Medullary Cystic Disease
Medullary cystic kidney disease (MCKD) and nephronophthisis (NPH) refer to 2 inherited diseases with similar renal morphology characterized by bilateral small corticomedullary cysts in kidneys of normal or reduced size and tubulointerstitial sclerosis leading to end-stage renal disease (ESRD). These disorders have traditionally been considered as parts of a complex (the NPH complex) because they share many of the clinical and histopathological features. The major differences are in the modes of inheritance, the age of onset of ESRD, and the extrarenal manifestations. In this article, the 2 diseases are discussed as a single clinicopathologic entity of NPH–MCKD to reflect current recommendations for the classification of renal cystic diseases. 
NPH was first described by Smith et al in 1945, and then by Fanconi et al in 1951, as a familial disorder leading to progressive renal damage and death in late childhood. NPH has an autosomal recessive inheritance pattern. Positional cloning and candidate gene approaches have led to the identification of 11 causative genes to date, all of which appear to encode for proteins expressed in the primary cilia of renal epithelial cells; hence, these disorders are now referred to as ciliopathies. [1, 2, 3, 4, 5, 6]
NPH presents in childhood or adolescence with progressive renal insufficiency and is frequently associated with extrarenal organ involvement such as retinitis pigmentosa, hepatic fibrosis, skeletal defects, and cerebellar aplasia. Three clinical variants have been described, based on the age of onset of ESRD.
The juvenile form is the most common, in which ESRD usually occurs in the second decade of life (mean age, 13 y). It is characterized by the presence of small medullary cysts, extensive tubular atrophy, thickened tubular basement membranes, and prominent interstitial fibrosis. Recent advances in molecular genetics have identified mutations in 9 distinct genes (designated as NPHP1, NPHP4, NPHP5, NPHP6, NPHP7, NPHP8,NPHP9, NPH11, and NPH1L) that are associated with defects in distinct proteins that lead to heterogeneity in clinical manifestations.
The adolescent form is characterized by ESRD developing around age 20 years. It is associated with defects in the NPHP3 gene but with histologic features similar to the juvenile form. The genotype-phenotype correlations are not always clear-cut, and some patients with an NPHP3 mutation can progress to ESRD before age 10 years.
The infantile form is characterized by progression to ESRD before age 4 years. It is associated with defects in the NPHP2 gene. Histopathology reveals cystic dilatations of the collecting ducts, but the typical tubular basement changes seen in juvenile NPH are usually absent. In contrast with the other 2 forms, these children usually demonstrate severe hypertension and moderately enlarged kidneys on ultrasonography.
Aside from NPH, a number of conditions have now been recognized and considered to also represent ciliopathies. [1, 2, 3, 4, 5, 6] These conditions include autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, Bardet-Biedl syndrome, Meckel-Gruber syndrome, oral-facial-digital syndrome, Jeune asphyxiating thoracic dystrophy, and the tuberous sclerosis complex. All these conditions are associated with renal cysts and abnormalities in the cilium, but each has additional features that distinguish them from NPH.
MCKD is inherited in an autosomal dominant pattern and usually presents with adult-onset renal failure and no extrarenal involvement. MCKD has also been referred to as autosomal dominant interstitial kidney disease (ADIKD), to highlight the most distinctive features, namely the autosomal dominant inheritance and slowly progressive kidney disease due to progressive interstitial fibrosis. It should be noted that medullary cysts may not be detected in many patients with MCKD/ADIKD, and the presence of medullary cysts is not required for the diagnosis. The following clinical variants have been described:
MCKD type 1 has a median onset of ESRD at age 62 years and is caused by defects in the MUC1 gene that encodes mucin 1. 
MCKD type 2 is also referred to as uromodulin-associated kidney disease (UAKD) and as familial juvenile hyperuricemic nephropathy (FJHN) because of the frequent association with hyperuricemia.
Dominant mutations in the REN gene, which encodes renin, have recently been described in families with hyperuricemia, anemia, progressive kidney failure, and progressive interstitial fibrosis.  These patients may also be considered to fall under the umbrella of MCKD or ADIKD.
Advances in molecular genetics have led to the identification of the gene defects underlying several forms of NPH-MCKD. [2, 3, 4, 5, 12] Characterization of the encoded proteins is revealing novel pathogenetic mechanisms. Many have been shown to localize to primary cilia, which are highly conserved structures that sense and process various extracellular signals. An important role of normal cilia in renal tubular cells is mechanosensation, whereby flow-mediated bending of primary cilia elicits signal transduction pathways that regulate the cell cycle, cell proliferation, and cell death. Defects in these cellular functions may contribute to cystogenesis. Because cilia are present in almost all cells and tissues, ciliary dysfunction may also account for the extrarenal manifestations encountered in some forms of NPH.
NPH type 1 is characterized by mutations in the NPHP1 gene, which encodes the protein nephrocystin-1. Nephrocystin-1 interacts with the products of other NPHP genes as well as components of cell-cell and cell-matrix signaling. Nephrocystin-1 and its interacting partners are localized to the cell-cell junction (adherens junction) and cell-matrix interface (focal adhesion), suggesting important roles in maintaining the integrity of the tubular epithelium. Thus, cystogenesis in NPH type 1 may result from defects in tubular cell-cell and cell-substratum contacts. Nephrocystin-1 and other NPHP gene products are also prominently localized to the primary cilia in the apical (luminal) membranes of renal tubular epithelial cells. Patients develop ESRD at the median age of 13 years and may also display extrarenal manifestations, including retinitis pigmentosa and oculomotor apraxia.
In NPH type 2, the mutated gene NPHP2/INVS encodes for inversin, which interacts with nephrocystin-1 and b-tubulin and localizes to primary cilia in renal tubular cells. B-tubulin constitutes the microtubule axoneme of primary cilia. Hence, defects in these interactions may impair ciliary function and thereby contribute to cyst development. The age of onset of ESRD is much earlier (< 5 y), and patients often display cardiac abnormalities such as situs inversus and ventricular septal defects.
Mutations in the NPHP3 gene (which encodes nephrocystin-3, another nephrocystin-1 and inversin-interacting protein) result in a variety of human phenotypes, including infantile and adolescent ESRD. Mutations in the other nephrocystin genes account for a minority of patients with NPH. All encode for proteins that similarly interact with other proteins that localize to different portions of primary cilia, basal bodies, centrosomes, or the mitotic spindle of cilia, providing ample evidence for the ciliopathy hypothesis.
MCKD type 2 is due to mutations in the UMOD gene, which encodes uromodulin (Tamm-Horsfall mucoprotein). [8, 9, 10] Uromodulin is produced in the thick ascending limb of the loop of Henle, where it is thought to maintain the water-tight integrity of that nephron segment. Uromodulin also plays a role in the regulation of the Na-K-2Cl furosemide-sensitive transporter as well as the ROMK potassium channel on the apical surface of the thick ascending loop epithelial cells. In MCKD type 2, the mutant uromodulin proteins cannot exit the endoplasmic reticulum, leading to intracellular accumulation of abnormal uromodulin protein, with resultant tubular cell death and chronic kidney disease. However, one of the hallmarks of patients with MCKD type 2 is that the hyperuricemia is disproportional to the degree of renal insufficiency. [13, 14] Hyperuricemia results largely from impaired uric acid excretion, although the mechanism remains unclear.
MCKD type 1 is caused by mutations in the MUC1 gene, which encodes mucin 1.  The abnormal mucin 1 protein accumulates intracellularly in the distal nephron segments. How this leads to the MDCK phenotype is unclear.
A study by Bleyer et al analyzed the clinical characteristics of families and individuals with the MUC1 mutation leading to MCKD type 1. The study concluded that MUC1 mutation results in progressive chronic kidney failure with a bland urinary sediment. The authors also added that the age of onset of end stage kidney disease is highly variable, suggesting that gene-gene or gene-environment interactions contribute to phenotypic variability. 
The incidence of juvenile NPH is 9 cases per 8.3 million population. Nephronophthisis is the most common genetic cause of ESRD in the first 2 decades of life, accounting for 5-15% of cases of ESRD. Medullary cystic kidney disease is rare and has been primarily reported in the United States. Approximately 200 families with MCKD type 2 have been reported, each having several affected individuals. This most likely represents an underestimation, owing to difficulties associated with making an accurate diagnosis.
The incidence of NPH is higher in Europe, where it accounts for 15-25% of cases of childhood ESRD.
ESRD develops in all patients, although the rate of progression is faster in the recessive form of the disease than in the dominant form. Mortality is related to the complications of renal failure.
No racial predilection is noted.
Both sexes are equally affected.
NPH occurs during childhood and progresses to renal failure before the age 20 years. The median age of onset of ESRD is 13 years in juvenile NPH, 1-3 years in infantile NPH, and 19 years in adolescent NPH. If ESRD has not developed by age 25 years, the diagnosis of recessive NPH is unlikely, and autosomal dominant MCKD should be considered. ESRD typically develops when patients with MCKS are aged 25-50 years. Median onset of ESRD is age 62 years for MCKD type 1 and age 32 years for MCKD type 2.
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Homozygous deletion, heterozygous deletion
*Co-localizes with familial juvenile hyperuricemic nephropathy
Prasad Devarajan, MD, FAAP Louise M Williams Endowed Chair in Pediatrics, Professor of Pediatrics and Developmental Biology, Director of Nephrology and Hypertension, Director of the Nephrology Fellowship Program, Medical Director of the Kidney Stone Center, Co-Director of the Institutional Office of Pediatric Clinical Fellowships, Director of Clinical Nephrology Laboratory, CEO of Dialysis Unit, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine
Prasad Devarajan, MD, FAAP is a member of the following medical societies: American Heart Association, American Society of Nephrology, American Society of Pediatric Nephrology, National Kidney Foundation, Society for Pediatric Research
Disclosure: Received none from Coinventor on patents submitted for the use of NGAL as a biomarker of kidney injury for none.
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
Frederick J Kaskel, MD, PhD Director of the Division and Training Program in Pediatric Nephrology, Vice Chair, Department of Pediatrics, Montefiore Medical Center and Albert Einstein School of Medicine
Frederick J Kaskel, MD, PhD is a member of the following medical societies: American Association for the Advancement of Science, Eastern Society for Pediatric Research, Renal Physicians Association, American Academy of Pediatrics, American Pediatric Society, American Physiological Society, American Society of Nephrology, American Society of Pediatric Nephrology, American Society of Transplantation, Federation of American Societies for Experimental Biology, International Society of Nephrology, National Kidney Foundation, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research
Disclosure: Nothing to disclose.
Craig B Langman, MD The Isaac A Abt, MD, Professor of Kidney Diseases, Northwestern University, The Feinberg School of Medicine; Division Head of Kidney Diseases, The Ann and Robert H Lurie Children’s Hospital of Chicago
Disclosure: Received income in an amount equal to or greater than $250 from: Alexion Pharmaceuticals; Horizon Pharmaceuticals); ; Dicerna, Jannsen Pharmaceuticals.
Deogracias Pena, MD Medical Director of Dialysis, Medical Director of Pediatric Nephrology and Transplantation, Cook Children’s Medical Center; Clinical Associate Professor, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Medical Director of Pediatric Nephrology, Florida Hospital for Children
Disclosure: Nothing to disclose.
Medullary Cystic Disease
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