Nephronophthisis (NPHP), a recessive cystic kidney disease, is the most frequent genetic cause of end-stage kidney disease in children and young adults. Positional cloning of nine genes (NPHP1 through 9) and functional characterization of their encoded proteins (nephrocystins) have contributed to a unifying theory that defines cystic kidney diseases as "ciliopathies." The theory is based on the finding that all proteins mutated in cystic kidney diseases of humans or animal models are expressed in primary cilia or centrosomes of renal epithelial cells. Primary cilia are sensory organelles that connect mechanosensory, visual, and other stimuli to mechanisms of epithelial cell polarity and cell-cycle control. Mutations in NPHP genes cause defects in signaling mechanisms that involve the noncanonical Wnt signaling pathway and the sonic hedgehog signaling pathway, resulting in defects of planar cell polarity and tissue maintenance. The ciliary theory explains the multiple organ involvement in NPHP, which includes retinal degeneration, cerebellar hypoplasia, liver fibrosis, situs inversus, and mental retardation. Positional cloning of dozens of unknown genes that cause NPHP will elucidate further signaling mechanisms involved. Nephrocystins are highly conserved in evolution, thereby allowing the use of animal models to develop future therapeutic approaches.

Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease and is one of the most common genetic disorders causing end-stage renal disease (ESRD) in children and adolescents. NPHP is a genetically heterogenous disorder with 20 identified genes. NPHP occurs as an isolated kidney disease, but approximately 15% of NPHP patients have additional extrarenal symptoms affecting other organs [e.g. eyes, liver, bones and central nervous system (CNS)]. The pleiotropy in NPHP is explained by the finding that almost all NPHP gene products share expression in primary cilia, a sensory organelle present in most mammalian cells. If extrarenal symptoms are present in addition to NPHP, these disorders are classified as NPHP-related ciliopathies (NPHP-RC). This review provides an update about recent advances in the field of NPHP-RC.The identification of novel disease-causing genes has improved our understanding of the pathomechanisms contributing to NPHP-RC. Multiple interactions between different NPHP-RC gene products have been published and outline the interconnectivity of the affected proteins and shared pathways.The significance of recently identified genes for NPHP-RC is discussed and the complex role and interaction of NPHP proteins in ciliary function and cellular signalling pathways is highlighted.

目的 报道两例肾单位肾痨-髓质囊肿病（NPH-MCKD）的临床病理特点。 方法 分析本院诊断的两例NPH-MCKD 的临床资料及肾活检组织的病理改变，并结合文献复习，探讨NPH-MCKD的临床病理特点及其诊断方法。 结果 两例均为青年患者，首发症状为烦渴、多尿，低相对密度尿，轻度蛋白尿，尿沉渣无明显异常，肾小管浓缩功能及酸化功能下降。2例均有轻度肾功能不全，无肾脏病家族史，无肾外损害表现。B超可见肾实质回声增强，皮髓质分界结构不清；其中1例CT可见双肾的多发小囊肿，主要分布于皮髓质交界处。肾活检病理检查：2例均以弥漫性肾小管间质损伤为特点，表现为肾小管基底膜破坏、肾小管萎缩及囊性扩张、肾间质纤维化的三联征；可见部分肾小球硬化。皮髓质交界处肾小管扩张形成多发囊肿是NPH-MCKD的特征性病理改变。 结论 以肾小管功能受损为突出表现的青少年患者要高度怀疑NPH-MCKD。B超或CT检查可提供重要线索。肾活检病理检查见到皮髓质交界处多发性小囊肿形成可确诊本病。

Nephronophthisis (NPHP) is an autosomal recessive kidney disorder characterized by chronic tubulointerstitial nephritis and leading to end-stage renal failure. NPHP as a renal entity is often part of a multisystem disorder and has been associated with many syndromes including Joubert syndrome (and related disorders) and Senior-Loken syndrome. Recent molecular genetic advances have allowed identification of several genes underlying NPHP. Most of these genes express their protein products, named nephrocystins, in primary cilial/basal body structures. Some nephrocystins are part of adherens junction and focal adhesion kinase protein complexes. This shared localization suggests that common pathogenic mechanisms within the kidney underlie this disease. Functional studies implicate nephrocystins in planar cell polarity pathways, which may be crucial for renal development and maintenance of tubular architecture.

Senior-Løken syndrome is a rare autosomal recessive disease with a prevalence of 1:1,000,000. Retinopathy may progress as Leber congenital amaurosis (LCA), retinitis pigmentosa (RP), or sector RP (Figs. 34.1 and 34.2). Onset of photophobia, nystagmus, and hyperopia can occur in the first few years of life or later in childhood. Patients experience nephronophthisis, characterized by cystic kidney disease (medullary cystic kidney disease), reduced concentrating ability, and chronic tubulointerstitial nephritis, which progresses to end-stage renal disease. Hypertension is common.

The polycystic kidney diseases (PKDs) are a group of genetic disorders causing significant renal failure and death in children and adults. There are no effective treatments. Two childhood forms, autosomal recessive PKD (ARPKD) and nephronophthisis (NPH), are characterized by collecting-duct cysts. We used animal models orthologous to the human disorders to test whether a vasopressin V2 receptor (VPV2R) antagonist, OPC31260, would be effective against early or established disease. Adenosine-3',5'-cyclic monophosphate (cAMP) has a major role in cystogenesis, and the VPV2R is the major cAMP agonist in the collecting duct. OPC31260 administration lowered renal cAMP, inhibited disease development and either halted progression or caused regression of established disease. These results indicate that OPC31260 may be an effective treatment for these disorders and that clinical trials should be considered.

Autosomal-dominant polycystic kidney disease (ADPKD) is a common genetic disorder that frequently leads to renal failure. Mutations in polycystin-1 (PC1) underlie most cases of ADPKD, but the function of PC1 has remained poorly understood. No preventive treatment for this disease is available. Here, we show that the cytoplasmic tail of PC1 interacts with tuberin, and the mTOR pathway is inappropriately activated in cyst-lining epithelial cells in human ADPKD patients and mouse models. Rapamycin, an inhibitor of mTOR, is highly effective in reducing renal cystogenesis in two independent mouse models of PKD. Treatment of human ADPKD transplant-recipient patients with rapamycin results in a significant reduction in native polycystic kidney size. These results indicate that PC1 has an important function in the regulation of the mTOR pathway and that this pathway provides a target for medical therapy of ADPKD.

The ciliopathies are a class of rare human genetic disease whose aetioligies lie in defective primary cilia. Typical ciliopathies include Bardet-Biedl syndrome (BBS), nephronophthisis (NPHP), Jeune, Joubert, oro-facial-digital (OFD1) and Meckel (MKS) syndromes. All ciliopathies have the common denominator of renal disease, often including tubular cysts. In this study, we have modelled a range of ciliopathies in zebrafish and shown in all cases that knocking down these genes causes cystic lesions in the kidney. We have identified two drugs, rapamycin and roscovitine, which ameliorate the renal phenotype, both morphologically and functionally. This is the first study in which zebrafish has been used to identify potential therapeutic modalities for ciliopathic renal disease, and the results pave the way for further investigations in mammalian models.