Abstract. Alport syndrome (AS) is a type IV collagen hereditary disease characterized by progressive hematuric nephritis, hearing loss, and ocular changes. Mutations in the COL4A5 collagen gene are responsible for the more common X-linked dominant form of the disease characterized by much less severe disease in girls and women. A "European Community Alport Syndrome Concerted Action" (ECASCA) group was established to delineate the Alport syndrome phenotype in each gender and to determine genotype-phenotype correlations in a large number of families. Data concerning 329 families, 250 of them with an X-linked transmission, were collected. Characteristics of heterozygous girls and women belonging to the 195 families with proven COL4A5 mutation are compared with those of hemizygous boys and men. Hematuria was observed in 95% of carriers and consistently absent in the others. Proteinuria, hearing loss, and ocular defects developed in 75%, 28%, and 15%, respectively. The probability of developing end-stage renal disease or deafness before the age of 40 yr was 12% and 10%, respectively, in girls and women versus 90 and 80%, respectively, in boys and men. The risk of progression to end-stage renal disease appears to increase after the age of 60 yr in women. Because of the absence of genotype-phenotype correlation and the large intrafamilial phenotypic heterogeneity, early prognosis of the disease in X-linked Alport syndrome carriers remains moot. Risk factors for developing renal failure have been identified: the occurrence and progressive increase in proteinuria, and the development of a hearing defect.

Alport syndrome (AS) is an hereditary disease of basement membranes characterized by progressive renal failure and deafness. Changes in the glomerular basement membrane (GBM) in AS suggest that the type IV collagen matrix, the major structural component of GBM, is disrupted. We recently isolated the genes for two type IV collagens, alpha 3(IV) and alpha 4(IV), that are encoded head-to-head on human chromosome 2. These chains are abundant in normal GBM but are sometimes absent in AS. We screened for mutations in families in which consanguinity suggested autosomal recessive inheritance. Homozygous mutations were found in alpha 3(IV) in two families and in alpha 4(IV) in two others, demonstrating that these chains are important in the structural integrity of the GBM and that there is an autosomal form of AS in addition to the previously-defined X-linked form.

Childhood renal osteodystrophy (ROD) is the consequence of disturbances of the calcium-regulating hormones vitamin D and parathyroid hormone (PTH) as well as of the somatotroph hormone axis associated with local modulation of bone and growth cartilage function. The resulting growth retardation and the potentially rapid onset of ROD in children are different from ROD in adults. The biochemical changes of ROD as well as its prevention and treatment affect calcium and phosphorus homeostasis and are directly associated with the development of cardiovascular disease in pediatric renal patients. The aims of the clinical and biochemical surveillance of pediatric patients with CRF or on dialysis are prevention of hyperphosphatemia, avoidance of hypercalcemia and keeping the calcium phosphorus product below 5 mmol 2 /l 2 . The PTH levels should be within the normal range in chronic renal failure (CRF) and up to 2-3 times the upper limit of normal levels in dialysed children. Prevention of ROD is expected to result in improved growth and less vascular calcification.

Over the past 20 years children have benefited from major improvements in both technology and clinical management of dialysis. Morbidity during dialysis sessions has decreased with seizures being exceptional and hypotensive episodes rare. Pain and discomfort have been reduced with the use of chronic internal jugular venous catheters and anesthetic creams for fistula puncture. Noninvasive technologies to assess patient target dry weight and access flow can significantly reduce patient morbidity and health care costs. The development of urea kinetic modeling enables calculation of the dialysis dose delivery, Kt/V, and an indirect assessment of the intake. Nutritional assessment and support are of major importance for the growing child. Even if the validity of these "urea only" data is questioned, their analysis provides information useful for follow-up. Newer machines provide more precise control of ultrafiltration by volumetric assessment and continuous blood volume monitoring during dialysis sessions. Buffered bicarbonate solutions are now standard and more biocompatible synthetic membranes and specific small size material dialyzers and tubing have been developed for young infants. More recently, the concept of "ultrapure" dialysate, i.e. free from microbiological contamination and endotoxins, has developed. This will enable the use of hemodiafiltration, especially with the on-line option, which has many theoretical advantages and should be considered in the case of maximum/optimum dialysis need. Although the optimum dialysis dose requirement for children remains uncertain, reports of longer duration and/or daily dialysis show they are more effective for phosphate control than conventional hemodialysis and should be considered at least for some high-risk patients with cardiovascular impairment. In children hemodialysis has to be individualized and viewed as an "integrated therapy" considering their longterm exposure to chronic renal failure treatment. Dialysis is seen only as a temporary measure for children compared with renal transplantation because this enables the best chance of rehabilitation in terms of educational and psychosocial functioning. In long term chronic dialysis, however, the highest standards should be applied to these children to preserve their future "cardiovascular life" which might include more dialysis time and on-line hemodiafiltration with synthetic high flux membranes if we are able to improve on the rather restricted concept of small-solute urea dialysis clearance.

Benign familial hematuria (BFH) is characterized by autosomal dominant inheritance, thinning of the glomerular basement membrane (GBM) and normal renal function. It is frequent in patients with persistent microscopic hematuria, but cannot be clinically differentiated from the initial stages of Alport syndrome, a severe GBM disorder which progresses to renal failure. We present here linkage of benign familial hematuria with the COL4A3 and COL4A4 genes at 2q35-37 (Z max ϭ 3.58 at ⍜ ϭ 0.0). Subsequently, a glycine to glutamic acid substitution was identified in the collagenous region of the COL4A4 gene. We conclude that type IV collagen defects cause both benign hematuria and Alport syndrome. Furthermore, our data suggest that BFH patients can be carriers of autosomal recessive Alport syndrome. ( J. Clin. Invest. 1996. 98:1114-1118.)

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Abstract. Alport syndrome (AS) is a type IV collagen hereditary disease characterized by the association of progressive hematuric nephritis, hearing loss, and, frequently, ocular changes. Mutations in the COL4A5 collagen gene are responsible for the more common X-linked dominant form of the disease. Considerable allelic heterogeneity has been observed. A “European Community Alport Syndrome Concerted Action” has been established to delineate accurately the AS phenotype and to determine genotype-phenotype correlations in a large number of families. Data concerning 329 families, 250 of them with an X-linked transmission, were collected. Characteristics of the 401 male patients belonging to the 195 families with COL4A5 mutation are presented. All male patients were hematuric, and the rate of progression to end-stage renal failure and deafness was mutation-dependent. Large deletions, nonsense mutations, or small mutations changing the reading frame conferred to affected male patients a 90% probability of developing end-stage renal failure before 30 yr of age, whereas the same risk was of 50 and 70%, respectively, in patients with missense or splice site mutation. The risk of developing hearing loss before 30 yr of age was approximately 60% in patients with missense mutations, contrary to 90% for the other types of mutations. The natural history of X-linked AS and correlations with COL4A5 mutations have been established in a large cohort of male patients. These data could be used for further evaluation of therapeutic approaches.

Biliary pseudolithiasis has been reported in patients who received ceftriaxone therapy. In addition to biliary sludge formation occasional reports of ceftriaxone-induced nephrolithiasis have been published. In general, these adverse effects will develop after seven to ten days of treatment. We report on a seven-year-old boy with ceftriaxone-associated biliary pseudolithiasis and nephrolithiasis four days after initiation of treatment. Patients receiving a high dose of ceftriaxone and developing colicky abdominal pain should be considered for ultrasound and a change in antibiotic therapy if appropriate.