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Hocaoglu C. Clozapine-induced rabbit syndrome: a case report

Conservative management, immunosuppressive treatment or both for patients with primary immunoglobulin A nephropathy?

Dimitrios S. Goumenos

Department of Internal Medicine, Nephrology, University Hospital of Patras, Greece



Correspondence: Dimitrios S. Goumenos, Department of Internal Medicine, Nephrology, University Hospital, Patras 26500, Greece. E-mail: dgoumenos@upatras.gr

Key words: IgA nephropathy, management, treatment.

Received for publication: 17 April 2010.
Revision received: 30 June 2010.
Accepted for publication: 8 July 2010.

©Copyright D.S. Goumenos et al., 2010
Licensee PAGEPress, Italy
Nephrology Reviews 2010; 2:e13
doi:10.4081/nr.2010.e13

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Abstract

Immunoglobulin A nephropathy (IgAN) is the most commonly encountered primary glomerulonephritis and it usually follows an indolent clinical course. However, hypertensive patients with proteinuria and renal insufficiency at presentation and patients with severe histological involvement are at high risk to develop end-stage renal failure. Patients with normal renal function, mild proteinuria (<1 g/24h) and mild histopathological involvement need only observation, whereas patients with heavy proteinuria, impaired renal function and moderate to severe histopathological involvement are usually treated with immunosuppressive drugs. Angiotensin converting enzyme (ACE) inhibitors are used in patients with arterial hypertension and/or proteinuria 1-2 g/24h. Corti­costeroids are indicated in patients with heavy proteinuria (>3 g/24h) and in progressive disease despite treatment with ACE inhibitors. Combinations of corticosteroids and cytotoxic drugs are saved for patients with IgA nephropathy and a rapidly progressive course. Fish oil might be an alternative to corticosteroids in cases with renal insufficiency and chronic histological lesions.





Introduction

Immunoglobulin A (IgA) nephropathy is the most common primary glomerulonephritis (GN) in many developed countries around the world.1 Episodes of macroscopic hematuria following viral infections usually of the upper respiratory tract and asymptomatic microscopic hematuria with proteinuria (<2 g/24h) represent common manifestations of the disease. Nephrotic syndrome and acute renal failure can also occur but less frequently.2,3 The severity of histological involvement ranges from minimal lesions to advanced glomerular and tubulointerstitial injury.4,5
Although the clinical course is usually benign, about 25% of patients reach end-stage renal failure (ESRF) over 20 years. Various parameters, such as arterial hypertension, renal function impairment, heavy proteinuria at presentation and during follow up as well as severe histological involvement have been correlated with a poor clinical outcome.6,7 The new Oxford classification of the histological activity seems to represent a prognostic factor and, as recent studies show, it should be taken into consideration for future studies.8,9
Patients with normal renal function and lack of proteinuria have a favorable outcome and are not usually treated, whereas patients with deteriorating renal function and severe histological involvement show an unfavorable clinical course and are usually treated agressively. Various therapeutic regimens including angiotensin converting enzyme inhibitors, fish oil, corticosteroids, cytotoxic drus and mycophenolate mofetil have been used in the treatment of immunoglobulin A nephropathy (IgAN) patients in order to achieve remission of proteinuria and long-term preservation of renal function. In this review, the large trials of IgAN treatment are described and some suggestions for the management of patients with IgA nephropathy, based on both evidence and clinical practice, are made.

Conservative management

Angiotensin converting enzyme inhibitors and angiotensin II

The use of angiotensin converting enzyme (ACE) inhibitors in patients with IgAN is mainly based on their antihypertensive and antiproteinuric effect via reduction of intraglomerular pressure.
In a large retrospective study, Cattran et al. showed that patients treated by ACE inhibitors experienced a significantly slower rate of renal function decline and a higher remission rate of proteinuria (18.5% vs. 1.8%) compared to patients receiving other antihypertensive drugs.10 A favorable effect of ramipril in the clinical course of chronic proteinuric nephropathies was also found in the REIN trial.11 In a recent prospective trial, the effect of enalapril was compared to that of other antihypertensive drugs in 44 IgAN patients with normal renal function and proteinuria more than 0.5 g/24h.12 For the same blood pressure levels (target <140/80 mmHg), enalapril was found to be more effective in proteinuria reduction and renal function preservation over a follow-up period of seven years.12 Similar results were observed in a recent randomized prospective trial by Coppo et al. in which 66 young patients with proteinuria (between 1 and 3.5 g/day) and good renal function (creatinine clearance >50 mL/min per 1.73 m2) were allocated to benazepril or placebo.13 After a follow-up period of 38 months, deterioration of renal function (reduction of creatinine clearance by >30%) was observed more commonly in the placebo treated patients (14.7 vs. 3.1%) whereas remission of proteinuria was more frequently observed in benazepril treated patients (40.6% vs. 8.8%).13 Administration of ACE inhibitors and angiotensin II receptor blockers (ARBs) is also followed by a significant antiproteinuric effect14,15 whereas combination of ACE inhibitors with ARBs showed an additive effect on proteinuria reduction in some studies. 16,17

Fish oil

Fish oil, rich in omega-3-polyunsaturated fatty acids that are involved in the synthesis of arachidonic acid and lead to reduction of glomerular and interstitial inflammation, has been tried in various studies with conflicting results. Apart from its anti-inflammatory effect, fish oil also reduces mesangial cell proliferation and activation of transcription factors.18 A preliminary report showing a beneficial effect in stabilization of the reciprocal of serum creatinine19 was not confirmed in subsequent prospective studies20,21 or in a case series study.22 Donadio et al. showed a beneficial effect of fish oil in a large randomized prospecive trial in which 106 patients with proteinuria over 1 g/24h and serum creatinine between 1.5 and 3 mg/dL were randomized to either fish oil (12 g/day) or placebo for at least two years.23 However, a meta-analysis of all clinical trials of fish oil in IgA nephropathy failed to show a conclusive benefit.24 More recently, 2 studies showed a benefit of fish oil in high-risk patients25,26 and one study showed no effect.27
Fish oil, corticosteroids and placebo treatment were recently compared in a randomized controlled double blind trial including 96 patients with IgAN.28 All patients were under 40 years old, had estimated GFR higher than 50 mL/min per 1.73 m2 and proteinuria. According to the results, neither treatment group showed benefit over the placebo group with respect to time to failure but a dose-dependent beneficial effect of omega-3 fatty acids in the proteinuria reduction was found in a post hoc analysis.29 Furthermore, a higher degree of proteinuria reduction was observed after six months of combined therapy with renin-angiotensin blockers (ramipril and irbesartan) (RASB) and polyunsaturated fatty acids (3 g/day) in comparison to RASB alone in patients with proteinuria over 1 g/day.30

Tonsillectomy

Tonsillectomy is followed by decrease of hematuria, proteinuria and serum IgA levels but has no effect on renal function. Although in some retrospective studies from Japan tonsilectomy with or without corticosteroids administration is followed by long-term preservation of renal function in a large percentage of patients,31,32 there is no data from prospective studies. Furthermore, a recent retrospective study showed no association of tonsillectomy with progression of chronic kidney disease in IgAN patients.33 Tonsillectomy might be recommended in patients with reccurent episodes of macroscopic hematuria in conjuction with tonsillitis.

Other types of conservative management

Lipid lowering therapy, apart from decrease of triglyceride and cholesterol blood levels, shows a beneficial effect in reduction of proteinuria and preservation of renal function of patients with IgA nephropathy.34,35 The administration of fluvastatin 40 mg/day for six months in moderately proteinuric patients was followed by reduction of proteinuria.34 Further­more, the combination of fluvastatin and dipyridamole was followed by a more significant remission of proteinuria and amelioration of renal function in comparison to dipyridamole alone in a randomized prospective trial including 30 children with IgAN and proteinuria of moderate severity.35 Furthermore, the administration of oral calcitriol twice weekly was found to be effective in reducing proteinuria in a small number of patients with IgA nephropathy and persistent proteinuria despite angiotensin converting enzyme inhibitor treatment.36 However, further research is required in order to establish lipid lowering therapy and vitamin D administration in the treatment of IgA nephropathy.

Immunosuppressive regimens

Corticosteroids

Lai et al. described remission of nephrotic syndrome in 80% of patients with mild glomerular histopathological changes treated by oral prednisolone (40-60 mg daily) for four months in a randomized controlled trial.37 However, complications related to corticosteroids occurred in 40% of patients. A favorable long-term outcome (5- and 10-year renal survival rate of 100% and 80%, respectively) was reported by Kobayashi et al. using corticosteroids for a period of 18 months in patients with normal renal function and proteinuria 1-2 g/24h.38 In the most important randomized multicenter prospective trial, 86 patients with proteinuria (1-3.5 g/24h) and well preserved renal function (serum creatinine <1.5 mg/dL) were assigned to either a 6-month course of corticosteroids (1 g methylprednisolone intravenously for three consecutive days every other month and oral prednisolone 0.5 mg/ kgBW every other day) or supportive treatment alone.39 A significantly better outcome with more frequent remissions of proteinuria was observed in steroid treated patients along with lack of important side-effects. These favorable results of corticosteroids were confirmed after a follow-up period of ten years (preservation of renal function and reduction of proteinuria below 1 g/24h in 97% and 72% vs. 57% and 30% of conservatively treated patients).40 Shoji et al. noticed that administration of corticosteroids for one year in patients with serum creatinine less than 1.5 mg/dL and proteinuria less than 1.5 g/d was followed by reduction of proteinuria and significant improvement of mesangial proliferation in repeat renal biopsies. 41 A beneficial effect in the reduction of proteinuria and kidney survival was observed by Katafuchi et al. using low prednisolone dose (20 mg/day) in patients with moderate histological changes42 and intravenous pulse steroid therapy for three days followed by oral steroid in patients with more severe IgA nephropathy.43
The beneficial effect of corticosteroids in remission of proteinuria and reduction of the risk of development of end-stage renal disease in IgAN patients was confirmed in a recent meta analysis of all randomized prospective trials.44 Patients with high activity index (mesangial proliferation, crescents, interstitial inflammation) and low chronicity index (glomerular sclerosis, adhesions, interstitial fibrosis) respond more frequently to corticosteroids.45

Cytotoxic drugs

Cytotoxic drugs have been used in combination with corticosteroids in patients with severe IgA nephropathy and deteriorating renal function.
The administration of methylprednisolone pulse intravenously for three days and cyclophosphamide 0.5 g/m2 intravenously per month for six months, in patients with rapidly progressive IgA nephropathy resulted in improvement of renal function, reduction of proteinuria and reduction of cellular crescents in repeat biopsies.46,47
Ballardie et al. allocated 38 patients with progressive disease (serum creatinine between 1.4 and 2.8 mg/dL) and proteinuria to either treatment with prednisolone (initial dose 40 mg/day) and cyclophosphamide (1.5 mg/kgBW/day for three months), followed by azathioprine for two years or conservative management in a randomized prospective trial.48 A better renal survival rate (72% vs. 0%, respectively) after five years of follow up and remission of proteinuria was observed in patients treated with immunosuppressive drugs. Similar results were observed by Rasche et al. in an uncontrolled study including 21 patients.49
A beneficial effect of a 24-month course of prednisolone and azathioprine in renal function preservation was observed in patients with heavy proteinuria (>3 g/24h) and impaired renal function at presentation (serum creatinine between 1.4 and 2.5 mg/dL), in a retrospective study with a follow-up period of ten years.50 However, no effect of treatment was found in patients with severe chronic lesions and serum baseline creatinine above 2.5 mg/dL. Although minor side effects were observed in 10 treated patients (24%), squamous-cell carcinoma and low-grade non-Hodgkin’s lymphoma developed in 2, after discontinuation of treatment. A superior effect of combination of corticosteroids, azathioprine, warfarin and dipyridamole to that of corticosteroids alone was observed in a randomized controlled trial by Yoshikawa et al. including 80 children with IgA nephropathy.51 However, no difference was observed in the 5-year renal survival rate (90% vs. 87%) and decrease in proteinuria between patients, treated by either combination of corticosteroids and azathioprine or a 6-month course of corticosteroids monotherapy in a recent Italian randomized prospective trial including 251 patients with proteinuria over 1 g/day.52 Furthermore, serious side-effects (diabetes, infections, gastrointestinal symptoms, hypertension, anemia and leucopenia) were more frequently observed in patients who received azathioprine.52
Recently, the results of the long-term follow up (mean 7.8 years) of 18 IgAN patients treated for ten weeks with an oral regimen of 40 mg prednisolone and 100 mg cyclophosphamide were reported.53 Although persistent remission of proteinuria and preservation of renal function was observed in the majority of patients, malignancies developed in 2 patients (renal cell carcinoma after eight years and rectum carcinoma after six years). These studies clearly show that combinations of corticosteroids and cytotoxic drugs should be used with caution and only in patients with aggressive disease, such as those with deteriorating renal function and crescents in the renal biopsy, because of the risk of serious side-effects.

Mycophenolate mofetil

Mycophenolate mofetil has been recently tried in 4 randomized controlled trials in patients with IgAN and proteinuria.54,55,56,57 Chen et al. reported that MMF monotherapy (1.5 g/day) for at least 12 months was superior to prednisone in reducing proteinuria in patients with an unfavorable histological grading.54 Also a beneficial effect of MMF (1.5-2 g/day) in lowering proteinuria was observed by Tang et al. in patients with less advanced histological lesions and proteinuria over 1 g/day resistant to a 6-month course of ACE inhibitors or ARBs.55 The long-term results of the same study (after six years of follow up) showed a better preservation of renal function in the MMF treated group of patients.58 However, MMF showed no benefit on renal outcome or proteinuria reduction in patients with decreased renal function (insulin clearance between 20 and 70 mL/min), proteinuria over 1 g/day and histologically advanced disease, who were previously treated by ACE inhibitors.57,58 A recent meta analysis including 162 patients from the above randomized controlled trials showed no difference in the reduction of proteinuria and preservation of renal function between MMF and placebo treatment.59 In these trials, MMF was used as monotherapy and future trials with a large number of patients may be conducted to explore the effectiveness of combination therapy versus monotherapy. The effect of ramipril and MMF versus ramipril alone is estimated in an ongoing Italian multicenter randomized controlled trial.60

Combination of conservative and immunosuppressive treatment

Angiotensin converting enzyme inhibitors and corticosteroids

Recent studies show that both steroids and angiotensin converting enzyme inhibitors improve kidney survival and decrease proteinuria in IgAN patients. In a randomized controlled trial, 63 patients with proteinuria of 1-5 g/day and estimated GFR of over 30 mL/min/1.73 m2 were assigned to either cilazapril alone or steroids plus cilazapril. Patients treated by combination therapy showed a significantly better kidney survival, defined as a 50% increase in basesine serum creatinine (96.6% vs. 66.2% at 36 months) and significant reduction of urine protein excretion.61 Similar results were observed in 97 patients with IgAN and moderate histological lesions with proteinuria over 1 g/day and estimated GFR over 50 mL/min who were randomly allocated to a 6-month course of oral prednisolone plus ramipril or ramipril alone. After a follow-up period of 96 months, 4.2% of patients from the combination treatment group and 26.5% of the monotherapy group reached the combined outcome of doubling serum baseline creatinine or end-stage kidney disease. Furthermore, a decrease of proteinuria to less than 1g/day was observed in 75% of patients treated by combination therapy and in 67% of patients from the monotherapy group.62 We also noted a remission of proteinuria and preservation of renal function in all 17 patients with proteinuria 1-3 g/24h and serum creatinine over 1.5 mg/dL treated with combination of ACE inhibitor and oral corticosteroids for 12 months.63 Furthermore, attenuation of histological progression was found in repeat biopsies of a small number of children with severe IgA nephropathy and proteinuria over 2 g/day treated by corticosteroids, cytotoxic drugs and combination of enalapril and losartan in comparison to patients treated by immunosuppressives alone.64 More studies using combination of ACE inhibitors and immunosuppressive drugs are ongoing. In a large randomized controlled trial in Germany, combination of steroids or steroids plus cyclophosphamide to ACE inhibitors and ARBs will be estimated versus ACE inhibitors and ARBs alone in patients with proteinuria over 0.75 g/day after six months of treatment with ACE inhibitors and ARBs.65 The results of this study are expected to clarify the indication of combination treatment.

Recommendations based on evidence and clinical practice

The main therapeutic targets in patients with IgA nephropathy are control of blood pressure below 130/80 mmHg, long-term preservation of renal function, proteinuria reduction to below 1 g/24h and correction of lipid abnormalities with diet and drugs.
There is general agreement that patients with normal renal function, mild proteinuria (<1 g/24h) and mild histopathological involvement need only observation, whereas patients with heavy proteinuria, impaired renal function and moderate to severe histopathological involvement, need immunosuppressive treatment. ACE inhibitors and ARBs should be used for blood pressure control.
Persistent proteinuria represents a risk factor for an unfavorable outcome. In cases with proteinuria over 1 g/24h and well preserved renal function at presentation, treatment starts with ACE inhibitors and /or ARBs. If proteinuria persists after six months of treatment, corticosteroids are usually added. However, recent studies show that the combination of corticosteroids with ACE inhibitors from start of therapy is more effective than administration of ACE inhibitors alone. Thus combination of both ACE inhibitors and corticosteroids may represent the treatment of choice for proteinuric patients with IgA nephropathy.
In patients with more aggressive disease (deteriorating renal function, presence of cellular/fibrocellular crescents and severe interstitial inflammation), combination of corticosteroids with cyclophosphamide or azathioprine represents the most suitable immunosuppressive regimen.
In patients with serum creatinine above 2.5-3 mg/dL with extensive fibrosis in the kidney tissue, immunosuppressive treatment is not indicated. These patients receive conservative management and possibly fish oil. However, the clinical course of such patients is poor and end-stage renal disease ensues after a short period of time.

Conclusions

IgA nephropathy is an immune mediated-disease characterized by chronic inflammation within the glomeruli and tubulointerstitial area. Although ACEi and ARBs might be effective in stabilizing systemic and renal blood pressure and slowing the decline of glomerular filtration rate, it is not certain if these drugs have a long-term beneficial effect. On the other hand, corticosteroids and cytotoxic drugs having a significant anti-inflammatory action may reduce proliferative and exudative lesions in the acute phase of IgA nephropathy. Furthermore, their use is followed by improvement or stabilization of active histological changes in some studies with repeat renal biopsies after treatment. Thus, combination of conservative management with immunosuppressive drugs seems to be a reasonable approach in patients with proteinuria and severe histological involvement in order to delay the progression of IgA nephropathy.

 


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