| Abstract|| |
Medullary cystic kidney disease (MCKD) belongs with nephronophthisis (NPH) to the NPH-MCKD complex, a group of inherited tubulointerstitial nephritis which share some morphological and clinical features. Juvenile NPH, the most frequent variant of the complex, is a recessive disease with onset in childhood leading to end stage renal disease (ESRD) within the 2nd decade of life. The most frequent extrarenal involvement is tapetoretinal degeneration. MCKD is a less frequent disease with dominant inheritance; it is recognized later in life, leading to ESRD at the age of 50 years, and may be associated with hyperuricemia and gout. In an early phase, both NPH and MCKD are pauci-symptomatic, major signs being confined to polyuria. Later in the course, clinical findings are related to the progressive renal insufficiency, such as anemia, uremic symptoms and, in NPH, growth retardation. On renal ultrasound, the kidneys present an increased medullary echogenicity with diminished cortico-medullary differentiation. Renal cysts may be present, usually at corticomedullary boundary. Due to the clinico-pathological identity, the two diseases were considered to be a single disorder, and the compromise appellation of NPH-MCKD complex was suggested. This unifying conception was subsequently refuted following the identification of MCKD dominant families. The recent advances of the molecular genetics changed the traditional classification of NPH-MCKD complex. The majority of cases of juvenile NPH are due to deletion of the NPHP1 gene on chromosome 2q13. Genes for infantile and adolescent NPH have been localized to chromosome 9q22-q31 and 3q22, respectively. A new locus, NPHP4, has been recently mapped on chromosome 1p36. Two genes predisposing to dominant MCKD, MCKD1 and MCKD2, have been localized to chromosome 1q21 and to chromosome 16p12. Moreover, a gene for familial juvenile hyperuricemic nephropathy (FJHN), a phenotype very similar to MCKD, was mapped to 16p12 in a region overlapping with the MCKD2 locus. The proof of the allelism between MCKD2 and FJHN has been recently provided by the identification of four novel uromodulin (UMOD) gene mutations, segregating with the disease phenotype in three families with FJHN and one with family with MCKD2. These data provide the first direct evidence that MCKD2 and FJHN arise from mutation of the UMOD gene and are allelic disorders.
Keywords: Familial Juvenile Hyperuricemic Nephropathy, Medullary Cystic, Kidney Disease, Molecular Genetics, Nephronophthisis, Tubulointerstitial Nephritis
|How to cite this article:|
Scolari F, Ghiggeri GM. Nephronophthisis-Medullary Cystic Kidney Disease: From Bedside to Bench and Back Again. Saudi J Kidney Dis Transpl 2003;14:316-27
|How to cite this URL:|
Scolari F, Ghiggeri GM. Nephronophthisis-Medullary Cystic Kidney Disease: From Bedside to Bench and Back Again. Saudi J Kidney Dis Transpl [serial online] 2003 [cited 2020 Jun 6];14:316-27. Available from: http://www.sjkdt.org/text.asp?2003/14/3/316/33010
| Introduction|| |
Nephronophthisis (NPH) and medullary cystic kidney disease (MCKD) belong to a heterogeneous group of inherited tubulo-interstitial nephritis named NPH-MCKD complex. The two diseases share several features regarding clinical symptoms (polyuria, polydipsia, and anemia), macroscopic pathology (cysts primarily located at the cortico-medullary border) and renal histology (tubular atrophy, interstitial fibrosis, cell infiltration). The two disorders, however, are also characterized by three distinguishing features, such as mode of inheritance (recessive in NPH and dominant in MCKD), age of onset for endstage renal disease (developing in the child hood or adolescence in NPH and in adult hood in MCKD), and extrarenal organ involve ment (tapeto-retinal degeneration in NPH; gout and/or hyperuricemia in MCKD). ,
The term of NPH-MCKD complex has been proposed as compromise appellation, because of the inability to clearly distinguish clinically and pathologically between NPH and MCKD. The term medullary cysts of the kidney was first used in the American literature by Smith and Graham, who reported an 8-year-old girl with refractory anemia, hyposthenuria and uremia.  Since then, other patients have been described with a similar clinical picture and medullary cysts. The disease was rarely familial and occurred more frequently in adults than in children.  In 1951, in the European literature, Fanconi et al described a familial renal disease that affected children, being fatal at the age of 4-14 years. The disease, characterized by renal insufficiency, anemia, polyuria, tubulo-interstitial lesions, was termed with the restrictive name of NPH. Although in the original report Fanconi et al. did not describe cysts, several cysts might be seen in the published photograph of one case. 
Thus, NPH and MCKD were originally considered to be separate entities. Subsequent reports, however, suggested that NPH and MCKD were a single disorder. The inability to establish diagnostic criteria to clearly separate NPH and MCKD forced many authors to the conclusion that the disorder known in Europe as NPH and the disorder known in the United States as MCKD were the same disease.  This approach was later refuted on the basis of the identification of large MCKD families with vertical transmission.  This suggested that, from a genetic point of view, NPH and MCKD were not likely to be the same disease entity, since they had different modes of inheritance. Moreover, ESRD was usually reached later in most dominant forms than in the recessive forms. Thus, in spite of the similar phenotype, a return to the recognition of MCKD and NPH as distinct clinical entities was suggested and it was proposed to use the term MCKD for the disease occurring in adults with a dominant inheritance and the term NPH for the juvenile recessive forms. ,,,
In the last decade, molecular genetics has revolutionized the nosologic classification of the NPH-MCKD complex. The distinctness of the recessive juvenile NPH and the dominant MCKD has been definitely indicated by the fact that the disorders map to different chromosomal loci. In the early1990s the first gene locus for NPH to human chromosome 2q12-q13 was mapped.  In the subsequent years, three other loci for different forms of NPH have been mapped in different chromosomal areas and two loci for dominant medullary cystic kidney disease, MCKD1 and MCKD2, were localized to chromosome 1q21 and 16p12, respectively. ,
In this review we will discuss the main clinico-pathologic features and the recent molecular genetic advances of the NPHMCKD complex.
| The First Variant of the Complex: Recessive NPH|| |
Nephronophthisis (NPHP) is an autosomal recessive disease that is the most frequent genetic cause of uremia in children.  It invariably progresses to end-stage renal failure in the second decade of life, at which time almost 100% of affected patients require a substitutive program, based on dialysis or renal transplant. Among 438 children who received renal allografts in three Italian centers afferent to the North Italy Transplant Program (NITP) between early 1980 and 1998, about 20% were affected by NPH (Ghiggeri, personal communication). Data on the prevalence and incidence of NPH in Europe are now available. Three recent large studies from Germany, ,[ Italy  and Finland  collectively identified 300 patients with clinical features of NPHP, 60-70% of whom shared the molecular diagnosis of NPHP1. There is now evidence of extensive genetic and clinical heterogeneity, with at least three disease loci already identified and a minor proportion of patients with a still unidentified gene locus.
| Clinical Features and Variants|| |
The clinical picture of NPHP is related to the structural defect of the renal tubule segment which is involved, leading to alterations of urine concentrating capability and of sodium conservation. In the early phase the disease is pauci-symptomatic, major signs being confined to polyuria and polydipsia which are usually recognized "a posteriori" when renal failure has developed and the clinical diagnosis of NPH appears clear. Border defects can be determined with the DDAVP test, which fails to increase urine osmolarity, even in conditions of water deprivation. Urinary abnormalities such as hematuria and proteinuria are minor, if present, and evidence for proximal tubule defects such as aminoaciduria, hyperphosphaturia, hypercalciuria, tubular acidosis, is absent. Anemia and growth retardation are frequently anonymous initial symptoms and become serious when ESRD develops. At the preazotemic stage, the kidneys maintain a normal or slightly reduced size and on renal ultrasound, they present increased medullary echogenicity with diminished corticomedullary differentiation. Renal cysts, solitary or multiple, may be present.
The age of onset of ESRD is variable and partially dependent on the extensive genetic heterogeneity, but in most cases uremia develops within the first two decades of life. There is juvenile, infantile and adolescent forms of NPHP which are referred to as NPHP1-NPHP4, NPHP2 and NPHP3 respectively, for which different molecular features have been described (see Molecular Genetics of NPHP). ,,,,, The most remarkable clinical difference is between the infantile form (NPHP2), which is characterized by a very early onset of ESRD (1-3 years) and diffuse parenchymal cysts, and the other 3 forms (NPHP1, NPHP3 and NPHP4) which present later onset of ESRD (10-13 and 19 years, respectively) and only occasional cysts. Considering the infantile NPHP2  and autonomous forms, mostly resembling polycystic kidney disease (PKD) and limited to a geographic area of the desert inhabited by Bedouins, the differentiation of the other two forms (NPHP1 and NPHP3) with respect to the age of onset of early symptoms and of ESRD appears more artificial than clinically important. Omran et al  described a late occurrence of ESRD in patients affected by NPHP3 in a large (340 member) consanguineous Venezuelan kindred.
NPHP1 is among the different forms of NPHP the most frequent. It usually appears without significant extrarenal organ association with the exception of a particular type of retinitis pigmentosa which occurs late in the natural history of the disease and is actually mild in intensity. 23 This has been defined as late onset Senior-Loken syndrome. NPHP1 can also occur in combination with ocular motor apraxia (Cogan type). 
The most definite and important extrarenal associations in NPHPX are early retinitis pigmentosa  (also known as early onset Senior-Loken syndrome) and liver fibrosis.  Finally, other associations in NPHPX are with coloboma of the optic nerve, and cerebellar vermis aplasia in Juobert syndrome,  with pulmonary ciliary dyskinesia.  The different characteristics of NPHP1 and of the variants including the extrarenal localization are reported in [Table - 1].
| Pathology|| |
Microscopic alterations in NPH are restricted to the tubule and the interstitium, where changes are due to chronic tubulointerstitial inflammation with diffuse macrophage infiltration and, at later stages, fibrosis. Tubular epithelia are sometimes atrophic with basement membrane duplication and thickening on electron microscopy.  They may also appear dilated and look like true cysts endowed at the corticomedullary junction. Glomeruli are typically normal in early stages, and immuno-deposits are absent. When diffuse interstitial and peri-glomerular fibrosis develop, glomeruli may appear sclerotic at least confined to most prominent peri-glomerular lesions. The pathological picture, with the exception of TBM alteration, is not specific for NPHP and is indistinguishable from MCKD.
| Molecular Genetics of NPH1|| |
By gnome-wide search, in 1993 Antignac et al  and Hildebrandt et al  identified a gene locus for NPHP1 to human chromosome 2q , . Within this region, the presence of a large homozygous deletion of 250 kb was demonstrated in a good proportion of cases ranging from 60 to 70%.  The gene responsible for NPHP1 was identified in 1997 by Hildebrandt et al  who detected loss of function point mutations on a gene that spans 83 kb and consists of 20 exons. The NPH1 gene, also called nephrocystin (NPHP1), is flanked by two large (330-kb) inverted duplications with a 45 kb sequence where the deletion breakpoints have been localized. 
Besides the homozygous deletion involving the region of NPHP1, which occurs in most NPHP1 patients, heterozygous deletion associated to point mutation of nephrocystin can also be occasionally detected; homozygous point mutation at NPHP1 has never been reported. Most point mutations had been described by Hildebrandt or by members of the Freiburg Laboratory in exons 2, 14 and 18.  Saunier et al  have described mutations in exons 9 and 10; finally Caridi et al  described point mutations in exons 15 and 17.
The product of the NPHP1 gene is nephrocystin.  Experimental studies on this protein have been done utilizing the full-length cDNA and tissue expression was observed with Northen Blotting primarily involving pituitary gland, spinal cord, thyroid, testis, skeletal muscle, trachea and kidney. The broad tissue distribution of nephrocystin contrasts to kidney specific alterations of NPHP1 and extensive studies, involving animal models, are necessary to define this point.
Nephrocystin is a novel protein, unrelated to so far known protein families; it contains domains of protein-protein interactions which are conserved in evolution starting from Caenorhabditis elegans by maintaining an amino acid sequence similarity of 45%. The protein contains three putative coiled-coil domains and a Src homology 3 (SH3) domain which is similar in sequence to human protooncogene Crk. In parallel, two negative charged domains containing glutamic residues flank the SH3 domain and represent the site of interaction with other proteins which present proline-rich consensus sequences.
The functional hypothesis on nephrocystin is based on the fact that SH3 domains are very frequent in nature, especially in protein, which act as adapters in cell to matrix contact and function in the network of the focal adhesion signalling. Future studies will focus on the interaction of nephrocystin with other proteins through the coiled-coil sites and other additional binding sequences. This could allow elucidation of the mechanisms leading to fibrosis.
| Other Loci and Genes for NPH|| |
As illustrated in [Table - 1], besides NPHP1 which roughly represents the 60-70% of all cases with a clinical and pathological diagnosis of NPHP, three minor variants with different molecular characteristics have been described. Moreover, a further molecular entity defined as NPHPX for which a molecular localization is not available, account for 15% of total NPH.
The minor variants are infantile (NPHP2) and adolescents (NPHP3) nephronophthisis, whose definite clinical features have been described in a previous section, and NPHP4 that has a juvenile onset and may be associated with retinitis pigmentosa (SLS4). Gene loci for NPHP2 and NPHP3 have been mapped to chromosome 9q22-31 and 3q21222 respectively. The gene responsible for NPHP4-SLS4 has been recently cloned by two independent groups. , It encodes a novel protein of unknown functions, nephroretinin that interact with nephrocystin  and probably participates to a common signalling pathway.
| The Second Variant of the Complex: Dominant MCKD|| |
The designation MCKD denotes the second and less common dominant variant of the NPH-MCKD complex. The distinguishing features of MCKD are dominant mode of inheritance, onset for end-stage renal disease in adulthood, and extrarenal organ involvement characterized by hyperuricemia and gout. ,, The term medullary cysts of the kidney was first used by Smith and Graham, who reported an 8-year-old girl with anemia, hyposthenuria, uremia, and medullary cysts.  Since then, other patients with a similar clinical picture and medullary cysts were described. The renal disease was rarely familial and occurred more frequently in adult than in children.  In spite of the similarity in phenotype with NPH, in the early 1970s it was proposed to use the term MCKD for the disease occurring in adults with a dominant inheritance.  The prevalence of the disease is unknown. MCKD has been considered rare, based on the reports of isolated kindreds in different countries worldwide, mainly in Europe and North America.
The pathogenesis of MCKD is still obscure. The renal lesions are functionally and morphologically characterized by a tubular defect with interstitial inflammation and fibrosis. How the underlying genetic abnormality leads to renal disease is unknown. Further advances in molecular genetics of MCKD, through identification of the disease genes, might enable us to better understanding the pathogenesis of the disease.
| Clinical and Pathological Features|| |
The symptoms of MCKD develop insidiously, and diagnosis in the pre-azotemic stage is uncommon. MCKD presents late in life, with an average age of onset of 28 years. ESRD typically occurs in the thirdfifth decade of life or later. MCKD may also present in young adults or children, suggesting that the age at onset cannot be of diagnostic value. The first sign is reduced urinary concentrating ability, which is the only renal dysfunction found during early investigations, and may precede the decline in glomerular filtration rate. Proteinuria is mild or absent; and few formed elements can be seen in the urine sediment. Clinical symptoms appear when the urinary concentrating ability is markedly reduced, producing polyuria. No abnormality of proximal tubular dysfunction is detected. Later in the course, the clinical findings are related to the progressive renal insufficiency, such as anemia and uremic symptoms (nausea, anorexia, weakness). Many patients are hypertensive at later stages; however, hypertension may be absent in patients who present a salt losing syndrome.
The prominent macroscopic feature is the presence of cysts of variable sizes, located at the corticomedullary border and/or in the medulla. Light microscopy shows diffuse tubulo-interstitial nephritis, with focal areas of tubular atrophy, interstitial fibrosis, and inflammatory cell infiltration. Groups of atrophic tubules usually alternate with viable hypertrophic, dilated tubules. Atrophic tubules are usually surrounded by fibrotic interstitial tissue, accompanied by a sparse inflammatory infiltrate. The glomeruli are often normal, some being sclerotic and others showing peri-glomerular fibrosis. Immunofluorescence study using standard antibodies is negative. The tubulo-interstitial changes are the hallmark of the disease; however, they cannot be considered pathognomonic for MCKD. In particular, MCKD is histologically indistinguishable from NPH. ,, The natural history of MCKD is characterized by a slow progression of chronic renal failure leading to ESRD. There is no specific therapy for MCKD other than correction of water and electrolyte imbalance that may occur. Dialysis followed by renal transplantation is the preferred approach for ESRD. The tubular injury does not recur in kidney graft. 
The most important extrarenal involvement is represented by hyperuricemia and/or gout, which have been reported in a minority of MCKD families. ,,, The significance of this association is not yet established, and it is not clear whether this association identifies a single nosological entity. It is of note that strong phenotypic similarities can be observed between MCKD with hyperuricemia and gout and familial juvenile hyperuricemic nephropathy (FJHN). FJHN is a dominant progressive tubulo-interstitial renal disease in which the biochemical hallmark is hyperuricemia resulting from a grossly reduced fractional uric acid clearance. Traditionally, the main differences between MCKD with hyperuricemia and gout and FJHN are the presence of medullary cysts in MCKD patients and the juvenile onset of renal failure in FJHN. However, cases of MCKD without medullary cysts, reduced fractional uric acid clearance, and early onset of renal failure have been described. On the other hands, medullary cysts have been recently reported in patients with FJHN. , Finally, interstitial fibrosis, tubular atrophy, and infiltration of the interstitium by inflammatory cells are characteristic of MCKD and also seen in FJHN.
Thus, it can be suggested that, in the past, the same disease was termed FJHN when the first manifestation was early gout and it was classified as MCKD with hyperuricemia and gout when macroscopic cysts, primarily located at cortico-medullary boundary, were detected.
| Diagnosis|| |
The renal presentation of MCKD is relatively non-specific. Urinalysis is not helpful, generally revealing few cells or casts. The diagnosis is made by inference from the family history, polyuria due to decreased concentrating ability, the relatively normal urinalysis and the presence of hyperechogenic kidneys of slightly reduced or normal size on renal ultrasonography. Multiple small and occasionally larger cysts at the corticomedullary junction may be found. Although computed tomography imaging is the most sensitive technique, to detect cysts as small as 5 mm in diameter, ultrasound is reliable and noninvasive. Traditionally, finding medullary cysts has been regarded as the hallmark of the condition. However, the high frequency of macroscopic cysts in older reports may be considered the consequence of the original definition of the disorder. A careful review of the literature shows that medullary cysts have not been found in all patients for whom this diagnosis was made. ,, Moreover, medullary cysts develop mainly during the later phases of the disease, suggesting that medullary cysts bear no major diagnostic importance and are not required for diagnosis of MCKD. The diagnosis can be confirmed histologically, with the most important criteria being the tubulo-interstitial changes. However, MCKD can not be diagnosed exclusively on a specific histological picture. Clinical and familial history must be taken in consideration. In conclusion, the presence of a positive family history consistent with MCKD, the classical findings of long-standing polyuria and renal insufficiency in an adult patient aged from 30 to 50 years old make the diagnosis of MCKD likely.
| Differential diagnosis|| |
The differential diagnosis of MCKD should include a variety of diseases causing chronic tubulo-interstitial disease, including chronic pyelonephritis and polycystic kidney disease. These diseases should be excluded on the basis of intravenous urography, D-mercaptosuccinic acid (DMSA) scintigraphy or renal ultrasonography findings, showing focal parenchymal scarring and multiple bilateral cysts with enlarged kidneys, respectively. Furthermore, MCKD must be distinguished from medullary sponge kidney (MSK), a disease presenting a sponge-like appearance of the kidney due to the multiple small cysts in its structure. MSK is a renal development abnormality with ectasia and cystic formation in the medullary collecting ducts, affecting one or more renal pyramids in one or both kidneys. On pathologic sections, multiple cysts representing dilated terminal collecting tubules are seen, measuring from 1-7 mm. The cysts usually communicate proximally with collecting tubules and distally with papillary ducts or calyx. 
MSK may be associated with a variety of congenital abnormalities, including congenital hemihypertrophy and the Beckwith-Wiedemann syndrome, sometimes clinically subtle.  Although MSK is generally felt to be sporadic, few hereditary cases have been reported in several generations of families. MSK may be an incidental finding on ultrasound or intravenous urography performed for other indications, particularly early in its course. Later, patients often present with symptoms related to the passage of renal calculi, including flank pain and hematuria. In addition to the urinary stasis in the ectatic collecting ducts caused by an underlying anatomic abnormality, low levels of urinary inhibitors are believed to have an important role in stone formation in patients with MSK.  Renal function is usually normal, except in very advanced cases. However, renal insufficiency is rarely due to progression of disease per se, and it is usually the consequence of obstructive uropathy secondary to renal stones. The principle method for diagnosis of MSK is excretory urography, which demonstrates the presence of medullary nephrocalcinosis (with a typical pattern of linear and rounded medullary calcifications) and linear and cystic areas in the medullary pyramids where calcifications are not present. These findings enable a specific diagnosis of MSK as opposed to other causes of medullary nephrocalcinosis such as renal tubular acidosis and hyperparathyroidism. Ultrasonographic and CT findings are more sensitive in showing medullary calcifications, but they are less specific than urography findings. CT can be helpful in confirming the presence of nephrocalcinosis, when it is suggested on ultrasonographic images, and CT scans can demonstrate tubular ectasia.
| Molecular Genetics|| |
In 1998, a Cypriot group  localized the first genetic locus for dominant medullary cystic kidney disease, MCKD1, to chromosome 1q21 in two families with MCKD, hyperuricemia, and gout. The two families shared the same disease haplotype, suggesting a founder effect. No obvious candidate genes were proposed. At the same time, the Italian MCKD Consortium described 5 MCKD families with 28 affected members. In one family, MCKD was associated with hyperuricemia and gout. The NPHP1 locus was excluded from linkage to dominant MCKD, suggesting the existence of a MCKD responsible locus. 3 In 1999, the Italian Consortium reported the genome-wide linkage mapping of a new locus for medullary cystic kidney disease, MCKD2, on chromosome 16p12 in a four-generation Italian family of MCKD with hyperuricemia and gout.  Thus, despite the clinical homogeneity with the Cypriot families, the molecular data were consistent with genetic heterogeneity. The 10.5-cM MCKD2 critical region resulted to be dense with transcripts. The considerable size of the genomic area made a positional cloning approach very difficult. Nonetheless, the localization of uromodulin (Tamm-Horsfall protein) gene to the MCKD2 critical region was intriguing, since uromodulin is a specialized protein having unique renal localization.
Independent confirmations of the locations of MCKD1 and MCKD2 in other families have been reported. In 2001, Auranen et al reported six Finnish MCKD families.  Five families showed linkage to chromosome 1q21. These five families did not present hyperuricemia and gout, suggesting that the absence of these symptoms does not exclude genetic linkage to the MCKD1 locus. One family, presenting hyperuricemia, was not linked to either the MCKD1 or MCKD2 gene loci, suggesting the existence of at least a third locus. Confirmation of MCKD2 locus was reported by Hateboer et al in 2001 in a large Welsh family  The family did not have hyperuricemia and gout, indicating that hyperuricemia and gout are not obligatory features of MCKD2 mutations.
Recently, the gene for FJHN was mapped to 16p12 in a region overlapping with the MCKD2 locus ,, These molecular results, and the remarkable phenotypic similarities of MCKD2 and FJHN raised the question as to whether MCKD2 and FJHN are allelic variants of the same disease entity. More recently, the ultimate proof of the allelism between MCKD2 and FJHN has been provided by the identification of the responsible gene. In 2002, Hart et al. identified four novel uromodulin (UMOD) gene mutations segregating with the disease phenotype in three families with FJHN and one with family with MCKD2, providing the first direct evidence that MCKD2 and FJHN arise from mutation of the UMOD gene and are allelic disorders.  The future identification of the function of the uromodulin gene product will help to clarify the pathogenesis of these hereditary tubulo-interstitial nephritidis and it will also contribute to a deeper understanding of the mechanism of urate hypoexcretion and perhaps of cystic disease formation. Finally, the absence of specific clinico-morphological features may result in an under ascertainment of cases of hereditary tubulointerstitial nephritis, particularly in individuals without a family history. Recognition of distinct mutations in the identified gene may allow a more accurate estimate of the incidence of these conditions and an early diagnosis in such patients.
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Divisione di Nefrologia, Spedali Civili, Ple Spedali Civili, 1, 25125 Brescia
[Table - 1]