What is a crescent?
Crescent: 2 or more layers of proliferating cells in the Bowman’s capsule –> histological marker of severe glomerular injury
Tamm Horsfall Protein
Tamm Horsfall Protein = Uromodulin
Generated in the loop of henle
Also component of hyaline casts
Casts = Tamm + Extras (eg: WCC, RCC)
Due to Tamm there is normal range proteinuria
Urine PCR < 30mg/mmol
UACR < 3.5mg/mmol
Glomerular VS Tubular Proteinuria
Glomerular Proteinuria = Albuminuria
In glomerular disease: ACR = PCR x 0.84 (approx)
Tubular Proteinuria = PCR > ACR
eg: myeloma, Fanconi syndrome, tubular injury
Function of aldosterone
- Act on the proximal tubule to increase reabsorption of salt and water
- Act on the distal tubule/collecting duct to increase excretion of potassium
- Also cause metabolic alkalosis as it gets rid of H+ ions from body (side hustle)
Metabolic alkalosis, hypokalaemia, (hypernatremia)
Function of PTH
- Acts on the bone to increase serum calcium and phosphate
- Acts on kidney to increase calcium reabsorption and increased urinary phosphate excretion
- Stimulates a1 hydroxylase to activate vit D
Why does low Mg cause low Ca?
Low magnesium suppresses PTH –> hypoparathyroidism and PTH is required to reabsorb Ca via gut/kidney and acquire from bone
Therefore, you must normalise magnesium before you can replenish the calcium
Why does low Mg cause low K?
Magnesium blocks ROMK
Magnesium deficiency –> lose more K in urine
Causes of low Mg
- Renal Wasting
○ eg: thiazide diuretics, loop diuretics (however often compensatory mechanisms are available so this rarely occurs
○ Calcineurin inhibitors - reduce the expression of TRPM6 in the renal tubule which causes renal wasting of Mg
○ EGFR blockers, eg: cetuximab - reduce expression of TRPM6
○ Distal tubule toxins, eg: cisplastin, carboplatin, amphotericin - Impaired GI absorption
○ Nutritional
○ Diarrhoea
○ PPI - alter intestinal pH which can affect the TRPM6/7 impairing Mg absorption
§ However, magnesium uptake is not only via the TRPM6/7 where it can be uptake via the paracellular route (tight junctions) so tend to occur in those who have a genetic predisposition
Gitelman Syndrome
- Autosomal recessive disorder
- Impaired sodium chloride cotransporter (NCC) in the distal convoluted tubule (where thiazide diuretics act on) –> lose salt and water –> activate RAS –> high aldosterone causing metabolic alkalosis and hypokalaemia
- Salt and water wasting that occurs in the distal nephron causes the proximal tubule to compensate and increase salt/water reabsorption in proximal tubule which also drags calcium along with it and thus there is increased calcium uptake in the proximal tubule –> hypocalciuria (good to prevent renal stones)
- ?TRPM6 low –> renal Mg wasting in mouse models
Fanconi Syndrome
- Defect of proximal tubule
- Blood: low phosphate, low uric acid
- Urine: glycosuria, aminoaciduria, phosphaturia, uricaiduria
Proximal (T2) RTA Pattern
Normal anion gap metabolic acidosis (low bicarb)
High chloride
Hypokalaemia
Urine pH < 5.5 when acidotic
Where in the nephron does vitamin D get activated?
proximal tubule
Pathophysiology of MM and AKI
Light chains can damage tubular cells causing proximal tubule dysfunction (and fanconi syndrome)
Monoclonal vs Polyclonal Antibodies
Polyclonal antibodies are part of the normal immune system where more than one antibody is produced to more than one antigen
Monoclonal antibodies are abnormal and the B cell or plasma cell clones are producing the SAME antibody again and again
Is the monoclonal antibody B cell or plasma cell situation?
If B cell
- IgM can be made directly by B cells without plasma cells
- Monoclonal gammopathies with IgM usually B- cell clone
- Therefore tx = kill the B cells
If Plasma cell:
- IgG, IgA require class switching and plasma cells
- Monoclonal gammopathies of IgG, IgA = usually plasma cell clone
- Therefore tx = kill the plasma cells
Where is tamm horsfall protein made?
Healthy urine protein - Thick ascending LOH
Pathophysiology of cast nephropathy
Light chains move to the distal nephron –> come in contact with Tamm causing casts to form –> severe AKI due to obstruction and inflammation of tubules –> casts are promoted by luminal sodium, chloride, calcium, acidic pH
Why does frusemide promote light chain cast formation?
Frusemide blocks NaKCl co-transporter –> more Na and Cl in urine which leads to precipitation of LC casts
Biopsy findings for amyloid
- Congo red stain positive on light microscopy
- Apple green birefringence polarised light microscopy
How does hypercalcaemia cause AKI
- Dehydration, where inhibition of aquaporins in collecting duct cause polyuria –> volume depletion –> cause a reversible diabetes insipidus
(If there is hypercalcaemia, aquaporins are inhibited where you don’t want to reabsorb water and you want to have as much water as possible in the urine to prevent the formation of stones ) - Vasoconstriction –> reduced GFR
- Loop of henle senses high calcium –> inhibits NaKCl cotransporter –> lose more Ca in urine –> but also polyuria
- Causes direct tubular toxicity –> calcium deposition –> tubulointerstitial inflammation
TLS
- Elecytrolyte derangements
- Clinical features
- Risk factors
Electrolytes:
High K
High uric acid –> can cause uric acid crystals leading to AKI
High phosphate
Low Ca (as phosphate binds to Ca)
AKI due to microscopic bone formation (uric acid and calcium phosphate crystals)
Clinical features are secondary to biochemical abnormalities
- AKI
- Seizures
- Tetany
- Arrhythmia
Risk Factors:
- High tumour burden
- High proliferative rate
- Chemosensitivity
- Haem malignant > solid organ
- Renal impairment is a risk factor for TLS
Treatment of TLS
- IV fluids
- Phosphate binders
- Allopurinol - inhibit xanthine oxidase to prevent the production of uric acid
- Rasburicase- recombinant form of urate oxidase, an enzyme that converts uric acid to allantoin water soluble product more easily excreted by the kidney in the urine
- Urine alkalinisation
What is a cryoglobulin?
Protein/immunoglobulin that precipitates at < 37 degrees (in vitro)
Symptoms of cryoglobulinaemia
Cryo-my eyes out…..
(A) Immune complex –> inflammation
- 80% have Meltzer’s triad: Purpura, Arthralgia, Weakness (purpura is the most suggestive of vasculitis)
- Peripheral neuropathy - polyneuropathy more common than mononeuritis multiplex
- GN - MPGN most common
- Fever
Symptoms can flare and remit
(B) Vascular Occlusion –> Ischaemia
- Digital necrosis/ulcers
(C) Hyperviscosity
- Neuro symptoms
- Oronasal bleeding
- Sometimes heart failure
