Improving the Recognition of Hereditary Interstitial Kidney Disease
Anthony J. Bleyer
Section on Nephrology, Wake Forest University School of Medicine, Winston Salem, North Carolina
Correspondence: Dr. Anthony J. Bleyer, Section on Nephrology, Wake Forest University School of Medicine, Medical Center Boulevard Winston Salem, NC 27157. Phone: 336-716-4513; Fax: 336-716-4318; E-mail: ableyer{at}wfubmc.edu
Autosomal dominant tubulointerstitial kidney disease is characterizedby the poorly recognized inheritance of slowly progressive renalfailure leading to ESRD in later life. Patients with this conditionhave bland urinary sediment, and renal ultrasound typicallyreveals normal to small kidneys, with occasional individualshaving small medullary cysts. Diagnosis relies on the clinicalacumen of the nephrologist. Obtaining a thorough family historyand records of affected family members is especially helpful.Kidney biopsy is frequently unhelpful, whereas genetic linkagestudies or mutations in the UMOD gene may identify the problem.
Autosomal dominant tubulointerstitial kidney diseases are frequentlymisunderstood. Little is taught about these conditions duringnephrology fellowship, and what is taught is often incorrect.1Characteristic findings of slowly progressive kidney failure,bland urinalyses, and unremarkable renal ultrasounds make thecorrect diagnosis elusive. As in polycystic kidney disease,there is a high frequency of ESRD, with morbidity and earlymortality in affected parents, siblings, and children. Familiesare rarely given a specific diagnosis2 and rather are told theyhave "some type of familial kidney disease"—informationwith which they are already too familiar. This commentary providesa clinical assessment for the proper diagnosis and evaluationof this condition.
A number of hereditary interstitial kidney diseases are includedin the grouping of nephronophthisis or medullary cystic kidneydisease (MCKD). Advances in molecular genetics have better delineatedthese syndromes, but many nephrologists are unaware of theserecent developments. Nephronophthisis refers to a group of autosomalrecessive disorders associated with renal failure, salt wasting,anemia, urinary concentrating defects, and occasional medullarycysts on ultrasound. These disorders have been extensively studiedby Hildebrandt et al.,3 and many result from mutations in genesencoding proteins that are components of the tubular cell cilia.
In contrast to these autosomal recessive diseases, there isanother group of autosomal dominant interstitial kidney diseases.There are two well-recognized types that have been given a numberof different names,4 causing considerable confusion in the literature(see Table 1). The first type is called autosomal dominant interstitialnephropathy,5 or MCKD 1,2,6,7 with linkage to chromosome 1.The second type is due to mutations in the UMOD gene that encodesuromodulin (also known as Tamm-Horsfall protein)8 and has beencalled uromodulin-associated kidney disease, MCKD 2, or familialjuvenile hyperuricemic nephropathy in some families. There areother forms of autosomal dominant interstitial kidney diseasewith similar clinical manifestations that are either linkedto another area of chromosome 1 or not linked to one of theseareas.9,10
MCKD 1 demonstrates linkage to chromosome 1q21 in a number ofreports,5–7,11 but only a few studies provide detailsof the clinical picture. The predominant and perhaps only clinicalcharacteristic is insidious progression to kidney failure, withmost other clinical manifestations being secondary to renalfailure per se.2,6 Age at onset of clinical renal failure isvariable within and between families. Renal insufficiency mayfirst be noted in the teenage years, although some affectedindividuals have relatively well-preserved renal function intothe fourth decade of life. The rate of progression to renalfailure is poorly documented, because many family members areinitially identified late in the course of their disease. Inthe best characterized families, the average age of onset ofESRD is approximately 50 yr, ranging from 36 to 80 yr.2,6 Hypertensionoccurs but is likely related to underlying renal failure. Hypertensionwas particularly severe in one family whose disease was linkedto 1q21.12 In a large cohort from Greece,6 hypertension wasfound in approximately 50% of individuals linked to the affectedgenomic region but in only 12% of linked individuals who hadnormal renal function. Polyuria and anemia, which may be presentin autosomal recessive nephronophthisis, are usually not clinicallyevident in early MCKD 1. Gout also occurs but typically in thesetting of advanced renal failure. Urinalyses are usually blandwith urinary protein excretion <1 g/d in most patients. Renalcysts are observed in fewer than half of affected individuals,and medullary cysts are uncommon; in some families, they arenot found. In this large Greek cohort,6 renal cysts were presentin 40% of patients, with unilateral solitary cysts in 12.3%,bilateral single cysts in 5.3%, and tiny bilateral medullarycysts in 5.3%. The presence of renal cysts is nonessential tothe diagnosis. The findings on kidney biopsy are often unimpressive.Focal global sclerosis of glomeruli (likely secondary to thetubulointerstitial disease process) is often present, and tubularatrophy and interstitial fibrosis are most common.2 Some investigators6noted tubular basement membrane thickening with "splitting andlamellation"; however, definitive and specific pathologic changesare not present in this disease, and the diagnosis is usuallynot made by a pathologist.2
The approach to diagnosis may be troublesome for the nephrologist.In many cases, a young to middle-aged patient presents withrenal insufficiency and a strong family history of kidney disease.A normal urinalysis and unremarkable renal ultrasound excludepolycystic kidney disease, leaving the diagnosis uncertain.Renal biopsy, when performed, typically reveals only chronicinterstitial kidney disease, and a specific diagnosis is notmade. One is then inclined to search the medical literature—butfor what? A Medline search for hereditary interstitial kidneydisease reveals few relevant articles. Articles on MCKD 1 areincorrectly overlooked, because patients are unlikely to havemedullary cysts detected on either their renal ultrasound orbiopsy material; therefore, it is difficult to determine thecorrect diagnosis without some previous knowledge of the condition.
Appropriate diagnosis of MCKD 1 relies primarily on clinicalacumen (see Figure 1). The key to diagnosis is obtaining a proper,extended family history. When this is performed, it will becomeclear that a large number of family members have had this condition.The clinical history and biopsy reports of other family membersshould be obtained, because these will reveal similar featuresas that of the presenting patient. Screening to rule out mutationsin the UMOD gene should be performed (see MCKD 2). If mutationalanalysis is negative, then one should consider referring thefamily to an interested research group for genetic linkage studies.
Figure 1. Schema for evaluation of families with hereditary renal tubulointerstitial disease.
The nonspecific features of the disease and the inability tofind the causative gene have hampered research into the causeof MCKD 1. Wolf et al.7 reported linkage of MCKD 1 to a 1.19-Mbregion on chromosome 1q21; however, mutational analysis of 37genes under the linkage peak did not reveal any causative mutations.The inability to identify the genetic cause of this diseaseis attributable, in part, to the lack of coexisting systemicfeatures and late age at onset of symptomatic illness. It maybe difficult to identify clearly the affection in the youngmembers of multiplex families. The rarity of the disease anddifficulty in diagnosis have led to relatively few familiesbeing referred for genetic linkage analysis. Despite these difficulties,linkage has been detected, and it is hoped that identificationof additional families will help to identify the causative gene(s).Clinical characterization will remain difficult until the geneticcauses are identified. Genetic diagnosis will then allow usto study the disease at earlier stages.
MCKD 2 is similar to MCKD 1, with the exception that familymembers often experience repeated attacks of gout. The associatedprecocious gout makes for an easier diagnosis, because it occursin approximately 50% of affected family members, often beginningin the teenage years. Patients frequently present after theirfirst gouty attack, because the family realizes gout is a harbingerof progressive renal failure. Individuals who do not have goutmay be evaluated for this disease because of their family historyor as part of routine evaluations. Kidney failure is slowlyprogressive, usually beginning in the teenage years and leadingto ESRD in the fourth through sixth decades. As in MCKD 1, theurinalysis is bland, renal ultrasound may reveal small kidneys,and medullary cysts occur infrequently. The cause of MCKD 2is a mutation in the UMOD gene, encoding uromodulin or Tamm-Horsfallprotein. Commercial testing is available to make the diagnosis,13and is preferable to a kidney biopsy. Several recent reviewshave detailed the characteristics of this condition.14
At present, no specific treatments are available for MCKD 1given that it is often diagnosed late. Potential therapies forMCKD 2 include allopurinol or angiotensin-converting enzymeinhibition, although the effectiveness of these treatments isunclear.
The epidemiology and clinical characteristics of MCKD 1 andMCKD 2 will be better understood with better genetic testing.Their true prevalence is difficult to determine because theseconditions are infrequently recognized by clinicians. We haveformed a registry for affected individuals and families (ableyer@wfubmc.edu),in an attempt to better understand the factors associated withdisease progression and to test novel therapies.
When faced with a family who has an extensive history of chronickidney disease with inactive urinary sediment and unremarkablerenal ultrasounds, one should consider the causes of hereditarytubulointerstitial nephritis in the differential diagnosis andaggressively pursue the correct diagnosis. These endeavors mayultimately help the many families whose conditions have longbeen overlooked or ignored.
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Abstract
Introduction
