Topic Discussion: Amyloidosis and Renal Infarction

Usually when we think of amyloidosis in the kidney- we think of paraprotein mediated amyloidosis (AL or AH) leading to nephrotic syndrome and in some rare cases- vascular amyloid presenting as AKI.

A recent study published in Mayo Clinic Proceedings suggests that renal infarction might be a common finding in patients with cardiac amyloidosis. Three groups of patients were identified according to the underlying amyloidosis disorder: AL amyloidosis in 24 patients, mutated-transthyretin amyloidosis in 24 patients, and wild-type transthyretin amyloidosis in 39 patients. Patients with AL amyloidosis had significantly higher N-terminal pro-B-type natriuretic peptide levels (P=.02) and were more likely to have nephrotic syndrome (P<.001). Renal infarction was detected in 18 patients (20.7%), at similar frequencies in the various groups. The likelihood of RI diagnosis was 47.1% (8 of 17) in the presence of AKI and 14.5% (10 of 69) in its absence (P=.003).  Renal infarction (defined by defect(s) on the DSMA scan) was reported in 20.7% of patients with and 25% without evidence of cardiac amyloidosis. Prior studies have not really shown any association like this before of amyloidosis and infarction. Renal infarcts were described in an autopsy study in 3 kidneys that had either cast nephropathy, plasma cell nodules, or autolysis but not with amyloid deposits. Dang et al interesting are reporting is a high percentage of abnormal DSMA scans in patients with wild-type transthyretin amyloidosis (wtATTR) and mutant transthyretin amyloidosis (mATTR) amyloidosis.

These findings are intriguing. The 20% to 25% prevalence reported by Dang and colleagues was therefore unexpected. Renal involvement in ATTR is thought to be rare, especially in patients with wtATTR amyloidosis. Recent drugs used to treat this form of amyloidosis might lead to a glomerulonephritis( my recent post). The finding from the current study suggests that we may be vastly underestimating the prevalence of kidney involvement in ATTR amyloidosis. These patients usually don’t present with nephrotic range proteinuria but more with AKI and subacute AKI. Perhaps, instead of labeling all of these as cardio-renal syndrome, we should consider looking for renal infarction in these patients. And as I have always thought about ruling out amyloidosis in young males who present with renal infarction, I usually stop at AL-AH amyloidosis testing. Given the above findings, perhaps an amyloid scan to look for wtATTR and mATTR might be important as perhaps renal infarction could be a potential relationship here. 

Quite an interesting association!!

Topic Discussion: Tumor Lysis Syndrome with immunotherapy

At this point the nephrology and oncology community is very aware of the AIN, glomerular diseases including vasculitis and ATN seen with check point inhibitors… but we might not be aware of tumor lysis syndrome that this drug can entice in certain patients. 

In the last 2 years, I found several published reports of TLS with check point inhibitors.

Here is a table I created to help with the theme on this one

Immunotherapy	Age	Gender	Cancer type	Time to TLS	Dialysis needed?	Outcome	Reference
Nivolumab	76	Male	Melanoma	5	Yes but declined	Disease progression-death	http://www.alliedacademies.org/articles/acute-tumor-lysis-syndrome-after-antipd1-immunotherapy-nivolumab-for-metastatic-melanoma-8038.html
Atezolizumab	77	Female	GU cancer	14	Yes	Disease progression-death	http://www.acanceresearch.com/cancer-research/tumor-lysis-syndrome-following-a-single-atezolizumab-infusion-for-metastatic-urothelial-carcinoma-involving-both-upper-and-lower-t.php?aid=18193
Atezolizumab	-	-	Solid tumor	-	-	-	https://www.ncbi.nlm.nih.gov/pubmed/25428504
Atezolizumab	-	-	Solid tumor	-	-	-	https://www.ncbi.nlm.nih.gov/pubmed/25428504
Ipilumumab	73	Male	Melanoma	6	No	Death	https://www.ncbi.nlm.nih.gov/pubmed/27256718
Nivolumab	74	Male	RCC	2	No	Death	https://medcraveonline.com/JCPCR/JCPCR-08-00271.php

Based on this, it is seen with PD-1, PDL1 and CTLA4 inhibitors and melanoma and urological cancers. A recent review in JON showed a case of a patient getting TLS with melanoma.  So it’s hard to tell if these agents are causing it or is it the burden of tumor- usually solid tumors in these cases.

Concept map: Hyponatremia in the cancer patient

This concept map was adapted and inspired by Umut Selamet and Ala Abudayyeh, both onconephrologists.

Consult Rounds: Causes of Osmotic Demyelination unrelated to hyponatremia correction

Osmotic Demyelination syndrome (ODS) is classically been associated with rapid correction of hyponatremia. But sometimes, in some rare cases, we observe other causes of this syndrome.
Here is a list that encompasses other known causes of ODS

Hyperglycemia
Hypernatremia( acute formation)
Hypoglycemia
Hypokalemia( this is well known entity causing it)
Alcoholism( This is probably the most important one)
Liver disease and liver transplantation
Malnutrition( another important one)
Hypophosphatemia
Use of CNI( not sure of the mechanism of this one)
Lithium use

This article from AJKD is an amazing reference.

Detective Nephron: Next Venture

Check out the next episode of Detective Nephron in ASN Kidney News

https://www.kidneynews.org/kidney-news/fellows-corner/detective-nephron/detective-nephron-june-2019

Consult Rounds: Novel Sofosbuvir based Hep C agents and AKI

Can the novel agents used to treat hepatitis C cause AKI?

Most of the novel agents used to treat Hep C now in the current era are Sofosbuvir based. It has low rate of drug-drug interaction but kidney excretes over 70% of it’s major metabolite. This metabolite know as GS-331007 increases by ten fold in patients with renal dysfunction.

To my knowledge, no initial trials had any cases of AKI reported with this agent. Based on some recent trials using this agent, AKI might happen in 1-15% of patients treated with this agent.  Higher incidences were seen ( 45%) in liver transplant patients getting this agent. 

https://www.ncbi.nlm.nih.gov/pubmed/26923436

https://onlinelibrary.wiley.com/doi/full/10.1111/apt.14117

When?- 9-22 weeks of treatment.
Risk factors:- CKD, NSAID use, other nephrotoxic agent, DMII and ascites

Pathology:- what is the mechanism? There are only 4 published cases of kidney biopsy findings. We had published the first case of this in 2016 that showed AIN.  Subsequently, 3 other cases with AIN have been published and in one case ATN was also reported. It appears that the most likely mechanism is interstitial disease. In 2 of the 4 cases, 8 weeks was the time frame of injury, in remaining was 14 and 22 weeks of injury. It seems to be reversible in most cases.

https://accpjournals.onlinelibrary.wiley.com/doi/abs/10.1002/phar.1803

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496585/

https://europepmc.org/abstract/med/28656492

This is an interesting trend to watch. As we see less and less of Hep C induced renal disease, it is more likely we may see more treatment induced renal disease now.

A recent review of this topic is a good read.

Consult Rounds: High Dose IV Insulin and new avenues of treatment..

Traditional therapies for beta-blockers or calcium channel blocker toxicity are:
Glucagon, Calcium, Atropine and Vasopressors.

What I learned is that now high-dose insulin therapy has emerged as a preferred treatment of cardiogenic shock induced by calcium channel blockers or beta blockers. When used at doses 10 times that of the normal antidiabetic dose, insulin has positive inotropic effects even in the presence of beta-blocker or calcium channel blocker toxicity. What insulin dose at these high doses is improve hemodynamic stability and improve response to pressors. This takes almost 30 min to take effect.

There is a toxicology guidelines for this listed below: Consensus recommendations for the management of calcium channel blocker poisoning in adults. There is a  linear dose-response curve where increasing doses of insulin produce increasing positive hemodynamic effects. Goals for treatment can be a heart rate of at least 50 beats per minute and a systolic blood pressure of at least 100 mmHg. Obviously, one has to give dextrose to combat the severe hypoglycemia that might result of this and monitor K and phos levels s well.

Interestingly, this is being used commonly in beta blocker toxicity as well. In one large study looking at using high dose insulin in beta blocker and CCB toxicity, median insulin bolus was 1U/kg and peak infusion was 8 Units/kg/h.  Interestingly and expectedly, hypokalemia occurred in close to 30% of patients and hypoglycemia in 30% of patients.

 This is an interesting concept and a creative use of a common agent.