This is one topic where my boss tells me everyone remembers it and believe they have finally understand it for that few seconds – then POOF, it is gone out of the mind almost immediately.
I so TOTTALLY agree.
I mean, who can be bothered to remember all these details about random stuff?!??! There is so much more important things to do! But remember I must and recall it I will.
I’m someone who gets confused easily. Different terms and english names means not much to me to be honest. Apical? Basolateral? Up, down, left, right? Whatevs. I’ll simplify it for the sake of my space constrained brain.
So what we are really interested in in tubular pathology is where sodium is reabsorbed, what we can do to modify it And all the genetic deficiencies of certain transporters that leads to all these RARE diseases.
I’ll do my best to make it simple. Let’s start with the basic renal epithelial cell.
So random terms like apical membrane denotes the surface of the cell that is in contact with the urine, and basolateral membrane is the surface with blood.
Few things to note:
The apical membrane can vary its permeability to allow Na+ in
It can have other transporters on its surface to allow movement of solutes in and out of the cell up and down the concentration gradient.
Na+ movement is really INEFFICIENT
So moving down the glomerulus, we first encounter the proximal tubule.
The Proximal Tubule consists of 2 parts:
Descending loop of Henle
The PCT has 3 main functions:
via carbonic anhydrase (carbonic anhydrase inhibitors eg acetazolamide works here)
Na+ dependant mechanism
Reabsorbed via apical membrane
endocytosed in cell
Glucose, amino acids and phosphate is reabsorbed here and if not, it is lost forever
a lot of drugs are excreted in the proximal tubules
Manipulation of the PCT can be achieved for therapeutic purposes
e.g. to increase penicillin concentration in the serum, probenecid blocks the organic anion transporter inhibiting excretion of penicillin
Trimethoprim blocks the organic anion transporter too, competing with creatinine secretion.
Problems with the PCT
global breakdown of proximal tubule transport
loss into urine of
phosphate -> rickets/osteomalacia & bone pain
glucose -> glycosuric but normal plasma glucose concentration
bicarbonate -> metabolic acidosis (proximal RTA)
Vitamin D is not hydroxylated
apical membrane abnormality
energetic failure of ATP
back leak of solutes
episodes of hypovolaemia (polyuria due to loss of concentrating ability)
muscle weakness (hypokalaemia)
X-linked recessive: 2 types: Type 1 ( mutation in CLCN5; Chloride voltage channel 5 gene), Type 2 (missense mutation in ORCL gene; also encodes Lowe Syndrome. Lowe syndrome sufferers have cataracts, RTA and mental retardation (oculocererbrorenal syndrome) which Dent sufferers do not have)
CLCN5 codes for ClC5 (a H+/Cl- exchanger) in the endosome of the PT – its role is to maintain pH reabsorption of amino acids and proteins.
ORCL gene codes for an enzyme that regulates phosphatidylinisitol 4,5 – diphosphate that is part of the membrane phospholipid. The ORCL enzyme is also found in the kidney endosome and in the actin skeleton and primary cilia
Hypercalciuria, leading to
Nephrocalcinosis and kidney stones
Proximal Tubule Acidosis (Type 2 RTA)
Failure to reabsorb bicarbonate
3 types that can all present with Fanconi’s
Autosomal recessive with ocular abnormalities
Autosomal recessive with osteopetrosis and cerebral calcification (inherited carbonic anhydrase II deficiency)
What is it:
HCO3 reabsorptive failure
Lowering of threshold for HCO3 absorption in proximal tubule
Distal acidification intact
Can lower pH <5.5 (when given ammonium chloride test)
Isolated or Fanconi
AR – SLC4A4 (Na-HCO3 transport)
AR – mutation in CTNS gene
Lysosomal transporter disease
Cystine accumulates in cells of PT –> toxic
Presents in infancy
Extra renal manifestations:
Lowe Syndrome (XLR, oculocerebralrenal syndrome)
Type 1 glycogen storage disease (Von Gierke)
CA inhibitors (topiramate)
Will lose LMW proteins
Clinical phenotype in acquired adult disease predominantly bone (osteomalacia)
HCO3 12-20 mmol/l
Urine pH variable
>5.5 if given alkali (bicarbonaturia)
<5.5 when [HCO3] at threshold (ammonium acidification tests causes consumption of HCO3 when ammonia is converted to urea in the liver; in T2RTA, urine can be acidified further at the distal tubule hence urine pH can fall < 5.5)
Urine AG NEGATIVE (nb direct NH4+ measurement)
Moving down the nephron, we next encounter the thick ascending limb (TAL).
Probably by favourite cell in the nephron.
Pretty self explanatory, 25% of Na is reabsorbed here so this is where we try to stop that from happening. It is also where the weird and wonderful problem known as Bartter Syndrome starts.
Loop diuretics – knock out NKCC2, decreased Na+ reabsorption into the blood, hence H2O moves into the urine via osmosis (with Na+)
Recessive mustations of:
SLC 12 A1 gene, codes for NKCC2 : Bartter Type 1 – a primary defect of SALT wasting.
Loss of water from the body +++ –> hypotensive (low BP)
Hypotension activates aldosterone
Aldosterone activates the transcription of more ENAC channels at the apical membrane in the intercalated cells of the Collecting Duct to retain more Na+ in the blood, but of course, K+ is lost –> hypo K+
Loss of K+ into the urine –> intracellularly, H+ accumulation occurs to maintain electro-neutrality. Therefore, less H+ in the serum –> metabolic alkalosis (when you lose K+, you lose H+ too)
Ca2+/Mg2+ is reabsorbed as there is a net positive charge in the urine when NKCC is working properly (as K+ diffuses freely across to the urine when 2 Cl- are reabsorbed into the blood via the Cl- channels ). When ROMK is not working, positive charge in the lumen reduces and X transporter stops working, hence more Ca2+ is lost in the urine –> hypercalciuria & nephrocalcinosis
2. KCNJ1 gene, coding for the K+- voltage gated channel; i.e. ROMK knockout ; Bartter Type 2
3. Cl Ckb gene, coding for the chloride-voltage gated channel Kb; i.e. Cl Ckb knockout; Bartter Type 3. Also present in DCT – overlap with Gitelman’s
5. BSND and Cl Ckb/ClCka gene – BSND : Bartin Cl Ck beta accessory subunit ; Bartter Type 4a, and the ClCka/b channel knockout – Bartter Type 4b
Types 1, 2 and 4 are present from birth. Type 4 is also associated with sensorineural deafness as ClCk gene is also present in the ear.
Children present with:
Failure to grow
Histology : JGA hyperplasia
Rx : NSAIDs
FHHNC – Familial hypomagnesemia, hypercalciuria and nephrocalcinosis
Moving further down the nephron, we now arrive at the Distal convulated tubule which gets tubular glomerular feedback from the juxtaglomerular apparatus;
The DCT senses Na/Cl in the filtrate via the NCC receptor
On the apical membrane, NCC absorps 1 Na+ with 1 Cl-, making the process electroneutral. Loss of function of the NCC transporter causes Gitelman Syndrome (familial hypokalaemia-hypomagnesaemia):
SLC 12A3 gene, recessive mutation
Loss of Na –> water follows Na –> hypovolaemia –> normal or low BP
Low BP activates aldosterone (and renin and angiotensin)
Aldosterone activates the transcription of more ENAC channels at the apical membrane of the intercalated cells of the Collecting Duct to retain more Na+ in the blood, but of course, K+ is lost –> hypo K
Patients are also hypercalcaemic (+ hypocalciuric) –> chondrocalcinosis. Why?
Theory 1: During contraction of ECV, PT cells are alerted to increase Na+ reabsorption. Passively, Ca2+ is driven down the electrochemical gradient, hence higher Ca2+ levels in the body
Theory 2: enhanced basolateral Na/Ca exchange due to decreased intracellular Na+ concentration, leading to increased apical Ca2+ entry through Trpty5
Hypomagnesaemia also happens. Why?
K+ deficiency –> increased passive Mg+ secretion
?reduced abundance of Mg channels in the apical membrane
To more minor part of the Gitelman syndrome
CLCNKB gene mutation
Also present in the TAL – overlap with Bartter Type 3
Type 3 Bartter
Age at diagnosis
Differences of Gitelman vs Type 3 Bartter
EAST Syndrome (Epilepsy, Ataxia, Sensorineural deafness, salt wasting renal Tubulopathy)
KCNJ10 mutation – also found in brain (glial cells) and ear (inner ear).
Similar presentation as Gitelman’s (renal wise)
And if you gain function of the NCC transporter:
Gordon Syndrome / Pseudohypoaldosteronism Type II
salt sensitive hypertension
normal anion gap metabolic acidosis – NAGMA
normal renal function
Mutation in 2 different genes :
WNK 4 – loss of function
responsible for inhibition of NCC –> loss of inhibition –> unregulated Na+ uptake.
Leads to decreased Na+ delivery in the CD and reduced tubular electronegativity –> H+ and K+ not secreted
Expansion of ECV –> Hypertension –> shut down aldosterone and RAS activity
WNK 1 – negative regulator of WNK 4, hence mutation in WNK 1 is called gain of function
And finally the Collecting Duct
There are 2 cell types:
Properties of ENAC
Na+ is reabsorped by ENAC and with that K+ is secreted out via ROMK (not shown here on the apical membrane)
Regulated by aldosterone. Aldosterone is mediated by the mineralocorticoid receptor (MR) in the principal cells –> activated –> increase serine-threonine-kinase SGK1 (protein) –> increases more ENAC channels
Inhibited by atrial natriuretic peptide (ANP). ANP is involved in cardiorenal homeostasis. High BP –> ANP activated via membrane-bound natriuretic peptide receptor-A –> generates second messenger cGMP –> down regulates ENAC/inhibits renin and aldosterone production
can also be stimulated by vasopressin (ADH); but the net effect of vasopressin is to lower Na+ concentration
Properties of AQ receptors
stimulated by vasopressin (ADH = antidiuretic hormone)
water enters through AQ2 and exits via AQ3 and AQ4.
water movement is driven via the tubulo-interstitium osmotic gradient
Problems with over activation of ENAC:
Mutations in SCNN1B or SCNN1G – both genes code for breakdown of ENAC
ENAC ++++ –> +++ Na reabsorption and +++ K secretion (via ROMK)
Become hypertensive and hypokalaemic
H+ is loss –> metabolic alkalosis
Aldosterone is deactivated –> mimics apparent mineralocorticoid excess syndrome (AME)
urine shows low levels of renin, aldosterone and angiotensin
urine cortisol:cortisone =1, much higher ratio in AME as AME patients make less cortisone
Treatment : Block the ENAC receptor –> amiloride/trimethoprim
Apparent mineralocorticoid excess syndrome
mutations in HSD11B2 gene – codes for 11 beta hydroxysteroid dehydrogenase type 2 (kidney isozyme expressed in principal cells) –> role is to inactivate cortisol by converting it to cortisone (less active metabolite).
Loss of inactivation –> ++++ cortisol –> cross react and activate MR as it is non selective
Hence act like aldosterone activation –> +++ ENAC –> hypertension, hypokalaemia, metabolic a and hypernatraemia.