Nephrology Hypertension

Hereditary Renal Cystic Diseases: Familial Juvenile Nephronopthisis

Does this patient have autosomal recessive familial juvenile nephronophthisis?

Nephronophthisis is a chronic tubulointerstitial nephritis with autosomal recessive inheritance (Figure 1) that progresses to end-stage renal failure early. A historical term "juvenile nephronophthisis-medullary cystic disease complex" was created to describe two histopathologically similar diseases: familial juvenile nephronophthisis (FJN) and medullary cystic kidney disease (MCKD). Besides the histological similarities, they are distinct disorders with different inheritance patterns and ages of onset.

Figure 1.

Pedigree of a family affected with familial juvenile nephronophthisis.

The earliest clinical manifestation of nephronophthisis is a urinary concentrating defect that results in the clinical symptoms of polyuria, constant thirst, secondary enuresis, and drinking through the night.

Other characteristic features include early onset renal failure, usually prior to age 30; reduced kidney function in adolescence or childhood, lack of significant hypertension or detectable proteinuria and bland urine sediment, normal to reduced kidney size on ultrasound with increased echogenicity and loss of the corticomedullary junction. Small cysts (1-15 mm in diameter) are irregularly distributed at the corticomedullary junction and in the medulla. Cysts may be observed on ultrasound examination at a late stage, but is not required for diagnosis. One third of patients with FJN will become anemic before the onset of renal insufficiency.

Unlike patients with polycystic kidney disease, patients with FJN rarely develop flank pain, hematuria, hypertension, urinary tract infections (UTIs), or renal calculi. The most common extrarenal manifestations are retinitis pigmentosa (RP), which often leads to blindness in the first decade of life and occurs in about 10% of the patients. In addition, congenital hepatic fibrosis, oculomotor apraxia, and skeletal anomalies can be present. Growth retardation in children is secondary to reduced kidney function. Hypertension is less prevalent than expected for the degree of kidney functional impairment, typical of tubulointerstitial disorders.

FJN belongs to a family of nephronophthisis with the similar renal histopathology. The use of positional cloning has resulted in identification of at least 11 different genetic causes of nephronophthisis (NPHP1-11, NPHP1L).

Their gene products, the nephrocystins, participant in multiple protein-protein interaction, suggest that they may be part of a common functional network. The similar appearance of the renal histology in cases of FJN and MCKD lead to the historical association of these two disorders. Clinically, FJN is different from MCKD from its early onset and autosomal recessive inherent pattern. For accurate diagnosis, genetic testing is necessary.

Glomerulocystic kidney disease (GCKD) is a set of diseases that have the common features of cystic dilation of Bowman's capsule and the initial proximal convoluted tubule. A biopsy may be necessary to distinguish FJN from GCKD. GCKD can also be inherited in an autosomal dominant fashion.

Autosomal recessive polycystic kidney disease (ARPKD) is characteristic by renal enlargement, often detected in utero, and ectatic dilatation of the distal collecting ducts, leading to renal cysts. ARPKD is also associated with congenital hepatic fibrosis. Therefore, although both FJN and ARPKD are pediatric renal diseases, inherited in an autosomal recessive manner, they can be distinguished from each other if renal biopsies, ultrasonography or genetic testing are available.

The disease prevalence and number of FJN families may be underestimated, since patients often come to clinical attention after reaching ESRD, and a definitive diagnosis may not be established. With the usually bland urinalysis, aggressive diagnostic approaches such as a kidney biopsy are often less likely to be pursued.

What tests to perform?

The laboratory evaluation of FJN patients includes a urine dipstick and microscopic urinalysis, which usually is normal except for a low specific gravity reflection a significant urinary concentration defect. The absence of proteinuria or of hematuria may differentiate nephronophthisis from other heritable kidney diseases, such as focal segmental glomerulosclerosis and Alport’s syndrome, respectively.

Plasma or serum analyses: Complete blood count (CBC) diff platelets and comprehensive chemistry panels with phosphorus: provides all biochemical information, such as electrolytes, creatinine, phosphate, and parathyroid hormone levels.

Vit D 25 and Vit D 1,25: for those with advanced renal insufficiency (chronic kidney disease [CKD] Stage 3 or 4) are also indicated.

Lipid panel: All patients with underlying renal disease will need a lipid panel since they are at higher risk for cardiovascular disease.

For individuals with extrarenal manifestations, such as retinitis pigmentosa, ophthalmologic examination (visual acuity, slit lamp biomicroscopy, ophthalmoscopy, and retinal electrophysiology) are necessary.

The most relevant diagnostic test is the ultrasound examination of the kidneys (Figure 2), which demonstrates normal to slightly reduced kidney size, increased echogenicity, and loss of the corticomedullary border. Cysts, when present, maybe observed at the corticomedullary junction, but cysts visible on imaging are not required for the diagnosis of FJN. Thin-section CT is more sensitive than sonograph in detecting these cysts.

Figure 2.

Ultrasound of a patient with familial juvenile nephronophthisis.

Typically a biopsy is not necessary for a diagnosis. However, in unclear cases, it may be of assistance. Renal histopathology is characterized by a chronic sclerosing, tubulointerstitial nephropathy with sparse inflammatory cell infiltration.

There is irregular thickening or thinning of the tubular basement membrane (TBM) and the novel expression of α5- integrin by tubular epithelial cells.

In the early stages of FJN, neither renal imaging nor histopathology can confirm the clinical diagnosis. However, since defects in NPHP1 have been shown to cause FJN in the vast majority of patients with pure renal abnormalities, recent molecular findings may allow genetic tests to becomethe diagnosis method of choice. As a result, molecular testing may replace renal biopsy in establishing the diagnosis of FJN for most suspected cases.

Due to the pediatric nature of FJN, once diagnosed, the parents should understand that they are most likely carrier of the disease and every one of their children has a 25% chance to inherit the disease gene in familial cases.

Given the rarity of the disease, sporadic cases are common.

Geneticists may provide counseling on family planning. Each at-risk family member should be informed of the availability of diagnosis. However, before a diagnostic test is performed, every subject also needs to be informed about the consequences of diagnostic screening, particularly regarding insurability, to permit informed judgment.

Nephronophthisis has long been recognized as a rare cause of ESRD worldwide and is one of the most common genetic causes of ESRD in the pediatric population. The prevalence has been quoted as between 1/50,000 to 1/100,000 live births.

An affected sibling or affected relatives on family history suggest the diagnosis, however, the parents of an affected individual are not affected, and are rather carriers because the disease inherited in an autosomal recessive pattern. Therefore imaging of parents of an affected individual should be negative. In addition, confirmation of the sequence variations in the FJN gene from each parent should be completed if the sequence variation found is not confirmed as a disease-causing variant.

In summary, the diagnosis of nephronophthisis should be entertained when an individual presents in the first three decades of life with reduced kidney function, a bland urine sediment, normal to small kidneys on ultrasound with increased echogenicity and loss of the corticomedullary junction. Cysts may be observed on ultrasound examination of the kidneys, but that finding is not required for the diagnosis.

How should patients with autosomal recessive familial juvenile nephronophthisis be managed?

No disease-specific therapy is recommended. Conservative therapies known to slow the progression of kidney disease and those appropriate to treat the attendant manifestations of reduced kidney function (including anemia, acidosis, and hyperparathyroidism, urinary tract infections, hypertension if present) remain the standard of care.

Due to the nature of the pediatric condition, growth retardation should be addressed.

There is no evidence of recurrent disease after successful transplantation.

What happens to patients with autosomal recessive familial juvenile nephronophthsis?

Patients with FJN will experience urinary concentrating defect, frequent urination and constant thirst. Decline in kidney function usually results in ESRD in adolescence. Renal replacement therapy is required in this stage. Disease reoccurrence is not observed after transplant.

Patients may develop extrarenal manifestations, of which the most significant are RP (in NHPH4) and congenital oculomotor apraxia. Individuals who develop to RP first experience defective dark adaptation or nyctalopia (night blindness) and peripheral visual field (tunnel vision), which could be followed by incurable blindness. Patients with oculomotor apraxia lose the ability to voluntarily move their eye horizontally and need to thrust their head to look at objects to the side.

Linkage studies have mapped a gene (NPHP1) for FJN to the chromosomal region 2q13. Large, homozygous deletion have been detected in 80% of affected members of FJN NPHP1 families and 65% of sporadic cases.

The gene product, nephrocystin1, interacts with other proteins with similar structure and genetic origin, which probably work in a common functional network. The nephrocystin protein from NPHP1 has been found commonly localized to the primary cilia-basal body –centrosome complex, which led to the development of several hypotheses regarding the role of the protein complex in the generation of renal cysts.

Localization of the nephrocystin proteins to the primary cilia-basal body-centrosome complex has implicated them in the pathogenesis of kidney cysts. However, interstitial fibrosis and tubular atrophy are more prominent than cyst formation in the histopathology of FJN.

Although the pathogenetic mechanism for interstitial fibrosis and tubular atrophy is not clear, nephrocystin protein probably plays a role in the signaling pathway that regulates transcription and cell division in the process of kidney fibrosis.

Some pharmacologic studies have been done in the mouse model of FJN. For example, mice that received an antagonist of the vasopressin 2 (V2) receptor had reduced cyst formation and slower progress of renal failure.

Nephrocystin also plays a significant role in intracellular signaling networks intermediate products including intracellular calcium, intracellular cAMP and other compounds. Studying this approach may be essential to find treatments of FJN besides genetic modification.

How to utilize team care?

Specialty consultations

Genetic Counselors: At the point of diagnosis, a geneticist /genetic counselor plays important role in determine the disease and its mutation. Family members of patients with FJN should receive patient education regarding the inheritance pattern of the disease and risk for progression for affected individual if possible.

Due to the pediatric nature of FJN, once diagnosed, the family proband needs to be carefully examined. In familial cases, patients’ parents should understand that they are carrier of the gene and have a 25% chance to pass the gene to every child they have. Geneticists may provide counseling on family planning.

Each at-risk family member should be informed of the availability of diagnosis. Before a diagnostic test, family members need to be informed about the consequences of diagnostic screening, particularly regarding insurability.


Nurses should educate their pediatric and adult patients to take adequate water and sodium supplementation appropriately.

Nurses should help with performing blood pressure checking, remind patients to have the right dose of medication, and assist physician-patient communication. Home blood pressure monitoring is an important feature of management/administration of required subcutaneous and intravenous medications such as erythropoietin will be supported by nurses


Conservative therapies known to slow the progression of kidney disease and those appropriate to treat the attendant manifestations of reduced kidney function (including hypertension, anemia, acidosis, and hyperparathyroidism) remain the standard of care. In case of growth retardation, appropriate methods should be employed.


Dietitians should help individuals with FJN understand the role of renal diet in helping preserving kidney function, reducing the amount of phosphate, protein, sodium and acid in the diet.

Therapists (physical, occupational, speech, other)

Patient who develop ESRD and require renal replacement therapy will need their nephrologists and transplant team to cooperate well for a successful transplant. A physical therapist may be involved in post-surgery care. For those patients with RP and blindness, occupational or physical therapy may improve quality of life.

Are there clinical practice guidelines to inform decision making?


An autosomal recessive inherent pattern in the family history helps diagnosis and provides parents at risk for additionally affected children. A geneticist may explain that FJN, as an autosomal recessive disease, 25% of the time would be passed down from both carrier parents to the next generation. Each of the carrier parents’ children will have a 25% possibility to develop the disease regardless of the child’s gender. Given the rareness of the disease, current clinical practices lack evidence-based guidelines for this condition.


Given the rare prevalence of the disease, spontaneous individual cases (no previous case occurred /diagnosed in family history) are often observed.

Other considerations

  • MIM code: 256100

What is the evidence?

Niaudet, P. "Nephronophthisis".

(European review of nephronophthisis.)

Guay-Woodfoud, LM, Jafri, ZH, Bernstein, J, Johnson, RJ, Feehally, J. "Other Cystic Kidney Disease". Comprehensive Clinical Nephrology. Harcourt. 2000. pp. 9.50.4-9.50.5.

(A chapter in textbook discusses cystic kidney disease.)

O’Toole, JF, Hildebrandt, F, Greenberg, A. "Nephronophthisis and Medullary Cystic Kidney Disease". Primer on Kidney Disease. Saunders. 2009. pp. 354-357.

(Comparison of nephronophthisis and MCKD.)

Antignac, C, Kleinknecht, C, Habib, R. "Toward identification of a gene for familial nephronophthisis (autosomal recessive medullary cystic kidney disease)". Adv Nephrol. vol. 24. 1995. pp. 379-393.

(An earlier European study on the genetic nature on hereditary nephronophthisis.)

Wolf, MT, Hildebrandt, F. "Nephronophthisis". Pediatr Nephrol Feb. vol. 26. pp. 181-94.

(A comprehensive review of nephronophthisis in general on molecular level; highlights on various hypotheses on the disease’s pathomechanism.)

Ecder, T, Godelam, FM, Schrier, RW, Schrier, RW. "Polycystic kidney disease". Diseases of the Kidney and Urinary Tract. pp. 502-540.

(A chapter covers polycystic kidney disease.)

Borges Oliva, MR, Hsing, J, Rybicki, FJ, Fennessy, F, Mortele, KJ, Ros, PR. "Glomerulocystic kidney disease: MRI findings". Addom Imaging,. vol. 28. 2003. pp. 889-892.

(An earlier image study of glomerulocystic kidney disease)

Sharp, CK, Bergman, SM, Stockwin, JM, Robbin, ML, Galliani, C, Guay-Woodford, LM. "Dominantly transmitted glomerulocystic kidney disease: a distinct genetic entity". J Am Soc Nephrol. vol. 8. 1997. pp. 77-84.

(The first known direct linkage study conducted in a GCKD family.)

Chapman, AB, Greenberg, A. "Polycystic and other cystic kidney disease". Primer On kidney disease. Saunders. 2009. pp. 349-350.

(A textbook chapter introducing cystic kidney disease.)

Sellami, D, Makni, K, Chaker, H. "Ocular manifestations associated with nephronophthisis and genetic study in three Tunisian families". J FrOphtalmol Nov. vol. 29. 2006. pp. 1019-1023.

(A study of correlation of ocular manifestation with nephronophthisis genotype.)

Rahilly, M, Fleming, S. "Abnormal integrin receptor expression in two cases of familial nephronophthisis". Histopathol. vol. 26. 1995. pp. 345-349.

(A pathological study of familial nephronophthisis. Authors concluded that altered cell-substratum adhesion contributes to nephronophthisis.)

Busskamp, V, Duebel, J, Balya, D. "Genetic reactivation of cone photoreceptors restores visual responses in retinitis pigmentosa Science".

(A therapeutic attempt on retinitis pigmentosa.)
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