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.

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

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.

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.

Fellow nephrons have you seen inclusion body nephritis in mice?
An Atypical Parvovirus Drives Chronic Tubulointerstitial Nephropathy and Kidney Fibrosis https://t.co/afcgYrILuV pic.twitter.com/ffa0wYnXZ8

— Katalin Susztak (@KSusztak) September 14, 2018

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.

Concept Map: NSAIDS and their effects on the Kidney

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.

Topic Discussion: HSCT associated TMA

Recently, 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.