Stones + Ca, Phos, Mag from KSAP

Question 1

What is Dent disease

Answer 1

X linked recessive condition.

Proximal tubular disorder. Nephrocalcinosis occurs in 75% characterised by low molecular weight proteinuria, nephrolithiasis, CKD.

The first cases of Dent disease had hypophosphataemia + rickets,

Question 2

Is there a benefit to O formigenes?

Answer 2

No.
Oxalobacter formigenes is an anaerobic colonic bacterium that is capable of oxalate degradation and promotes intestinal oxalate excretion. Unfortunately, a randomized trial failed to demonstrate a significant change in urinary oxalate in patients with primary hyperoxaluria who received O. formigenes compared with those given placebo

Question 3

19 yo presents with calcium phosphate monohydrate stones, hyperoxaluria, CKD and nephrocalcinosis. Whats the diagnosis?

Answer 3

Primary hyperoxaluria.

Primary hyperoxaluria is a rare autosomal recessive disorder, which results in overproduction of oxalate. Type 1 is the most common of the three types of primary hyperoxaluria, accounting for approximately 80% of the cases. This disorder is due to deficiency of the hepatic peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT). There have been >150 mutations identified of the AGXT gene that encodes AGT. Pyridoxine is a cofactor for AGT and has been shown to significantly decrease urinary oxalate excretion in individuals with 2 of the most common primary hyperoxaluria type 1 mutations.
Liver transplant is considered curative.

Question 4

Symptoms of hypermagnesaemia

Answer 4

Neuromuscular effects of acute hypermagnesemia include diminished deep tendon reflexes, quadriplegia, somnolence, and respiratory arrest. Cardiovascular effects include hypotension, bradycardia, complete heart block, and cardiac arrest.

Give IV calcium gluconate.

Magnesium is an effective calcium channel blocker, resulting in vasodilation, flushing, and hypotension when the concentration is elevated. Intracellular magnesium also blocks several cardiac potassium channels, which causes cardiac conduction defects. Bradycardia is seen when magnesium levels exceed 4–5 mEq/L. Additional EKG changes are apparent at concentrations of 5–10 mEq/L. These changes include prolongation of PR and QT intervals and increased QRS duration. Hypermagnesemia can also decrease the release of acetylcholine, blocking transmission at the neuromuscular junction and causing hypotonia and hyporeflexia.

Question 5

Symptoms of hypocalcaemia

Answer 5

n abrupt decrease in serum ionized calcium level increases neuromuscular excitability, causing tetany, paresthesias, laryngospasm, and focal and generalized seizures. Cardiovascular complications include T-wave alternans, prolonged QT interval, and reversible congestive heart failure. Psychiatric complications include depression, confusion, and psychosis. Papilledema and optic neuritis have also been reported.

Troussea - Carpal Spasm with BP cuff

Chvostek sign - is a facial muscle spasm

Question 6

How do you approach hypokalaemia?

Answer 6

Calculate urine K: Urine Cr ratio. (i.e. urinary K divided by urinary Cr ( x100) ) If <15 it suggests appropriate renal K conservation in the presence of hypokalaemia.

• Can be caused by hypomagnesaemia (cetuximab )

OR they might give you the urinary K
The expected renal response to hypokalaemia is potassium conservation so a daily potassium excretion of less than < 20

Question 7

A trial examining the influence of type 2 diabetes, BMI, age, and sex on uric acid stone formation found that which factor ________ was the strongest risk factor independently associated with uric acid kidney stone disease.

Answer 7

However, a trial examining the influence of type 2 diabetes, BMI, age, and sex on uric acid stone formation found that type 2 diabetes was the strongest risk factor independently associated with uric acid kidney stone disease.

Question 8

39 year old female is evaluated for hypercalcaemia - asymptomatic. PTH is 65 - Their upper limit of normal.
How do you evaluate her hypercalcaemia?
- Sestamibi
- PTHrp
- 24 hour urine calcium + creatinine clearance
- DEXA
- CASR mutation analysis

Answer 8

Ans: 24 hour urine calcium + creatinine clearance.

The combination of asymptomatic hypercalcaemia and PTH level that is normal but not suppressed can be seen in both primary hyperparathyroidism and familal hypocalciuric hypercalcaemia.

Urine calcium excretion >200mg/d is consistent with PHPTH, whereas normal or low urinary calcium excretion favours FHH.

Or can use calcium- to creatinine clearance ratio:

Ratio of >0.02 is suggestive of PTPTH, ratios from 0.01- 0.02 are indeterminate and those less than <0.01 are suggestive of FHH.

Question 9

Elevated Urinary N-telopeptide

Answer 9

Urinary N-telopeptide is a sensitive and specific marker of bone resorption and has been demonstrated to increase significantly in patients with immobilization.

Question 10

Whats the mechanism of hypokalaemia in PPI use

Answer 10

The proposed mechanism of urinary potassium wasting in hypomagnesemia is insufficient intracellular magnesium causing persistently open potassium channels (renal outer medullary potassium channel, or ROMK) in the distal tubule and cortical collecting duct.

Question 11

Whats the differential diagnosis for renal potassium wasting?

Answer 11

• Gitelman.
• Vomiting
• Diuretic use.
  PPI is the only one that will also have a low magnesium,

Question 12

Electrolyte abnormalities with surreptitious vomiting

Answer 12

metabolic alkalosis
Renal potassium wasting
normal serum mag

Question 13

42 year old woman- 
On calcium in the past 
Dad and cousin also have a problem with calcium 
High 24 hour urinary calcium 
High serum phosphate low serum calcium 
PTH low normal
Has CKD
nephrocalcinosis in her kidneys

Answer 13

autosomal dominant hypercalciuric hypocalcemia (ADHH), a condition of overactivity of the calcium-sensing receptor (CaSR).

ADHH is a genetic disorder characterized by an activating mutation of the CASR gene. The result of this mutation is that the relationship between calcium and PTH is altered such that calcium concentrations that normally trigger PTH release no longer do so. PTH levels are often low or low-normal. Patients with ADHH have low calcium levels due to insufficient PTH release. In the kidney, insufficient PTH leads to a decrease in active calcium reabsorption and hypercalciuria. Activation of the CaSR in the kidneys also exerts a loop diuretic-like effect in the thick ascending loop of Henle (TAL), reducing sodium chloride reabsorption and decreasing lumen positivity, leading to a decrease in renal calcium reabsorption. Medullary nephrocalcinosis can be precipitated by attempts to normalize the serum calcium via administration of calcium and vitamin D.

Question 14

Inappropriate renal magnesium excretion in the setting of hypomagnesemia, in addition to hypokalemia, metabolic alkalosis, and undetectably low urine calcium =

Answer 14

Gitelman Syndrome.
Fractional excretion of mag is > 2%
Give amiloride.

Question 15

How do you calculate fractional excretion of magnesium? And what figure is consistent with renal magnesium wasting?

Answer 15

FEMg = (urine Mg ÷ urine creatinine)/([serum Mg × 0.7] ÷ serum creatinine) × 100%

The serum Mg is multiplied by 0.7 to discount Mg bound to albumin. In the presence of hypomagnesemia, FEMg >2% indicates renal Mg wasting.

Question 16

Patient with nephrotic syndrome complaining of bony pain + weakness.
Low Ca, Low Phos.Low Vit D. PTH 115

Answer 16

Patients with nephrotic syndrome can develop significant vitamin D deficiency because of urinary losses of vitamin D bound to vitamin D-binding protein. Prolonged, severe vitamin D deficiency with serum values <10 ng/mL results in secondary hyperparathyroidism and osteomalacia. In this setting, patients may complain of bone pain and tenderness, and muscle weakness. The spine, pelvis, and lower extremities are most commonly involved.

Hypocalcaemia itself does not cause bony pain.

Question 17

Which of the following is a risk factor for calciphylaxis?

• Gadolinium
• Cinacalcet
• Male sex
• Ciprofloxacin
• Calcitriol

Answer 17

Ans: Calcitriol

• Associated factors with development of the lesions include:
• Obesity
• Female sex
• Long dialysis vintage
• DM
• Insulin injection
• Hypercoagulable states
• Autoimmune disease
• Liver disease
• Malignancy

Mineral metabolism disorders such as high levels of serum calcium, phosphate + PTH have been implicated as well as an elevated calcium phosphate product, low serum albumin + elevated ALK phos level.,

Meds associated with the development of calciphylaxis include: steroids, warfarin, calcitriol, calcium containing supplements and phosphate binders and IV iron.

Question 18

How does zolendronic acid work for hypercalcaemia

Answer 18

Zoledronic acid is a bisphosphonate that interferes with osteoclast-mediated bone resorption and inhibits calcium release

Question 19

43 yo with ESRD presents to the ED with bilateral lower extremity pain that began after dialysis 2 days ago. No hx of trauma, seizure, exercise or cocaine use. Phos is 2.5 (lower limit of normal for them is 3)

Whats the cause of his elevated CK?

Answer 19

Ans: Hypophosphataemia

They like asking this. Be care of metabolic acidosis now resolved then patient seizes…

Patients who are chronic alcohol abusers are prone to severe hypophosphatemia. Such patients have decreased intestinal phosphate absorption due to poor intake of both phosphate and vitamin D. Decreased absorption may be further exacerbated in the presence of chronic diarrhea. Alcohol abuse may lead to generalized proximal tubular dysfunction, increasing urinary phosphate excretion as well as decreasing phosphate absorption caused by hyperparathyroidism associated with vitamin D deficiency. Chronically low total body stores of phosphorus place patients with chronic alcoholism at an elevated risk of developing severe hypophosphatemia during refeeding syndrome.

Refeeding syndrome is a potentially fatal medical complication that occurs as a result of shifts in fluids and electrolytes in malnourished patients during the initial stage of oral, enteral, or parenteral nutritional replenishment. Hypophosphatemia is the most common complication and is also considered a surrogate marker for refeeding syndrome. When patients are fed carbohydrates after a period of nutritional deficiency, the glucose load causes the release of insulin, triggering cellular uptake of glucose, phosphate, potassium, and magnesium, with corresponding reduction in their respective serum concentrations. Insulin also stimulates protein and glycogen synthesis, which require phosphate for adenosine triphosphate and 2,3-bisphosphoglycerate, further depleting total body phosphate stores. The ensuing acute hypophosphatemia can lead to acute respiratory failure, cardiac arrhythmias, hemolytic anemia, rhabdomyolysis, colonic ischemia, altered mental status, and seizures.

Patients at risk for refeeding syndrome should receive supplemental phosphorus, magnesium, potassium, and thiamine. Oral phosphate supplementation (40–80 mmol/d divided as 3–4 times daily) may be sufficient in asymptomatic patients with serum phosphorus <2 mg/dL. Symptomatic patients with serum phosphorus levels 1–1.9 mg/dL can also be managed with oral phosphorus if they are able to ingest the medication safely. However, critically ill patients with seizures or cardiac arrhythmias, and those with phosphorus <1 mg/dL, should be treated with intravenous phosphate, typically provided at a rate of 0.08–0.16 mmol/kg per hour (2.5–5 mg/kg per hour). The amount of phosphate needed to replenish total body stores is difficult to estimate given the variable and largely intracellular distribution but may be as high as 100 mmol/d for 7–10 days.

Question 20

17 yo boy, nephrocalcinosis, increased creatinine, calcium kidney stone, + predominantly non- albumin proteinuria is …..

Answer 20

Dent disease.
Hallmarks are progressive CKD and low molecular weight proteinuria

Dent disease is an X-linked disorder also known as X-linked recessive nephrolithiasis, X-linked recessive hypercalciuric hypophosphatemic rickets, and low molecular weight proteinuria with hypercalciuria and nephrocalcinosis. The majority of patients have Dent disease 1, caused by an inactivating mutation in the lysosomal chloride transporter gene located on the X chromosome, CLCN5. A minority of patients have Dent disease 2, which is caused by a mutation in the OCRL1 gene, also on the X chromosome. Lowe oculocerebral renal syndrome is also caused by mutation in the OCRL1 gene, but renal tubular acidosis, congenital cataracts, and intellectual disability characterize this syndrome. There are other patients with the phenotype of Dent disease but without identified mutations in either of these genes.

The pathophysiology of Dent disease is incompletely understood. The chloride channel defect impairs endosome acidification and trafficking, whereas the OCRL1 gene encodes a phosphatase that also influences endosome trafficking. Failure of the endosome to properly degrade normally filtered low molecular weight proteins leads to the appearance of these proteins in the urine. Retinol binding protein and β-2 microglobulin are often chosen as index proteins for diagnosis. In this case, low molecular weight proteinuria is implied by proteinuria without albuminuria.

Question 21

45 yo women with morbid obesity, Coronary artery disease, EF of 15%, angina on walking one block, type 2 DM found to have struvite nephrolithiasis.

Answer 21

Administration of acetohydroxamic acid

The best option for management of a staghorn calculus in this patient is the oral administration of acetohydroxamic acid. Acetohydroxamic acid is a urease inhibitor that has been shown to reduce stone growth and progression in patients with residual or recurrent struvite stone disease after surgery, as well as those in whom stone removal is not feasible. Unfortunately, this agent is associated with significant side effects that include palpitations, edema, nausea, vomiting, and diarrhea, among others.

Question 22

How do you calculate daily protein excretion? (Given the urine urea nitrogen result)

Answer 22

16% of your mixed protein diet is converted to urea.
So divide urea nitrogen result by 16 and multiply by 100 - (get approx 57 g/ day in their example )

Normal protein intake and excretion should be 0.8g/ kg per day.

Question 23

How does animal protein intake cause stones?

Answer 23

Specific question has a patient with stones 50% calcium oxalate and 50% uric acid.

Low urinary pH is likely due to increased dietary intake of protein.

The high dietary intake of protein is confirmed in this question by: 
- High ammonia
- High urine sulfate
- High urine nitrogen
And increased protein catabolic rate. 

Dietary protein has been shown to increase the acid load –> which leads to a reduction in urinary citrate secretion and a reduction in urinary pH

Question 24

Most appropriate imaging technique for uric acid stones for follow up?

Answer 24

Renal US

Uric acid stones are generally radiolucent so dont use CT.

Question 25

Dialysis patient who has had calciphylaxis previously presents with nausea and a raised anion gap metabolic acidosis

Answer 25

Hold and then reduce dose of sodium thiosulfate.

Limited data in retrospective studies and case reports suggest that treatment with STS may have a survival benefit with a 1-year mortality of 35% compared with a historically reported mortality of 55%. It has been speculated that this agent is efficacious because it may increase solubility of calcium, but it may also have antioxidant and vasodilatory properties. Side effects are common and must be recognized. Nausea and vomiting are the most common symptoms, but hypotension and an anion gap metabolic acidosis have also been reported; symptoms are usually manageable with dose reduction.

Question 26

19 year old with three stones on the left, two on the right. Urine microscopy shows hexagonal crystals, 24 hour quantification reveals - >950 of urinary cystine

How do you treat?

Answer 26

Tiopronin.

The most appropriate treatment for this patient with cystinuria is the thiol-containing medication tiopronin. Cystinuria is an autosomal recessive disorder that results from a defect in the amino acid transporter responsible for reabsorption of dibasic amino acids (cysteine, ornithine, lysine, and arginine) in the proximal tubule. Lysine, arginine, and ornithine are all relatively soluble in an acid urine and do not form stones. Cystine, however, is insoluble, and this accounts for the only clinical manifestation of this disorder.

The solubility of urinary cystine is approximately 250 mg/L when the urine pH is 7, so patients with mild cystinuria may be able to maintain the urinary cystine concentration below its solubility with conservative measures such as high fluid intake and urinary alkalinization. In patients with high urinary cystine and those who fail conservative therapy, use of a thiol-containing medication is appropriate to reduce the urinary cystine concentration by splitting it into its 2 constituent molecules, cysteine, whose solubility is greater when bound to the thiol donor. Although penicillamine was used historically, the orphan drug tiopronin is preferred because side effects are less common with this agent. The dose can be titrated upward to decrease the urinary cystine.

Captopril also contains a sulfhydryl group, and this agent may also contribute to the reduction of urinary cystine, but only a fraction of the dose is renally excreted, so large doses would be required to affect the 24-hour urinary excretion of cystine.

Question 27

Medication used for the treatment of cystinosis (lysosomal storage disorder)

Answer 27

Cysteamine.