Evidence-based recommendations for immunosuppression in IgA nephropathy: handle with caution

Jürgen Floege

Division of Nephrology and Immunology, University of Aachen, Aachen, Germany

Keywords: evidence-based recommendations; hypertension, ACE inhibitor; grading system; IgA nephropathy; immunosuppression; proteinuria

Introduction

In 1999, Nolin and Courteau [1] published evidence-based recommendations (Table 1Go) for the management of IgA nephropathy (IgAN). They concluded that ‘... patients with mild histopathological changes, proteinuria over 3 g/day, and a creatinine clearance above 70 ml/min should be treated with prednisone for 4–6 months. An initial dose of 1 mg/kg/day is recommended, with alternate day administration and gradual tapering after eight weeks in response patients. Steroids reduce proteinuria (grade B recommendation) and stabilize kidney function (grade C) ...’ [1]. These recommendations were based on a small randomized controlled trial by Lai et al. [2] as well as a retrospective [3] and a prospective controlled trial by Kobayashi et al. [4]. Nolin and Courteau also concluded that the therapeutic usage of cyclophosphamide, cyclosporin A and azathioprine was not supported by sufficient data and that ‘... hypertension should be treated promptly, if possible with an angiotensin-converting enzyme inhibitor (grade B) ...’ [1]. Therefore, apart from the treatment of hypertension, recommendations on immunosuppressive therapy were only given for a small group of patients, i.e. those with (almost) normal renal function and nephrotic-range proteinuria. Have we advanced in 2002?


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Table 1.  Grading system for evidence-based recommendations [26]

 

Available new studies since 1999

Over the last 3 years several studies have provided convincing data for an effectiveness of corticosteroid and/or cytotoxic therapy in patients with either high risk of progressive IgAN [5], e.g. patients with proteinuria exceeding 1 g/day and/or impaired renal function at presentation, or those with documented progressive renal insufficiency due to IgAN (Table 2Go). Studies with the highest power and evidence levels include the following.


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Table 2.  Summary of treatment studies in patients with primary IgAN published since 1999

 
  1. In 1999, Pozzi et al. [6] published a randomized controlled multi-centre trial that included 86 consecutive IgAN patients. Patients were randomly assigned to receive supportive therapy only or additional corticosteroids. Nine of 43 patients in the steroid group and 14 of 43 in the control group reached the primary end-point by year 5 of follow-up (P=0.048). All 43 patients assigned to steroids completed the treatment without experiencing any significant side-effects except for one case of secondary diabetes mellitus.
  2. In 1999, Yoshikawa et al. [7] published a randomized controlled trial in 78 Japanese children who received either supportive therapy or immunosuppression with corticosteroids plus azathioprine. At study entry, the children had a normal renal function. During the 2-year follow-up, mean proteinuria decreased from 1.02 to 0.88 g/day in controls and from 1.35 to 0.22 g/day in the immunosuppressed group. GFR remained normal in all children except for one in the control group. Side-effects in immunosuppressed children included an overall growth retardation, alopecia (n=1), anaemia (n=1), leukopenia (n=3), mild glaucoma or cataract (n=1 each) and peptic ulcer (n=1).
  3. In 2000, Shoji et al. [8] published a small randomized trial in which patients were randomized to receive either antiplatelet therapy only (n=8) or additional oral prednisolone for 1 year. End-points, i.e. proteinuria and histology, were only examined at 1 year and were improved in the steroid group. Very low systolic pressures were described both in the corticosteroid group (mean 108 mmHg at baseline and 109 mmHg at 1 year) and in the control (118 and 116 mmHg, respectively) without any antihypertensive therapy. Given that in this study mean GFR was normal and mean proteinuria was 0.75 g/day, it is apparent that, in contrast to all other studies in Table 2Go, this study dealt mainly with low-risk patients.
  4. In 2002, Ballardie and Roberts [9] published a randomized controlled single-centre study on IgAN patients with progressive loss of renal function. Patients were randomized to treatment with prednisolone and cytotoxic agents or supportive therapy only. Renal survival in treated patients showed significantly better preservation of function at 5 years (72% compared with 6% in controls). Proteinuria was reduced by treatment from 12 months, compared with pre-treatment levels or controls. Morbidity attributable to treatment included one case of azathioprine-induced bone marrow suppression and one of secondary diabetes mellitus.

In view of the increasing evidence favouring immunosuppressive therapy, should it now become part of the routine therapy in patients with progressive IgAN or a high risk of progression? To answer this question, it appears important to have a closer look at how well the studies shown in Table 2Go were controlled for variables that govern progression, and in particular how well such factors were managed. Although the role of few of these variables has been specifically established for patients with progressive IgAN (and probably never will be), there is at present little evidence to suggest that different glomerular diseases require conceptually different approaches with respect to best supportive care. Evidence-based recommendations for reno-protection have recently been reviewed extensively [10] and will therefore be discussed only in part in the following.

Control of hypertension

With respect to the most important progression factor, namely hypertension, several of the studies shown in Table 2Go contain either no or incomplete data on blood pressures achieved during the study period and/or on antihypertensive medication used [7,1115]. These studies will therefore be excluded from the further discussion.

In the two major studies, i.e. those of Pozzi et al. and Ballardie and Roberts [6,9,16], detailed information on blood pressures throughout the study duration was published. In both studies, no difference between the blood pressures achieved in treated and control patients was present. In the study of Pozzi, mean systolic and diastolic blood pressures were around 135 and 85 mmHg, respectively, during the study period. In the study of Ballardie and Roberts, only mean arterial pressures were given, which fluctuated around 105 mmHg (corresponding, for example, to 135/90 mmHg) during most of the study period. This is clearly different from today's recommended target blood pressure of 125/75 mmHg in patients with renal disease and proteinuria exceeding 1 g/day [17]. Similar concerns apply to the study of McIntyre et al. [18].

Convincing evidence for the importance of a low normal blood pressure in patients with progressive IgAN is provided by the study of Kanno et al. [19]. These authors showed that lowering blood pressure to mean levels of 129/70 mmHg at 1 year after the start of observation vs 136/76 mmHg in a control group determined whether patients with IgAN, (almost) normal renal function and a mean proteinuria of 1 g/day either lost none or 15% of their renal function, respectively, over 3 years [19] (evidence level C). Of equal importance is the fact that even so-called normotensive patients, usually defined as having blood pressures below 140/90 mmHg and not being treated, may not have a ‘normal’ blood pressure. Thus, it has been shown that IgAN patients with office blood pressures below 140/90 mmHg and no antihypertensive therapy have an inadequately elevated 24 h pressure as compared to healthy, age- and body mass index-matched controls and, more importantly, that they exhibit subtle, yet significant cardiac changes suggestive of hypertensive damage [20].

It also appears important to have a look at the types of antihypertensives employed. In the study of Pozzi et al. [6] only 12 of 86 patients had received ACE inhibitors at study entry and during follow-up, 24 other patients were given ACE inhibitors (13 in the steroid group and 11 the control group). All 36 patients took ACE inhibitors for at least 6 months (range 6–96). In the study of Ballardie and Roberts [9] ‘... ACE inhibitors were permitted to be continued if patients were receiving these at the time of referral, but such therapy could not be subsequently altered ... and ... as first-line therapy, calcium antagonists and ß-blockers were used’. Finally, McIntyre et al. [18] state that four of nine patients had an ACE inhibitor added during the study period. Angiotensin-II receptor blockers were not used in either study. Thus it is apparent that overall usage of ACE inhibitors was not optimal as judged by today's recommendations [10,17].

Control for other progression factors

None of the studies shown in Table 2Go contains information on dietary protein intake, which is a recognized progression factor (evidence level B) [10,21]. Apart from dietary protein intake, level B to C evidence is now available to link, for example, smoking and regular consumption of analgesics such as acetylsalicylic acid or acetaminophen to the progression of renal failure in glomerular diseases [22,23]. Again, both parameters appear to be uncontrolled variables in the studies cited above and shown in Table 2Go.

Conclusion

The answer to the introductory question is yes, we have advanced in 2002.

In low-risk patients [5], i.e. those with proteinuria <1.5 g/day and normal GFR, a grade B recommendation in support of steroid therapy for reduction of proteinuria can be made [8]. However, it is unknown whether steroid therapy in such patients also affects hard end-points such as renal failure. In contrast, as discussed above, such end-points can be affected by ACE-inhibitor therapy in this patient group (grade C recommendation) [19].

In patients at higher risk for or even established progressive renal failure, we now can provide grade A recommendations in support of immunosuppressive therapy for a large percentage of patients (Table 2Go): (i) a 6 month steroid course in IgAN patients with proteinuria ranging from 1 to 3.5 g/day and preserved renal function [6]; and (ii) for steroid plus cytotoxic treatment in patients with progressive renal failure as long as the serum creatinine does not exceed 2.84 mg/dl at first presentation [9].

However, it has to be stressed that even these high-level recommendations are based on studies designed in the late 1980s and early 1990s, i.e. at a time when recommendations on supportive care differed from those of today. Therefore, enthusiasm for immunosuppressive therapy in IgAN patients is dampened by the lack of evidence that such therapy is superior to present-day optimal supportive care. Very early data suggest that this may indeed not be the case [24,25], but such studies clearly need to be expanded.

In 2002 it still appears prudent to limit immunosuppressive therapy to those patients who do not achieve the targets of best supportive care and/or continue to either excrete >1 g/day of protein or even continue to lose renal function. Unless IgAN is of the rare necrotizing, crescentic sub-type, and clinically follows a rapidly progressive course, immunosuppression still should not be first choice.

Notes

Correspondence and offprint requests to: Jürgen Floege MD, Klinikum der RWTH Aachen, Medizinische Klinik II (Nephrology and Immunology), Pauwelsstrasse 30, D-52057 Aachen, Germany. Email: juergen.floege{at}post.rwth-aachen.de Back

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