Functional and molecular variations of a2-macroglobulin, apolipoprotein E and protein S in patients with nephrotic syndrome and control individuals
Date
2014-03-19
Authors
Nel, Margaretha Johanna
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Abstract
Nephrotic syndrome is a group of kidney diseases in which the glomerular basement
membrane is far more permeable than normal, such tL J large amounts of proteins are lost
in the urine. Tubular abnormalities are present, and cause abnormal reabsorption or lack of reabsorption of certain substances. In children, nephrotic syndrome is often an idiopathic disorder, whilst secondary nephrotic syndrome due to diabetes, amyloidosis or systemic lupus erythematosis also occurs but is more prevalent in adults. General complications of nephrotic syndrome include oedema; hyponatraemia; infections; low ionised calcium;diarrhoea; vomiting; thrombosis; hyperlipidaemia and abnormal thyroid function.
Little is known about the genetic factors that contribute to this group of disorders.
Nephrotic syndrome is a polygenic disease and the approach of this study was to determine whether molecular variation of certain candi, :- te genes might play a role in the prevalence of nephrotic syndrome in black and white South African children. The present study involved comparing azMacroglobulin levels; apolipoproteinE allele frequencies and
genotypes as well as protein S allele frequencies in nephrotic syndrome patients and
control individuals. These three factors were chosen for this study as c^Macroglobulin and
apolipoproteinE share the same receptor, cbMacroglobulin levels are high in children,
whilst apolipoproteinE is involved in lipid metabolism and hyperlipidaemia is a
complication of nephrotic syndrome, and protein S is implicated in thrombosis which is
also a complication o f nephrotic syndrome.
This study determined a 2Macroglobulin levels, using the elastase binding capacity assay
on plasma of paediatric nephrotic syndrome patients and control individuals. The results
confirmed that the levels found in paediatric patients were similar to those found in control
children, but were significantly increased compared to adults. A significant difference was
thus found between the a 2Macroglobulm plasma levels of children compared to adults,
which confirms the literature. No significant difference was found between the
a2Macroglobuiin plasma levels o f paediatric patients with FSGS compared to MLNS/(MCNS), as all children have high a 2Macroglobulin levels.
The polymerase chain reaction was used to screen for the various apolipoproteinE
genotypes in FSGS patients compared to MLNS/(MCNS) patients, but no significant
difference was found in .....of the three apoE allele frequency distributions between the
two groups o f patients. A significant difference was found in the apolipoprotein E
genotypes between white nephrotic syndrome patients and white control individuals, as the apoEs/Eg genotype frequency is decreased and the apoEg/E4 and the apoEz/Eg genotype frequency is increased in white nephrotic syndrome patients. The apoEg allele frequency is decreased in black as well as white nephrotic syndrome patients, indicating less efficient binding and removal o f lipids in these patients. The apoE2 allele, which is the least efficient in lipid binding, was significantly increased in the black nephrotic syndrome patients. This could contribute to the fact that focal segmental glomerulosclerosis, which is the more severe form of this disease and associated with renal scarring, is more prevalent in the black population, as was also shown by this study.
It is known that protein S deficiency cause thrombosis, which is common in nephrotic
syndrome, but little is known about the genetic contribution o f protein S to thrombosis. In
the present study, the polymerase chain reaction and Bst XI restriction enzyme analysis
were used to determine the prevalence of the Bst XI cut (+) protein S allele, and the Bst XI
uncut (-) protein S allele in black and white nephrotic syndrome children patients and
control individuals. The + allele, which is the mutated protein S allele, was significantly
more prevalent in the black nephrotic syndrome children patients. A significant difference
was found in the frequency distribution of the + and the - protein S allele between black
and white individuals as a group, as the + protein S allele was far more prevalent in the
black population. This finding could further contribute to the fact that black individuals
are predisposed to more severe glomerular pathology, and secondarily to interstitial
pathology as well i.e. increased renal scarring. Regarding thrombosis, there could be an
increased risk with the + protein S allele. This could also possibly increase the risk of
scarring in the glomerular microcirculation if thrombosis occurs there.
In condition, the present study demonstrated the extent and complexity of nephrotic
syndrome and it highlighted the need for further investigations.