Senior-Løken syndrome misdiagnosed as nephrosclerosis related to hypertensive disorders of pregnancy

Background

Senior-Løken syndrome (SLS) is a very rare inherited disorder characterised by progressive kidney and eye problems, and a mutation in NPHP1 (OMIM#266900) has been identified as its cause.1 The prevalence of SLS is estimated to be 1 per million people worldwide.1 SLS affects the eyes by causing varying degrees of retinal dystrophy, which is progressive wasting of the retina. A severe type of retinal dystrophy is induced by SLS, called Leber congenital amaurosis (LCA). SLS patients without LCA also develop symptoms a retinal dystrophy called retinitis pigmentosa (RP). In addition, SLS causes nephronophthisis (NPH), which usually begins in early childhood.1–3 NPH is characterised by a reduced renal concentrating ability, chronic tubulointerstitial nephritis, cystic renal disease and progression to end-stage renal disease (ESRD). Patients with NPH type 1, which is one cause of juvenile NPH, results from changes affecting the NPHP1 gene that induce ESRD around 13 years old.3 NPH, including SLS, has been considered a paediatric disease. However, in a recent report, 88% of adult-onset (≥18 years old) ESRD patients with homozygous NPHP1 gene deletion had not been diagnosed with NPH.4 Therefore, some adult-onset ESRD patients with NPH might have been misdiagnosed, such as with nephrosclerosis or drug-induced tubulointerstitial nephritis.

We herein report a 31-year-old woman with SLS who developed stage 4 chronic kidney disease (CKD).

Case presentation

A 31-year-old woman was referred to our hospital with an elevated serum creatinine level in preparation for renal replacement therapy. She had no family history of renal diseases and had tunnel vision due to RP diagnosed at 10 years old. At 29 years old, she was diagnosed with pregnancy-induced hypertension during her first pregnancy because of an elevated blood pressure and reduced renal function (serum creatinine 1.2 mg/dL). Caesarean delivery was performed at 39 weeks and 4 days. Although the patient’s blood pressure returned to the normal level after surgery, her serum creatinine level gradually increased. Blood tests and a urinalysis were unremarkable except for an elevated serum creatinine level. She was diagnosed with CKD due to nephrosclerosis related to the hypertensive disorders of pregnancy and was treated with 25 mg of losartan daily.

Two years after this childbirth, when she was referred to our hospital, her serum creatinine level was elevated at 4.6 mg/dL (estimated glomerular filtration rate (eGFR): 10 mL/min/1.73 m²). At referral, her blood pressure was 125/75 mm Hg, and a physical examination revealed no abnormalities.

Investigations

A laboratory analysis revealed the following results: total protein, 8.3 g/dL; total cholesterol, 182 mg/dL; serum sodium 142 mmol/L; potassium, 3.2 mmol/L; chloride, 103 mmol/L; serum creatinine, 4.69 mg/dL; blood urea nitrogen, 43 mg/dL; haemoglobin, 97 g/L; white cell count, 7.48×10⁹/L and platelet count, 397×10⁹/L. Her eGFR was 9.9 mL/min/1.73 m². A serological test showed a C-reactive protein level of 0.29 mg/day. Immunological tests revealed that the patient was negative for antinuclear antibodies. A urinalysis showed trace proteinuria (protein–creatinine ratio, 0.2 g/g) without haematuria. Abdominal ultrasonography revealed multiple cysts on the right and left kidneys. The MRI of the kidneys demonstrates multiple corticomedullary cysts (figure 1). Her renal function had been declining without haematuria or overt proteinuria. In addition, at referral, she had RP with multiple corticomedullary renal cysts.

Figure 1

MRI findings revealing multiple bilateral corticomedullary cysts in the kidneys.

These findings indicated that she had NPH, although NPH has been recognised as rare cause of adult-onset end stage renal failure. Therefore, we performed renal biopsy. We identified 30 glomeruli by light microscopy and global sclerosis was found in 60% of them. Interstitial fibrosis with mild infiltration of monocytes was also noted. The tubules were tortuous and atrophic with segmented tubular basement membrane thickening (figure 2). Clinical and histological findings of the patient were compatible with NPH. In the ophthalmic examinations, the diagnosis of RP was confirmed based on by peripheral visual field loss, pigment deposits in fundus, loss of photoreceptors at the optical coherence tomography scan of the retina and decreased responses as measured by electroretinography. NPH with early-onset retinal dystrophy, including RP, indicated that she had SLS. To confirm the diagnosis and to establish the genetic cause, molecular genetic analysis was performed and homozygous deletion of the gene encoding nephronophthisis-1 (NPHP1) was found in white cell count of the patient.

Figure 2

Light microscopy of the renal biopsy specimen showed advanced interstitial and periglomerular fibrosis with sclerotic glomeruli (left). The renal tubules were tortuous and atrophic with segmented basement membrane thickening (left. middle). Thickening and multiplication of the tubular basement membrane were seen on electron microscopy (right). Left: periodic acid methenamine stain (×100). Middle: periodic acid methenamine stain (×400). Right: electron microscopy.

Differential diagnosis

The differential diagnoses is any cause of chronic renal failure without overt proteinuria and/or haematuria. These include hypertensive nephrosclerosis, interstitial nephritis, reflux nephropathy, polycystic kidney disease and NPH, including SLS. In the present case, the histological and genetic analyses showed that she had NPH. Because this patient had no neurological disorders, Joubert Syndrome and Cogan syndrome were ruled out. In addition, because she had RP, she was diagnosed with SLS.

Treatment

Since there is no curative treatment for NPH, the management includes correction of the water and electrolyte imbalances (including mineral bone disorders) and treatment of the anaemia and hypertension.

Patients may require treatment with erythropoiesis-stimulating agents to maintain haemoglobin levels at target levels. In cases of end-stage renal failure, patients require dialysis or renal transplantation.

Outcome and follow-up

Because her home blood pressure was <120/70 mm Hg, losartan was discontinued. Her home blood pressure was controlled to <125/75 mm Hg without antihypertensive agents. She was treated with 0.25 µg of calcitriol and 20 mg of febuxostat daily for hypocalcaemia and hyperuricaemia, respectively. Because her renal function was gradually worsening, she was scheduled to receive living donor kidney transplantation.