| Abstract|| |
Summary: Treatment options for IgA nephropathy (IgAN) must take into consideration the pathophysiology, namely the role of eicosanoids, angiotensin II and monocytemacrophages releasing reactive oxygen species (ROS). Angiotensin converting enzyme inhibitors and early corticosteroid usage are prime therapies. Tonsillectomy should be considered. Other components of a therapeutic cocktail could be; (a) thromboxane antogonist, (b) leukotriene antagonist, (c) platelet activating factor antagonist, (d) an antioxidant and (e) an anti-fibrotic agent like pentoxyfylline. In the new millenium, there will be focus on anti-proliferative measures like platelets dependent growth factor aptamers. For unusual cases with rapid progression, the use of FK-506 or mycophenolate mofetil can be considered.
Keywords: IgA glomerulonephritis, Renal interstitial fibrosis, Angiotensin II, Complement, Reactive oxygen species. Eicosanoids.
|How to cite this article:|
Wardle E N. Ways of Treating IgA Nephropathies. Saudi J Kidney Dis Transpl 2000;11:325-33
Following my recent article  on the mechanisms involved in the pathogenesis of IgA nephropathy (IgAN), I will now focus on those patients with IgAN who need treatment and what therapies can be considered.
| Prognostic Assessment|| |
Adverse outcome in IgAN is indicated by the presence of hypertension, proteinuria or renal impairment at presentation. In an Australian study,  when the serum creatinine was 1.2 to 2.4 pmol/L, cumulative renal survival at 10 years was 0.97. The patients with good prognosis had normal urinary protein loss, or certainly not more than 1 gm per day. Periodic assessment of the urine protein/urine creatinine ratio is advisable.  Persistent microscopic hematuria foretells trouble.  When there is any degree of proteinuria, measurement of 24-hour excretion of β2 -microglobulin is recommended, because, when performed in correct manner  during oral sodium bicarbonate administration to the patients, its excretion reflects tubular damage and interstitial fibrosis of the kidneys.
Standard therapy of glomerulonephritis
One will be familiar with the general measures  for treatment of glomerulonephritis (GN) [Table - 1].
Since angiotensin converting enzyme (ACE) inhibitors effectively lower intraglomerular pressures and reduce proteinuria,  and additionally protect against renal interstitial fibrosis and glomerulosclerosis because of reduced expression of tumor growth factor beta (TGFβ),  they must be used as primary agents in any therapeutic cocktail. ACE inhibitors can be combined with endothelin antagonists for IgAN that is progressive. For the usual case with insidious progression, use of ACE with pentoxifylline can be recommended. The drug pentoxifylline helps curtail any glomerulonephritis,  and adds it own vasodilator action. Furthermore, pentoxifyline has a specific anti-fibrotic action. 
There are some patients who cannot tolerate ACE inhibitors, usually on account of cough. For them, an angiotensin II blocker like losartan is probably just as good. 
Immunosuppressive therapy will be used for patients with active disease with heavy proteinuria and progressive renal impairment. The meta-analysis by Schena et al  clarified that two-thirds of patients with heavy proteinuria (more than 3 gm/day) will have a complete remission when treated with corticosteroids and cytotoxic drugs. One should start with prednisolone (1-2 mg/kg/day) decreasing soon to 10 mg per day and, cyclophosphamide 2-3 mg/kg/day. , Others have used prednisolone and azathioprine. ,
A recent report showed how prednisolone with oral cyclophosphamide could slow the progression of advanced IgAN. Prednisolone was started in a dose of 30 mg per day with reduction to 5 mg/day, and cyclophosphamide was given in a dose of 50 mg per day orally.  This is encouraging because a therapeutic effect was obtained using a prednisolone dosage that is not likely to cause serious side-effects, and the small dose of cyclophosphamide would not cause serious leucopenia or liability to infections. Rocattello et al  have reported a better 5-year survival for IgAN patients with acute florid histology who received corticosteroids plus cyclophosphamide in a dose of 1.5 mg/kg for two months, compared with controls.
Recently too, Pozzi et al  have described how an early intensive course of corticosteroid therapy (in a controlled trial) was able to protect against deterioration of renal function in IgAN with proteinuria and serum creatinine less than 1.5 mg/dl. Shoji et al,  in a prospective, randomized controlled trial, treated patients with serum creatinine less than 1.5 mg/dl, proteinuria less than 1.5 gram/day and mesangial cell proliferation affecting more than 50% of their glomeruli, for one year. Control patients received only dipyridamole in a dose of 300 mg per day. Treatment patients received a tapering dose of prednisolone. Anti-hypertensive therapy was also used.
All the study patients had abnormal urinary findings for less than 36 months. After one year, the corticosteroid therapy group showed a reduction of proteinuria from 750 mg per day (mean) to 290 mg per day (mean). Mesangial cell proliferation was reduced from 65% to 43%, and mesangial matrix deposition, from 62% to 45%. Expression of alpha-smooth muscle actin (SMA), a marker of myofibroblasts, was reduced in the glomeruli of the prednisolone treated patients. Moreover, there was no increase of alpha SMA in the renal interstitium of treated patients.
It must be said that relatively short duration corticosteroid administration, at moderate dosage, is surely now acceptable for IgAN cases, that on renal biopsy look set for progression. Long-term corticosteroid therapy has now been discounted. There is a suspicion that glucocorticoids can promote release of TGFβ,  or certainly, that they do not stop its release.
Upper respiratory infections or tonsillitis often precede or accompany the exacerbations of IgAN. There is IgA 1 antibody in the follicular dendritic cells (FDC) of tonsils of IgAN patients, and not in the FDCs of non-IgAN controls.  The tonsils are important sites for induction of local and systemic antibody responses.  There are circulating immune-complexes containing IgA1 in IgAN.  Furthermore, superimposed streptococcal infection is known to be an adverse feature in IgAN.
A Chinese group have recorded how Addis counts were improved after tonsillectomy in IgAN patients.  In a controlled study in Japan,  35 patients with IgAN who underwent tonsillectomy were compared with 15 who did not. Proteinuria was reduced, and hematuria and serum IgA levels lessened, over three years of followup, only in those patients whose serum creatinine levels were less than 1.4 mg/dl.
Thus, one can hardly expect any improvement when there is already renal functional deterioration.
Dealing with Mediators of Immunopathological Injury
The mediators that ought to be neutralized in order to prevent glomerular and interstitial injury in IgAN are illustrated in [Figure - 1].
Anti-eicosanoid and anti-platelet activating factor therapy.
Prostaglandins, thromboxanes and leukotrienes are eicosanoids, since they are derived from the 20-carbon unsaturated (C20, n-4) arachidonic acid. Platelet activating factor (PAF), is a phospholipid derivative.  In my previous article  emphasis was laid on the actions of thromboxane A2, since they are relevant to all aspects of the genesis of GN. It is clear that an anti-thromboxane agent should be beneficial in IgAN.  The available drugs are either inhibitors of thromboxane synthesis or thromboxane receptor antagonists. The agent picotamide is a combined thromboxane synthase inhibitor and receptor antagonist. Its dosage is 400 mg thrice daily. Thromboxane synthase is demonstrable in kidney biopsies of patients with IgAN.  Unfortunately, trials of thromboxane inhibitors in nephritides to date have only been short-term.  In those cases, proteinuria has been reduced.
One can turn for evidence to experimental studies of IgAN.  In a rat model of IgAN, Gesualdo et al  showed that there was increased synthesis of thromboxane A 2 and that this was not counterbalanced by available prostaglandin E 2 . Local glomerular angiotensin II  is undoubtedly involved in glomerular damage and ensuing fibrosis. This action of angiotensin II is largely mediated through the action of thromxane A 2 at the cellular level. 
Aspirin inhibits synthesis of thromboxanes. We use it to inhibit platelet aggregation in the coronary circulation. It is well known that one might use aspirin with dipyridamole for therapy of GN. Yet, in the controlled trials of Chan et al  of aspirin and dipyridamole in patients with slight elevation of serum creatinine, there was no difference in proteinuria or creatinine clearances between treatment and control groups after 33 months. We realize now that dipyridamole is an antioxidant and cyclic-AMP-elevating agent, that might help reduce proteinuria.  In theory, it will stop mesangial cell proliferation.  Aspirin and dipirydamole together with an ACE inhibitor were used to good effect in a trial of IgAN in Korea. 
The leukotrienes are very important for attracting and subsequent activation of white cells.  It is easy to prove their role in GN in experimental situations.  Presently, both leukotriene synthase inhibitors like zileuton,  and receptor antagonists like montelukast, zafirlukast or pranlukast are available.  To date, they have been used only in treating in asthma, but their properties indicate that they should benefit patients with acute nephritides.
Almost nothing is known of anti-PAF agents in GN, although they can do remarkable things like stopping the release of myeloperoxidase from neutrophils. PAF is known to cause proliferation of renal medullary fibroblasts that contributes to interstitial fibrosis. 
Fish oil therapy has been promoted for the prevention of atherosclerotic vascular disease, although the results are contentious.  When fish oils are given to humans, they do tend to cause lipid peroxidation as shown by elevated plasma lipid peroxides. , One can argue that oxidation of polyunsaturated fatty acids is integral to their action in preventing leucocyte-endothelial inter-actions.  Yet, in the context of GN, any fuel that adds to oxidising reactions in the glomeruli , must be viewed with suspicion.
The use of eicosapentaenoic acid (EPA), present in fish oils, as adjunctive antiinflammatory therapy in rheumatoid arthritis  has received some acclaim, since such therapy reduces pro-inflammatory cyctokines like interleukin-1 (IL-I) and tumor necrosis factor alpha (TNFa). In theory, ingestion of fish oils, meaning W-3, C20:5 unsaturated fatty acids EPA and DHA, will reduce the synthesis of harmful thromboxane A2 and instead, a weak thromboxane A 3 is formed. Correspondingly, synthesis of the chemotaxin LTB4, that attracts and activates leucocytes, and the peptidoleukotrienes LTC 4 /D/E, that have renal vasoconstrictor actions, is thwarted, and instead ineffectual 5-series leukotrienes are produced. Fish oil therapy should be good because elevated lipoxygenase products have been demonstrated in GNs, including IgAN.  However, a thromboxane inhibitor like picotamide and the new leukotrine inhibitors have much more to offer, in my opinion.
When one looks closely at what fish oil therapy means, there are some very uncomfortable facts. Fish oils are not exactly drug therapy but dietary therapy. In the vast literature, one will find that their action can depend on the other foods that are being consumed (e.g., a Mediterranean diet or meat/fats), and whether the patient is concurrently taking aspirin (or even ACE inhibitors). In animal studies, the fish oils have produced a whole variety of discrepancies. In the first decent human trial, conducted at the Mayo Clinic,  fish oil therapy seemed to be beneficial and yet proteinuria was not significantly reduced. We know now that persistent proteinuria means that tubulo-interstitial fibrosis will develop. In the Mayo Clinic follow-up report  of 106 patients followed beyond two years of therapy, 29 patients in the placebo group reached the primary endpoint of rise of serum creatinine by 50% and only 17 patients, who had taken fish oil. So fish oil had some benefit. Nevertheless, eight patients who had taken fish oil reached end-stage renal failure, and 19 in the placebo group. This means that fish oil therapy did not prevent progression in 15% of the patients. Results of other fish oil trials are awaited.  Note that fish oils produced only a modest reduction in proteinuria. It is worth noting that it has been reported (personal communication) that fish oil therapy for one year only halved the urinary excretion of thromboxane A2 and that a thromboxane synthetase inhibitor will do better than that.
Preventing Mesangial Proliferation and Glomerular/Tubular Fibrosis.
I did not emphasize that an ACE inhibitor like ramipril can inhibit mesangial cell proliferation and release of PDGF release.  No doubt, this explains why many nephrologists treating IgAN will be happy to use an ACE inhibitor as primary therapy and will use an extra drug only if there are signs of progression.
One extra drug that is innocuous is pentoxifylline.  This drug reduces expression of "tissue factor" thromboplastin and it curtails development of Th-1 lymphocytes. It also reduces proteinuria in patients with diabetic nephropathy, and other GNs should behave likewise. Also, it has been shown to reduce renal myofibroblast proliferation  and collagen secretion. In vivo it is known to reduce fibrosis. 
I will not dwell on heparins  or pentosan polysulphate,  which are known to reduce mesangial cell prolfieration. So far, clinicians seem to have been resistant to their use. Rather, I will point onwards to the use of PDGF aptamers as a developing methods of opposing PDGF-induced mesangial cell proliferation. 
Progressing IgA Nephropathy
One does see the rare patient whose renal function is declining rapidly. I have used cautiously, monthly melphalan with prednisolone for such patients, as if one has treating myeloma or trying to eliminate a clone of B cells forming amyloid. Today, I am sure that I would elect to use tacrolimus (FK-506). In experiments with B cells in culture, it has been shown how tacrolimus prevents B cell mitogenesis, and how, it also can induce tolerance to self-antigens.  This recommends FK-506 for use as a transplant immunosuppressive. Additionally it has been demonstrated that FK-506 augments glucocorticoid mediated downregulation of cyclooxygenase-2 in fibroblasts.  In that process, it represses nuclear transcription factor NF-KB. This is the key signal for formation of cytokines and chemokines, for leucocyte adhesion molecules and expression of tissue factor. 
I have given my personal opinion (as it is at the moment) about the possible therapies for IgAN, as summarised in [Table - 2]. I have avoided pontificating on the basis of controlled trials.  Unfortunately in IgAN context, most of them have not been done.
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E Nigel Wardle
c/o 81 Gloucester Avenue, Grimsby, England DN34 5BU
[Figure - 1]
[Table - 1], [Table - 2]