An Unusual Cause of Acute Kidney Injury in Pregnancy: Beware of HELLP Look-Alikes
Anja Susanne Mühlfeld
Round 1
Reviewer 1 Report
The paper “An unusual of acute kidney injury in pregnancy: beware of 2 HELLP look-alikes” by
Orozco-Guillén et al.
The authors describe the case of a women with HELLP syndrome under their care. After delivery by cesarean section the typical laboratory features of HELLP syndrome resolve spontaneously. However, the patient develops anuric renal failure. During followup urinary output gradually increases and reveals nephrotic range proteinuria. The patient was biopsied and acute tubular necrosis, active tubulointerstitial nephritis as well as focal segmental glomerulosclerosis were diagnosed. The patient was treated with steroids and kidney function returned to normal. At the same time proteinuria decreased to 0,5g/d.
Minor points:
Title: an unusual of acute… should probably be: an unusual cause of acute….
Page 2 line 52: „it may first appear of flare up” > it should probably be “or flare up”
Major points that should be addressed in the discussion:
In the abstract the authors state that they aim to discuss the differential diagnoses of pregnancy related acute kidney injury. For this there are some major points missing in the discussion.
1. In my opinion the kidney biopsy shows three distinctive pathologies. One of them is the FSGS with focal segmental glomerulosclerosis and tip lesions. The other one is acute tubular injury and the third one interstitial nephritis. The first one might be responsible the nephrotic range proteinuria, the last two for the acute anuric renal failure which is not a typical feature of minimal change disease/FSGS. The features of interstitial nephritis and their contribution to acute renal failure are not discussed enough. Did the patient receive any medication that can typically cause interstitial nephritis (PPI, antibiotics etc.), what are the typical features of interstitial nephritis in the biopsy, what are the treatment options etc. In addition, the authors exclude typical causes for acute tubular injury such as hypovolemia, hypotension etc. However, these differential diagnosis need to be discussed in more detail for a teaching case.
2. The other most important differential diagnosis of HELLP syndrome associated acute renal failure is thrombotic microangiopathy. The authors should discuss in the discussion part, why acute renal failure in this patient is not due to thrombotic microangiopathy, which facts would suggest this diagnosis and which features are not consistent with it.
In general, I think this is a very interesting case and it is important to be aware of underlying, previously not diagnosed kidney disease in cases of acute renal failure. And this case is a good case to exemplify this. However, in the discussion the different aspect of the renal biopsy and the differential diagnosis should be discussed in more detail to strengthen the teaching case aspect.
Author Response
Dear Reviewers:
Thank you very much for your kind comments.
We would like to submit now a point by point answer to your comments.
First reviewer:
Minor points:
Title: an unusual of acute… should probably be: an unusual cause of acute….
Answer - Thank You for the correction:
“ A unusual cause of acute kidney injury in pregnancy: beware of 2 HELLP look- alikes”
Page 2 line 52: „it may first appear of flare up” > it should probably be “or flare up”
Answer.- FSGS is a relatively frequent cause of nephrotic syndrome in pregnancy and, as such, it may first appear or may flare up, becoming clinically manifest in
Major points that should be addressed in the discussion:
In the abstract the authors state that they aim to discuss the differential diagnoses of pregnancy related acute kidney injury. For this there are some major points missing in the discussion.
- In my opinion the kidney biopsy shows three distinctive pathologies. One of them is the FSGS with focal segmental glomerulosclerosis and tip lesions. The other one is acute tubular injury and the third one interstitial nephritis. The first one might be responsible the nephrotic range proteinuria, the last two for the acute anuric renal failure which is not a typical feature of minimal change disease/FSGS. The features of interstitial nephritis and their contribution to acute renal failure are not discussed enough. Did the patient receive any medication that can typically cause interstitial nephritis (PPI, antibiotics etc.), what are the typical features of interstitial nephritis in the biopsy, what are the treatment options etc. In addition, the authors exclude typical causes for acute tubular injury such as hypovolemia, hypotension etc. However, these differential diagnosis need to be discussed in more detail for a teaching case.
Answer Thank you for your comments
Point 1.- We asked about all kind of pills, including antibiotics, herbs, homeopathic drugs, and dietary supplements, and she denied all of them.
We detailed in the text that the patient had a bleeding of about 400 ml during C- section. We reviewed all charts, including obstetrical, anesthesiology and nursing records and found no report of even transitory hypotension.
We added this in the description.
Furthermore, we added the following remarks in the discussion, with a further reference:
The presence of a peritubular infiltrate rich in eosinophils evokes the diagnosis of interstitial nephritis, which may have played a role both in the clinical manifestations of the disease and in the good response to steroid treatment. While it is not possible to formally exclude a role for an added interstitial damage, in the majority of cases this is associated with the use drugs, herbs, homeopathy, and food supplements. However, our patient denied use of drugs and over-the-counter- toxins. The association between glomerular lesions and interstitial infiltrates is common, incompletely described, and not necessarily associated with a classic interstitial diseases, as it has been described for example in diabetic nephrology. The sensitivity of eosinophils to steroids may be one of the reasons for the rapid response to steroids.
- The other most important differential diagnosis of HELLP syndrome associated acute renal failure is thrombotic microangiopathy. The authors should discuss in the discussion part, why acute renal failure in this patient is not due to thrombotic microangiopathy, which facts would suggest this diagnosis and which features are not consistent with it.
In general, I think this is a very interesting case and it is important to be aware of underlying, previously not diagnosed kidney disease in cases of acute renal failure. And this case is a good case to exemplify this. However, in the discussion the different aspect of the renal biopsy and the differential diagnosis should be discussed in more detail to strengthen the teaching case aspect.
Answer: Thank you for this remark, we absolutely agree, and we added in the sentence a in the discussion.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
An interesting case report which shows the association between KD and HELLP.
Was the FSGS precipitated by HELLP?
Typos and defects in English expression are detailed in PDF.
There is no comment on advisability of long term followup
Comments for author File: Comments.pdf
Author Response
Reviewer 2
Thank you for your kindly comments.
Was the FSGS precipitated by HELLP?
Answer: We think that there is no association between HELLP and FSGS in our case; we think that in this case pregnancy was the trigger for a different glomerular disease. We further discussed this more in detail:
However, our patient presented some clues for the differential diagnosis between “primary” HELLP and HELLP superimposed on a glomerular disease2. Indeed, while HELLP syndrome may be associated with AKI, this often occurs in more severe HELLP, while in our case the main biochemical alterations resolved rapidly, and we observed dissociation between rapid healing of the biochemical alterations (elevated liver enzymes, low platelets and signs of hemolysis) and the persistence of anuria. Furthermore, in keeping with a diagnosis different from HELLP syndrome the kidney biopsy didn’t shows fibrin thrombi in glomerular capillaries or in arterioles thus excluding a thrombotic microangiopathy severe enough to cause anuria. Since, at least in cases associated with placental ischemia, a derangement in the ratio angiogenic-antiangiogenic drugs is observed, we would like to underline the importance of using more extensively these important biomarkers, also for facilitation the differential diagnosis between hypertensive disorders of pregnancy and CKD.
Pont 2.- There is no comment on advisability of long term follow-up
In addition to showing the nephrologist facing a woman with HELLP syndrome who does not improves possible differential diagnoses in the puerperium, this case emphasizes the importance of pregnancy for diagnosing kidney disease and the importance of follow-up by the nephrologist, because these episodes condition to long-term chronic kidney disease.
Thank you for making this fundamental point: we added this in the conclusions, as follows:
In addition, this case emphasizes the importance of pregnancy for diagnosing kidney disease and the need for further follow-up, to avoid the shift from AKI to chronic kidney disease.
Author Response File: Author Response.pdf
