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The therapeutic response to vincristine was examined in seven children (aged 215 years) with

corticosteroid-resistant (CR) nephrotic syndrome (NS) with focal and segmental glomerulosclerosis
(FGS). Five were also resistant to cyclophosphamide. Vincristine was given weekly (1.5 mg/m2
intravenously) for 8 weeks. Simultaneously, prednisone (60 mg/m2 per day, orally) was given for 4 weeks
and then gradually tapered. Two of these patients had a complete and stable remission; in five no
benefit was observed. It was not possible to identify any characteristics to predict the response to
vincristine. Although there is a case for trying vincristine therapy in CR NS with FGS, the results of this
study are not encouraging and a better understanding of its action and indications is necessary.

The prognosis of idiopathic nephrotic syndrome was transformed with the use of corticosteroids and
immunosuppressive drugs. The high percentage of initial remission in minimal change lipoid nephrosis
should not obscure the frequency of development to corticodependence or of multiple relapses which
lead to the complications of protracted corticosteroid therapy. Focal-segmental glomerulonephritis and
membranous glomerulopathy often evolve to relentless chronic renal failure. The use of
immunosuppressive therapy has reduced the percentage of unfavourable evolution, but these cytotoxic
agents are not devoid of short-term side effects and entail some long-term risk of malignancy [6, 26, 27].
The prognosis in cases which resist any form of treatment is distinctly unfavourable. As for the earlier
forms of therapy, the use of cyclosporin in treating idiopathic nephrosis is empirical: the mechanism of
immunosuppression with CyA is a continuing puzzle and the physiopathology of nephrosis is poorly
understood. Moreover, cyclosporin, in contrast with conventional treatments, entails a definite risk of
renal toxicity. Despite these drawbacks, preliminary results showed that approximately two-thirds of
patients with idiopathic nephrotic syndrome resistant to other therapy clearly benefited from
cyclosporin treatment, whereas only 7% suffered severe side effects. These results justify studies of
cyclosporin treatment on a larger scale. The goal of these studies should be threefold: first, to delineate
more precisely the indications and contra-indications of cyclosporin in glomerular diseases, to avoid
anarchic prescription of this powerful but expensive and potentially dangerous drug; second, to
determine the percentage of patients who will become dependent on long-term cyclosporin; and third,
to specify the risk of nephrotoxicity in case of such protracted treatment.

A Single-Gene Cause in 29.5% of Cases of


Steroid-Resistant Nephrotic Syndrome
1. Carolin E. Sadowski*,
2. Svjetlana Lovric*,
3. Shazia Ashraf*,
4. Werner L. Pabst*,
5. Heon Yung Gee*,
6. Stefan Kohl*,
7. Susanne Engelmann*,
8. Virginia Vega-Warner,
9. Humphrey Fang*,
10. Jan Halbritter*,
11. Michael J. Somers*,
12. Weizhen Tan*,
13. Shirlee Shril*,
14. Ins Fessi*,
15. Richard P. Lifton,
16. Detlef Bockenhauer,
17. Sherif El-Desoky,
18. Jameela A. Kari,
19. Martin Zenker,
20. Markus J. Kemper**,
21. Dominik Mueller,
22. Hanan M. Fathy,
23. Neveen A. Soliman,
24. the SRNS Study Group and
25. Friedhelm Hildebrandt*

+ Author Affiliations

1. *
Division of Nephrology, Department of Medicine, Boston Childrens Hospital, Harvard
Medical School, Boston, Massachusetts;
2. Department of Pediatrics and Communicable Diseases, University of Michigan, Ann
Arbor, Michigan;
3. Department of Genetics and Howard Hughes Medical Institute, Yale University School
of Medicine, New Haven, Connecticut;
4. Institute of Child Health, University College London, London, United Kingdom;
5. Pediatric Nephrology Unit, King Abdulaziz University Hospital, Jeddah, Kingdom of
Saudi Arabia;
6. Department of Human Genetics, Otto von Guericke University, Magdeburg, Germany;
7. **Department of Pediatrics, University Hospital Hamburg-Eppendorf, Hamburg,
Germany;
8. Department of Pediatric Nephrology, Medical Faculty of the Charit, Berlin, Germany;
9. The Pediatric Nephrology Unit, Alexandria University, Alexandria, Egypt;
10. Department of Pediatrics, Center of Pediatric Nephrology & Transplantation, Kasr Al
Ainy School of Medicine, Cairo University, Cairo, Egypt;
11. Egyptian Group for Orphan Renal Diseases, Cairo, Egypt; and
12. Howard Hughes Medical Institute, Chevy Chase, Maryland
1. Correspondence:
Dr. Friedhelm Hildebrandt, Howard Hughes Medical Institute, Division of Nephrology,
Department of Medicine, Boston Childrens Hospital, 300 Longwood Avenue, Enders
561, Boston, MA 02115. Email: friedhelm.hildebrandt@childrens.harvard.edu

Received for publication May 19, 2014.


Accepted for publication September 10, 2014.

Abstract
Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of ESRD in the
first two decades of life. Effective treatment is lacking. First insights into disease mechanisms
came from identification of single-gene causes of SRNS. However, the frequency of single-gene
causation and its age distribution in large cohorts are unknown. We performed exon sequencing
of NPHS2 and WT1 for 1783 unrelated, international families with SRNS. We then examined all
patients by microfluidic multiplex PCR and next-generation sequencing for all 27 genes known
to cause SRNS if mutated. We detected a single-gene cause in 29.5% (526 of 1783) of families
with SRNS that manifested before 25 years of age. The fraction of families in whom a single-
gene cause was identified inversely correlated with age of onset. Within clinically relevant age
groups, the fraction of families with detection of the single-gene cause was as follows: onset in
the first 3 months of life (69.4%), between 4 and 12 months old (49.7%), between 1 and 6 years
old (25.3%), between 7 and 12 years old (17.8%), and between 13 and 18 years old (10.8%). For
PLCE1, specific mutations correlated with age of onset. Notably, 1% of individuals carried
mutations in genes that function within the coenzyme Q10 biosynthesis pathway, suggesting that
SRNS may be treatable in these individuals. Our study results should facilitate molecular genetic
diagnostics of SRNS, etiologic classification for therapeutic studies, generation of genotype-
phenotype correlations, and the identification of individuals in whom a targeted treatment for
SRNS may be available.