Saturday, July 13, 2019

Friday, June 28, 2019

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!!

Thursday, June 20, 2019

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

Atezolizumab
77
Female
GU cancer
14
Yes
Disease progression-death

Atezolizumab
-
-
Solid tumor
-
-
-

Atezolizumab
-
-
Solid tumor
-
-
-

Ipilumumab
73
Male
Melanoma
6
No
Death

Nivolumab
74
Male
RCC
2
No
Death



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.

Saturday, June 15, 2019

Concept map: Hyponatremia in the cancer patient


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

Sunday, June 9, 2019

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.

Wednesday, June 5, 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. 


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.

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.

Monday, June 3, 2019

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.

Saturday, May 18, 2019

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 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

Wednesday, May 1, 2019

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

Wednesday, April 17, 2019

Topic Discussion: Newer Gadolinium agents and risk of NSF? is it extinct?


Gadolinium is known to have an association with Nephrogenic Systemic Fibrosis(NSF). The first case of this was described in Yale and published in Lancet. A potential link between NSF and the application of gadolinium-based contrast agents (GBCAs) was first described by Grobner et al in 2006. The risk of gadolinium based contrast agents to trigger NSF seems to be related to the stability of the agent. Thus, nonionic linear gadolinium based contrast agents are more likely to trigger NSF than ionic linear agents both of which are distinctly more likely to trigger the disease than the macrocyclic agents in patients with reduced renal function. Gadobutrol (Gadovist, Gadavist) is a second-generation nonionic, multipurpose, extracellular, macrocyclic gadolinium based contrast agent provided in a 1 molar concentration. As a macrocyclic contrast agent, gadobutrol provides high chelate stability with substantially less—if any—in vivo release of Gd ions as opposed to linear gadolinium (old school agents). The release of gadolinium ions has been linked to an increased risk of NSF in patients with impaired renal function. The highest prevalence of NSF was associated with Omniscan, Optimark as most of these have a weak binding of gadolinium to the chelate. 



Image result for new gadolinium agents and NSF

So are these safer? A large study published in 2017 was a prospective, international, multicenter, open-label study in 55 centers. Patients with moderate to severe renal impairment scheduled for any gadobutrol-enhanced MRI were included. All patients received a single intravenous bolus injection of gadobutrol at a dose of 0.1 mmol/kg body weight. The primary target variable was the number of patients who develop NSF within a 2-year follow-up period. A total of 908 patients were enrolled, including 586 with moderate and 284 with severe renal impairment who are at highest risk for developing NSF. Overall, 184 patients (20.3%) underwent further contrast-enhanced MRI with other gadolinium-based contrast agents within the 2-year follow-up. No patient developed symptoms conclusive of NSF.

Another study by Lauenstein et al, investigated gadoxetate disodium in 357 patients. No case of NSF was recorded. Another recent study by Amet et al investigated the risk of gadoteric acid in 255 patients on dialysis with no findings of NSF. In addition, Soulez et al reported 2 prospective 2-year studies in 534 patients with either stage 3 chronic kidney disease (CKD) or stage 4 to 5 CKD. No signs or symptoms of NSF were reported after administration of gadobenate dimeglumine or gadoteridol. Smorodinsky et al retrospectively evaluated 1167 patients with chronic liver disease where 72% also had some degree of renal insufficiency. They did not report any case of NSF.

A recent Canadian society published their analysis and concluded that “In patients with AKI and category G4 and G5 CKD (eGFR < 30 mL/min/1.73 m2) and in dialysis-dependent patients who require Gadolinium based contrast agentss-enhanced MRI, they can be administered with exceedingly low risk of causing NSF when using macrocyclic agents and newer linear agents at routine doses.”

Here are images online from medscape education that are very useful on this matter.






A lot of centers in the world are now carrying and using Gadovist and perhaps we won’t see any NSF? 

Tuesday, April 16, 2019

In the NEWS: Credence, Rise of the Nephron Throne

A positive light at the end of the tunnel for nephrology, the Credence trial just got published this week in NEJM, put the glucoretics on top for diabetic nephropathy. When you search “credence” in the oxford dictionary it means” belief in or acceptance of something as true”.  I think the time has come to believe that SGLT-2 inhibitors are here to stay and are going to change the disease of diabetic nephropathy.

In summary, this large RCT was stopped early. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group. The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34%  and the relative risk of end-stage kidney disease was lower by 32%. The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke and hospitalization for heart failure. There were no significant differences in rates of amputation or fracture.



Some of the twitter world made some amazing comments on this

Susan Quaggin‏ @SusanQuaggin19 years since RENAAL and IDNT..followed by a series of negative trials...but the drought is over! New therapies for our patients with diabetic kidney disease are a reality - #CREDENCE marks the beginning of a new era in Kidney Medicine "#SockItToKidneyDisease"

Juan Manuel Mejía‏ @Meyaix "Every nephrologist is now talking of #CREDENCE ."

Jennie Lin, MD MTR‏ @jenniejlin"#CREDENCE, landmark clinical trial for patients with T2DM and kidney disease, is now published: 30% lower relative risk for primary renal outcome in canagliflozin arm, with pretty darn significant p-value of 0.00001! It was thrilling to watch the results stream live from #ISNWCN!"

And my personal favorite....

Steven Coca‏ @scoca1 "You had me at “hello” before the gasp & applause for the tiny p value The separation of the KM curves (effect size) and 95% CI are what had me leaping And more fist pumping when the difference in eGFR slopes were shown"


While this drug was developed and marketed to treat diabetes, it is more than that. Someone on social media world rightly said” We have an anti HTN and renal protective med that has a nice side effect of lowering your A1c”

It decreases blood pressure
It induces weight loss
It decreases intraglomerular pressure
It is a proximal tubular diuretic
It is anti-inflammation
It decreases proteinuria




This is a nephrologist's drug! Finally, we have a positive trial in the making that is going to change the practice of nephrology. Diabetics, non-diabetics, HTN, CHF patients- all might benefit from this discovery!
 

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