Spontaneous remission of minimal change nephrotic syndrome in an elderly man

Abstract

Minimal change nephrotic syndrome (MCNS) cases achieving spontaneous remission without external factors are rarely reported. We report a case of MCNS that achieved spontaneous remission without external factors that triggered its onset. An 82-year-old male patient was admitted to the hospital for close examination of nephrotic syndrome. Renal biopsy was performed and MCNS was diagnosed. Owing to the patient’s age and history of foot and microvascular arteriovenous thrombosis, we did not start immunosuppressive drugs, including steroids, and opted for conservative management. After conservative treatment, proteinuria gradually decreased, and the patient achieved complete remission. Given that the patient had a history of urinary protein and thrombosis, recurrence of MCNS was considered again this time. In addition, the involvement of external factors that trigger the onset of MCNS was not found. In conclusion, in elderly-onset MCNS, clinicians generally hesitate to initiate treatment with an immunosuppressive drug, containing steroids, because of its many complications. Thus, our data provide valuable insight into MCNS.

Introduction

Minimal change nephrotic syndrome (MCNS) is a type of primary glomerulopathy that develops rapidly and presents with primary nephrotic syndrome. It accounts for 41.4% of primary nephrotic syndrome cases in Japan [1]. MCNS is a disease mainly occurring in children, but it may also occur in individuals of varying ages, including the elderly [2]. Pathological findings are characterized by the absence of histological changes in glomeruli and lack of deposition of immunoglobulins or complement observable by light microscopy. Corticosteroids are used for treatment, and the response is usually good, but recurrences may be seen [3, 4]. Idiopathic MCNS is also prevalent among patients with adult-onset MCNS. However, infections due to bacteria or viruses, allergic diseases, malignancies including those of hematopoietic origin, drugs such as nonsteroidal anti-inflammatory drugs, and autoimmune diseases can cause secondary MCNS [2]. Immunosuppressive therapy is often used in MCNS cases, but several reports have shown spontaneous remission. Infections and drugs were reportedly showing transient nephrotic syndrome [5–7]. The pathophysiology of secondary MCNS suggests that lymphocytes are involved in the development of MCNS. While there are few reports showing a natural course of such remission of MCNS without external factors, these factors have not been fully elucidated. Now we present a case of spontaneous remission in MCNS.

Case report

An 82-year-old man was referred to our hospital with symptoms of edema, hypoalbuminemia, and urinary protein (UP) that had worsened over the past 6 months. His comorbidities included hypertension, type 2 diabetes, and atrial fibrillation since his 50 s. In addition, he underwent lower limb amputation due to acute arterial occlusion at the age of 68 and had left branch retinal vein occlusion at the age of 73. On examination, edema was seen over his face and both legs (from the foot to the knees). Laboratory findings showed a serum albumin (Alb) level of 1.4 g/dL and a UP level of 3.8 g/g Cre, resulting in a diagnosis of nephrotic syndrome. He was hospitalized for close examination with possible etiologies, including MCNS and membranous nephropathy.

The physical findings on admission were as follows: height: 167.0 cm; weight: 67.8 kg (65.0 kg, 10 days prior to admission); body mass index: 24.3 kg/m²; body temperature: 36.7 °C; blood pressure: 90/37 mmHg; heart rate: 92 beats per minute; and oxygen saturation on room-air, 95%. There were no abnormalities of the conjunctiva, heart, lungs, or abdomen. The laboratory data on admission were as follows: total protein, 5.2 g/dL; Alb, 1.9 g/dL (3.4 g/dL, 6 months ago); blood urea nitrogen, 20 mg/dL; creatinine, 1.08 mg/dL; estimated glomerular filtration rate, 50.0 mL/min/1.73 m²; total cholesterol, 299 mg/dL; immunoglobulin (Ig)G, IgA, IgM, complement 3, and complement 4 within normal parameters; and total hemolytic complement borderline elevated. In addition, hemoglobin was increased to 16.6 g/dL and d-dimer was 2.0 µg/mL. Urinalysis showed a UP level of 4.50 g/gCre and was negative for occult blood (Table 1).

Table 1.

Laboratory Data on Admission

< Complete blood count data >		< Biochemistry data >		< Biochemistry data >		C3	115 mg/dL
WBC	5400/μL	AST	25 IU/L	TP	5.2 g/dL	C4	26 mg/dL
Neu	72.1%	ALT	13 IU/L	AIb	44.2%	CH50	59.5 U/mL
Eos	3.7%	ALP	231 IU/L	α1–g1	4.8%	ANA	≦ × 40
Bas	0.6%	LDH	294 IU/L	α2–gl	18.4%	MPO–ANCA	≦1.0 IU/mL
Mono	6.5%	CHE	374 IU/L	β–gl	18.3%	PR3–ANCA	≦1.0 IU/mL
Lymph	17.1%	Na	138 mEq/L	γ–gl	14.3%	< Urine Analysis >
RBC	514 × 104/μL	K	4.5 mEq/L	Alb	1.9 g/dL	Protein	4.50 g/gcre
Hb	16.6 g/dL	Cl	102 mEq/L	T-Cho	299 mg/dL	Sugar	(–)
PLT	20.5 × 104/μL	Ca	10.0 mg/dL	HDL-Cho	71 mg/dL	Sediment
< Coagulation >		P	3 mg/dL	Glucose	92 mg/dL	RBC	(–)
PT	38.1%	BUN	20 mg/dL	HbA1c	6.6%	WBC	1 ~ 4/HPF
APTT	37.8 s	CRE	1.08 mg/dL	IgG	767 mg/dL	CAST
Fibrinogen	374 mg/dL	UA	5.1 mg/dL	IgA	625 mg/dL	Hyaline	100~999/HPF
d-dimer	2.0 μg/mL	CRP	0.13 mg/dL	IgM	78 mg/dL	Epithelial	1~9/HPF

WBC white blood cell, Neu neutrophils, Eos eosinophils, Bas basophils, Mono monocytes, Lymph lymphocytes, RBC red blood cell, Hb hemoglobin, PLT platelet, PT prothrombin, APTT activated partial thromboplastin time, AST aspartate aminotransferase, ALT alanine aminotransferase, ALP alkaline phosphatase, LDH lactate dehydrogenase, CHE cholinesterase, Na sodium, K potassium, Cl chlorine, Ca calcium (corrected), P phosphorus, BUN urea nitrogen, CRE creatinine, UA uric acid, CRP C-reactive protein, TP total protein, Alb albumin, α1-gl α1-globulin, α2-gl α2-globumin, β-gl β-globulin, γ-gl γ-globulin, T-Cho total cholesterol, HDL-Cho high density lipoprotein cholesterol, HbA1c hemoglobin A1c, IgG immunoglobulin G, IgA immunoglobulin A, IgM immunoglobulin M, C3 complement 3, C4 complement 4, CH50 50% hemolytic complement unit, ANA antinuclear antibody, MPO-ANCA myeloperoxidase-anti-neutrophil cytoplasmic antibody, PR3-ANCA proteinase 3-anti-neutrophil cytoplasmic antibody

Serum protein electrophoresis demonstrated no monoclonal spikes. Chest X-ray imaging showed left pleural effusion and a dilated heart. The electrocardiogram showed atrial fibrillation (Fig. 1). Renal ultrasound examination showed bilateral normal-sized kidneys. He was also prescribed the following daily antihypertensive, antihyperglycemic, anticoagulant, and antiplatelet medications: losartan (25 mg), carvedilol (5 mg), pioglitazone (15 mg), vildagliptin (100 mg), glimepiride (0.5 mg) warfarin (3.5 mg), and aspirin (100 mg). These medications to treat the patient’s comorbidities were continued during the course of hospital stay.

Fig. 1.

The chest X-ray, on admission, shows left pleural effusion and heart dilation. Electrocardiogram showing atrial fibrillation

On the fourth day of hospitalization, a percutaneous renal biopsy was performed. Seven glomeruli were observed in the collected sample, one of which showed global sclerosis. Light microscopy showed no significant glomerular abnormalities (Fig. 2a–c). Electron microscopy demonstrated extensive foot process effacement, without deposits or basement membrane abnormalities (Fig. 2d). Immunohistochemistry showed no significant deposition of IgG, IgA, IgM, C1q, C3c, C3d and fibrinogen. The diagnosis of MCNS was made based on these findings. Owing to the patient’s advanced age, conservative management with losartan administration was continued, without the use of immunosuppressants including corticosteroids, and he was discharged in a stable condition. After discharge, the UP levels had decreased after treatment with the conservative approach, which included an angiotensin receptor blocker and dietary and lifestyle modifications. No changes were made to the medications taken during the treatment. He had taken losartan orally for some time, and the blood pressure remained low, but renal function remained unchanged. Spontaneous complete remission was achieved after 3 months from discharge, with no recurrence for 1 year since the patient’s first visit (Fig. 3).

Fig. 2.

Histological features of the renal biopsy specimen. a–c Proliferative or basement membrane changes are not observed in the light microscopy sections of the glomerular lesions. Tubular atrophy is mild. a PAS (original magnification × 40). b PAS (original magnification × 200). c PAM (original magnification × 200). d Electron micrograph showing diffuse effacement of glomerular foot processes (black arrows). No immune complex deposits were observed (original magnification × 4000). PAS periodic acid-Schiff; PAM periodic acid-methenamine silver

Fig. 3.

Clinical course of the patient. Conservative management was instituted. The urinary protein levels gradually decreased, and complete remission was achieved at approximately 100 days after renal biopsy. At 1 year since the renal biopsy, no recurrence of MCNS was observed. The mean blood pressure did not fluctuate significantly, and no decrease in renal function was observed. MCNS minimal change nephrotic syndrome

Discussion

The literature describes very few reports of spontaneous remission of MCNS without external factors. Corticosteroids, the first-line treatment of MCNS, are widely used for various pathological conditions in anticipation of anti-inflammatory and immunosuppressive effects [8]. However, multiple adverse effects, such as hypertension, impaired glucose tolerance, osteoporosis [9], and increased incidence of pulmonary embolism, at the beginning of use may pose a problem [10]. The renal prognosis of MCNS in the elderly is relatively good over the long term [11, 12]. However, the use of corticosteroids should be carefully judged in this population because mortality due to infections [11] and the risk of thrombosis due to nephrotic syndrome [13] are both increased. Since our patient was elderly and had a history of thrombosis, the risk of using corticosteroid therapy was considered high. The plan of care was discussed with the patient and his family, corticosteroids and other immunosuppressive therapies were deferred, and conservative management, such as the oral administration of the angiotensin receptor blocker, rest, and dietary modifications centering on salt reduction were instituted. After initiating conservative treatment including continued oral losartan, the UP levels decreased and spontaneous remission was achieved without major complications. In this patient, the time period from the appearance of edema to complete remission was approximately 6 months. Immunosuppressants lead to complete remission in approximately 50% of MCNS patients within 4 weeks and approximately 80% of MCNS patients within 8 weeks [3, 14]. At the same time, approximately 20–30% of membranous nephropathy cases and 10% of MCNS cases are known to have spontaneous remission [15, 16].

Spontaneous remission of MCNS has not been adequately studied so far, because the drug treatment centered on corticosteroids is started soon after onset. Past reports indicate that many factors, such as nontuberculous mycobacterial disease [6], virus infections such as influenza [7], chickenpox [17], drugs [5, 18], and vaccination [19] may induce spontaneous remission. Moreover, measles and hepatitis A virus infection may lead to remission of MCNS [20, 21]. According to these reports, the period for achieving spontaneous remission varied from 4 days to over half a year, but most of these cases reached spontaneous remission within approximately 1 month, which is no different than when treated with corticosteroids. Notably, the majority of the cases that achieved spontaneous remission had secondary MCNS. This patient is likely to have experienced spontaneous remission. However, there are many other external factors that cause MCNS besides those mentioned above. The possibility of developing nephrotic syndrome due to external factors such as infectious diseases and drugs cannot be ruled out. The pathophysiology of MCNS was hypothesized in 1974 [22] to be caused by glomerular permeability enhancers. Humoral factors such as interleukin (IL)-4 and IL-13 secreted by T cells, and B7-1/CD80, a T-cell activating factor targeted by humoral factors, are thought to play the role of such glomerular permeability enhancers [23–28]. It has also been suggested that an imbalance between Th1 and Th2 cells may lead to MCNS [29]. In addition, T-cell dysfunction may have been increased in the cases, where external factors were added or removed, that subsequently reached remission. On the other hand, rituximab, a CD20 monoclonal antibody targeting B cells, has been shown to be effective against steroid-dependent MCNS [30, 31] and has been used in Japan. The depletion of B cells by rituximab may lead to remission because it suppresses T-cell activation [32], but it is also believed that humoral factors derived from B cells may be involved.

In nephrotic syndrome, including MCNS, edema associated with hypoproteinemia, decreased effective circulating blood volume, increased coagulation factor production, and other factors may cause hypervascular coagulation in the blood vessels, increasing the likelihood of arteriovenous thrombosis [33–36]. The patient in this study was previously diagnosed with proteinuria. Owing to the tendency of MCNS to relapse, we suspected that recurrence followed by spontaneous remission may have been repeating in this patient. Hence, his previous episodes of thrombosis may be associated with proteinuria [37, 38]. Such thrombosis is more likely to occur with severe hypoalbuminemia, edema associated with advanced UP, and intravascular dehydration [39]. However, in this patient, the Alb level at the onset of thrombosis was relatively maintained at approximately 3.0 g/dL, and UP was qualitatively approximately 1 + , not quantified (Fig. 4). At the time of onset, we propose that the production of coagulation factors and leakage of anticoagulation factors into the urine may have occurred, which in addition to old age, hypertension, and diabetes, increased his risk of thrombosis. Even in MCNS, it is necessary to consider using anticoagulant therapy when the risk is high, such as in the elderly.

Fig. 4.

Clinical course of the patient. Urinary protein was recognized before renal biopsy. The patient developed lower limb arterial occlusion at X-14 years and retinal vein occlusion at X-9 years. These results suggest that the patient had repeated remissions and recurrence of MCNS linked to the thrombotic events. The antihypertensive drug was changed during the period, but no significant decrease in blood pressure was observed. Renal function has not changed significantly. MCNS minimal change nephrotic syndrome

To provide conservative management as one of the treatment modalities that could allow for spontaneous remission, we believe that the accumulation of spontaneous remission cases, as well as the elucidation of the pathophysiology of MCNS, are important.

Compliance with ethical standards

Conflict of interest

All authors have declared that no conflict of interest exists.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Informed consent was obtained from the patient described in this study.