Concept Map: Sickle Cell Disease and the Kidney

Topic Discussion: HSCT associated TMA, a renal endothelial variant of GVHD

Kidney injury post HSCT is a mystery. While the initial AKI is from multiple causes, the chronic damage we see in the survivors of HSCT is not well understood. In a recent review in AJKD, we did consider this to be mostly TMA related. But is TMA a form of GVHD ( renal limited) is what some including us have proposed. When one looks at the literature from GVHD and links to the kidney- one thinks of secondary membranous, but perhaps this is a rare finding- endothelial glomerular damage might be more common(TMA).

In a recent mice study, the authors looked at HSCT effect on kidney in various murine models of GVHD. The most common finding was glomerular with classic mesangiolysis, mesangial proliferation and edema with subendothelial widening and microthombi. These are features of HSCT- associated TMA. So, it is very possible that getting a HSCT might be a second hit to several folks who might carry a complement deficiency and perhaps there is some activation of complement system.

Some of the literature proposes that TMA and GVHD are not related but both affect the complement cascade. As clinicians we have seen several cases of TMA and concurrent GVHD and a recent reported case series confirms this. It is intriguing and possible that renal-limited TMA might be a variant of GVHD.  GVHD is usually an epithelial cell disease but having an “endothelial” target might be possible in the kidney. In most cases, when TMA is diagnosed in a patient with HSCT, the knee jerk response is to discontinue CNIs. Whether this is of potential benefit or harm is not clear.

This figure is from AJKD article 

Detective Nephron: Next case

Next Venture for Detective Nephron for Nov 2019

Concept Map: Polyuria

A solute diuresis is defined -- urine osmolality >600 mosmol/kg and a total daily osmolar output >1000 mosmol (calculated as the urine osmolality multiplied by the 24-hour urine output).

A water diuresis is defined with a urine osmolality <600 mosmol/kg and often <300 mosmol/kg and a total daily osmolar output <900 mosmol.

Another way to look at it from pure Uosm perspective is U osm <100mOsm/kg is generally a water diuresis from polydipsia or DI.  

Uosm between 100-300 mosm/kg is usually a mixed polyuria( either a central and nephrogenic partial DI and maybe simultaneous water and solute intake and CKD)

U Osm >300 is generally solute diuresis 

Topic Discussion: Do Renal consultations matter in surgical and cardiac ICU patients

AHA moment arrived when I saw this article in AJKD on interdisciplinary collaboration of nephrology with surgical and cardiac surgery ICUs. It was a qualitative study highlighting some of the conversations that happen in the CTICU with the nephrologists and what is “felt” about renal consultations.

https://www.ajkd.org/article/S0272-6386(19)30853-4/fulltext

This is an important topic that we encounter as consultants. Often, we get urgent calls from the ICU, for example CTICU , “ Doc, we need an urgent consult, this patient post CABG is oliguric now and crt rose from 1 to 1.4mg/dl and we need urgent CRRT, and we placed the dialysis catheter already for you…”
Now this situation is not uncommon… how does one respond to that..
Either you say, “ gee. Thanks for that and I will come evaluate and decide if I even need to use that catheter as they might not need dialysis..”  What is the role of the Nephrologist in some of the surgical run ICUs.? Are we seen merely as technicians or truly thoughtful physicians that make decisions that will or not alter the care of the patient..

The article really highlights this very important issue. Some of the major themes highlighted are listed below

1.      There was almost an absent influence of renal decisions in some of the surgical and CTICUs; this stemmed from many surgeons and intensivists not sure of the renal fellows decisions not going along with attending nephrologists decisions. In my opinion, many times and at many centers-they bypass fellow based consult services and call attendings only for that reason.

2.      Nephrology fellows and attendings found it hard to communicate to CTICU staff as the PA or NP would not really be making that decision and the final decision came from the surgical head of that patient ( who often is not in the unit)

3.      Nephrology fellows might not realize the hierarchy noted in some of the surgically based ICUs compared to MICUs.  This is interesting as the first time we encounter surgical culture in depth is during renal fellowship( 3 years in medicine- we usually are kept away from SICU, CTICU and NSICU)

4.      What I found totally astonishing was one of the comments made in box 2 by an NP that was interviewed is that “renal was the only service we had to call to get something done as We can’t just order dialysis” – and hence making us seem like just a dialysis ordering physician

5.      It also goes into details on who manages the fluid removal once CRRT has been started. It is an ongoing battle. Often this leads to conflict and at many centers, Nephrologists have given up CRRT ordering and management to ICU intensivists( sad but true)

6.      Due to our consult note and recommendations have no value- many times- there was early signing off of the consult- as “ if they are not listening to our recommendations anyway – why bother writing a note everyday…” Not uncommon to see in this unit.

7.      While Nephrologists thought they were best valued to understand AKI and noted a good nephrologist is a good internist. Meanwhile, surgical staff didn’t believe that and felt nephrologists were mostly dialysis gatekeepers and didn’t feel we understood AKI in the overall ICU status and ordering tests of diagnostic significance were not very valuable.

8.      The role of nephrologists being dialysis proceduralist clashed nephrologists value of preventive medicine mainly in the CTICU. From a surgical perspective, a consultation that doesn’t offer any valuable intervention such as dialysis to help the acutely ill patient is useless. – heard that one before many times

9.      The most common disagreements were on when to do dialysis, timing of initiation and managing fluids—the most common we see in practice anyway. It is not uncommon where I have written “ stop diuretics” but they are continued and then days later I am starting them on RRT.  But there have been also times where I have said “ stop diuretics” and they continued and they did better by not listening to me.  So in general, does our opinion matter?

10.   Interesting, surgical and CT ICU staff viewed dialysis as a tool to get rid of the kidney problem whereas we see it as a last resort before trying all medical maneuvers.  One comment was really funny, In box 3, one of the nephrologists interviewed said “ they view most of us as technicians. Just like anesthesia can just put the person to sleep, just put a tube and no big deal- anyone can do it, you can slap someone on dialysis, no big deal.”.  My favorite one I get called is “ can you come and spin him”

11.   Finally, due to history of these interactions, nephrologists and nephrology fellows avoided the controversial issues. Many times, this led to resignations from the case.

12.   Lot of these changes are due to different medicine vs surgical cultures.

How do we fix this? Can we fix this? The authors describe this is discipline siloing leading to ineffective collaboration amongst fields of medicine. This is important to break and learn. This will be critical as it can harm patients if gets escalated and neglect ensues. We need to understand the other persons perspective and realize that all physicians have one medical school, residency and fellowship—we all bring in some value to the patient. We need to respect and honor each other’s fields of medicine.

When I showed this article to one of our CT surgeons, his/her reaction was merely to dismiss it. My fellow and I were hoping for more of a conversation to improve this encounter.

Then the next day, in the CTICU, we see that the curtains are closed and one of the rooms was having open heart surgery happening in the middle of the ICU – for an urgent mater.  We were just amazed at the life saving nature of their field in medicine… it is just amazing what they can do. And I told my fellow, “ if they can make the ICU bed an OR instantly, their assumption is that dialysis can happen instantly and at any place- even in the OR..” We have to understand that they come from a different perspective.  Once we start understanding that, we may be more welcoming of their way of thinking. Similarly, at some point, perhaps they can understand our physiological approach to certain things and preventive nature of AKI and that dialysis is a procedure and not the first thing we should be doing..”

Topic Discussion: Artificial Intelligence in Nephrology

Artificial intelligence(AI) is on a rise in science. Using it in medicine and specifically nephrology is sure to come.

According to the dictionary, AI is “the theory and development of computer systems able to perform tasks that normally require human intelligence, such as visual perception, speech recognition, decision-making, and translation between languages.”

Dr Eric Topol has been a big proponent of this concept in medicine for years and recently has written a book called “Deep Medicine “ that details the potential uses of this in medicine.

Basically, AI can help in three main ways: 1) diagnosis that is often challenging in various challenging syndromes and even basic common ones. 2) make the physician’s life easier and decrease paper work and finally leading to the third -the most important 3) spending more time at the bedside.

AI is done via creating an  artificial neural network (ANN ) which is simply a collection of artificial neurons organized in layers. In a recent article in AJKD, authors discuss the potential use of this concept in Nephrology. They describe using it for IgA nephropathy(IgAN) as a recognizable cause for AKI. The ability to identify the patients that will progress to ESRD with IgAN would be useful for prognostic and therapeutic reasons. Geddes et al hypothesized that there exists a function that associates clinical and biological parameters measured at the time of IgAN diagnosis (namely age, sex, blood pressure, proteinuria, serum creatinine level, and antihypertensive treatments) to the probability of developing progressive IgAN. The authors designed and implemented an ANN to approximate this function. The results showed that their ANN could predict the occurrence of progressive IgAN more accurately than experienced nephrologists (correct predictions, 87% vs 69.4%; sensitivity, 86.4% vs 72%; and specificity, 87.5% vs 66%). Hmm, now this might be interesting to help guide a lot of therapies in Nephrology. This might be very useful in transplantation and prognosticating even need for dialysis for the elderly CKD patients.

Interestingly, many AI algorithms have been approved by FDA that are used in clinical practice:- some examples are of Atrial fibrillation detection, EF ECHO determination, Coronary calcium scoring, CT brain bleed diagnosis, device for paramedic stroke diagnosis, breast density via mammography to name a few.  No nephrology related such algorithms are approved to my knowledge.

There is an entire journal dedicated for this in medicine now

https://www.journals.elsevier.com/artificial-intelligence-in-medicine

Nephrologists, let’s get started and catch on!

Topic Discussion: Osmotic Nephrosis

Osmotic nephrosis describes a morphological pattern with vacuolization and swelling of the renal proximal tubular cells.

What does the pathology show:

Usually there is acute tubular necrosis–like changes. Histologically, osmotic nephrosis is characterized by a focal or, less often, diffuse “clear-cell” transformation of proximal tubular epithelial cells showing isometric fine vacuolization of the cytoplasm . The straight part of the proximal tubule primarily is involved and, in severe cases, also the convoluted part. Severely affected tubules are often seen side by side with normal-appearing tubules. Distal tubules and collecting ducts are more or less unchanged

Classic known causes of this entity are:

Intravenous immune globulin preparation(sucrose based)

Mannitol Dextrans
Contrast media
Hydroxyethyl starch
Glucose

How does one differentiate this from vacuolization seen with tacrolimus and cyclosporine? Is that a form of osmotic nephrosis?

Renal Pathologist Dr Lynn Cornell nicely describes this on twitter with these images. The image below shows isometric vacuolization in CNI toxicity. This leads to have focal tubules with this change( see arrow)

In osmotic nephrosis, tends to show vacuolated cytoplasm in tubules diffusely( see below)

Osmotic nephrosis describes a morphological pattern with vacuolization and swelling of the renal proximal tubular cells.

In addition, In paraffin sections, the isometric vacuolization seen in patients with calcineurin-inhibitor toxicity may be indistinguishable from osmotic nephrosis. However, electron microscopy shows dilated endoplasmatic reticulum as the cause of vacuolization in the former.  Osmotic nephrosis cannot be differentiated from lipid storage in tubular cells (foam cells), as seen in patients with nephrotic syndrome, liver failure, or intoxication. In such cases, foam cells also are often found in large amounts in the interstitial space. This does not occur in osmotic nephrosis.

The above image shows  osmotic nephrosis in a kidney biopsy specimen. (A, B) Tubular cross-section with seemingly no lumen. Epithelial cells are massively swollen, cytoplasm is completely filled by vacuoles of about the same size (isometric vacuoles), and nuclei are displaced to the base of the cells and distorted by adjacent vacuoles( source https://www.ajkd.org/article/S0272-6386(07)01592-2/pdf