Renal Regulation of Calcium and Phosphate
In serum, how much calcium is biologically active?
The ionised free Ca is 45%.
P.g. 10, Renal regulation of Ca & PO₄
Provide examples of active myeloma therapies, minimum 3!
Alkylating agents (melphalan)
Cyclophosphamide and other conventional chemotherapeutic agents
Steroids (alone or combination)
IMiDs: Thalidomide, Lenalidomide, Pomalidomide
Proteosome Inhibitors: Bortezomib, Carfilzomib
Monoclonals: elotuzumab, datatumumab
BCMA and or GPRC5D Targeted Therapy
CAR-T Cells
Which two factors from myeloma cells drive osteoclast activation and bone disease?
MIP-1α (and NF-kB) and RANKL.
Osteoclast activating factors!
Pg. 44/63 smyth - myeloma.
Zoe, a mid-20's wellness influencer and enthusiast takes high-dose vitamin D drops. She’s hypercalcaemic; 25-OH vitamin D is 420 nmol/L. What is the most likely cause of her hypercalcaemia?
Vitamin D intoxication from excessive dosing.
• Becoming increasingly common
• Usually result from taking very excessive doses
for a long period of time
• 25-OHD levels usually >375 nmol/L (RR 50-200)
PTH Independent Hypercalcemia
P.g. Bruno lec
Q (Case): Robbie, A 70-year-old male with 3 months of back pain, fatigue and recurrent sinusitis has Hb 98 g/L, Ca 2.62 mmol/L and normal ALP. You suspect a plasma-cell disorder. Which two initial laboratory tests best screen for a paraprotein?
Serum protein electrophoresis with immunofixation and a serum free light-chain assay.
What enzyme in the kidneys makes calcitriol, and what is it's main regulator?
α-hydroxylase (CYP27B1); PTH is the main regulator.
Vit D --Liver/CYP2R1--> 25OHD (Calcifediol) --Kidney/CYP27B1(1a-hydroxylase)) --> 1,25(OH)2D (Calcitriol).
What is the preferred imaging in a myeloma diagnostic work up?
Skeletal survey (not a bone scan), MRI (whole body or thoracolumbar), low dose CT skeletal survey (used frequently).
PET Scans are used in some selective cases.
What is the classic radiographic appearance of myeloma bone lesions, and what does it put patients at risk of?
Punched-out” lytic lesions with risk of pathological fractures.
Smyth: 46/63
PTH-Independent Hypercalciemia has 3 mechanisms, what are they? Please provide an example pathology for each mechanism
3 Mechanisms:
Humoral (Most common, 80%): tumbrel production of PTHrP (SCC of lung, head and neck), renal, prostate, breast, ovarian etc).
Osteolytic bone metastasis or local production of cytokines (20%): Multiple Myeloma, breast cancer
Increased 1,25-D due to extra renal 1a-hydroxylase activity (Lymphomas).
Joanna, A 74-year-old with metastatic breast cancer presents with confusion and dehydration. Corrected Ca is 3.7 mmol/L. What is the first immediate treatment step, and what may be added next to enhance calciuresis?
Aggressive IV isotonic saline for volume expansion first, then loop diuretic (furosemide) only after rehydration; give IV bisphosphonate (e.g., zoledronic acid).
Bruno slide 27
Please explain how ionised calcium concentration can be affected by serum pH?
Acidosis: decreased pH leads to dissociation of Ca from albumin, thus increases iCa (ionised calcium)
Alkalosis: Increased pH favours binding of Ca to albumin, thus a decrease in iCa
p.g. 11, Bruno
What is the Criteria for Diagnosis of Multiple Myeloma?
Monoclonal plasma cells present in the bone marrow ≥10%, and/or presence of a documented plasmacytoma
Plus
Presence of M component in serum and/or urine*
Plus
Calcium elevation (serum calcium >2.85 mmol/L)
Renal insufficiency (serum creatinine >170 umol/L)
Anemia (hemoglobin <100 g/L or 20 g/L <normal)
Bone disease (lytic lesions or osteopenia)
Marrow plasma cells of > 60 %
Free light chain ration > 100
Multiple lytic lesions on MRI
*Monoclonal M spike on electrophoresis IgG>35g/L, IgA>20g/L, light chain >10 g/L in 24-hr urine sample
McQuillin pg. 16/34
What is the common peripheral blood film finding that reflects paraproteinaemia in multiple myeloma?
No bonus points, but bonus respect, explain it's cause.
Rouleaux formation.
An aggregation of erythrocytes with the appearance of a stack of coins on peripheral blood smear. This aggregation is caused by increased concentrations of plasma proteins (e.g., fibrinogen, immunoglobulins). Associated with multiple myeloma but is not specific to this condition.
Case Based Type Q:
Jonah, a 66-year-old newly diagnosed myeloma patient has β₂-microglobulin 6.0 mg/L and albumin 32 g/L (3.2 g/dL). What ISS stage is this?
ISS Stage III (β₂-microglobulin ≥5.5 mg/dL).
ISS uses β₂-microglobulin and albumin:
Stage III when B2M ≥5.5 mg/dL;
Stage I is B2M <3.5 mg/dL
Stage II = <3.5mg/dL
Path of Myeloma (Smyth) -> pg 35.
Revision Q!!
Ben, a 14 year old boy from Switzerland, presents to ED with weeks of 'shin' pain and a low grade fever. Upon imaging, you notice an onion skin appearance of the periosteum. What is your differential?
Ewing Sarcoma.
Presents in 10-20 year old white males (more than females).
On the parathyroid chief cell, what is the receptor that senses Ca2+, and what drug classes act on it?
Receptor: Calcium-sensing receptor (CaSR).
Drugs
- Calcimimetic drugs (cinacalcet) are CaSR activators, used to decrease PTH in some situations
- Calcilytic drugs are CaSR antagonists (limited clinical use)
What are the two genomic instabilities which may lead to myeloma progression?
1. Translocations at 14q32 (50%)
2. Deletion of chromosome 13 (50%)
A patient with suspected Multiple Myeloma, what signs, symptoms and laboratory evidence would be supportive of this differential?
(based on JAMA: Multiple Myeloma Review)
Fatigue,
Bone Pain
Anemia
Kidney Failure
Hypercalcemia
Increased total serum protein levels
Lytic Lesions on bone imaging studies
Compression or pathological fractures on radiography
What are the clinical features of Waldenstrom's Macroglobulinaemia? Name at least 4 (not including fatigue).
– Fatigue and weight loss
– Hyperviscosity syndrome (may cause chronic oral or nasal
bleeding, visual upset, headache, vertigo, hearing loss,
ataxia, somnolence, and coma)
– Retinal haemorrhages
– Venous congestion (sausage formation) in retinal veins
– Recurrent infection
– Lymphadenopathy
– Hepatosplenomegaly
Q (Case): Emanuel, a 45-year-old ranch worker with CKD stage 3 has normal Ca/PO₄, low calcitriol, and rising PTH. Which hormone rises early in CKD-MBD and drives the low calcitriol, and what renal effect does it have?
FGF23 rises early; it suppresses renal 1α-hydroxylase (↓1,25-D) and reduces renal phosphate reabsorption.
Rationale: CKD-MBD paradigm: declining nephron number → ↑FGF23 (with relative klotho deficiency) → ↓1,25-D, later ↑PTH; FGF23 decreases phosphate reabsorption
See slide 30 of Bruno's lecture.
Describe the Pathophysiology (current paradigm) for CKD-MBD, as per Bruno's slides!
For each 1/5 points correct, you get 100 points. (Sorry in advance). Group decides how many you got right haha.
Pathophysiology (current paradigm)
Progressive decrease in number of functional nephrons, accompanied by reduced expression of klotho in the kidney
Phosphate excretion is compromised
Increase in FGF23 levels
To maintain phosphate balance with declining nephron number, and/or
To compensate for reduction in klotho expression (relative insensitivity)
Decrease in 1,25-D
Due to rise in FGF23 (inhibits 1,25-D)
Due to declining nephron number
Increase in PTH
To maintain phosphate balance, and/or
To maintain calcium homeostasis given the decline in 1,25-D
When all compensating mechanisms fail, PO₄ rises
Nice work for having a crack at a harder one! Free points!
Free points!!!!!!!
What are conditions associated with M Proteins? (At least 5).
• Multiple myeloma (IgG, IgA, free light chains, IgD, IgE)
• Plasma cell leukaemia
• Solitary plasmacytoma of bone
• Extramedullary plasmacytoma
• Waldenström's macroglobulinaemia (IgM)
• Chronic lymphocytic leukaemia
• Malignant lymphoma
• Primary amyloidosis
• Heavy chain disease
Smyth P.g. 55/63
As per last week, explain the total vs ionised Ca; and, what happens with respect to iCal / Corrected Ca, based on either Hyper/Hypo albuminaemia.
(if Hetvi picked this and answers correctly, bonus 2 points).
Group consensus; we agree? If so, 500 points. if not. better luck next time.
Refer to slides 9/10 in Bruno's lecture.
Q (Case): Annabelle, a 62-year-old has 12% clonal marrow plasma cells, involved/uninvolved FLC ratio 110 with involved FLC 120 mg/L, normal Ca, Hb and Cr, and two focal lesions on MRI. Does he meet diagnostic criteria for myeloma requiring therapy, and on what basis?
Yes. He meets IMWG myeloma-defining events: FLC ratio ≥100 (with involved FLC ≥100 mg/L) and >1 focal lesion on MRI; in the presence of ≥10% clonal marrow plasma cells, this establishes myeloma (even without CRAB).
Rationale: Diagnosis requires ≥10% clonal marrow plasma cells plus MDEs: CRAB or any of the three biomarkers (≥60% plasma cells, FLC ratio ≥100, or >1 MRI focal lesion)