A case of minimal change nephrotic syndrome with hypothyroidism deterioration

Abstract

A 73-year-old woman with Graves’ disease underwent total thyroidectomy and was being treated with levothyroxine. She developed edema in the lower region of both legs 1 month before hospitalization. She had a high concentration of urine protein and was hospitalized for further assessment. A urine protein concentration of 4.4 g/day was observed, and she was diagnosed with minimal change nephrotic syndrome (MCNS) after kidney biopsy. The patient’s thyroid function had declined, as indicated by a thyroid-stimulating hormone (TSH) level of 139.0 μIU/mL and a free thyroxine (fT4) level of 0.66 ng/dL. She was prescribed 40 mg/day of prednisolone (PSL) and achieved remission. fT4 level normalized on the 36th hospital day. She was in remission subsequently. However, MCNS recurred when PSL was tapered to 10 mg/day. When she was rehospitalized, thyroid function decline was noted once more, with a TSH level of 29.8 μIU/mL and an fT4 level of 0.74 ng/dL. Her oral PSL dose was increased to 30 mg/day, but she did not achieve remission. However, she achieved remission after steroid pulse therapy. After remission, the thyroid function normalized. During the course of her treatment, the levothyroxine dose was maintained at 87.5 μg/day. Therefore, we predicted that the loss of thyroid hormone in urine due to nephrotic syndrome may have led to the aggravation of hypothyroidism. We have reported this case because of its rarity.

Introduction

Although minimal change nephrotic syndrome (MCNS) is a disease commonly observed in children with nephrotic syndrome, it accounts for 10–25 % of adult nephrotic syndrome cases [1]. According to the Japan Renal Biopsy Registry [2], MCNS accounts for 13.8 % of nephrotic syndrome cases in the elderly (>65 years). There has been an increasing incidence of patients with a variety of complications at the time of nephrotic syndrome onset, especially in the elderly.

We report a case of MCNS in a patient with hypothyroidism, receiving levothyroxine supplementation. We hypothesized that the trends seen in MCNS would be associated with hypothyroidism in nephrotic syndrome.

Case report

The patient was a 73-year-old woman who was receiving treatment for bronchial asthma, depression, and osteoporosis. She was diagnosed with Graves’ disease 15 years ago, and she had a history of treatment for thyroid-associated ophthalmopathy. She had undergone total thyroidectomy 7 years ago and had started taking levothyroxine. Before the onset of nephrotic syndrome, her free thyroxine (fT4) level was normal with oral levothyroxine therapy. She was diagnosed with polymyalgia rheumatica 6 years ago; at the time of onset, the initial oral prednisolone (PSL) dose was 6 mg/day. She was found to have a high level of urine protein during the urine test for edema. She was admitted to our hospital for examination.

She was observed to have edema in the lower region of both legs during the initial examination. Hypoproteinemia was observed on a blood test. According to the urine test, her urine protein level was 4.4 g/day. Her hypothyroidism had deteriorated with a thyroid-stimulating hormone (TSH) level of 139 μIU/mL and an fT4 level of 0.66 ng/dL.

The patient underwent a percutaneous renal biopsy on the 9th hospital day. According to the biopsy, 38 glomeruli were sampled for light microscopy, but there was no evidence of mesangial cell proliferation or basement membrane thickening. Immunofluorescent staining showed no deposition of immunoglobulin (Ig) G, IgA, IgM, complement 3, and complement C1q. Based on these findings, she was diagnosed with MCNS (Fig. 1).

Fig. 1.

Renal biopsy findings. a Light microscopy. Left periodic acid-Schiff staining; right periodic acid methenamine silver staining, b immunofluorescent staining

She commenced her treatment with an oral PSL dose of 40 mg/day, and her urine protein became negative after 2 weeks of the treatment course. Her fT4 level normalized to 0.98 ng/dL on the 36th hospital day.

Following discharge, the patient was followed up, and her PSL dose was gradually decreased from 40 mg/day. The patient relapsed when the PSL dose was reduced to 10 mg/day. She was rehospitalized for medical treatment and, she was observed to have recurrent hypothyroidism with a TSH level of 29.8 μIU/mL and an fT4 level of 0.74 ng/dL. The selectivity index was 0.09 (highly selective). Therefore, we increased the oral PSL dose to 30 mg/day, and she was diagnosed with MCNS relapse, which did not lead to remission. Furthermore, her thyroid function did not normalize. The clinical course of the patient (Fig. 2) was complicated by influenza infection and consequent pneumonia, which were treated by oral oseltamivir (150 mg/day) and intravenous injection of cefotaxime sodium. C-reactive protein level was reduced by the 29th hospital day. Therefore, we administered methylprednisolone dose of 1 g/day for 3 days, followed by an oral PSL dose of 30 mg/day. Negative urine protein was observed approximately on the 50th hospital day, until the patient achieved remission.

Fig. 2.

Clinical course of the 2nd admission. U-Pro/Cre urine protein/creatinine ratio, U-fT4 urine free thyroxine

On the 33rd hospital day, the patient showed a decrease in daily activities, her speech deteriorated, and she experienced disturbance of consciousness (Glasgow Coma Scale: E4V2M5). Magnetic resonance imaging of the brain did not show cerebrovascular disease or encephalitis; there was no paralysis or convulsions. We continued to administer PSL and levothyroxine using a nasogastric tube because of feeding difficulty.

The patient’s speech and consciousness returned to conservative levels on the 40th hospital day. The free triiodothyronine(fT3) and fT4 levels were lowest at that time, suggesting that the patient’s symptoms resembled those of a mild myxedema coma. The levothyroxine dose remained unchanged during this period.

After nephrotic syndrome remission, the patient’s fT3, fT4, and TSH levels were normal. fT4 urine concentration decreased from 2.31 ng/dL on the 7th hospital day to 0.14 ng/dL on the 55th hospital day after remission.

Discussion

Thyroid hormones are classified into T3 and T4. T4 metabolizes into T3. T3 is the most physiologically active form of thyroid hormone, and T4 has the highest concentration in the blood circulation.

Normally, only small amounts of protein are found in the urine. However, in nephrotic syndrome, owing to dysfunction of the glomerular basement membrane, protein in the blood is excreted in the urine. Thyroxine is strongly lipophilic and is transported in the blood by binding to the thyroxine-binding globulin (TBG). Thyroxine expresses its physiological activity by binding to receptors that are expressed in cells throughout the body. In fact, TBG, thyroxine-binding prealbumin (TBPA), and albumin all bind to T4. Approximately 65, 10, and 20 % of the T4 in the blood is bound to TBG, TBPA, and albumin, respectively [3]. The molecular weight of TBG is 54 kDa, which is similar to that of albumin (69 kDa).

The patient in this case had undergone a total thyroidectomy. Therefore, the thyroid hormone supply depended on exogenously prescribed levothyroxine. In this case, we observed that the thyroid function abnormalities during remission were consistent with the exacerbation of nephrotic syndrome, in which the excretion of TBG was increased. Based on this information, we presumed that thyroxine was deficient. Nephrotic syndrome is a condition involving the loss of a large amount of albumin, which has a molecular weight similar to TBG, and therefore, TBG can be predicted to also have been excreted in the urine. As a result, we believe that fT4 should also have been excreted in the urine; however, an increased level of fT4 was observed in the urine of this patient. Furthermore, we did not measure the actual TBG. Afrasiabi et al. reported variation of thyroid hormone and TBG levels during nephrotic syndrome. They reported that the T3, T4, and TBG levels in blood were within the normal range, whereas the T4 and T3 levels in urine were increased [4].

Only a few sporadic cases of hypothyroidism with nephrotic syndrome are reported in the literature. Chandurkar et al. reported a case of hypothyroidism complicated by MCNS in a patient who was administered levothyroxine [5]. In that case, the patient had been stable after oral administration of levothyroxine at 125 μg/day. However, the oral levothyroxine dose after the onset of MCNS had to be increased to 225 μg/day. In addition, they reported that urinary T4 excretion in patients with a high urine protein level was significantly higher than that in patients with negative urine protein (18.0 ± 18.2 vs. 3.8 ± 1.8 μg/L, respectively). Iwazu et al. reported a MCNS case that was complicated by Hashimoto disease and was later complicated by acute renal failure during the disease course [6]. Prednisone and levothyroxine administration was started at the same time in this case, but the authors observed a significantly low blood pressure and an acute renal failure, immediately after the start of drug administration. Iwazu pointed out that the possibility of a lack of thyroid hormone was the cause of the decrease in blood pressure. After MCNS remission, this case no longer experienced hypothyroidism under levothyroxine administration. We speculate that there was a possibility that hypothyroidism was improved because levothyroxine was no longer being excreted.

In cases where there is no hypothyroidism before disease onset (Hashimoto’s disease), there have been reports of hypothyroidism complications during the disease course. Dagan et al. reported steroid-resistant nephrotic syndrome (SRNS) in five pediatric cases of non-autoimmune hypothyroidism [7]. Kapoor et al. reported six subclinical hypothyroidism cases in 20 children with SRNS [8]. Kinoshita et al. reported diabetic nephrosis cases complicated with autoantibody-negative hypothyroidism [9]. Although the urine protein level was not reduced in the study by Kinoshita, hypothyroidism improved after the reduction of edema and pleural effusion.

Disturbance in consciousness without a clear cause was complicated during the course of our case. There is a possibility of hypothyroid coma when the lowest fT3 level corresponds with a disturbance in consciousness, which was observed in this case. If a patient with hypothyroidism develops nephrotic syndrome, it is necessary to consider that the patient might rapidly exhibit hypothyroidism symptoms.

Nephrotic syndrome can develop at different ages, and it even occurs in the elderly. In particular, large amounts of urine protein can sometimes rapidly appear in MCNS patients who are in remission. These patients may exhibit rapid fluctuations in their general condition in a short term, and therefore, it is necessary to carefully monitor their symptoms. In elderly people with multiple comorbidities, it is necessary to administer medical treatment while paying attention to each disease. The main treatment for MCNS is a steroid and it is also important to consider screening and evaluation for endocrine function.

Compliance with ethical standards

Conflict of interest

The authors have declared that no conflict of interest exists.