DEPARTMENT OF MOTHER and CHILD HEALTH, NELSON R MANDELA SCHOOL OF MEDICINE, UNIVERSITY OF KWAZULU-NATAL, DURBAN, SOUTH AFRICA
In children with idiopathic nephrotic syndrome (NS), minimal change disease accounts for approximately 90% of cases under seven years of age and for more than 50% of cases in older children. This condition is characterized by a predictable and gratifying response to steroids and an excellent long-term prognosis. On the other hand steroid resistant (SR) forms of NS are characterized by frequent relapses, an increased propensity to complications such as growth retardation, infections, thrombosis and progression to end stage renal disease.
Why a proportion of children develop resistance to steroids remains an unresolved issue. Recent work however has shown the presence of specific genetic mutations as being a principle mechanism for the development of steroid resistance.
In treating this condition, the management is primarily aimed at abrogating proteinuria and by so doing, aiming to preserve renal function. In the past, children with SRNS were treated with long-term alternate day steroids, alkylating agents, levamisole, azathioprine and cyclosporine. Newer agents include high dose pulse methylprednisolone, mycophenolate mofetil, and tacrolimus are now being used, often in combination with low doses of steroids.
This article reviews the pathogenetic mechanisms leading to the development of steroid resistance and the current therapies used in the management of this condition.
The idiopathic nephrotic syndrome (NS) of childhood is a heterogenous disorder characterised by massive proteinuria, hypoalbuminemia, hyperlipidemia and edema. Histological characteristics are non-specific and range from minimal change disease, focal and diffuse mesangial proliferation to focal and segmental glomerulosclerosis (FSGS). Immunofluorescence is usually negative and electron microscopy shows fusion of the epithelial cell foot processes . Over 80% of children presenting with an initial episode of NS respond to steroids (steroid sensitive), whilst the remaining 20% do not respond and are considered steroid resistant (SR) . On follow up, 50-60% of children in the steroid responsive group have frequent relapses or develop steroid dependant disease. This group of children are at risk for extrarenal complications of NS as well as progression to end-stage renal disease necessitating renal replacement therapy. In these children who undergo transplantation, the overall risk for recurrence of the primary disease is about 25% . The aim of therapy is to control the nephrotic state and thus prevent complications and to especially try and halt or delay progression to end-stage renal disease. To date the plethora of agents in our therapeutic armamentarium has failed to produce a drug that is the panacea for this condition. Thus management of SRNS therefore poses a major therapeutic challenge to the attending clinician.
There are certain clinical and histological characteristics that may predict the likelihood of steroid resistance. These include:
- Hypertension (50-60% likelihood)
- Hematuria (30%)
- Hypertension plus hematuria (20%)
- Elevated plasma creatinine
- Massive proteinuria (>10g/day)
- Age of first presentation in infancy, after 8 years or post puberty
- Tubulointerstitial disease on renal biopsy or collapsing FSGS and percentage of globally sclerosed glomeruli
- Black race
- Selectivity index >0.2
- Tubular proteinuria (Increase excretion of B2 -microglobulin retinol-binding protein, lysozyme .
Patients with SRNS are more likely to have complications from their disease compared to those with steroid sensitive NS.
- Acute Renal Failure
During relapses, children have a reduced glomerular filtration rate secondary to hypovolemia . Other causes of acute renal failure include bilateral renal vein thrombosis and interstitial nephritis. The latter is often found in association with overzealous diuretic therapy e.g. furosemide.
- Chronic Renal Failure
Progression to end-stage renal disease occurs in at least 50% of children with SRNS. As patients develop ESRD, all features of their NS may improve because of a decrease in urinary protein excretion that parallels their glomerular filtration rate. Progression to end stage renal failure is more rapid in children with African or Hispanic descent.
In children with unremitting relapse, growth retardation secondary to their state of malnutrition is common. The development of hypoparathyroidism secondary to urinary loss of iodinated proteins is an additional contributory factor.
Factors predisposing to the increased risk of infection in these children include:
- Low IgG levels due to impaired synthesis.
- Urinary loss of factor B
- Impaired T-lymphocyte function
The most common infection is peritonitis. Organisms involved include Streptococcus pneumonia, Escherichia coli, Streptococcus bovis, Haemophilis influenzae.
Several factors contribute to the increased risk of thrombosis in these children. These include:
- Hypercoagulability state
Haemostatic abnormalities encountered in these children include :
- Increased platelet aggregability, fibrinogen, and factors V, VII, VIII, X, and XIII.
- Decreased levels of antithrombin III, heparin cofactor, protein C and S, and factors XI and XII.
- Increased fibrinolytic system components (eg. tissue plasminogen activator, plasminogen activator inhibitor-1)
The majority of thrombotic events are silent and symptomatic disease is found in only about 30% of patients. However in a study by Hoyer et al , systematic ventilation perfusion scans demonstrated defects consistent with pulmonary embolism in 28% of patients with steroid dependant or resistant NS. Thrombosis can occur in both arteries and veins.
The pathogenesis of glomerulosclerosis is still unknown. Several factors, including hemodynamic factors, cytokines and growth factors, hyperlipidemia, and platelet activation, lead to an increase of mesangial matrix production by resident cells in patients with FSGS. These patients have glomerular hypertrophy even if typical findings of FSGS are absent. There are several growth factors involved in the sclerotic process including platelet derived growth factor, TGF-ß, angiotensin II, thromboxane A2, coagulation factors and lipids [6,7,8].
Mechanism of Steroid Resistance
Why some children develop resistance to steroids is not well understood . Recent studies have shown that specific genetic mutations constitute a principle mechanism for steroid resistance. Mutations of NPHS1, NPHS2, ACTN4 and WTI genes are responsible for severe forms of SRNS in childhood, progressing to end-stage renal failure . Positional cloning has revealed defects in these 4 different genes as monogenic causes of SRNS in familial cases . See table 1.
Table 1: Genetic mutations associated with SRNS in childhood.
TYPE OF NS
Recessive mutations, encoding nephrin, (OMIM No. 602716) causes congenital NS of the Finnish type.
Recessive mutations, encoding podocin (OMIN no. 604766), causes SRNS
Mutations encoding actinin 4, (OMIN no. 604638), causes autosomal dominant form of SRNS. An additional locus for an autosomal dominant form of NS has been mapped to chromosome 11q21-q22 (OMIN no. 603965).
Mutations are associated with congenital NS and diffuse mesangial sclerosis in the Denys-Drash syndrome and Frasier syndrome.
The Denys-Drash syndrome is characterised by early onset of NS progressing rapidly to end-stage renal disease, male pseudohermaphroditism, and Wilm's tumour . The Frasier syndrome is characterised by the association of male pseudohermaphroditism and progressive glomerulopathy [13,14].
Podocin mutations Podocin, a 383-amino-acid protein, is a lipid raft-associated protein at the filtration slit, which is exclusively expressed in the podocytes at the foot processes . Podocin interacts with nephrin . Podocin also interacts with CD2AP, an adaptor protein that anchors CD2, a protein that stabilizes contact between podocytes . The podocin plays a major role in the structural integrity and function of the slit diaphragm, which is the maintenance of glomerular permselectivity. Mutations in this gene can be observed in patients with both familial and sporadic disease. In a study by Weber et al,  NPHS2 mutation analysis was performed in 338 children from 272 families with SRNS: 81 families had autosomal recessive (AR) SRNS, 72 patients had sporadic SRNS, and 19 diffuse mesangial sclerosis . The following results were obtained:
- The detection rate of NPHS2 mutations (homozygous or compound heterozygous) for AR SRNS was 43%. The average age of onset was 58 months.
- For those with sporadic forms of SRNS, it was 11%. The average age of onset was 103 months.
- Relatively late onset of NS was observed in patients with only one pathogenetic NPHS2 mutation.
In a second large study by Ruf et al  direct sequencing of the NPHS2 gene was performed in 190 patients with SRNS (from 165 different families) as well as 124 patients with steroid-sensitive NS (from 120 families). The following results were obtained:
- In the SR families, 43 (26%) of 165 SRNS families had homozygous or compound heterozygous mutations in NPHS2. Of the 29 patients with such mutations treated with cyclosporin or cyclophosphamide, more experienced a complete remission.
- No homozygous or compound heterozygous mutations in NPHS2 were observed for the 120 steroid-sensitive NS families.
- Recurrence of FSGS in a renal transplant was noted for 7 of 20 patients with SRNS (35%) without NPHS2 mutations, whereas it occurred for only 2 of 24 patients with SRNS (8%) with homozygous or compound heterozygous mutations in NPHS2.
It was concluded that patients with SRNS with homozygous or compound heterozygous mutations in NPHS2 do not respond to standard steroid therapy and have a reduced risk for recurrence of FSGS in a renal transplant. The authors further advocate that mutational analysis of NPHS2, if the patient consents, be done in parallel with the first course of standard steroid therapy in children with NS to avoid unnecessary side effects from prolonged or repeated course of steroids and cytotoxic agents. They further concluded that because patients with SRNS and homozygous or compound heterozygous mutations in NPHS2 have reduced risk for recurrence of FSGS in a renal transplant, compared to children without mutations, living related donor transplants might be considered more readily. However, given that 85% of children are steroid-sensitive and only approximately 20% of SR patients have NPHS2 mutations, screening for abnormalities at this gene locus will identify less than 5 percent of all cases . Also, not all familial cases of SRNS are associated with NPHS2 mutations, suggesting that yet to be identified genes are responsible in these cases . These genes may in fact be responsible for a higher proportion of sporadic SRNS.
The WT1 gene, which encodes a transcription factor, contains ten exons . WT1 is strongly expressed during embryofetal life . In the mature kidney, WT1 expression persists only in podocytes and epithelial cells of Bowman's capsule. Disruption of the WT1 gene in mice results in the absence of both kidneys and gonads, suggesting a crucial role of WT1 in the development of the genitourinary tract. Mutations in WT1, the Wilm's tumour suppressor gene, have been reported in children with sporadic SRNS and several forms of hereditary NS.
CD2AP anchors CD2 receptors of T-lymphocytes to the cytoskeleton. It is also expressed in the podocyte. It has been shown in murine studies that CD2AP and nephrin interact directly, suggesting an important role of this protein in the anchoring of nephrin to the slit diaphragm or into the signalling pathways . No mutations of the CD2AP gene to date have been reported to be associated with SRNS.
HLA associations with SRNS
Several studies have failed to demonstrate any significant association of SRNS with class II antigens [24,25,26,27]. Other studies from Europe and the United States have shown an association of HLA-DR7 with the frequency of relapses in steroid sensitive NS [28,29,30,31,26]. Bakr et al  studied 20 Egyptian children with frequent relapses/steroid-dependant NS and 14 children with SRNS. The DRBI * 07011 allele frequency was significantly higher among patients than the 121 unrelated healthy controls (64.3% vs. 16.5%, Pc <0.001). The aetiological fraction was high at 0.57 (RR=9.6, Cl 2.9-31.7).
The majority of patients present between 2-7 years of age. There is a preponderance of males with a ratio of males: females of 2:1. The disease is characterized by the sudden onset of oedema. Anasarca may develop with ascites, pleural and pericardial effusions. Blood pressure is usually normal but is sometimes elevated. Abdominal pain is occasionally due to complications such as peritonitis, thrombosis, or rarely pancreatitis. Sometimes the rapid development of ascites with concomitant hypovolemia leads to abdominal pain and malaise. In some patients, oedema is minimal and the nephrotic state is only discovered during routine urine analysis. Macroscopic hematuria may occur in a few cases. SRNS may also present with an infection or thrombotic complication.
Symptomatic treatment is similarly to that of children who are steroid sensitive. This includes dietary recommendations if no added salt and adequate intake of proteins and vitamins with reduced intake of foods high in cholesterol. Diuretics are used for the treatment of edema. If there is anasarca, salt free albumin with loop diuretics are given for control of edema. In addition, prevention and appropriate treatment of infections and thromboembolic complications, and treatment of hypovolemia, hypertension and hyperlipidemia. If the latter is not controlled by dietary restriction alone, lipid lowering agents are used.
The optimal approach to SRNS is uncertain. The reports of the large number of agents used as specific therapy bears testimony to the lack of a single effective agent for the treatment of this condition.
Cyclophosphamide and chlorambucil have been used either alone, in combination with oral steroids or with high dose pulse steroids. These regimens have met with variable success rates of inducing remission ranging from 10% to 70% [33,34,35,36,37,38]. Many patients exhibit features of steroid toxicity. The use of pulse dose cyclophosphamide over a few months induced remission in 25-60% of children with SRNS [38,39,40].
Initial studies evaluating the efficacy of cyclosporin in patients with SRNS showed a relatively small benefit. In eight uncontrolled studies involving 60 patients, complete remission was induced in only 12 (20%) . In the study by the French Society of Pediatric Nephrology involving 65 children with SRNS, complete remission was observed in 42% of children (48% with minimal change disease and 32% with FSGS). Eight of the 27 responders became steroid-sensitive when they subsequently relapsed . Patients who respond to cyclosporin often relapse when the dose is tapered or discontinued . Many reports indicate that the prolonged use of cyclosporin is associated with chronic nephrotoxicity. The most prominent histological feature of chronic cyclosporin nephrotoxicity is the presence of tubulointerstitial lesions, characterised by striped interstitial fibrosis containing groups of atrophic tubules. Cyclosporin associated arteriolopathy is rarely observed. Other side effects include elevation of blood pressure, hyperkalaemia, hypertrichosis, gum hypertrophy, and hypomagnesaemia.
Mycophenolate Mofetil (MMF) is the prodrug of mycophenolic acid which is formed by hydrolysis. Mycophenolic acid is a potent, selective, uncompetitive, and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). The latter is an enzyme required for de novo purine synthesis. Mycophenolic acid inhibits B and T-lymphocyte proliferation, as these cells are critically dependant upon de novo purine synthesis for their proliferation whereas other cell types can utilize salvation pathways for purine synthesis. Mycophenolic acid also prevents glycosylation of lymphocyte and monocyte glycoproteins that are involved in the intracellular adhesion of leucocytes to endothelium . Mycophenolic acid also induces lymphocyte apoptosis and alters cell-surface adhesion molecules and cytokine gene expression . MMF has been used in a few children with SRNS and FSGS . Although in this study it was shown to decrease proteinuria, none of the patients achieved complete remission. In a study by Mendizabal et al , MMF was given to 5 children with SRNS. Only one achieved complete remission. Withdrawal of the drug led to relapse with one patient developing chronic renal failure. To date a paucity of data exists concerning the use of MMF in SRNS. The advantage with the use of MMF is its benign side effect profile compared to prednisone and cyclosporine. Its use is not associated with nephrotoxicity, hepatotoxicity, neurotoxicity, hyperglycaemia or abnormalities of lipid metabolism.
The main mechanism of action of tacrolimus is through the inhibition of 1L-2 dependant T-cell activation, a process occurring during the early phase of T-cell activation . Tacrolimus also inhibits B-cell activation, in part through its action on T-cells and also directly by blocking TNF- a gene transcription by anti-Ig antibody . The drug only becomes active when complexed with a distinct endogenous intracellular receptor (cystocolic binding protein-FRBP12) known as immunophilin . The immunophilin drug complex interferes with intracellular calcium-dependent signal transduction pathways, processes that are central to T-cell activation [50,51,52,53]. The common biological target for the resulting complex is the calcium and calmodulin-dependent protein phosphatase, calcineurin. Case reports and single centre studies have shown tacrolimus to be effective in treating SR FSGS [54,55,56,57].
Other agents used in steroid dependent or SRNS include inter alia vincristine, azathioprine, sirolimus and mizoribine. Immunoglobulin transfusions have also been used with varying success.
Childhood SRNS continues to pose a major challenge to the attending physician. Although specific genetic factors such as mutations in the NPHS2 and other genes have been identified, suggesting a possible genetic basis for the SRNS with FSGS in a subgroup of patients, in the majority of patients, the pathogenesis remains elusive. The plethora of agents used in the treatment of this condition bears testimony to the lack of an optimal approach in managing this condition. Although data are lacking, use of these drugs, often in combination, is warranted in children with SR idiopathic NS together with adjunctive therapy.
Last Updated : Thursday, December 01, 2005 Vol 2 Issue 12 Art #52
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