Hereditary Renal-Retinal Dysplasia and the Medullary Cystic Disease-Nephronophthisis Complex

Transcription

1 Hereditary Renal-Retinal Dysplasia and the Medullary Cystic Disease-Nephronophthisis Complex PRATAP S. AVASTHI, M.D., DALE G. ERICKSON, M.D., and KENNETH D. GARDNER, M.D., F.A.C.P., Albuquerque, New Mexico Nine of 81 members of two families were found to have renal problems. Three patients in one family had renal-retinal dysplasia with probable recessive inheritance. Of the 6 patients in the second family, one received a kidney transplant from his brother who initially had no detectable renal abnormality but later developed renal failure. In this family, the mode of inheritance seems to be dominant. Hereditary renal-retinal dysplasia differs from medullary cystic disease and nephronophthisis in its pattern of uniformly recessive inheritance and its accompaniment by retinitis pigmentosa. Because genetic considerations have important implications in selection of donors for renal transplant, these entities should be considered distinct despite the similarities in their clinical and pathologic features. HEREDITARY RENAL DISEASE ranks third among the various renal diseases that lead to the development of irreversible renal failure (1). Of the inherited nephropathies, polycystic kidney disease is by far the most common. Medullary cystic disease and nephronophthisis are less common forms of renal cystic diseases (2, 3), and in children and adolescents they represent an important cause of chronic renal failure (4). There are a number of reports of families in whom renal disease similar to that found in the medullary cystic disease-nephronophthisis complex is accompanied by retinal degenerative changes (5-8). The name "hereditary renal-retinal dysplasia" has been given to this clinical variant. We studied two families afflicted with renal disease. Hereditary renal-retinal dysplasia was diagnosed in one family and adult-onset medullary cystic disease in the other. We compared various features of these two conditions and believe that there are practical advantages of regarding them as separate variants. Subjects and Methods Eighty-one persons from two families were evaluated by history, physical examination, urine analysis, creatinine clearance, quantitative 24-hour protein excretion, and urinary concentrating ability after a 14-hour dehydration period. In Family 1, 30 members were alive. They were evaluated From the Renal Section, Veterans Administration Hospital; and the University of New Mexico School of Medicine; Albuquerque, New Mexico. as outlined above. Funduscopic examination for retinitis pigmentosa was included in their evaluation. Audiometric examination was done on 17 family members. Two affected siblings had chromosomal analysis. All 3 affected family members had needle biopsy of the kidney. Renal tissue was evaluated by routine light microscopy in 3 and, in addition, by immunofluorescent and electron microscopy in 2. Out of 73 living members in Family 2, 51 were evaluated by history, physical examination, and the indicated renal investigations. Nephrectomy had been done in 2, and their renal tissues were evaluated by light, immunofluorescent, and electron microscopy. Results CLINICAL CHARACTERISTICS OF FAMILY 1 The pedigree of Family 1 is shown in Figure \A. Three of the 30 family members had chronic renal disease. The propositus (111-10) became symptomatic at age 17. A brother and a sister (III-8, III-9) developed symptoms at ages 25 and 23, respectively. All 3 became symptomatic because of anemia and uremia, and all had retinitis pigmentosa. Significant negative features included absence of family history of consanguinity, absence of polyuria and polydypsia, lack of significant proteinuria, and lack of hypertension on initial presentation, except in 1. Chromosomal studies of the 2 affected siblings were normal. The propositus has had two cadaveric renal transplantations; renal biopsy from the propositus is shown in Figure IB. The 2 siblings are on chronic hemodialysis. All 3 now are in stable states of health. The remaining 27 family members had no renal or retinal abnormality. From the genetic viewpoint it is significant that the mother (II-l) of these three siblings has had six children from another marriage. None had evidence of retinitis pigmentosa or renal disease. The father of the afflicted members was investigated and was found to have no renal abnormality. Two years later he developed acute glomerulonephritis, possibly poststreptococcal. An open renal biopsy was done, which showed features of immune-complex mediated glomerulonephritis. No cysts were seen. The absence of a similar renal or retinal anomaly in the father and the absence of renal or retinal abnormalities in the mother and her six children by another marriage suggest that the mode of inheritance in this family was recessive. RENTAL HISTOLOGY OF FAMILY 1 Biopsy specimens were available from the three affected Annals of Internal Medicine 84: ,

2 Figure 1A. The pedigree of Family 1. The absence of any renal or retinal abnormality in the six children from another marriage is noteworthy. B. Renal biopsy from the propositus. Moderate diffuse interstitial fibrosis with prominent collections of lymphocytes is apparent. Tubules are atrophic and collapsed but not ectatic. Periglomerular fibrosis is seen. (Hematoxylin and eosin; original magnification, x 140.) C. Electron micrograph of the renal tissue from the propositus showing scalloped, irregular, and greatly thickened tubular basement membranes (*). (Magnification, x 9600.) siblings. No gross cysts were seen. The morphologic features of these specimens were identical. At light microscopy a majority of glomeruli were completely sclerosed, but some showed periglomerular fibrosis, and mononuclear infiltration of the interstitium was striking. Dilatation of tubules was apparent, but no cysts were seen. Morphologically, the changes were indistinguishable from those of chronic interstitial nephritis. Immunofluorescent studies showed no immunoglobulins, complement, or fibrinogen in either specimen. Ultrastructural studies were done on two biopsy specimens. Glomerular basement membranes were normal in thickness, and no deposits were seen. Epithelial cells, their foot processes, and endothelial cells were relatively normal. However, tubular basement membranes were markedly thickened and distorted (Figure 1C). Renal tissue obtained from the father showed changes characteristic of immune-complex-induced glomerulonephritis by light, immunofluorescent, and electron microscopy, a distinctly different lesion. CLINICAL CHARACTERISTICS OF FAMILY 2 The pedigree of family 2 is shown in Figure 2. Six of the 51 members investigated had definite renal disease, but no retinal abnormalities were found. The propositus (111-13) developed polyuria, polydypsia, and malaise at age 26. Two years later he was started on chronic hemodialysis for uremia. Nine months later he underwent pretransplant bilateral nephrectomy at another institution. Both kidneys were found to have cysts at corticomedullary junction (Figure 3B). The significance of Figure 2. The pedigree of Family 2. Note that only women are afflicted in one generation and men in the other. 158 February 1976 Annals of Internal Medicine Volume 84 Number 2

3 Figure 3A. Microscopic section of a kidney removed at the time of renal transplantation showing a large cyst, extensive interstitial fibrosis with cellular infiltration, and periglomerular fibrosis. (Hematoxylin and eosin; original magnification, x 100.) B. Low-power photomicrograph of the kidney of the propositus (111-13). C. Gross anatomy of a kidney removed from 11-9 at the time of renal transplantation. Large multiple cysts are indicated by arrows. this finding was overlooked, and a diagnosis of chronic pyelonephritis was made on the basis of the remaining microscopic findings (Figure 2>A). He received an uneventful renal transplant from his brother (111-14). Three years later gradual loss of function of the transplanted kidney necessitated a second renal transplant, this time from a cadaver. The second transplanted kidney is functioning well. His 28-year-old brother (111-14), who had normal renal function at the time of kidney donation, remained asymptomatic for 4 years and then developed polyuria and polydypsia. His daily urine output now is in the range of 1700 to 2000 ml, with 380 mg of proteinuria/day. His serum creatinine level is 2.2 mg/dl, and his creatinine clearance is 47 ml/min. He is unable to raise his urine osmolality to a level greater than 683 mosmol/kg H L,0 after 14 hours of dehydration. His kidney, which had been transplanted into his brother and had been rejected, was subjected to needle biopsy. Changes consistent with rejection were found. No cysts were seen. Another brother (111-15) of the propositus is 30-years old and shows renal abnormalities similar to those found in other siblings. Serum creatinine level is 1.6 mg/dl, and his creatinine clearance is 52 ml/min. His concentrating ability after 14 hours of dehydration is less than 560 mosmol/kg H 2 0 on several occasions. At age 47, the mother (II-6) of the propositus was found to have polyuria, with daily urine volumes being in excess of 4 litres; azotemia, with serum creatinine level 3.0 to 3.6 mg/dl; and poor visualization of both kidneys on intravenous pyelography. She was operated on for carcinoma of the stomach and died a year later. Postmortem examination was not permitted. A maternal aunt (II-7) of the propositus underwent a subtotal gastric resecton for a massively bleeding duodenal ulcer at age 45. Her kidneys were reported to be very small by the operating surgeon, and preoperatively her serum creatinine level was 12 mg/dl. She died in the postoperative period. Permission for postmortem examination was not granted. Another maternal aunt (II-9) developed polydypsia and polyuria at age 46 and became uremic 2 years later. An open biopsy was done and was interpreted as showing chronic pyelonephritis. No cysts were seen. She was transferred to Bernalillo County Medical Center, Albuquerque, New Mexico, for dialysis and transplant. Pretransplant nephrectomy showed multiple cysts at the renal corticomedullary junction (Figure 3C). A cadaveric transplant was done for end-stage renal disease, and she has progressed well. The affected persons in this family became symptomatic with polyuria and polydypsia in the third and fourth decades of life and gradually progressed to uremia. Morphologically, gross cysts were seen in nephrectomized specimens, and microscopically the features of interstitial nephritis were present. Immunofluorescent studies did not show immunoglobulins. Ultrastructural studies were not distinctive except for tubular basement membrane thickening. From a genetic viewpoint, the vertical transmission suggests a dominant trait of inheritance. No history of consanguineous mating was found in the family. Significant negative features were the absence of red hair and of eye, ear, and skeletal abnormalities (9). Discussion The combination of retinitis pigmentosa and familial renal problems characterized by polyuria, polydypsia, anemia, a relatively normal urinalysis, and slowly progressive renal failure are characteristic features of renalretinal dysplasia (5-8). Patients in Family 1 had most of these features. Although a majority of the reported patients have been of Swiss ancestry, both families reported here are of Spanish-American descent. The ocular component of the familial renal-retinal dysplasia is a pigmentary retinal dysplasia that is characterized by a progressive course leading to blindness (10). The three patients described here have had stable night blindness for 6 to 7 years. This observation suggests that patients with renal-retinal dysplasia need not be denied treatment with dialysis or a renal transplant, or both, be- Avasthi et al. Genetic Renal Disease 159

4 cause of their retinal lesion, which does not necessarily progress to blindness. The renal component of this entity is identical to that of nephronophthisis and adult-onset medullary cystic disease. Clinical similarities include insidious onset, polyuria and polydypsia, relatively normal urine analysis, absence of hypertension, severe anemia, and onset of renal failure in the second decade of life. Except for cysts, the microscopic anatomy of medullary cystic diseases is indistinguishable from that of chronic interstitial nephritis, inasmuch as periglomerular fibrosis, patchy glomerular hyalinization, tubular atrophy and dilatation, and interstitial mononuclear cell infiltrations are found in both. Immunofluorescent studies are not helpful, and the only striking change in electron microscopy is tremendous thickening of tubular basement membranes (11). In addition to the retinal involvement, renal-retinal dysplasia differs from the medullary cystic-nephronophthisis complex in its mode of inheritance, which has always been reported to be recessive (5-8, 11-13). The mode of inheritance in Family 1 also seems to be recessive. Renal-retinal dysplasia is more likely attributable to a pleiotropic gene rather than a coincidental association of two recessive genes because, in the nine reported families, 8 siblings had either kidney or retinal involvement, while 25 had both organs affected (5-8, 11-13). The proportion of persons having single organ involvement would be anticipated to be much higher if two recessive genes were to be coincidentally involved. Inheritance in the medullary cystic disease-nephronophthisis complex has been reported as both dominant and recessive (2-4, 14, 15). The former has been associated with the onset of renal failure after the second decade of life in most reported instances, while with the latter mode of inheritance renal failure typically, but not invariably, has appeared before age 20 (3). This evidence has been used to support the concept that at least two different genotypes are associated with the phenotypic expression of renal disease in the complex (16). In Family 2, dominant inheritance is suggested by the vertical transmission of disease in two generations. Whether the dominant trait is autosomal or sex-linked in this family is not clear, since male-to-male transmission has not appeared to date. Recognition of genetic variants in these conditions is vital if one is to avoid taking a kidney for transplantation from a person who himself may be at risk of developing the disease. Furthermore, once made, a diagnosis should stimulate a search for asymptomatic disease in other family members. The combination of retinitis pigmentosa and renal disease or a family history of renal problems is the alerting signal. However, if the history is not known to the patient or not obtained by the physician, the familial nature of the disease can be easily overlooked. This evidently occurred with the propositus (111-14) from Family 2, who had a kidney transplanted from his brother (111-15) at another institution. Although bilateral pretransplant nephrectomy was done and cysts were observed, the condition was misdiagnosed as chronic pyelonephritis, and the familial nature of the illness was not explored. In many centers pretransplant bilateral nephrectomies are now being carried out for specific indications only, such as intractable hypertension or infection (17). Since the diagnosis of medullary cystic disease often is first suspected when cysts are found in a nephrectomized specimen (3), it can be anticipated that the condition will be missed more often as fewer pretransplant nephrectomies are done. These considerations lead us to suggest that if the transplant recipient's renal morphology is suggestive of chronic interstitial nephritis and a live renal transplant is contemplated, an extensive search should be made to detect renal disease within the family. If present, unilateral nephrectomy of the recipient's kidney should be considered for diagnosis, since cysts frequently are absent from biopsy tissue (3). If cysts are found at nephrectomy, every attempt should be made to use either a cadaveric donor or a blood relative from an unaffected branch or generation of the family. The mode of inheritance in renal-retinal dysplasia can assist in selection of a transplant donor. Renal-retinal dysplasia has, so far, always been found to be recessive in its transmission, which would permit a parent-to-sibling transplant with reasonable safety. The same consideration is applicable to the families with known recessive transmission of the medullary cystic disease-nephronophthisis complex. ACKNOWLEDGMENTS: Grant support: in part by National Institutes of Health Training Grant HE5633. This paper was presented at the Western Section Meeting of the American Federation for Clinical Research, Carmel, California, 7 February Received 21 October 1975; revision accepted 5 November Requests for reprints should be addressed to Pratap S. Avasthi, M.D., Renal Section, Veterans Administration Hospital, 2100 Ridgecrest Drive, S.E., Albuquerque, NM References 1. LOWRIE EG, LAZARUS JM, MOCELIN AF, et al: Survival of patients undergoing chronic hemodialysis and renal transplantation. N Engl J Med 288: , STRAUSS MB, SOMMERS SC: Medullary cystic disease and familial juvenile nephronophthisis. Clinical and pathological identity. N Engl J Med 277: , GARDNER KD JR: Juvenile nephronophthisis and renal medullary cystic disease: an analytical review, in Cystic Diseases of the Kidney, edited by GARDNER KD JR. New York, John Wiley & Sons, Inc., in press 4. BETTS PR, FORREST-HAY J: Juvenile nephronophthisis. Lancet 2: , SENIOR B, FRIEDMAN AT, BRAUDO JL: Juvenile familial nephropathy with tapetoretinal degeneration. A new oculorenal dystrophy. Am J Ophthalmol 52: , MEIER DA, HESS JW: Familial nephropathy with retinitis pigmentosa. A new oculorenal syndrome in adults. Am J Med 39:58-69, SCHIMKE RN: Hereditary renal-retinal dysplasia. Ann Intern Med 70: , MAINZER F, SALDINO RM, OZONOFF MB, et al: Familial nephropathy associated with retinitis pigmentosa, cerebellar ataxia and skeletal abnormalities. Am J Med 49: , Renal cysts and red hair (editorial). Br Med J 1: , DUKE-ELDER S, DOBREE JH: Disease of the retina, in System of Ophthalmology, vol. 10, edited by DUKE-ELDER S. London, Henery Klimpton, 1967, p FAIRLEY KF, LEIGHTON PW, KINCAID-SMITH P: Familial visual defects associated with polycystic kidney and medullary sponge kidney. Br Med J 1: , SENIOR B: Familial renal-retinal dystrophy. Am J Dis Child 125: , HERDMAN RC, GOOD RA, VERNIER RL: Medullary cystic disease in two siblings. Am J Med 43: , February 1976 Annals of Internal Medicine Volume 84 Number 2

5 14. ALEXANDER F, CAMPBELL S: Familial uremic medullary cystic disease. Pediatrics 45: , MANGOS J A, Opirz JM, LOBECK CC, et al: Familial juvenile nephronophthisis. An unrecognized renal disease in the United States. Pediatrics 34: , GARDNER KD JR: Cystic diseases of the kidney: a perspective on medullary cystic disease. Birth Defects 10:29-31, MITCHELL TS, HALASZ NA, GITTES RF: Renal transplantation. Selective preliminary bilateral nephrectomy. J Urol 109: , 1973 Avasthi et al. Genetic Renal Disease 161