S4C7 Flashcards
What are the different types of proteinuria?
Glomerular Tubular Overflow Post-exercise Post-prandial Infection associated
What are the characteristics of glomerular proteinuria?
Most common form
90%
Feature of chronic kidney disease
Loss of albumin and higher molecular weight protein
What are the characteristics of tubular proteinuria?
Low molecular weight proteins
E.g. Β2-microglobulin
What are the characteristics of overflow proteinuria?
Increased production
Light chains in multiple myeloma
What are the characteristics of post-exercise proteinuria?
Transient benign
Can be up to 10g/day
What are the characteristics of post-prandial proteinuria?
Transient physiological proteinuria
Possibly through insulin action in podocytes
What are the characteristics of infection associated proteinuria?
Physiological response
Mediated by toll-receptors
Possibly involved in clearing pathogens from the circulation
What is the epidemiology of nephropathy?
2025: 300 million with diabetes
40% develop nephropathy
Genetic susceptibility
Most common cause of kidney failure worldwide
What are the stages of injury involved in nephropathy?
Hyperfiltration Microalbuminuria Macroalbuminuria Proteinuria Declining renal function
What is the pathology of hyperfiltration?
Glomerular GBM thickening Mesangial expansion Nodular sclerosis Advanced sclerosis Tubulo-interstitial Vascular
What can cause hyperfiltration?
Pregnancy
Diabetes
Autosomal-dominant polycystic kidney disease
Glomerulosclerosis
What are the goals for treating nephropathy?
Glycaemic control BP control RAAS blockade ACEi/ARB Lipid lowering Reduce other CV risks
What are the 2 types of dialysis?
Peritoneal dialysis
Haemodialysis
What are the advantages of peritoneal dialysis?
Immediate use reduces fluid overloads No anticoagulation Cheapest Continuous Least likely to cause fluid shifts and hypotension
What are the conditions of using heamodialysis and hemofiltration?
Specialist nursing care Tertiary units Need for good central venous access High and efficient solute clearance Anticoagulation Intermittent: not tolerated when haemodynamically unstable Continuous: Hemofiltration
What are the key issues with transplantation?
Immunosuppression
Severe progressive complications
5 year survival rate SPK 70-80% (pancreas)
What is the physiology of beta cells?
pancreatic β-cells express GLUT2 glucose transporters, which permit rapid glucose uptake regardless of the extracellular sugar concentration
What is the effect of insulin on the liver, muscles, adipose tissue and blood?
Liver - Increased glucose uptake and glycogen synthesis
Muscle - Increased glucose uptake and glycogen synthesis
Adipose - Increased glucose uptake and storage as fat, decreased breakdown to fatty acids
Blood - glucose levels fall
What is associated with a 1% decreas in HbA1c
43% decrease in amputations or fatal peripheral blood vessel disease
37% decrease in micro-vascular complications
21% decrease in deaths related to diabetes
14% decrease in heart attack risk
12% decrease in stroke risk
What is the MOA for loop diuretics
inhibits water reabsorption in the nephron by blocking the sodium-potassium-chloride cotransporter (NKCC2) in the thick ascending limb of the loop of Henle.
This is achieved through competitive inhibition at the chloride binding site on the cotransporter, thus preventing the transport of sodium from the lumen of the loop of Henle into the basolateral interstitium.
Consequently, the lumen becomes more hypertonic while the interstitium becomes less hypertonic, which in turn diminishes the osmotic gradient for water reabsorption throughout the nephron
What is the MOA for thiazide diuretics?
inhibit the active reabsorption of chloride in the ascending loop of Henle. (it may also do sodium)
These actions subsequently alter electrolyte transfer in the proximal tubule resulting in excretion of sodium, chloride, and water
also inhibits sodium ion transport across the renal tubular epithelium through binding to the thiazide sensitive sodium-chloride transporter. This results in an increase in potassium excretion via the sodium-potassium exchange mechanism.
What is the MOA for Potassium-sparing diuretics?
competitively inhibits aldosterone dependant sodium potassium exchange channels in the distal convoluted tubule. This action leads to increased sodium and water excretion, but more potassium retention. The increased excretion of water leads to diuretic and also antihypertensive effects.
What are the main points from the Human tissue act 2004?
Permits donation post mortem – opt-in
Allows family members to refuse if you have not registered on the Organ Donor Register (and occasionally even if you have)
Permits (some) live organ donation to be targeted to specific individuals
Makes paid donation illegal
Allow 12yo+ to make their own decisions
What point was ammended from the Human tissue act 2004 in the organ donation bill 2019?
Deemed consent
The person concerned is to be deemed, for the purposes of …(transplantation).. to have consented to the activity unless a person who stood in a qualifying relationship to the person concerned immediately before death provides information that would lead a reasonable person to conclude that the person concerned would not have consented
What are the 4 types of renal tubule acidosis?
Type 1 - Distal RTA
Type 2 - Proximal RTA
Type 3 - combination of types 1+2
Type 4 - Hyperkalaemia RTA (Hyperaldosteronism)
What is the pathphysiology of Type 1 RTA?
Distal RTA
Defective H+ excretion by distal segment of nephron
Inability to acidify urine – serious systemic consequences (Metabolic acidosis)
May be incomplete (compensatory mechanisms of proximal tubule)
But treatable by HCO3- supplementation
Several transporter mutations - mainly affecting the α-intercalated cells:
kAE1, V-type H+-ATPase, CAII
What is the pathphysiology of Type 2 RTA?
Proximal RTA
Rare autosomal-recessive disease
Impaired HCO3- reabsorption in proximal tubule
Severe metabolic acidosis
Not treatable by HCO3- supplementation (80% of bicarbonate is reabsorbed in PCT)
Attributed to mutations in kNBCe1
Ocular abnormalities too because of kNBCe1 and pNBCe1 expression there too
What are the features of respiratory/metabolic acidosis?
Increased PCO2 (resp.) or decreased [HCO3-] (metab.)
both directly stimulate increased H+ secretion and increased NH4+ synthesis by proximal tubule
chronic leads to increased expression of NHE3 and kNBCe1
What are the features of respiratory/metabolic alkalosis?
Decreased PCO2 (resp.) or Increased [HCO3-] (metab.) both directly stimulate decreased H+ secretion and decreased NH4+ synthesis by proximal tubule chronic leads to more β-intercalated cells (HCO3- secreting) in collecting tubule
What is NHE3?
NHE3 is a sodium-hydrogen exchanger
For absorption in the intestine and renal proximal tubule, where it accounts for the majority of total Na absorbed
What is kNBCe1?
Electrogenic sodium bicarbonate cotransporter, a membrane transport potein found in the kidney.
How is plasma pH regulated?
dominated by the HCO3- /CO2 buffering system
How does the body balance acids and bases?
15000 mmol CO2 produced per day
Potential acid - secreted by lungs so not a problem
Metabolism produces ~40 mmol H+ per day
Non-volatile acids - sulphuric, phosphoric, organic acids
~30 mmol H+ net uptake by the GI tract
Kidneys have to:
Excrete ~ 70 mmol H+ per day pH=1.3 without buffering
Reabsorb all the filtered HCO3- (Equivalent to ~4000 mmol H+ per day)
How is H+ secreted? (overview)
Reabsorption of filtered HCO3-
Excretion of H+ as a titratable acid
Excretion of H+ and NH4+
How is filtered HCO3- filtered?
H+ secretion at apical membrane reclaims HCO3- as CO2 + H2O
HCO3- extruded at basolateral membrane
Involves carbonic anhydrases II and IV
Net transfer of HCO3- from lumen to blood
How is H+ excreted as a titratable acid?
H+ and HCO3- generated from CO2 + H2O
Secreted H+ is mostly buffered by filtered phosphate - Also creatinine, urate etc
New HCO3- enters circulation and neutralizes acidity
How is H+ secreted as NH4+?
NH4+ is synthesized by the kidney
Comes from glutamine metabolism
New HCO3- enters circulation and neutralizes acidity
NH3+ binds to H+
What are carbonic anhydrases?
Zn- containing enzymes 16 isoforms Catalyse the reactions Two important isoforms CAII - soluble cytoplasmic CAIV - Extracellular, linked to the membrane (by a GPI anchor)
Where is HCO3- reabsorbed?
Mostly in PCT (80%)
Where is NH4+ secreted?
Mostly PCT
How is HCO3- reabsorbed in early PCT?
NHE3 is dominant in proximal tubule
Large capacity but limited gradient generation
(pH 6-ish in the lumen)
Vacuolar-type H+ATPase can generate a bigger gradient
(pH 4-5 - More important later in the tubule where lumen is more acidic)
1:3 stoichiometry of kNBCe1 make it electrogenic - This allows HCO3- efflux from the cell because of extra drive from membrane potential
NOTE: Unusual to have Na+ leaving the cell on a cotransporter
How is HCO3- reabsorbed in the thick ascending limb and distal tubule?
H+ generated from CO2 and H20
Luminal CAIV less important
AE2 for HCO3- exit at the basolateral membrane
How is HCO3- reabsorbed in α-intercalated cells of collecting tubule and duct cells
kAE1 has shorter N-terminus than eAE1
Main site of V-type H+-ATPase activity
Uses H+,K+-ATPase as well (mainly to reabsorb K+)
V-type H+-ATPase in apical membrane of α-intercalated cells
absent from principal cells
What is the calculation for GFR?
GFR= filtration coefficient x (Glomerular capillary hydrostatic pressure - (Bowman’s capsule hydrostatic pressure + glomerular capillary oncotic pressue))
What is blood flow to the kidneys like?
Cardiac output = 5L/min Kidneys receive 20% (1L/min) RBF 10-50 times greater than other organs RBF exceeds O2 requirements of kidneys RBF not regulated metabolically
What are the 2 ways the kidney autoregulates pressure?
Myogenic - Vascular smooth muscle responds to stretch by vasoconstricting
Tubuloglomerular feedback - distal tubular flow regulates vasoconstriction
What happens in the tubuloglomerular feedback?
Increased arterial pressure increases glomerular pressure and plasma flow.
This increases GFR and PCT-DCT flow.
The macula densa sense this and cause afferent arteriole constriction by Ca2+
Also stimulates granules contained renin to be released for juxtaglomerular cells
This increases preglomerular resistance
What is renal clearance? What is the equation?
Volume of plasma which is cleared of substance x per unit of time
([Urinary X] x Urine volume per unit time)/[Plasma X]
What are the ranges for the PCR?
Protein:creatinine ratio
<20mg/mmol - normal
200mg/mmol - nephrotic range
What are the ranges for the ACR?
Albumin:creatinine ratio
>3mg/mmol - microalbuminuria
>30mg/mmol - albuminuria
How many people in the UK need long-term dialysis or transplantation?
~65,000
How many people per month will reach ‘end stage kidney disease’ in UK?
600
How is sodium secreted into the blood in the late PCT? (H+ mechanism)
Na+ brought into cell by NHE-3
K+ absorbed from the blood in exchange for Na+
How is sodium secreted into the blood in the late DCT/ collecting duct? (H+ mechanism)
Na+ brought in by aldosterone
K+ absorbed from the blood in exchange for Na+
What are the different carriers for glucose transport?
Solute carrier family SLC5 (Sodium-linked co-transporter) SGLT1 - 1 glucose: 2 Na SGLT2 - 1 glucose: 1 Na GLUT gene family - facilitated diffusion GLUT1 GLUT2
How is sodium secreted into the blood in the early PCT? (glucose mechanism)
Brought in with glucose by SGLT2
K+ absorbed from the blood in exchange for Na+
GLUT2 allows glucose to diffuse into the blood
How is sodium secreted into the blood in the late PCT? (glucose mechanism)
Brought in with glucose by SGLT1
K+ absorbed from the blood in exchange for Na+
GLUT1 allows glucose to diffuse into the
How is NH4+ secreted in the proximal tubule?
NH4+ produced by glutamine metabolism.
This splits to make NH3 and H+
This also makes new HCO3- which is secreted into the interstitial space with Na+
Na+ is brought into the cell, in exchange for H+ which is pumped into the tubule lumen
NH3 binds with H+ to make NH4+ in the lumen.
How is NH4+ reabsorbed in the thick ascending loop?
Via ROMK2 channel, and NKCC1 accepts NH4+ in place of K+
Low NH3 permeability at apical membrane, so it leaves across basolateral membrane
How is NH4+ re-secreted in collecting duct?
Most crosses epithelium as NH3 Some NH4+ is carried in by Na+K+ATPase NH4+ splits to H+ and NH3 NH3 crosses epithelium into lumen H+ is transported across Bind together to create NH4+
Describe the RAAS system.
Liver produces Angiotensiongen
Kidney produced renin which converts this to ANG1
ACE (produced in lungs) converts this the ANG11
This stimulates the pituitary gland to produces ADH which binds to V2 receptor on kidneys
Also stimulates Adrenal gland to release aldosterone which causes the collecting ducts to retain water increasing BP.
