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.

In the NEWS: New biomarkers for AIN

Acute interstitial nephritis (AIN) is the cause of over 15% cases of acute loss of kidney function Unlike many other causes of acute loss of kidney function, AIN is treatable with steroids if culprit is stopped in many occasions. Diagnosis of AIN is often difficult and there have been various markers in the history of AIN

Currently, AIN commonly occurs because of various non–β-lactam antibiotics, proton pump inhibitors, nonsteroidal antiinflammatory drugs, and cancer immunotherapy agents.

The classical triad of rash, fever and AKI doesn’t always exist in all cases. In addition, while seen many times, not all cases have a peripheral eosinophilia. A trend of rising eosinophils is often noted in several cases. 

The classically used urine eosinophils was thrown under the bus few years ago. Yet, many still order that test that is very non specific and not sensitive for AIN.

Imaging studies such as MAG-3 scans are rarely used and not as sensitive or specific for AIN. A kidney biopsy is often needed before giving steroids. Often this is not possible due to active infection, recent infection, anticoagulation.

A recent study published in JCI shows some novel urinary markers that might be used to diagnosis AIN. In a single center, 15% of patients had AIN. Participants with AIN had consistently higher levels of urine TNF-α and IL-9 than those with other diagnoses, including acute tubular injury, glomerular diseases, and diabetic kidney disease, and those without any kidney disease. The higher the TNF and IL-9, the higher the index of renal biopsy injury. The kidney biopsies with AIN also stained highly with TNF and IL-9.  In addition, the clinicians diagnosis index improved significantly with addition of these urinary markers.

AIN is a tough diagnosis to make. This study adds value in perhaps using other biomarkers that show signs of T cell activation. Is this specific for renal disease is a trend to watch? To me, there are no clinical signs that are real obvious clues. Urine eos- most useless, MAG-3 scans,- not useful. Serum eos trends- maybe useful. Urine WBCS casts and WBCS- not specific. The current study adds to the most specific findings thus far for an AIN diagnosis

Consult Rounds: Heavy Chain Deposition Disease

Heavy-chain deposition disease (HCDD) is the least common non-organized monoclonal immunoglobulin deposition disease (MIDD), with close to 50 documented cases in world literature to date. The existence of this entity was postulated for many years until the first case was reported by Tubbs et al. in 1982 followed by another report by Aucouturier et al. in 1993.

It is mostly characterized by γ-heavy chain(HC), and occasionally α-HC, μ--HC,  or δ-HC deposits. Nearly half of HCDD cases were in patients without a symptomatic B-cell disorder, a condition now referred to as monoclonal gammopathy  of renal significance (MGRS).  A constant biochemical characteristic of deposited HC is the deletion of the first constant domain (CH1), which is required for the secretion of an isolated free HC. Other pathologic and clinical features differ from those of LCDD, including the higher frequency of nodular glomerulosclerosis, hypertension, hematuria, and serum hypocomplementemia in g-HCDD.

Recent studies have confirmed that the heavy chain with complement components, mostly C3 and C1q, is frequent in γ 3- and γ 1-HCDD with hypocomplementemia. These findings have been attributed to the capacity of IgG3 and, to a lesser extent, IgG1, to activate the complement classic pathway through C1q binding to the CH2 domain. Whether local and/or systemic complement classic pathway activation is involved in the pathogenesis of γ -HCDD remains unclear.

So what really happens?

When there is the CH1 domain lacking in the heavy chain, this doesn’t allow for the heavy chain binding to it’s chaperone protein in the endoplasmic reticulum, resulting in a truncated heavy chain by the B cell or plasma cell clone. This then starts depositing as it has a higher affinity to tissue- mainly the kidney! Even a small amount of it can cause damage. Hence, most of these cases didn’t have full blown myeloma but bone marrow showed in most as MGUS or smoldering myeloma.  Interestingly, in this latest study by Bridoux et al in 2017, they showed that in over 60% of the cases they reported, there was an abnormal serum free light chain ratio and a positive free light chain immunofixation as well. Interestingly, free light-chain assay levels correlated with disease response in the majority of patients. This suggests that the underlying B- or plasma cell clone produces a monoclonal light chain in addition to the pathogenic heavy chain, and thus the serum-free light-chain assay can be useful in HCDD diagnosis and monitoring after treatment.

Earlier studies had shown that there is a grim prognosis for HCDD. I think this might have been before MGRS was defined and many of them never got treated with anti-plasma cell agents. In the post bortezomib era, the newer data suggests otherwise. Bridoux et al from France data suggests that the outcomes were not that grim and the response to proteasome inhibitors were excellent. Recent mouse models have shown that this efficient response to proteasome inhibitors mostly relies on the presence of the isolated truncated heavy chain that sensitizes plasma cells to bortezomib through an elevated unfolded protein response.

So in summary

HCDD is rare but is a form of MIDD

Most commonly associated with MGUS or smoldering myeloma

The most common HC involved is γ and IgG3 specific

It is not unusual to see hypocomplementemia with this entity

Nodular sclerosis is the pathology finding on light microscopy

Response to proteasome inhibitors appears promising