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.

Topic Discussion: Pre eclampsia and APOL1

 This ASN 2021, I heard an interesting lecture and realized some novel associations with pre-eclampsia(PEC) and APOL1 gene mutations. 

Here are some interesting findings.

1. Black women have a higher risk of PEC their White counterparts.
2. Reidy et all showed that it is the FETAL not maternal APOL1 renal risk variant that is associated with PEC in Black women.

3. Some other studies showed that PEC was associated with the maternal G1 and not the G2 allele

4. In Blacks in Ohio, INFANT APOL1 genotype was associated with PEC

5. Recent study in AJKD, found that APOL1 kidney risk variants in Black mother and infant pairs of women of African American origin had higher risk of PEC compared to Haitian women. PEC was higher with maternal and fetal APOL1 genotype discordance, an effect driven by the African American mother-infant pairs. 

6. None of the published studies assessed if the mother’s APOL1 genotype conferred preeclampsia risk independently of the fetal APOL1 genotype, although in African Americans both the maternal and fetal APOL1 renal risk variants appear to increase risk if an APOL1 genotype discordance exists.

7. Experimental data support the hypothesis that APOL1 renal risk variants mediate preeclampsia. APOL1 levels, APOL1-derived peptides, and APOL1 autoantibodies have been linked to preeclampsia. Sedor's team showed that transgenic mice that expressed APOL1 using the nephrin promoter developed a pregnancy-associated phenotype characterized by hypertension, proteinuria, and seizures, which was more severe in transgenic animals with an APOL1 kidney risk variants transgene compared to reference. 

Overall, this is fascinating as we learn regarding the risk of PEC and APOL1 risk variants. It appears that fetal variants of the gene may be more important here.. the story continues to evolve... Stay tuned..

Consult Rounds: Pathology of Pre-eclampsia

Image source: JASN 2007

What do you find in the kidney biopsy of a patient with pre-eclampsia?
The immunofluorescence findings are somewhat variable with fibrin deposition often being a prominent feature.

The renal biopsy findings of preeclampsia closest to look in the context of the pathologic patterns seen in thrombotic microangiopathies (TMA). The lesions of preeclampsia share some similarities with and also some differences from those of non-preeclamptic TMA, likely owing to their differing pathogenesis.

What is the LM finding?

The glomeruli are enlarged and solidified (“bloodless”), as a result of narrowed or occluded capillary lumens that are the result of swelling of the native endothelial cells and, to a lesser extent, mesangial cells. The endothelial changes are limited to the glomerular capillaries; arterioles are typically unaffected. Thrombosis by light microscopy is decidedly unusual. In marked contrast, in nonpreeclamptic TMA, thrombosis of vessels and/or glomeruli is a central finding. Cases of severe preeclampsia with accompanying vascular thrombosis often have clinical signs suggesting a superimposed nonpreeclamptic TMA. In severe cases of preeclampsia, in particular as the lesions evolve/resolve, mesangial interposition can be seen, a finding shared with other entities resulting from chronic endothelial insult, such as “chronic” TMA or transplant glomerulopathy. So essentially, it may appear on LM in some cases- as an MPGN pattern of injury ( without the IF being positive for complements or immunoglobuins). This form of injury is termed “Glomerular endotheliosis” 

What is the EM finding?

Ultrastructural analysis will show endothelial cells with loss of fenestrations with cytoplasmic swelling, owing to fluid and lipid accumulation and capillary occlusion.

What is the IF finding?

How is it different from your “classic” non preeclamptic TMA that you might see with SLE or APLAS or in TTP?

The main finding in the “classic” TMA is thrombosis of vessels and glomeruli as the main finding with some endotheliosis. This is a rare finding in pre-eclampsia related TMA unless it is very severe.

Here is a link to a nice review:

http://m.jasn.asnjournals.org/content/18/8/2281.full

http://m.cjasn.asnjournals.org/content/2/3/543.full.pdf

CLINICAL CASE 61: Answers and Summary

PREGNANCY STATE CAN LEAD TO THROMBOTIC MICROANGIOPATHY. WHICH OF THE FOLLOWING ARE MECHANISMS VIA WHICH TMA HAPPENS DURING PREGNANCY?( MULTIPLE ANSWERS POSSIBLE)

HELLP syndrome associated 35%

ADAMTS 13 deficiency associated 10%

Complement alternative pathway associated 13%

VEGF deficiency associated 35%

Unknown mechanism associated 5%

Obstetric nephrology is a field with significantly complex patients who have high risk of maternal and fetal complications. Thrombotic microangiopathy(TMA) during pregnancy can have a vast differential. There is a new way of thinking of TMA after the advent of the atypical HUS diseases. Pregnancy associated TMA accounts for 8-18% of all cases of TMA. Its a secondary form of TMA.

Acquired causes of TMA from ADAMTS13 is a cause that is definitely one form that can be see in pregnancy and non pregnancy states that clinically would present as TTP more than HUS.

Dysregulation of the complement cascade especially the alternative pathway would lead to the newly discovered forms of atypical HUS and this can also be noted in pregnancy. Unknown mechanisms would be the other big category in the this as well.

HELLP syndrome: is this really a TMA or not a TMA? AKI is associated with fair amount of cases of HELLP syndrome. The pathology in the liver suggestive of TMA and some forms of HELLP syndrome share same genetic features as some atypical HUS syndromes. Kidney biopsies have rarely been done and those have shown TMA.

VEGF deficiency: Pre eclampsia has now been associated with antiangiogenic factors that might lead to anti VEGF state just like what we might see in cases of avastin toxicity. The biopsy in such cases might be also suggestive of  TMA. 

A recent review in CJASN reviews this nicely. Figure 1 has a nice timeline of when these syndromes might best fit during the three trimesters. 

IN THE NEWS: Soluble FLT-1 and ANCA... Not just pre eclampsia!

A recent study published in the Feb JASN 2012 issue showed that there is an elevated soluble FLT-1 that is inhibiting the endothelial repair of PR3 ANCA vasculitis.  This is very interesting as sFLT-1 now is not just associated with pre eclampsia.  Vasculitis causes endothelial damage. VEGF is a factor that leads to endothelial repair. The authors show that in the PR3 ANCA vasculitis state, the VEGF factors are inhibited by sFLT-1 and leads to decreased endothelial repair and hence worse vasculitis.
sFLT1 are elevated in placental vascular dysfunction and pre eclampsia. sFLT1 is produced by placental cytotrophoblasts but also monocytes and endothelial cells and it inhibits VEGF.  This study is interesting as it showed that sFLT1 was elevated in patients with PR3 ANCA vasculitis and this was due to monocyte activation activating the alternate complement components. They were increased in anti GBM and anti MPO disease but not significantly as in patients with anti PR3 related disease when compared to controls in their experiment. Interestingly, postulated that anti sFLT1 agents might be useful.

Take a look at the full reference
http://www.ncbi.nlm.nih.gov/pubmed/22034638

CLINICAL CASE 44: ANSWERS AND SUMMARY

34 YEAR OLD FEMALE, RECENT PREGNANCY,HAS SIGNIFICANT HYPERTENSIVE EPISODES AND IS ADMITTED. LABS SHOW MG OF 0.8. SHE HAS SLE ON STEROIDS AND TACROLIMUS. HX OF ITP NEEDING IVIG. WHAT(IN HER) ARE CAUSES OF POSTERIOR REVERSIBLE LEUKOENCEPHALOPATHY SYNDROME?

Pregnancy 22%

IVIG 25%
Tacrolimus 58%
Steroids 11%

SLE 38%

Hypomagnesemia 19%

Hmm... tough question but good try all.  In this particular patients, unfortunately she had all the risk factors and potentially known causes of Posterior Reversible Leukocencephalopathy Syndrome(PRES).

Known causes of PRES are: Pregnancy- pre eclampsia or eclampsia. SLE, Vasculitis, Uncontrolled hypertension from essential causes or secondary causes like medications ( steroids, tacrolimus), drug induced from chemotherapy like vincristine, anti VEGF agents, steroids, CNIs, IVIG are all risk factors.

TTP, HUS are known risk factors

Interestingly, hypomagnesemia, and hypocalcemia are noted to be risk factors as well.  

Ref:

http://www.ncbi.nlm.nih.gov/pubmed/21572160

http://www.ncbi.nlm.nih.gov/pubmed/18495165

http://www.ncbi.nlm.nih.gov/pubmed/21856490

In the NEWS: A novel treatment for Pre eclampsia- A renal method

Soluble fms-like tyrosine kinase 1 (sFlt-1), an alternatively spliced variant of the vascular endothelial growth factor receptor 1, induces a preeclampsia-like phenotype in experimental models and circulates at elevated levels in human preeclampsia. This is the factor that leads to decreased VEGF in pre eclampsia and causes the kidney related findings. Mice studies have shown that giving VEGF can alleviate the findings; but giving VEGF might pose significant risk to the fetus. Investigators at Harvard have shown for the first time that sFLT-1 can be removed via apheresis. Dextran sulfate apheresis lowered the levels of sFlt1 and reduced proteinuria, blood pressure and allowed for fetal growth in their observational paper. This pilot study is published in the August Circulation Issue and further testing is needed in a randomized fashion with more subjects to prove this will work.  

Ref:

http://circ.ahajournals.org/content/124/8/940.abstract

http://www.thekidneydoctor.org/2011/09/preeclampsia-syndrome-affecting-5-of.html