Recent IgA Nephropathy Review
Substantial Review of IgAN From Major Medical Journal
This 2018 review covers IgAN from Glomerule to Ureter, not quite A-Z
Challenges and Future Ideas are discussed
Researchers: Rose S Penfold, Maria Prendecki, Stephen McAdoo, Frederick WK Tam of the Renal and Vascular Inflammation Section, Department of Medicine, Imperial College London, London, UK
To begin I am breaking the typical breathless, and nigh unto impossible to read ‘abstract’, into more understandable paragraphs. My comments are in italics as ‘translation.’
Abstract: IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide, exhibiting a variable clinical and pathological course and significantly contributing to the global burden of chronic kidney disease and end-stage renal disease. Current standards of care focus on optimization of antihypertensive and antiproteinuric therapies (typically renin-angiotensin system blockade) to reduce disease progression.
Translation: If you are reading this you already know this is a serious disease. The standard treatments mentioned here suggest the blood pressure medications known as ACE inhibitors (renin-angiotensin) are best. Anti-proteinuric therapies are not specified here, most often this means steroids, used as an immune-suppressing medication. Alas, there is no mention of the dramatic remission results that are seen by the steroid alternative, that being tonsillectomy, minor surgical immune suppression.
Much recent attention has focused on whether additional immunosuppression confers better outcomes than supportive management alone, and indeed, several trials have demonstrated renoprotective effects following the use of oral corticosteroids. However, results have been inconsistent, and perceived benefits must be balanced against risks and adverse effects associated with generalized immunosuppression, as highlighted by the high-profile STOP-IgAN and TESTING clinical trials.
Recent translational research in vitro and animal models of IgAN have generated greater insight into potential therapeutic targets for this complex autoimmune disease. Deeper understanding of the roles of the mucosal immune barrier, complement activation and deposition, T-cell dependent and independent mechanisms of B cell activation, and of the deposition and downstream inflammatory signaling pathways of nephritogenic polymeric IgA1 complexes (e.g., signaling of immune receptors via spleen tyrosine kinase) has formed the rationale for the development of novel agents and clinical trials of more targeted therapies.
However, translating research findings into clinical practice is challenging, with many immunopathological features of IgAN specific to humans. Recent comprehensive reviews outline the current understanding of mechanisms of IgAN as well as ongoing and future clinical trials; it is not our aim to replicate this here. Instead, we take a mechanistic approach to current treatment strategies, outlining advantages and limitations of each before exploring ongoing research with potential translation into future targeted therapies for this complex disease.
Ed Note: I have found in reading this review paper some few new insights, never-the-less it has been a good read to remind me of the complexity of IgAN. I am disturbed by what is missing, especially any mention of tonsillectomy which is a multifaceted therapy that acts to remove a substantial amount of the offending IgA from the patient and at the same time acts as a surgical immune suppressant. That such minor and low-cost surgery produces, in most, such great benefit ought to have provided it a credible treatment in this ‘review’ paper.
This is especially true in light of the controversy swirling around some of the ‘therapeutic’ treatments especially steroid immune suppression that have been in the news. One such steroid treatment Acthar Gel which has been on the market for more than 50 years as a low-cost pharmaceutical. When it became a new ‘therapeutic target’, upon becoming a ‘terapeutic target’ for IgAN and several other kidney and related autoimmune disorders saw its $40 per dose price rise by 100,000 times to $40,000 per dose!
The notion that ‘therapeutic targets’ for diseases like IgAN are looked upon as ‘golden handshakes’ for the banksters of the ‘medical-pharmaceutical industrial complex’ is something we should all revile against.
Selected Excerpts From This Paper
Epidemiology and clinical features
IgA nephropathy (IgAN) is the most common form of glomerulonephritis (GN) worldwide, with an estimated incidence of at least 2.5/100,000/year in adults. There seems to be geographical variation in disease prevalence, with data from biopsy and organ replacement registries suggesting a higher burden of disease in East and Pacific Asian countries.
The disease is variable in both its clinical and histopathological presentations. While presentation may occur at any age, peak incidence is in the second and third decades of life. Most patients present with either single or episodic macroscopic hematuria (characteristically following an upper respiratory tract infection – “synpharyngitic” Ed Note: This means a bad sore throat, as in tonsillitis. – or athletic exertion) or following detection of microscopic hematuria and/or proteinuria on routine urine testing (Ed Note: blood tinted and/or foamy urine). A much smaller proportion present with acute kidney injury, usually as a result of crescentic IgAN or gross hematuria causing tubular obstruction. While the latter is often reversible, renal recovery may be incomplete. Nephrotic syndrome (severe protein loss through urine) usually occurs only in more advanced stages of the disease.
Definitive diagnosis is established by kidney biopsy to identify for IgA deposits.
Insights into pathological mechanisms
Most recent models of immuno-pathogenesis in IgAN propose a “multi-hit” process, with contribution of both genetic and environmental factors. A dysregulated mucosal immune system with defective immune tolerance to commensal or commonly encountered pathogens may be a key factor in triggering the disease. Characterization of both circulating and glomerular immune complexes in IgAN patients has revealed complexes comprising galactose-deficient IgA1 (Gd-IgA1) and C3. The pathophysiology underlying the formation and deposition of these is reviewed extensively elsewhere.
The notion that IgAN is a systemic condition is supported by high rates of disease recurrence following renal transplant. Histologic evidence of recurrent IgAN is observed in over 35% of patients who receive renal allografts as treatment for ESRD due to IgAN despite these patients being on antirejection immunotherapy.
What triggers the production of aberrant Gd-IgA1 in susceptible individuals? It has been suggested that exposure to environmental triggers, such as pathogenic or commensal bacteria, may lead to excess production of aberrantly glycosylated IgA in mucosal-associated lymphoid tissue. IgA reacting with pathogens, including Haemophilus parainfluenzae, parvovirus, cytomegalovirus, Epstein–Barr virus, and Helicobacter pylori has been detected in both serum and glomerular samples from patients with IgAN. Furthermore, reported IgA deposition in patients with methicillin-resistant Staphylococcus aureus infection indicates a possible role for microbial superantigens.
Therapeutic approaches
If we consider IgAN to be an autoimmune disease with both systemic and local immunopathological mechanisms, it seems logical that both generalized and targeted immunosuppression may be effective. Of course, any therapy needs to be assessed against optimized supportive care, taking into account associated risks and side effects. Here, we outline current treatments, discuss evidence surrounding supportive and immunosuppressive approaches, and outline some of the current progress toward targeted therapies.
Current standards of care
Optimal management of IgAN remains a contentious topic. Latest Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend a long-term RAS blockade (with angiotensin-converting enzyme inhibitors [ACE-I] or angiotensin receptor blocker [ARB]) for proteinuria >1 g/day, with up-titration of the dose as far as tolerated, depending on blood pressure, to achieve proteinuria of <1 g/day. An RAS blocker is also suggested for proteinuria of 0.5–1 g/day. Recommended blood pressure targets are <130/80 mmHg or <125/75 mmHg when initial proteinuria is >1 g/day.
A 6-month course of corticosteroid therapy is suggested for patients with persistent proteinuria despite 3–6 months of optimized supportive care (including ACE-I/ARB and blood pressure control) and glomerular filtration rate (GFR) >50 mL/min/1.73 m2. Further immunosuppression with cyclophosphamide may be needed for those with crescentic IgAN with rapidly deteriorating renal function – analogous to the treatment of ANCA vasculitis.
Supportive therapy
Supportive care, particularly antihypertensive and antiproteinuric therapy, remains a cornerstone of management for IgAN. As for other causes of chronic kidney disease (CKD), elevated blood pressure, proteinuria, and lower GFR have been associated with higher risk of underlying disease progression and adverse long-term outcomes. These features have been used to derive a prognostic scoring system that may be used to estimate progression toward ESRD in IgAN.
Meta-analysis of clinical trials has demonstrated that RAS blockers (ACE-Is or ARBs) have a statistically significant effect on renal protection and reduction of proteinuria in IgAN. This association appears to be stronger amongst those demonstrating reduced estimated glomerular filtration rate (eGFR), proteinuria, acute inflammatory pathological findings, and those receiving methylprednisolone pulse therapy. ACE-I demonstrates variable therapeutic efficacy in slowing disease progression, which may in part be genetically determined. Mechanisms of secondary protection are likely similar to those in other causes of proteinuric CKD, mediated at least in part through lowering of both systemic blood pressure and intraglomerular pressure through inhibition of angiotensin II-mediated efferent arteriolar vasoconstriction.
Tight lipid control is also important. Statins, in addition to their well-documented cardioprotective effects in renal disease, may also delay the progression of CKD.
A “multimodal” approach with close monitoring and careful up-titration of supportive therapies has been shown to achieve remission or regression of proteinuria and stabilization of kidney function in other clinical settings and emphasizes the importance of high-quality supportive care. Ongoing work is needed to identify clinical biomarkers of patients demonstrating the best response to intensive supportive care and to offer maximally tolerated therapy to prevent or reduce progression toward ESRD.
Note should also be made here of reported beneficial effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA; omega-3 polyunsaturated fatty acids) as anti-inflammatory and inflammation-convergent drugs in the treatment of IgAN. Successful treatment of several cases of IgAN was reported recently with a combination of aspirin and EPA. While the precise mechanism for this combination is unknown, it is plausible that aspirin potentiates the effect of anti-inflammatory lipid mediators. Furthermore, the addition of DHA to EPA was found to stabilize renal function of IgAN patients.
Ed Note: Skipping a lot about Immunological Ideas, read for yourself in the full paper.
Conclusion and future directions
IgAN remains a common cause of glomerular disease and a significant contributor to the global burden of CKD and ESRD. Studies in vitro and in vivo animal models continue to shed light on mechanisms of disease, identifying key players in the immunopathological interaction between Gd-IgA1 antigen and circulating antiglycan antibodies and formation and deposition of immune complexes.
International treatment guidelines, supported by multicenter clinical trials, advocate high-quality supportive care, including RAS blockers and carefully titrated blood pressure control. Steroids and further immunosuppressive therapies are considered for those with persistently high proteinuria or rapidly progressive disease, respectively. Notably, the recent STOP-IgAN trial did not demonstrate benefits of broad immunosuppressive therapy, including steroid, in IgAN to justify use in routine care (although note that patients with >3.5 g/day proteinuria were excluded from the study). Trials of other immunosuppressants have not provided conclusive evidence of overall benefits for disease progression and patient outcomes when balanced against risks associated with these therapies.
Recent research has generated greater insight into potential therapeutic targets for IgAN. A deeper understanding of the roles of the mucosal immune barrier, complement activation and deposition, and T-cell dependent and independent mechanisms of B-cell activation and downstream signaling of immune receptors via Syk has formed the rationale for the development of novel agents and clinical trials of more targeted therapies. Results of a Phase IIb trial of targeted oral budesonide appear promising. Meanwhile, results of the Phase II RCT of oral Syk inhibitor fostamatinib are eagerly awaited. It is hoped that continuing research will generate further putative therapeutic targets to change the future landscape of treatment strategies for IgAN.
There is much more in the full paper, including scores of referenced papers.
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