Concept Map- Causes of Renal Amyloidosis

 

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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: Hereditary transthyretin amyloidosis, inotersen and the kidney

Hereditary transthyretin amyloidosis is caused by pathogenic single-nucleotide variants in the gene encoding transthyretin (TTR) that induce transthyretin misfolding and systemic deposition of amyloid. Progressive amyloid accumulation leads to multiorgan dysfunction and death. Renal involvement is not as common as CNS and or cardiac involvement. A review in CJASN in 2012 had commented on the renal manifestations of this entity. Renal presentation usually is chronic kidney disease, proteinuria and kidney biopsy showing amyloid deposition.

Recently, novel therapies have emerged in the treatment of this entity in the neurology and the cardiology literature. Inotersen, a 2′-O-methoxyethyl–modified antisense oligonucleotide, inhibits hepatic production of transthyretin.  This study was published in NEJM last year and it was a randomized, double-blind, placebo-controlled, 15-month, phase 3 trial of inotersen in adults with stage 1 (patient is ambulatory) or stage 2 (patient is ambulatory with assistance) hereditary transthyretin amyloidosis with polyneuropathy. Inotersen improved the course of neurologic disease and quality of life in patients with hereditary transthyretin amyloidosis. What was interesting was that the most frequent serious adverse events in the inotersen group were glomerulonephritis(GN) (in 3 patients [3%]) and thrombocytopenia (in 3 patients [3%]), with one death associated with one of the cases of grade 4 thrombocytopenia. Apparently, it’s a black box warning now with this agent that is given SQ.

In reviewing the NEJM paper, they discuss that each of these three patients that developed the GN carried the Val30Met TTR mutation (148G→A) mutation. Two had shown a decline in the eGFR. In all three cases, the kidney biopsy showed complex pathologic features, consistent with crescentic glomerulonephritis superimposed on a background of amyloidosis and (in two cases) interstitial fibrosis. One patient was successfully treated with glucocorticoids and cyclophosphamide and regained clinically significant renal function. Another patient did not receive immunosuppressive therapy owing to delayed diagnosis, and permanent hemodialysis was initiated. A third patient was identified as having clinically significant proteinuria after the implementation of more frequent renal monitoring of every 2 to 3 weeks; this patient did not show a decline in renal function. Urinary protein excretion returned to baseline levels after treatment with glucocorticoids. There is no discussion on the serologies sent or if this was a vasculitic reaction that we see sometimes with anti TNF agents. After the notice of the GN in these patients, they instituted an enhanced monitoring system. After the implementation of enhanced monitoring, no additional cases of severe thrombocytopenia occurred, and a single case of glomerulonephritis was identified early without loss of renal function. There was also a single case of antineutrophil cytoplasmic autoantibody (ANCA)–positive systemic vasculitis reported. It is possible(speculative) that this drug induces an ANCA associated crescentic GN in certain cases. On a pubmed and google search, I found no further published cases of any GNs with this agent. Since the advent of this agent, several other agents are in the market for treatment of Transthyretin Amyloid neuropathy and cardiomyopathy.

A similar drug called Patisiran, an RNAi therapeutic for similar indication was published in 2018 as well. The investigators found that this drug significantly improved neuropathy in patients with hereditary transthyretin amyloidosis. This drug had no renal side effects reported in the side effect profile. This is an IV drug compared to the SQ version previously discussed. 

In another NEJM paper, in patients with transthyretin amyloid cardiomyopathy, tafamidis( oral transthyretin stabilizer)  was associated with reductions in all-cause mortality and cardiovascular-related hospitalizations and reduced the decline in functional capacity and quality of life as compared with placebo. The renal side effects were not significant in this drug and in equal frequency as the placebo arm.

So as the field of transthyretin amyloidosis is expanding, some of these novel targeted therapies can change the renal effects of this disease. As nephrologists, we need to be watchful for the glomerular side effects of inotersen.

In the NEWS: Amyloidosis and potential novel treatment

Systemic amyloidosis contains non fibrillar protein called serum amyloid P ( SAP).   Novel agent that is called CPHPC depletes SAP from the plasma but leaves some SAP in the amyloid deposits.  Following giving CPHPC, if given anti SAP antibodies, it can clear the remainder of the free SAP. A recent study in NEJM did an open label single dose phase 1 trial to look at 15 patients with systemic amyloidosis using the above strategy and there was clearance of amyloid deposits from liver and other tissues.

Few interesting and key points
What type of amylodosis: the patients included had AA, AFib, AL, AApoA1 type of amyloidosis.

What tissues involved: Liver, spleen, kidney, bone marrow, ( no patients with cardiac or severe renal involvement)

Any renal adverse events:- None in liver or kidney

This is a fascinating new pathway of treating patients with fibril based disease like amyloidosis. Wonder if this similar approach might be useful in other renal fibril forming disease such as fibrillary GN or immunotactoid GN. 

Concept Map: Hereditary Amyloidosis and Renal involvement

CONSULT ROUNDS: AA vs AL Amyloidosis

How do we differentiate AA from AL Amyloidosis? 

Accurate typing of amyloid is mandatory because the treatment modalities of various types of amyloid are very different. Renal amyloidosis can at times be easy to classify into AL and AA types depending on immunofluorescence and immunohistochemistry studies. Technically, AL amyloidosis or AH amyloidosis are plasma cell diseases and either light chain or heavy chain disorder that have one chain predominance on IF and then subtypes using staining for AL or AH.  AA amyloidosis is usually secondary to chronic illness such as RA, FMF, Infections, sometimes malignancies like renal cell and Hodgkin's Lymphoma.

A novel technique has come into light in helping diagnosis Amyloidosis. It is the LMD/MS technique or Laser micro dissection combined with mass spectrometry. From the Mayo Clinic, using this technique, they were able to diagnosis even rare cases that might not have been picked up on regular staining via AA or AL and perhaps even medullary Amyloidosis.  They showed that LMD/MS is a useful and sensitive technique for the diagnosis of amyloid and for accurate typing of the amyloidosis, particularly problematic cases of amyloid. To show the usefulness of LMD/MS in typing renal amyloidosis, they demonstrate four cases of renal amyloidosis that were diagnostically challenging.  What is this method?

About 10-μm-thick sections of formalin-fixed paraffin-embedded tissues were stained with Congo red. Glomeruli with positive Congo red areas viewed under a fluorescence light source appeared bright red. The Congo red deposits were identified under fluorescence light and microdissected with LMD.  The microdissected material was collected analyzed by liquid chromatography electrospray tandem mass spect.  The MS result value indicates the total number of mass spectrum collected on the mass spectrometer and matched to the protein using the proteomic software. A higher number of mass spectra is indicative of greater abundance and will typically yield greater amino acid sequence coverage.

Thus specific proteins were identified and diagnosis was made

Check out the two references:

http://www.ncbi.nlm.nih.gov/pubmed/21900878

http://www.ncbi.nlm.nih.gov/pubmed/20876678

http://www.ncbi.nlm.nih.gov/pubmed/22131817

TOPIC DISCUSSION: Vascular Amyloidosis and the Kidney

Most of the pathology in the kidney from AL Amyloidosis is glomerular in origin. Cases have been noted of pure selective amyloid deposition in the vessels walls of different organs. The clinical presentation of renal amyloidosis basically depends on the distribution and severity of amyloid deposits. Vascular localization represents an uncommon pattern of renal amyloidosis, generally associated with chronic renal failure with minimal or no proteinuria. 
An old series in 1983, of nine patients with secondary (AA type) renal amyloidosis with little or no proteinuria has been reported. Renal failure was the presenting sign of renal disease in seven patients. Renal biopsy revealed a predominantly vascular deposition of amyloid in all patients. Three patients had no glomerular amyloid deposits. This pattern of amyloid deposition was found in 12.5% of our renal biopsies from patient with amyloidosis.
Another recent paper from Japan describes the vascular distribution of amyloid and how that changes when it affects the kidney. This paper looked at patient biopsy samples with AL amyloidosis and divided them into a group with capillary form and a group with small vessel form.  The small vessel form was associated with more cardiac involvement, and left ventricular thickening compared to the capillary form. There was no significant differences in rates of survival and renal survival.
In summary, vascular amyloid can been seen in the kidney, usually when you are suspecting it even without nephrotic syndrome.


http://www.ncbi.nlm.nih.gov/pubmed/6839564
http://www.ncbi.nlm.nih.gov/pubmed/20922533
Image Source: http://www.pathconsultddx.com/pathCon/diagnosis?pii=S1559-8675(06)70652-0