IgA nephropathy (IgAN) is the most common glomerular disease worldwide. However, the treatment of primary IgAN is still largely based on expert consensus or weak evidence. There is no large randomized controlled trial (RCT) to provide an exact immunosuppressive program for IgAN.
Non-immunosuppressive therapy
Blocking the renin-angiotensin system (RAS) is the main non-immunosuppressive therapy for IgAN.
Cheng et al. analyzed 585 patients in 11 RCT studies, and found that treatment with angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) had significant renal protective effect and reduced proteinuria.
A meta-analysis showed that the combination of ACEI and ARB was not superior to ACEI or ARB alone in reducing daily proteinuria, and the risk of hyperkalemia was not increased. The long-term effect of combined therapy on renal outcomes is unclear.
Another meta-analysis showed that the benefit of blocking RAS seemed to outweigh the harm to IgAN patients. However, this meta-analysis failed to prove the benefits of using any antihypertensive drug in addition to controlling blood pressure, and did not evaluate the major renal and/or cardiovascular end points or long-term mortality risk.
Aligilen is a relatively new, oral direct renin inhibitor (DRI), which has been used in the treatment of hypertension and diabetes nephropathy. Two pre-experiments conducted at present suggest that Aligilen has the effect of reducing proteinuria in IgAN patients who still have persistent proteinuria after receiving ACEI or ARB treatment.
RCT evidence is not strong enough, including the effectiveness of fish oil, anticoagulant therapy, tonsillectomy and other non-immunosuppressive treatment measures.
Immunosuppressive therapy
Research in this field, like many other kidney diseases, is hindered by the nature of slow progression of the disease (10-year survival rate of more than 85%), significant patient heterogeneity and the lack of animal models that resemble human IgAN.
1. Glucocorticoids
The KDIGO clinical practice guidelines for glomerulonephritis suggest that the level of evidence for additional benefits provided by glucocorticoids on the basis of optimized supportive treatment is low. The KDIGO working group recommends that patients with continuous proteinuria>1g/day after sufficient use of ACEI or ARB, good blood pressure control, and GFR>50ml/min/1.73m2 can receive hormone treatment for 6 months.
2. Cyclophosphamide combined with glucocorticoid
Several research groups around the world have provided evidence that glucocorticoid pulse therapy combined with cyclophosphamide intravenous or oral therapy delays the progression of advanced IgAN. These studies suggest that the combined treatment of cyclophosphamide and hormone may benefit patients with very high risk of renal failure (that is, those with very rapid GFR reduction and/or severe crescent damage).
Because of the side effects, it is reasonable to use cyclophosphamide combined with glucocorticoid in short term in IgAN patients with real crescent formation or progressive glomerulonephritis. The KDIGO clinical practice guidelines for glomerulonephritis suggest similar protocols (low quality evidence).
3. Tonsillectomy combined with glucocorticoid
Tonsillectomy has long been a treatment option for IgAN, aiming to remove pathogens from relevant sources. In Japan, tonsillectomy/hormone pulse therapy is often used to treat IgAN patients with good early prognosis. However, the clinical effectiveness of tonsillectomy in IgAN has been completely destroyed by the latest two studies. Sato et al. found that tonsillectomy before kidney transplantation did not affect the recurrence of IgAN. More importantly, Japan's first national multi-center RCT study failed to confirm that tonsillectomy combined with hormone shock has any beneficial effect than hormone shock alone. In a cohort study of 112 Chinese patients, tonsillectomy was not independently associated with clinical remission, nor did it improve renal survival. The 2010 KDIGO clinical practice guidelines for glomerulonephritis do not recommend tonsillectomy for IgAN patients (low quality evidence).
4. Calmodulin inhibitor
The early experience of using cyclosporine in IgAN is not beneficial. The proteinuria level of patients treated with cyclosporine combined with hormone was significantly lower than that of patients treated with hormone alone, and the remission rate was higher in patients with mild pathology. However, the combined treatment would cause the increase of renal function compared with the baseline serum creatinine level and temporary deterioration of renal function.
In addition, there were more patients with severe infection in the combined treatment group. Due to the potential nephrotoxicity, these data hinder the abuse of cyclosporine in IgAN.
5. Azazapurine (Aza)
A retrospective analysis of a 10-year follow-up showed that long-term use of Aza combined with low-dose prednisone did not change the clinical course of disease compared with untreated control group. However, in patients with large amount of proteinuria (>3g/day) and baseline serum creatinine 1.4~2.5mg/dl, it can reduce the risk of doubling serum creatinine level and delay the progression to end-stage renal failure. A Japanese study found that Aza treatment reduced urinary protein and serum IgA levels. An Italian study showed that among IgAN patients with proteinuria ≥ 1g/day and plasma creatinine ≤ 2.0mg/dl, Aza on the basis of glucocorticoids could not obtain additional benefits in renal survival compared with glucocorticoids alone. Therefore, the current data suggest that Aza has limited therapeutic advantages and may have potential toxicity.
6. mycophenolate mofetil (MMF)
So far, six RCT studies have been published using MMF in IgAN, with more disputes than consensus. In general, MMF seems to be effective in reducing proteinuria in Chinese people, but not necessarily in white people.
Therefore, racial differences may be a possible reason for the different results observed in these experiments. Another possible reason is that the patients involved in different studies have different degrees of disease, which may lead to more favorable results for MMF in patients with severe IgAN disease.
The 2012 KDIGO clinical practice guidelines for glomerulonephritis do not recommend the use of MMF (low-quality evidence) in IgAN patients.
Treatment recommendations under different clinical conditions
1. Progressive/vasculitis type
This type is characterized by a short history and rapid deterioration of renal function. Renal biopsy showed crescent formation>50% of glomeruli. Despite monocyte infiltration, chronic tubulointerstitial atrophy and fibrosis are not prominent. Sequential oral hormone combined with short-term intravenous/oral cyclophosphamide therapy should be used reasonably after hormone pulse therapy.
2. IgAN and minimal pathological nephropathy overlap syndrome
This type is characterized by a short history of nephrotic syndrome and normal deterioration of renal function. The renal biopsy showed that the pathological changes of glomerulus and renal tubules were very slight except for IgA deposition in mesangial area. These patients should be treated as microlesion nephropathy, and use glucocorticoids and slowly reduce the dose.
A recent cohort study of Chinese patients confirmed the effectiveness and safety of this method. The clinical manifestation of this type is similar to that of microlesion nephropathy, which is easy to recur, but chronic renal damage is rare.
3. Typical patients with microscopic hematuria, significant but non-nephrotic proteinuria, hypertension and varying degrees of renal failure
For patients with proteinuria<1g/day, stable renal function (eGFR>60ml/min/1.73m2), and normal blood pressure (BP<125/75mmHg), the main treatment is long-term regular follow-up to detect the progression of renal disease and hypertension. The optimal supportive treatment aimed at reducing proteinuria<1g/day is preferred.