gregor guron gerald dibona
TRANSCRIPT
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CLINICAL RENAL PHYSIOLOGY & PATHOPHYSIOLOGY – AN
OVERVIEW & SOME EXAMPLES
Gregor GuronGerald DiBona(Robert Unwin)
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First Case
• Emergency hospital admission of a middle-aged woman, accompaniedby her husband, with anxiety and confusion
• Smoked all her adult life, despite developing COPD
• Retired early, because of COPD
• Also, longstanding treatment for mild hypertension
• For the last two weeks she was noted to have slow or slurred speechand to be unsteady on her feet
• For the last three days she had become acutely agitated and confused
• Medication: bronchodilators, vitamin D supplement, thiazide diuretic2
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On Examination ‐ 1• Awake, but agitated and confused• Raised BP 170/90• No sign of peripheral oedema• Heart sounds normal• Lungs clear• No focal neurology
Blood tests:• Hb 124 g/L• P-Glucose 6.5 mM• S-Na 118 mM (normally 137-145 mM)• S-K 4.1 mM• S-Creatinine 50 microM• Ionized Ca 1.12 mM• S-Urea 7 mM• (S-Na was normal (137-145 mM) when measured routinely 6 months ago)
IS THIS A HYPO-OSMOLAR HYPONATRAEMIA?3
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• P-Glucose 6.5 mM• S-Na 118 mM (normally 137-145)• S-Urea 7 mM• IS THIS A HYPOOSMOLAR HYPONATRAEMIA?
• P-Osmolality = 253* mOsm/L (measured by osmometry)
Calculated:• P-Osm (mOsm/ L) = 2 x [Na] + [glucose] + [urea] (conc. in mmol / L) POsm
(mOsm / L) = 2 x [118] + [6.5] + [7] = 249.5* mOsm / L (normal Posm = 280-290 mOsm / L)
• i.e. hyposmolar hyponatraemia, indicating that the patient has a relative excess ofwater over Na, and is ’diluted’
• GENERAL RULE: HYPONATRAEMIA = WATER EXCESS AND NOT A SODIUM LACK OR DEFICIT 4
On Examination ‐ 2
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CCBrain
H2O
H2OH2O
H2O
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Cause of symptoms?
• The skull is a rigid box
• When the brain swells, because the ECF osmolality is low and water enters cells to equilibrate, intracranial pressure rises and cerebral blood flow is reduced
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•Altered Na balance is not (of itself) usually a cause hyponatraemia
•While loss of Na may transiently lower plasma osmolality, normal renal water excretion should correct it promptly
Body fluid compartments:Body water (TBW) = 60% in men and 50% in women of BW (kg)~2/3 TBW is in the intracellular volume (ICV) – K+ rich~1/3 TBW is in the extracellular volume (ECV) – Na+ rich~¼ ECV is intravascular volume (CV)
70 kg man:TBW = 42 LICV = 28 LECV = 14 LPV = 3.5 L
Free movement of water between compartments is determined by the difference in ‘effective’ osmoles
PNa is an index of TBW osmolality
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How has the hyponatraemia and dilution occurred?
POsm = 253 mOsm/L AVP = 0 7
Vasopressin (AVP/ADH) release is determined by
POsm and in turn determines water reabsorption
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At >10% loss, defence of BP (and therefore circulating volume) becomes more important than osmolality
Control of AVP/ADH (vasopressin) Secretion
**
*
*
(Body wt.)(Note different y-axis scales)
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Physiological response to hyponatraemia:
At POsm = 253 mosm / L, ADH should be = 0 and UOsm <100 mosm / L (very dilute urine)
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Regulatory mechanisms that determine sodium balance are separate from those that determine water balance:
67% 29%
2%
1.5%
80%
~0.5% = ~150 mmol/d
~20% (36 L) arrives here‘end-proximal/distal delivery’
AVP
H2O 180 L/dNa 25,500 mmol/d
CH2O (maximally dilute urine - <100 mOsm/kg ) = 22 ml/min
300
100*
1200
PGE2
CH2O = Free water generation
1.5 kg(1 g NaCl = 17 mmol Na)
18,000mmol
8,000
~500
~500
Na
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Classification and causes?
U-Osmolality = 485 mOsm / kg (should be <100)UOsm / POsm = 485/253 = 1.9 > 1.0, so ADH present ’inappropriately’, indicating non-osmotic release, e.g., SIADH (syndrome of inappropriate ADH secretion)
CXR diagnosis of Ca lung with ectopic ADH production
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PAVP versus POsm in patients with SIADH
A. PAVP independent of Posm (20%)
B. Shift to left (reduced) of threshold (‘osmostat’ re-set) for AVP release (35%)
C. Normal response, but impaired suppression (35%)
D. A normal pattern (another AVP-like factor or increased renal sensivity?) (10%)
A
B
C
D
Unfortunately, there is no correlation with the underlying disease
Robertson & Berl, The Kidney, 1986
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Second CaseA 30-year-old woman with fatigue and headache
Seeking advice for abnormal fatigue and headache for a month - "something is wrong", previously healthy with 3 children
Examination and sampling shows:• Blood pressure 190/110 mmHg• S-creatinine normal (indicates normal GFR) • S-potassium 3.1 mmol / L (normal 3.6-4.6 mmol / L) • No detectable albuminuria or haematuria on U-stick • Otherwise normal
Could this be a form of secondary hypertension?? Plasma renin concentration ↑? Plasma aldosterone concentration ↑(? Urinary catecholamine excretion ↑)
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Plasma aldosterone/renin ratio
Plasma aldosterone / renin ratio
Interpretation of aldosterone / renin ratio in hypertension
• Aldosterone / renin high: primary hyperaldosteronism
• Aldosterone / renin ratio normal, both values high: renal artery hypertension (renal artery stenosis - RAS)
• Aldosterone / renin ratio normal, both values are low in non-aldosterone and non-renin mediated hypervolemia with hypertension, e.g. large licorice intake, Liddle's syndrome (very rare disease)
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Why hypertension in renal artery stenosis?
renin
RAS
angiotensin II
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Why hypertension in renal artery stenosis?
Angiotensin II-dependent hypertension:• increased total peripheral resistance• increased sympathy activity• increased tubular Na retention via both Ang II and aldosterone right
displacement of the pressure natriuresis curve
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Why hypokalaemia?
lumen interstitium
3 Na+
2 K+
K+
Na+
ENaC: Epithelial Na Channel inhibited by Amiloride (K-sparingdiuretic)
_ +
AldoAldo‐rec
Na/K‐ATPase
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Principal cell in the collecting duct
Spironolactone is an aldosteronereceptor antagonist and K-sparing diuretic
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Doppler US of Kidney
Slower systolic pulse acceleration, "muted” flow curve
Normal Abnormal
Blood flow (pulse wave) pattern in intrarenal arteries 17
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Renal Angiogram”string of beads”
Fibromuscular dysplasia can cause renal artery stenosis (RAS) 18
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afferent arteriole efferent arterioleglom
pressure behind stenosis sensed by renal baroreceptor (afferent arteriole) JGC renin release
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Why is renin released from a stenotic kidney?
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Treatment of renovascular hypertension (RVH) caused by fibromuscular dysplasia (FMD):
1. Percutaneous renal angioplasty ("balloon dilatation") with or without a stent
2. Blood pressure lowering drugs can usually be reduced
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20-year-old man with acute generalised oedema
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Weight gain 5 kg in last month, with swollen ankles and hard to wear shoes
Test results show:
• normal S-creatinine concentration (indicating normal GFR)• S albumin 18 g / l (usually about 40 g / L)• U albumin 7 g / d (normal <30 mg / d)!• Normal blood pressure
Diagnosis? Nephrotic syndrome
Third Case
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Nephrotic Syndrome
Nephrotic syndrome: albuminuria (> 3.5 g / d in adults)
•Hypoalbuminaemia•Oedema• Hyperlipidaemia• Increased synthesis of lipoproteins (due, among other
things, to increased activity of HMG-CoA reductase)•Decreased lipoprotein degradation
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Where in the kidney is the problem?
Pitting pedal oedema
Periorbital oedema
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Renal Biopsy
Focal and Segmental Glomerulosclerosis (FSGS)24
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Why oedema in the nephrotic syndrome?
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Two theories
1. Hypovolaemia with "underfilling” due to hypoalbuminemia and reduced plasma colloid oncotic pressure with fluid shift from the intravascular space to the interstitial fluid; reduced plasma volume activates of RAS, aldosterone, sympathetic renal Na retention (increased post-reabsorption)
OEDEMA
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Why oedema in the nephrotic syndrome
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2. Primary renal Na and water retention "overfilling”Primary renal Na + H2O retention (mechanisms partially unknown) plasma volume ↑hydrostatic capillary pressure ↑Increased ENaC activity independent of angiotensin II, aldosterone and sympathetic via plasmin (secondary to filtration of plasminogen)?
OEDEMA
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50-year-old man found lying on the floor at home
Single, history of alcohol abuse, otherwise healthy
Fall in the home, rib fractures, an on the ground for about 24 hours
On examination:• weak and dehydrated, BP 140/80• S-creatinine 500 micromol / L (normal value <90)S-albumin normal• S-potassium 5.7 mmol / L (usually 3.6-4.6)• U-stick shows 2+ for "red blood cells"
Previous records showed that the man usually had a normal S-creatinine for 6 months, since he was in the hospital previously because of an infection
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Fourth Case
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Causes of acute renal failure (ARF)
afferent arteriole efferent arteriole
1. Pre‐renal (hypotension, hypovolaemia)
3. Post‐renal (obstructive)
2. Renal
P ≈60
mmHg
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Further investigation
• Ultrasound of urinary bladder and kidneys – normal
• Drug toxicity or poisoning?• Eaten mushrooms (poisoning)?• Drug and poisons screen negative
• Increased ethanol S-myoglobin 20,000 μg / L (normally <80)
• Probable diagnosis:
• Rhabdomyolysis (compression damage to skeletal muscle) with acute renal failure secondary to myoglobinuria
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How does the kidney handle myoglobin?
• Myoglobin 17,000 Da (albumin 69,000)
• Sieving coefficient of myoglobin ≈ 0.75 (albumin 0.001) so is filtered almost free due to small size
• Reabsorbed completely by proximal tubules via megalin-mediated endocytosis
• S-myoglobin> about 5000 μg / L
• Myoglobinuria occurs when reabsorbing capacity via endocytosis is saturated
• Risk of "precipitation" of myoglobin at low urine flow and low (acid) U-pH → obstruction of urinary flow at the tubular level
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Managing ESRD
Dialysis1. Haemodialysis (HD)2. Peritoneal dialysis (PD)
Transplantation
Renal replacement is usually started when GFR 5-10% of normal - life-sustaining treatment
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‘Uraemic Frost’
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ESRD
• Approximately 6500 patients in Sweden receiving RR
• About 50% have a functioning kidney transplant
• About 35% on HD
• About 15% on PD
• About 1000 new patients per year
• This number of patients increases by 3-5% per year and patients are getting older
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Hemodialysis
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Dialysis filter
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Peritoneal dialysis
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Kidney transplantation
• Best treatment (for those who tolerate it)
• Most cost-efective treatment
• Ideal option for ESRD
• Problem: need for more kidneys and organ donation – CONSIDER CARRYING A DONOR CARD
• 3300 patients in Sweden with a functional kidney transplant and about 300 kidney transplants in Sweden / year (about 100 in Gothenburg Region)
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Where do kidneys come from?
• 1. Deceased (cadaveric) donors (≈60%), e.g., deceased patient on a respirator following an RTA
• Waiting time for a Tx is about 2-3 years
• 2. Kidney from a living donor (≈40%) – matched or unmatched relative or altruistic
• Waiting time about 4-8 months after pre-Tx investigations
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Kidney transplant surgery
1. Ischaemia during retrieval
2. Ischaemia and reperfusion during implantation
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