contraction → Reduce volume of blood through lumen
    • No stretch → Hyperpolarize → Vasodilation
  • Tubuloglomerular feedback
  • Reduced GFR slows rate of flow in loop of Henle → Increased reabsorption of NaCl thus less detected by macula densa
  • Macula densa
    • increases renin release from afferent arteriole JG cells → AT2 (constrict efferent → increase GFR to normal)


GFR = Kf x  NFPRenal clearance ©: Volume of plasma from which solute is completely cleared by kidney in a given time
e.g. clearance for urea is 65 ml/min - removes all of the urea in 65 ml of plasma in one minute.
C (mL/min) = UV / P
• U = [solute] in urine
• V = rate of urine formation (NOT VOLUME!!!) volume of urine/min
• P = [solute] in arterial plasma
Renal plasma flow (RPF): 625mL of plasma goes to kidney every minute
  • Of the 625 mL/min of plasma to glomerulus, 125 mL/min into Bowman’s capsule, remaning 500 mL/min into peritubular capillaries.

The composition in Bowman’s capsule is identical to the plasma (except no proteins)!

For a substance to be in the urine, it is either
  • Filtered and not reabsorbed (e.g. inulin 125 filtered, 500 not reabsorbed)
  • Not filtered but secreted from peritibular capillaries
Clearance of
  1. Glucose: Freely filtered, no secretion, complete reabsorption - hence C is 0 (as U is 0)!
  2. Inulin (NOT INSULIN!!!): Freely filtered but not secreted nor reabsorbed in the lumen, hence - 125
  3. PAH: Free filtered, not reabsorbed, completely secreted by PCT of kidney  (all PAH entering kidney - those filtered and those not filtered - ends up in urine) - all plasma entering kidneys would be cleared of PAH thus same as renal plasma flow 625 ml/min

Urea clearance 65mL/min
Is it completely reabsorbed? If so, then clearance will be 0
Is it freely filtered and no reabsorption/secretion? If so, clearance will be 125.
Thus urea is PARTIALLY reabsorbed


Urea recycling

Urea permeable in thin descending
Urea impermeable in thick ascending and onwards up to inner medullary collecting duct

Urea gets increasingly concentrated as it moves along the thick ascending. Once it reaches the inner medullary collecting duct, it diffuses across the apical urea transporter into the medullary interstitutium.

Medullary interstitum [urea] rises, thus urea diffuses into descending limb of loop of Henle


AT2 angiotensin 2
  • constricts efferent arteriole in glomeruli to increase FF to preserve renal function (increase GFR) in low volume state (low RPF)
  • general Vasoconstriction to increase BP
  • Stimulate Na/H exchange in PCT → alkalotic
  • Aldosterone release from adrenal cortex (salt G sugar F sex R) - mineralocorticoid
    • Increase Na/K+ atpase on principal cell → More sodium absorption and more potassium secretion
    • Increase H+ Atpase in intercalated → alkalosis
  • Stimulates thirst center in hypothalamus → Hypothalamus produce ADH to posterior pituitary
    • ADH acts on V2 receptors on principal cell to increase aquoporin in principal cell → More water reabsorbed


ANP A-type Natriuretic Peptide is released in response to atrial stretch
  • inhibits the synthesis and release of renin, aldosterone and ADH.
  • Blood vessel: cGMP → Vasodilation
  • Renal: Dilates afferent, constrict efferent, increase GFR

B-type Natriuretic Peptide (BNP) - first found in brain! - made by ventricles!!!!; made in response to ventricular stretch
  • Action similar to ANP i.e. decrease BP (and afterload) to yield increase in CO
    • decrease in TPR via cGMP (vasodilation)
    • Increase in natriuresis

BNP is cosecreted with proBNP (inactive). Both BNP and proBNP is used to screen patients with acute decompensated heart failure.


PTH ParaThyroid Hormone
  • Inhibit apical Na+/HPO4- cotransport in PCT → Phosphate excretion
  • Stimulate basolateral Ca2+/Na+ exchanger in DCT → Calcium absorption

  • JG (granular) cell: Part of the afferent arteriole, store and produce renin; contain B1 adrenoreceptors (when stimulated by NE or E, release renin)
  • Macula densa: Columnar thickening of DCT, senses NaCl
    • Less GFR → Less NaCl sensed → Upregulate NOS → NO catalyze prostaglandin formation → Gs → cAMP → Increased renin release
  • Mesangial cell: Between macula densa and afferent arteriole, contain actin and myosin. Sympathetic stimulation (e.g. low BP) → Contract to decrease GFR

Pitting edema
- Pitting if drainage
- Non-pitting if no drainage (blocked lymphatic by cancer/parasite)


Kidney
  • Cortical nephrons
  •  
    • Most nephrons
    • Located in the cortex
    • Short loop of henle
  • Juxtamedullary nephrons,
  • juxta = next to renal medulla
  • loops of Henle extends deep into the renal pyramids



Conn’s syndrome
AT 1 + Renin → AT2 → Aldosterone
Primary hyperaldosteronism (Conn’s syndrome): overproduction of aldosterone by adrenal gland (cortex - zona glomerulosa) NOT due to excess renin secretion
  • Most common cause of secondary hypertension
  • Aldosterone increases sodium retention and potassium excretion (Na/K pump), water retention, and Na/H exchange (H+ out to lumen and Na+ inc ell)
    • Thus hypertension, hypernatremia, hypokalemia
    • Greater activity in passive Na/H exchange in PCT → Consequently more carbonic acid dissociates and so increased bicarbonate excretion → metabolic alkalosis
    • Little H+ in blood → Hypocalcemia
  • Causes: Adrenal hyperplasia, carcinoma

* Hyperaldosteronism
considered in patients with difficult-to-control hypertension and hypokalemia in the absence of diuretic use.
* Hyperaldosteronism should be considered in patients with difficult-to-control hypertension even in the absence of hypokalemia.

aldosterone:renin ratio for primary hyperaldosteronism

distinguishing between essential hypertension (accounts 95% cause of HT - genetic factors that reduce Na excretion, obesity, stress) and primary aldosteronism.

High ARR

Renovascular hypertension is not associated with hypokalemia in the absence of diuretic use. Renovascular hypertension may cause resistant hypertension, but this patient's presentation is more consistent with primary aldosteronism. In

imaging of the adrenal glands is indicated in patients with suspicion for primary hyperaldosteronism only after results of biochemical and hormonal testing (such as low plasma renin activity, high aldosterone secretion, or elevated ARR) are shown to be consistent with this diagnosis.

Hypertension: secondary hypertension causes
CHAPS:
Cushing's syndrome:
Hyperaldosteronism [aka Conn's syndrome]:
Hypertension.
Hypokalaemia (usually <3.5 mmol/L, although 70% of patients may be normokalaemic).
Metabolic alkalosis.
Sodium may be normal or at the high end of normal.
Aorta coarctation
Phaeochromocytoma
Stenosis of renal arteries
· Note: only 5% of hypertension cases are secondary, rest are primary.


Greater hydrostatic pressure → Increase GFR and decreased renin release
  • high aldosterone-to-renin ratio in Conn’s syndrome
  • CT scan to confirm adenoma

Net Filtration Pressure



Hydrostatic pressure is much higher in the glomerulus than in ordinary capillaries due to the concentration difference - enabling 20% (125/625) of plasma that flow through glomerulus to enter Bowman’s (the filtration fraction = GFR / RPF)


glomerulus retains erythrocytes and plasma proteins (creates the oncotic pressure, and filters an almost protein free “filtrate” into the Bowman's capsule (no oncotic pressure). Oncotic pressure in Bowman’s is negligible so....

NFP = HPg – (OPg + HPc)... 45... 25.... 10.. 10...
  • Net Filtration Pressure (NFP)  pressure responsible for filtrate formation = 10mmHg
  • NFP equals the glomerular hydrostatic pressure (HPg - 45) minus the oncotic pressure of glomerular blood (OPg - 25) plus capsular hydrostatic pressure (HPc - 10)


Oncotic pressure lowered if nephrotic syndrome





0) Normal kidney function – GFR above 90mL/min/1.73m2 and no proteinuria
1) CKD1 – GFR above 90mL/min/1.73m2 with evidence of kidney damage
2) CKD2 (Mild) – GFR of 60 to 89 mL/min/1.73m2 with evidence of kidney damage
3) CKD3 (Moderate) – GFR of 30 to 59 mL/min/1.73m2
4) CKD4 (Severe) – GFR of 15 to 29 mL/min/1.73m2
5) CKD5 Kidney failure - GFR less than 15 mL/min/1.73m2 Some people add CKD5D for those stage 5 patients requiring dialysis; many patients in CKD5 are not yet on dialysis.



NEPHROTIC SYNDROME (NS) is characterized by the

N = Na + water retention
Hypovolemia → Increased aldosterone and ADH secretion.

E = Edema
Hypoproteinemia, sodium and water retention Edema is soft, pitting
and starts in the periorbital region.

P = Proteinuria >3.5gm/1.74sq. ml/24hrs

H = Hypertension + hyperlipidemia (due to increased lipoprotein
synthesis in liver , abnormal transport of circulating lipoproteins, decreased
catabolism.)

R = Renal vein thrombosis

O = "Oval fat bodies" in the urine. Lipiduria follows hyperlipidemia.
Albumin as well as lipoproteins are lost. Lipoproteins are reabsorbed by
tubular epithelial cells and they shed along with degenerated cells-
this appears as "oval fat bodies" in urine.

T = Thrombotic + thromboembolic complications owing to loss of
anticoagulant factors (eg. anti-thrombin III )

I = Infection. These patients are prone to infection, especially with
staphylococci and pneumococci. Vulnerability is due to loss of
immunoglobulins.

C = hyperCoagulable state

Nephritic S
PHAROH =
Proteinuria,
Hematuria,
Azotemia,
RBC casts,
Oliguria, low urine output <400 mL/day)
Hypertension


If the protein content of the subcutaneous fluid is low, pressing on the edematous area will cause a depression ('pitting'). Vice versa, edema in diseases like acute glomerulonephritis will be hard ('non-pitting').

This is evident in location of edema as well. Pitting edema is evident in lower extremities, especially ankles. On the other hand, edema of eyelids is seen in glomerulonephritis.

Maybe one point to make here is about thyroid diseases. In hypothyroidism and Graves' disease, connective tissue elements (esp. GAG) are deposited in subQ tissue, resulting in myxedema - which is a non-pitting edema (again, this is due to the nature of the deposit).

I think of it like a water balloon (transudate) vs a sand-packed balloon (exudate). Transudate is pure liquid ecf and will allow your finger to push in more easily to cause a dimple/pit (water balloon), while exudate is proteinaceous and has more bulk in the ecf which resists your finger pushing into it (sand-balloon).

pitting edema is a problem with your circulation so think cardio related, but nonpitting is more likely lymphatics related, eg elephantiasis - wucheria bancrofti

or pretibial myxedema

Cause of the edema
  1. increase in hydrostatic pressure
  2. decreased oncotic pressure
  3. lymphatic obstruction


A bit of Plasma protein is tissue fluid... and It is all about whether lymphatics are blocked.

If 1 and 2 but no 3, the plasma protein can be drained. Thus when you press on it, a pit is formed as fluid is dispersed.

But if 3, i.e.plasma protein is not drained by lymphatics, it will be non-pitting.


NFP = 50 – (25 + 10) = 10 mmHg

Increased Bowman’s capsule hydrostatic pressure
  • e.g. Obstructed  urinary tract (urinary stones) → Decreased GFR


GFR = Kf x NFP, Kf = GFR / NFP
Total GFR is 125 ml/min NFP is 10 mmHg. Thus Kf is 125/10 → 12.5mL/min/mmHg


Kf (membrane characteristics) = S (glomerular capillary surface area) x Lp (membrane permeability)
  • Diseases that reduce number of funtional glomeruli reduce S → Lower Kf
  • Diseases that increase thickness of GBM (gomerular basement membrane) and damage glomeruli (e.g. HT, DM) → Lower Kf
  • Mesangial cells have contractile properties, and podocytes near filtration slits - affect surface area
    • relax → + S → + GFR


GFR increases from birth and in children: GFR = height (in cm) x 40 / plasma creatinine
GFR in healthy young men and women is about 125mL/minute/1.73 sq m respectively. After the age of 40 years GFR drops by 1 mL/minute per year.

Contraction alkalosis: Alkalosis due to fluid loss (volume contraction)
Decreased ECF → DECREASED renal perfusion.
  1. Renin release
  2. AT2 release → Increased Na/H exchange in PCT (so more H+ out), so also more bicarb absorbed (out)
  3. Aldosterone release: Stimulate H+ ATPase of intercalated cells which cause new bicarb to be formed!, activate Na/K pump so more K+

aldosterone: upregulates epithelial sodium channel (ENaC) increasing apical membrane permeability for Na+., and also the K+ channel

Additionally, increased aldosterone secretion causes increased distal tubule K+ secretion, in turn causing the hypokalemia seen with contraction alkalosis. Alkalosis also induces H+-efflux from cells through the K+-H+ exchanger, leading to hypokalemia.

Creatinine clearance
One person’s urine for 24h
Person’s blood is centrifuged to obtain the plasma
[Creatinine] in urine and blood measured using colorimeter

Cuvettes for plasma
  1. Standard serum + working reagent
  2. My serum + working reagent

Cuvettes for urine
  1. Standard urine + working reagent
  2. My serum + working reagent


Measure the optical density (absorbance) 1 minute and 5 minutes after addition of working reagent

[Creatinine] = (OD1[5] - OD 1[1] / OD[2]5 - OD 2[5]) x [Standard]...
otherwise difference between sample / difference between standard x [standard mg/dL]
to give it a unit...

Finally UV/P
But as V is (mL/day) thus
Clearance in mL/min is UV / Px24x60
e.g. find the clearance of creatinine (ml?min) if....
Volume of urine collected is 1.5L in 24 hrs, Urine [creatinine] is 144mg/dl and Plasma [creatinine] is 2mg/dl
V is rate of urine formation. convert to ml/min
144 x 1.5 x 1000 / 2 x 24 x 60 = 75mL/min

Creatinine clearance gives an estimate of GFR. Clearance = U[creatinine]V / P[creatinine]

Creatinine clearance tends to overestimate GFR due to creatinine secretion (made by body creatinine + ADP <-(creatinine kinase)-> Creatinine phosphate + ATP... ATP for muscle contraction) , whilst urea clerance underestimates GFR, as about 50% of the filtered urea is reabsorbed.
An average of both clearances is more accurate.

Disadvantages of creatinine clearance
extremes of muscle mass - bodybuilders, amputees or muscle wasting disorders - serum creatinine is proportional muscle mass
  • Lots of muscle: low GFR
  • little muscle: high GFR


Stages of Chronic Kidney Disease
Stage 1 to 5
Stage 5: GFR <15 (end stage)

, hypokalemia maintains metabolic alkalosis by 5 different mechanisms.
First, hypokalemia results in the shift of hydrogen ions intracellularly. The resulting intracellular acidosis enhances bicarbonate reabsorption in the collecting duct.
Second, it results in stimulation of the apical H+/K+ ATPase in the collecting duct. Increased activity of this ATPase leads to teleologically appropriate potassium ion reabsorption but a corresponding hydrogen ion secretion. This leads to a net gain of bicarbonate, maintaining systemic alkalosis.
Third, it stimulates renal ammonia genesis. Ammonium ions (NH4+) are produced in the proximal tubule from the metabolism of glutamine. During this process, alpha-ketoglutarate is produced, the metabolism of which generates bicarbonate that is returned to the systemic circulation.
Fourth, it leads to impaired chloride ion reabsorption in the distal nephron. This results in an increase in luminal electronegativity, with subsequent enhancement of hydrogen ion secretion.
Fifth, it reduces the glomerular filtration rate (GFR). Animal studies have shown that hypokalemia, by unknown mechanisms, decreases GFR, which decreases the filtered load of bicarbonate. In the presence of volume depletion, this impairs renal excretion of the excess bicarbonate.