Variable presentations of rare genetic renal interstitial diseases.

  • Howard A. Trachtman
  • Published 2014 in Clinical journal of the American Society of Nephrology : CJASN


Inhis bookentitledHowDoctors Think, JeromeGroopman uses case studies to shed light on the thought processes that physicians use when they encounter a patient and attempt to make a diagnosis and formulate a treatment plan (1). One of the points that he emphasizes is how much doctors rely on a variety of cognitive heuristics, or shortcuts, in order to expedite the decision making process. When cognitive heuristics are based on solid reasoning and applied thoughtfully, they can be life saving.However, if they areflawed, the outcomes for patients can be disastrous. One such potential heuristic error is “availability,” or the tendency to judge the likelihood of an event based on the ease with which relevant examples come to mind (1). If this psychologic insight is correct, then it would suggest that if doctors cannot easily think of a clinical category that is germane to a case, theywill not consider the diagnosis. Onemight call this the “inaccessible” heuristic. The report by Anthony Bleyer and his colleagues in this issue of CJASN vividly illustrates the problem encountered by nephrologists who must make the diagnosis of supposedly rare conditions (2). Over a 14-year period, this international team has assembled a sample of approximately 400 families with hereditary interstitial kidneydisease. In 24 families (8with prior evidence of linkage to chromosome-1) who had evidence of an autosomal dominant pattern of inheritance for renal disease and negative testing for the uromodulin (UMOD) and renin (REN) genes that cause medullary cystic kidney disease type-1 (MCKD1) (3), therewas an identifiable disease-causing mutation in the gene encoding mucoprotein-1 (MUC1). MUC1 was recently linked to the development of MCKD1 (4). There were 186 individuals from these 24 families who underwent MUC1 genetic testing, and 95 were found to have a cytosine insertion after a string of seven cytosines in the variable number of tandem repeat-coding sections of MUC1. These patients with genetically confirmed MCKD1 were combined with 111 historically affected patients (i.e., they were related to a genetically affected person in away that ensured that theywere genetically affected and they had CKD stage 4 or worse). Practicing nephrologists will be interested in the fact that clinical findings and routine laboratory testing results from the total sample of 206 patients were unremarkable except for the abnormal serum creatinine level in patients with CKD. There was no hypertension or peripheral edema and there were no striking abnormalities in the urinalysis. The mean BP was 126/76 mmHg and only 21% of patients had any proteinuria. The age at onset of ESRD in the 147 patients who reached this outcome was widely variable within and between pedigrees, ranging from 16 to .80 years. Finally, there were no prominent extrarenal findings. How does one go about assessing the possibility of this new genetic cause of MCKD1 in particular and interstitial disease in general? One could assert that it should be considered in any family in which there are people in successive generations with evidence of impaired kidney function without signs of glomerular involvement. However, in the initial stages of the disease when early detection may be most valuable, the inaccessible heuristic rears its head. If the patients have no obvious clinical clues pointing to the kidney, it is unlikely that the diagnosis of chronic interstitial disease will be entertained and genetic testing will not be pursued. Is there any way to change the dynamic and make MCKD1 an “available” disease that easily comes to mindwhen evaluating patients with interstitial kidney disease? A first step might be to consider a name change. MCKD is a misnomer because the anatomic distinction between the renal cortex and medulla has no clinical traction and medullary cysts are often not present at the time of diagnosis. The term medullary cystic kidney disease evokes images of abnormal cilia and enlarged kidneys, neither of which is involved in the diseases that fall under the type 1 rubric. In the report by Bleyer et al., although nearly half of the 27 patients who had renal imaging done had renal cysts, none of them had characteristic medullary cysts. The adoption of a term like renal interstitial disease might broaden nephrologists’ field of vision and spur identification of new cases and more intensive investigation of genetic causes. If MCKD is considered a rare cause of chronic tubulointerstitial disease (TID), because of the inaccessibility heuristic, nephrologists may be less likely to consider it as a possibility when encountering a patient with a reduced GFR. The disparity between the supposedly low incidence of UMOD, REN, and MUC1 mutations and the epidemic nature of CKD stages 3–5 (5) suggest a mismatch between the two entities. It fosters the view that the genetic entities are clinically Division of Nephrology, Department of Pediatrics, New York University Langone Medical Center, New York, New York


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