Background

Nephronophthisis (NPHP) is a chronic tubular interstitial injuries and is the most common genetic causes of renal failure in children and young adults [1]. The estimated incidence of NPHP is 1:50,000 to 1:70,000 [2, 3], and account for approximately 10 to 15% of end-stage of renal disease (ESRD). Clinical features of NPHP are usually not specific, thus common features of chronic kidney disease (CKD), such as, urinary abnormalities, edema, and hypertension are rarely observed in patients with NPHP. Impairment ability to concentrate urine and retain body fluid induce polyuria, polydipsia, and decreased maximum urine concentration. Several patients with NPHP show extrarenal abnormalities, such as cerebellar ataxia, liver fibrosis, situs inversus, abnormal skeleton and facial features, Senior-Loken syndrome, Cogan syndrome and Joubert syndrome [4, 5].

NPHP is divided into three types based on the onset of ESRD, viz., infant type (approximately 5 years old), juvenile type (approximately 13–14 years old), and adolescent type (approximately 19 years old) [6]. It is not easy to diagnose as NPHP because of lack of specific clinical symptom. Thus, many of patients with NPHP progresses to ESRD in childhood or early adolescence. The diagnosis of NPHP is usually made by genetic analysis, as the findings in renal biopsy are not specific. The histopathology of NPHP is characterized by tubulointerstitial abnormalities, such as tubular atrophy, thickening or thinning of the tubular membrane, interstitial fibrosis and inflammation. However, those pathological phenotypes are not disease specific. Therefore, it is important to perform genetic analysis in suspected NPHP patients. Although NPHP has genetic heterogeneity, the most common NPHP mutation is a homozygous deletion of NPHP1, which is identified in 20% of patients with NPHP harboring NPHP gene mutations [7, 8]. Overall, a greater consideration of the diagnosis of NPHP is necessary to prevent expedited decline of renal function.

In the current report, we describe a case of NPHP diagnosed by genetic analysis at 26 years of age in a patient with atypical histological abnormalities.

Case presentation

The patient was a 26-year-old Japanese woman who showed no growth disorders or urinary abnormalities at school check-ups. However, during a medical check-up at 26 years of age, she showed renal dysfunction (serum creatinine 2.2 mg/dL). The estimated glomerular filtration rate (eGFR) was 26 mL/min/1.73 m2, and urine tests indicated low specific gravity of urine (1.004); however, proteinuria and microscopic hematuria were not detected. Urinary β2-microglobulin (β2-MG) was high (805 μg/L; Table 1). Analysis of her family history revealed that her father had chronic myelogenous leukemia and her mother had Sjogren’s syndrome and renal dysfunction. At the time of renal biopsy, the patient’s height, weight, and blood pressure were 155.6 cm, 51.4 kg, and 122/91 mmHg, respectively. Physical examination findings were normal. An abdominal computed tomography scan revealed that both kidneys were normal in size. We performed a percutaneous renal biopsy for definitive diagnosis.

Table 1 Clinical examination at the renal biopsy
Full size table

Histological findings showed global sclerotic lesions in approximately half of glomeruli (Fig. 1a). Moderate fibrosis was observed in the interstitial area, and moderate atrophy was observed in the tubules. Irregular splitting of the tubular basement membrane (ISTBM) [9] was also observed in some tubules (Fig. 1b). There were no significant findings in immunofluorescence analysis (Fig. 1c), and no electron dense deposits were detected by electron microscopy (Fig. 1d). Although cyst-like expansion of the tubules was unclear, tubular atrophy was dominantly found in the distal tubules by cytokeratin 7 (CK7) staining (Fig. 1e).

Fig. 1
figure 1

Renal biopsy histopathology. a Light microscopic findings indicate global sclerosis in half of the glomeruli. However, the other glomeruli showed minor lesions (periodic acid-silver methenamine stain; original magnification, 200×). b Moderate fibrosis was observed in the interstitial area, and moderate atrophy was observed in the tubules (periodic acid-silver methenamine stain; original magnification, 100×). Irregular splitting TBM was also observed in some tubules (arrowhead). c There were no significant findings in immunofluorescence analysis. d No electron dense deposits were detected by electron microscopy. e Cyst-like expansion of the tubular was unclear. Tubular atrophy was dominantly found in the distal tubule by CK7 staining (original magnification, 100×)

Full size image

Next, we analyzed the NPHP1 gene, the most common gene responsible for NPHP. No exons of NPHP1 (1, 9, and 19) were amplified (Fig. 2a). Furthermore, multiplex ligation-dependent probe amplification analysis indicated complete deficiency of the NPHP1 gene (Fig. 2b). Based on these results, both alleles of NPHP1 were considered to be deleted in the current case, leading to a diagnosis of a total deletion of NPHP1.

Fig. 2
figure 2

Genetic analysis of the NPHP1 gene. a No exons from NPHP1 were amplified. b Multiplex ligation-dependent probe amplification analysis indicated complete deficiency of the NPHP1 gene

Full size image

Discussion and conclusion

NPHP is the most common genetic cause of kidney failure in children and young adults [8, 10], with an estimated incidence of 1:50,000 [11, 12]. NPHP accounts for 6–10% of cases of kidney failure and 15% of renal transplants among children [13, 14]. NPHP has significant genetic heterogeneity, with biallelic pathogenic variants in 20 different genes identified as causative [15] with NPHP1 (20%) being the most common gene [8, 16, 17]. Although NPHP is the most common genetic cause of chronic kidney disease (CKD) in children, its prevalence in the adult population is thought to be low. However, Snoek R, et al. recently reported that the frequency of NPHP in adult onset ESRD is substantially higher than previous report [18]. Genome-wide association study using adult renal transplant recipients from several cohorts revealed median age of adult onset of ESRD was 30, ranged from 18 to 61 years old, in patients with NPHP [18]. Thus, NPHP should be considered as a differential diagnosis in adult patients with unidentified ESRD. With no specific management available, treatment focuses on supportive and preventative strategies to preserve kidney function. However, a greater consideration of the diagnosis of NPHP in adult patients with kidney failure and progressive CKD is required to allow informed prognosis, targeted screening of at-risk family members, and expedited preventative and management strategies of kidney function decline [19, 20].

The findings of this case report emphasize the importance of CD10 and CK7 staining in cases in which the cause of renal dysfunction is unclear. Irregular splitting TBM in tubules is an important finding suggesting autosomal dominant tubulointerstitial kidney disease [9]. In patients with renal failure with tubular interstitial disease dominantly in the distal tubule, it is necessary to discriminate NPHP, even in adult patients. Moreover, it is important to perform genetic testing to obtain a definitive diagnosis, which will enable appropriate genetic counseling and treatment. Further studies are necessary to clarify the mechanisms leading to wide variance in age of disease onset.

In summary, NPHP often progresses to ESRD at an average age of 13–14 years old. However, NPHP is not merely a pediatric disease and is relatively high incidence in patients with adult onset ESRD. Even in cases without typical histological abnormalities, such as cyst-like expansion of tubular lesions, differential diagnosis of NPHP is critical. Thus, wider application of genetic testing is recommended to patients with unidentified ESRD.