IgA nephropathy (IgAN) is the most common glomerular disease worldwide. However, treatment options for primary IgAN remain largely based on expert consensus or very weak level of evidence. Large randomized controlled trials (RCTs) providing definitive immunosuppressive regimens for IgAN are lacking. Almost all of the recommendations and suggestions in the recent KDIGO clinical practice guidelines on glomerulonephritis related to IgAN are low-level evidence.
In this regard, Prof. Lai Ka-Nang and Prof. Tong Chi-Wai from Queen Mary Hospital of the University of Hong Kong have written a review of the evidence-based medical aspects of IgAN treatment in the journal Kidney Disease.
I. Non-immunosuppressive therapy
Blockade of the renin-angiotensin system (RAS) is the main non-immunosuppressive treatment for IgAN.
Cheng et al. analyzed 585 patients in 11 RCT studies, including 7 trials using placebo or no treatment as a control and 4 trials using other antihypertensive agents as controls. Treatment with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) had a significant renoprotective effect and reduced proteinuria compared with controls.
A meta-analysis reviewing 6 RCT studies totaling 109 patients showed that the combination of ACEI and ARB was not superior to ACEI or ARB alone in reducing daily proteinuria, with no increased risk of hyperkalemia. The long-term effects of combination therapy on renal outcomes are unclear. Another meta-analysis included 27 RCT studies totaling 1577 patients treated with ACEI, ARB, or a combination of both vs other antihypertensive agents, other drugs, or placebo.
The results showed that the benefits of blocking the RAS appeared to outweigh the harms for patients with IgAN. However, this meta-analysis failed to demonstrate a benefit beyond blood pressure control with any of the antihypertensive agents and did not evaluate the risk of major renal and/or cardiovascular endpoint events or long-term mortality.
Aliskiren is a relatively new oral direct renin inhibitor (DRI) that has been used in the treatment of hypertension and diabetic nephropathy. 25 patients with IgAN who had persistent proteinuria (24-h urine protein >1 g/day) despite receiving the maximum recommended dose of cloxacin (100 mg/day) were recruited by Tang et al. to receive further DRI therapy. The average reduction in urinary albumin/creatinine ratio after 12 months of aliskiren treatment was 26%, with a ≥50% reduction in proteinuria in 24% of patients. Aliskiren treatment was associated with significant reductions in plasma renin activity, serum IL-6 and TGF-β levels. Notably, transient hyperkalemia was found in 24% of patients.
Another group of investigators from Hong Kong studied 22 patients with IgAN who had persistent proteinuria despite treatment with ACEI or ARB. Patients were randomized to either the oral aliskiren group or the placebo group for 4 months and then interchanged to the other group after a washout period. After 4-16 weeks of treatment, proteinuria levels were significantly lower in the aliskiren group compared to the placebo group. Aliskiren treatment resulted in a moderate but significant reduction in eGFR and systolic blood pressure. Severe hyperkalemia (>6 mmol/L) was not observed in these patients.
These two pretests suggest a hypoproteinuric effect of aliskiren, a DRI, in patients with IgAN who have persistent proteinuria despite ACEI or ARB therapy. Larger RCT studies are needed to confirm the renoprotective effect of direct renin inhibition.
The RCT evidence is not strong enough to include the effectiveness of any other non-immunosuppressive therapeutic measures such as fish oil, anticoagulation therapy and tonsillectomy.
II. Immunosuppressive therapy
A previous meta-analysis that included 13 RCT studies with a total of 623 patients concluded that immunosuppression is a promising strategy and that further research into this approach is needed. Research in this area, as in many other renal diseases, has been hampered by the slow-progressing nature of the disease (10-year survival rate over 85%), significant patient heterogeneity, and the lack of animal models that resemble human IgAN.
1. Glucocorticoids
A relatively large amount of data on glucocorticoids was contributed by Japanese researchers in the early days. A meta-analysis that included 7 RCTs with a total of 386 patients suggested that glucocorticoids had a significant effect on protecting renal function and reducing proteinuria, but the gastrointestinal response required attention.
Another meta-analysis including 15 quasi-randomized controlled and uncontrolled trials with 1542 patients suggested that glucocorticoid therapy was associated with reduced proteinuria and a significantly lower risk of end-stage renal failure. In addition, subgroup analyses revealed that long-term hormone therapy was more effective than standard and short-term therapy.
A recent meta-analysis of 9 trials including 537 patients with urinary protein excretion >1 g/day and normal renal function suggested that high-dose, short-term hormone therapy was significantly more nephroprotective than low-dose, long-term hormone use.
The KDIGO clinical practice guidelines for glomerulonephritis suggest that the level of evidence for the additional benefit of glucocorticoids in addition to optimal supportive therapy is low. The KDIGO Working Group recommends a 6-month course of hormone therapy in patients with persistent proteinuria >1 g/day and GFR >50 ml/min/1.73m2 despite adequate ACEI or ARB use and good blood pressure control. Hormonal therapy.
A multicenter clinical trial to determine the efficacy and safety of hormonal therapy in IgAN is underway.
Recently, an EU VALIGA study included 1147 patients from 13 countries covering the entire spectrum of IgAN disease. With a median follow-up of 4.7 years, 86% of patients were treated with RAS blockers and 42% with glucocorticoids or immunosuppressive agents. Renal pathology was classified according to the Oxford pathological typing of IgAN, and pathological MEST scores with independent predictive value were reduced by glucocorticoid or immunosuppressive therapy.
A retrospective subgroup analysis comparing patients treated with glucocorticoids combined with RAS blockers to matched patients treated with ACEI/ARB alone confirmed the former’s effect of reducing proteinuria and slowing the rate of renal decompensation. These benefits extended to patients with eGFR ≤ 50 ml/min/1.73m2, increasing in proportion to the severity of proteinuria.
2. Cyclophosphamide in combination with glucocorticoids
Several study groups worldwide have provided evidence that glucocorticoid shock therapy combined with cyclophosphamide intravenous or oral therapy slows the progression of advanced IgAN. These studies all suggest that the combination of cyclophosphamide and hormone therapy may benefit patients at very high risk of renal failure (i.e., those with very rapid progression of GFR reduction and/or severe crescentic damage).
Because of the side effects, short-term treatment with cyclophosphamide in combination with glucocorticoids is reasonable in patients with IgAN with true crescent formation or advanced glomerulonephritis. The KDIGO clinical practice guidelines for glomerulonephritis suggest a similar regimen (low-quality evidence).
3. Tonsillectomy combined with glucocorticoids
Tonsillectomy has long been a treatment option for IgAN aimed at removing pathogens of relevant origin that can colonize the tonsillar crypts and macrophages and B cells that can colonize the tonsillar follicles. This specific antigen challenge is thought to cause hyperactive IgA synthesis because lymphocytes from the tonsils of patients with IgAN exhibit higher production of dimers and unglycosylated IgA1 than controls.
In Japan, tonsillectomy/hormone shock therapy is commonly used to treat patients with IgAN who have a better early prognosis. A recent meta-analysis including 7 non-randomized studies (6 from Japan and 1 from China) with a total of 858 patients (534 tonsillectomized and 324 unresected) showed that tonsillectomy in combination with either standard hormone therapy or hormone shock therapy had higher remission rates and favorable long-term effectiveness (after 5 years and 10 years of follow-up) than either tonsillectomy alone or hormone therapy alone. data were obtained after 5-year follow-up and 10-year follow-up).
With the exception of Japan, the benefit of tonsillectomy has been largely less impressive. A retrospective review analysis that included 61 white patients showed that tonsillectomy did not change the rate of disease progression after 20 years of follow-up.
More recently, a Hungarian study enrolling 166 patients with IgAN who did not undergo tonsillectomy and 98 patients who underwent tonsillectomy suggested that tonsillectomy may have delayed the progression of renal disease, especially in patients with sarcoid hematuria. An interesting finding was that serum galactose-deficient IgA1 levels were reduced after tonsillectomy, suggesting that the palatine tonsils are the primary site of production of galactose-deficient IgA1 cells.
However, the clinical effectiveness of tonsillectomy in IgAN has been completely ruined by two recent studies. sato et al. found that tonsillectomy before renal transplantation did not affect the recurrence of IgAN. More importantly, the first national multicenter RCT in Japan failed to demonstrate any beneficial effect of tonsillectomy combined with hormonal shock over hormonal shock alone. In a cohort study including 112 Chinese patients, tonsillectomy was not independently associated with clinical remission and did not improve renal survival.
The 2010 KDIGO clinical practice guideline for glomerulonephritis does not recommend tonsillectomy for patients with IgAN (low-quality evidence).
4. Calcium-regulated phosphatase inhibitors
Early experience with cyclosporine in IgAN has not been favorable. Patients receiving cyclosporine in combination with hormone therapy have greater reductions in proteinuria levels and higher remission rates in patients with milder pathology than those treated with hormone therapy alone, but combination therapy is associated with increased renal function compared with baseline serum creatinine levels and temporary deterioration in renal function. In addition, more patients in the combination therapy group developed severe infections. These data discourage the misuse of cyclosporine in IgAN due to potential nephrotoxicity.
Data on other calcium-regulated phosphatase inhibitors (e.g., tacrolimus) are scarce. Zhang et al. reported the induction of remission of proteinuria with tacrolimus in 14 patients with refractory IgAN and suggested that it may be mediated by stabilization of the podocyte cytoskeleton. kim et al. demonstrated that tacrolimus effectively reduced proteinuria in patients with normotensive IgAN and suggested that tacrolimus may Kim et al. demonstrated that tacrolimus was effective in reducing proteinuria in normotensive IgAN patients and suggested that tacrolimus could be used as an alternative treatment to glucocorticoids and ACEI/ARB in patients who cannot tolerate antihypertensive drugs.
5. Azathioprine (Aza)
A retrospective analysis of 74 patients with IgAN over 10 years showed that long-term treatment with Aza in combination with low-dose prednisone did not change the clinical course compared to untreated controls. However, in a subgroup of patients with massive proteinuria (>3 g/day) and baseline serum creatinine of 1.4-2.5 mg/dl, this immunosuppressive regimen reduced the risk of doubling serum creatinine levels compared with controls (27% vs 78%) and also delayed progression to end-stage renal failure (17% vs 55%).
The Japanese Pediatric IgAN Treatment Study Group randomized 78 children with newly diagnosed IgAN to receive a combination of prednisolone, Aza, heparin-warfarin, and dipyridamole or heparin-warfarin and dipyridamole only. Treatment with Aza included reduced urinary protein and serum IgA levels. The weakness of the study was the lack of data on baseline proteinuria and creatinine clearance and on blood pressure control in both groups.
A prospective randomized study in Italy enrolling 207 patients showed no additional benefit in renal survival with the addition of Aza to glucocorticoids over glucocorticoids alone in patients with IgAN with proteinuria ≥ 1 g/day and plasma creatinine ≤ 2.0 mg/dl. Interestingly, in the same patient cohort, the investigators looked at patients with plasma creatinine ≥ 2.0 mg/dl. Renal survival at 6 years was similar in both groups. In the Cox analysis, the addition of Aza may have been more effective than glucocorticoids alone in patients with chronic renal insufficiency, despite the increased side effects.
Therefore, the current data suggest that the addition of Aza has limited therapeutic benefit and may have potential toxicity.
6. morte-macrolimus (MMF)
To date, six RCTs have been published on the use of MMF in IgAN, with more controversy than consensus. Although these trials have produced conflicting results, they are notable for significant differences in patient selection and treatment regimen.
Overall, MMF appears to be effective in lowering proteinuria in Chinese, but not necessarily in whites. Thus racial differences may be a possible reason for the different results observed in these trials. Another possible reason is that patients included in the different studies had different degrees of lesions, and it is possible that MMF yielded more favorable results in patients with severe IgAN lesions.
In addition to reducing IL-6 production and thylakoid binding to IgA, MMF may also reduce IgAN lesions through other mechanisms. A recent study showed that mycophenolic acid (from MMF) can upregulate the expression of core 1β3-Gal-T cell-specific molecular chaperones (Cosmc) and therefore reverse the levels of aberrant O-glycosylated IgA1 in peripheral lymphocytes from patients with IgAN. impaired Cosmc expression and aberrant O-glycosylation deficient IgA1 play an important role in the pathogenesis of IgAN.
Further observations and studies are needed to provide more definitive answers about the effectiveness of MMF in IgAN.
The 2012 KDIGO clinical practice guideline for glomerulonephritis does not recommend the use of MMF in patients with IgAN (low-quality evidence).
III. Other therapeutic approaches
In vitro studies have shown that peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists can attenuate the inflammatory response in IgAN-activated renal tubular epithelial cells by downregulating the expression of angiotensin type 1 receptors. Dual treatment with PPAR-γ and ARB provides synergistic effects in reducing inflammatory responses and angiotensin II signaling in renal tubular epithelial cells, and this therapeutic benefit has been demonstrated in animal models of IgAN.
Budesonide enemas targeting Peyer’s nodes in the ileocecal tract were administered to 16 patients for 6 months, followed by 3 months of observation, and showed a 23% reduction in proteinuria and a moderate 8% increase in GFR. Based on these encouraging results, a multicenter phase IIb trial is being planned in Europe.
The pleiotropic renoprotective effect of statins was studied in 24 patients with IgAN not treated with glucocorticoids or immunosuppressive drugs. After one year of statin therapy, there was an 8% increase in eGFR, although there was no significant reduction in proteinuria.
Complement activation, including the alternative and lectin pathways, plays an important role in the pathogenesis of IgAN. ekulizumab (anti-C5) treatment given to IgAN patients with rapidly progressive disease leading to renal failure due to refractory immunosuppressive therapy by Rosenblad et al. resulted in stable renal function and reduced proteinuria. Renal function deteriorated rapidly after discontinuation of therapy and temporarily recovered after a single dose of eculizumab therapy.
The potential role of splenic tyrosine kinase (SYK), an intracellular protein tyrosine kinase involved in the downstream pathway of immune receptor cell signaling, in IgAN is still being investigated. Increased expression of total and phosphorylated SYK was observed in kidney biopsy specimens from IgAN patients, and pharmacological inhibition of SYK or knockdown of SYK with siRNA significantly reduced the proliferation and synthesis of inflammatory mediators in human thylakoid cells exposed to IgA1 isolated from IgAN patients and also inhibited thylakoid cell proliferation. An RCT is currently underway to investigate the clinical utility of fostamatinib, a selective oral tyrosine kinase inhibitor, in patients with IgAN.
IV. Recommendations for treatment in different clinical situations
1. Acute vasculitis type
This type is characterized by a very short history and rapid deterioration of renal function. Renal biopsy shows crescent formation in >50% of glomeruli. Chronic tubular interstitial atrophy and fibrosis are not prominent, although mononuclear cell infiltration is present. Hormone shock therapy followed by sequential oral hormone therapy combined with short-term intravenous/oral cyclophosphamide should be used appropriately.
2. Overlapping syndrome of IgAN and microscopic lesions nephropathy
This type is characterized by a short history of nephrotic syndrome and normal deterioration of renal function. Renal biopsy shows minimal glomerular and tubular pathology except for IgA deposits in the thylakoid region. These patients should be treated as microscopic nephropathy with glucocorticoids and slow dose reduction. The efficacy and safety of this approach was confirmed in a recent cohort study of Chinese patients. The clinical presentation of this type resembles microscopic nephropathy and is prone to recurrence, but chronic renal damage is rare.
3. Typical patients presenting with microscopic hematuria, significant but non-nephrotic range proteinuria, hypertension and varying degrees of renal failure
In those patients with proteinuria <1g egfr="">60ml/min/1.73m2) and normal blood pressure (BP<125/75mmHg), the main treatment is long-term regular follow-up to detect renal disease progression and hypertension. The preferred treatment is optimal supportive therapy aimed at reducing proteinuria <1g/day.