Is mycophenolate mofetil combined with low-dose prednisone a treatment option for advanced IgA nephropathy? A 10-year follow-up case and brief literature review

Abstract

IgA nephropathy (IgAN) is now widely recognized as the most common primary glomerulonephritis worldwide, especially in China. The immunosuppressive treatment option for IgAN is still controversial. Previously, we proved that mycophenolate mofetil (MMF; Shanghai Roche, China) combined with low-dose prednisone was an effective and safe option for biopsy-proven mild to moderate IgAN patients in a short term of follow-up. This article we first reported the safety and efficacy of this regimen in a 42-year-old male biopsy-proven advanced 10-year follow-up IgAN case (Lee’s Class V; the patient was biopsied 10 years ago, so the Oxford Mesangial hypercellularity Endocapillary hypercellularity Segmental glomerulosclerosis Tubular atrophy/interstitial fibrosis (MEST) classification was not used). The mycophenolate and prednisone were only given for a limited time. The other main medications included calcium channel blockers and antiplatelet agents. Clinical and laboratory indexes were aperiodic assessed during the 10-year follow-up. The serum creatinine decreased from 356 to around 210 μmol/L and urine excretion protein reduced from 3.4 g/d to about 0.5 g/d after 6 months of the initiation of this regimen, respectively. These perfect treatment effects could maintain well during the whole follow-up period. No obvious complications were observed.

Introduction

IgA nephropathy (IgAN) is now widely recognized as the most common primary glomerulonephritis worldwide. ¹ In China, IgAN is found in more than 40% of kidney biopsy specimens obtained for primary glomerulonephritis patients. About 20%–40% of IgAN patients reach end-stage renal disease by 20 years. Unfortunately, the treatment regimen of IgAN is still controversial. Corticosteroid was only suggested to estimated glomerular filtrate rate (eGFR) >50 mL/min per 1.73 m² while mycophenolate mofetil (MMF) was not recommended in IgAN. ²

Clinically, the effectiveness of prednisone and MMF in IgAN has been tested respectively in several short-term randomized trials, but most of these studies have been done only in mild or moderate IgAN. ³ In our previous study, ⁴ MMF combined with low-dose prednisone regimen was proven to be an effective and safe option for mild IgAN patients in a 1-year follow-up. This article aimed to report a successful 10-year follow-up of an advanced IgAN (Lee’s Class V) case on MMF combined with low-dose prednisone regimen and review the literatures briefly.

Case reports

A 42-year-old male was referred to our nephrology department because of increased nocturia, dizzy and blurred vision in March 2006. He was once admitted to a local hospital in February 2006 due to dizzy and foamy urine. This study was conducted in accordance with the declaration of Helsinki and with approval from the Ethics Committee of Shenzhen University. Written informed consent was obtained from participant.

Urinalysis revealed nephrotic-range proteinuria (24-Urine Total Protein [UTP] 3.5 g/d) and microscopic haematuria. There was obvious deterioration of renal function as determined by serum creatinine (276 μmol/L, eGFR: 23.6 mL/min/1.73 m²) analysis (eGFR: according to the modified Modification of Diet in Renal Disease (MDRD) equation for Chinese). ⁵ His blood pressure was 180/140 mmHg. Two weeks later the patient was transferred to the other local hospital. Urinalysis and blood test showed rapidly deteriorated in proteinuria excretion (24-UTP 5.68 g/d) and renal function (serum creatinine: 316μmol/L, eGFR: 21.8 mL/min/1.73 m²). The patient was treated with antihypertensive drug (calcium channel blocker) and antiplatelet drug. The patient was not suggested renal biopsy due to severe renal function and renal atrophy at the two local hospitals. In early March 2006, the patient was admitted to our department. On examination, his temperature was normal. His height was 173 cm and his body mass index was 26 kg/m². He had no rash, no cyanosis and no splinter haemorrhage. His blood pressure was 170/106 mmHg. The other signs were normal. His haemoglobin was 9.6 g/L with normal white cell count and platelet count. His biochemistry tests showed that his sodium was 136 mmol/L and his potassium was 5.3 mmol/L. Renal function test showed further deteriorated by serum creatinine (356 μmol/L, eGFR: 20.6 mL/min/1.73 m²). Gross proteinuria (4+ by a dipstick test, UTP: 3.4 g/d) and microscopic haematuria were detected by urinalysis. Further serologic testing revealed normal IgA, IgG, IgM, C3 and C4 levels. Test results for anti-nuclear antibodies, anti-neutrophil cytoplasmic antibodies, anti-glomerular basement membrane antibodies, anti-streptolysin O antibodies, rheumatoid factor and cryoglobulin were all negative. Serologic tests for hepatitis B, hepatitis C and human immunodeficiency viruses were also negative. Renal ultrasonographic studies indicated that his kidneys were mild atrophy (left kidney: 8.8 cm × 3.8 cm × 3.9 cm, right kidney: 8.7 cm × 4.4 cm × 4.1 cm) with increased cortical echogenicity and without hydronephrosis, the bladder appeared to be normal. No renal tract calcification was seen on plain X-ray film. No prerenal and postrenal acute kidney injury proofs were found in this case. Renal biopsy findings revealed, in the mesangium, immunofluorescence assays revealed 2+ diffuse fine granular staining for IgA and 2++ staining for C3. One cellular crescent and 14 global scleroses were seen in 17 glomeruli. Light segmental mesangial matrix and mesangial cell proliferation were seen in the other three glomeruli. Severe chronic inflammatory cells had infiltrated into the interstitium. Mild tubular atrophy with interstitial fibrosis was observed by light microscopy (Figure 1(a)–(c)). The patient was subsequently diagnosed with focal segmental sclerosis IgAN (Lee’s Class V). The main treatment regimen was described in abstract. The other medications included calcium channel blockers and antiplatelet agents. The main clinical and laboratory parameters including blood urea nitrogen (BUN), serum creatinine, eGFR, 24-h urine protein excretion, serum albumin, lipid metabolism, drug side effects were recorded every 1 month. The renal function and urine protein excretion were rapidly improved 6 months after the initiation of this treatment regimen. During the 10-year follow-up, the serum creatinine and urine protein excretion were fluctuating nearly 210 μmol/L (Figure 1(d)) and 0.5 g/d (Figure 1(e)), respectively. No severe adverse effects such as infection and gastrointestinal tract haemorrhage were recorded.

Figure 1.

(a) Histological findings of the renal tissues immunofluorescence staining were positive for IgA in the mesangial regions. (b) Crescent formations of the glomeruli were observed with periodic acid–Schiff (PAS) staining in light microscopy (100× magnification). (c) Glomerular sclerosis and chronic inflammatory cells infiltration into the interstitium were showed with HE staining (100× magnification). (d) The serum creatinine of clinical course and treatment of the patient from March 2006, the regimen was initiated (mentioned above). (e) Urine protein excretion when prednisone and MMF were stopped after the successive use of 6 months and 1 year later, respectively.

Discussion

Here we reported a successful 10-year follow-up of an advanced IgAN (Lee’s Class V) case on MMF combined with low-dose prednisone regimen. The patient had the biopsy safely though with severe renal insufficiency and no obvious side adverse effects were observed until now.

Although the risk of renal biopsy was much higher in patients with insufficiency, this patient had to be diagnosed since no specific treatment could be given to protect the residual renal function and gross proteinuria had happened. ⁶ Therefore, we did renal biopsy for the patient and no severe complications were observed except transient micro haematuria.

MMF combined with low-dose corticosteroid should be an option for advanced IgAN, especially with gross proteinuria. Clinically, growing data show that steroid regimen is proved to be safe and capable of reducing proteinuria levels and stabilizing renal function in patients with IgAN who are proteinuric but have relatively preserved kidney function. ⁷ However, the safety and effectiveness of steroid in advanced IgAN patients are still unclear.

Despite MMF was first used to treat IgAN in 1997, ⁸ some meta-analysis shows the efficacy of MMF in IgAN. ⁹ To date, the four published randomized controlled trials from China and western countries have shown different clinical profile in patients with IgAN. ¹⁰

Clinically, renal histologic features should not be considered a criterion for excluding patients from active treatment. According to the literature,^6,11,12 proteinuria, especially the change in proteinuria levels during follow-up, seems to be an important prognostic factor; however, histologic features at renal biopsy should not be considered a criterion for excluding patients from treatment. ¹¹

In summary, the patient’s initial blood pressure was 180/140 mmHg which would have deteriorated the renal function and proteinuria. But because of the satisfactory response to MMF combined with low-dose corticosteroid regimen, the renal function and urine protein excretion could maintain at an acceptable and safety range.

Our study has some limitations. First, it is only a single case. Second, repetition of renal biopsy is lack. Further observation, especially repetition renal pathology scores to assess the treatment effects and follow-up of more case series are needed to provide more useful information about the safety and effectiveness of MMF in advanced IgAN patients.