Concept Map: Pre eclampsia (PEC)

 

Here is a figure based concept map of pre-eclampsia using biorender.com 

Topic Discussion: Capillary Leak Syndrome

A recent review in KI summarizes the pathophysiology of capillary leak syndrome and numerous etiologies that can cause it along with an interesting management strategy.

Besides sepsis, capillary leak syndrome(CLS) can be seen in:

1.       Drug induced CLS—classically interleukin 2, gemcitabine and certain monoclonal antibodies such as OKT3, anti CD-28 antibody TGN1412  ( steroids can help treat)

2.       Engraftment syndrome- seen post HSCT ( usually 4-7 days post) with increased inflammatory markers and AKI( 12-25% in most HSCT patients)( steroids can help treat)

3.       Differentiation syndrome( retinoic acid) – steroids help in this situation as well

4.       Ovarian hyperstimulation syndrome(OHSS)—two variants( early time course, vs late following HCG treatment)—supportive care

5.       Hemophagocytic lymphohistiocytosis

6.       Hemorrhagic fever( viruses such as Ebola, Marburg, Puumala)

7.       Clarkson’s disease( idiopathic CLS)—supportive therapy, IVIG, theophylline

8.       Others:- snake bites, Ricin overdose, APLAS, Kawasaki disease

In addition to hypotension, cytokines are likely to be important in the pathophysiology of acute kidney injury in capillary leak syndrome. Fluid management is a critical part of the treatment of capillary leak syndrome; hypovolemia and hypotension can cause organ injury, whereas capillary leakage of administered fluid can worsen organ edema leading to progressive organ injury.

The first phase of treatment is volume resuscitation including fluids, pressors and or IV albumin. The second phase includes loop diuretics, diuretics with albumin and finally renal replacement therapy.

Full article here

https://www.ncbi.nlm.nih.gov/pubmed/28318633

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

In the NEWS: US Nephrologists, dialysis and pregnancy

Pregnancy occurs among 1–7% of women on chronic dialysis. Data on how dialysis is provided in ESRD patients who get pregnant in the US is lacking. A recent survey published reveals the latest update on this topic. 

While the response rate is small, the information might be important. Limited providers might have this experience of providing for dialysis for the pregnant patient. Of the respondents, 45% had cared for pregnant females on HD and 78% of pregnancies resulted in live births. In 44% of the pregnancies a diagnosis of preeclampsia was made. There were no maternal deaths. Nephrologists most commonly prescribe 4–4.5 h of HD 6 days/week for pregnant women on dialysis. More dialysis time is associated with better volume and electrolyte control. The frequency of preterm delivery and intrauterine growth restriction tends to correlate with BUN levels. There is an inverse association between BUN level and birthweight and adverse fetal outcome, with more favorable outcomes when the serum urea level is <75 mg/dL. The survey shows that most US nephrologists target a BUN of <50 mg/dL (66%) and 21% aim for a target predialysis BUN of <20 mg/dL. Intensive dialysis is a necessary important finding that is now becoming norm for patients who are pregnant.  Both maternal and fetal outcomes have improved.

What was interesting in the study was "Women dialyzed cumulatively for >20 h/week were 2.2 times more likely to develop preeclampsia than those who received ≤20 h of HD per week."
Why would that be?.  The authors think that it might be for two reasons: increased hours on HD leading to more vasoconstriction and tighter volume control leading to pre eclampsia. Also since this was a survey, the diagnosis of preeclampsia was dependent on the nephrologist recognizing it and perhaps a "diagnosis" labeling problem. 

Pregnancy on dialysis is becoming frequently encountered, pregnancy care should be part of the health maintenance plan of women of childbearing age on dialysis. OB-Nephrology should be considered a sub field in Nephrology and should become part of academic centers as a career paths for nephrologists and training of fellows. 

Nephrology Crosswords: Obstetric nephrology

Check out the next installment of Nephrology Crosswords in Kidney International on
Obstetric nephrology

Topic Discussion: Glomerular Diseases and Pregnancy

Many times, primary GN presents during pregnancy and diagnosis is tough. Other times, patients with known primary GN get pregnant.  Three questions come to mind.

1.       Does the pregnancy change the natural course of the glomerular disease?

A study done in over 120 pregnancies looked at this question. The clinical course of 123 pregnancies in 86 patients with biopsy-proven glomerular diseases was evaluated. No complications were observed in more than half of the pregnancies. The lowest incidence of complications was observed in patients with membranous nephropathy and the highest in membranoproliferative glomerulonephritis(MPGN) patients. Renal function deteriorated in 10 cases during pregnancy. The authors note that in most patients pregnancy did not change the natural history of glomerular disease.

2.       What are the risk factors in GN with pregnancy for maternal and fetal outcomes?

Hypertension and impaired renal function at conception seem to carry increased risk for mothers and fetuses. A study done at a single center looked at these complications. 24 pregnancies in 17 women with biopsy-proven glomerular disease was analyzed. The underlying renal histology was IgA nephropathy in 8 cases, lupus nephritis in 7, MPGN in 1, and focal segmental glomerulosclerosis in 1.

                Fetal survival rate was 75%. The perinatal mortality was 5.5%. De novo hypertension occurred in 8 pregnancies (33.3%). In 11 pregnancies (46%) increased proteinuria was diagnosed and in 6 (25%) a decline in maternal renal function was recorded. Maternal hypertension and renal function impairment were found to lead to more ob complications.  

3. Which GN fare the worse?

Many GN have been reported with pregnancy( Membranous GN, MCD, MPGN, IgA, FSGS). A single center study looked at outcomes based on type of GN in pregnancy. In all cases diagnoses were established by biopsy before pregnancy. They were: MPGN in 16 patients, focal glomeruloesclerosis in 13, IgA nephropathy in 10, membranous nephropathy in seven and focal glomerulonephritis in two women. Women with membranoproliferative glomerulonephritis appeared to fare worse, and those with IgA nephropathy and membranous nephropathy better than the rest.

IN THE NEWS: New guidelines for Hypertension in Pregnancy

A recent task force from ACOG ( included high risk OB, anesthesiologists, nephrologists) in 2013 re-evaluated the definition and concept of using proteinuria in the diagnosis of pre-eclampsia. Proteinuria is not going to be considered a hard finding anymore for the diagnosis of pre-eclampsia. The ACOG felt that this would delay diagnosis in many cases. The entire report is found here.
Proteinuria seemed to have been down graded in many instances in the report. 

Diagnosis:

BP criteria remained
Proteinuria over 5gm has been eliminated from the term of severe preclampsia.
Severe features of pre-eclampsia now include: BP changes, SBP>160mmHg, low platelets, impaired liver function, AKI, pul edema and new onset cerebral disturbances.

Some other changes:

• Screening to predict preeclampsia beyond taking an appropriate medical history to evaluate for risk factors is not recommended.
• Vitamin C or vitamin E to prevent preeclampsia is not recommended.
• Daily low-dose aspirin to help prevent preeclampsia is suggested in very high-risk women with a history of preeclampsia and preterm delivery.
• Antihypertensive medication is recommended for severe hypertension during pregnancy.
• A decision to deliver should not be based on the amount of proteinuria or change in the amount of proteinuria.
• The use of magnesium sulfate is recommended for severe preeclampsia, eclampsia, or HELLP syndrome.

Risk factors the task force came up with for pre-eclampsia:

Primiparity

Prior pre eclampsia

CKD

Chronic HTN

Thrombophilia history

Multi-fetal pregnancy

IVF

Family history

DM I or II

Obesity

SLE

Advanced maternal age ( >40)

CONSULT ROUNDS: PRES in Pregnancy

                

Posterior reversible encephalopathy syndrome (PRES) is a clinic-neuroradiological syndrome associated with various clinical conditions, presenting with headache, encephalopathy, seizures,
cortical visual disturbances or blindness. Imaging predominantly shows parieto-occipital white matter changes, with vasogenic edema being the most accepted pathophysiology.
Common clinical conditions include hypertensive encephalopathy, renal failure, autoimmune disorders and treatment with immunosuppressant or cytotoxic medications.
Uncommon clinical conditions include acute intermittent porphyria and cryoglobulinemia.

Some of the earlier cases of PRES were seen with SLE patients and in kidney transplant patients the classic association is with CNIs in rare circumstances. Preeclampsia and eclampsia may be the most common  causes of PRES during pregnancy and most cases are managed without neuroimaging, and the incidence remains unknown.  However, it is uncertain whether a cause and effect relationship truly exists between the two or if these represent independent processes with some element of clinical overlap.
By definition, all patients with posterior reversible encephalopathy syndrome have a characteristic MRI pattern with bilateral hemispheric boundary zones of hyperintensities on T2 and FLAIR imaging, with increased apparent diffusion coefficient values, affecting the cortex and subcortical and deep white matter to varying degrees. The pathogenesis of PRES remains unclear, but it appears to be related to disordered cerebral autoregulation and endothelial dysfunction. Cerebral venous and sinus thrombosis (CVST) in the postpartum period is also a common cerebrovascular incident during the puerperium. Clinical manifestations consist of headache, vomiting, focal or generalized seizures, confusion, blurred vision, focal neurologic deficits, and altered level of consciousness. It is in the differential diagnosis when considering PRES in pregnancy in the post partum period.

                                                                               

Image source: radiopaedia.org           

PitFalls in GFR: Pregnancy

A 29 year old pregnant female with a serum crt of 0.8mg/dl and eGFR of 90cc/min.
During Pregnancy, GFR increases by 40-65%, as a result, crt will fall and be lower than usual state of health in most part of pregnancy. 

Per studies, the MDRD formula underestimates the true GFR on the basis of inulin clearance by more than 40ml.min.  Another study found the bias to be less- around 20cc/min. There are currently no published data on the accuracy of the MDRD formula in pregnant subjects with GFR <60 ml/min. Given these issues, 24-h urine collection for CrCl remains the gold standard for GFR estimation in pregnancy. In the above case, it may reflect diminished renal function in the setting of pregnancy. 

Ref:
http://www.ncbi.nlm.nih.gov/pubmed/17970797
http://www.ncbi.nlm.nih.gov/pubmed/17909992

Clinical Case 65: Answers and Summary

A 34 YEAR OLD FEMALE ON HEMODIALYSIS GETS PREGNANT. HOW WOULD YOU ADJUST THE PRESCRIPTION ON DIALYSIS TO HAVE THE BEST OUTCOME FOR MOTHER AND BABY?

Change to Peritoneal dialysis

  7 (9%)

 

Since the largest data suggests poor outcomes, would suggest to not continue pregnancy

  2 (2%)

 

Daily dialysis for total of 12-15 hours per week

  38 (50%)

 

Three times a week dialysis as her regular prescription

  6 (7%)

 

Three times a week dialysis but goal pre-dialysis BUN<35-40mg/dl

  23 (30%)

 

Pregnancy has been reported in dialysis patients. Over 70% of 80 pregnancies reported in one large series, had resulted in surviving infants and no maternal deaths. The largest case series to date of pregnant HD patients is 52 patients over 20 years. In that experience, HD was performed daily but total weekly treatments were shorter( 12-15 hours per week). UF was avoided and over 85% of pregnancies ended up with surviving infants. Most were pre terms. BUN concentration is <35mg/dl. In other words, pregnancy can be successfully tried in HD patients in the right circumstances and in the experienced centers. Most answered the question correctly. 

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

Hypercalcemia in Pregnancy

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

TOPIC DISCUSSION: Renal Function in Pregnancy

A recent review in ASN Kidney News nicely summarizes the renal function in pregnancy- By Dr.August.

Here are some summary points:
1. GFR will increase by 50%, practical pointers:- crt of 0.4mg/dl is not abnormal and going up to 1.0mg/dl might be a sign of renal dysfunction.
2. Renal Blood Flow increases by 80%
3. There is early decrease in blood pressure to the extent of 5-10mmhg SBP and 2-5mmhg in DBP even letting people come off BP medications
4. There is little evidence that the increased GFR is leading to increased intraglomerular pressures and there is hyperfiltration injury.
5. RR, Tidal Volume and Alveolar ventilation increases in pregnancy
6. Partly compensated resp alkalosis ensues
7. There is a decreased osmotic threshold for thirst and ADH release. Hence, there is a decrease in Serum Osm and plasma Na.
8. Increase 1,25 Vitamin D levels have been observed in Pregnancy and pth is decreased, urinary Ca excretion is decreased.

The last concept is interesting and why these levels increase and perhaps that's the reason we might encounter a slight hypercalcemic state.  There is some data that placenta can make pthrp as well.

Interesting physiologic changes

Ref:
ASN KIDNEY NEWS 2011:-Page 7-9
http://www.ncbi.nlm.nih.gov/pubmed/8588110
http://www.ncbi.nlm.nih.gov/pubmed/1992673

In the NEWS:-Pregnancy and the Kidney

http://onlinedigeditions.com/publication/?m=15191&l=1
ASN Kidney News July 2011 has an entire issue on Pregnancy and Kidney Disease from basics to transplant related issues.

CONSULT ROUNDS: Pre Eclampsia

**Preeclampsia usually begins in the third trimester, but can occur earlier in patients with preexisting renal disease or hypertension; as early as 20 weeks.
** It can also occur postpartum with hypertension, even up to 6 weeks after delivery.
**.It presents with weight gain andedema, particularly of the hands and face, proteinuria and HTN.  Nephrotic syndrome is noted.  Other lab parameters are elevated uric acid, LDH, liver function tests, and can progress to oliguria.  Fatty liver of pregnancy, HELLP syndrome, TMA associated with pregnancy all have to be ruled out.  
** The severe HTN can itself lead to TMA like picture causing schistocytes to be noted on smear, down-trending haptoglobin and hemolysis ensues. 
**There is a fall in renal blood flow and GFR that can lead to hyperuricemia and hypocalciuria as well as acute renal failure.  The acute renal failure is thought to be due to glomerular endotheliosis withswelling of endothelial cells and subendothelial hyaline and fibrin deposition.  Acute tubular necrosis and cortical necrosis can also occur.
**Pulmonary edema can occur due to changes in pulmonary capillary permeability. 
**Hyperreflexia reflects increased nervous system excitability.When preeclampsia is more severe, it can progress to the HELLP syndrome with hemolysis, elevated liver enzymes,and low platelets.
**Due to decreased placental perfusion, fetal growth restriction and oligohydramnios can occur. 


For more information take a look at this review for all.
http://www.ncbi.nlm.nih.gov/pubmed/21240869
http://www.ncbi.nlm.nih.gov/pubmed/17261438

Pregnancy in Chronic Kidney Disease

A review of this on NOD.

Pregnancy in Chronic Kidney Disease

TOPIC DISCUSSION: Magnesium for pre eclampsia?

Magnesium sulphate increased prostacyclin production and that is a potent vasodilator.  Some people think this might be the reason for prevention of pre eclampsia and eclampsia where cerebral vasospams and decreased blood flow are thought to be contributory.  It prevents seizures by binding to Ca sites and not letting the muscles work as they are supposed to. 

Cardiac output usually increases following magnesium administration, compensating for the vasodilatation and minimising hypotension.  It is the first-line anticonvulsant for the management of pre-eclampsia and eclampsia, and it should be administered to all patients with severe pre-eclampsia or eclampsia. Magnesium is a moderate tocolytic but the evidence for its effectiveness remains disputed. 

What is the data?

1. Two studies randomized showed Mg sulfate over placebo to be preventive of seizures in severe pre eclampsia.

2. Overview of all controlled randomized trials comparing mg sulfate in pre eclampsia as an anticonvulsants show its superiority versus placebo

3. ACOG recommends that use of mg sulfate in women with severe pre eclampsia and that there is lack of consensus as to women in mild pre eclampsia require such treatment or not given small data on that.

Can acute magnesium toxicity occur in the obstetric literature and patients? Magnesium levels when checked are high in these patients getting doses of magnesium but no toxicity is seen.  It is rare. Literature has few cases reported but mostly were due to accidental overdosing of the agent. 

The normal plasma concentration of magnesium is 0.8-1.0 mmol/L  or 1.7 to 2.2 mg/dL. and the suggested therapeutic range in pregnancy 1.7 to 3.5 mmol/L  or 4.8-8.4mg/dl. Complicating the interpretation of serum magnesium is that it can be reported in milligrams per decilitre (mg/dL), milliequivalents per litre (mEq/L) or millimoles per litre.  As a divalent ion, the latter two are not the same. Deep tendon reflexes are diminished or lost between 3.5 and 5.0 mmol/L, with respiratory paralysis thought to occur at  >= 7.5 mmol/L, although significant ventilatory changes occur at lower concentration. Central nervous system depression in conjunction with serious cardiac conduction abnormalities is seen at 7.5 mmol/L and cardiac arrest possible at >=12.5 mmol/L. It also depends on when you draw the level and initially you might get a very high value. 

The most common regimen for prevention in pregnant females is a loading dose of 6 g intravenously over 15 to 20 minutes followed by 2 g per hour as a continuous infusion. If someone is in renal failure, lower doses are suggested as main route of clearance is kidney. Following serum magnesium levels is not required if the woman's clinical status is closely monitored for evidence of potential magnesium toxicity. So we don't need to be chasing mg values.

Ref:

http://www.ncbi.nlm.nih.gov/pubmed/21154341

http://www.ncbi.nlm.nih.gov/pubmed/20861112

http://www.ncbi.nlm.nih.gov/pubmed/20669783

http://www.ncbi.nlm.nih.gov/pubmed/20005782