2017 marks the first year that glomerulonephritis has its own region, which is quite remarkable given the emphasis it is given in nephrology education and clinical trials. Some nephrologists address this issue with a old-school John Wooden-esque approach, reaching for the oral cyclophosphamide when treating vasculitis. Others that are more traditional (Coach K, maybe?) might be more comfortable with intravenous dosing. Some of the young cowboys/cowgirls (think Will Wade at VCU) will go straight for rituximab, and tack on a few sessions of plasma exchange just to be sure. Then there is the debate over pulse solumedrol or standard 1 mg/kg dosing of oral prednisone, not to mention maintenance therapy. The beauty of this region is that all the above therapies are appropriate options under the right lens, and valid arguments can be made for each of them. When the discussion at biopsy conference turns to treating glomerular disease, there is bound to be controversy, and that’s when the real learning begins!
Selection Committee Member for the Glomerulonephritis Region:
Dr. Glassock, MD, is an Emeritus Professor at the Geffen School of Medicine at UCLA. He is an internationally recognized expert in the field of Glomerular Diseases and Clinical Nephrology (Kidney Disease). He has published over 650 original papers, books, book chapters, and reviews. He is the past-president of the American Society of Nephrology (1984), the National Kidney Foundation (USA) (1985), and past-Chairman of the American Board of Internal Medicine (1991).
Competitors for the Glomerulonephritis Region
If you can convince me that there is anything more complicated or diverse in kidney disease than lupus, then I owe you tickets to the Final Four. For the first time in the history of human existence, we will attempt to discuss lupus nephritis without arguing about the treatment options. Instead let’s address the controversial option of using repeat (or protocol) biopsies to assess histological remission.
Most of us are at least familiar with the concept of protocol biopsies in kidney transplant recipients. The idea is that a biopsy is performed on Day X to assess if there is histological evidence of rejection, regardless of the clinical status of the patient and graft. Proponents of this argue that our markers of serum creatinine and urine output fail to detect subclinical rejection until there is already permanent damage, and that earlier detection and treatment will preserve longterm renal outcomes.
A similar justification is being made for lupus nephritis. It has long been known that a biopsy is necessary in patients with suspected lupus nephritis, as our clinical acumen and markers of serum creatinine, urine proteinuria, and serologic activity are not able to predict the class or degree of activity in the biopsy specimen. To quote from a seminal paper published in Medicine in 1978 by someone named Gerard Appel:
“Determination of histological class was of prognostic value regardless of the absence or severity of clinical renal disease and was the single most important prognostic indicator.”
After the diagnostic biopsy, treatment is initiated accordingly. Typically, Classes III, IV, and V need induction therapy. Maintenance usually extends for months to years after a remission is hopefully obtained, but there is sparse data to suggest whether and when maintenance can be discontinued. Data is now appearing that suggests serial protocol biopsies can help to inform decisions on discontinuing maintenance immunosuppression in addition to providing useful longterm prognostic information.
Interpreting information from the protocol biopsy is another challenging issue. Malvar et al showed that 1/3 of patients in complete remission had persistent high histologic activity on the repeat biopsy. Conversely, nearly 2/3 of patients who had minimal activity on the protocol biopsy were still clinically active. This discordance between clinical and histological outcomes was also noted by groups in Argentina and Sweden.
This conundrum leads me to ask more questions than the data can answer. At what time interval should we re-biopsy? Should we base our treatment decisions more on the clinical or histological activity? Like all decisions in medicine, is the benefit of this information worth the risk of the extra procedure? Some authorities in this community such as Brad Rovin from “THE” Ohio State University (Buckeyes, Big Ten, 14-10 men’s basketball record for those of you that are curious) believe that repeating kidney biopsies offer value even in patients who achieve complete remission. A sample flowchart from a recent update by Dr. Rovin is provided below:
The idea of protocol biopsies in lupus nephritis adds controversy to an already controversial entity. Hopefully now you are ready to back up your trash talk with some data the next time this comes up at biopsy conference!
Steroids Use for IgA Nephropathy
First described by Jean Berger in 1968, IgA nephropathy is often cited as being “the most common glomerular disease worldwide.” Yet over the past 50 years, we have struggled with treatment for this disorder due to its varied presentation. In some ways, the histologic diagnosis is easy – IgA dominance or co-dominance on immunofluorescence. With light microscopy, you can see endocapillary proliferation, segmental scars, mesangial hypercellularity, crescents, necrotizing lesions…. just about any finding. With EM, the deposits can be mesangial, endothelial, epithelial, or intramembranous. To top it off, some patients do great and live their whole lives without any renal deterioration whatsoever. Others progress to ESRD rapidly. In this latter group, immunosuppression may be indicated to alleviate the glomerular inflammation, but how do we know if we should use it, and whether or not it helps?
This topic certainly falls into the “old” category of glomerulonephritis. Newer ongoing trials look at many different therapies – bortezomib, enteric budesonide, blisibimob, fostamatanib, and rituximab all have ongoing clinical trials in IgAN. For this discussion, we will only be looking at steroids.
The most recent study to examine this question is the STOP-IgAN, which was published in NEJM in 2015. For a more detailed discussion, see this excellent summary of this study at NephJC: This multicenter randomized controlled trial examined patients with IgAN with proteinuria > 750 mg/day with eGFR between 30-90 ml/min. After a 6-month run-in to optimize blood pressure and proteinuria, the patients were randomized to continued supportive therapy or additional immunosuppression (methylprednisone if GFR > 59 ml/min, oral cyclophosphamide followed by azathioprine if GFR was between 30-59 ml/min). The two primary endpoints after 3 years were: 1) complete clinical remission (proteinuria <0.2 g/d) and 2) decrease in GFR ≥ 15ml/min/1.72 m^2.
“trial showed that the addition of immunosuppression to ongoing comprehensive supportive care was not beneficial in patients with IgA nephropathy that was characterized by moderate proteinuria and chronic kidney disease stages 1 through 3”
In contrast, let’s turn our attention to the Therapeutic Evaluation of Steroids in IgA Nephropathy (TESTING) study, which may come to a different conclusion. The data from this was presented at ERA-EDTA in Vienna, and is currently submitted for peer-reviewed publication. In this study, 262 patients were randomized to methylprednisolone 0.8 mg/kg/day (weaned over 6-8 months) vs placebo. Patients were all on optimized ACE inhibition and had persistent proteinuria > 1 gram/day with GFR 20-90 ml/min.
Interim results from the TESTING trial at 1.5 years are interesting. Proteinuria in the treatment group was significantly reduced in the steroid arm (p<0.001). The percentage of patients that met the composite primary outcome (40% decrease in eGFR, dialysis, transplant, or kidney related death) in the steroid group (5.9%) was also significantly reduced compared to the placebo group (15.9%). Unfortunately, due to the daily high dosage of steroids, 14.7% of the treatment arm had a serious adverse event (mostly infectious, and 2 of them fatal), which led to early termination of the trial! Even taking this into account, these results from TESTING clash with the conclusion from STOP-IgAN, and we await the full results from the study. Even more tantalizing is the fact that a follow up study using lower steroid dosage and pneumocystis prophylaxis (TESTING-II) is planned.
Anti-PLA2r in Membranous Nephropathy
This concept is the undoubted #1 seed in the region and for good reason. When the discovery of the PLA2R antigen-antibody system in primary membranous nephropathy (MN) was published in NEJM in 2009, I was but a first-year fellow.
Active and passive Heymann nephritis were foreign concepts to me, and I thought the Ponticelli protocol was a recipe for pizza. It wasn’t until later in my training when I realized how big this breakthrough was, and how long it had taken to go from the animal model of megalin/gp330 to PLA2R in humans.
In the past 8 years, several developments have come about due to this breakthrough. Immunofluorescent staining for PLA2R in kidney biopsy tissue is now routinely performed and can be effective to differentiate primary from secondary membranous nephropathy. A new paradigm has evolved where serum PLA2R antibody testing may even replace the kidney biopsy to make the diagnosis of primary membranous nephropathy! I won’t dispute that you can still glean valuable information from the biopsy, but consider the following scenario: If membranous nephropathy is suspected based on clinical findings, a positive serum anti-PLA2R Ab test can diagnose a lesion of MN with 99% certainty! This is not unlike vasculitis where we have ANCA as a serum marker, but comparing ANCA to PLA2R is like discussing a #16-#1 seed matchup. Anti-PLA2R Ab testing is about 80% sensitive and 99% specific for MN, and when anti-PLA2R antibody is present in the circulation, primary MN needs to be strongly suspected based on a recent meta-analysis. Meanwhile, ongoing research has identified other antigens such as thrombospondin in primary membranous patients who are PLA2R negative.
The next step for PLA2R testing is using it beyond the diagnosis. Can we use it for prognosis, or to monitor for response and relapse? The answer to all of the above appears to be an emphatic “YES”.
PROGNOSIS – We know that about 1/3 of patients with primary membranous nephropathy will have spontaneous remission, thus avoiding the need for immunosuppression. Thus far, we have relied on urine proteinuria to stratify the likelihood of a favorable long-term outcome and the need for immunosuppressive therapy. Patients who present with < 4 grams/day of proteinuria can often be monitored with supportive care alone, whereas patients with > 8 grams/day will often need immunosuppression to achieve remission. PLA2R serum antibody titers can be used similarly. Timmermans et al showed that low anti-PLA2R Ab levels were predictive of spontaneous remissions, whereas high levels were associated with persistent proteinuria and required further immunosuppressive treatment. So in the initial setting, PLA2R testing has both diagnostic and prognostic value! For the subset of patients that present with low PLA2R titers, initial supportive care with ACE inhibition and close follow up is an appropriate option in anticipation of spontaneous remission, thus avoiding the need for 6 months of steroids and cyclophosphamide.
TREATMENT – Likewise with treatment, we have relied on urine protein excretion and GFR to assess response. Several studies in patients who have received induction immunosuppression for primary membranous nephropathy have noted that serum anti PLA2R Ab titers fall many months prior to reduction in proteinuria. As typical induction for primary disease lasts six months, this information can be used to individualize and potentially shorten toxic exposure for patients during this crucial time. Conversely, persistent elevation of anti PLA2R Ab after completion of induction suggests the patient is at high risk of relapse. Additionally, re-emergence of circulating antibodies also predicts disease relapse, and precedes the development of proteinuria by weeks to months. A suggested way to integrate anti-PLA2R antibody testing and PLA2R antigen staining in kidney biopsy into the management of MN has recently been published in JASN.
Rituximab for Minimal Change Disease
Minimal change disease (MCD) is probably the first glomerular disease you learned about as a medical student. It’s the least flashy player on the court, but the one that you can always rely on to contribute. Light microscopy is normal, immunofluorescence is negative, and you see diffuse podocyte foot process effacement on EM. The negative immunofluorescence was always interesting to me, since it implies that this disease is not immune-complex-mediated. Yet the hallmark of this disorder is its steroid responsiveness. The small minority of patients who fail to respond to steroids often are thought to fall on the spectrum of FSGS, and perhaps the biopsy missed a segmental scar due to a sampling error.
The biggest problem with minimal change disease is not inducing a remission, but dealing with the eventual relapse. More than half of patients with minimal change disease will relapse, and there are obvious issues with repeated doses of high dose steroids. Patients who frequently relapse are often defined as being steroid dependent (defined as 2 relapses during a steroid taper or within 1 month of ending treatment), and need additional immunosuppression. Again, there are a plethora of options – cyclophosphamide, cyclosporine, tacrolimus, levamisole, ACTH and mycophenolate mofetil have all been studied and demonstrate the ability to induce and maintain remission in patients with frequent relapses. Rituximab is entering the starting lineup on the treatment team, and looks like it’s a serious player!
The use of rituximab in minimal change disease goes back ten years, and the literature was initially comprised of promising anecdotes and observational case series. Recently a larger case series published in JASN demonstrated near 100% remission rate using rituximab in 30 patients with steroid dependent MCD. A small randomized controlled trial in CJASN evaluated rituximab in 54 children in conjunction with lower doses of prednisone and calcineurin inhibitors. This showed 70% reduction in proteinuria and lower relapse rate in the patients treated with rituximab compared to standard therapy.
A multicenter, double-blind, randomized, placebo-controlled trial was conducted in Japan with 52 patients randomized to rituximab or placebo. All had relapsing nephrotic syndrome and were on MMF, cyclosporine, or mizoribine (an antimetabolite, similar to azathioprine). The rituximab group ended up with a reduction in relapses, less treatment failure, and lower steroid use over 19 months. Similar results were seen in an Italian RCT, where rituximab was used to permit early steroid withdrawal at one month, and proteinuria was re-evaluated and remained low at 3 and 12 months.
Rituximab may be the Magic Johnson of glomerular disease. It is that rare player that can play any position and do everything on the court. Add frequently relapsing/steroid-dependent minimal change disease to the growing list of diseases where it can be considered!