Topic Discussion: Calcium and Pre-eclampsia- using AI

 I now am re-doing the post on using calcium to prevent pre-eclampsia using artificial intelligence website- https://chat.openai.com/chat 

Prompt: Can calcium prevent PEC?

Response: 

Calcium supplementation has been shown to reduce the risk of pre-eclampsia in pregnant women who have low dietary calcium intake or are at high risk for pre-eclampsia. However, it is important to note that calcium supplementation is not a guaranteed prevention method for pre-eclampsia and should only be taken under the guidance of a healthcare professional.

The World Health Organization (WHO) recommends that pregnant women receive at least 1,500 mg of calcium per day, either through diet or supplementation, to reduce the risk of pre-eclampsia. In cases where dietary calcium intake is insufficient, calcium supplements may be recommended.

It is important to note that pre-eclampsia is a complex condition that can have various causes, and calcium supplementation alone may not prevent it in all cases. Other preventative measures such as maintaining a healthy lifestyle, attending regular prenatal checkups, and managing pre-existing health conditions can also help reduce the risk of pre-eclampsia.

Several studies have investigated the effectiveness of calcium supplementation in preventing pre-eclampsia. Here are some key findings:

1. A Cochrane review of 13 randomized controlled trials involving over 15,000 women found that calcium supplementation reduced the risk of pre-eclampsia by 55% in women with low calcium intake and by 24% in women at high risk for pre-eclampsia.

2. A meta-analysis of 21 trials involving over 23,000 women found that calcium supplementation reduced the risk of pre-eclampsia by 24%, with a greater effect seen in women with low dietary calcium intake.

3. A study published in the British Medical Journal found that calcium supplementation reduced the risk of pre-eclampsia by 66% in women with a history of pre-eclampsia.

Overall, the data suggests that calcium supplementation can be an effective preventative measure against pre-eclampsia, especially in women with low dietary calcium intake or a history of pre-eclampsia. However, it is important to note that calcium supplementation should only be taken under the guidance of a healthcare professional, as excessive calcium intake can have adverse effects.

When I asked to provide references:

Sure, here are some references for the information I provided:

1. Hofmeyr GJ, Lawrie TA, Atallah AN, Duley L, Torloni MR. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database Syst Rev. 2018;10(10):CD001059. doi:10.1002/14651858.CD001059.pub5

2. Hofmeyr GJ, Manyame S, Medley N, Williams MJ, Kramer MS, Duley L. Calcium supplementation commencing before or early in pregnancy, or food fortification with calcium, for preventing hypertensive disorders of pregnancy. Cochrane Database Syst Rev. 2019;10(10):CD011192. doi:10.1002/14651858.CD011192.pub2

3. Villar J, Abdel-Aleem H, Merialdi M, et al. World Health Organization randomized trial of calcium supplementation among low calcium intake pregnant women. Am J Obstet Gynecol. 2006;194(3):639-649. doi:10.1016/j.ajog.2005.10.831

4. Buppasiri P, Lumbiganon P, Thinkhamrop J, Ngamjarus C, Laopaiboon M. Calcium supplementation (other than for preventing or treating hypertension) for improving pregnancy and infant outcomes. Cochrane Database Syst Rev. 2015;(2):CD007079. doi:10.1002/14651858.CD007079.pub3

5. Levine RJ, Hauth JC, Curet LB, et al. Trial of calcium to prevent preeclampsia. N Engl J Med. 1997;337(2):69-76. doi:10.1056/NEJM199707103370201

Topic Discussion: Calcium and Pre-eclampsia

Interesting data is emerging that calcium supplementation may help prevent pre-eclampsia(PEC). There are in vitro studies that have demonstrated that calcium has an anti-inflammatory effect and reduces the endothelial activation and dysfunction resulting from trophoblastic debris in pre-eclampsia. This may be mediated through the effect of calcium on the nitric oxide synthetase pathway, and the subsequent increased production of nitric oxide. 

At a population level, there is some evidence that dietary calcium intake and incidence of PEC is inverse. This cochrane based review back in 2017 showed that High-dose calcium supplementation (≥ 1 g/day) may reduce the risk of PEC and preterm birth, particularly for women with low calcium diets (low-quality evidence). The treatment effect may be overestimated due to small-study effects or publication bias. It reduces the occurrence of the composite outcome 'maternal death or serious morbidity', but not stillbirth or neonatal high care admission. There was an increased risk of HELLP syndrome with calcium supplementation, which was small in absolute numbers. The limited evidence on low-dose calcium supplementation suggests a reduction in PEC, hypertension and admission to neonatal high care. 

A recent review in JACC does put calcium in the benefit category for prevention of PEC.

Then came the CAP study published in Lancet. The CAP study was a double-blind RCT, which aimed to assess whether 500 mg of calcium supplementation before pregnancy and in early pregnancy prevents pre-eclampsia in a population group of women at a high-risk for PEC and with a generally low dietary calcium intake. In this study of 1,355 women with a history of PEC, there was no difference in the incidence of PEC between the treatment or placebo group (RR 0.80, 95% CI 0.61–1.06). However, the compliance rates were low (only 50% of the population took at least 80% of the expected tablets), which may limit the validity of these results. Interestingly, in a subgroup analysis of participants with adequate compliance (defined as >80%), the rate of PEC was significantly lower in the calcium group in comparison to the placebo controls (RR 0.66, 95% CI 0.44–0.98). Another limitation of this study was the dosage of calcium used, which at 500 mg appeared to be lower than the doses prescribed in previous trials.

(Image from https://pre-empt.obgyn.ubc.ca/home-page/past-projects/cap/) 

Finally, a more recent meta-analysis published is adding some mixed data. The meta-analysis included 30 trials (N = 20 445 women), and the network meta-analysis to evaluate calcium dosage included 25 trials (N = 15 038). Calcium supplementation prevented PEC similarly with a high dose (RR 0.49, 95% CI 0.36–0.66) or a low dose (RR 0.49, 95% CI 0.36–0.65). By network meta-analysis, high-dose (vs low-dose) calcium did not differ in effect (RR 0.79, 95% CI 0.43–1.40). Calcium was similarly effective regardless of baseline PEC risk, vitamin D co-administration or timing of calcium initiation, but calcium was ineffective among women with adequate average baseline calcium intake.

The authors conclude that by using direct and indirect trial evidence in meta-analysis and network meta-analysis, calcium supplementation (vs placebo/no therapy) decreases the incidence of PEC, defined traditionally as gestational hypertension and new proteinuria. This effect is similar with high- or low-dose calcium, regardless of baseline PEC risk, timing of calcium initiation. But, the effectiveness of calcium is restricted to populations with low average baseline calcium intake. The small increase (of an absolute 0.2%) in HELLP syndrome with calcium was more than balanced by a reduced incidence of death or severe maternal morbidity (by 1.0%). 

In summary, very fascinating science here and perhaps something that needs a closer look. At this point, based on data, perhaps women with low calcium intake maybe the best that benefit from this preventive strategy. The International Federation of Gynecology and Obstetrics (FIGO), women with low calcium intake (<80 mg/day) calcium replacement (<1 g/day) or supplementation (1.5–2 g/day) is recommended. In populations where baseline dietary calcium intake is low, the World Health Organization recommends for 1500 to 2000 mg elemental calcium supplementation per day for pregnant individuals to reduce the risk of PEC, particularly among those at higher risk of developing hypertension. The WHO recommendation is based on positive results from systematic reviews as discussed above.

Concept Map: Hypomagnesemia and it's effect on other electrolytes

Concept Map: Hypocalcemia

Consult Rounds: Tamoxifen induced hypercalcemia

A forgotten cause of hypercalcemia we need to remember is the drug- tamoxifen

This chemotherapy agent used in breast cancer has had a track record of causing hypercalcemia.
It was first described in 1980s.  In that large study, 470 patients with metastatic breast cancer treated with tamoxifen, ten patients (2.3%) developed hypercalcemia. All patients with hypercalcemia had osteolytic or mixed lytic and blastic bone metastases. Hypercalcemia developed after a median period of seven days (range 4-11 days) of tamoxifen administration. Hypercalcemia was treated with conventional measures and serum calcium levels normalized in nine patients, either with a brief interruption of tamoxifen therapy or in spite of continued treatment. Four patients experienced partial remissions with continued tamoxifen therapy. These results indicate that hypercalcemia is a potentially serious complication of tamoxifen therapy but is generally short-lived, and can be controlled with supportive measures, thus allowing continued tamoxifen administration.

Other published reports are

https://www.ncbi.nlm.nih.gov/pubmed/8241000

http://annals.org/aim/article/692303/tamoxifen-hypercalcemia

http://www.sciencedirect.com/science/article/pii/0002961081901744

One recent study looked at a large series of breast cancer patients who were hypercalcemic post tamoxifen- happened within 9 days of start and peaked at a level of 13. All patients also had bone lesions as well.  Gallium nitrate was used to reverse the abnormality while keeping tamoxifen on.

https://link.springer.com/article/10.1007%2Fs00774-005-0678-4

No mention of this in any renal literature. Unclear mechanism of this entity. 

#Dream RCT: Ca-HIL Study ( diuretic use in hypercalcemia)

#DreamRCT: Ca-HIL Study

Dream RCT is a project that many of us online are involved in. The assignment is to target the most important question you see in nephrology today and design a trial to answer it. Per Dr Topf, “Money no object, forget about pesky IRBs, let your mind free and create the trial which will meaningfully push back the walls of knowledge.”

After you post your entry at your site of choice, UKidney will host a summary with a link for each entry and gather votes for the best. Check out what others have proposed. This is a novel project on ideas online for nephrology projects.

http://www.pbfluids.com/2014/02/dreamrct-deadline-approaches.html

Here is my entry.

My idea for a dream RCT is very simple. There are many simple questions unanswered in nephrology.
Hypercalcemia is a common problem we encounter in the hospital setting. The most common cause usually is malignancy. While the long term treatment is dependent on the cause, the initial treatment is usually IV fluids and diuretics, calcitonin and so forth.  The data to give IVF followed by diuretics have been questioned. The initial observational experiences of many physicians have driven this practice.

 Usually aggressive IV hydration is warranted sometimes even at 150-200-250 CC/HR. 

Once volume depletion is addressed, a loop diuretic MAY be used for augmentation of calcium excretion.
A recent review and analysis published in Annals of Internal Medicine sheds some light about use of loop diuretic in this setting.
The review suggests the following points:

1. Aggressive hydration is necessary
2. Use of diuretics without aggressive hydration might be harmful
3. Found only 9 articles documenting the use of furosemide in hypercalcemia and latest one published in 1983 and total was only 37 patients.
4. Average dose was 1120mg over 24 hours ( really??)
5. Normalization of Ca occurred in only 14 of 39 cases
6. Study with lower doses didn't achieve normalization ( and what do we use????)
7. Complications of other electrolyte disorders ensued
8. Finally, recommended against the use of this agent routinely except for cases of volume overloaded with hypercalcemia.
I think the tile of the paper listed below nicely puts it:- Furosemide in hypercalcemia is an unproven but common practice ( really not evidence based)

·                     My suggestion is we study this in a standardized fashion: Hypercalcemia IVF and Lasix  ( HIL study)

Venue: Multi Center
Design: Randomized control trial
Primary end point:   1. AKI  2. Need for HD
Secondary end points: 1. Length of stay, 2. Mortality

Monitor closely other electrolyte disorders in both cohorts.

·                     Inclusion Criteria

o                  Age >18

o                  Sex males and females

o                  Primary known history of a malignancy related hypercalcemia

·                     Exclusion Criteria

o                  Other causes of hypercalcemia

o                  Hypercalcemia requiring dialysis at first visit with nephrologist

o                  History of known CHF requiring diuretics on a chronic basis.

Enroll all patients with acute hypercalcemia that are inpatient setting that are initially evaluated for treatment with aid of a nephrologist. To make it a uniform setting, perhaps only hypercalcemia of malignancy should be considered ( most common cause anyway). 

Randomize to IVF ( normal saline) alone for 48 hours followed by long term therapy with bisphosphanates, steroids or denosunab.
Or IVF (normal saline) for 48 hours and furosemide ( dose dependent escalation) followed by long term therapy with similar agents

I think this study or a variant of this concept should answer the question of need and use of diuretics in treatment of hypercalcemia.  Problem is who is going to fund this? 

Clinical Case 79: Answers and Summary

Which one of these agents are potential treatment options for sarcoidosis induced hypercalcemia?

Steroids	41 (78%)
ACTH	8 (15%)
Ketaconazole	7 (13%)
Hydroxychloroquine	4 (7%)
Pamidronate	9 (17%)

In a earlier study in JAMA years ago, it was established that the hypercalcemia in sarcoidosis is 1,25 vitamin d production mediated.  Classically, for 1,25 Vitamin D mediated hypercalcemia such as in lymphoma, TB. etc, steroids are the mainstay of treatment. A dose of 15-25mg/day of prednisone is usually effective.  Ketoconazole is the next line of treatment for patients who cannot tolerate steroids.  Since its an imidazole antifungal that inhibits enzymes in steroid synthesis, it works well. Hydrocholoroquine also causes inhibition of 25(OH), D3 1 alpha hydroxylase and can be used in some patients that have side effects to prior two meds.  MTX and Azathioprine can be used to treat systemic disease that might have effect on calcium as well. ACTH has not been studied in this arena.  Pamidronate has been used in case reports but the mechanism of hypercalcemia doesn't really support the use of that agent. 

References:

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(98)08251-8/fulltext

http://www.ncbi.nlm.nih.gov/pubmed/6287893?dopt=Abstract

http://www.ncbi.nlm.nih.gov/pubmed/3755800?dopt=Abstract

Topic Discussion: Hypercalcemia and leukemias..( not lymphomas)

Classically, one associates hypercalecmia of malignancy with solid tumors such as breast cancer, kidney cancer and so forth. In regards to hematologic cancers, the lymphomas, and myelomas are the two disease states that have shown to have hypercalcemia.

Does AML, ALL and other leukemias have associated hypercalcemia? It’s rare. T cell leukemia classically associated with HTLV-1 has been widely reported and is the most common leukemia to have hypercalcemia. Besides that, the rest of them are 1-2 case reports. NEJM had one of the earlier cases of this association. Recently, childhood ALL was reported with hypercalcemia of malignancy as a result of parathyroid hormone-related peptide and E2A-HLF from translocation 17; 19.  Shu et al discuss the mechanism involved in leukemias and hypercalcemia. Cancer type T cell leukemia has a 50-90% incidence of hypercalcemia and its pthrp mediated or interleukin mediated or perhaps RANKL mediated. Acute non lymphocytic leukemia has a rare incidence but its pthrp and or 1,25 Vitamin D mediated.

Hypercalcemia and hypokalemia- is there a link?

Interestingly, we do encounter this combination sometimes and likely has no connection.  This was indeed studied in a 1977 paper in Annals of Internal Medicine. They studied 103 patients with hypercalcemia in a cancer hospital with normal renal function and no history of taking potassium depleting agents. Interestingly, 32% were hypokalemic.  The cause of hypercalcemia is most cases was malignancy followed by primary hyperparathyroidism. Also, as the calcium levels were higher, the frequency of hypokalemia was greatest.

Why does hypercalcemia cause hypokalemia?

Perhaps the calcium delivery increases the na delivery to the distal tubule which in turn results in na-k exchange with loss of potassium. This is what might be postulated based on animal studies and prior human trials.  This above study was only done in the cancer ward and hence might have many other confounders that were not accounted for such as chemotherapy agents that cause low K, diarrhea in setting of infections, chemotherapy and so forth.  While the pathophysiology is plausible, the more likely explanation might be true-true and unrelated.

TOPIC DISCUSSION: FUROSEMIDE in HYPERCALCEMIA

Treatment of symptomatic hypercalcemia is treating the underlying cause but also some symptomatic management.  Usually aggressive IV hydration is warranted sometimes even at 150-200-250 CC/HR.
Once volume depletion is addressed, a loop diuretic MAY be used for augmentation of calcium excretion.
A recent review and analysis published in Annals of Internal Medicine sheds some light about use of loop diuretic in this setting.
The review suggests the following points:

1. Aggressive hydration is necessary
2. Use of diuretics without aggressive hydration might be harmful
3. Found only 9 articles documenting the use of furosemide in hypercalcemia and latest one published in 1983 and total was only 37 patients.
4. Average dose was 1120mg over 24 hours ( really??)
5. Normalization of Ca occurred in only 14 of 39 cases
6. Study with lower doses didn't achieve normalization ( and what do we use????)
7. complications of other electrolyte disorders ensued
8. Finally, recommended against the use of this agent routinely except for cases of volume overloaded with hypercalcemia.
I think the tile of the paper listed below nicely puts it:- Furosemide in hypercalcemia is an unproven but common practice ( really not evidence based)

Ref: http://www.ncbi.nlm.nih.gov/pubmed/18711156

Hypercalcemia in Pregnancy

Check out a nice review on the NEJM Blog regarding
Hypercalcemia in Pregnancy

Prolia or Xgeva, Denosumab and The Renal world!

Bisphosphonates are established treatment for metastatic bone disease in many cancers.  Recently the RANK ligand inhibitors had come into the picture for treatment of osteoporosis under the name of Prolia. Osteoclasts are activated in part by a signal made by osteoblasts called RANKL (receptor activator of NFkB ligand), which binds to its receptor on osteoclasts( see figure below). Denosumab(Prolia) is a monoclonal antibody against RANKL. It thus prevents activation of osteoclasts and the initiation of resorption. Denosumab is given every six month subcutaneously. A trial called the Freedom trial( listed below in references) enrolled over 7800 women between the ages of 60 and 90 with a T score on their dexa scan between -2.5 and -4.0, denosumab prevented the radiological evidence of vertebral fractures, as well as reduced the risk of hip fractures, non vertebral fractures. It also increased bone mineral density at the lumbar spine and hip.  The side effects were not many. No patients with ESRD were included, but there were a fair amount of CKD stage II, III and IV patients in the trial and in those subgroups, fractures were less as well in the Prolia arm. Following that, three recent randomized trials also showed denosumab under the trade name Xgeva showed non inferior to bisphosphonates in prostate cancer and breast cancer and metastatic cancer to bone and myeloma patients in terms of skeletal related events and preventing bone lesions. And perhaps even preventing hypercalcemia of malignancy???

The studies are interesting and apparently renal monitoring is not needed.  Compared to zoledronic acid(comparison agent), no renal monitoring is required for these agents.  It appears at closer look at the trials that the renal events were similar in both with no significant statistically. 
For us these trials might be important to follow as perhaps this agent might be something that might be used in the near future and we have to monitor for any renal side effects. Besides, it causes significant hypocalcemia in normocalcemic individuals as a common side effect. Hence, it might be an interesting agent to consider in treatment of malignancy associated hypercalcemia. A more recent trial in the US on using this agent that included few myeloma patients as well showed non inferiority to bisphosphonates. Overall survival and disease progression were similar between groups. Hypocalcemia occurred more frequently with denosumab.  Osteonecrosis of the jaw occurred at similarly low rates in both groups. Renal adverse events and elevations in serum creatinine were more in the bisphosphonates arm.

Denosumab represents a potential novel treatment option with the convenience of subcutaneous administration and no requirement for renal monitoring or dose adjustment.
Let’s keep a close watch for it. For now, it is expensive and can only be given as an outpatient basis in the oncology clinics.


Check out the references below:
http://www.ncbi.nlm.nih.gov/pubmed/21411557
http://www.ncbi.nlm.nih.gov/pubmed/19671655
http://www.ncbi.nlm.nih.gov/pubmed/21353695
http://www.ncbi.nlm.nih.gov/pubmed/21060033
http://www.ncbi.nlm.nih.gov/pubmed/21343556
http://www.ncbi.nlm.nih.gov/pubmed/20682374
Image sources: medscape.com, cancergrace.org,
  

CLINICAL CASE 33, ANSWERS and SUMMARY

Which one of the following is NOT related to an elevated PTHrp level and leading to hypercalcemia? What you all answered:

SLE 29% 

Malignancy 6%

HIV associated Lympadenopathy 8%

Massive mammary hyperplasia during pregnancy 6%

Manganese toxicity 23%

During late pregnancy and lactation in hypoparathyrodism 25%

Close race between SLE, Manganese and Late pregnancy. Correct answer is Manganese toxicity. Rest of all are associated with pthrp production.

All above causes mentioned are rare causes of hypercalcemia to begin with.

Lets get to one by one.

We all know that malignancy such as ovary, lung and kidney can be associated with pthrp associated hypercalcemia.  SLE, HIV associated lymphadenopathy has also been associated with pthrp associated hypercalcemia.  Apparently, massive mammary hyperplasia during pregnancy, late pregnancy via placenta production of pthrp and lactation in hypoparathyroidism all have been associated with pthrp associated mechanism of hypercalcemia. The hypercalcemia associated with manganese toxicity is due to an unknown mechanism that we don't know( not pthrp).

Below are few causes that I saw in a very interesting article on rare causes of hypercalcemia.  Take a look.
Ref is below. 

**Rare causes of hypercalcemia associated with elevated 1,25-dihydroxyvitamin D

1. Wegener’s granulomatosis 

2. Cat scratch fever 

3. Crohn’s disease 

4. Acute granulomatous pneumonia 

5. Hepatic granulomatosis in chronic dialysis 

6. Talc granulomatosis 

7. Silicone granulomatosis 

8. BCG therapy 

9. 8-Cl-cAMP therapy 

10. Lipoid pneumonia 

11. Subcutaneous fat necrosis of the newborn 

**Rare presentations of the milk-alkali( calcium alkali) syndrome

1. Oyster shell calcium in betel nut chewing 

2. Overdose with buffered aspirin 

3. Massive cheese ingestion ( tofu perhaps as well)?

4. Munchausen’s syndrome 

**Unusual PTHrP-mediated hypercalcemic conditions

1. SLE 

2. HIV-associated lymphadenopathy 

3. Lymphedema of chest and pleural cavities 

4. Massive mammary hyperplasia during pregnancy 

5. During late pregnancy and lactation in hypoparathyroidism

6. With benign tumors of ovary and kidney, and in benign pheochromocytoma

** Medications that have been unusually associated with hypercalcemia

1. Omeprazole in acute interstitial nephritis 

2. Theophylline toxicity 

3. GH in intensive care unit patients 

4. Parenteral nutrition 

5. Foscarnet 

6. Hepatitis B vaccination 

7. 8-Cl-cAMP chemotherapy 

8. Manganese toxicity 

**Rare causes of hypercalcemia in which the mechanism is not known

1. Eosinophilic granuloma 

2. Leprosy in rheumatoid arthritis 

3. Mycobacterium avium complicating AIDS 

4. Cytomegalic virus infection in AIDS

5. Chronic berylliosis 

6. Nocardia asteroides pericarditis 

7. Diffuse octeoclastosis 

8. Paraffin granulomatosis 

9. Brucellosis 

10. Isolated ACTH deficiency 

11. Glucocorticoid withdrawal 

12. Hypocaloric diet in hypoparathyroidism 

13. Advanced chronic liver disease 

14. Type I Gaucher’s disease with acute pneumonia 

15. Lymphedema in SLE 

16. Juvenile rheumatoid arthritis 

17. Lymphadenopathy with high IL-6 

**Causes of Pseudohypercalcemia

1. High serum albumin 

2. Thrombocythemia 

3. Calcium binding to M-proteins 

Ref: 

http://www.ncbi.nlm.nih.gov/pubmed/16131579