SLE

Like Dr House said, it’s always LUPUS!

What is it?

  • Common (clinical disease >50%)
  • Black / hispanic / asian > white

Presentations:
–Isolated urinary abnormalities
–Nephrotic syndrome
–Progressive renal impairment
–RPGN
–Other (eg TMA)
– Joint pains
-Rash

6 Classes:

  1. Class I – Minimal mesangial
  2. Class II – Mesangial proliferation
  3. Class III – Focal proliferative
  4. Class IV – Diffuse proliferative
  5. Class V – Membranous nephropathy
  6. Class VI – Advanced glomerulosclerosis

and a final class that is coming :

Lupus podocytopathy

  • Indistinguishable from MCN
  • Serologic or clinical features of SLE
  • Normal or minimal mesangial
  • Mesangial deposits only
  • Typically steroid responsive
  • > common than chance

Lupus path copy

Treatment?

By no means 100% correct, but based on guidelines

Lupus treatment copyFor Class III – V :

  • EUROLUPUS : NIH recommends HIGH dose cyclophosphamide
  • ACCESS trial : abatacept; confirms comparable efficacy in black + hispanic patients, but no benefit as add on therapy
  • ALMS : MMF vs NIH Cyc – no difference in outcomes but possible MMF > Cyc benefit in black patients, but equivalent in all with GFR < 30

Relapse:

Mild : Increase steroids +/- aza / MMF
Moderate /  severe :  Repeat initial successful induction therapy. Can repeat CYC. Consider RTX

In pregnancy:

  • Wait until remission > 6/12
  • Continue HCQ
  • No – MMF / ACE / ARB / cyclophos
  • Yes – Aza / CNIs / labetalol / nifedipine/ steroids
  • KDIGO: do not taper steroids or Aza during pregnancy or for three months after
  • Aspirin

 

Bad prognostic factors:

  • Male
  • Younger age < 24 yrs
  • Low socioeconomic status
  • Black race
  • high Cr at presentation
  • HTN
  • Severe anaemia
  • Hypocomplementaemia
  • High proteinuria
  • Elevated dsDNA
  • Delay in starting treatment
  • Nephritic relapse
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Tubular Pathology

Golden rule : Water tends to follows sodium

na-reabsoprtion-in-the-tubule

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.

renal-epithelial-cell
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.

Comprehende?

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:

  1. Convulated tubule
  2. Descending loop of Henle
renal-pct
PCT cell

The PCT has 3 main functions:

  1. Bicarbonate excretion
    • via carbonic anhydrase (carbonic anhydrase inhibitors eg acetazolamide works here)
    • Na+ dependant mechanism
  2. Proteins reabsorption
    • Reabsorbed via apical membrane
    • endocytosed in cell
    • Glucose, amino acids and phosphate is reabsorbed here and if not, it is lost forever
  3. Drug transport
    • 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 

 Fanconi Syndrome

  • global breakdown of proximal tubule transport
  • loss into urine of
    • phosphate -> rickets/osteomalacia & bone pain
    • aa
    • LMW proteins
    • glucose -> glycosuric but normal plasma glucose concentration
    • bicarbonate -> metabolic acidosis (proximal RTA)
    • K+
  • Vitamin D is not hydroxylated
  • Pathogenesis?
    • apical membrane abnormality
    • energetic failure of ATP
    • back leak of solutes

fanconi-syndrom-causes

In children:

  • growth failure
  • episodes of hypovolaemia (polyuria due to loss of concentrating ability)
  • rickets/osteomalacia
  • constipation
  • muscle weakness (hypokalaemia)

Special Mention:

Dent’s Disease

Print

  • 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

Sufferers get:

  • Fanconi syndrome
  • Tubular proteinuria
  • Hypercalciuria, leading to
  • Nephrocalcinosis and kidney stones
  • CKD

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)
    • Autosomal dominant

In adults:

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

Causes

Primary (isolated)

  • AD
  • AR – SLC4A4 (Na-HCO3 transport)
    • Short stature
    • Ocular abnormalities

Secondary

  • Familial
    • Cystinosis
      • AR – mutation in CTNS gene
      • Lysosomal transporter disease
      • Cystine accumulates in cells of PT –> toxic
      • Presents in infancy
      • Extra renal manifestations:
        • Corneal deposits
        • Hypothyroidism
        • Growth retardation
        • Hypophosphataemic rickets
    • Tyrosinaemia
    • Wilson’s disease
    • Lowe Syndrome (XLR, oculocerebralrenal syndrome)
    • Type 1 glycogen storage disease (Von Gierke)
  • Monoclonal gammopathies
  • Drugs
    • Tenofovir
    • Ifosfamide
    • CA inhibitors (topiramate)
  • Heavy metals
    • Lead
    • Cadmium
    • Mercury
  • Sjogrens
  • PNH

Will lose LMW proteins

  • Albustix neg
  • uACR normal
  • uPCR ↑
  • Usu <2g/d

Can measure:

  • RBP:cr
  • NAG:Cr

Clinical phenotype in acquired adult disease predominantly bone (osteomalacia)

loosers fracture
Looser’s zone (pseudofracture)
  • 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)

OK.

Moving down the nephron, we next encounter the thick ascending limb (TAL).

renal-talh
TAL cell

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+)

Bartters Syndrome

Recessive mustations of:

  1. 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

renal-talh-x-trasnporter

 

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
  • Nocturnal eneuresis
  • Weakness
  • Polyuria
  • Low IQ

Histology : JGA hyperplasia

Rx : NSAIDs

Special Mention

FHHNC – Familial hypomagnesemia, hypercalciuria and nephrocalcinosis

  • AR
  • Mutations in CLDN 16 and CLDN19
  • Hypercalciuric & HypoMg –> Nephrocalcinosis –> Renal failure

Moving further down the nephron, we now arrive at the Distal convulated tubule which gets tubular glomerular feedback from the juxtaglomerular apparatus;

The DCT

renal-dc

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
Gitelman Type 3 Bartter
Age at diagnosis Variable Variable
Symptoms Tetany

Chondrocalcinosis

Variable
K+ Low Low
Mg2+ Low Normal
Urine Ca2+ Low High/Normal
Nephrocalcinosis No Sometimes
Gene NCCT CLCNKB

Differences of Gitelman vs Type 3 Bartter

 

EAST Syndrome (Epilepsy, Ataxia, Sensorineural deafness, salt wasting renal Tubulopathy)

  • Autosomal recessive
  • 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
  • hyperkalaemia
  • 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:

  1. Principal Cells

renal-cd-principal-cell

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:

Liddle Syndrome

  • Autosomal dominant
  • 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)
  • Testing :
    • 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

Special mention:

Apparent mineralocorticoid excess syndrome

  • Autosomal recessive
  • 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.
  • Low renin/angio/aldo levels
  • Liquorice intake blocks 11 beta hydroxysteroid dehydrogenase activity too –> hence mimics AME
  • Treatment : Block ENAC or MR —> spironolactone/amiloride
    • To differentiate Liddle’s and AME –> Liddle’s responds to just ENAC blockade but AME will respond to MR and ENAC blockade (spironolactone blocks MR)
  • Treatment 2 : dexamethasone/steroids to inhibit ACTH

 

Problems with AQ receptors;

Nephrogenic Diabetes Insipidus

  • Autosomal dominant or recessive, X linked or acquired
    • Aut dom/recessive:
      • mutation of AQP2 gene – defect in the AQ receptor
    • X-linked
      •  mutation of AVPR2 gene – mutation of the vasopressin receptor (90%)
    • Acquired causes:
      • Lithium
      • Antibiotics/antifungals/antivirals/antineoplastic meds/tolvaptan/foscarnet/amphotericin
      • Prolonged electrolyte deficiencies e.g. hypokalaemia, hypercalcaemia
      • Pregnancy
      • Protein malnutrition
      • Tubular disease
        • Sickle
        • OBstructive uropathy
        • Sjogren’s
        • Amyloid
  • affects AQ2  – complete or partial resistance to ADH –> no AQ2 to reabsorb water
  • Severe polyuria and polydipsia
  • Volume deplete hypernatraemia —> body wants to retain water –> high circulating ADH levels
  • Signs & symptoms :
    • Variable neurological deficit
      • Calcification on brain imaging
      • Hypernatraemia causes brain to shrink leading to intracerebral bleeds
    • Functional obstructions
      • constant/chronic large vols micturition –> patients hold urine in –> megacystis / hydroureter / hydronephrosis
  • Investigations :
    • Water deprivation test – patients who are affected cannot concentrate their urine
    • DDAVP – patients who respond to DDAVP has a cerebral DI
  • Treatment :
    • Low salt, low protein diet
    • Thiazides +/- amiloride
      • thiazides increases secretion of Na+ into the urine, and decreases osmolarity of the serum, helping break the excessive thirst –> drinking +++ –> polyuria cycle
      • Causes mild dehydration/vol depletion –> Enhances PT Na+/H20 reabsorption
    • NSAIDS
      • PGE2 antagonises ADH
      • PG depletion enhances concentration
      • Indomethacin > ibuprofen
    • Desmopressin
      • For non hereditary DI

 

2. Intercalated Cells (ICC) of which there are 2 types – α and β

renal-cd-icc

 

Involved in acid-base control

In the PT, HCO3 is reabsorbed.

In the ICC of the CD, HCO3 is generated to titrate acid and can also reabsorb HCO3 but to a lesser extent that the PT

Type A (α) ICC

  • Acidifies urine (secrete H+)
  • AE1 and HTPase is unregulated during metabolic acidosis

Type B (β) ICC

  • Pendrin can transport Cl, Iodide and HCO3
  • Pendrin is also present in the thyroid
  • Pendrin over expression will lead to increased NaCl absorbtion

Type 1 Distal RTA – mutations in AE1

  • unable to excrete the daily acid load, pH of urine >5.3
    • Ammonia secretion is then impaired
  • Proton accumulation –> normal anion gap metabolic acidosis + very low HCO3 levels
  • will be buffered by phosphate from bone; bone adjustment with liberation of Ca2+ too –> osteomalacia
  • Urine is very alkaline + buffering of acidosis + Ca2+ from bone –> hypercalciuria –> nephrocalcinosis and precipitation of urinary stones (which are Ca phosphate)
  • Urine will have a negative charge –> to balance it, K+ is secreted –> hypokalaemia and hyperkalaeuria

Causes

Primary (isolated)

  • AD – AE1 / Band-3 / SLC4A1 (CL-/HCO3- XC)
  • AR – Apical H+-ATPase (sensorineural deafness)

Secondary

  • Autoimmune disease
    • Sjogrens
    • Rheumatoids arthritis
    • SLE
  • Dysproteinaemias -myeloma
  • Drugs
    • Amphotericin
    • Toluene toxicity
    • Ifosfamide
    • Lithium
  • Hypercalciuric conditions (nephrocalcinosis)
    • Hyperparathyroidism
    • Idiopathic hypercalciuria
    • Sarcoid
  • Medullary sponge kidney

Clinical phenotype

  • Hypercalciuria (acidosis ‘leaches’ bones)
  • Hypocitraturia
  • Nephrocalcinosis
  • CaPO4 stones (alkaline urine)
  • Propensity to UTI
  • No Fanconi syndrome
  • HCO3 variable (may be <10)

Diagnosis

  • Urine pH always >5.5
  • Caveats:
    • Urea-splitting organism (exclude)
    • AKI; low urine Na; prolonged ↓K
  • Presence of nephrocalcinosis
  • UAG POSITIVE (nb measure NH4+)

If doubt:

  • Acidification test (NH4Cl)
  • Frusemide and fludro (F’n’F test)

Special mention:

  • Lithium is the same size and charge as Na+
  • Li enters ENAC and disturbs the cell causing nephrogenic DI
  • Amiloride can block ENAC and stop Lithium entering the cell

Type 4 Distal RTA

  • occurs in the principal cell
  • deficiency or resistance in the aldosterone receptor (MR) –> mimics aldosterone deficiency/hypoaldosteronism
  • No ENAC –> no Na+ reabsorbtion –> urine is very ++ –> K+ is reabsorbed via ROMK —> hyperkalaemia
  • Normal anion gap metabolic acidosis (hyperchloraemic met acidosis)

Causes

  • Hereditary
    • Primary pseudohypoaldosteronism type 1
      • Renin and aldo elevated
      • Sodium wasting
      • Phenotype often mild in AD disease
      • >Exacerbations (dehydration)
      • AD (MR mutations)
      • AR (ENAC mutations)
  • Type 2 (Gordon syndrome) – AD
  • Diabetes
  • Adrenal failure
  • HIV
  • Drugs (block ENAC)
    • NSAIDs
    • ACE / ARB
    • CNIs
    • Heparin
    • Amiloride
    • Spiro
    • Trimethoprim
  • Structural renal disease
    • Sickle
      • Urinary tract obstruction

The Anion Gap

Positive : Na+ K+

Negative : HCO3- Cl –

Increased AG —

  1. not measuring H+ in:
  • methanol
  • ethylene glycol
  • salicylates
  • lactate
  • ketones

or

2.  HCO3 is low

  • Barrter/Gitelman’s
  • Diuretics
  • Conn’s

 

Approaching Hypokalaemia

Hypokalaemia copyHypokalaemia&amp;metabolic alkalosis copy

Special Mention

If NAGMA, measure the Urinary Anion Gap

  • Na + K -Cl
  • Measurement of NH4+
  • In the presence of acidaemia, Kidney increases NH4 + excretion
  • NH4+ is a counterion to Cl-

UAG NEGATIVE – large quantities of NH4+ in urine, distal acidification is intact

  • All GI disturbances
  • Proximal RTA

UAG POSITIVE – H+ secretion is impaired, or there is delivery of HC03 to the DT, or other ions eg ketones/hippurate is excreted

  • Distal RTA
  • T4 RTA
  • Renal Failure

Not useful in polyuria / UNa < 20

table for tubular disorder copy

 

Tubulointerstitial Kidney Disease (MCKD, Nephronophtisis etc)

Type 1 NPHP, a type of ciliopathy

  • Autosomal recessive
  • 25% from NPHP 1 but 30 other genes
  • ESRF by 30 yrs
  • Cysts  typically located at the corticomedullary junction and usually ise from the DCT or  CD, but small.
  • Kidney size reduced, increased echotexture and loss of CM differentiation
  • Lots of genes, but 85% of mutations in NPHP1 consists of large deletions

Type 2 NPHP / Infantile NPHP

  • mutations in iversin gene (INVS / NPHP 2)
  • ESRF by 10 years old
  • cystic enlargement of kidneys bilaterally
  • Cortex cysts prominence, kidneys usually enlarged
  • Tubulointerstitial nephritis

Pathogenesis

  • Encodes proteins localised to the primary cilium.
  • Urinary concentration defect

Clinical manifestations

  • Renal cysts
  • Retinitis pigmentosa (10%)
  • Growth retardation
  • Anaemia
  • NPHP6 : Joubert syndrome (brain developmental defect: cerebellar vermis hypoplasia, ataxia, other motor incoordination)
  • NPHP 1 & 4 : Occulomotor type Cogan
  • NPHP 2 : situs inversus / congenital heart defects

Investigations:

  • Early morning urine void
    • Low Specific Gravity representing a concentration defect
    • No haematuria or proteinuria

 

Medullary Cystic Kidney Disease (MCKD)

  • Autosomal dominant
    • MCKD1
      • MUC1 gene
      • NO gout in childhoood
      • Mean ESKD 50 yrs old
    • MCKD 2
      • uromodulin /  UMOD , Tamms-Horsfall protein
      • FKHN – manifest by 30 yrs old
      • GCKD – manifest by 30 yrs old
      • Gout present +++
      • Mean ESKD < 40 years old
      • Renal cysts often late & small

Only other clinical manifestation : Gout, esp in MCKD 2

REN- related Kidney Disease

  • 20 – 30 years
  • Have gout early
  • Renin – angiotensin pathway disturbance
    • anaemia due to low EPO levels (occur as early as 12 months old)
      • Low EPO due to low angiotensin
      • EPO responsive
    • Low BP due to low renin
      • Can have hyperkalaemia
    • Hyperuricaemia
      • relative aldo deficiency due to ‘fluid-deplete’ state
      • leads to increased uric acid reabsoprtion in PCT

Renal Cysts & Diabetes (RCAD)

  • HFN1β
  • 50% mutation
  • Unilateral cysts
  • Diabetes
  • Gout

Cystic workup

 

Minimal Change Disease

Most common cause of nephrotic syndrome in children under the age of 10,  >90%

Light microscopy : Looks normal. No Ig deposition

EM : Diffuse effacement of foot processes.

Underlying pathophysiology:

  • ?a permeability factor
    • T cell dysfunction produce a glomerular permeability factor that circulates and directly affects the glom cap wall causing foot process fusion
    • Implication of T helper cells type 2 and IL-13
    • Association with T cells
      •  Hodgkin’s
      • Remission in Measles
      • Steroid / CYC efficacy
      • Absence of Ig and complement deposition
      • Association with atopy (TH2)
      • GVHD

Secondary causes:

  1. Drugs : NSAIDs, Lithium, Pamidronate, Sulfasalazine
  2. Malignancy : Haematological; Hodgkin’s (0.4%), NHL and leukemia. Solid tumour; Thymomas
  3. Infection : Strongyloides, syphillis, TB
  4. Allergy

causes of MCD copy

MCD in adults:

  • slower responders than children
    • 10-25% takes up to 3-4 months
    • 80% steroid responsive
    • 50% will relapse
    • 1/3 will be come frequent relapsers or steroid dependant

Treatment:

  • 1st line : Prednisolone @ 1mg/kg/d (max 80mg) or 2mg/kg/alt day (max 120mg)
    • Min 4 weeks, max 16 weeks
    • Do not taper until remission achieved
    • Taper over 6 months
      • steroid Contraindications – treat as frequently relapsing MCD
      • If relapse – use same initial dose and duration of steroids

Frequent relapsing / Steroid dependant

Definition
Steroid resistant Failed to achieve remission with 16 wks of steroids
Steroid dependant 2 or more relapses during steroid taper OR

within 2 wks of discontinuing steroid therapy

Frequently relapsing 2 or more relapses within 6 months OR

4 or more relapses within 1 yr of achieving remission

The table is adapted from the FSGS guidelines : KDIGO suggests repeating steroid course with a relapse for 6 months

KDIGO

1st line: Cyclophosphamide orally as a single course @ 2-2.5mg/kg for 8 weeks. 63% remission

2nd line (relapsed despite cyclophosphamide or childbearing age):

  • Cyclosporin @ 3-5mg/kg/d in divdied doses : Observational data 70-90% remit; 1 year treatment
  • Tacrolimus @ 0.05-0.1mg/kg/d in 2 divided doses: Observational data, similar remission rates to CyA.
  • Following 3 months of stable remission, tapered to reach the min dosage that maintains remission for 1-2 year

3rd line: If intolerant to the above:

  • MMF 500-1000mg/day for 2 years

MCD variants

  1. IgM nephropathy
    • Mesangial proliferation
    • IgM/complement deposition
    • EDDs on EM
    • less steroid responsive than MCD
  2. C1q nephropathy
    • Mminimal change, FSGS or mesangial proliferation
    • C1w- predominant with mesangial EDDs
    • No  clinical or serological evidence of lupus

DD MCD 1 copy

 

IgA Nephropathy

  • Commonest glomerular disease in Western world
  • Dominant / co-dominant mesangial IgA
  • Berger and Hinglais 1968
  • White and Asian >> Black
  • M:F 2:1 (except Pacific rim)
  • Often familial (AD trait)
  • Wide spectrum of disease
  • Generally indolent but not benign
  • ESRD in 30-50% after >25 years follow-up

Lesions

  • Normal
  • IF shows mesangial IgA deposition, IgG and C3
  • MCGN pattern
  • Capillaritis /HSP : segmental necrosis with crescent
  • EM : minimal change lesion appearances : ie widespread effacement of foot processes
MEST
Oxford MEST score

Pathogenesis

IgA

There is mesangial cell affinity to deposit IC complexes
The kidney tend to  mount a deleterious response with fibrosis and glomerulosclerosis instead of resolution of injury

Primary Causes:

  • IgAN – Berger’s

Secondary Causes:

  • Coeliac disease, raised circulating IgA
  • Cirrhosis, decreased Kupffer cells ability to remove IgA
  • HIV
  • Crohn’s
  • Lymphoma
  • Leprosy
  • SCLC
  • Sero-negative spondyloarthropathies

 

Bad prognostic factors

  • Proteinuria >500mg/d
  • Macroscopic haematuria >10days
  • Crescentic IgA >50% (75% ESRD in 10 years)

Treatment:

  • BP control with ACEi/ARB with goals:
    • Proteinuria < 1g/day aim BP <130/80
    • Proteinuria > 1g/day aim BP <125/75
      • After 3-6 months
        • GFR decline < 30% in 6 months, proteinuria <1g/day
          • Continue supportive therapy
        • GFR> 50 (+/- slowly declining GFR), proteinuria >1g/day
          • Steroids for 6 months
          • Fish oil
        • GFR < 30 + crescents
          • Treat as Crescentic IgAN
  • No consensus for IS but;
    • Crescentic IgAN
      • Treat like ANCA vasculitis
      • steroids + cyclophosphamide. Maintanance Aza
    • Minimal change appearances with IgAN (Nephrotic syndrome)
      • Treat like MCD
      • Steroids
    • HSP + proteinuria > 0.5-1g/day
      • As per IgA guidelines

 

Cystic Kidney Disease

ADPKD

Mutations

PKD 1   – short arm of chrom 16, codes for polycystin-1       85%
PKD 2   – long arm of chrom 4, codes for polycystin-2           15%
GANAB       1%

Normal polycystin increases intracellular calcium, initiates a signaling cascade leading to vesicle fusion and a change in gene transcription.

PKD 1 & 2 — same phenotype but;

PKD 2 :

  • milder disease
  • less cysts
  • later onset of HTN
  • less ESKD

GANAB :

  • milder disease
  • hepatic cysts predominate

Diagnosis:

ADPKD criteria

Prediction of deterioration:
Total kidney volume + Cyst growth

TKV can be calculated based on height

= <600ml/m (TKV/height) —> low risk of progressive loss of kidney function in 8 years 

 

ProPKD score for age at onset of ESKD:

PRO PKD score

Low risk (0-3 points) : 70.6 years old

Intermediate risk (4-6 points) : 56.9 years old

High risk (7-9 points) : 49 years old

 

Extrarenal manifestations:

  1. Liver cysts
    • 80% of patients have it by the age of 30
    • equal sex representation
      • but higher burden in women
        • previous birth control pills
        • HRT
        • pregnancy
    • Raised ALP only usually
    • Complications from liver compressing on surrounding organs
    • Rx: Octreotide –> decreases liver volume
  2. CVS
    • Intracranial aneurysms
      • 9-12% prevalence
      • 22-27% in those with + FH of haemmorhagic stroke or ICA
      • Often at anterior cerebral circulation
      • Average age of rupture 40 years old
      • Screening: indicated in those with positive FH or previous hx of intracranial haemorrhage, high risk occupations or before major surgery. Screen every 5 years

      • If larger than 10mm –> elective surgical intervention recommended
    • LVH
      • in 48% of HTN patients
    • MV prolapse
      • 26%
    • Coronary aneurysms
    • MVR
    • Aortic regurge
      • 11%
  3. Most common stone type in ADPKD : Uric acid (50%) followed by calcium oxalate

Management:

  • BP control as per CKD guidelines < 140/90.
    • ACEi/ARB first line
    • Salt restriction
  • Tolvaptan
    • Indications as per NICE to start:
      • CKD stage 2-3
      • Loss of GFR rapidly in 6 months (5-10 points)

AVOID :

  • Diuretics  in absence of ACE-I (primes RAAS, ↑VP)
  • CCBs as 1st line therapy (animal data to suggest CCBs accelerate cyst growth)

 

ARPKD

Mutations:

PKHD1 gene  – short arm of chromosome 6, codes for fibrocystin/polyductin

Clinical manifestations:

  1. Fibrocystic kidney, cysts often small, <3mm
    • fusiform dilatation of renal collecting tubules
    • 90% affected
    • enlarged kidneys with poor CM differentiation can be detected in utero
  2. Liver involvement – ALL develop liver disease
    • Caroli syndrome : dilation of intrahepatic and extrahepatic bile ducts
      • recurrent ascending cholangitis
    • Congenital hepatic fibrosis
      • biliary dysgenesis
      • periportal fibrosis
        • portal hypertension
        • splenomegaly
        • oesophageal varices
  3. Affected fetuses:
    • oligohydramnios
    • Potter phenotype with pulmonary hypoplasia , deformed facies, spine and limbs
    • 30% perinatal mortality due to hypoxia from pulmonary hypoplasia
  4. Hypertension in 80% of children
    • Rx with ACEi/ARB
  5. Hyponatraemia in 26% of neonates

 

Tuberous sclerosis complex

Autosomal Dominant

TSC1 – chromosome 9 – hamartin

TSC 2 – chromosome 16; 50 base pairs away from PKD1 – tuberin

TSC1/2 complex inhibits mTOR

Deletions TSC2 and PKD1 : severe early onset of cutaneous and neurological manifestations of TSCS

Presentation:

  • Seizures
  • Developmental delay
  • Skin lesions – ash leaf/shagreen/angiofbromas
  • Interstital lung disease
  • Tumours (hamartomas inc AML)
  • Renal
    • AMLs (85%)
    • Multiple, bilateral
    • Nb pregnancy risk ↑
    • Cysts (40% – nb PKDTS, GCKD)
    • RCC / epithelioid AMLs (3%)
    • commonest cause of death

Diagnosis:

  • Clinical criteria
  • Genetic testing
  • 1-3yr renal imaging (MRI)
  • USS poor for fatty lesions

Treatment:

  • Embolise bleeding AML
  • Growing AML >3cm
  • mTORi (NB avoid ACEi) – everolimus reduce volume of AML
  • Embolisation (+steroids —> to reduce post embolisation syndrome)
  • Kidney-sparing resection

 

von Hippel Lindau

Autosomal dominant

Tumour suppressor syndrome

VHL gene -> pVHL

Two hit disease: need a hit in ‘good’ allele to get cancer.
Type 1 – large deletions or truncations of VHL;
Type 2 – missense mutations, partial activity of VHL

Type 1: Absence of phaeo
Type 2A: Phaeo + no RCC + spinal/cerebellar haemangio
Type 2B: Phaeo + RCC + spinal/cerebellar haemangio
Type 2C: Phaeo ONLY

Mechanism of tumours:
Absence of functioning pVHL —> HIF upregulates —-> upregulates hypoxia-inducible genes : VEGF, EPO, TGFalpha, Platelet-derived growth factor —> tumour formation

Absence of functioning pVHL —-> unstable microtubules —-> diminished integrity of primary cilia

Presentation:

  • CNS haemangioblastomas
  • Retinal HABs
  • Phaeochromocytomas
  • Islet cell tumours (+ cysts)
  • Endolymphatic sac tumours – pathognomonic when bilateral
    • from membranous labyrinth of the inner ear
    • tinnitus, vertigo, hearing loss
  • RCC (+ cysts) – leading cause of death
    • RCCs multiple and bilateral
    • Often low grade
      • If RCC >3cm , high risk of mets
    • Type 1 or type 2b
    • Cysts in 60% (bilateral)
    • CKD very uncommon
    • Kidneys normal size

Diagnosis:

Sporadic
 – 2+ retinal or CNS HABs
or 1 HAB + visceral tumour

Familial
-Single HAB or RCC/PCT

Genetic studies

-Genotype – phenotype

-Pre-symptomatic

-All PCT?

Type 2: USS / MRI from age 2

Annual abdominal MRI 16+

MIBG useful

Treatment:

  • Surgical
  • Nephron-sparing
  • VEGF inhibitors (adjunct) ;  sunatinib/sofaranib
  • Anti PD-1