Nephrogenic systemic fibrosis–related pulmonary restriction: An under-appreciated manifestation potentially reversible with imatinib therapy

Abstract

Nephrogenic systemic fibrosis typically occurs in patients with renal failure and is strongly associated with gadolinium exposure through stimulation of macrophage-activated fibrosis. Patients present with prominent fibrosis of the skin and internal organs. Quality of life is significantly diminished due to impairment from restrictive mobility of large and small joint contractures, pain, and ensuing psychological stress. Nephrogenic systemic fibrosis can be severe and life-threatening. Nephrogenic systemic fibrosis patients reliant on hemodialysis with cutaneous symptoms, defined as hyperpigmentation, hardening, and tethering of skin on the extremities, experience rates of mortality as high as 48%. Physician awareness and preventive strategies coincided with a reduction in the incidence of nephrogenic systemic fibrosis. Several treatments, of which physical therapy may be a key adjuvant, have been used to treat nephrogenic systemic fibrosis, with variable and inconsistent results, lacking wide consensus. Improvement of renal function may improve nephrogenic systemic fibrosis, with some patients demonstrating stabilization or improvement after renal transplantation or resolution of acute renal failure. Imatinib, a tyrosine kinase inhibitor, demonstrates antifibrotic effects in the skin and recently was used to successfully treat nephrogenic systemic fibrosis. We report a case of severe nephrogenic systemic fibrosis with extensive skin fibrosis causing extrapulmonary restriction who demonstrated improved lung function following treatment with imatinib.

Introduction

Nephrogenic systemic fibrosis (NSF) occurs in patients with reduced kidney function and is strongly associated with exposure to magnetic resonance imaging (MRI) gadolinium-based contrasts which rely upon renal excretion.^1,2 These agents dissociate into Gd cations that subsequently activate macrophages and monocytes to produce cytokines such as interleukin (IL)-1 and IL-6 through toll-like receptor stimulation and inflammasome pathways. These cytokines such as transforming growth factor (TGF)-β stimulate fibroblast activation and migration of circulating fibrocytes which produce excessive collagen in affected tissues. Renal impairment leads to higher and prolonged circulating concentrations of Gd cations which expose patients to higher risk of toxicity and subsequent NSF. ² In early stages, patients with NSF may present with nonspecific edema, pain, and patchy cutaneous induration that progresses to characteristic woody-type induration and “peau d’ orange” initially sparing distal hands and feet. Fixed contractures of large and small joints are characteristic of this disorder. Although initially believed to be limited to the skin, fibrosis was found to also occur in other organs including skeletal muscle, heart, and the vessel walls of the lungs and kidney. ¹ NSF is distinguished from systemic sclerosis (SSc) by history and examination. The recent criteria for SSc weigh Raynaud’s, nailfold capillary abnormalities, digital ulcerations and pitting, telangiectasias, and specific antibodies of which each are likely to be absent in NSF. ³ Skin presentation and biopsy can help distinguish between NSF, SSc, eosinophilic fasciitis, and scleromyxedema. Unlike SSc, NSF skin thickening occurs weeks after contrast exposure and is characterized by a brawny texture, progressing from lower extremities superiorly typically with erythema. These changes can be under-appreciated in populations with less-pigmented skin types. Contrasted to SSc, NSF spares the face and may involve the skin over the spine. ³

In addition to potentially severe impairment from restrictive mobility of large and small joint contractures, NSF causes significant pain and discomfort. This results from pressure, destruction, and distortion of periarticular, cutaneous, and subcutaneous neural networks resulting in long-term disability. ² Pruritus and a burning sensation are commonly noted, and patients report skin and joint tenderness. Patients progressively worsen until many lose ambulation. ⁴ Bangsgaard et al. ⁵ showed that patients with NSF have significantly poorer scores on the Daily Life Quality Index compared to controls.

The best treatment is prevention by evaluating risk of NSF when administering gadolinium-enhanced contrast. ⁶ In light of this, rigorous screening is required prior to administering gadolinium and has reduced new cases of NSF significantly. Other treatments are supportive and include physical therapy and improvement of renal function, but no therapy is known to be curative. Of note, imatinib has been shown to inhibit dermal fibroblast synthesis of type-I collagen and fibronectin-reducing extracellular matrix synthesis. In humans, there are limited reports of imatinib improving fibrosis of the skin and joint contractures in NSF. ⁷

Case description

Our patient is a 40-year-old African-American woman with a remote history of focal segmental glomerulosclerosis that progressed to end-stage renal disease with hemodialysis dependency since age 15. She also experienced two failed renal transplantations. Over the years, she was exposed to multiple contrasted MRI studies secondary to complications of a hemorrhagic stroke occurring in 2008.

From 2009, non-specific intermittent symptoms arose; and in 2013, symptoms became more discrete with hyperpigmentation along with progressive skin thickening and hardening of the extremities. Progressive shortness of breath coincided with the skin changes from 2013 onward. Review of a 2015 rheumatology consultation note documented a presumptive diagnosis of SSc based on diffuse skin thickening and flexion contractures, and lower extremity ulceration, as well as patient-reported dyspnea, heartburn, nausea, and intermittent diarrhea and constipation. No pulmonary work-up or pharmacological treatment ensued at that time.

With progressing symptoms and concern for the lack of treatment, in January 2018, the patient’s primary-care physician referred her to dermatology. A left lower-extremity skin biopsy was performed revealing dermal fibrosis and scant lymphocytes; however, lacking descriptions of dermal mucin, extent of immature collagen, prominent collagen bundles, or CD34+ spindle cells. The patient was referred to the SSc center in New Orleans.

By this time, the patient was unable to walk and completely reliant upon wheelchair for mobility. Her mother aided her in activities of daily living such as bathing and dressing due to contractures and pain of the ankles, knees, and hips. Pain in her limbs was constant and intrusive to daily living. She reported that breathing difficulties were maximal (NYHA IV), occurring at rest, while speaking, and while being aided with dressing. Pain and tenderness on assessment was not consistent with distinct inflammatory arthritis but predominantly related to contracture-related tension and distortion of subcutaneous myofascial layers and peri-articular structures. The patient’s absence of Raynaud’s phenomenon and facial skin thickening as well as the presence of skin thickening over the vertebral spine were not consistent with common SSc features. Nailfold capillaroscopy demonstrated diffuse and evenly distributed dropout suggestive of robust extracellular matrix infiltration without patterns consistent intrinsic vascular abnormalities or disorganization. Laboratories were negative for antibodies associated with an autoimmune phenomenon including SSc. Pulmonary function testing (PFT) demonstrated globally reduced levels suggesting restriction; however, the high-resolution computed tomography (HRCT) scan of the chest revealed markedly reduced lung volumes bilaterally but without evidence of interstitial lung disease (ILD) (Figure 1). Echocardiogram was unremarkable: with normal biventricular function, chamber sizes, and a normal estimated pulmonary artery systolic pressure. PFTs on presentation are seen in Table 1.

Figure 1.

CT performed on 29 April 2019 reveals no evidence of interstitial lung disease but demonstrates smaller than expected lung volumes.

Table 1.

Lung function before and after imatinib therapy.

(% of predicted)	Baseline	1 year after starting imatinib
TLC	52%	85%
FVC	66%	79%
FEV1	66%	79%
DLCO	44%	56%

TLC: total lung capacity; FVC: forced vital capacity; FEV1: forced expiratory volume in 1 s; DLCO: diffusing capacity of carbon monoxide.

Imatinib therapy was initiated and dosed for renal failure at 100 mg daily titrating up to 200 mg daily with the hope that the skin fibrosis would remit. Within the first 2 months, the patient noticed significant improvement in contractures, skin softening, and increased energy levels and mobility, whereby she was able to walk again. She also noted almost complete resolution of her pain and improvement of gastrointestinal symptoms. Ten months after treatment was initiated, PFTs were significantly improved with total lung capacity (TLC) increasing from 52% predicted at baseline to 85% (Table 1). Clinically, the patient increasingly reported improvement in dyspnea. She currently has stable disease and only experiences shortness of breath with walking long distances. Repeat chest imaging was not warranted, given improvement of lung function. She continues to take Imatinib as she currently notes worsening symptoms with dose reduction.

NSF is a very rare disorder and reports of pulmonary involvement are even scarcer with few recorded cases in the literature. No estimates of incidence or prevalence are available for NSF-associated lung involvement. While a rare presentation, the symptoms associated with NSF are considerably debilitating, and there is ample need for therapies in this patient population with little ongoing research. In addition, imatinib is a therapy with some promise, but also very little research in NSF. An open-label non-randomized uncontrolled clinical trial of imatinib in NSF enrolling only four patients demonstrated positive effects on skin but did not provide convincing evidence that imatinib improves joint mobility. ⁸

This report highlights the systemic impact of NSF. Previous NSF case reports described abnormal PFTs, pulmonary fibrosis, as well as extrapulmonary involvement affecting the diaphragm. ¹ However, this case highlights two important considerations regarding screening and treatment in NSF. First, it is very important to perform an appropriate evaluation for multi-organ system symptomatology and function. This may provide additional metrics to gauge treatment responsiveness in a rare, poorly understood disease entity. This may include collecting additional PFT values such as inspiratory and expiratory pressures as well as imaging. Second, this patient had remarkable improvement of dyspnea and near complete resolution of skin tightness, joint contractures, and pain. This report corroborates previous publications regarding the responsiveness of NSF to imatinib. Weighting imatinib’s relative safety, NSF’s, potential for permanent and devastating disability, and NSF being a rare disorder hampering higher-level investigational evidence, we feel that in addition to physical and occupational therapy, imatinib should be considered a first-line treatment for NSF.^9,10

Conclusion

This is the first case report of a patient with NSF with restricted pulmonary function due to extrapulmonary fibrosis with demonstrated improvement in lung function and reported dyspnea after treatment with imatinib. In addition, this patient experienced remarkable improvement in joint mobility, skin tightness, and pain. NSF may have multi-system impact which should be carefully assessed at baseline and followed over time by physical exam, diagnostic studies, and patient report. Imatinib demonstrates promise in improving health-related quality of life and morbidity in patients with NSF, along with physical and occupational therapy, should be a first-line treatment consideration.

Patient Experience  “I fell sick when I was 12 years old. My kidneys were putting out protein in my urine and I was swollen everywhere. At that time, they transferred my care from Chabert in Louisiana to a pediatric nephrologist in New Orleans where I got care from 12 to 21 years old. I was diagnosed with Focal Segmental Glomerulosclerosis (FSGS). The doctor thinks a childhood strep throat infection caused the disease.  Despite being on prednisone from ages 12 to 15, my kidneys continued to worsen and at 15 they had completely stopped functioning and I was put on peritoneal dialysis (PD). I did PD throughout high school up until 1998, when as a senior getting ready to graduate, I received a kidney transplant at age 17. The doctor didn’t know at the time of the transplant, but the kidney was infected with a Polyomavirus and started failing immediately, lasting only three months, and then, there was no treatment or cure; and I was back on PD again. At age 19, a fungal infection caused peritonitis. I had to go on hemodialysis—which was a big change. PD doesn’t drain you and doesn’t interfere with your life schedule—you can go about your business as normal. But after hemodialysis, I feel really and exhausted with very low energy. I received my second kidney transplant at 24 which lasted a little over two years because the FSGS came back and damaged my new kidney. I am 40 years old and have been on hemodialysis since my second kidney failed at age 26.  When I was 27, I had a bleed on my brain which left me in the hospital for a while. They did several MRIs of my brain with contrast which I later learned was not a good idea for patients with kidney problems. I didn’t start to get the effects of NSF until a year later, it took a few years for them to appear more fully. When the symptoms did start everything hurt. My arms, my feet, all my joints. I noticed that I couldn’t walk far because I would get short of breath and eventually just talking made me lose my breath. My mom had to push me in the wheelchair everywhere. I was total care. I couldn’t lay down in bed because my body hurt so bad. When I first started getting the skin tightening and the joints in my arms, legs were fixed, I went to see a rheumatologist who said it was scleroderma however no treatment was started.  I was sent to dermatology who sent me to my current rheumatologist, where I finally received my diagnosis of Nephrogenic Systemic Fibrosis and was started on Imatinib. In a few weeks, my body and skin felt looser. I was in less and less pain. I was able to do more because my joints were becoming flexible again and breathing wasn’t as hard. I was able to start standing and then walking with a walker. I really felt great. I started leaving the walker in the car because I didn’t need it. I could breathe better. Physical therapy was very helpful, as my body was loosening to get me back to what is almost my normal self.  Since then, I have had good and bad days. I try to take things day by day. The whole experience has been difficult. I was so young with NSF and saw others doing things—and I couldn’t do anything. There are a lot of things I wanted to do that my illness stopped me from doing. I went to college close to home because of my health. I’ve had chronic anxiety and depression because of my health. I was able to graduate from cosmetology school. I thank God every day that I’m still here. People are going through things worse than me. I often talk to other patients at dialysis. I share my story with them. So many people in dialysis think it’s a death sentence and I want them to know that it gives you life.”