Golden Era in therapeutics for IgA Nephropathy

Just in the last 1 year, we have two new drugs being approved for IgA Nephropathy. In addition, we have seen an emergence in using SGLT2i perhaps in IgAN and other GNs. The DAPA-CKD trial IgAN patients were evaluated and the use of dapagliflozin was superior than placebo. The EMPA-Kidney had close to 800 IgAN patients, we shall await those results soon.

MMF has just made a come back with a recent Chinese study showing some promise in a RCT. 

Finally, a targeted release steroid called budesonide has been FDA approved. This was developed to deliver the active drug in the distal ileum, where the Peyer's patches are -- the likely culprit where a large amount of galactose deficient IgA is made. The data was just published in KI.

And finally, the first single molecule Dual Endothelin Angiotensin Receptor Antagonist (DEARA) approved for use in patients with IgAN. The data is not published yet in a journal.

There are still ongoing trials of other DEARAs, and complement inhibitors, APRIL inhibitors for IgAN. In my opinion, the future of treatment of IgAN can be perhaps summarized in the below figure: ( created using biorender.com)

KDIGO 2021: GN Management Guidelines: IgA nephropathy

 

The three figures from the recent KI GN update 2021 summarizes IgA nephropathy.

Basically, At this point, given negative studies for steroids, only thing we have that has strong evidence is conservative management. Interestingly, SGLT2i did not make it to the guidelines.  ACEI/ARB+ SGLT2i might be the best treatment options we have for IgA Nephropathy. 

The one place where immunosuppressive meds will help is Crescentic IgA nephropathy and IgA with MCD. 

Here is the final table on all meds and their data from KDIGO

Does immunosuppressive meds help IgA nephropathy? Do we await the budesonide directed therapy approval, do we await more supportive agents such as ET1 antagonists or Aldo antagonists? Time will tell. Till then, IgA nephropathy is still the hardest GN to treat as we don't have clear options for treating the pathophysiology of the disease. 

Clinical Case 87: Answers and Summary

34 y old Indian Male with IgA nephropathy, crt is 2.4mg/dl and 2.5gm of proteinuria: treatment?

RAAS blockade only

  6 (12%)

 

RAAS blockade and Fish oil

  9 (19%)

 

Steroids with RAAS blockade

  19 (40%)

 

Treatment depends on Biopsy Oxford Classification of IgA Nephropathy

  13 (27%)

 

The KDIGO recommends no specific guidance for treatment with steroids in IgA nephropathy patients when they present with GFR between 30-50cc/min. A recent study published in JASN in 2015 looked at steroid use in IgA Nephropathy patients. It is called the VALIGA study.  A retrospective study that studied over 140 patients with IgA nephropathy from European registry and classified based on Oxford classification MEST score.   46% received immunosuppresive agents and of them 985 were steroids.  The ones who were treated had all the features of clinical progression( rising crt, or proteinuria).  All also received RAAS blockade.  The patients who got steroids had a significant reduction in proteinuria, a slower rate of renal function decline and greater chance of not being on dialysis.  While, initially we had thought that the benefit of such treatment was only in patients with mild- moderate AKI, this study found benefit even in the GFR<50cc/min cohort with levels of proteinuria.  

So in the above patient, the best answer would be Steroids with RAAS blockade. If the biopsy did show crescentic GN, the treatment ofcourse would be with cytotoxic agents in addition. 

TOPIC DISCUSSION: IgA nephropathy and FSGS

What is the significance of findings of FSGS in biopsies that are predominately IgA nephropathy?

Two studies have looked into this matter in 2009 and 2011.

The NDT study in 2009 looked at 75 patients ( split into IGA with FSGS, IGA without FSGS).  In the multivariate model, the FSGS+ group showed a worse GFR decline.  It is no surprise that when there is sclerotic lesions, the prognosis is going to be worse. The question arises if this is part of IGA progression or it is two processes happening independently? Would steroids be indicated in such settings?

The KI study from 2011 looked at over 100 patients and used the Oxford classification for IgA and Columbia classification for FSGS to evaluate the two seen in the same biopsy.  Collapsing FSGS with IgA had worse outcomes.  Overall, worse outcomes were noted with any form of FSGS was present when compared to IgA alone.  In addition, when FSGS was present with any other glomerular findings( mesangial hypercellularity, necrosis, deposits), outcomes were worse compared to “pure” FSGS.
Staining studies they performed showed that the changes related to the podocytopathy were present even with mild IgA disease suggesting that the two processes might be independent and not just an end pathway for any glomerular disease. 

IgA can present with preserved renal function and MCD like podocytopathy.  Presenting with FSGS is more challenging and treatment may be difficult to decide upon.  If there is good preservation of IFTA on biopsy and if there is >1gm of proteinuria, perhaps it’s worth treating with steroids or at least a trial of steroids.  

IgA Nephropathy and Minimal Change Disease?- a potential association

IgA nephropathy can take many variants. Classically, it can present as the nephritic syndrome but can be just benign hematuria with no other complaints. Sometimes it can be aggressive with crescents and or TMA.  Proteinuria usually suggest a bad prognostic marker in IgA nephropathy.  Sudden onset proteinuria might suggest a dual glomerular process or IgA nephropathy with a minimal change disease variant.  A recent series of cases have been described in CJASN.  A retrospective review of pathology cases in the Columbia Univ path database revealed 17 such cases.  Most had normal creatinine, proteinuria was over 8g for average and biopsy showed co dominant IgA with mesangial deposits and MCD.  14/17 patients got complete remission with steroids and additional agents.

Another case presented in this case report.

Consult Rounds: IgA nephropathy and TMA- does it have a connection?

IgA and thrombotic microangiopathy?- is there a link?

Does IgA nephropathy present with biopsy findings  of TMA? A paper in JASN in 2012 looked at this exact question.

1.      They studied over 100 patients retrospectively at a single center and looked at biopsy findings of IgA nephropathy patients with follow up for 44 months

2.      Over 50% had TMA findings on biopsy.

3.      One would presume most of this might be HTN related to the IgA that leads to TMA.  4% were normotensive, 25% had controlled hypertension, and 71% had uncontrolled hypertension.

4.      The biopsies with TMA had most fibrosis and tubular atrophy

5.      TMA with IgA nephropathy also had significant protienuria.

6.      Renal survival was 52.2% at 44 months among the TMA patients versus 93.5% among those without TMA (P=0.00001).

7.      IgAN-associated TMA remains a primarily arterial/arteriolar lesion resembling like scleroderma

8.      What else besides HTN can lead to this in IgA? Endothelial damage is what is presumed to the most likely cause.

9.      Anti-phospholipid syndrome antibodies have also been described in IgAN. In their series, it was no the major cause.

10.  Decreased VEGF and or anti endothelial antibodies are presumed to be other causes

11.  Could this resemble some form of secondary variant of IgA nephropathy perhaps from a virus or infection or other systemic disease?

12.  If the incidence of TMA in Ig A nephropathy is this high, then why is this not part of the Oxford classification?

13.  Other studies that have looked at this

http://www.ncbi.nlm.nih.gov/pubmed/17176910/

Does IgA nephropathy have lambda pre dominance?

IgA nephropathy is the most common GN in the world.  Does IgA molecule in this disease have a light chain predominance? Yes it does.

In early 1990s, Lai K ( 30 patients) et al evaluated this concept.  Compared to kappa staining, the lambda staining was higher in IgA nephritic patients and in addition there was pre dominance of IgA lambda chains in circulation.  Interestingly the same authors published the same results in AJKD in 1998 showing the same concept.  In the same year, the same group of authors showed that IgA had strong lambda mesangial binding in another journal.  Interestingly, a JASN review later refers to the Lai studies as well regarding the lambda dominance of IgA.

A more thorough study done recently is more intriguing. The pattern of light chain IF and light microscopic diagnosis in 306 cases of various nephropathies was reviewed in one center in India. Light chain deposits were seen in 240 (78.43%) cases. In IgA nephropathy, lupus nephritis and post-infectious glomerulonephritis (PIGN), lambda positivity was more as compared to kappa. Light chain deposits in LCDD and membranous nephropathy were more kappa type.

In other words, there is some lambda predominance of kappa in IgA nephropathy but we have to keep in mind the number of patients that the first 1990s this was evaluated in. It was interesting to see that the retrospective review confirmed this from India and it also showed that PIGN and lupus also had a more lambda predominance.  There is also IgA myeloma which is important to keep in the differential if the pathologist says there is significant more dominance( but the light microscopy and EM findings will be much different in myeloma related disease)

KDIGO Glomerular Diseases Guidelines: IgA Nephropathy

KDIGO just released guidelines for GN in a supplement in KI

Topic: IgA Nephropathy


1. Long term ACEI or ARB for proteinuria >1gm( Grade 1B)
2. ACEI or ARB treatment if proteinuria between 0.5gm to 1gm ( Grade 2D)
3. Patients with persistent proteinuria >1g/d despite 3-6 months of conservative management, and GFR >50ml/min get 6 month course of steroids (Grade 2C)
4. Not use cyclophosphamide or aza in IgA unless there is RPGN with crescents ( Grade 2D)
5. Not use cytotoxic agents for GFR< 30ml/min unless there is RPGN ( Grade 2C)
6. Fish oil is recommended if proteinuria is >1gm/d ( Grade 2D).
7. Not using antiplatelet agents in IgA( Grade 2C).
8. Minimal change with IgA:- treat like minimal change ( Grade 2B)
9. AKI associated with MCD:- perform a kidney biopsy in AKI with macroscopic hematuria if no change in renal function for 5 days
10. General supportive care for AKI in IgA for biopsy showing ATN( Grade 2C)
11. Steroids and cyclophosphamide in crescentic IgA( Grade 2D).
12. Tonsillectomy is not recommended ( Grade 2C)

For full recs see http://www.nature.com/kisup/journal/v2/n2/pdf/kisup201223a.pdf

eAJKD: IgA Nephropathy Word Search

Check out the fun to do quiz on IgA Nephropathy using a word search on the eAJKD website.

eAJKD: IgA Nephropathy and Vitamin D therapy

White vitamin D has shown to be beneficial in reducing proteinuria in patients with chronic kidney disease (CKD), the role of activated vitamin D replacement in IgA Nephropathy is not well studied.  A recent open-label, nonplacebo-controlled randomized study published in the American Journal of Kidney Diseases looks at this particular question.  Check out the latest blog post from eAJKD.

CLINICAL CASE 39: ANSWERS AND SUMMARY

Which one of the following is NOT associated with Hepatitis B virus?

Membranous Glomerulopathy	5 (5%)
Membrano proliferative GN	1 (1%)
Mesangio proliferative GN	6 (7%)
IgA nephropathy	37 (43%)
Poly Arteritis Nadosa	8 (9%)
All above are associated with Hepatitis B	28 (32%)

Tough battle between All above and IgA Nephropathy. Traditionally, we think of Hep B and kidney disease as classically as Membranous GN.  So the most common finding is that.  MPGN, Mesangioproliferative and PAN have been also noted with Hep B.  Ig A has some rare associations with Hep B as well.  So the most probable answer should be All above are associated with Hep B.  The presence of immune complexes in the kidney suggests an immune complex basis for the disease like in MPGN sometimes, but a direct antigenic effect is the most likely cause of the proteinuria. Studies have shown that clearance of HBV antigens, either spontaneous or following antiviral treatments results in improvement in proteinuria. Thus, prompt recognition and specific antiviral treatment are critical in managing patients with HBV and renal involvement. Check out ref 1 and 2 for oldest literature on this topic. The last few references are linking IgA nephropathy and Hep B in endemic areas.

Here are some references:
http://www.ncbi.nlm.nih.gov/pubmed/605896
http://www.ncbi.nlm.nih.gov/pubmed/2023605
http://www.ncbi.nlm.nih.gov/pubmed/14988643
http://www.ncbi.nlm.nih.gov/pubmed/21677438
http://www.ncbi.nlm.nih.gov/pubmed/3293854
http://www.ncbi.nlm.nih.gov/pubmed/12970894