Lupus Nephritis classification: Does it help us?

I recently went to a talk by Stephen Korbet on Lupus Nephritis and it got me wondering on if the current way of classification of lupus nephritis works or not?

MPGN- old way of classification was EM based but the recent updated IF based classification is very clinical and aids the clinician in treating the disease better as a root cause is identified.

In lupus, the story starts back in 1970s and eventually leading to the WHO classification and then the updated ISN classification. A recent review  published in JASN in 2015 summarizes the history and concerns regarding the classifications. The suggestions to improve are more detailed and pathology related and I am not sure if they will help clinically.

What might help a nephrologist help treat the lupus nephritis patient?

1. Is the lesion Proliferative?- segmental or diffuse- most of us will treat. Only context of not treating will be the IFTA present on the biopsy- so does it matter if its segmental or diffuse? as treatment is either MMF or cyclophosphamide anyway.

2. Is the lesion crescentic? - yes this matters to us-- as most crescentic GN( RPGN) and specifically lupus have been excluded in most trials- so treatment might be leaning towards cytotoxic agents and not standard therapy.

3. Is it a podocytopathy ( would like to include membranous GN in this section)- More and more we are seeing MCD, FSGS with this entity and treatment might be slightly different as some of them respond faster with a steroid based regimen.

4. Is there a second entity with it?- ANCA disease or TMA?- as treatment might then entail pheresis and or a different prognosis.


I think the talk by Korbet hinted towards this but not sure which direction the field will go but it's time that we have a less confusing classification but more meaningful one that helps the nephrologists treat the disease better.

What do others think?

IN the NEWS: A transplant like multi target protocol for Lupus Nephritis

A transplant type protocol for treating Lupus nephritis has arrived. This makes a lot of sense as recurrence post transplant of Lupus nephritis is very low.
If we had just used MMF alone with steroids, most lupus might have recurred in transplant but we use CNI + MMF in most cases or some equivalent of those agents.  In addition, transplant patients get induction with thymoglobulin like agents and perhaps’ it those agents that keep lupus under control.  A new study in Annals of internal medicine used this multitarget approach to attack lupus nephritis and directly compared to IV cytoxan given monthly.

To summarize:

It was a 24 week randomized open label multicenter trial in China in adults with biopsy proven lupus nephritis.  One arm received tacrolimus and MMF and the other got monthly IV cytoxan for 6 months. Both got pulse steroids and PO steroids.  After 6 months, more patients in the tacro+MMF group showed complete remission and there was a higher response rate in a shorter period of time.  In addition, less adverse events were noted in the MMF+tacro arm as well. 

Few things to ponder on:

1.       This worked in a cohort of Chinese patients; will this work in AA, whites and others?

2.       Most of our patients present sometimes with rising creatinine and it might be concerning to place them on CNIs as well in that setting, but we do in many transplant cases..

3.       Most of these studies include the prior ALMS and so forth never include the sick of the sickest with crescentic GN.  Those might still require IV cytoxan.

4.       Also, this study had a 6 month follow up.  Long term data might be needed for toxicity profile as well.

Overall, encouraging and worth considering in US based population.  A transplant like multi drug protocol for lupus nephritis makes sense.  What’s next? Thymo for lupus nephritis?

Consult Rounds: Repeat biopsy in lupus nephritis

Two questions:
1. What is the value of repeat biopsy in Lupus Nephritis? You have a Class III on biopsy A and improvement following treatment; 7 months later similar presentation: would you re biopsy or consider Class III and treat accordingly? 

One retrospective trial in NDT in 2012 had looked at this. Twenty-five patients had one repeat biopsy, 6 patients had two and 4 patients had three repeat biopsies. Forty-nine comparisons between reference and repeat biopsies could be made. In 25 cases (54.3%), there was no shift in ISN/RPS class on repeat biopsies. In 41 instances, paired biopsies showed proliferative lesions both on reference and repeat biopsies, whereas five of six cases with non-proliferative lesions on a reference biopsy switched to
proliferative lesions on a repeat biopsy. Clinically significant class switches during lupus nephritis flares were more frequent in patients with non-proliferative lesions in their reference biopsy. The authors conclude that the repeat bx was most necessary when the index biopsy was non proliferative. With lupus nephritis, the main rule to remember is that " lupus nephritis follows no rule". It appears that many instances, class switches are common and a repeat biopsy might add value re class switches. The other factor that most studies don't discuss is that the repeat biopsies can offer a choice of "not treating" as there might be substantial scarring and make a more informed decision regarding tough immunosuppresive agents.

2. After induction, is a repeat biopsy needed?

Another NDT paper in 2012 looked at this question. 77 patients followed up for a median duration of 8.7 years.  One-third of the patients with partial remission and 14% of patients with non remission had no histological evidence of active disease on second biopsy. At the second biopsy, but not at the baseline biopsy, activity index was predictive of survival. The 10-year renal survival rate was
100% for those with an activity index of 0, 80% for those with an activity index of 1 or 2 on the second biopsy and 44% for those with an index of >2, regardless of remission status. The authors conclude that a second kidney biopsy at the end of maintenance phase of therapy is an important diagnostic and prognostic tool that could guide physicians to safer practices with better outcomes. Interestingly, patients we would think were not in remission had no histological evidence of active disease on second biopsy- which would allow us to consider stopping treatment in some cases. This an observational retrospective trial with limitations and it would be interesting to see what experiences of others holds on this notion of repeat biopsy after induction?

Per UptoDate.com, the indications for repeat biopsy are:
1 Increasing proteinuria
2. Active sediment with rising crt
3. Rising crt
4. Unrelated to SLE as the cause of renal disease ( other GNs and drug induced diseases)

CONSULT ROUNDS: Minimal Change and Lupus?

A 34 year old female presents with sudden onset nephrotic syndrome. A kidney biopsy confirms minimal change disease. Subsequently, labs reveal a + ANA and + dsDNA and + anti smith antibody.
Is the glomerular disease secondary to SLE?

Initially described in 2005, lupus associated minimal change disease is also called lupus podocytopathy.

A series of patients SLE and proteinuria were studied to determine whether nephrotic range

proteinuria was associated with diffuse epithelial cell foot process effacement in the absence of peripheral glomerular immune aggregate deposition.  Eighteen biopsies were studied, eight from patients with nephrotic-range proteinuria (>3 g/d) and 10 from patients with nonnephrotic proteinuria. Seven of eight biopsies from nephrotic patients demonstrated at least 80% foot process

effacement, whereas no biopsy from a nonnephrotic patient exhibited >20% effacement. No IF or LM findings were found. Interestingly, no full house pattern was noted as well. The single common morphologic feature associated with nephrotic proteinuria was diffuse visceral epithelial cell foot process effacement. That initially manuscript revealed that this entity is more likely SLE related rather than co existence of SLE and minimal change separately, 

In 2009, a letter to the editor in Rheumatology suggested another case of such matter. 

Subsequently, more cases have been described. 

Of recently, cases of collapsing FSGS is described as a variant of lupus podocytopathy. 

Lupus usually presents with a proliferative manifestation in the kidney but perhaps a podocytic variant might exist. More data is needed in this variant of lupus. 

KDIGO Guidelines for Glomerular Diseases: LUPUS NEPHRITIS

KDIGO is publishing guidelines in Glomerular Diseases in Kidney International

Topic: Lupus Nephritis


1. Class I LN be treated by extra renal manifestations rather than renal ( 2D)
2. Class II LN - No specific renal treatment if <1gm of proteinuria( 2D)
3. Class II LN- Proteinuria >3gm be treated with steroids or CNI like a minimal change disease (2D)
4. Class III LN- Steroids (1A) + either cyclophosphamide or MMF (1B)
5. Class III LN- if first option is not working to change to the alternative option above in 3 months (2D)
6. Class III Maintenance - Imuran or MMF ( 1B) and low dose steroids for one year (2D)
7. Class IV - same as Class III as above
8. Class V- If normal kidney function, and non nephrotic range proteinuria, conservative management and treatment dictated by extra renal manifestations( 2D)
9. Class V- persistent proteinuria:- steroids + cyclophosphamide and or CNI or MMF or Imuran ( 2D)
10. All patients should be on hydroxycholoroquine (2C)

For other detailed recommendations look at http://www.nature.com/kisup/journal/v2/n2/pdf/kisup201225a.pdf

IN THE NEWS:ACR Lupus Nephritis Guidelines

Expert panel published recently the first ever guide to Lupus Nephritis treatment. The medical news community and lay press has mentioned it at numerous occasions already
Some summary points after looking at it

1. Definition of Lupus Nephritis included the usual persistent proteinuria, active sediment but noted that if a kidney biopsy showed immune complex mediated GN compatible with lupus nephritis would also qualify for the diagnosis. Finally, an opinion of the nephrologist or rheumatologist was good as well.
2. The panel recommended that all with active lupus nephritis, previously untreated undergo a renal biopsy but evidence for this was LEVEL C.
3. Treatment of disease be based on the class of lupus identified on biopsy.
4. Class I and II- conservative management and no active treatment ( Level C evidence)
5. Class III, IV and V- require treatment
6. Class III and IV- MMF induction or IV CYC along with steroids ( Level A evidence based on ALMS trial)
7. Myfortic was mentioned by the expert panel as equivalent to MMF in inducing lupus nephritis
8. Euro Lupus ( 500mg of IV CYC every 2 weeks) for total of 6 doses be used for Caucasians and patients of European origin and the NIH protocol( 500-1000mg/m2 IV once a month for 6 doses) be used for the rest.
9. Pulse IV steroids for 3 doses and then 0.5mg-1mg/kg daily dosing is needed( level C evidence)
10. Induction for Class IV/V with crescents included steroids but no recommendations made strongly regarding use of IV CYC or MMF for this group.  Both are mentioned.
11. Pure Class V:- MMF with steroids ( PO only) ( level A evidence)
12. AZA or MMF can be used for maintenance therapy ( level A evidence)

Some of the other things the task force discusses is changing regimen when initial treatment fails, pregnancy related to SLE treatment options and monitoring of lupus nephritis.

Take a look at the original article 
Take a look at a critical review by the Kidney Doctor Blog.

In the News: Collapsing Glomerulopathy and SLE

Collapsing FSGS has many causes but its relationship with SLE has been sparse.  Salvatore et al present the largest series of 19 patients with SLE and 3 patients with SLE like disease presenting with Collapsing FSGS.
Findings:
1. Confirmed the proliferative podocyte theory using dedifferentiation and proliferative markers in most biopsy cases.
2. Secondary causes that are more common such as HIV, Parvovirus and medications were ruled out as much as possible in most cases.
3.  Of the 19 patients, 7 had no remission, 5 had partial remission and one had complete remission and some had no follow up
4. Treatment was mainly steroids in most cases and MMF and + dialysis if needed.
5. AA race and female gender predominated.
6. Only 25% progressed to ESRD or death in this group.  This is a surprise as Collapsing FSGS usually has a 99% progression to ESRD.  The authors think this might be because of shorter follow up and or less stringent criteria for the diagnosis of collapsing FSGS.

Check out the article in CJASN

CONSULT ROUNDS: Minimal Change Disease and lupus

Sudden onset proteinuria, lower extremity swelling, low albumin and biopsy showing complete foot process effacement with a some mesangial fullness and serologies positive for ANA and dsDNA and low complements.  Hmm!!  Minimal Change disease(MCD) with SLE?

The estimated prevalence of MCD in biopsy-proven lupus nephritis is 2.3% in childhood and 1.1% in adults. Now there are a few cases in the literature.  Most patients presented with nephrotic syndrome and not an active sediment. The patient described in the literature have  responded promptly to high-dose glucocorticoids but four (31%) had relapse of proteinuria during their course of SLE. MCD is an uncommon histological class of lupus nephritis. The prognosis of MCN in SLE appears to be good because of its rapid response to glucocorticoids. 

In 2002, another series was reported by Columbia group that had 7 patients.  All 7 patients presented with full nephrotic syndrome including peripheral edema, nephrotic range proteinuria.  In all cases, renal biopsy revealed diffuse foot process effacement in the absence of significant peripheral capillary wall immune deposits, findings consistent with minimal-change disease. In addition, 5 cases displayed mesangial electron-dense deposits, with or without associated mesangial proliferation, consistent with underlying lupus nephritis class II. It is interesting as it might be usually co existing with Class II lupus and sometimes read as possibly atypical lupus presentation.

If and individual is destined is to have lupus\, the phenotype that they present with might be different based on the individual genetic make up. It is unclear why minimal change is not a pre dominant variant of lupus, perhaps in children?

Ref:

http://informahealthcare.com/doi/abs/10.3109/03009740903456300

http://www.ncbi.nlm.nih.gov/pubmed/11863121

IN THE NEWS: LUNAR TRIAL

The LUNAR trial that compared using rituximab to placebo for treatment of Lupus Nephritis is finally in publication.  It was a well designed randomized trial that wanted to show the impact of Rituximab given at 4 doses of 1gm each along with steroids and MMF with Class III and IV compared to a group with no rituximab arm.  At one year, there was no difference in complete or partial remission.  The "lab values" of C4 and C3, and dsDNA were much improved in the rituximab arm but patient outcomes didn't change.
Interestingly, this study suggests that there might be no secondary role for treatment of Lupus with rituximab if MMF and steroids are being used. Steroids were not spared in the rituximab arm, so its hard to see what would have happened if there were no steroids.  Also, authors state that the power was not strong enough for better outcomes.

Judge for yourself. Does anti CD20 agents have a future in Lupus Nephritis?

Ref: http://www.ncbi.nlm.nih.gov/pubmed/22231479

IN THE NEWS: Increased excretion of urinary podocytes in lupus nephritis

Increased excretion of urinary podocytes in lupus nephritis Bollain-y-Goytia JJ, González-Castañeda M, Torres-del-Muro F, Daza-Benitez L, Zapata-Benavides P, Rodríguez-Padilla C, Avalos-Díaz E, Herrera-Esparza R, - Indian J Nephrol

TOPIC DISCUSSION: Urinary Snapshot of Lupus Nephritis does not equal what you see on the Kidney Biopsy

What degree of Class IV lupus nephritis presents with just hematuria?

What degree of Class I lupus nephritis presents with just hematuria?

Take a look at this data from a recent paper in 2009 by Seshan et al.

Of 541 patients studied for classification of lupus nephritis,

40% of Class I, 19% of Class II, 22% of Class III, 4% of Class IV and 6% of Class V presented with asymptomatic hematuria.

40% of Class I, 42% of Class II, 25% of Class III, 7% of Class IV and 13% of Class V present with asymptomatic proteinuria

20% of Class I, 15% of Class II, 17% of Class III, 40% class IV and 65% of Class V presented with Nephrotic Syndrome.

20% of Class II, 34% of Class III, 27% of Class IV and 7% of Class V presented with Nephritic Syndrome

4% of Class II, 2% of Class III, 18% of Class IV and 2% of Class V presented with Acute renal failure

4% of Class IV and 8% of Class V had presented with Chronic renal injury.

So in summary: Lupus can present on kidney biopsy much more differently than clinically.  Look at the wide spectrum of just hematuria and proteinuria.

Ref:

http://www.ncbi.nlm.nih.gov/pubmed/19195967