Renal Physiology Flashcards
What is GFR influenced by?
Age and gender
What does dipstick measure?
-Specific gravity: urine osmolality
- Blood
- Albumin
- Glucose
- Ketones: positive for acetoacetic acid, not B hydroxybutyrate so some alcoholic ketoacidosis doesn’t show positive ketones
Captopril can result in false positive urine dipstick for ketones.
- Blood
- Nitrites, Leukocytes
- Bilirubin: the presence of
conjugated bilirubin is suggestive of severe liver disease or obstructive jaundice. False-positive results occur with chlorpromazine, and false-negative results occur with ascorbic acid.
- Urobilinogen: produced in the gut from the metabolism of bilirubin and is then reabsorbed and excreted in the urine. A positive urine dipstick for urobillinogen usually results from hemolytic anemia or hepatic necrosis but not from obstructive causes.
What can lower creatinine?
Reduction of muscle mass, eg: amputees
Malnutrition
Muscle wasting
Liver disease
Because of decreased muscle mass, serum creatinine overestimates kidney function in elderly people.
Trimethoprim can cause a higher creatinine without a change in GFR
What bacteria can cause false negative nitrites?
Gram positive organisms such as Enterococcus
What are causes of sterile pyuria?
Sterile pyuria refers to the presence of leukocytes in the urine in the setting of a negative bacterial culture.
- Mycobacterium tuberculosis is an important infectious cause of sterile pyuria.
- Acute interstitial nephritis is associated
with sterile pyuria and low-grade proteinuria; it is often caused by antibiotics, NSAIDs, or proton pump inhibitors.
Kidney stones and kidney transplant rejection can also cause
sterile pyuria.
Why does hyperglycaemia cause hyperosmolar hyperglycaemia?
- Hyperglycemia causes the osmotic trans location of water from the intracellular to the extracellular fluid compartment, which
results in a decrease in the serum sodium level by approximately 1.6 mEq/L (1.6 mmol/L) for every 100 mg/dL (5.6 mmol/L) increase in the plasma glucose above 100 mg/dL (5.6 mmol/L).
What happens in cerebral salt wasting
Hypovolemic Hyponatremia
The syndrome of cerebral salt wasting
is a rare cause due to inappropriate natriuresis from intracranial
disease such as subarachnoid hemorrhage, traumatic brain injury. craniotomy, encephalitis, and meningitis.
Clinical features and management of hyponatremia
Symptoms and signs ranging
from headache, nausea, and/or vomiting, to altered mental status, seizures, obtundation, central herniation. or death.
Acute Management
- Correcting hyponatremia too rapidly can lead to central pontine myelinolysis or osmotic demyelination (symptoms include altered mental state, diplopia, paraparesis/quadriparesis, arthria, coma, long tract signs (clonus, hyperreflexia) - will require a MRI brain
- Fluid restrict and treat underlying cause
• If hyponatremia is severe of if the patient is significantly symptomatic (eg: comatose, seizing), cautiously give hypertonic saline. Patients must be monitored in ICU to prevent central pontine myelinolysis.
§ Goal of therapy is to raise serum sodium concentration by 4-6mmol/L, not more than 6-8mmol/24 hours
§ Use: sodium chloride 3% 100mL IV over 10 minutes, repeat as need up to a maximum of 3 infusions
Demeclocycline (ADH receptor antagonist) or vasopressin receptor antagonist (conivaptan) can help normalise serum sodium
ODS classically affects the pons, resulting in
central pontine myelinolysis: patients may present days after
overcorrection of hyponatremia with para- or quadriparesis,
dysphagia, dysarthria, diplopia, a “locked-in” syndrome. and/
or loss of consciousness
Clinical features of hyponatremia
Acute treatment
- Correcting hyponatremia too rapidly can lead to central pontine myelinolysis or osmotic demyelination (symptoms include altered mental state, diplopia, paraparesis/quadriparesis, dysphagia, dysarthria, “locked in syndrome” and LOC long tract signs (clonus, hyperreflexia) - will require a MRI brain
- Fluid restrict and treat underlying cause
If hyponatremia is severe of if the patient is significantly symptomatic (eg: comatose, seizing), cautiously give hypertonic saline. Patients must be monitored in ICU to prevent central pontine myelinolysis.
- Goal of therapy is to raise serum sodium concentration by 4-6mmol/L, not more than 8mmol/24 hours
- Use: sodium chloride 3% 100mL IV over 10 minutes, repeat as need up to a maximum of 3 infusions
- Demeclocycline (ADH receptor antagonist) or vasopressin receptor antagonist (conivaptan, tolvaptan) can help normalise serum sodium
SIADH
Causes: Malignancy Nausea Pain ( post op) Medications: SSRI, AntiPsychotics Infections: Respiratory
Causes of SIADH
- small cell lung cancer
- Stroke/SAH
- Drugs: carbamazepine, SSRIs, sulfonylureas,
- Pulmonary : pneumonia, TB, abscess
- Porphyrias
Low serum sodium/osmolality
High urine sodium/osmolality
Fluid restriction
If FR fails
- Oral demeclocycline (30s ribosomal subunit) acts on collecting tubule cells to diminish their responsiveness to ADH, in effect essentially inducing nephrogenic diabetes insipidus - induces nephrogenic water loss. However, demeclocycline can be associated with acute kidney injury from natriuresis and/or direct
renal toxicity and is contraindicated in patients with cirrhosis.
- Vasopressin antagonists (oral tolvaptan and intravenous conivaptan) have been shown to be effective in normalizing
serum sodium concentration in SIADH
Liddle Syndrome
- Autosomal dominant gain of function mutation in the SCNN1A, SCNN1B and SCNN1G genes on chromosome 16p leading to increased epithelial sodium channel (ENaC) in COLLECTING DUCT leading to INCREASED REUPTAKE OF SODIUM + WATER
- Cause HYPERTENSION and HYPOKALAEMIA
- LOW RENIN + ALDOSTERONE
- METABOLIC ALKALOSIS
Tx
Lifelong potassium supplementation with potassium sparing diuretics that directly block the ENaC in the collecting duct (amiloride)
Like PSEUDOHYPERALDOSTERONISM
Gitelman Syndrome
- Autosomal recessive condition
- Mutations in SLC12A3 (solute carrier family 12 member 3)
- Defect in the Na/Cl transporter in the distal convoluted tubule (thiazide)
- HYPOTENSION, HYPOKALAEMIA, METABOLIC ALKALOSIS
- Serum: hypokalaemia, low Na/Cl/Mg, metabolic alkalosis, hypercalcaemia
- Urine: high Mg/K, low Ca,
HIGH CHLORIDE IN URINE
LOW CALCIUM IN URINE
Tx: lifelong oral potassium substitution with potassium-sparing diuretics
(spironolactone, amiloride)
Bartter Syndrome
- Autosomal recessive genetic disorders affecting sodium chloride reabsorption in nephrons
- Bartter –baby-childhood onset, more severe, can cause perinatal death
- More severe phenotype
- Mimick therapy with loop diuretics
- Impairment of transporters in loop of Henle
- High levels of prostaglandins production –> stimulates renin causing secondary hyperaldosteronism
- Bartter syndrome is an inherited cause of hypokalaemia, due to defective chloride absorption at the Na+ K+ 2Cl- cotransporter in the ascending loop of Henle. It usually presents with failure to thrive and/or polyuria and polydipsia
- Volume depletion and activation of RAAS causing secondary hyperaldosteronism
- Serum: low Na/K/Cl
- Urine: high Na/K/Cl/Ca, polyuria
HIGH CL IN URINE
NORMAL CA IN URINE - Metabolic alkalosis
- HYPOKALAEMIA + HYPOTENSION
Tx:
- lifelong oral potassium substitution with potassium-sparing diuretics (spironolactone, amiloride)
- inhibition of prostaglandin production with indomethacin or ibuprofen to reduce sodium and chloride delivery to the
distal tubule.
Bartter syndrome can be caused by mutations in at least five genes. Mutations in the SLC12A1 gene cause type I. Type II results from mutations in the KCNJ1 gene. Mutations in the CLCNKB gene are responsible for type III. Type IV can result from mutations in the BSND gene or from a combination of mutations in the CLCNKA and CLCNKB genes.
The genes associated with Bartter syndrome play important roles in normal kidney function. The proteins produced from these genes are involved in the kidneys’ reabsorption of salt. Mutations in any of the five genes impair the kidneys’ ability to reabsorb salt, leading to the loss of excess salt in the urine (salt wasting). Abnormalities of salt transport also affect the reabsorption of other charged atoms (ions), including potassium and calcium. The resulting imbalance of ions in the body leads to the major features of Bartter syndrome.
Cause of normal anion gap metabolic acidosis (8-12)
Normal Anion Gap acidosis
GI loss of HCO3: Diarrhoea
Renal loss of HCO3: type 2 proximal RTA, carbonic anhydrase
Inability to excrete H+: type 1 distal RTA, type 4 RTA
AG: (Na+K) - (Cl + HCO3)
Renal tubular disorders summary
• Hypokalaemic
○ Classic Distal Type 1: defects in distal hydrogen ion excretion (rare)
pH > 5.5
○ Proximal Type 2: impaired reabsorption of bicarb,
pH > 5.5, early finding of proximal RTA attributed to continuous HCO3 excretion in the urine
pH < 5.5: typical finding of proximal RTA attributed to serum HCO3 depletion.
• Hyperkalemic
○ Type 4: hypoaldosteronism (common)
• Type 3 RTA - combined Type 1 and 2 - very rare (extremely rare)
Normal anion gap metabolic acidosis
• Type 1 RTA: Acid secretion impairment at distal tubule, treatment with Alkali
• Type 2 RTA: Bicarbonate wasting at proximal tubule, treatment with Base (alkali)
• Type 3 RTA: Carbonic anhydrase deficiency, treatment with Citrate (sodium/potassium)
pH > 5.5
• Type 4 RTA: AiDosterone disorDer, treatment with 4rusemide.
pH < 5.5
TYPE 1/2/3 = HYPOKALEMIA
TYPE 4 = HYPERKALEMIA
Type 1 Renal Tubular Acidosis (Distal)
Distal RTA (Type 1) Hyperchloremic Metabolic Acidosis (normal anion gap)
- The a cells of the distal tubules are unable to secrete H+ where there is a defect in urine acidification
- Urine pH > 5.5 (no H+ in urine)
- Cause: Sjogrens, SLE, PBC, autoimmune hepatitis
Sporadic/hereditary
Autoimmune: SLE, sjogrens, autoimmune hepatitis
Chronic obstructive uropathy
Sickle cell nephropathy
Drugs: amphotericin, lithium, NSAIDs
Features:
- Bone involvement: bone demineralisation without overt rickets or osteomalacia (due to increased bone turnover)
- Urine pH > 5.5 (unable to acidify urine)
- Hypokalaemia
- Hypercalciuria, hypocitraturia = Nephrolithiasis - RTA1 causes kidney stONES, calcium phosphate stones
- Tx: alkali treatment with sodium bicarbonate, K replacement, sodium/potassium citrate can be used to reduce stone formation
Type 2 Renal Tubular Acidosis (Proximal)
Proximal RTA (Type 2) Hyperchloremic Metabolic Acidosis (normal anion gap)
- Caused by a defect in the proximal convoluted tubule (PCT) resulting in inability to reabsorb bicarbonate (renal loss of bicarbonate)
- Urine pH < 5.5 (distal tubules secrete the excess H+ as in any acidosis)
- Causes: myeloma, drugs, tenofovir
myeloma, wilson disease, drugs (tenofovir, acetazolamide) - Usually not an isolated phenomenon but rather part of Fanconi syndrome, a generalised defect in proximal tubule function
- “RTA type 2 has two variants - isolated proximal RTA and Fanconi Sydndrome”
pH > 5.5, early finding of proximal RTA attributed to continuous HCO3 excretion in the urine
pH < 5.5: typical finding of proximal RTA attributed to serum HCO3 depletion.
Isolated Proximal RTA
- Only HCO3 reabsorption is impaired
- Causes: sporadic, familial
Drugs: acetazolamide
Fanconi Syndrome
- Impaired reabsorption of HCO3 and other compounds (potassium, glucose, phosphate, amino acid, uric acid reabsorption) in PCT.
- Causes:
Inherited conditions: wilson’s disease, type 1 glycogen storage disease
Multiple myeloma
Amyloidosis
Ischaemia: acute tubular necrosis
Vit D deficiency
Paroxysmal nocturnal haemoglobinuria
Drugs: tenofovir, aminoglycosides, cisplastin
Heavy metal poisoning (lead, mercury)
- Low bicarbonate, hypouricemia, hypophosphatemia
Urine: Aminoaciduria, glucosuria (despite normal or low serum glucose), phosphaturia
Hyperchloremic metabolic acidosis
Hypokalaemia that worsens with alkali therapy
Hypotension
Low bicarbonate
Fanconi:
Serum - hypouricemia, hypophosphatemia
Urine - aminoaciduria, phosphaturia, glucosuria despite normal or low serum glucose
Tx:
- Alkali therapy with orally administered potassium citrate + thiazide diuretic which causes mild volume depletion that enhances the proximal
reabsorption of sodium and bicarbonate.
REMEMBER: BICARBONATE REPLACEMENT CAN DROP POTSSIUM
IN PROXIMAL RTA: ALKALI RX WORSENS HYPOKALAEMIA
IN DISTAL RTA: ALKALI RX IMPROVES HYPOKALAEMIA
What is Fanconi Syndrome
- Defect of the proximal tubule that leads to type 2 renal tubular acidosis
- Inability to reabsorb HCO3, potassium, phosphate, glucose, amino acids and uric acid
- Serum: low bicarbonate, hypokalaemia, hypophosphatemia (hallmark), hypouricemia
- Urine: aminoaciduria, phosphaturia, glucosuria despite normal or low serum glucose
Type IV RTA, hypoaldosteronism
- Common due to decrease aldosterone secretion or aldosterone resistance in the DCT and collecting duct
Causes: DM (commonest), NSAIDs, ACEi, calcineurin inhibitors (cyclosporin, tacrolimus), K sparing diuretics, high dose heparin.
Cause
1. Hypoaldosteronism:
- Primary adrenal insufficiency (Addison disease)
- Hyporeninemic Hypoaldosteronism
Acute GN
Chronic nephropathies - Diabetic nephropathy, SLE
Drugs (NSAIDs, cyclosporin/calcineurin inhibitors)
- Drugs: ARB, ACEi, Heparin
- Aldosterone resistance: chronic interstitial or obstructive nephropathy, drugs (potassium sparing diuretics, bactrim).
Pathophysiology
Aldosterone deficiency and/or resistance in the collecting duct and distal convoluted tubule –> hyperkalaemia + metabolic acidosis –> inhibits ammonia synthesis in the proximal convoluted tubule –> decreases urinary ammonium excretion
“RTA type 4 leads to decreased NH4 excretion”
Clinical features
- Polyuria –> polydypsia, dehydration
- Impaired growth in children
- Features of hyperkalaemia
- Hyperchloremic metabolic acidosis
- Hyperkalaemia
Tx
- Frusemide
- Mineralocorticoid replacement (fludrocortisone)
- Low potassium diet
Treatment of type 4 (hyperkalemic distal) renal tubular acidosis includes correction of the underlying cause, treatment of hyperkalemia, discontinuation of offending medications, and dietary potassium restriction.
Initial treatment includes correction of the underlying cause if possible, with discontinuation of offending medications.
In most cases, treatment of hyperkalemia with sodium bicarbonate or sodium polystyrene sulfonate results in
improvement of the acidosis. Replacement of mineralocorticoids
with fludrocortisone is indicated for patients with Addison disease and should be considered for those with hyporeninemic hypoaldosteronism unless hypertension or heart failure is present. Management should also include dietary
potassium restriction to approximately 2000 mg/ct.
- In those not hypertensive or volume loaded: fludocortisone
- In patients with hypertension or fluid overload: thiazide or loop diuretic may help by decreasing distal delivery of Na and consequently increase urinary secretion of H+ and K+
Type III RTA
- Combination of type 1 and type 2
- Aetiology: carbonic anhydrase II deficiency, autosomal recessive, topiramate
- Pathophysiology: impaired H+ secretion by DCT and impaired HCO3 reabsorption by proximal convoluted tubule.
Hypokalaemia
Hypocalcaemia
Hypercalciuria
Tx
Alkali therapy with sodium/potassium citrate
What is the most commonest glomerular disease worldwide?
IgA Nephropathy
What are the barrier qualities of the GBM?
Charge selective - negative molecules
Size selective > 60kD molecules
What are the features of the filtration barrier of GBM?
Filtration Barrier
- Highly permeable: H2O, small solutes, ions (Na, Cl)
- Poorly permeable: macromolecules, albumin
Size of Selection of Slit Diaphragm
- <1.8nm passes freely
- > 4nm totally restricted
Summary of GN and damage involved
- Nephrotic Disease: podocyte damage
- Nephritic Syndomre: sub-endothelium (GBM) damage
What are the major components of the GBM?
- Type 4 collagen (a3, 4, 5)
- Laminin (A5, B2, y1 chains)
- Heparan sulfite which allows it to have its NEGATIVE charge
What are diseases of the GBM?
- Type IV collagen molecules are composed of three alpha chains that form triple-helical rope like structure
- GBM and alveolar capillary basement membrane collagen consist of alpha3,4 and 5 chains unlike other basement membranes with alpha1, alpha1 and alpha2 chains
- Goodpasture disease characterised by antibody against alpha3 chain of type IV collagen (anti-GBM antibody )
- Alport syndrome results from mutations in genes encoding the alpha-3, 4, and 5 chains of type IV collagen (80% due to alpha-5 mutation)
