Renal Flashcards
Acid base regulation in kidneys
- HCO3 reabsorption into blood
- HCO3 in tubule lumen binds to hydrogen H+ secreted by the brush border cell in exchange for a sodium ion from the tubule to form carbonic acid (H2CO3)
- Carbonic anhydrase type 4 splits carbonic acid into CO2 and H20 which can both then diffuse across membrane into the brush border cell
- Inside the brush border cell carbonic anhydrase type 2 combines them back to form carbonic acid which dissolves into HCO3 and H+ which are shuttled into blood using a cotransporter - H+ excretion in urine Proximal tubule uses Na-H counter transporter
- Na reabsorbed in exchange for H which is excreted into tubule lumen Distal tubule uses H+ATPase to pump H+ from blood into tubule lumen
Buffer systems used to ensure urine doesn’t become too acidic (pH>= 4.5): Ammonia and phosphate
- Ammonia combines with H+ in tubule lumen to form Ammonium (NH4+) which is excreted in urine
- H+ also combines with HPO42- to form H2PO4- which is excreted in urine
Formula for plasma clearance rate of X
(Concentration of X in urine x urine flow rate ml/min) divided by (plasma concentration of X)
Importance of inulin on clearance ratio
Inulin is a polysaccharide product by plants It is the only substance that is freely filtered (100% excreted) and NOT reabsorbed at all
Gives an accurate estimation of the GFR
Clearance ratio = Cx/Cinsulin
CR of 1 = substance X is completely filtered (same as inulin)
CR >1: substance X excreted more than it is reabsorbed
CR <1: substance X is reabsorbed more than it is excreted
Pathophys behind body’s response to dehydration
- Osmolarity increases (less fluid but same solute load) - Osmoreceptors in hypothalamus sense this -> production of ADH (vasopressin)
- Baroreceptors in atrium, aortic arch and carotid sinus sense decrease in blood volume and signal to hypothalamus to produce ADH
ADH → water reabsorption in collecting duct (aquaporin insertion) and vasocontriction → incr BP
ADH - what is it produced by - what effects does it have
- Produced by hypothalamus
- Binds to receptors in collecting ducts of kidneys and in smooth muscle of vessel walls
- In collecting duct, causes insertion of aquaporins -> H20 flows down concentration gradient from duct lumen into blood
- Causes vasoconstriction to increase BP
What happens when you drink a lot of water in terms of osmoregulation?
Decr plasma osmolarity inhibits osmoreceptors firing in anterior hypothalamus -> inhibits H20 reabsorption Baroreceptors sense increase stretch -> inhibits osmoreceptors firing in anterior hypothalamus -> inhibits H20 reabsorption
- NO aquaporin insertion into CD so H20 cannot be reabsorbed in CD so H20 is excreted
- Vasodilation to decrease BP
Cellular mechanism of ADH action on insertion of aquaporins in collecting duct
ADH binds to receptor in basolateral membrane of collecting duct (vasopressin receptor 2 which is G-protein coupled, involves conversion of ATP to cAMP via signaling cascade using enzyme adenyl cyclase)
Ultimately results in phosphorylation of aquaporin2 which is inserted into luminal membrane
Water travels down its concentration gradient from tubule lumen into bloodstream -> incr blood volume
Where is K mostly found?
Inside cells (concentration is 150) Small amount found in the plasma (4.5)
K homeostasis regulation in kidneys
REABSORPTION
- 67% K is reabsorbed in PCT (passively by ‘solvent drag’, follows the water that is reabsorbed)
- 20% K is reabsorbed in ascending LOH (Na/K/Cl co-transporter, loop diuretics inhibit)
EXCRETION
- K excretion occurs in the DCT/Collecting duct
- ‘fine tuning’ regulated by aldosterone (Na reabsorption via Na-K ATPase which exchanges Na for K)
Things that decrease ECF K concentration (and increase uptake into cells)
Ingestion of K -> plasma [K] increases
- Insulin causes glucose and K uptake into cells (via increased activity of Na/K ATPase)
- Adrenaline increases activity of Na/K ATPase to increase K uptake into cells
- Alkalosis
- Bicarb
- Ventolin/sabutamol
Things that increase ECF K concentration (excretion of K out of cells into ECF)
ATP (exercise) Cell lysis - Burns - Rhabdo - Chemo (TLS) Hyperosmolality Acidosis
Alport syndrome
X linked
Mutation in gene coding for type IV collagen (COL4a) in kidney glomerulus, eye, ear
- Kidneys: Persistent microscopic haematuria -> gross haematuria -> proteinuria -> kidney failure by age 18+
- Ears: Bilateral sensorineural hearing loss (born with normal hearing, loss occurs over time)
- Eyes: Anterior lenticonus
Ix - renal bx, genetic testing
tx - ACE inhibitor, hearing airs, replacement of occular lens, RRT/transplant
Anterior lenticonus is path pneumonic for what?
Alport syndrome
Mutation in what gene causes alport syndrome?
COL4A
Pathophys of Anaemia of CKD
Tx
Primarily the result of inadequate EPO production by failing kidneys
Other contributory factors = Fe deficiency, folic acid or B12 deficiency, decreased erythrocyte survival
Recombinant EPO used as treatment if other above causes are treated
Findings of renal tubular acidosis (biochemical and clinical)
Biochemical: Normal anion gap metabolic acidosis Hyperchloraemic
Normal renal function despite this
K low in types I,2 and high in type 4
Clinical: Poor growth, Polyuria, Dehydration, Ricketts (from chronic metabolic acidosis leading to reabsorption of minerals (Ph) from bone to buffer this)
What is the primary defect that causes type II RTA?
Impaired bicarb reabsorption in prox tubule leads to aciodosis in blood
Urine pH>7
Serum bicarb usually >10
Hypokalaemia
What is the primary defect that causes type I RTA?
Impaired hydrogen ion secretion (H+ ATPase isn’t working) into tubule > leads to acidosis in blood
Present with Ca renal stones (due to high tubular Ca)
Urine pH >5.5
Serum bicarb <10
Hypokalaemia
What is the primary defect that causes type IV RTA?
Decr aldosterone secretion or resistance to aldosterone
> impaired hydrogen ion secretion into tubule (Aldosterone stimulates secretion of H+ via the H+/ATPase in the collecting tubules)
> leads to acidosis in blood
Hyperkalaemia (Aldosterone stimmulates Na/K ATPase)
Urine pH < 5.5
Serum bicarb usually >10
Nephrotic syndrome Key ft Causes and treatment
Key fts: proteinuria (>3.5g protein lost/day), hypoalbuminaemia, oedema, hypercholesterolaemia
Causes
- Primary/idiopathic due to minimal change disease (85%) or focal sclerosis glomerulonephritis (10-15%) or membraneous nephropathy
- Secondary - alport syndrome, SLE, HSP, GN Pathophys - Leaky glomerulus -> proteinuria and low serum albumin
Ix - Urine - protein, lipids, fatty casts Bloods - incr lipids
Cx - Hypercoagulable state (antihrombin III lost in urine) - Incr infx risk (Ig lost in urine)
Tx Daily urine dips Daily weight No added salt in diet Albumin + furosemide Oral pred
Cyclophosphamide - second line if relapsing or steroid dependent nephrotic syndrome Penicillin if suspected peritonitis
Mx of nephrotic syndrome with ATYPICAL features (and what are atypical features)
ATYPICAL: HTN, haematuria, age <12mo or >12yrs
Further ix (atypical nephrotic syndrome)
Complement - low C3/4 in SLE and MPGN
ANA - SLE ‘
Hep B if at risk
Biopsy if steroids resistant after 4-6 wk therapy or atypical features
Causes of normal anion gap metabolic acidosis
Pneumonic = CAGE
C = chloride excess (eg. NaCl)
A = acetazolamide (Carbonic anhydrase inhibitor, incr bicarb excretion), Addison’s
G = GIT causes – diarrhoea, vomiting, fistula (pancreatic, ureters, biliary, small bowel, ileostomy)
E = extra – RTA
Causes of widened anion gap metabolic acidosis
K = ketoacidosis
U = uraemia (renal failure)
L = lactic acidosis (ischaemia)
T = toxins [ethylene glycol, methanol, aspirin (salicyclates), metformin]
What is the most common genetic mutation in autosomal recessive polycystic kidney disease
Mutation in PKHD1 gene (polycystic kidney and hepatic disease)
Mx of hyperkalaemia
Uptake of K from serum into cells
- Bicarbonate – Causes K+ to move intracellularly
- Insulin + glucose – insulin causes K+ to move intracellularly
- Nebulised salbutamol - by stimulation of β1 - adrenergic receptors, leads to rapid intracellular movement of K+
Cardioprotection
- Calcium – stabilizes cell membrane of heart cells
Excretion of K from body
- Resonium
- Furosemide (only if not anuric)
- Dialysis in setting of severe renal failure
Autosomal recessive PCKD
→ How does it affect the kidneys?
→ Associations
AR - mutations in PKHD1 gene
Both kidneys affected
Enlarged polycystic kidneys (many small cysts)
Antenatally diagnosed, oligohydramnios
Renal failure requiring RRT from birth/infancy
Associated liver fibrosis and liver failure
HTN
Often assoc w pulmonary hypoplasia/potter phenotype +/- resp distress and spontaneous pneumothorax (30% mortality rate)
What is the potter phenotype and what is it assoc with
Group of findings associated with lack of amniotic fluid and kidney failure often in setting of autosomal recessive PCKD
→ low-set ears, micrognathia, flattened nose, limb positioning defects, IUGR, pulm hypooplasia
Diabetes Insipidis
What is it? Pathophys?
Presentation
What is the classic electrolyte disturbance?
Rare congenital or more commonly acquired disorder of water metabolism Inability to concentrate urine even in the presence of ADH
Deficiency of or resistance to ADH (acts to insert aquaporins for water reabsorption)
Presentation - massive polyuria, hyperNa/hyperCl (hyperosmolar serum), poor weight gain
Goodpasture’s Syndrome
Pathophys
What organs does it affect and what are the clinical symptoms
How is it diagnosed?
Type II hypersensitivity reaction
Autoantibodies (IgG) target type IV collagen fibres (alpha 3 chain) that make up the basement membrane in lungs and kidneys -> activates C’ system -> neutrophils release free oxygen radicals which damage the basement membrane
Affects:
- Lungs - inflammation and bleeding -> haemoptysis, cough and restrictive lung disease
- Kidneys -> Haematuria and proteinuria = nephritic syndrome
Diagnosis w renal bx
Tx
- corticosteroids
- immunosuppression
- plasmapheresis
Nephritic syndrome
Pathophys
Causes
Sx
Ix
Pathophys
- inflammation, damage to glomeruli of kidney -> incr permeability -> RBC and protein can leak into urine
Causes
- IgA nephropathy
- Post-strep GN
- MPGN/C3 nephropathy
- HUS
- Goodpastures syndrome
- Alport syndrome
- SLE
Sx
- haematuria, edema, HTN
Ix
- Haematuria, proteinuria
- Uremia (less waste excreted)
- Decr GFR
- Kidney bx (changes under light/electron microscopy, immunofluorescence)
IgA nephropathy Pathophys Presentation Diagnosis Tx
Most common form of nephropathy worldwide
Type III hypersensitivity reaction
Type of nephritic syndrome
Abnormal IgA form immune complexes with IgG and deposit in Mesangium (within Bowmans capsule) of kidneys -> activation of alternative C’ pathway -> glomerular injury -> RBC and proteinuria
Typically presents in childhood with asymptomatic hematuria +/- HTN ~2/7 following URTI and reoccurs with subsequent infx
Over time with subsequent damage can cause ESRF (25–40% of patients progress to uremia within 10–20 years after the diagnostic biops)
Ix - Renal bx with light microscopy (mesangial proliferation) and electron microscopy (immune deposits) and immunofluoresnce (IgA deposits)
Tx - control BP (low salt diet, antihypertensives)
- corticosteroids (prevent formation of immune complexes)
Lupus nephritis
- Pathophys
- Presentation
- Diagnosis/ix
- Tx
Can be cause of nephritic AND nephrotic syndrome
Caused by type III hypersensitivity reaction
DNA damage -> apoptosis -> DNA, histones, other nuclear proteins exposure -> antibodies target these nuclear antigens -> Ab-Ag complexes form and move through blood and deposit in various places, including KIDNEYS
Complexes can deposit (location of deposition depends on where complexes deposit):
- Endothelial capillary wall
- Bowmans space
- Baselement membrane
- Mesangial cells
Presentation
- Proteinuria -> edema
- Hyperlipidemia -> lipiduria
- Haematuria
Diagnosis
- Bloods: Raised ESR, dsDNA (50%), anti-sm (20%), ANA, RhF (50%); Low C3 and normal CRP
- Kidney bx
Tx = immunosuppression
- Corticosteroids
- Mycophenolate
- Cyclophosphamide
Post Strep GN
- pathophys
- ix/diagnosis
- treatment
Type III HS reaction to Group A beta haemolytic streptococci (1-2 weeks post staph skin infx or pharyngitis, 6 weeks post impetigo)
- Immune complexes (IgG, IgM) form, deposits in Glom BM between podocytes
- Initiates inflammatory reaction in glomerulus, deposition of C3’, oxidants etc damage glomerulus -> haematuria, proteinuria -> peripheral and periorbital oedema
- Self-resolves within 1 month in most cases
- Minority of cases may progress to renal failure or rapidly progressive GN (-> renal failure)
Ix
- Bloods: ASOT, Anti-DNAse B, decreased C’ levels (should return to normal by 3 mo)
- Urine: dysmorphic RBCs + casts
- Renal bx
- Light micro: enlarged, hypercellular
- Electron micro: sup epithelial deposits or ‘humps’
- Immunofluorescence: “starry sky”, granular, GBM + mesangium
Tx
- 10 days of penicillin if positive throat swab
- Supportive tx: fluid restrict, Na restrict, furosemide to correct any vol overload
Rapidly progressive GN
Pathophys
Causes
Dx
Tx
Or ‘Crescentic GN’
Type of nephritic syndrome
Inflammation in glomeruli -> crescent shaped cell proliferation -> damage to glomerular BM -> sclerosis -> acute renal failure in weeks to months
Causes - idiopathic or autoimmune
- type I: anti-GBM Ab (Goodpastures)
- type II: immune-complex mediated (post strep GN, SLE, IgA nephropathy, HUS)
- type III: pauci-immune, pANCAs, cANCAs in blood (Ab against neutrophils)
Dx
- ANCAs in blood for type III
- Renal bx: crescents
- Differentiation between different types on immunofluorescence 1: linear 2: granular 3: negative (nothing lights up)
Tx - Anticoagulation reduces fibrin deposition in crescenes
- plasmapheresis
- immunosuppression
- dialysis
- kidney transplant
Membranoproliferative GN (MPGN)
- Pthophys
- Presentation
- Ix
- Tx
= mesangiocapillary GN
Immune complex and/or C’ deposits in glomerulus -> inflammation and damage of glomerular basement membrane and mesangium -> decr kidney function, proteinuria
Presentation - nephrotic syndrome (proteinuria, edema) or nephritic syndrome most commonly (haematuria, oliguria, HTN)
Ix - Renal bx and light microscopy and immunofluorescence ; low C3, C4
Tx
- steroids (but doesn’t always work)
- can progress to Chronic RF
Nephrotic syndrome
- Pathophys
- Clinical Features
Inflammation/damage to glomeruli of kidneys -> glomeruli more permeable -> leak proteins from blood into urine
Features:
- Proteinuria (>3.5/day) -> hypoalbuminaemia -> edema
- Also get hyperlipidema and lipiduria (-> foamy urine)
Pathophys of 3 types of MPGN
3 types:
Type 1 most common: SUBENDOTHELIAL deposits of circulating immune complexes or C’ deposits -> Results in BM thickening and proliferation of mesangial cells (sometimes surround BM -> ‘tram tracking’ = double BM)
Type 2 - C3 deposits (no immune complexes) in BASEMENT MEMBRANE (get low circulating plasma C3) triggered by nephritic factor (IgG ab that binds to C3 convertase making it more stable, active longer)
Type 3 - immune complexes and C’ deposits are found in SUBENDOTHERLIAL AND SUBEPITHELIAL space of mesangium. poorly understood (idiopathic).
Type 1 MGPN PAthophys
SUBENDOTHELIAL deposits of
- circulating immune complexes or C’ deposits made of Ag and Ab form (may form because of Ag release from CHRONIC INFECTION such as Hep B or Hep C)
- can have inappropriate activation of ALTERNATIVE C’ pathway and C’ complexes deposit
- if nephritic factor present, binds to C3 convertase, making it more stable so it can work longer -> get C’ deposit (not immune complexes) -> Results in BM thickening and proliferation of mesangial cells (sometimes surround BM -> ‘tram tracking’)
Minimal change
- causes
- pathophys
- ix
- tx
Most common cause of nephrotic syndrome in kids
Causes - idiopathic but can be triggered by recent infx/vaccination or immune stimulus (insect sting)
Pathophys - T cells release cytokines that damage podocytes in glomerulus -> leaky
Note - this condition causes SELECTIVE proteinuria (don’t lose Igs)
Ix
- Light microscopy: NORMAL glomerulus
- *Electron microscopy: effacement of podocyte foot processes*
- Immunofluorescence: NEGATIVE
Tx Responds well to corticosteroids
Focal segmental glomerulosclerosis
- causes
- pathophys
- ix
- tx
Primary cause of nephrotic syndrome (2nd most common in kids)
More common in adults
Can be idiopathic or triggered by hx HIV infx, IFN treatment, congenital malformations
Pathophys unknown but ultimately results in effacement of podocyte foot processes AND hyalinosis (deposits of lipids and proteins in glomerulus) -> sclerosis and fibrosis
Ix:
- Light microscopy: sclerosis and hyalinosis among glomerulus
- Immunofluorescence: often NEG but can be positive for C1/C3 or IgM deposits
Tx - inconsistent response to corticosteroids, some ppl can progress to CKD
Membraneous nephropathy
- causes
- pathophys
- ix
- tx
Associated with HBV, malignancy (lymphomas)
Primary cause of nephrotic syndrome
Causes
- Primary OR Secondary (SLE, NSAIDs, infections hep B/C/syphyllis) or solid tumours such as lymphomas
Pathophys
- Damage caused by immune complexes depositing in supeithelial space -> damages podocytes and mesangial cells
Ix
- Light microscopy: diffuse capillary and GBM thickening caused by immune complex deposition
- When stained with silver methanamine, irregular expansions from GBM can be seen
- Immunofluorescence: immune complexes IgG and C3
- Electron microscopy: flattening of popdycte processes and sub epithelial immune complex depositions
Tx: Poor response to corticosteroids → Progression to CKD
Thin glomerular basement membrane disease Presentation Genetics Mgmt
=BENIGN FAMILIAL HAMEATURIA
- Presence of persistent microscopic haematuria AND isolated thinning of GBM on EM
- Presents with episodic gross haematuria can also be present – particularly after respiratory illness often on bg of episodic microscopic haematuria throughout childhood
- Family history of isolated haematuria WITHOUT renal dysfunction (proteinuria, renal impairment, HTN) referred to as benign familial haematuria
-> most patients will not undergo renal biopsy – presumed TBMD
- Genetics: sporadic or inherited (AD, Heterozygous mutations in COL4A3 and COL4A4). NOTE - homozygous mutations in these gene = AR alport syndrome (later onset, later progression to ESRF than the x-linked form, mut in col4A5)
- Annual BP an urine PCR screening warranted • Very rare progression to ESRF
Membranous nephropathy Presentation Causes Pathophys Ix Tx
Presentation - nephrotic syndrome Causes - Primary OR Secondary (SLE, NSAIDs, infections hep B/C/syphyllis) or solid tumours such as colorectal carcinomas Pathophys - Damage caused by immune complexes depositing in supeithelial space -> damages podocytes and mesangial cells Ix - C3 and C5 levels normal in idiopathic MN [Depressed in MN secondary to SLE or hep B] Renal bx LM - Diffuse capillary and GBM thickening caused by immune complex deposition When stained with silver methanamine, irregular expansions from GBM can be seen EM - flattening of podoycte processes and sub epithelial immune complex depositions IF: Immune complexes IgG and C3 Tx - Inconsistent response to corticosteroids 20% progression CKD 40% ongoing active disease 40% remission
Pathogenesis of CKD
Hyperfiltration i. As nephrons are lost, the remaining nephrons undergo structural and functional hypertrophy characterized by an increase in glomerular blood flow ii. Compensatory hyperfiltration temporarily preserves total renal function progressive damage to surviving glomeruli Proteinuria – toxic effect on tubular cells HTN – causes arteriolar nephrosclerosis and by increases the hyperfiltration injury Hyperphosphataemia - calcium deposition in the renal interstitium and blood vessels Hyperlipidaemia – oxidant-mediated injury
Stages (eGFR cut offs) for CKD
- Stage 1 = GFR > 90 with kidney damage 2. Stage 2 = 60-90 3. Stage 3 = 30-60 4. Stage IV = 15-30 5. Stage V = < 15 plan for RRT
Consequences of CKD
Reduced waste excretion
- uraemia (-> pericarditis)
- acidosis
- hyperK
- hyperPh, hypoCa, hyperPTH
- Fluid retention or dehydration
- HTN
- Proteinuria
- Anaemia of chronic disease
- Renal osteodystrophy from secondary Hyperparathyroidism
- Growth impairment
Slowing disease progression in CKD
• Control HTN • ACEi or ARBs in children with proteinuria, even in absence of THN • Maintain normal Serum Ph • Treat infx promptly
Mechanism and management of renal osteodystrophy in CKD
High turnover bone disease caused by secondary hyperPTH
b. ↓ Activated vitamin D = reduced calcium absorption in SI and renal tubules -> hypocalcaemia + ↑PTH secretion
c. ↓ Phosphate excretion by kidneys -> hyperphosphatemia -> hypocalcaemia (Ph binds Ca) + ↑ PTH secretion
↑ PTH = bone resorption (wants to free up Ca, Ph by resorbing bone -> blood)
Leads to bone deformities, bone pain, fractures
Mx
i. Low Ph diet
ii. Vit D supplements (calcitriol)
iii. Ph binders (Ca carbonate/acetate, Mg carbonate, sevelamer hydrochloride)
Tx of anaemia in CKD
a. Due to inadequate epo production +/- deficiencies in Fe, B12, folate b. Tx – recombinant EPO (neorecormon, darbopoeitin) +/- Fe supplements +/- folic or B12 supplementation
Tx of proteinuria in CKD
Treatment w ACEi (arteriole dilatation reduces intraglomerular pressure)
Helps decr proteinuria by 50% but can incr Cr up to 25% (acceptable)
Is actually nephroprotective
Mx of fluid retention in CKD
Later CKD – salt and water retention Mx i. Low Na diet ii. Fluid restriction iii. RRT
Mx of acidosis in CKD
Due to reduced acid excretion by failing kidneys
Sodium bicarb supplements (ural sachet or sodibic)
What is the pathophys of gitelman syndrome
What is this condition
Minimal change disease (normal glomerulus)
What is this condition
FSGS
What is this condition
Alport syndrome (abnormally split glomerular basement membrane)
EM of membranous nephropathy
- featuring ‘spike and done’ sub epithelial deposits
Poststreptococcal glomerulonephritis.
(a) Light microscopy: global endocapillary hypercellularity/proliferation with prominent influx of inflammatory cells, including many neutrophils in capillary lumina and swollen endothelial cells
(b) Immunofluorescence: Coarse granular pattern of C3 deposition in peripheral capillary walls and mesangial regions of a glomerulus, showing in some areas a “starry sky” pattern.
(c) Electron microscopy: Characteristic subepithelial hump-like deposits (arrows) over the subepithelial aspect of the glomerular basement membranes
Mx of (L) PUJ obstruction
Pyeloplasty
Causes of hypokalaemia metabolic acidosis in Children and how to differentiate them
What does aldosterone do to BP and how?
Increases BP - ‘fine-tuning’
Released from adrenal cortex, activated by RAAS
Acts on distal tubule/collecting duct to reabsorb Na (and water along with this) in exchange for excretion of K
