Calciphylaxis

An ESRD patient on CAPD was recently admitted to our hospital with possible pneumonia. It was noticed that he had painful plaque-like necrosis, with areas of ulceration. Even in the absence of a skin biopsy, the consensus was that he had calciphylaxis based on gross appearance alone and as a result, he was started on intravenous Sodium Thiosulfate 5g three times weekly.

Calciphylaxis (or calcific uremic arteriolopathy) is an uncommon but dreaded complication of renal failure characterized by painful nodular or plaque-like subcutaneous calcification often leading to ischemia, necrosis, ulceration and secondary infection. Calciphylaxis mostly occurs in patients with ESRD receiving hemo- or peritoneal dialysis although it is known to occur also in patients with CKD. Well described risk factors include female sex, hyperphosphatemia, hypercalcemia, hyperparathyroidism, the use of Ca-containing phosphate binders, vitamin D, and hypercoagulable states.

The diagnosis usually is made easily by characteristic clinical, bone scan and x-ray findings of well-defined tumor-like masses of Ca. (see previous posts)

Treatment recommendations have included reduction of serum Ca and P (and the CaxP product) by the use of low Ca dialysis baths, cessation of Ca-containing phosphate binders and vitamin D supplements, use of sevelamer, and possibly parathyroidectomy in refractory cases. Several case reports have reported the successful treatment of calciphylaxis with Sodium Thiosulfate. Sodium thiosulfate pentahydrate (Na2S2O3) has a molecular weight of 248. It distributes throughout extracellular fluids and is normally is excreted unchanged in the urine. It has been used as antidote for acute cyanide poisoning and as a topical treatment for acne and pityriasis versicolor. The theory is that sodium thiosulfate inhibits the precipitation of Ca salts and also leads to dissolution of Ca deposits into a more soluble form (Ca thiosulfate salts). The treatment is required for up to 4-12 months although a reduction of pain is usually seen within a couple of weeks. The main side effect is an anion gap metabolic acidosis that is related to the retention of sulfate salts. It has been suggested that patients who develop this complication can be treated with a high bicarbonate dialysis.

Back to our patient, we increased the dose of sodium thiosulfate to 25g. After 2 weeks treatment, the patient was tolerating the medication well and reported a significant improvement both in the pain, and in the necrotic lesions.

Posted by Tarek Alhamad

Hypercalcaemia induced polyuria

So Leo’s post got me thinking about the pathophysiology of hypercalcaemia-induced polyuria. I wanted to share what I have learned in relation to the mechanisms of this phenomenon.


Calcium-sensing receptors (CaSR) are found on the basolateral membrane of the cells of the thick ascending limb of the loop of Henle. Binding of calcium, with subsequent receptor activation, appears to induce a downstream message to close off the luminal K channel. This in turn inhibits potassium recycling and thereby shuts off the NKCC2 cotransporter, leading to decreased reabsorption of sodium, potassium and chloride in this segment.


Following on from this, the medullary concentration gradient is diminished, leading to an inablility to concentrate urine and subsequent polyuria.


CaSR are also found on the luminal surface of cells in the inner medullary collecting duct. Activation of these, in the setting of increased distal calcium delivery, down-regulates AQP2 expression, again resulting in an inability to concentrate the urine.


Finally, there may be hypercalcaemia-induced PGE2 production in the thick ascending limb, which can further inhibit sodium chloride reabsorption.


Thankfully, the polyuria and concentrating defects associated with hypercalcaemia tend to regress with correction of the calcium levels. One caveat to this may be patients who have developed an interstitial nephritis (secondary to calcium deposition in the medulla ) from prolonged hypercalcaemia.

NKF Spring Clinical Meeting - Calcium reabsorption

Here are some points from one of the cases presented at the electrolyte workshop this afternoon:

The major teaching point was that the reabsorption of calcium closely follows that of sodium. Therefore, in sodium avid states, calcium tends to be reabsorbed also – conversely, in natriuretic states, calcium tends to be lost in the urine.

What about thiazides – they are associated with hypercalcaemia and hypocalciuria, but what is the mechanism there?
In the distal convoluted tubule, thiazides act by blocking the luminal Na/Cl cotransporter. There is also a luminal calcium channel called TRPV5, which allows calcium to be reabsorbed in the DCT via a transcellular route. Overall, this is felt to contribute around 15% of total tubular calcium reabsorption. It was thought that this channel might have played a role in the pathogenesis of thaizide-induced hypercalcaemia.


However, when they created a knock-out mice without TRPV5 and treated them with thiazides, hypercalcaemia still developed. So, it would appear that the mechanism simply involves decreased extracellular volume caused by the diuretics, leading to increased sodium reabsorption more proximally and consequent enhanced proximal calcium absorption. See this review.

Of note, the paracellular route for calcium reabsorption in the thick ascending limb is guarded by tight junctions between the cells. These are made up of proteins called Claudins. Genetic defects in Claudin proteins have been associated with impaired calcium reabsorption and subsequent hypercalciuria and stone formation, giving us some insight into the molecular level of calcium handling by the kidney.

This was a great meeting with lots of interesting discussions and talks. Roll on next year in Washington!

Windows to the Soul...and the Vasculature

Continuing the theme of useful Nephrology bedside clinical signs, today we’ll focus on band keratopathy (BK). Often overlooked, this is a band of calcium deposition across the central cornea commonly seen in patients with advanced CKD. It reflects chronic positive calcium balance or hypercalcemia, and is seen in a wide variety of calcium overload states, including myeloma, sarcoid, hyperparathyroidism and renal tubular acidosis. Interestingly, it can regress with treatment of hypercalcemia, (occasionally dramatically, as in this patient) and will often regress following renal transplant too. Calcium is deposited on the corneal surface (directly under the epithelium) as a horizontal band that begins at the periphery and moves centrally as BK becomes more severe. The BK severity grading system reflects this process, with the mildest grades most peripheral (see figure). Deposits begin as a gray haze, progressing to dense white with a pebbly surface. They can lead to pain, a foreign body sensation and recurrent erosions, but are not a cause of visual loss.

The pathophysiology is not fully understood, but passive calcium precipitation is believed to be responsible. Tears and aqueous humor contain calcium and phosphate at concentrations approaching their solubility product. As tears evaporate from the intrapalpebral area, the concentration increases and precipitation occurs. The most severely affected area is the junction of the middle and lower thirds of the cornea, which is the area of maximum atmospheric exposure. Elevated serum calcium increases the likelihood of precipitation occurring. It is worth remembering that a passive precipitation model used to be proposed as the mechanism of vascular calcification in calcium overload states. This has since been debunked; vascular calcification is an active process involving a phenotypic switch in the vascular smooth muscle cell, which comes to resemble an osteoblast. We may yet learn that calcification occurring on the eye is also more complex than just passive deposition.

This last point is relevant as BK and vascular calcification are closely linked: the presence of BK is associated with a ten-fold increased prevalence of vascular calcification, and over half of dialysis patients with BK have radiologic evidence of VC. Furthermore, BK has recently been shown to independently predict 1-year mortality in dialysis patients, with each increment in the BK severity index being associated with a 25% increased mortality risk in multivariate analyses. It would be interesting to study whether BK also predicts calciphyllaxis. When I encounter BK clinically, I tend to treat it as I would extraskeletal calcification at any other site. As it implies chronic positive calcium balance, it prompts me to consider measures to reduce calcium balance in the patient, such as reducing the dialysate calcium bath, switching to a non-calcium containing phosphate binder and/or a non-calcemic vitamin D analog.

Revealed: my "covert" project with Nate a.k.a TRP channels in the kidney

Nate Hellman’s bench was three benches down from my lab. Nate and I trained together as clinical fellows. He and I had also brainstormed on research projects involving TRP channels and kidney disease. TRP channels are my research area of interest. It therefore seems appropriate to discuss some aspects of what Nate and I jokingly referred to as our “covert” project in my first blog posting.

What are TRP channels? And why do they matter in terms of kidney health and disease?

TRP stands for Transient Receptor Potential, a large family of non-selective cationic channels with diverse tissue distribution and diverse cellular functions. They were initially discovered in Drosophila (fruit fly) photoreceptors where they mediate fly vision. Some refer to them as “the last bastion of ion channels” since there is still much we do not understand about their role in health and disease. There are a few TRP subfamilies, indicated by letters which are there for various historical reasons (a discussion for another day – just take my word for it for now, or refer to a review by Ramsey et al., Annu Rev Physiol. 2006;68:619-47), but there are the TRPCs, the TRPVs, the TRPMs, the TRPPs, the TRPMLs and the TRPAs.

A few fun facts:
- TRP channels (TRPV1) are responsible for the hot taste of chili peppers in your mouth.
- TRP channels (TRPM8) also give you the cold sensation of menthol.

But how are TRP channels pertinent to your kidneys? It turns out that they are actually involved in many aspects of kidney physiology and disease (called “channelopathies”):

We’ll start from my favorite: Proteinuric kidney disease. Mutations in TRPC6 were found in a number of families with adult onset Focal Segmental Glomerulosclerosis. Many of us are now actively involved in research to identify the precise mechanisms by which disease occurs in these patients, but deleterious effects due to channel mutations in glomerular podocytes are strongly suspected.

Another channel, TRPV5, mediates vitamin D dependent calcium uptake in tubular epithelial cells. The absence of TRPV5 channels (at least in mice) causes renal calcium wasting and bone loss.

Perhaps more intriguingly, mutations in TRPM6 have been implicated in human hypomagnesemia with secondary hypocalcemia (HGH) as this channel is involved in renal magnesium uptake.

And rather famously, of course, polycystic kidney disease (ADPKD) emerges due to mutations in two slightly more distant relatives in the TRP family, the polycystins, known as TRPP1 and TRPP2.

This of course brings us full circle back to Nate and his research, which was focused on cystic disease, and specifically cystic kidney disease.

As this is my first time blogging, please let me know what you think, your comments and suggestions are welcome!

Warfarin and Vascular Calcification

Warfarin has recently been associated with an increased risk of stroke in ESRD patients with atrial fibrillation. This makes the decision whether to initiate warfarin therapy in dialysis patients with atrial fibrilltion anything but clear cut. Add to this the emerging evidence that it also promotes vascular calcification, and you have a real dilemma.

This latter side effect hinges on Matrix Gla protein, or MGP. In ESRD, vascular smooth muscle cells (VSMCs) undergo a phenotypic switch to take on the appearance of osteoblasts, in a well-described process thought to be driven by hyperphosphatemia. Once this has occurred, VSMCs lay down a protein matrix which can undergo calcification, similar to normal bone. MGP is an essential endogenous inhibitor of this process, mediated in part by it’s ability to bind calcium. This ability to bind calcium is a Vitamin K dependant process, explaining how warfarin may increase the risk of vascular calcification.

Warfarin has been linked to aortic valve calcification in both the general population and in ESRD, as well as calcific uremic arteriopathy in the latter. In fact, the odds ratio for severity of aortic valve calcification after 18 months of warfarin in ESRD was almost 4. Prospective trials are clearly needed, but for now, adopting a restrictive policy towards warfarin use in ESRD seems wise, such as reserving it for patients with a CHADS score > 2.

Hypercalcemia of Malignancy

Cancer-associated hypercalcemia is the #1 cause for hypercalcemia in the inpatient setting (in the outpatient setting, the main cause is primary hyperparathyroidism). In general, hypercalcemia of malignancy portends a poor prognosis, and there are three main mechanisms by which hypercalcemia can occur:

1. PTHrP (PTH-related peptide): this is the most common cause of hypercalcemia of malignancy, and is sometimes referred to as "humoral hypercalcemia of malignancy." The PTHrP essentially mimics the effects of PTH by virtue of its interaction with the PTH receptor, though since PTHrP is not detected by standard PTH assays the measured PTH level is typically very low. Sending a PTHrP level may be helpful, though in my experience it often takes several days to come back. PTHrP is most commonly secreted by solid tumors, such as breast cancer.

2. osteolytic metastases: this is the 2nd most common mechanism of hypercalcemia of malignancy, and is due to osteoclast-mediated bone breakdown. It occurs in characteristic tumor types, which can be recalled by this nifty mnemonic, "BLT with a Kosher Pickle, Mustard & Mayo":
B = breast cancer
L = lymphoma, lung cancer
T = thyroid cancer
K = kidney cancer
P = prostate cancer
M & M = multiple myeloma

3. tumor production of calcitrol: the mechanism is here is similar to that of granulomatous disease: tumor cells provide enzymatic synthesis of 1,25 OH-vitamin D, the active form of vitamin D, leading to unregulated GI uptake of calcium. It is most commonly seen in Hodgkin's lymphoma and some cases of NHL as well. It can be diagnosed by finding an elevated 1,25 OH vitamin D level in the presence of malignancy.

Very, very rarely one can observe ectopic PTH secretion as a mechanism for hypercalcemia of malignancy.

On the mechanism of thiazide-induced hypocalciuria

Back from the 2009 ASN Meeting in San Diego!  I'll admit to a few lapses in blogging, but the meeting kept me pretty busy.  Thanks to everybody who stopped by the Renal Fellow Network poster and their encouraging words.

The 2009 ASN Homer Smith Award went to Rene Bindels, a master physiologist from the Netherlands who has made great advances in our understanding of renal calcium and magnesium handling via the Trp channels.  Amongst the highlights of his Saturday morning talk was a good explanation for why hypocalciuria results from thiazide diuretic treatment.  

The hypocalciuric effect of thiazide diuretics is well-known:  we frequently put patients prone to develop calcium nephrolithiasis on thiazides with this effect in mind, and patients with Gitelman's Syndrome (caused by mutations in the thiazide-sensitive Na channel, NCC) also have significant hypocalciuria.  There were two general mechanisms postulated to account for this.  Either:

(1).  blockage of NCC results in increased active Ca uptake via TrpV5 channels in the distal tubule, or

(2). thiazide-induced hypovolemia results in enhanced passive Ca uptake in the proximal convoluted tubule.  

The generation of TrpV5 knockout mice provided an opportunity to see which of these possibilities was correct.  Interestingly, these mice still developed hypocalciuria when given thiazide diuretics, indicating that hypocalciuria does NOT require TrpV5 (that is, the 2nd explanation above is true while the 1st explanation is not).  Just another example of how the physiology in one segment of the nephron strongly influences the ion uptake in another segment.  

The Electrolyte Composition of the Dead Sea

The Dead Sea, located between Israel and Jordan, is considered one the saltiest bodies of water on earth, giving swimmers a peculiar buoyancy when immersed. Interestingly, the electrolyte composition of the Dead Sea is quite different from that of ordinary seawater. The salt composition of most ocean water is 97% sodium chloride, whereas the salt composition of the Dead Sea surface water is only 30.4% sodium chloride with additional contributions from calcium chloride (14.4%), potassium chloride (4.4%), and a shockingly high magnesium chloride (50.8%).

This latter point explains why near-drowning victims from the Dead Sea can exhibit profound elevations in the serum calcium and serum magnesium levels, which according to this article by Porath et al can reach levels up to 28.8 and 33 mg/dL, respectively! The authors make the case that early dialysis to rapidly lower serum calcium and magnesium levels is necessary to prevent the major electrophysiologic and hemodynamic consequences of hypercalcemia and hypermagnesemia. Interestingly, in this article and another by Oren et al, the authors point out that the presence of hypercalcemia in these patients is actually protective, in that high calcium levels help protect against the catastrophically high magnesium levels which might otherwise cause respiratory arrest in the setting of hypocalcemia.

Bone Scan for Diagnosis of Calciphylaxis?

Calciphylaxis (also called calcific uremic arteriolopathy) is a syndrome of vascular calcification, thrombosis, and necrosis, occurring almost exclusively in ESRD patients.  The diagnosis is typically achieved by clinical exam--demonstrating painful, necrotic, and sometimes ulcerating lesions usually on the lower extremities. Because there are other clinical entities which can cause similar lesions (e.g., nephrogenic sclerosing dermopathy, cryoglobulinemia, cholesterol emboli, vasculitis, etc), sometimes we need a "gold standard".  Not uncommonly, a skin biopsy is carried out for the definitive diagnosis of calciphylaxis.  

However, there is some danger in biopsy:  many of these patients have a difficult time with wound healing, and it would be preferable to have a non-invasive manner by which to support the diagnosis of calciphylaxis.  A 2002 KI article by Fine and Zacharias provides evidence that a bone scan is fairly sensitive for this diagnosis and could be used in lieu of a biopsy. Their analysis indicated that 34 out of 36 patients with a diagnosis of calciphylaxis had an abnormal bone scan--most commonly reflected as showing increased uptake in the calves, typically in the areas of pain/ulceration (as shown on the left).  Of note, this particular study does not really address how specific a bone scan is at excluding alternative causes of this type of dermopathy, but could still potentially be useful in the right clinical setting. Unfortunately, calciphylaxis still carries with it a very high mortality rate.

Re-Evaluating the Ca x P Product

Heard an excellent presentation at our Renal Grand Rounds today by Dr. Charles O'Neill of Emory University, regarding the process of pathologic calcification in CKD/ESRD patients.

One of the points I took away from this talk is that we need to re-evaluate the role of the "calcium-phosphate product" in clinical medicine.  Presently, the KDOQI guidelines state that nephrologists should attempt to maintain the Ca x P product below 55 in order to minimize pathologic calcification.  I had always been taught that if the Ca x P product exceeds 55, there is a tendency for calcium phosphate to precipitate and deposit within the walls of blood vessels.  Is this true?

This 20007 KI review ("The Fallacy of the calcium-phosphorus product") makes the case that this view is erroneous.  The majority of medial calcification seen in CKD/ESRD patients is in the form of hydroxyapatite, which is much more complex than calcium phosphate; the chemical structure is Ca10(PO4)6(OH)2.  As the formation of hydroxyapatite involves multiple separate steps, it is very unlikely to occur spontaneously. A more likely scenario is that a local balance between specific calcification inhibitors (e.g., pyrophosphate) and activators (e.g., alkaline phosphatase) maintained at a local level determines whether or not pathologic calcification occurs.  Furthermore, experiments in which exogenous calcium and phosphate were added to samples of human plasma  demonstrated that calcium-phosphate precipitation did not occur until the Ca x P product exceeded over 200--a number which is never achieved in human patients.  

Nonetheless, despite these potential flaws in the physiologic rationale for the Ca x P product, there is abundant epidemiologic evidence showing an association between the Ca x P product and cardiovascular mortality.  Perhaps this simply reflects the observation that serum calcium and serum phosphate levels each independently potentially contribute to pathologic calcification.  In any case, the prevailing current approach is to control serum phosphate levels with binders to within the normal range as much as possible while tolerating some degree of mild hypocalcemia.  

Renal TB

TB is classically thought of as a pulmonary disease--and in general, this is true, as pulmonary TB is by far the most common (and often very severe) manifestation of infection by Mycobacterium tuberculosis. However, the most common NON-pulmonary manifestation of TB worldwide is infection of the genitourinary tract, accounting for about 27% of non-pulmonary TB in most series according to this 2001 JASN review.

The name "renal tuberculosis" is a little misleading, since TB infection can actually cause renal problems by a variety of different mechanisms. Renal involvement may occur as part of a constellation of symptoms with miliary TB, in which there is mycobacterial "bacteremia/septicemia". The preferred site for mycobacteria in the kidney is the renal medulla, where caseating granuloma can lead to necrosis and tissue destruction, occasionally resulting in papillary necrosis. Large caseating necrotic areas can lead to a clinical picture very similar to pyelonephritis. Alternatively, infection in the lower urinary tract can lead to anatomic abnormalities, such as ureteric strictures, which over time can progress to frank obstruction and even ESRD. In addition to these more "mechanical" explanations for renal failure, there have been several reports that chronic tuberculosis infection is a potential cause for tubulointerstitial nephritis. In India, where TB is very common, AA amyloidosis secondary to the chronic inflammatory state induced by TB infection is a well-recognized cause of kidney damage.

Genitourinary TB may be diagnosed by culture or PCR of the organism from the urine (or sputum, if there is pulmonary involvement). Detecting acid-fast bacilli from the urine is another possibility though apparently this is less specific than culture or PCR as there are some environmental mycobacterial species which may colonize the lower urinary tract. Renal TB may be suspected if the patient has signs and symptoms of a urinary tract infection with a workup that demonstrates pyuria but a negative urine culture. Obviously, travel/occupational history plays an important role in identifying individuals who are at higher risk for TB. Another clue to the diagnosis of renal TB is hypercalcemia: instead of being mildly hypocalcemic like most advanced CKD patients, patients with TB infection may have high levels of 1,25(OH) vitamin D as a result of granulomas having the ability to synthesize active vitamin D, similar to the situation in sarcoidosis. In the U.S., a very low percentage of patients (.004%) list TB as a cause for their ESRD, but in some European countries (e.g. Greece) the percentage is as high as 5%, and likely much much higher than this in many African countries. It is important to recognize in that TB is very much a treatable disease (and therefore a preventable cause of CKD/ESRD).

the von Kossa Stain for Acute Phosphate Nephropathy

One of the hot topics in Nephrology over the past few years has been the epidemiologic and histopathologic studies suggesting oral sodium phosphate colonoscopy preparations as a cause of acute phosphate nephropathy. As evidence continued to mount, the FDA in December 2008 forbade the over-the-counter sale of oral sodium phosphate products; however, they are still available by prescription under the names "Visicol" and "Osmoprep." These preps are still favored by many gastroenterologists (and patients) based on the fact that it is much easier to take than the more traditional polyethylene glycol-based colonoscopy prep (e.g., "Go-Lytely").

Biopsies of patients with acute phosphate nephropathy tend to show abundant calcium phosphate crystal deposition, mostly within the distal convoluted tubules and collecting ducts, but sometimes also in the interstitium. A good detection method is the use of the von Kossa stain, which stains certain calcium-containing salts such as calcium phosphate a brownish-blackish color.

Sensipar for APKD?

Following on the heels of studies showing a potentially beneficial effect for vasopressin receptor antagonists and rapamycin in the treatment of renal cystic disorders, an article in this month's JASN by Gattone et al suggests another class of commonly-used nephrology-related drug which may be of use: calcimimetics (such as cinacalcet, or sensipar).

The logic is as follows: The growth of cysts in PKD is thought to be driven by low intracellular calcium levels and elevated cAMP levels. The calcium sensing receptor (upon which cinacalcet acts) is activated by binding to serum ionized calcium, and results in a G-protein-mediated decrease in cAMP levels & increase in intracellular calcium concentration. The investigators therefore suggested that cinacalcet might be an effective way to reduce cyst growth in late PKD.

To test their hypothesis, they took a rat model of PKD (Cy/+) and treated them either with placebo or with the calcimimetic R-568, which is similar in function to cinacalcet. Interestingly, rats in the treatment group showed less advanced cyst formation and fibrosis at later time points, suggesting that their hypothesis may be correct. This study is somewhat unique in that it looks at fairly advanced stages of cystic kidney disease, whereas other animal studies have focused on a more prophylactic approach to cyst growth.

Cautious optimism for ADPKD patients--if I were a young guy with the PKD1 or PKD2 gene, I would seriously consider enrollment in one of the ongoing trials.

Differentiating FHH from Primary Hyperparathyroidism

One of the diagnostic dilemmas which frequently comes up in the outpatient evaluation of hypercalcemia (and also, I'm told, on boards-type exams) is how to differentiate familial hypocalciuric hypercalcemia versus primary hyperparathroidism--both of which are common causes of hypercalcemia. The short answer: check the urine calcium--it should be low in FHH but normal to high in primary hyperparathyroidism.

Primary hyperparathyroidism, as we are all aware, usually results from either a parathyroid gland adenoma or 4-gland parathyroid hyperplasia. The PTH level is either high or inappropriately normal, and as a result there is constant high urinary calcium reabsorption, constantly high Ca reabsorption from bone, and increased 1,25-OH vitamin D synthesis leading to increased Ca uptake in the gut. The urine calcium concentration is high; hence, the increased risk of nephrolithiasis in these patients. Also, the urine concentrating ability may be diminished in primary hyperparathyroidism.

In contrast, the defect in familial hypocalciuric hypercalcemia is genetic--an autosomal-dominant-inherited mutation in the calcium-sensing receptor gene. Despite hypercalcemia, PTH levels are normal to only mildly elevated. The urine calcium concentration is low (often measured as the urine calcium:creatinine ratio, which in FHH should be <0.01). The urine concentration ability is usually intact in FHH. It is important to make the distinction between primary hyperparathyroidism and FHH because parathyroidectomy surgery is usually highly effective in the former but not the latter.

Betel Nut Chewing

Following up on the discussion of milk-alkali syndrome, a similar syndrome (hypercalcemia, metabolic alkalosis, and acute renal failure) may also occur due to betel nut chewing. Betel nut chewing is a common habit and cultural practice amongst Indian and Southeast Asian populations. Generally, betel leaves are used to wrap a type of nut (the areca nut) and then chewed. Because of its bitter taste, alkaline calcium salts--mineral-slaked lime in the form of calcium hydroxide--are traditionally added to the mixture. Because of the presence of calcium & base, a small fraction of individuals who frequently participate in betel nut chewing can develop milk-alkali syndrome. So add "Chew any betel nuts recently?" to your list of bizarre questions to ask patients with unexplained hypercalcemia.

In Taiwan, "betel nut beauties" refer to scantily-clad young women who sell betel nuts and cigarettes at small kiosks, apparently a common site in big cities.

History of the Milk-Alkali Syndrome

Heard about a case of milk-alkali syndrome at Renal Grand Rounds yesterday. This is an interesting condition whose pathophysiologic mechanism really tests your knowledge of calcium and acid-base homeostasis. I won't attempt to chart the pathway but a really good overview can be found in this 2006 CJASN review by Felsenfeld and Levine. Briefly, patients who have large intakes of calcium and bicarbonate develop hypercalcemia, metabolic alkalosis, and acute renal failure.

The milk-alkali syndrome first rose to prominence when Bertram Sippy in 1915 developed a regimen for the treatment of peptic ulcer disease that involved drinking large volume of milk on an hourly basis along with "Sippy powders" that contained significant amounts of sodium bicarbonate. This provides really an ideal setup of a situation in which hypercalcemia, metabolic alkalosis, and acute renal failure can occur simultaneously, the hallmark of the milk-alkali syndrome.

It was not until 1936 that the toxicities associated with the Sippy protocol were tied to hypercalcemia by a Dr. Cope, who determined that in patients with milk-alkali syndrome the hypercalcemia and metabolic alkalosis could be relatively rapidly reversed by stopping calcium/base input and giving fluids. Although it is seldom used, the moniker "Cope's Syndrome" is occasionally used to refer to the acute- or subacute- forms of milk-alkali syndrome.

In 1949, Burnett et al described a chronic form of milk-alkali syndrome which involved the long-term toxicities of these metabolic derangements, including manifestations such as renal failure secondary to nephrocalcinosis and band keratopathy, in which calcium deposition on the cornea occurs. Fittingly the chronic form of milk-alkali syndrome is sometimes called "Burnett's Syndrome."

With the advent of H2-blockers to more effectively deal with peptic ulcer disease, the milk-alkali syndrome became quite rare for several decades as the general population's intake of popular antacids such as TUMS was greatly reduced. However, there has been a more recent increase in milk-alkali syndrome, particularly in women, with the increased attention to osteoporosis prophylaxis with calcium supplements. Several recent reviews cite milk-alkali syndrome as the third-most-common reason for hypercalcemia requiring hospitalization, after malignancy and primary hyperparathyroidism.

Lithium-Induced Hyperparathyroidism

Lithium, a very effective medication in the treatment of bipolar disorder, has a variety of well-documented renal side effects, including interstitial nephritis and nephrogenic diabetes insipidus.  A less well-recognized complication is an increased prevalence of hyperparathyroidism in chronic lithium users.

Individuals with chronic Li use frequently have both elevated calcium levels as well as elevated PTH levels, and it can be very difficult to differentiate from primary hyperparathyroidism or familial idiopathic hypercalciuria.  The mechanisms for why patients on Li therapy have these lab abnormalities is still up for debate, but this interesting article describes three potential mechanisms:  first, Li has been shown to block Ca2+ influx into a variety of cells by competitive inhibition of Ca2+ transport across the cell membrane.  The elevated ionized Ca2+ would then drive up PTH levels.  In addition, there is some evidence that Li raises the threshold of the Ca-sensing receptor in parathyroid cells, and increased Ca2+ levels are necessary to keep PTH secretion under check.  Finally, it is postulated that Li directly increases PTH transcription by virtue of its inhibitory effects on the enzyme glycogen synthase kinase 3b (GSK-3b), a known transcriptional repressor of PTH mRNA.  

By the way, I learned today that Lithium is reabsorbed in the kidney via both the Na/H antiporter in the proximal tubule as well as ENac in the collecting duct.  Therefore diuretics which block these transport mechanisms (e.g., amiloride) can have a dramatic lithium-lowering effect when acutely given to somebody on chronic Lithium.  

Hypoparathyroidism

One logical way to classify the different etiologies of hypocalcemia is to break them down into LOW PTH STATES and HIGH PTH STATES. Today I'll review the HYPOCALCEMIA WITH LOW PH STATES, or in other words, the causes of hypoparathyroidism.

The most common cause of hypoparathyroidism is surgical hypoparathyroidism. This occurs in the setting of surgery of the thyroid gland, parathyroid glands, or other neck surgeries. In patients who have undergone a parathyroidectomy for HYPERparathyroidism, the sudden loss of PTH can lead to "the hungry bone syndrome"--a condition which is explained by the rapid absorption of calcium by bone once the PTH stimulus causing calcium efflux from bone has been removed. Fortunately most cases of surgical hypoparathyroidism are transient.

The most common cause of hypoparathyroidism other than surgical causes is autoimmune-mediated hypoparathyroidism. This can be caused either due to immune-mediated destruction of the parathyroid glands or due to activating antibodies against the calcium-sensing receptor on parathyroid chief cells. Autoimmune hypoparathyroidism may be an isolated disorder or may be part of a larger autoimmune dysfunction termed polyglandular autoimmune syndrome type I, in which hypoparathyroidism occurs in conjunction with chronic mucocutaneous candidiasis and adrenal insufficiency.

Abnormal parathyroid development--which can be seen in complex syndromes such as DiGeorge's synrome--can also logically result in low circulating PTH levels.

More rare causes of hypoparathyroidism include radiation-induced hypoparathyroidism and infiltrative diseases of the hypoparathyroid glands (e.g., Wilson's disease, sarcoidosis, hemochromatosis, or metastatic cancers).

Finally, there are various genetic mutations that can result in hypocalcemia, which are most relevant to pediatric nephrologists. For example, autosomal dominant hypoparathyroidism is caused by gain-of-function mutations in the calcium-sensing receptor gene: you can think of this as akin to being on sensipar all the time.

Symptoms and Signs of Hypocalcemia

Calcium is a critical ion for a number of cellular signaling events. As such, it is not surprising that hypocalcemia leads to a wide variety of signs and symptoms.

The dominant presentation of hypocalcemia is usually neurologic in origin. Individuals with profound hypocalcemia will present with lethargy and altered mental status, and may even present with seizures. More commonly individuals with hypocalcemia will present with numbness or tingling in the perioral and distal fingers and toes which over time will progress to carpopedal spasm, or tetany.

Two named tests of the physical exam--Chvostek's sign & Trousseau's sign--are used to detect neurologic effects of hypocalcemia. In Chvostek's sign, tapping the area over the facial nerve causes an ipsilateral contraction of the facial muscles. While suggestive of hypocalcemia, it can apparently be found in up to 10% of the general population however. In Trousseau's sign, a blood pressure cuff is inflated to slightly above the systolic blood pressure and maintained for over 3 minutes (ouch!). In the presence of hypocalcemia this can lead to carpal spasm and involuntary wrist flexion.

In addition to these neurologic signs & symptoms, hypocalcemia can also have effects on the pulmonary system (wheezing secondary to bronchospasm), cardiovascular system (hypocalcemia is associated with a shortened QTc interval and arrhythmias), and dermatologic findings (chronic hypocalcemia can result in dry skin, brittle nails, and petechiae).