Thursday, September 20, 2018

Topic Discussion: Hormonal levels with various RAAS blockade medications

Class of RAAS agent
Renin level
Plasma renin activity
Ang II level
Aldosterone level
Renin inhibitor
Elevated
Low
Low
Low
ACEI inhibitor*
Elevated
Elevated
Low
Low
ARB*
Elevated
Elevated
Elevated
Low
Aldo receptor blocker
Elevated
Elevated
Elevated
Elevated

* after being on ACEI/ARB for long periods, due to aldosterone escape, aldosterone levels could be high in some cases.

Tuesday, September 18, 2018

Topic Discussion: Common Nephrotoxic drugs and their mode of enteries


Common Renal toxic drugs and their mode of entering the tubule and mechanism of toxicity

Drug Name
Mode of entry
Mechanism
Clinical Presentation(s)
Tenofivir(TDF)
Secreted via the basolateral side via OAT and then enters lumen via MRP2 in the urine.
Mitochondrial dysfunction
ATI
Proximal tubulopathy
Diabetes Insipidus(rare)
Gentamicin(Aminoglycosides)
They are all filtered and they are attracted to negative phospholipids and bind to megalin cubulin receptor and enter the cell.
Lysosomes binding and then cause mitochondrial damage and tubular injury—myelin bodies
ATI
Bartter’s syndrome( via activating of the CaSR in the TAHL)
Fanconi syndrome(rare)
Polymixin
All filtered, punch holes enter cells via organic cationic transporter(OCT) on apical surface
Apoptosis and necrosis
ATI
Vancomycin
Unclear how it enters
Complement activation
Activation of reactive oxygen species
Mitochondrial injury
Vancomycin cast formations
ATI
Worse when combined with Piperacillin / Tazobactam
Amphotericin B
Unclear how it enters
Principal cell defect via holes in the apical membrane
Distal hypokalemic RTA
ATI
Hypomagnesemia
Nephrogenic DI
Heta-Starch, Dextran, Sucrose, Mannitol
Filtered and enter proximal cell – pinocytosis and build up and swell up cells. Cannot be metabolized
Osmotic nephrosis
ATI
Atazanavir
Minimal renal excretion, poorly soluble in urinary ph- leading to crystallization
Crystal formation
Crystal Nephropathy
Cisplatin
Enters via OCT on the basolateral side, enters and activates apoptosis
Oxidative stress

ATI
Hypomagnesemia
Proximal tubulopathy
Salt wasting nephropathy
Nephrogenic DI

Ifosfamide
Enters proximal tubular cell via OCT on the basolateral side and then metabolized to its metabolized that causes the damage
Increased oxidative stress and mitochondrial injury
ATI
Fanconi syndrome

Monday, September 17, 2018

In the NEWS: Atypical parvovirus causing interstitial fibrosis and AKI


An interesting pathology study just got published in Cell.  It describes an atypical parvovirus infection in the kidney presenting as interstitial disease and fibrosis. Classically, the three lesions that have been described with parvovirus B19 infection are collapsing GN, FSGS and Minimal change disease. Both native kidneys and post transplant cases have been described.

In this study, using metagenomics, the authors identified a spontaneous nephropathy with intranuclear inclusions and the causative agent as an atypical virus, termed “mouse kidney parvovirus” (MKPV), belonging to a divergent genus of Parvoviridae. Detailed analysis of the clinical course and histopathological features demonstrated a stepwise progression of pathology ranging from sporadic tubular inclusions to tubular degeneration and interstitial fibrosis and culminating in AKI. 

Below is the visual abstract of the study from the journal abstract.

https://www.cell.com/cms/attachment/dce9cee6-aba6-4ffc-b2d4-386514152d74/fx1.jpg
Courtesy: Journal Article from Cell


This study highlights an interstitial inclusion type nephritis associated with parvovirus in mice. While clinically, to my knowledge, interstitial nephritis like this has not been reported with parvovirus.
A recent online discussion on twitter regarding this paper is linked below.

Conceptually we have always known that in humans viruses can induce kidney disease and fibrosis such as seen in BK, CMV, Parvovirus and so forth. This is definitely worth studying in humans.

Monday, September 10, 2018

Consult rounds: CRRT calculations primer


Two must know concepts in CRRT is clearance and filtration fraction.

How does one calculate clearance in CRRT?
Let’s start with convection first- so mainly CVVH (like you are making coffee) 
Clearance = V (u/p) but here dialysate/plasma eventually equilibrates, so the Clearance =Volume. What is your volume in CVVH? – IT is your total effluent—so it is your Replacement fluid rate + UF rate
If you had post filter replacement- just add replacement fluid rate + UF
If you had pre filter replacement- you need to have a correction factor, because the blood that enters the filter pre filter has a different concentration and gets diluted. The correction factor is an equation that reduced the replacement fluid rate by a certain percentages that includes the blood flow rate.
The formula for the fudge factor is BFR/ BFR+ Replacement fluid rate. An amazing you tube video explaining this concept.

Now let’s do the diffusive clearance (like making tea with a tea bag) - you need to basically add all the rates- DFR+ UFR+ post filter rate. You tube video link for this calculation.
So the Clearance = Diffusive + convective if it’s CVVHD ( Remember to only add UFR once)

Here is an example of a patient getting CVVHDF with order set

BFR=100cc/min or 6000cc/hr
DFR= 1400cc/hr
Pre filter- 800cc/hr
Post filter- 200cc/hr
UFR-100cc/hr

Let’s do diffusive first.  Clearance = DFR+ UFR = 1400+ 100= 1500cc/hour =25cc/min
Convective = pre filter + post filter +UFR( but we already counted UFR above) so can’t count again.
Also, pre filter needs a correction factor. 
The correction factor is Blood flow/ Blood flow +replacement fluid rate.  So that is 6000/6800= 0.88 for the pre filter part. So here the pre filter part will be 800 *0.88=705.

So the convective clearance = 705+ 200= 905cc/hr =15cc/min
So total prescribed dose gives you a clearance of 25+ 15= 40cc/min

So if this individual was 85kg
It would be 1500+ 905 cc/hr = 2405/85=28 cc/kg/hr
How does one calculate Filtration fraction?(FF)

FF===Effluent flow / blood flow with correction factor

Your effluent will include the DFR+UFR. You want the FF <20% to avoid clotting. So if you increase the numerator, your FF increases or if you decrease the denominator, FF increases. So, basically, you have to keep the blood flow high if you want to increase UFR or DFR to avoid the increased concentration of the plasma and increase clotting risk. Here is the FF YouTube video explanation.

Sunday, September 9, 2018

Topic Discussion: HSCT associated TMA


Image result for TMA kidneyRecently, we wrote an article on Bone marrow transplant or HSCT related TMA for AJKD.
Few things that we have seen in our experience and also what we learnt while writing on this topic is important for Nephrologists to understand.



1.       Diagnosis of TMA related to HSCT that effects the kidney is hard to diagnosis. It is likely the most common kidney biopsy finding post HSCT.  Besides the lab parameters of kidney injury, TRENDING the LDH, haptoglobin, platelets and hemoglobin is critical. In addition, HTN might be the first and most important sign of impending TMA. If the patient requires more than 2 meds for HTN control, one for CNI and other for steroids, it is possible that there is a smoldering TMA . Perhaps we miss some of these cases due to this. Early Nephrology referral might be key as urinalysis is not uniformly done in most centers years post HSCT.
2.       Once infections such as parvo, BK and CMV have been ruled out, a complement mediated process is the likely cause.
3.       CNIs are usually portrayed as the most likely culprit but not all allogenic HSCTS are on CNI and none of the autologous HSCT are on CNIs, yet TMA ensues. In many instances, TMA still gets worse.
4.       Based on some recent findings in the basic science world and few case reports, we propose that TMA following HSCT in many cases might be an “endothelial” variant of GVHD. Treating the underlying GVHD might be the best option in these cases. This might open certain treatment avenues that we haven’t really encountered.
5.       If the TMA is not a ADAMTS13 process, or a “antibody” being removed, TPE doesn’t really help in most cases. Rituximab can be a potential option as this might also help treat GVHD. Alternatively, in many pediatric patients, eculizumab has been used with some success to halt the activated complement  process.

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