Treatment of Severe IgA Nephropathy With Omega‐3 Fatty Acids: The Effect of a “Very Low Dose” Regimen

Abstract

Background. The effect of a “very low dose” of purified omega‐3 fatty acids (PFA) in the progression of severe IgA nephropathy (IgAN) was tested, in a randomized, prospective, controlled trial. Methods. Fourteen patients were assigned to receive a “very low dose” of PFA (0.85 g EPA and 0.57 g PHA) and 14 patients were treated symptomatically and used as controls. Both groups were similar in terms of serum creatinine (Scr) and glomerular filtration rate (GFR) at baseline. Patients were treated for 4 years. The primary end‐points were an increase of 50% or more in Scr or a decrease of 50% or more in GFR at the end of the study. Results. During treatment, 1 patient (7%) in the PFA group and 6 (43%) in the control group had an increase of 50% or more in their Scr (p < 0.01). Also, 1 patient (7%) in the PFA group and 7 (50%) in the control group had a decrease of 50% or more in GFR (p < 0.007). The mean annual change in Scr was 0.2 mg/dL in the PFA group and 1.0 mg/dL in the control group (p < 0.01). The mean annual change in GFR was − 1.4 mL/min in the PFA group and − 3.0 mL/min in the control group (p < 0.001). One patient in the PFA group (7%) and 6 patients in the control group (43%; p < 0.01) developed end‐stage renal disease during the period of observation. Conclusions. A “very low dose” of PFA is also effective in slowing renal progression in high‐risk patients with IgAN and particularly those with advanced renal disease.

• IgA nephropathy
• Fish oil treatment
• Omega‐3 fatty acids

Introduction

Idiopathic immunoglobulin IgA nephropathy (IgAN) is well recognized as the most prevalent glomerular disease worldwide.[1] The natural history of the disease is quite variable. A proportion of patients may follow a chronic progressive course and reach end‐stage renal disease while others, experience a protracted indolent and nonprogressive course. The factors discriminating progressive from nonprogressive disease remain largely undetermined. Among clinical factors, multivariate survivorship analysis of numerous studies confirmed that an elevated serum creatinine at presentation and severe proteinuria were powerful independent predictors of poor outcome in adult patients.[2], [3] Of the histologic parameters, the severity of glomerulosclerosis and interstitial fibrosis appear to be strong independent predictors of a progressive course, even at multivariate analysis.[2], [4], [5]

Treatment of IgAN has not been well established. Fish‐oil rich in omega‐3 polyunsaturated fatty acids (PFA) may favorably influence the disease by acting on potential mediators that stem from the initial glomerular injury.[6] Earlier studies failed to show a beneficial effect of fish‐oil supplementation in the course of IgAN.[7], [8], [9], [10] Recent studies, however, by Donadio et al.[11], [12] demonstrated that PFA significantly reduced renal disease progression in patients with IgAN. In a more recent report, the same group also showed that low‐dose and high‐dose PFA were equally effective in slowing the rate of renal function loss in patients with IgAN and advanced renal disease.[13] This study was designed to determine whether an even lower dose of PFA is effective in preserving renal function in patients with severe IgAN and renal insufficiency at presentation.

Subjects and Methods

The study was a prospective randomized controlled trial. The inclusion criteria for patients included 1) biopsy‐proven IgA nephropathy, 2) persistent proteinuria more than 1 g/24 h, 3) persistently elevated serum creatinine > 1.5 mg/dL during the preceding 6 months and 4) no previous treatment with PFA or immunosuppressive agents. Patients were excluded if they had diabetes mellitus, systemic lupus erythematosus, chronic liver disease or evidence of systemic autoimmune diseases. Patients with a diastolic blood pressure of > 90 mmHg or a systolic pressure > 140 mmHg were considered hypertensive. End‐stage renal disease (ESRD) was the point at which dialysis treatment was started or serum creatinine exceeded 10 mg/dL. All renal biopsy samples were examined by a pathologist (A.P.), who was not provided with any clinical information about the patients. For histologic gradation of biopsy specimens a simplified scoring system was used in which 0 indicated no change, 1 mild change, 2 moderate change and 3 severe change. The sum of the degree of mesangial and glomerular proliferation, interstitial inflammation and the percentage of crescent formation comprised the activity score, with a maximum score of 9. The sum of the degree of tubular atrophy and interstitial fibrosis, the percentage of glomeruli demonstrating global or segmental sclerosis and the percentage of fibrous or fibrocellular crescents composed the chronicity score, with a maximum of 12.[14] All patients were followed at the Department of Nephrology, Hippokration Hospital, Thessaloniki and gave informed consent.

Study Design

The patients eligible for this study were randomly assigned to receive either fish‐oil or supportive treatment. The fish‐oil supplement (Maxepa, Seven Seas Ltd, United Kingdom) was given in a dosage of three 1‐g soft‐gelatin capsules twice daily providing 0.85 g of eicosapentaenoic acid (EPA) and 0.58 g of docosahexanoic acid (DHA). The majority of patients with hypertension were treated with angiotensin‐converting enzyme inhibitors (ACE) alone or in combination with other drugs such as beta‐blockers or calcium channel blockers (CCB). Diuretic therapy was avoided unless the patient had severe edema or congestive heart failure.

At study entry complete physical examination and laboratory investigation were performed in all patients. Follow‐up examinations of the patients were scheduled every month for the first 3 months and every 3 months subsequently. At each scheduled visit, the compliance with the prescribed medication was determined and complete blood and urine investigation was repeated, including the lipid profile of the patients.

Glomerular filtration rate (GFR) was estimated before entry using the clearance of ⁵¹Cr‐EDTA and expressed per 1.73 m² of body surface area. The GFR estimation was repeated every year thereafter. On two occasions, where GFR measurement was not available, it was estimated according to the Cockcroft‐Gault formula.[15]

Study End Points

The primary end point of the study was the loss of renal function, defined as an increase of 50% or more in the serum creatinine concentration or a decrease of 50% or more in GFR during the 4‐year treatment period. Secondary end points included the annual rate of change in serum creatinine, GFR and urinary protein excretion as well as the development of end‐stage renal disease (ESRD). Other variables monitored included changes in blood pressure, serum lipids, peripheral blood count and serum sodium and potassium. Treatment continued in all patients even after they had reached a primary end point. Treatment was discontinued when a patient reached ESRD.

Statistical Analysis

Student's test for unpaired data and chi‐square test were used for the comparisons between the two groups. Linear regression analysis was used to estimate the annual rates of change in serum creatinine, GFR and urinary protein excretion for each patient. Although, reciprocal serum creatinine values are more linear over the time than direct values, measurements of the direct values are presented here as they are more familiar to the readers. A p value of less than 0.05 was considered significant.

Results

From February 1994 to October 1996, 136 patients with idiopathic IgA nephropathy were evaluated for this study. Of those patients 34 were eligible for this study according to the criteria. Eighteen patients were assigned to receive PFA and 16 to receive supportive treatment. Six patients (4 in the PFA group and 2 in the control group) either did not comply with the treatment or were lost to follow‐up and excluded from the analysis. All the remaining (14 in the PFA group and 14 in the control group) fulfilled the criteria for inclusion and had an adequate follow‐up profile. Baseline clinical and laboratory characteristics of the patients are listed in Table 1. There was no difference in baseline values between the two groups. Also, there was no difference in the activity and chronicity scores of patients indicating that the extent of histopathologic lesions was similar in both groups.

Table 1. Baseline Characteristics of Patients in the PFA and Control Groups.a

	PFA‐treated (n = 14)	Controls (n = 14)
Age (yrs)	41 ± 12	39 ± 10
Male	10 (71%)	12 (86%)
Hypertension	12 (86%)	8 (57%)
Mean arterial blood pressure (mmHg)	113 (± 10)	109 (± 13)
Serum creatinine (mg/dL)	2.2 (± 0.7)	2.8 (± 1.4)
GFR (mL/min)	46 (± 12)	45 (± 23)
Proteinuria (g/24h)	2.0 (± 1.9)	1.6 (± 1.4)
Serum cholesterol (mg/dL)	290 (± 102)	243 (± 96)
Serum triglycerides (mg/dL)	215 (± 131)	200 (± 100)
Hematocrit (%)	37 (± 5)	38 (± 6)
Time from biopsy to randomization (years)	2.7 (± 0.7)	2.4 (± 1.0)
Morphologic indexesb
Activity score	2.3 (± 0.8)	2.5 (± 1.9)
Chronicity score	4.8 (± 1.6)	5.1 (± 1.6)

Abbreviations: PFA = omega‐3 fatty acids, GFR = Glomerular filtration rate.

^aPlus‐minus values are means ± SD. All p values for the comparison between groups were > 0.05.

^bBased on a scoring system proposed by Andreoli et al.[14]

Changes in Proteinuria and Renal Function

At the end of the period of treatment, mean proteinuria decreased in the PFA group from 2.0 ± 1.9 g/24 h to 0.8 ± 0.4 g/24 h (p < 0.02). Proteinuria decreased also slightly in the control group but this difference did not reach the level of significance (from 1.6 ± 1.4 g/24 h to 0.9 ± 0.6 g/24 h, p = NS). The mean annual changes in the 24‐hour urinary protein excretion were − 0.70 g (− 28%) in the PFA group and − 0.19 g (− 8%) in the control group (p < 0.04; Table 2). Mean serum creatinine remained stable in the PFA group (from 2.2 ± 0.7 mg/dL to 2.3 ± 2.2 mg/dL, p = NS) but increased in the control group (from 2.8 ± 1.4 mg/dL to 5.9 ± 3.9 mg/dL, p < 0.007). The mean annual changes in the serum creatinine concentrations were 0.2 mg/dL in the PFA group and 1.0 mg/dL in the control group (p < 0.01; Table 2, Fig. 1). Mean serum creatinine concentrations were significantly lower in the PFA group (2.3 ± 2.2 mg/dL versus 5.9 ± 3.9 mg/dL, p < 0.01) at the end of the 4‐year treatment.

Table 2. Occurrence of Primary and Secondary End Points in PFA‐Treated Patients and Controls After 4 Years

End point	PFA‐treated (n = 14)	Controls (n = 14)	p value
Primary
> 50% increase in serum creatinine	1 (7%)	6 (43%)	< 0.01
< 50% decrease in GFR	1 (7%)	7 (50%)	< 0.007
Secondary
Mean annual changes in
– Serum creatinine (mg/dL/yr)	0.2	1.0	< 0.01
– GFR (mL/min/yr)	− 1.4	− 3.0	< 0.001
– Proteinuria (g/24h)	− 0.70	− 0.19	< 0.04
ESRD
– number of events	1 (7%)	6 (43%)	< 0.01

Abbreviations: PFA = omega‐3 fatty acids, GFR = Glomerular filtration rate, ESRD = End stage renal disease.

Figure 1. Annual rate of change in serum creatinine in patients with IgA nephropathy treated with omega‐3 fatty acids (PFA) or controls. Mean values are indicated by the asterisk.

Mean GFR decreased slightly in the PFA‐group (from 46 ± 12 mL/min to 41 ± 13 mL/min, p = NS) and significantly in the control group (from 45 ± 23 mL/min to 34 ± 30 mL/min, p < 0.03). The mean annual changes in GFR were − 1.4 mL/min per year in the PFA group and − 3 mL/min per year in the control group (p < 0.001; Table 2, Fig. 2). At the end of the treatment mean GFR was significantly higher in the PFA group (41 ± 13 mL/min) as compared with the control group (34 ± 30 mL/min; p < 0.03).

Figure 2. Annual rate of change in glomerular filtration rate (GFR) in patients with IgA nephropathy treated with omega‐3 fatty acids (PFA) or controls. Mean values are indicated by the asterisk.

One patient in the PFA group (7%) and 6 patients in the control group (43%; p < 0.01) reached the primary end point of the study—an increase of 50% or more in the serum creatinine concentration at four years. In addition, one patient (7%) in the PFA group and 7 patients (50%) in the control group (p < 0.007) reached the other primary point—a decrease of 50% or more in GFR during the same period. One patient in the PFA group (7%) and 6 patients in the control group (43%; p < 0.01) reached ESRD requiring dialysis or transplantation during the treatment period (Table 2).

Treatment of Hypertension

Twelve patients in the PFA group (86%) and 8 in the control group (57%) were hypertensive during the study and received antihypertensive therapy. Eleven patients in the PFA group were treated with ACE inhibitors solely or in combination with beta‐blockers (n = 3) or CCB (n = 2). Only one patient in this group received a CCB as monotherapy. In the control group, 5 patients received ACE inhibitors alone or combined with beta‐blockers (n = 2) or CCB (n = 1). During treatment the changes in blood pressure did not differ significantly between the two groups. Mean arterial blood pressure at the end of the treatment was 107 ± 9 mmHg in the PFA group and 108 ± 11 mmHg in the control group (p = NS). The potential beneficial effect of ACE inhibitors on the outcome of renal function parameters was evaluated in the control group, since the majority of the patients in the PFA group were receiving these drugs. Five patients of this group received ACE inhibitors and 9 other antihypertensive drugs or no treatment. In both subgroups, mean proteinuria did not change significantly (from 1.6 ± 0.5 g/24 h to 1.5 ± 0.3 g/24 h, p = NS, in the ACE‐treated group and from 1.8 ± 1.7 g/24 h to 0.7 ± 0.6 g/24 h, p = NS, in the non‐ACE‐treated group). Also, mean serum creatinine increased in both subgroups (from 2.5 ± 0.9 mg/dL to 6.0 ± 4.1 mg/dL, p < 0.005, in the ACE‐treated group and from 2.6 ± 1.0 mg/dL to 6.8 ± 3.5 mg/dL, p < 0.003, in the non‐ACE‐treated group).

No significant changes in the lipid profile of the patients as well as in other parameters were recorded in both groups during the period of treatment (Table 3).

Table 3. Comparative Outcome of Renal Function and Other Parameters in the PFA‐Treated and Control Groups at the End of the 4‐Year Period of Treatment.a

	PFA‐treated (n = 14)			Controls (n = 14)
	Baseline	End	p	Baseline	End	p
Mean blood pressure (mmHg)	113 ± 10	107 ± 9	NS	109 ± 13	108 ± 11	NS
Proteinuria (g/24h)	2.0 ± 1.9	0.8 ± 0.4	< 0.02	1.6 ± 1.4	0.9 ± 0.6	NS
Serum creatinine (mg/dL)	2.2 ± 0.7	2.3 ± 2.2	NS	2.8 ± 1.4	5.9 ± 3.9	< 0.007
GFR (mL/min/1.73m^2)	46 ± 12	41 ± 13	NS	45 ± 23	34 ± 30	< 0.06
Hematocrit (%)	37 ± 5	39 ± 6	NS	38 ± 6	36 ± 9	NS
Cholesterol (mg/dL)	290 ± 102	250 ± 98	NS	243 ± 96	215 ± 92	NS
Triglycerides (mg/dL)	215 ± 131	200 ± 97	NS	200 ± 100	198 ± 101	NS
Potassium (mEq/L)	4.6 (± 0.5)	4.7 (± 0.8)	NS	4.3 (± 0.6)	4.5 (± 0.4)	NS
Sodium (mEq/L)	139 (± 11)	138 (± 9.0)	NS	141 (± 7.0)	140 (± 5.0)	NS

Abbreviations: GFR = Glomerular filtration rate, NS = Nonsignificant.

^aValues are mean ± SD.

Discussion

This randomized, controlled study showed that an even lower daily dose of purified PFA is effective in slowing renal progression for high‐risk patients with IgA nephropathy. The dose of PFA used in the present study provided 0.85 g of EPA and 0.58 g of DHA daily as compared with approximately 1.99 g of EPA and 1.4 g of DHA, which were defined as “low‐dose” in the study of Donadio et al.[13]

During the 4‐year treatment period only 7% of the PFA group had an increase in serum creatinine concentration of 50% or more as compared with 43% in the control group. Changes in serum creatinine were 0.2 mg/dL per year in the PFA group and 1.0 mg/dL per year in the control group. Interestingly, the annual rates of change in serum creatinine were higher in the PFA‐treated patients from the present study (0.2 mg/dL per year) compared with the rates obtained either in the “low‐dose” or in the “high‐dose” group of PFA‐treated patients (0.08 mg/dL per year and 0.10 mg/dL per year, respectively) in the report by Donadio et al.[13] This may suggest that the beneficial effect of fish‐oil therapy is dose dependent and that lower doses regimens are less effective in protecting renal function when compared with higher‐dose regimens. Such a comparison, however, needs to be interpreted with caution, given the extreme variability of clinical course of the disease even when no treatment is given.[2] For example, the annual increase in serum creatinine in the control group in this study (1 mg/dL per year) was greater than in the study of Donadio et al.[13] (0.45 mg/dL per year) suggesting that other factors (genetic, geographic, ethnic etc.) may play important roles in the progression of the disease in different parts of the world.[1], [2],[11]

Glomerular filtration rate was also better preserved in the PFA‐treated group. Only 7% of the PFA group had a decrease in GFR of 50% or more as compared with 50% in the control group. Also, 7% in the PFA‐group and 43% in the control group reached ESRD during the 4‐year period of treatment. The rate of development of ESRD was very similar to that reported by Donadio et al.[13] in PFA‐treated (15%) and placebo‐treated (41%) high‐risk patients with IgA nephropathy at 3 years. Although, a direct comparison between patients randomized to treatment in different trials cannot be made, it does examine the effects of treatment for patients with similar degrees of renal impairment.

The mechanism of this beneficial effect is not clear. Part of this effect could be attributed to the reduction in proteinuria observed in the PFA‐treated patients of this study. Reduction in the amount of urine protein excretion has been reported to predict or correlate with Reno protection[16] and fish‐oil reduces proteinuria in patients with chronic glomerular diseases.[17] Other reports, however, showed no effect of PFA treatment on daily proteinuria in patients with IgA nephropathy.[10], [11],[13] A potential beneficial effect of treatment with ACE inhibitors seems unlikely since neither changes in proteinuria nor the outcome of renal function differed between ACE‐treated and non‐ACE‐treated patients in the control group. An effect of blood pressure control should also be ruled out since similar target blood pressure levels were achieved during treatment in both groups. A beneficial effect of PFA treatment in lowering plasma triglyceride concentrations could also be an explanation for their beneficial effect, as it is the case with patients with the nephrotic syndrome.[18] Again, in this as in other studies[13] serum cholesterol and triglyceride concentrations did not change significantly in patients treated with PFA.

We believe, therefore, that the protective effect of PFA supplementation in high‐risk patients with IgA nephropathy is mediated by a reduction in proteinuria, perhaps in combination with other actions of fish‐oil such as the production of biologically less effective prostaglandins and leukotrienes, changes in membrane fluidity and reduced platelet agreeability.[6], [19], [20] The net effects could reduce glomerular injury. That the patients included in the present study were at high risk for developing progressive renal disease is evidenced not only by the renal function impairment but also by the observation that the majority of them were hypertensive and had significant proteinuria at study entry.[21],[23] In addition, the estimated chronicity score, which represents the severity of the chronic lesions on renal histopathology, was increased in the majority of the patients and this finding is associated with an unfavorable prognosis.[2]

Patient compliance with this lower‐dose regimen was excellent and the only drawback, rather superficial, was the unpleasant eructation and a fishy taste in the mouth. Also, no significant effects on serum lipids, hematocrit, white blood count and other biochemical parameters were noted.

In conclusion, this study showed that a lower dose of PFA is also effective in slowing the progression for high‐risk patients with IgA nephropathy. However, a more direct comparison between different dose regimens is needed, to determine the optimal dose of PFA supplementation.