The mutations were also tested for the position along the gene with the patients separated into four groups, which refer to the respective OCRL1 domains Figure 4. There were no significant differences in median ages between the analysed mutational groups. Similar analyses were done by Kaplan—Meier method. Furthermore, we observed strong inter-familial variability of eGFR. For example, among four patients with the same genotype c. We also found evidence of significant intra-familial variation of eGFR as illustrated in one of the families ls25 with four affected boys, of whom two had severe CKD, while the other two had stage 2 of CKD at a comparable age.
This study presents a comprehensive analysis of molecular defects, clinical phenotypes and treatments with respect to CKD. Whether this is related to genotype or to other as yet unidentified factors that explain the difference between developing LS or DD2 remains to be determined. As mutations of subjects with DD2 localize in exons 2—15, compared with exons 8—24 in LS patients [ 9 ], mutation localization does appear to correlate with disease severity. However, we also observed a strong inter- and intra-familial variability of eGFR in patients with the same mutation.
Suboptimal medical treatment, which in fact was demonstrated in our study, might be a significant determinant of the variability. This clinical variation in renal function might also be explainable by the individual ability to compensate for the loss of OCRL1 function.
It is questionable, however, whether this mechanism does explain the phenotypic differences, as Montjean et al.
On the other hand, they demonstrated an intermediate phenotype of DD2 fibroblasts in terms of the F-actin network, alpha-actinin and primary cilia. Hence, it has been proposed that a differential activity of modifying factors might contribute to the clinical variability between patients. Slowly progressive renal failure is a hallmark of LS and DD2. However, no report documented the longitudinal course of renal function in patients with LS and DD2.
In this study, we carried out for the first time longitudinal analyses of eGFR and found that in subjects with LS, renal function starts to decrease at around 10 years of age, predicting ESKD in the fourth decade not shown as was originally predicted by Charnas et al.
Unexpectedly, we demonstrated that in DD2, eGFR does not change significantly with time in childhood. One might speculate that the observed decline in eGFR in LS might result simply from the natural deterioration of damaged nephrons, but not due to puberty, which was demonstrated in patients with CKD with renal hypodysplasia [ 20 ].
In this regard, the limitation of our study is lack of puberty status that might account for the rate of renal function decline. In this study, we showed a high prevalence of CKD. When using original k-values, the calculation of eGFR tends to overestimate this value, thereby resulting in an underappreciation of CKD, as reported in previous case series [ 21 , 22 ].
This cohort study also provides an interesting observation regarding proteinuria. This finding calls into question the usefulness of this parameter in the population we studied. These parameters may be misleading, so that they cannot be reliably used in this group. In this regard, urinary protein to osmolality ratio may be preferable [ 23 ] or ideally h proteinuria, if feasible.
Nephrocalcinosis is another factor that is suspected to contribute to CKD progression, but again, our data could not show any association.
Importantly, since nephrocalcinosis was assessed by ultrasound in most of our cases, there is a possibility that the term nephrocalcinosis may have referred to just hyperechogenic kidneys. So, we cannot exclude the overrepresentation of patients with renal calcifications. Interestingly, our data showed that LS patients are more susceptible to severe dehydration, AKI and urinary tract infections. These observations are important and should inform the management of these patients. It clearly cautions against the use of thiazides and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.
These agents are typically prescribed to modify calci- and proteinuria under the assumption that these accelerate CKD progression. Yet, our data argue against this and the treatment could instead only predispose them to unfavourable events, such as dehydration and AKI.
Although the complete data set of proximal abnormalities was not available for all patients, the large cohort allowed us to get an idea of the frequency of tubular abnormalities. Since this parameter was assessed by dipstick and not tested repeatedly, its frequency shown in our study may be misleading. One should be aware of the usefulness of this abnormality as this is the key finding in predicting Fanconi syndrome, which was in turn evident in 5.
Glycosuria is easy to detect in a spot urine by dipstick; however, in case of polyuria, a formal urine glucose determination is recommended. An intriguing observation is the apparently suboptimal treatment in a substantial portion of patients. Importantly, we found a high proportion of patients with uncorrected acidosis, which corresponded with a high frequency of growth impairment and CKD. Potentially, part of the growth deficiency may result from acidosis.
Indeed, in our study in the LS group height strongly correlated with actual acidosis. Yet, no relationship could be disclosed between height and eGFR. The limitations of our study include its retrospective and multicentre nature, which is the reason for partially incomplete and non-uniform data acquisition.
The relatively small number of patients with DD2 in comparison with LS, as well as restriction of the study to children, also limits the power of our study to demonstrate renal survival. We did not identify an association between CKD and nephrocalcinosis and proteinuria, suggesting that modifying these factors will have no impact on the long-term kidney function.
We are grateful to the patients and their parents for their invaluable contributions. Hum Genet ; 99 : — Google Scholar. Dent disease with mutation in OCRL1.
Am J Hum Genet ; 76 : — Traffic ; 15 : — The oculo-cerebro-renal syndrome of Lowe—an update. Pediatr Nephrol doi Renal phenotype in Lowe syndrome: a selective proximal tubular dysfunction.
Clin J Am Soc Nephrol ; 3 : — Dent-2 disease: a mild variant of Lowe syndrome. J Pediatr ; : 94 — OCRL1 mutations in Dent-2 patients suggest a mechanism for phenotypic variability. Nephron Physiol ; : 27 — Clinical and laboratory findings in the oculocerebrorenal syndrome of Lowe, with special reference to growth and renal function.
N Engl J Med ; : — From Lowe syndrome to Dent disease: correlations between mutations of the OCRL1 gene and clinical and biochemical phenotypes. Hum Mutat ; 32 : — The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin North Am ; 4 : — Expressing glomerular filtration rate in children. Pediatr Nephrol ; 5 : 5 — Ghazali S , Barratt TM.
Urinary excretion of calcium and magnesium in children. Arch Intern Med ; 49 : 97 — Arch Intern Med ; 57 : — Agarwal I , Kirubakaran C , Markandeyulu , et al. Quantitation of proteinuria by spot urine sampling. Indian J Clin Biochem ; 19 : 45 — Characterization of 28 novel patients expands the mutational and phenotypic spectrum of Lowe syndrome.
Pediatr Nephrol ; 30 : — Pirruccello M , De Camilli P. Trends Biochem Sci ; 37 : — Hum Mol Genet ; 24 : — Puberty is associated with increased deterioration of renal function in patients with CKD: data from the ItalKid Project. Arch Dis Child ; 97 : — Renal manifestations of Dent disease and Lowe syndrome.
Pediatr Nephrol ; 23 : — Lowe syndrome: a single center's experience in Korea. Korean J Pediatr ; 57 : — Quantification of proteinuria in children using the urinary protein-osmolality ratio. Pediatr Nephrol ; 16 : 73 — Clin Nephrol ; 64 : — Nephrol Dial Transplant ; 29 : — CLDN16 genotype predicts renal decline in familial hypomagnesemia with hypercalciuria and nephrocalcinosis. J Am Soc Nephrol ; 19 : — Oxford University Press is a department of the University of Oxford.
It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign In. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation.
Volume Article Contents Abstract. Long-term renal outcome in children with OCRL mutations: retrospective analysis of a large international cohort. Marcin Zaniew , Marcin Zaniew. Correspondence and offprint requests to: Marcin Zaniew; E-mail: zaniewmarcin wp. Oxford Academic. Claudio La Scola. Federico Baronio. Anna Niemirska. Angela La Manna. Monika Miklaszewska. Jutta Gellermann. Argyroula Zampetoglou. Anna Wasilewska. Magdalena Roszak.
Jerzy Moczko. Dariusz Runowski. Patrizia Fonduli. Pediatric Nephrology, Hospital G. Brotzu, Cagliari, Italy. Franca Zurrida. Fabio Paglialonga. Zoran Gucev. Dusan Paripovic. Rina Rus. Valerie Said-Conti. Lisa Sartz. The small number of patients investigated in all reported series is the main limitation of the available studies. Study design: Retrospective case series. In addition, logistic regression models for a composite adverse fetal outcome perinatal death or extremely premature delivery and linear regression models for birth weight were built.
The same results were seen for birth weight. Limitations: Retrospective data analysis. The absence of creatinine clearance measurements did not allow evaluation of the impact of residual renal function on fetal outcome.
0コメント