Nephronophthisis and Medullary Cystic Kidney Disease

Nephronophthisis (NPHP) and medullary cystic kidney disease (MCKD) represent a set of rare genetic kidney diseases with a similar kidney histopathology, which includes interstitial fibrosis with tubular atrophy, changes in the tubular basement membrane (TBM), and cyst formation. These two diseases can be distinguished clinically by their inheritance pattern and often by their age of onset. NPHP has an autosomal recessive inheritance pattern and results in kidney failure within the first three decades of life. MCKD has an autosomal dominant inheritance pattern and usually results in kidney failure between the fourth and seventh decades of life. While NPHP is frequently accompanied by defects in various other organ systems, gout is the only extrarenal manifestation described in MCKD thus far ( Table 40.1 ). Clinical presentation, family history, and findings on kidney biopsy can suggest a diagnosis of NPHP or MCKD. However, the only definitive diagnostic modality is genetic testing. NPHP is genetically heterogenous with 20 different gene loci known to date. For MCKD, two gene loci are known, and researchers have finally succeeded in identifying the two underlying genes. As the term MCKD may be misleading in some cases, a Kidney Disease: Improving Global Outcomes (KDIGO) consensus report in 2015 suggested a new terminology for this syndrome, namely, autosomal dominant tubulointerstitial kidney disease (ADTKD) and proposed a gene-based subclassification. As a new development, recent genetic studies have shown that gene mutations thus far predominantly implicated in pediatric kidney disease appear to be more relevant in the adult-onset chronic kidney disease (CKD) than was previously assumed.

TABLE 40.1

Genetic Causes of Nephronophthisis and Medullary Cystic Kidney Disease

Disease	Gene	Protein	Mode of Inheritance	Chromosomal Localization	Extrarenal Manifestations
NPHP1	NPHP1	Nephrocystin 1	AR	2q13	Retinitis pigmentosa, oculomotor apraxia, cerebellar vermis hypoplasia (rare)
NPHP2	INVS	Inversin	AR	9q31.1	Retinitis pigmentosa, situs inversus , liver fibrosis, pulmonary hypoplasia
NPHP3	NPHP3	Nephrocystin 3	AR	3q22.1	Retinitis pigmentosa, liver fibrosis, Meckel-Gruber syndrome
NPHP4	NPHP4	Nephroretinin	AR	1q36.22	Retinitis pigmentosa, oculomotor apraxia
NPHP5	IQCB1	Nephrocystin 5	AR	3q13.33	Retinitis pigmentosa (all described cases)
NPHP6	CEP290	Nephrocystin 6	AR	12q21.32	Retinitis pigmentosa, cerebellar vermis hypoplasia, liver fibrosis, Meckel-Gruber syndrome
NPHP7	GLIS2	GLIS 2	AR	16p13.3	Not reported
NPHP8	RPGRIP1L	Nephrocystin 8	AR	16q12.2	Retinitis pigmentosa, cerebellar vermis hypoplasia, liver fibrosis, Meckel-Gruber syndrome
NPHP9	NEK8	NEK8	AR	17q11.2	Liver fibrosis, congenital heart defects, Meckel-Gruber syndrome
NPHP10	SDCCAG8	SDCCAG8	AR	1q43–q44	Retinitis pigmentosa, Bardet-Biedl syndrome
NPHP11	TMEM67	Meckelin	AR	8q22.1	Retinitis pigmentosa, cerebellar vermis hypoplasia, liver fibrosis, polydactyly, Meckel-Gruber syndrome
NPHP12	TTC21B	TTC21B	AR	2q24.3	Cerebellar vermis hypoplasia, skeletal involvement
NPHP13	WDR19	WDR19/IFT144	AR	4p14	Retinitis pigmentosa, skeletal involvement, liver fibrosis
NPHP14	ZNF423	ZNF423	AR	16q12.1	Retinitis pigmentosa, cerebellar vermis hypoplasia
NPHP15	CEP164	CEP164	AR	11q23.3	Retinitis pigmentosa, cerebellar vermis hypoplasia
NPHP16	ANKS6	ANKS6	AR	9q22.33	Liver fibrosis, congenital heart disease
NPHP17	IFT172	IFT172	AR	2p23.3	Retinitis pigmentosa, skeletal involvement, liver fibrosis
NPHP18	CEP83	CEP83/CCDC41	AR	12q22	Retinitis pigmentosa, brain involvement
NPHP19	DCDC2	DCDC2	AR	6p22.3	Liver fibrosis
NPHP20	MAPKBP1	MAPKBP1	AR	15q15.1	None reported
MCKD1 (ADTKD- MUC1 )	MUC1	Mucin 1	AD	1q22	Hyperuricemia, gout
MCKD2 (ADTKD- UMOD )	UMOD	Uromodulin	AD	16p12.3	Hyperuricemia, gout

AD , Autosomal dominant; ADTKD , autosomal dominant tubulointerstitial kidney-disease; AR , autosomal recessive; MCKD , medullary cystic kidney disease; NPHP , nephronophthisis.

Epidemiology

NPHP is recognized as a rare cause of ESKD worldwide, but it is one of the most common genetic causes of ESKD in the pediatric population. Historically, the incidence of NPHP alone has been quoted as between 1 in 50,000 and 1 in 1 million live births. The 2007 annual report of the United States Renal Data System (USRDS) indicated that the overall incidence and prevalence of ESKD related to NPHP or MCKD were both about 0.1% in the United States. For the period 2012–16, USRDS data reported a combined incidence of 1.5% for MCKD and NPHP in pediatric patients with ESKD.

The incidence and prevalence of these diseases reported in databases may be an underestimate because patients often come to clinical attention only after kidney failure when the identification of the underlying diagnosis may no longer be possible. In addition, urinalysis in these disorders is typically bland without significant proteinuria or hematuria, limiting opportunities for screening and making aggressive diagnostic procedures such as biopsy less likely to be pursued. Although a presumptive diagnosis of NPHP or MCKD can be made based on clinical features and kidney histopathology, the only way to definitively diagnose these disorders is through genetic testing. Unfortunately, despite recent advances in next-generation sequencing and drastic cost reduction, access to molecular diagnostics in clinical settings is still limited.

Pathology

The similar appearance of the kidney histology between NPHP and MCKD led to the historic association of these two disorders. The classic triad of kidney pathology findings that are shared by all genetic types of NPHP except NPHP type 2 (NPHP2) includes interstitial fibrosis with tubular atrophy, TBM disruption, and corticomedullary cysts. Periglomerular fibrosis and sclerosis have also been noted. Cysts range in size from 1 to 15 mm, are typically located at the corticomedullary junction, and usually arise from the distal convoluted tubule or medullary collecting duct. Kidney size is normal or reduced in these types of NPHP, and cysts may not be apparent by imaging early in the course of the disease. Although NPHP frequently presents with extrarenal involvement, cysts have not been observed in other organs in contrast to autosomal dominant and autosomal recessive polycystic kidney disease (ADPKD/ARPKD).

NPHP2, or infantile NPHP, is caused by mutations in the inversin (INVS) gene, and its kidney pathology and clinical course are distinct from those of other types of NPHP. NPHP2 results in kidney failure in the first decade of life, often within the first 2 years, and is characterized by the cystic enlargement of the kidneys bilaterally. Kidney pathology is characterized by more remarkable cyst formation, which appears more prominently in the cortex, but it can also be present in the medulla. Cysts seem to arise from the proximal and distal tubules, and cystic enlargement of the glomerulus has occasionally been noted. Tubulointerstitial nephritis is another prominent finding in NPHP2, which it shares with the other forms of NPHP. Compared to other types of NPHP, TBM disruption is less commonly observed in the setting of NPHP2.

The gross appearance of the kidney in MCKD is normal to slightly reduced in size, similar to NPHP. Histologically, the kidney pathology of MCKD is virtually indistinguishable from NPHP, which has led to the historic nomenclature of these diseases as the NPHP-MCKD disease complex .

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