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Clinical manifestations, diagnosis, and treatment of nephronophthisis

Clinical manifestations, diagnosis, and treatment of nephronophthisis
Literature review current through: Jan 2024.
This topic last updated: Apr 30, 2023.

INTRODUCTION — Nephronophthisis (NPHP) is a clinical condition caused by a group of autosomal recessive cystic kidney disorders that typically progresses to end-stage kidney disease (ESKD). It is caused by variants in a large number of genes that encode proteins involved in the function of primary cilia, basal bodies, and centrosomes, resulting in kidney disease and extra-renal manifestations including retinal degeneration, cerebellar ataxia, and liver fibrosis.

The clinical manifestations and management of NPHP will be reviewed here. The genetics and pathogenesis of NPHP are discussed separately. (See "Genetics and pathogenesis of nephronophthisis".)

OVERVIEW — Patients with NPHP have gene variants that encode components of the ciliary apparatus (centrosome, basal bodies, and primary cilia) [1,2]. The gene defects result in the following characteristic findings of NPHP (see "Genetics and pathogenesis of nephronophthisis"):

Autosomal recessive inheritance.

Impaired urinary concentrating ability and sodium reabsorption, resulting in polyuria, polydipsia, and secondary enuresis [3-5].

Urine sediment is typically bland with absence of red blood cells and cellular casts – Proteinuria is often absent, although some patients may show mild tubular proteinuria in early stages of the disease and glomerular proteinuria at late stages with evidence of chronic kidney disease (CKD).

Chronic tubulointerstitial nephropathy and progression to end-stage kidney disease (ESKD).

Extra-renal manifestations consistent with ciliary pathology in 20 percent of patients.

Three clinical variants have been described based upon the median age of onset of ESKD [6,7]:

Infantile − 1 year of age

Juvenile − 13 years of age

Adolescent − 19 years of age

These clinical variants are associated with variants of specific genes. In addition, extra-renal manifestations (eg, retinitis pigmentosa) are present in 20 percent of cases and are usually also associated with a specific gene defect. (See 'Extrarenal manifestations' below.)

CLINICAL MANIFESTATIONS — NPHP is characterized by the insidious onset of end-stage kidney disease (ESKD). Extra-renal manifestations are present in 20 percent of patients, including retinitis pigmentosa, hepatic fibrosis, and skeletal defects [1,8].

NPHP is a major clinical finding in several syndromes, including Senior-Loken, Joubert, Meckel-Gruber, Cogan, and Sensenbrenner syndromes and asphyxiating thoracic dystrophy (ATD; also known as Jeune syndrome). (See 'Associated syndromes' below.)

Renal disease — NPHP almost always progresses to ESKD, primarily before 20 years of age [6,9]. However, there have been case reports of patients who progressed to ESKD between the ages of 27 and 56 years [1,10-12]. In two patients, severe visual impairment due to retinal dystrophy presented in childhood preceding evidence of impaired kidney function. The clinical variants are classified based on the expected age for ESKD (table 1). (See "Genetics and pathogenesis of nephronophthisis", section on 'Genetics'.)

As chronic kidney disease (CKD) progresses, patients develop anemia, metabolic acidosis, and early uremic symptoms such as nausea, anorexia, and weakness. Unlike other conditions that progress to CKD, most patients with NPHP remain normotensive. Normal blood pressure is most likely due to hypovolemia caused by impaired urinary concentration and renal salt wasting [3,5]. In these patients, there is typically no proteinuria or mild tubular proteinuria in early stages of the disease, no hematuria, and no cellular elements. In late stages of the disease, glomerular proteinuria may develop due to secondary glomerulosclerosis [6]. (See "Chronic kidney disease in children: Clinical manifestations and evaluation".)

The rate of progression to ESKD is determined in part by the type and severity of the genetic defect. Among the identified NPHP genes, four of them account for 75 percent of identified disease-causing variants, namely NPHP1, NPHP3, NPHP4 and NPHP11/TMEM67. Kidney survival was analyzed in 383 individuals with variants in one of these genes [13]. Median age at onset of ESKD was as follows:

NPHP3, 4 years (interquartile range 0.3 to 12)

NPHP1, 13.5 years (interquartile range 10.5 to 16.5)

NPHP4, 16 years (interquartile range 11 to 25)

NPHP11/TMEM67, 19 years (interquartile range 8.7 to 28)

Kidney survival was significantly associated with the underlying variant type for NPHP1, NPHP3, and NPHP4.

Infantile — Infantile NPHP is rare and is the most severe form of NPHP [1,14,15]. Affected children develop ESKD between birth and three years of age (median age of one year). This form may present prenatally with a history of oligohydramnios. Unlike the other variants of NPHP, severe hypertension is common [1,16]. Prenatal ultrasound may detect kidney abnormalities by 22 weeks gestation [17]. Renal ultrasound demonstrates hyperechogenic kidneys that vary in size (large to small) and cortical microcysts [18].

Extra-renal findings are more common in patients with infantile NPHP compared with later-onset forms, occurring in approximately 80 percent of patients and includes hepatic involvement (50 percent), cardiac valve or septal defects (20 percent), and recurrent bronchial infections (18 percent) [18].

Infantile NPHP is typically caused by variants in the NPHP2 and NPHP3 genes [18]. Variants of the NPHP2 gene, which encodes the protein inversin (also referred to as nephrocystin-2), are also often associated with situs inversus. (See "Genetics and pathogenesis of nephronophthisis", section on 'NPHP2 gene' and "Genetics and pathogenesis of nephronophthisis", section on 'NPHP3 gene'.)

Juvenile — The most common form of NPHP is the juvenile variant. The clinical symptoms include polyuria, polydipsia, and secondary enuresis occurring at age of four to six years. These findings are due to tubular dysfunction resulting in impaired urinary concentrating ability and sodium reabsorption. Blood pressure usually is normal, in contrast to the infantile variant, in which hypertension is common. These patients develop ESKD by a median age of 13 years [1,2,8].

In affected children, even after a period of fluid restriction, urinary osmolality will remain low (<400 mosmol/kg) and is not increased by the administration of vasopressin (see "Evaluation of patients with polyuria") [6,19]. Sodium wasting can lead to hypovolemia, hyponatremia, and an elevation in the plasma creatinine concentration if sodium intake is diminished [3-5]. These abnormalities precede any decline in glomerular filtration rate (GFR).

Poor growth may be initially related to chronic hypovolemia and later due to growth retardation secondary to CKD. Anemia due to erythropoietin (which is secreted by interstitial fibroblasts) deficiency may be a presenting finding of tubulointerstitial involvement prior to a significant decline in GFR [6,20].

Ultrasonography demonstrates normal or slightly decreased-in-size kidneys with increased echogenicity and loss of corticomedullary differentiation [21]. There is no dilation of the urinary tract, and renal cysts are not typically identified on the initial ultrasound examination, but may appear at a later stage of the disease [22].

The juvenile form of the disease is primarily due to NPHP1 gene variants, which are the most common genetic defect associated with NPHP [2,8]. However, variants have been reported in all genes except the NPHP2 gene in patients with juvenile NPHP [23,24]. (See "Genetics and pathogenesis of nephronophthisis", section on 'Genetics'.)

Adolescent — Most patients with NPHP3 gene variants develop ESKD in late adolescence and young adulthood, with a reported median age of 19 years (range 4 to 37 years) at the time of ESKD [23,24]. Patients will also exhibit initial symptoms of polyuria and polydipsia due to reduced urinary concentrating ability and renal salt wasting but at a later age than those with the juvenile variant.

Extrarenal manifestations — Extra-renal manifestations reflect multisystem disease due to ciliary dysfunction and occur in approximately 20 percent of patients with NPHP. They are often seen in syndromic NPHP (see 'Associated syndromes' below) and include the following [1,25]:

Skeletal defects − Several skeletal defects have been associated with NPHP, including shortening of the limbs and ribs, scoliosis, polydactyly, brachydactyly, craniosynostosis, and cone-shaped epiphyses of the phalanges. The association of cone-shaped epiphyses with NPHP is known as the Mainzer-Saldino syndrome (image 1) [26].

Eye

Visual impairment due to retinitis pigmentosa [27] (also referred to as tapetoretinal degeneration (picture 1)) is seen in patients with Senior-Loken syndrome and Leber congenital amaurosis. Retinitis pigmentosa is observed in 10 to 15 percent of patients with NPHP, particularly in patients with variants in the NPHP1, NPHP2, NPHP3, and NPHP4 genes. Retinal coloboma can be observed in patients with Joubert syndrome [28]. (See 'Senior-Loken syndrome and retinitis pigmentosa' below and "Retinitis pigmentosa: Clinical presentation and diagnosis".)

Oculomotor apraxia seen in Cogan syndrome is less common and is characterized by impaired horizontal voluntary eye movements and nystagmus [27].

Nystagmus and ocular coloboma are seen in patients with the Joubert syndrome.

Neurologic – In addition to the abnormal ophthalmologic findings, significant neurologic abnormalities are often observed in children who present with NPHP as a syndromic component (eg, Joubert syndrome). These include cerebral ataxia, hypotonia, and severe developmental delay.

Liver − Hepatic involvement may be characterized by hepatosplenomegaly, congenital hepatic fibrosis, and portal fibrosis without or with mild bile duct proliferation [23,29-32]. Liver anomalies have been reported in patients with variants in the genes NPHP3, NPHP11, TMEM67, ANKS6, and DCDC2 [23,32-34].

Situs inversus − Situs inversus has been reported in patients with variants in NPHP2, NPHP3, and ANKS6 genes [15,18,33]. (See "Genetics and pathogenesis of nephronophthisis", section on 'Genetics'.)

Cardiac – Ventricular septal and valve defects have been reported in patients with NPHP2 and NPHP3 variants [15,18,35].

Associated syndromes — Syndromes associated with ciliary dysfunction and NPHP include Senior-Loken, Joubert, Meckel-Gruber, and Sensenbrenner syndromes, and ATD [36]. The term NPHP-related ciliopathies (NPHP-RC) is used for this group of autosomal-recessive cystic kidney diseases.

Senior-Loken syndrome and retinitis pigmentosa — Senior-Loken syndrome (OMIM #266900) is characterized by the concomitant presentation of retinitis pigmentosa with severe visual loss (also referred to as tapetoretinal degeneration (picture 1)) and NPHP [37,38]. Although this syndrome is observed in association with variants in most of the NPHP genes, variants of the NPHP5 and NPHP6 genes are the most common [39]. All patients with variants of these two genes have retinitis, which occurs early in life and is more severe than in patients with variants in other NPHP genes. In children with variants in the NPHP1, NPHP2, NPHP3, and NPHP4 genes, retinitis pigmentosa occurs in approximately 10 percent of families, and the kidney course of NPHP is similar in patients with and without ocular involvement [6,40,41]. (See "Genetics and pathogenesis of nephronophthisis", section on 'Genetics'.)

Joubert syndrome — Joubert syndrome (OMIM #213300) is an autosomal recessive neurologic disorder characterized by cerebellar vermis hypoplasia resulting in ataxia, polydactyly, hypotonia, developmental delay, neonatal respiratory dysregulation, and abnormal eye movements [42,43]. NPHP or cystic kidney dysplasia is seen in approximately one-fourth of cases [44]. A pathognomonic finding on axial magnetic resonance imaging (MRI) of the brain is the presence of prominent superior cerebellar peduncles, referred to as "molar tooth sign" of the midbrain-hindbrain junction (image 2) [45].

Joubert syndrome can be associated with juvenile NPHP and/or retinal involvement (Joubert syndrome type B). Several loci for Joubert syndrome associated with NPHP have been isolated, suggesting genetic heterogeneity [21,22,42-44,46-53].

Oculomotor apraxia with cerebellar vermis aplasia has also been reported in Joubert syndrome, which may be challenging to distinguish from Cogan syndrome [54].

Meckel-Gruber syndrome — Variants in the NPHP3, NPHP6, NPHP8, and MKS genes can cause Meckel-Gruber, an autosomal recessive lethal disorder characterized by central nervous system (CNS) malformation (eg, occipital encephalocele), bilateral renal cystic dysplasia, cleft palate, polydactyly, ductal proliferation in the portal area of the liver, pulmonary hypoplasia, and situs inversus [35,55,56]. Meckel-Gruber syndrome is lethal in early life.

Asphyxiating thoracic dystrophy — Asphyxiating thoracic dystrophy (ATD, also called Jeune syndrome) are autosomal recessive disorders characterized by skeletal dysplasia with multiorgan involvement. Variants in four genes have been identified: IFT80, DYNC2H1, TTC21B, and WDR19. Variants in the TTC21B gene, which encodes the retrograde intraflagellar transport protein IFT139, are associated with isolated NPHP and ATD [48]. (See "Chest wall diseases and restrictive physiology", section on 'Asphyxiating thoracic dystrophy'.)

Sensenbrenner syndrome — Sensenbrenner syndrome, also called cranioectodermal dysplasia, is an autosomal recessive ciliary disorder of the skeleton characterized by craniosynostosis, short limbs, brachydactyly, narrow thorax, and facial anomalies. Some patients have NPHP, retinitis pigmentosa, hepatic fibrosis, and brain anomalies [49]. Variants in four different genes have been reported in Sensenbrenner syndrome: IFT122, WDR35, IFT43, and WDR19. (See "Skeletal dysplasias: Specific disorders", section on 'Sensenbrenner syndrome'.)

DIAGNOSIS — The diagnosis of NPHP is suggested by characteristic clinical findings and confirmed by a positive genetic test. In the absence of a positive gene test, a kidney biopsy demonstrating chronic tubulointerstitial changes with a thickening of tubular basement membranes is suggestive of the diagnosis (picture 2).

Clinical diagnosis — The clinical characteristics suggestive of NPHP vary by age (table 1). However, regardless of age, the suspicion of a diagnosis of NPHP increases for a child with kidney disease who also presents with an associated extra-renal manifestations (retinal disease, abnormal ocular eye movements, ataxia, cardiac malformations, skeletal and neurologic abnormalities, and situs inversus). (See 'Clinical manifestations' above.)

Infantile – NPHP should be considered in any infant and young child (<5 years of age) who presents with end-stage kidney disease (ESKD), severe hypertension, and extra-renal anomalies [18]. (See 'Infantile' above.)

NPHP should be considered in older children and adolescents who present with the following (see 'Juvenile' above and 'Adolescent' above):

Polyuria and polydipsia, which often manifest as primary enuresis due to decreased urinary concentrating ability.

Progressive chronic kidney disease (CKD) with normal blood pressure.

Bland urinalysis (absence of proteinuria or mild tubular proteinuria, absence of hematuria and cellular elements).

Normal or slightly decreased-in-size kidneys with increased echogenicity, reduced corticomedullary differentiation, and renal cysts on ultrasound examination.

In some cases, a clinical diagnosis can be made in a child with characteristic findings of NPHP, including ultrasonography compatible with NPHP and extra-renal manifestations that are known to be associated with NPHP, such as retinitis pigmentosa as seen in patients with Senior-Loken syndrome. (See 'Associated syndromes' above.)

Genetic testing — Molecular genetic screening allows gene identification in 50 to 70 percent of NPHP cases. If available, we suggest genetic testing using high-throughput exon sequencing and whole-exome sequencing for any patient in whom there is a clinical diagnosis of NPHP [57,58].

If a whole-exome sequencing panel is not available, testing can be performed for individual genes. In patients in whom there is a high clinical suspicion for NPHP, screening for homozygous or heterozygous NPHP1 deletion should be performed as these variants are the most common.

Other gene variants are responsible for less than 3 percent of cases each. Based upon the clinical manifestations of individual patients, testing of specific genes may be performed (table 2):

NPHP5 gene in cases of severe retinitis pigmentosa

NPHP6 and NPHP8 genes in patients with neurological symptoms

NPHP2 and NPHP3 genes in cases of early onset of CKD [18]

Information regarding genetic testing for NPHP is available at www.renalgenes.org and www.ncbi.nlm.nih.gov/gtr.

Prenatal diagnosis can be performed by direct genetic testing if the specific variants have been identified in an affected sibling.

Kidney biopsy — A kidney biopsy is performed in the following settings for a patient with clinical findings compatible with NPHP:

Genetic testing is negative

When genetic testing is not available and the clinical diagnosis remains uncertain

In these patients, the diagnosis of NPHP is made based on the clinical diagnosis and histologic findings of chronic tubulointerstitial changes with an irregular thickening and multilayering of the tubular basement membranes (picture 2) [59].

DIFFERENTIAL DIAGNOSIS — The presence of the associated extra-renal findings (eg, retinitis pigmentosa) differentiates NPHP from the following chronic kidney disorders that present with a "bland" urine sediment (eg, no evidence of hematuria, cellular elements, or absence of proteinuria or mild tubular proteinuria) (see 'Extrarenal manifestations' above). However, in cases where extra-renal findings are absent, NPHP can be distinguished from these other conditions using a variety of diagnostic tools, including genetic testing, positive family history, renal imaging, and kidney biopsy.

Obstructive uropathy – Presence of hydronephrosis on renal imaging is suggestive of obstructive uropathy and is not usually present in NPHP. However, a large bladder may be observed in patients with NPHP due to chronic polyuria.

Genetic ciliopathies resulting in cyst formation in children include early onset autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD). These two disorders are often in the differential diagnosis for patients with the infantile form of NPHP. The diagnosis for either ADPKD or ARPKD is straightforward when there is a positive family history, including screening parents for ADPKD. Renal imaging may be equivocal in differentiating amongst these entities. In the setting where no family history is present and renal imaging is equivocal, genetic testing is performed to make a definitive diagnosis. (See "Autosomal recessive polycystic kidney disease in children" and "Autosomal dominant polycystic kidney disease (ADPKD) in children".)

Renal hypodysplasia – The presence of significantly smaller kidneys on renal ultrasonography (reduction by greater than two standard deviations) usually will differentiate renal hypodysplasia from NPHP with normal or slightly smaller kidneys. Renal hypodysplasia is observed in over 200 syndromic disorders where anomalies involving other organs are present. As a result, nonrenal findings not associated with NPHP would also be helpful in differentiating between these two disorders. (See "Renal hypodysplasia".)

MANAGEMENT — There is no specific therapy for NPHP.

Interventions include:

Replacing ongoing water needs to prevent episodes of hypovolemia and providing adequate salt intake, especially during intercurrent illnesses that may alter the fluid and electrolyte needs and status.

Administration of erythropoietin and iron to patients with anemia. (See "Chronic kidney disease in children: Complications", section on 'Anemia'.)

Providing active vitamin D analogues supplementation and phosphate binder to patients with evidence of secondary hyperparathyroidism. (See "Pediatric chronic kidney disease-mineral and bone disorder (CKD-MBD)", section on 'Management'.)

Administration of growth hormone to patients with growth retardation. (See "Growth failure in children with chronic kidney disease: Treatment with growth hormone".)

Patients with NPHP uniformly progress to end-stage kidney disease (ESKD). Kidney transplantation is the preferred replacement therapy because the disease does not recur in a transplant. In a report from the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) Registry, patients with NPHP had better outcomes after kidney transplantation when compared with all other patients registered in the NAPRTCS database, especially for those who received living donor kidney transplants [52].

Using cell culture and in vivo models, prostaglandin E2 receptor agonists have been shown to ameliorate several of the pleotropic phenotypes caused by the absence of NPHP1 [60]. This may be a future potential therapeutic option in NPHP-RC; clinical data are lacking.

SUMMARY AND RECOMMENDATIONS

Etiology – Nephronophthisis (NPHP) is the result of gene variants that encode proteins involved in the function of primary cilia, basal bodies, or centrosomes. (See "Genetics and pathogenesis of nephronophthisis".)

Clinical manifestations – NPHP is characterized by impaired urinary concentrating ability, a bland urinalysis (no proteinuria or mild tubular proteinuria, no hematuria or cellular elements), chronic tubulointerstitial disease, and progression to end-stage kidney disease (ESKD) generally by 20 years of age. Variants have been described based upon the median age of onset of ESKD (table 1). These variants are associated with specific gene defects. (See 'Renal disease' above and "Genetics and pathogenesis of nephronophthisis", section on 'Genetics'.)

The infantile form (median onset of ESKD by one year of age) is associated with variants in the NPHP2 and NPHP3 genes. Patients typically have large kidneys with large cysts and are more likely than other variants to have extra-renal abnormalities. (See 'Infantile' above.)

The juvenile form (median onset of ESKD is 13 years of age) is the most common variant. It is associated with variants in all the NPHP genes except NPHP2. These patients initially present with symptoms of polyuria and polydipsia due to impaired urinary concentration, anemia, and short stature, prior to a significant decline in kidney function and subsequent progression to ESKD. These patients typically have a "bland" urinalysis without evidence of hematuria or cellular elements. Ultrasonography demonstrates normal or slightly decreased-in-size kidneys with increased echogenicity and loss of corticomedullary differentiation. (See 'Juvenile' above.)

The adolescent form (median onset of ESKD by 19 years of age) is associated with variants in the NPHP3 genes. Patients also exhibit initial symptoms of polyuria and polydipsia due to reduced urinary concentrating ability but at a later age than those with the juvenile variant. (See 'Adolescent' above.)

Overall, extra-renal manifestations are observed in 20 percent of patients with NPHP. They include retinitis pigmentosa, skeletal defects, hepatic fibrosis, neurologic abnormalities, and cardiac defects. (See 'Extrarenal manifestations' above.)

Associated syndromes – The term NPHP-related ciliopathies (NPHP-RC) is used for the group of autosomal-recessive cystic kidney diseases which include nephronophthisis, including: Senior-Loken (retinitis pigmentosa), Joubert (cerebellar vermis hypoplasia (image 2)), Meckel-Gruber (occipital encephalocele), and Sensenbrenner syndromes (skeletal anomalies), and asphyxiating thoracic dystrophy (ATD, also known as Jeune syndrome). (See 'Associated syndromes' above.)

Diagnosis – The diagnosis of NPHP is suspected by characteristic clinical findings and confirmed by a genetic testing. In the absence of a positive gene test, a kidney biopsy demonstrating chronic tubulointerstitial changes with a thickening of tubular basement membranes is suggestive of the diagnosis. (See 'Diagnosis' above and "Genetics and pathogenesis of nephronophthisis", section on 'Pathology'.)

Differential diagnosis – The differential diagnosis for NPHP includes other chronic kidney disorders with a bland urinalysis. These disorders include renal hypodysplasia, urinary tract obstruction, and autosomal dominant and autosomal recessive polycystic kidney disease (ADPKD and ARPKD). The presence of associated extra-renal findings is useful to differentiate NPHP from these conditions. When extra-renal manifestations are absent, a variety of diagnostic tools, including renal imaging, genetic testing, and family history are used to distinguish NPHP. (See 'Differential diagnosis' above.)

Management – There is no specific treatment for NPHP. Management of children in the early stage of the disease without kidney function impairment is supportive focused on maintaining fluid and electrolyte balance, treating anemia and growth promotion. For patients with ESKD, we recommend kidney transplantation as the preferred renal replacement therapy (Grade 1B). The outcome of kidney transplantation is excellent, as tubular injury does not recur in the transplanted kidney. (See 'Management' above.)

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Topic 6132 Version 31.0

References

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