Professional Documents
Culture Documents
Nephrotic Syndrome in Childhood 2003 The Lancet
Nephrotic Syndrome in Childhood 2003 The Lancet
Seminar
Search strategy
We searched the PubMed on-line database for all Englishlanguage papers on nephrotic syndrome published between
1996 and 2002. Our key search terms were nephrotic
syndrome, limited to all children. We chose papers relevant
to the paediatric population and pertaining to the topics of
epidemiology, pathophysiology, diagnosis, and management
as the basis of further review for this seminar.
629
For personal use. Only reproduce with permission from The Lancet
SEMINAR
MCNS
Genetic disorders
Nephrotic-syndrome typical
Finnish-type congenital nephrotic syndrome
FSGS
Diffuse mesangial sclerosis
Denys-Drash syndrome
Schimke immuno-osseous dysplasia
Proteinuira with or without nephrotic syndrome
Nail-patella syndrome
Alports syndrome
Multisystem syndromes with or without nephrotic syndrome
Galloway-Mowat syndrome
Charcot-Marie-Tooth disease
Jeunes syndrome
Cockaynes syndrome
Laurence-Moon-Biedl-Bardet syndrome
FSGS
Secondary causes
Infections
Hepatitis B, C
HIV-1
Malaria
Syphilis
Toxoplasmosis
Drugs
Penicillamine
Gold
Non-steroidal anti-inflammatory drugs
Pamidronate
Interferon
Mercury
Heroin
Lithium
Immunological or allergic disorders
Castlemans disease
Kimuras disease
Bee sting
Food allergens
Associated with malignant disease
Lymphoma
Leukaemia
Glomerular hyperfiltration
Oligomeganephronia
Morbid obesity
Adaptation to nephron reduction
*May also be consequence of inflammatory glomerular disorders,
normally associated with features of nephritiseg, vasculitis,
lupus nephritis, membranoproliferative glomerulonephritis, IgA
nephropathy.
630
For personal use. Only reproduce with permission from The Lancet
SEMINAR
Era 1
Era 2
Dates
Population
India (biopsies)4
USA (biopsies)5
North America,2
and Hong Kong3
(all cases)
Saudi Arabia
(all cases)6
n (%)
65 (20)
Dates
n (%)
157 (47)
46 (15)
Jan 1990
June 1992
Before 1990
196774
68 (23)
521 (7)
July 1992
Dec 1996
After 1990
198495
198392
132 (5)
19972001
36 (47)
148 (23)
3
5
2
1
4
7
For personal use. Only reproduce with permission from The Lancet
631
SEMINAR
T cells
Circulating
permeability
factor
Permeability
inhibitory
factor
Proteinuria
Disease progression genes
(MCNS
FSGS?)
Angiotensin-converting enzyme
Genes dependent on ethnic origin
? immunosuppression responsiveness
? proteinuria susceptibility
? sclerosis susceptibility
Name
LMX1B
SMARCAL1
Location
Inheritance
Renal disease
19q13.1
1q25
19q13
11q2122
11p13
Recessive
Recessive
Dominant
Dominant
Dominant
Dominant
Recessive
Recessive
MCNS
LIM-homoeodomain protein
9q34
SW1/SNF2-related, matrix2q35
associated, actin-dependent regulator
of chromatin, subfamily a-like 1
Unknown
*Podocyte expression of SMARCAL1 presumptive but not yet established. Mutations in another protein, CD2-AP or NEPH1 (novel protein structurally related to nephrin)
cause congenital nephrotic syndrome in mice (reference 18). A mutational variant in the CD2AP gene has been identified in a few patients with steroid-resistant
nephrotic syndrome (reference 19).
632
For personal use. Only reproduce with permission from The Lancet
SEMINAR
Diagnosis
Once diagnosed, a series of questions should be asked to
establish a cause for the nephrotic syndrome (panel 1).
Since MCNS is by far the most common cause of
nephrotic syndromes in childhood, initial efforts are
devoted to the detection of features that are atypical of
MCNS (panel 2). A course of corticosteroid treatment
without a renal biopsy is indicated for children without
atypical features, since responsiveness to steroids is a
better indicator than kidney histology of long-term
prognosis for renal function. Renal biopsy is generally
limited to steroid-unresponsive and steroid-dependent
patients, although it has yet to be shown that this
information affects outcome.65,66 Most centres also
recommend biopsy before the use of nephrotoxic
treatments such as ciclosporin.
Management
This section will focus on the current treatment options
for children with idiopathic nephrotic syndrome due to
MCNS and FSGS. Given the rare occurrence of
idiopathic membranous nephropathy in children, there
are currently no published treatment guidelines based on
randomised paediatric trials. Therapeutic approaches are
extrapolated from experience with adult membranous
nephropathy patients.67
Treatment of steroid-responsive nephrotic syndrome
Roughly 95% of patients with MCNS and 20% with
FSGS achieve remission after an 8-week course of
prednisone (60 mg/m2 daily for 4 weeks followed by
40 mg/m2 on alternate days for 4 weeks). Traditionally,
patients receive divided doses but once-daily treatment
also seems to be effective.68 MCNS patients respond quite
quicklyaround 75% achieve remission by 2 weeks.69
Given the high relapse rate for MCNS patients, there has
been a shift in the past decade to longer courses of
corticosteroid treatment for first episodes of nephrotic
syndromes in an effort to decrease the relapse rate. In
support of this approach was the study by the
Arbeitsgemeinschaft fr Pdiatrische Nephrologie,70 in
which a lower relapse rate at 1 year (36 vs 62%) was
reported among patients treated with 60 mg/m2
prednisone daily for 6 weeks followed by 40 mg/m2
prednisone on alternate days for 6 weeks than among
patients who received the then standard 8-week
treatment.
In a meta-analysis of the five randomised controlled
trials involving children with a first episode of steroidresponsive nephrotic syndrome, longer duration of
treatment significantly decreased the risk of relapse at 12
and 24 months without an increase in adverse events.71 An
inverse relation was noted between the duration of
For personal use. Only reproduce with permission from The Lancet
633
SEMINAR
634
For personal use. Only reproduce with permission from The Lancet
SEMINAR
Thromboembolic complications
Nephrotic patients are at significantly increased risk of
thrombosis, with complication rates reported as high as
40% in adults.120 Although thrombosis risk is apparently
lower in nephrotic children (1850%), these events can
be severe.121 Multiple factors contribute to the
dysregulated coagulation state of nephrotic syndrome
(figure 5). No one laboratory test can reliably predict the
real thrombotic risk. Fibrinogen concentration has been
proposed as a surrogate marker. Other factors that
increase thrombotic risk in nephrotic patients include
diuretic use, corticosteroid treatment, immobilisation,
and the presence of in-dwelling catheters. If a clot is noted
in a nephrotic child, investigation for an inherited
coagulation
abnormality
is
still
recommended.
Prophylactic anticoagulation is not recommended because
of its own inherent risks. However, after treatment of a
documented clot, use of prophylactic warfarin has been
recommended for at least 6 months, and perhaps during
future relapses.122 In-dwelling venous catheters should be
avoided, but if absolutely necessary, prophylactic
anticoagulation should be considered. Low-molecularweight heparin is an attractive alternative agent, but it
requires sufficient antithrombin III substrate to be
effective.122 Aspirin may also be considered for
anticoagulation, especially if thrombocytosis is severe.
For personal use. Only reproduce with permission from The Lancet
635
SEMINAR
Cardiovascular disease
Multiple factors raise concerns for cardiovascular sequelae
in children with long-term nephrotic syndrome, including
exposure to corticosteroids, hyperlipidaemia, oxidant
stress, hypertension, hypercoagulability, and anaemia
(erythropoietin-responsive
anaemia
is
a
rare
complication123,124). Nephrotic syndrome in adulthood is
associated with an increased risk of coronary heart
disease.125 Myocardial infarction in young children with
nephrotic syndrome has been reported, but the relative
risk has not been calculated.126 In adults with nephrotic
syndrome, HMG-CoA-reductase inhibitors can control
hyperlipidaemia and limit its complications.127129 Whether
or not to treat hyperlipidaemia in nephrotic children has
been a source of controversy, especially since most
children have treatable renal disease.60 Adequate safety
and efficacy data for HMG-CoA-reductase inhibitors in
children are not available, despite small case series in
which decreased serum lipids have been reported.130,131
Persistent hyperlipidaemia in unremitting childhood
nephrotic syndrome is concerning, but there is little
evidence as yet to guide treatment or predict future
outcome.
References
Acknowledgments
Laura Finn and Joe Rutledge, Laboratory Medicine and Pathology,
Childrens Hospital and Regional Medical Center, Seattle, WA, USA,
assisted with the preparation of the photomicrographs. AAE is supported
by a grant form the National Institutes of Health (DK54500).
1
2
6
7
636
10
11
12
13
14
15
16
17
For personal use. Only reproduce with permission from The Lancet
SEMINAR
44 Sahali D, Pawlak A, Le Gouvello S, et al. Transcriptional and posttranscriptional alterations of IB in active minimal-change nephrotic
syndrome. J Am Soc Nephrol 2001; 12: 164858.
45 Winston JA, Bruggeman LA, Ross MD, et al. Nephropathy and
establishment of a renal reservoir of HIV type 1 during primary
infection. N Engl J Med 2001; 344: 197984.
46 Tanawattanacharoen S, Falk RJ, Jennette JC, Kopp JB. Parvovirus
B19 DNA in kidney tissue of patients with focal segmental
glomerulosclerosis. Am J Kidney Dis 2000; 35: 116674.
47 Li RM, Branton MH, Tanawattanacharoen S, Falk RA, Jennette JC,
Kopp JB. Molecular identification of SV40 infection in human
subjects and possible association with kidney disease.
J Am Soc Nephrol 2002; 13: 232030.
48 Stehman-Breen C, Alpers CE, Fleet WP, Johnson RJ. Focal
segmental glomerular sclerosis among patients infected with hepatitis
C virus. Nephron 1999; 81: 3740.
49 Humphreys MH. Mechanisms and management of nephrotic edema.
Kidney Int 1994; 45: 26681.
50 Vande Walle J, Donckerwolcke R, Boer P, van Isselt HW,
Koomans HA, Joles JA. Blood volume, colloid osmotic pressure and
F-cell ratio in children with the nephrotic syndrome. Kidney Int 1996;
49: 147177.
51 Geers AB, Koomans HA, Boer P, Dorhout Mees EJ. Plasma and
blood volumes in patients with the nephrotic syndrome. Nephron
1984; 38: 17073.
52 Dorhout Mees EJ, Geers AB, Koomans HA. Blood volume and
sodium retention in the nephrotic syndrome: a controversial
pathophysiological concept. Nephron 1984; 36: 20111.
53 Koomans HA, Geers AB, vd Meiracker AH, Roos JC, Boer P,
Dorhout Mees EJ. Effects of plasma volume expansion on renal salt
handling in patients with the nephrotic syndrome. Am J Nephrol
1984; 4: 22734.
54 Peterson C, Madsen B, Perlman A, Chan AY, Myers BD. Atrial
natriuretic peptide and the renal response to hypervolemia in
nephrotic humans. Kidney Int 1988; 34: 82531.
55 Palmer BF, Alpern RJ. Pathogenesis of edema formation in the
nephrotic syndrome. Kidney Int Suppl 1997; 59: S2127.
56 Ichikawa I, Rennke HG, Hoyer JR, et al. Role for intrarenal
mechanisms in the impaired salt excretion of experimental nephrotic
syndrome. J Clin Invest 1983; 71: 91103.
57 Usberti M, Gazzotti RM, Poiesi C, DAvanzo L, Ghielmi S.
Considerations on the sodium retention in nephrotic syndrome.
Am J Nephrol 1995; 15: 3847.
58 Schrier RW, Fassett RG. A critique of the overfill hypothesis of
sodium and water retention in the nephrotic syndrome. Kidney Int
1998; 53: 111117.
59 Vande Walle JG, Donckerwolcke RA. Pathogenesis of edema
formation in the nephrotic syndrome. Pediatr Nephrol 2001; 16:
28393.
60 Querfeld U. Should hyperlipidemia in children with the nephrotic
syndrome be treated? Pediatr Nephrol 1999; 13: 7784.
61 Vaziri ND, Liang K. Up-regulation of acyl-coenzyme A:cholesterol
acyltransferase (ACAT) in nephrotic syndrome. Kidney Int 2002; 61:
176975.
62 Shearer GC, Kaysen GA. Proteinuria and plasma compositional
changes contribute to defective lipoprotein catabolism in the
nephrotic syndrome by separate mechanisms. Am J Kidney Dis 2001;
37 (suppl 2): S11922.
63 Shearer GC, Stevenson FT, Atkinson DN, Jones H, Staprans I,
Kaysen GA. Hypoalbuminemia and proteinuria contribute separately
to reduced lipoprotein catabolism in the nephrotic syndrome.
Kidney Int 2001; 59: 17989.
64 Nakahara C, Kobayashi K, Hamaguchi H, Kanemoto K,
Kashiwagi R, Matsui A. Plasma lipoprotein (a) levels in children
with minimal lesion nephrotic syndrome. Pediatr Nephrol 1999; 13:
65761.
65 Webb NJ, Lewis MA, Iqbal J, Smart PJ, Lendon M,
Postlethwaite RJ. Childhood steroid-sensitive nephrotic
syndrome: does the histology matter? Am J Kidney Dis 1996;
27: 48488.
66 Gulati S, Sharma AP, Sharma RK, Gupta A, Gupta RK. Do current
recommendations for kidney biopsy in nephrotic syndrome need
modifications? Pediatr Nephrol 2002; 17: 40408.
67 Cattran DC. Idiopathic membranous glomerulonephritis. Kidney Int
2001; 59: 198394.
68 Ekka BK, Bagga A, Srivastava RN. Single- versus divided-dose
prednisolone therapy for relapses of nephrotic syndrome.
Pediatr Nephrol 1997; 11: 59799.
69 The primary nephrotic syndrome in children: identification of
patients with minimal change nephrotic syndrome from initial
response to prednisonea report of the International Study of
Kidney Disease in Children. J Pediatr 1981; 98: 56164.
For personal use. Only reproduce with permission from The Lancet
637
SEMINAR
638
For personal use. Only reproduce with permission from The Lancet
SEMINAR
124
125
126
127
128
129
130
131
Clinical picture
Retinal detachment
Jennifer Ng, James Cleland, Peter Bergin
Department of Neurology, Auckland Hospital, Park Road, Private Bag 92024, Auckland, New Zealand (J Ng
Memorial Hospital, University of Rochester, Minnesota, USA (J Cleland MBChB)
MRCP,
P Bergin
FRACP);
Strong
For personal use. Only reproduce with permission from The Lancet
639