Treatment of steroid sensitive nephrotic syndrome
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《美国医学杂志》
Department of Pediatrics, Faculty of Medicine, University of Peradeniya, Sri Lanka
Abstract
Childhood idiopathic nephrotic syndrome (NS) is a chronic glomerular disorder, and if untreated, is associated with increased risk of life-threatening infections, thromboembolism, lipid abnormalities, and malnutrition. The aim of the management of NS in children is to induce and maintain complete remission with resolution of proteinuria and edema without encountering serious adverse effects of therapy. Over 90% of cases in children are due to minimal change disease (MCD) and a majority of them will respond to corticosteroid therapy. Steroid sensitive NS is considered to be a relatively benign condition; progression to end stage renal failure is extremely rare and over 80% achieve spontaneous remission in later childhood. The early disease is characterized by a relapsing course, placing the child at risk of acute complications. The occurrence of frequent relapses necessitates clear therapeutic strategies in order to maintain sustained remission and minimize steroid toxicity. Numerous therapeutic regimens have been proposed utilizing steroid sparing agents such as alkylating agents, principally, cyclophosphamide and chlorambucil, calcineurin inhibitors namely cyclosporin A and immunomodulatory drug levamisole with variable success and associated side-effects. It is therefore important that the benefits and risks of these agents are weighed before considering their use in the treatment of patients with NS.
Keywords: Idiopathic nephrotic syndrome; Corticosteroid therapy; Minimal change disease
Idiopathic nephrotic syndrome (NS) is a common glomerular disorder in childhood characterized by heavy proteinuria, hypoproteinemia, edema and hyperlipidemia. Estimates of annual incidence range from 2 to 7 new cases in children under 16 yrs per 100,000 total populations, leading to a cumulative prevalence of 15.7 per 100,000 due to the chronic nature of the disease. There is however a racial variation in the susceptibility with a reported incidence of 9-16 per 100,000 in British Asian children.[1]
Most patients with NS have minimal changes in the glomeruli on histology and 90%-95% will respond to corticosteroid therapy.[2] There is a close correlation between steroid sensitivity and minimal change disease (MCD), and therefore at the initial presentation, a renal biopsy is not performed in the absence of risk factors suggesting other forms of NS. A minority of children with underlying focal segmental glomerulosclerosis (FSGS) and diffuse mesangial proliferative glomerulonephritis will also respond to corticosteroid therapy. Consequently, a clinically useful classification of NS is that of steroid sensitive NS (SSNS), or steroid resistant NS (SRNS). SSNS has a more favorable outcome with a high probability of long-term remission and preserved renal function, while the prognosis of SRNS is more guarded, with a significant proportion progressing to end stage renal failure.
A perturbation of the immune system was proposed by Shalhoub[3] to be important in the pathogenesis of NS. It was also known that following an attack of measles, patients with NS might have long-term remission.[4] It is now believed that a disturbance in the Th1 and Th2 immune mechanisms, mediated by cytokines, is involved in the pathogenesis of NS.[5], [6], [7] These observations represent the scientific rationale for use of cytotoxic and immunosuppressive drugs in childhood NS.
Arniel first proposed the use of prednisolone in children with NS.[8] Subsequently the International Study of Kidney Disease in Children (ISKDC) proposed 60 mg/m2/day of prednisolone for induction of remission of NS, which has been accepted as standard treatment.[9] Although a majority of children will respond to corticosteroid therapy, this therapy is not curative, and most patients relapse. Each relapse is associated with an increased risk of morbidity and mortality from infection, thromboembolism and hypovolemic shock.[2], [10], [11]
Steroid toxicity is a major cause for concern in children with NS and their families. In 1967, cyclophosphamide (CYC) was reported as an effective agent in maintaining sustained remission in steroid sensitive NS.[12], [13] Side effects of CYC have been a cause for concern, including alopecia, bone marrow suppression and opportunistic infections, hemorrhagic cystitis and long-term risk of malignancy and infertility.[14], [15] In the mid 1980's, levamisole (LEV) and calcineurin inhibitor cyclosporin A (CSA) were used with variable success. While the reported side effects with LEV therapy are low,[16], [17] the side effects of CSA include hirsutism, gingival hypertrophy and nephrotoxicity.
This article reviews the current approach to the therapy of NS in childhood, with emphasis on the use of corticosteroid and other immunosuppressive agents.
Initial laboratory evaluation
Urine
Urine deposits
Transient microscopic hematuria is found in 23% patients with steroid sensitive MCD.[1] Persistence of microscopic hematuria is more indicative of FSGS but this should not be used to discriminate between the two. The presence of macroscopic hematuria is suggestive of more aggressive forms of glomerulonephritis.[1]
Urine protein
The ISKDC definition of NS in children is proteinuria greater than 40 mg/m2/hour in an overnight specimen of urine, which is equivalent to 1.7 g/24 hours in adults. Some experts suggest that nephrotic range proteinuria be defined as greater than 100 mg/m2/hour.[18] Timed urine collections in children can be cumbersome and urine protein: creatinine or albumin: creatinine (UAlb: UCr ) ratios provide a convenient approximation. UAlb: UCr of 400 mg/mmol (3.5 mg/mg) or urine protein: creatinine ratio of 200 mg/mmol (1.8 mg/mg) indicate nephrotic range proteinuria.[19]
Urine sodium
Measurement of the urinary sodium concentration is a valuable tool for the diagnosis of suspected hypovolemia, which leads to renal sodium retention. A urinary sodium value less than 10 mEq/l is diagnostic of intravascular volume contraction, while a value above 20 mEq/l makes it unlikely. However, this is not applicable if the child has received potent diuretics such as frusemide.
Blood Investigations
Proteins
Hypoalbuminemia (< 25 g/dL) is essential for the diagnosis of nephrotic syndrome. IgG levels were also reduced, but to a lesser degree than the albumin, and IgM is usually elevated. Plasma complement proteins, namely the C3 and C4 fractions are usually not altered, which help to differentiate SSNS from other forms of NS.
Lipids
Total plasma cholesterol, low-density and very low-density lipoproteins are grossly elevated, while high-density lipoproteins remain within the normal range.
Creatinine, urea and electrolytes
Plasma creatinine and urea concentrations are usually normal at presentation in SSNS, but mild to moderate increases may result from hypovolemia and renal underperfusion. Plasma electrolytes too are usually normal at presentation but hyponatremia is occasionally seen as a complication of hypovolemia. If the plasma volume is contracted, then anti-diuretic hormone is secreted in response to the baroreceptor stimulation leading to water retention and dilutional hyponatremia.
Calcium
The total plasma calcium concentration is low in parallel to the reduction of albumin level as it is partly albumin bound. However, the ionized calcium concentration is normal and it is not necessary to treat the low total calcium concentration that eventually returns to normal with normalization of albumin concentration.
Definitions
Nephrotic syndrome : Edema, hypoalbuminemia (< 25 g/l) and proteinuria > 40 mg/m2/hour or protein/creatinine ratio > 1.8 mg/mg
Remission : Urinary protein excretion < 4 mg/m2/hour or reagent strip (Albustix) negative or trace for three consecutive days
Relapse : Urinary protein excretion > 40 mg/m2/hour or albustix 3+ or more for three consecutive days having previously being in remission
Frequent relapses : Two or more relapses during the first 6 months after the initial episode or four or more relapses within any 12- month period
Steroid responsive : Remission achieved with steroid therapy alone
Steroid dependence : two consecutive relapses occurring during corticosteroid therapy or within 14 days after its cessation.
Steroid resistance : Failure to achieve remission following 4 weeks of daily prednisolone at 60 mg/m2/day
Management
General Measures
Diet
In the past, both low and high protein diets have been recommended for SSNS. A low protein diet reduces albuminuria but increases the risk of malnutrition. Animal studies show that high protein diets increase the synthesis of albumin, but do not increase the albumin concentration or growth significantly. Based on current evidence, no specific dietary advice is necessary for uncomplicated cases of SSNS. Modest salt restriction is beneficial during severe relapses, especially in patients with edema.
Activity
All efforts should be taken to actively mobilize the child; bed rest should be avoided if possible to minimize the risk of thrombosis.
Immunizations
All killed vaccines are generally regarded as safe for administration when a child is in remission. However, relapses are noted to cluster following meningococcal C conjugate vaccination program in the United Kingdom.[20] Caution should be exercised and parents counseled regarding the risk of relapse before administering this vaccine. All live vaccinations should be avoided until children are off daily steroids for at least 6 weeks. Additionally, they should be avoided where cyclophosphamide or cyclosporine A therapy has been initiated.[1]
Complications
Infections
Children with NS are at a higher risk of infection, partly because of the disease itself and partly due to immunosuppressive therapy. They have a strong predilection for pneumococcal infections. Some experts propose that children with NS be administered oral penicillin prophylaxis during a relapse of the disease.[1] It is important to remember that gram-negative bacteria cause a significant proportion of infections in children with NS, and until an organism has been identified in a particular patient, broad-spectrum antibiotics should be prescribed. Patients on immunosuppressive medications, if exposed to varicella infection, should preferably receive the zoster immunoglobulin within 72 hours. Patients who develop varicella should be treated with intravenous acyclovir.[1]
Hypovolemia
Hypovolemia and shock generally occur with the development of edema. Fluid loss during diarrhea, vomiting, sepsis and injudicious diuretic therapy might precipitate development of hypovolemia. Clinical signs and symptoms include severe central abdominal cramps with or without vomiting, reduced urine output, cold extremities, low blood pressure or reactive hypertension. Laboratory findings of low urinary sodium (< 10 mEq/l) and increased hematocrit suggest impending hypovolemic shock. Prompt treatment is essential and colloid infusion is the mainstay of treatment; 4.5% albumin, 20% albumin or plasma should be infused slowly under careful monitoring. If evidence of pulmonary edema develops, the infusion should be stopped and intravenous frusemide (1 mg/kg) administered.
Hypertension
In SSNS, the blood pressure is usually normal. However, hypertension in children with SSNS should be evaluated very carefully. It may reflect hypervolemia or extreme vasoconstriction in response to hypovolemia mediated via the renin-angiotensin system. In the latter, urinary sodium will be very low. If blood pressure exceeds the normal limit, a short course of antihypertensives could be prescribed once hypovolemia is excluded. Commonly used antihypertensive medications are nifedipine, hydralazine or atenolol. Diuretics are useful when hypertension is due to fluid overload.
Thrombosis
Children with NS are prone to develop both arterial and venous thrombosis. The propensity for thrombosis is due to a combination of hemodynamic factors and hypercoagulable state associated with NS. This, along with loss of anti-thrombin[1] in urine, increases the risk of thrombosis in children with NS.[10] The usually affected sites are the deep veins of the legs and pelvis, mesenteric veins and pulmonary vasculature.
Acute renal failure
Acute renal failure rarely complicates SSNS, but a mild degree of prerenal azotemia is seen in association with hypovolemia which responds to volume replacement. Acute renal failure unresponsive to volume replacement with histological appearance of acute tubular necrosis is encountered occasionally with SSNS. Affected individuals usually make complete recovery but dialysis may be required if renal failure persists for a longer duration.
Malnutrition
Children with refractory NS may develop nutritional deficiencies due to poor intake and malabsorption due to gut edema. The effects of poor nutrition may be masked by fluid retention and will be evident only with the resolution of edema.
Hyperlipidemia
One of the cardinal features of NS is hyperlipidemia, characterized by elevated total cholesterol, low-density lipoproteins and very low-density lipoproteins. Whether intermittent hyperlipidemia associated with SSNS increases the risk of future atherosclerosis remains to be determined, and at present, the routine use of lipid lowering drugs is not recommended.
Refractory edema
While awaiting steroid induced diuresis, edema could be controlled by the judicious use of diuretics (frusemide 1-2 mg/kg, spironolactone), once hypovolemia is excluded. In difficult cases 20% albumin or plasma could be infused along with diuretics (frusemide).
Indications for Renal Biopsy
In practice, renal histology is less important than the response to corticosteroid therapy. Renal biopsy is performed only when there are features that suggest histology other than MCD or later when there is steroid resistance.[1]
The indications for renal biopsy are:
Before treatment
1. Onset < 6 months of age
2. Initial macroscopic hematuria
3. Persistent microscopic hematuria with hypertension
4. Acute renal failure not attributable to hypovolemia
5. Low plasma C3 level
A biopsy is discretionary if: (a) onset is between 6-12 months of age, (b) onset above 14-16 years or (c) there is persistent hypertension, microscopic hematuria
Post treatment
A renal biopsy is recommended in all patients with steroid resistance. It is discretionary in frequently relapsing disease before commencing second line drugs (especially CSA).
Specific therapy
Induction of Remission
Corticosteroids
Corticosteroids remain the drug of first choice for induction of remission. While there are no controlled trials that have compared the efficacy of prednisone with prednisolone, both medications are comparable.
The treatment protocol, prednisolone 60 mg/m2 daily in divided doses for 4 weeks followed by 40 mg/m2 / day prednisolone for 3 consecutive days of a week (intermittent) for the next 4 weeks, designed by ISKDC over 35 years ago was empirical.[9] However, current practice is to prescribe alternate day therapy in the second month of treatment in preference to intermittent therapy because it reduces the relapse rate more effectively.[21] In the past 20 years there has been considerable debate regarding the optimization of the initial corticosteroid protocol. Several controlled studies have examined the effects of the duration of prednisolone therapy in relation to long-term outcome. Shorter prednisolone courses are associated with a higher rate of relapse. In contrast, significantly greater sustained remission was achieved by intensifying the initial steroid therapy.[22] Meta-analysis of randomised controlled trials suggests that the total duration of corticosteroid therapy should exceed that used in the ISKDC regimen.[23] The relative risk of relapse at 12-24 months falls by 0.133 (13%) for every month of increase in therapy for seven months.[23] However, the clinical usefulness of this reduction in terms of reducing the incidence of steroid dependent disease and in the use of second-line immunosuppressive agents such as cyclophosphamide and cyclosporine remain unclear. Long-term therapy may also be associated with a higher risk of side effects.
Overall, the optimal initial dose and the duration of corticosteroid therapy that is most beneficial for the induction of sustained remission with minimal side effects remain controversial. Therefore until results of more controlled trials are available, remission should be induced with prednisolone 60 mg/m2/24 hours as a single morning dose and continued for 4-6 weeks, irrespective of the timing of remission, followed by a tapering regimen of alternate day prednisolone for a further 6 weeks in order to achieve sustained remission.[24]
Treatment of Relapses
The characteristic feature of SSNS is tendency to relapse. Intensification of relapse treatment with prednisolone has little effect on the subsequent relapse rate.[25] The response to steroids is much better in relapses when compared to the initial episode.[1] Induction of remission is achieved with prednisolone 60 mg/m2/day as for the initial episode, followed by alternate day prednisolone for a further 4-6 weeks.[24] In spite of the report of induction of remission achieved with prescription of prednisolone,[26] such therapy could lead to difficulties in defining children who develop secondary steroid resistance and therefore is not recommended.
Children with a frequently relapsing disease or steroid dependent disease need individualized treatment.[1], [24] Although there is no data on the merits of long term maintenance, there is prednisolone as opposed to repeated standard relapse treatment, and most pediatric nephrologists favor the former approach.[1], [24] The dose should be titrated to the lowest level possible, sufficient to maintain remission in order to minimize steroid side effects. Most primary school children can tolerate 0.1-0.6 mg/kg/body weight on alternate day while most preschool children will tolerate up to 1mg/kg/body weight on alternate days.[1], [24] The duration should be for a minimum of 3-6 months as alternate day therapy, although a selected group of children may benefit from long-term alternate day treatment.
Steroid toxicity
The side effects of steroids are numerous, well-recognized and of great concern to the patient as well as the family. There was a positive correlation between the side effects and cumulative dose of steroids in children with an initial episode of SSNS.[27] Obesity, hirsutism, arterial hypertension and psychological disturbances are usually reversible after cessation of steroid therapy.[27] However, striae and cataracts are not reversible.[27] Growth failure was observed only in children with prolonged daily steroid therapy, while alternate day steroids were not associated with significant growth impairment.[28], [29] In order to prevent toxicity, patients on long term steroid therapy should be reviewed every 3 months for blood pressure and growth measurements and annually for development of cataracts.[1]
Cytotoxic Therapy
SSNS represents a milder form of the disease and a majority of children could be controlled with corticosteroid therapy.[30], [31] Children with frequently relapsing or steroid dependent disease who show steroid toxicity are the candidates for treatment with alkylating agents or other immunomodulatory drugs.
Cyclophosphamide
Over the past 30 years, CYC has been used for the treatment of childhood NS. It has been effective in inducing sustained remission in frequently relapsing NS (FRNS), steroid dependent NS (SDNS) and inducing remission in SRNS.[14] The initial strategy in cytotoxic treatment using CYC was an increase of daily dosage at biweekly intervals until neutropenia developed and at which point CYC was abruptly discontinued. CYC given orally in a dosage of 3 mg/kg/day for 8 weeks induced sustained remission in 69% at one year and 44% at five years in SSNS.[12] However, in subsequent studies the proportion of sustained remission induced varied considerably.[32] In spite of this, meta-analysis of randomized controlled trials suggests that CYC is useful in inducing sustained remission in SDNS.[32] Although it was reported that prescription of CYC 2 mg/kg/day orally for 12 weeks achieved a higher proportion of sustained remission,[33] subsequent studies failed to confirm this finding.[34] A shorter regimen of CYC for 2 weeks was associated with a higher relapse rate.[35] Intravenous pulsed CYC at 600 mg/m[2] monthly for six months is being increasingly used with variable success for SDNS.[36], [37] Most studies include small number of patients and therefore it is difficult to interpret the advantages over oral therapy. Relapse following CYC is generally treated with steroids. Second course of CYC is effective in inducing long-term remission.[31] As the long-term side effects of CYC are cumulative, such therapy should be reserved for select patients. Response of CYC in SRNS is unpredictable, and the information from literature is limited. Steroid resistant MCNS is usually responsive to CYC and there is a tendency for the subsequent relapses to become steroid responsive.[38]
Chlorambucil
Chlorambucil (CHL) can induce a prolonged steroid free remission in children with FRNS or SDNS and its efficacy is similar or even better than CYC. As with CYC, its long-term toxic effects limit its prolonged or continuous use. The dosage used is 0.2 mg/kg/day for 8-12 weeks.[39] The risk of hematological malignancy is greater with CHL than with CYC.[20]
Cyclosporine A
In SSNS, cyclosporine A (CSA) is generally reserved for children who become steroid dependent following a course of cyclophosphamide.[31], [40], [41] It is now increasingly used in preference to CYC in children approaching puberty, especially boys who are more vulnerable for testicular damage from CYC and in whom the disease does not have a long run.[41] CSA is generally prescribed at a dosage of 3-5 mg/kg/day for a period of one year.[31],[40], [41] Unlike CYC or CHL, CSA loses its protective effectiveness after cessation of treatment.[41] Long lasting remissions were obtained when CSA was prescribed continuously for 5 years.[41] CSA is a difficult drug to use and requires monitoring of blood concentrations and regular measurement of the glomerular filtration rate because of its potential nephrotoxicity.[40], [41]
Other Immunosuppressive Drugs
Nitrogen mustard, azathioprine, tacrolimus, mycophenolate mofetil and vincristine have been tried with variable success but did not gain a great deal of popularity as a result of the initial successful results with CSA. However, success rates and the side effect profile of both vincristine[42] and mycophenolate mofetil[43] are encouraging and they are likely to emerge as attractive steroid sparing agents.
Immunomodulatory Drugs
Levamisole (LEV) is an antihelminthic drug which is an immunostimulant. It has been successfully used at a dosage of 2.5 mg/kg on alternate days alone or in conjunction with alternate day prednisolone for FRNS and SDNS.[16] The major advantage of LEV is its steroid sparing effect, with minimal side effects. LEV is less effective when used alone than in combination with corticosteroids. It is not clear from the literature how prednisolone should be withdrawn during LEV therapy in order to minimize the risk of relapse. Although a controlled trial questioned the early positive findings of LEV therapy,[44] a recent report where LEV therapy was extended to 2-3 years reduced the number of relapses per patient from 5.2 to 0.65 in the first year.[45]
Toxicity of Cytotoxic Drugs
Toxicity of alkylating agents has been well known for many years and includes short term as well as long-term side effects. Bone marrow suppression with neutropenia, lymphopenia and thrombocytopenia, alopecia, nausea, abdominal pain and discomfort, hemorrhagic cystitis and increased risk of malignancy constitute the short term side effects, while long term side effects include increased risk of future malignancy and potential gonadal toxicity.[15] Arterial hypertension, hypertrichosis, gingival hyperplasia, hypomagnesemia, hyperuricemia and nephrotoxicity may be encountered during CSA therapy.[41]
A particular concern regarding the use of cytotoxic drugs is the long-term cancer risk, but this risk has not been quantified in children.[15] There is a general paucity of data regarding cumulative dose toxicity for the various agents mentioned above, and this is an important factor to bear in mind and should be discussed with parents and children before the initiation of therapy. Other potential medium and long-term side effects such as teratogenicity and infertility are also important considerations, but they rarely become major concerns at the doses and durations of cytotoxic immunosuppression employed in the treatment of childhood NS.[15]
Cytotoxic and immunosuppressive drugs undoubtedly play an important role in the treatment of certain forms of childhood NS, even though these drugs in themselves are associated with significant rates of morbidity and even mortality. It is therefore of particular importance that the benefits and risks of these agents are meticulously balanced before considering their use in the treatment of patients with NS. This point is worthy of emphasis since majority of children with SSNS will outgrow the disease around puberty irrespective of therapy.
References
1. Consensus statement on management and audit potential for steroid responsive nephrotic syndrome. Report of a workshop by the British Association for Paediatric Nephrology and Research Unit, Royal College of Physicians. Arch Dis Child 1994; 70: 151-157.
2. Trompeter RS, Lloyd BW, Hicks J, White RH, Cameron JS (1985). Long-term outcome for children with minimal change nephrotic syndrome. Lancet i: 368-370.
3. Shalhoub RJ. Pathogenesis of lipoid nephrosis: a disorder of T-cell function. Lancet 1974; ii: 556-560.
4. Lander HB. Effects of measles on nephrotic syndrome. Am J Dis Child 1949; 78(5): 813-815.
5. Hulton SA, Shah V, Byrne MR, Morgan G, Barratt TM, Dillon MJ. Lymphocyte subpopulations, interleukin-2 and interleukin-2 receptor expression in childhood nephrotic syndrome. Pediatr Nephrol 1994; 8: 135-139.
6. Topaloglu R, Saatci U, Arikan M, Canpinar H, Bakkaloglu A, Kansu E. T-cell subsets, interleukin-2 receptor expression and production of interleukin-2 in minimal change nephrotic syndrome. Pediatr Nephrol 1994; 8: 649-652.
7. Trompeter RS, Layward L, Hayward AR. Primary and secondary abnormalities of T cell sub populations. Clin Exp Immunol 1978; 34: 388-392.
8. Arneil GC. Treatment of nephrosis with prednisolone. Lancet 1956; i: 409-411.
9. The primary nephrotic syndrome in children. Identification of patients with minimal change nephrotic syndrome from initial response to prednisone. A report of the International Study of Kidney Disease in Children. J Pediatr 1981; 98: 561-564.
10. Hoyer PF, Gonda S, Barthels M, Krohn HP, Brodehl J. Thromboembolic complications in children with nephrotic syndrome. Risk and incidence. Acta Paediatr Scand 1986; 75: 804-807.
11. Kresnsky AM, Ingelfinger JR, Grupe WE. Peritonitis in childhood nephrotic syndrome. Am J Dis Child 1982; 136: 732-736.
12. Barratt TM, Soothill JF. Controlled trial of cyclophosphamide in steroid-sensitive relapsing nephrotic syndrome in childhood. Lancet 1970; 2: 479-482.
13. Barratt TM, Bercowsky A, Osofsky SG, Soothill JF. Cyclophosphamide treatment in steroid-sensitive nephrotic syndrome of childhood. Lancet 1975; 1: 55-58.
14. Trompeter RS. Minimal change nephrotic syndrome and cyclophosphamide. Arch Dis Child 1986; 61(8): 727-729.
15. Etteldorf JN, West CD, Pitcock JA, Williams DL. Gonadal function, testicular histology, and meiosis following cyclophosphamide therapy in patients with nephrotic syndrome. J Pediatr 1976; 88: 206-212.
16. Levamisole for corticosteroid-dependent nephrotic syndrome in childhood. British Association for Pediatric Nephrology. Lancet 1991; 337: 1555-17.
17. Bagga A,.Hari P. Levamisole-induced vasculitis. Pediatr Nephrol 2000; 14: 1057-1058.
18. Gassock RJ. Normal physiology and pathophysiology of proteinuria. In Cameron JS, Gassock RJ eds. The nephrotic syndrome. New York; Marcel Dekker, 1988; 219-249.
19. Elises JS,Griffiths PD, Hocking MD et al. Simplified quantification of urinary protein excretion in children. Clin Nephrol 1988; 30: 225-229.
20. Abeyagunawardena A, Goldblatt D, Andrews N, Trompeter RS. Risk of relapse after meningococcal C conjugate vaccine in nephrotic syndrome. Lancet 2003; 9: 362(9382): 449-450.
21. Arbeitsgemeinschaft fr Pδdiatrische Nephrologie. Alternate-day versus intermittent prednisone in frequently relapsing nephrotic syndrome. Lancet 1979; i: 401-403.
22. Bargman JM. Management of minimal lesion glomerulonephritis: Evidence-based recommendations. Kidney Int 1999; 55(S70): S3-S16
23. Hodson EM, Knight JF, Willis NS, Craig JC. Corticosteroid therapy in nephrotic syndrome: a meta-analysis of randomised controlled trials. Arch Dis Child 2000; 83: 45-51.
24. Abeyagunawardena A, Brogan PA, Trompeter RS, Dillon MJ. Immunosuppressive therapy of childhood idiopathic nephrotic syndrome. Expert Opin Pharmacother 2002; 3(5): 513-519.
25. Nephrotic syndrome in children: a randomised controlled trial comparing two prednisone regimens in steroid-responsive patients who relapse early. A report of the International Study of Kidney Disease in Children. J Pediatr 1979; 95: 239-243.
26. Choonara IA, Heney D, Meadow SR. Low dose prednisolone in nephrotic syndrome. Arch Dis Child 1989; 64: 610-611.
27. Ehrich JH, Brodehl J. Long versus standard prednisone therapy for initial treatment of idiopathic nephrotic syndrome in children (Arbeitsgemeinschaft fr Pδdiatrische Nephrologie). European Journal of Pediatrics 1993; 150: 380-387.
28. Rees L, Greene SA, Adlard P, Jones J, Haycock GB, Rigden SP et al. Growth and endocrine function in steroid sensitive nephrotic syndrome. Arch Dis Child 1988; 63: 484-490.
29. Polito C, Oporto MR, Totino SF et al. Normal growth of nephrotic children during long-term alternate day prednisone therapy. Acta Paediatrica Scandinavica 1986; 75: 245-250.
30. Neuhaus TJ, Fay J, Dillon MJ, Trompeter RS, Barratt TM. Alternative treatment to corticosteroids in Steroid sensitive idiopathic nephrotic syndrome. Arch Dis Child 1994; 71: 522-526.
31. Abeyagunawardena A, Dillon MJ, Rees L, van't Hoff W, Trompeter RS. The use of steroid sparing agents in steroid sensitive nephrotic syndrome. Pediatric Nephrol 2003; 18: 919-924.
32. Latta K, von Schnakenburg C, Ehrich JH. A meta-analysis of cytotoxic treatment for frequently relapsing nephrotic syndrome in children. Pediatr Nephrol 2001; 16(3): 271-282.
33. Arbeitsgemeinschaft fr Pδdiatrische Nephrologie. Cyclophosphamide treatment of steroid dependent nephrotic syndrome: comparison with 8 week with 12 week course. Arch Dis Child 1987; 62: 1102-1106.
34. Ueda N, Kuno K, Ito S. Eight and 12 week courses of Cyclophosphamide in nephrotic syndrome. Arch Dis Child 1990; 65: 1147-1150.
35. Barratt TM, Cameron JS, Chantler C, Ogg CS, Soothill JF. Comparative trial of 2 weeks and 8 weeks cyclophosphamide in steroid- sensitive relapsing nephrotic syndrome of childhood. Arch Dis Child 1973; 48: 286-290.
36. Donia AF, Gazareen SH, Ahmed HA, Moustafa FE, Shoeib AA, Ismail AM, Khamis S, Sobh MA. Pulsed cyclophosphamide inadequately suppresses the recurrence of minimal change nephrotic syndrome in corticoid-dependant children. Nephol Dial Transplant 2003; 18(10): 2054-2058.
37. Bircan Z, Kara B. Intravenous cyclophosphamide is the drug of choice for steroid dependant nephrotic syndrome. Pediatr Int 2003; 45(1): 65-67.
38. Abeyagunawardena A, Collins S, Dillon MJ, Rees L, van't Hoff W, Trompeter RS. Alteration of disease course in steroid sensitive nephrotic syndrome following cyclophosphamide. Pediatr Nephrol 2002(
Abstract);17:C67
39. Grupe WE, Makker SP, Ingelfinger JR. Chlorambucil treatment of frequently relapsing nephrotic syndrome. N Engl J Med 1976; 295: 746-749.
40. Hulton SA, Neuhaus TJ, Dillon MJ, Barratt TM. Long-term cyclosporine A treatment of minimal-change nephrotic syndrome of childhood. Pediatr Nephrol 1994; 8: 401-403.
41. Brodehl J. Management of nephrotic syndrome in children. Clinical Immunotherapy 1996; 5: 175-192.
42. Abeyagunawardena AS, Abeysekera CK, Thalgahagoda RS, Dillon MJ. Pulsed vincristine therapy in steroid resistant nephrotic syndrome. Proceedings of the 13th Congress of the International Paediatric Nephrology Association 2004. Pediatr Nephrol 2004 (
Abstract);19:C66
43. Bagga A, Hari P, Moudgil A, Jordan SC. Mycophenolate mofetil and prednisolone therapy in children with steroid-dependant nephrotic syndrome. Am J Kidney Dis 2003; 42(6): 1114-1120.
44. Dayal U, Dayal AK, Shastry JC, Raghupathy P. Use of levamisole in maintaining remission in steroid-sensitive nephrotic syndrome in children. Nephron 1994; 66: 408-412.
45. Ginevri F, Trivelli A, Ciardi MR, Ghiggeri GM, Parfumo F, Gusmano R. Protracted levamisole in children with frequent-relapse nephrotic syndrome. Pediatr Nephrol 1996; 10: 550.(Abeyagunawardena AS)
Abstract
Childhood idiopathic nephrotic syndrome (NS) is a chronic glomerular disorder, and if untreated, is associated with increased risk of life-threatening infections, thromboembolism, lipid abnormalities, and malnutrition. The aim of the management of NS in children is to induce and maintain complete remission with resolution of proteinuria and edema without encountering serious adverse effects of therapy. Over 90% of cases in children are due to minimal change disease (MCD) and a majority of them will respond to corticosteroid therapy. Steroid sensitive NS is considered to be a relatively benign condition; progression to end stage renal failure is extremely rare and over 80% achieve spontaneous remission in later childhood. The early disease is characterized by a relapsing course, placing the child at risk of acute complications. The occurrence of frequent relapses necessitates clear therapeutic strategies in order to maintain sustained remission and minimize steroid toxicity. Numerous therapeutic regimens have been proposed utilizing steroid sparing agents such as alkylating agents, principally, cyclophosphamide and chlorambucil, calcineurin inhibitors namely cyclosporin A and immunomodulatory drug levamisole with variable success and associated side-effects. It is therefore important that the benefits and risks of these agents are weighed before considering their use in the treatment of patients with NS.
Keywords: Idiopathic nephrotic syndrome; Corticosteroid therapy; Minimal change disease
Idiopathic nephrotic syndrome (NS) is a common glomerular disorder in childhood characterized by heavy proteinuria, hypoproteinemia, edema and hyperlipidemia. Estimates of annual incidence range from 2 to 7 new cases in children under 16 yrs per 100,000 total populations, leading to a cumulative prevalence of 15.7 per 100,000 due to the chronic nature of the disease. There is however a racial variation in the susceptibility with a reported incidence of 9-16 per 100,000 in British Asian children.[1]
Most patients with NS have minimal changes in the glomeruli on histology and 90%-95% will respond to corticosteroid therapy.[2] There is a close correlation between steroid sensitivity and minimal change disease (MCD), and therefore at the initial presentation, a renal biopsy is not performed in the absence of risk factors suggesting other forms of NS. A minority of children with underlying focal segmental glomerulosclerosis (FSGS) and diffuse mesangial proliferative glomerulonephritis will also respond to corticosteroid therapy. Consequently, a clinically useful classification of NS is that of steroid sensitive NS (SSNS), or steroid resistant NS (SRNS). SSNS has a more favorable outcome with a high probability of long-term remission and preserved renal function, while the prognosis of SRNS is more guarded, with a significant proportion progressing to end stage renal failure.
A perturbation of the immune system was proposed by Shalhoub[3] to be important in the pathogenesis of NS. It was also known that following an attack of measles, patients with NS might have long-term remission.[4] It is now believed that a disturbance in the Th1 and Th2 immune mechanisms, mediated by cytokines, is involved in the pathogenesis of NS.[5], [6], [7] These observations represent the scientific rationale for use of cytotoxic and immunosuppressive drugs in childhood NS.
Arniel first proposed the use of prednisolone in children with NS.[8] Subsequently the International Study of Kidney Disease in Children (ISKDC) proposed 60 mg/m2/day of prednisolone for induction of remission of NS, which has been accepted as standard treatment.[9] Although a majority of children will respond to corticosteroid therapy, this therapy is not curative, and most patients relapse. Each relapse is associated with an increased risk of morbidity and mortality from infection, thromboembolism and hypovolemic shock.[2], [10], [11]
Steroid toxicity is a major cause for concern in children with NS and their families. In 1967, cyclophosphamide (CYC) was reported as an effective agent in maintaining sustained remission in steroid sensitive NS.[12], [13] Side effects of CYC have been a cause for concern, including alopecia, bone marrow suppression and opportunistic infections, hemorrhagic cystitis and long-term risk of malignancy and infertility.[14], [15] In the mid 1980's, levamisole (LEV) and calcineurin inhibitor cyclosporin A (CSA) were used with variable success. While the reported side effects with LEV therapy are low,[16], [17] the side effects of CSA include hirsutism, gingival hypertrophy and nephrotoxicity.
This article reviews the current approach to the therapy of NS in childhood, with emphasis on the use of corticosteroid and other immunosuppressive agents.
Initial laboratory evaluation
Urine
Urine deposits
Transient microscopic hematuria is found in 23% patients with steroid sensitive MCD.[1] Persistence of microscopic hematuria is more indicative of FSGS but this should not be used to discriminate between the two. The presence of macroscopic hematuria is suggestive of more aggressive forms of glomerulonephritis.[1]
Urine protein
The ISKDC definition of NS in children is proteinuria greater than 40 mg/m2/hour in an overnight specimen of urine, which is equivalent to 1.7 g/24 hours in adults. Some experts suggest that nephrotic range proteinuria be defined as greater than 100 mg/m2/hour.[18] Timed urine collections in children can be cumbersome and urine protein: creatinine or albumin: creatinine (UAlb: UCr ) ratios provide a convenient approximation. UAlb: UCr of 400 mg/mmol (3.5 mg/mg) or urine protein: creatinine ratio of 200 mg/mmol (1.8 mg/mg) indicate nephrotic range proteinuria.[19]
Urine sodium
Measurement of the urinary sodium concentration is a valuable tool for the diagnosis of suspected hypovolemia, which leads to renal sodium retention. A urinary sodium value less than 10 mEq/l is diagnostic of intravascular volume contraction, while a value above 20 mEq/l makes it unlikely. However, this is not applicable if the child has received potent diuretics such as frusemide.
Blood Investigations
Proteins
Hypoalbuminemia (< 25 g/dL) is essential for the diagnosis of nephrotic syndrome. IgG levels were also reduced, but to a lesser degree than the albumin, and IgM is usually elevated. Plasma complement proteins, namely the C3 and C4 fractions are usually not altered, which help to differentiate SSNS from other forms of NS.
Lipids
Total plasma cholesterol, low-density and very low-density lipoproteins are grossly elevated, while high-density lipoproteins remain within the normal range.
Creatinine, urea and electrolytes
Plasma creatinine and urea concentrations are usually normal at presentation in SSNS, but mild to moderate increases may result from hypovolemia and renal underperfusion. Plasma electrolytes too are usually normal at presentation but hyponatremia is occasionally seen as a complication of hypovolemia. If the plasma volume is contracted, then anti-diuretic hormone is secreted in response to the baroreceptor stimulation leading to water retention and dilutional hyponatremia.
Calcium
The total plasma calcium concentration is low in parallel to the reduction of albumin level as it is partly albumin bound. However, the ionized calcium concentration is normal and it is not necessary to treat the low total calcium concentration that eventually returns to normal with normalization of albumin concentration.
Definitions
Nephrotic syndrome : Edema, hypoalbuminemia (< 25 g/l) and proteinuria > 40 mg/m2/hour or protein/creatinine ratio > 1.8 mg/mg
Remission : Urinary protein excretion < 4 mg/m2/hour or reagent strip (Albustix) negative or trace for three consecutive days
Relapse : Urinary protein excretion > 40 mg/m2/hour or albustix 3+ or more for three consecutive days having previously being in remission
Frequent relapses : Two or more relapses during the first 6 months after the initial episode or four or more relapses within any 12- month period
Steroid responsive : Remission achieved with steroid therapy alone
Steroid dependence : two consecutive relapses occurring during corticosteroid therapy or within 14 days after its cessation.
Steroid resistance : Failure to achieve remission following 4 weeks of daily prednisolone at 60 mg/m2/day
Management
General Measures
Diet
In the past, both low and high protein diets have been recommended for SSNS. A low protein diet reduces albuminuria but increases the risk of malnutrition. Animal studies show that high protein diets increase the synthesis of albumin, but do not increase the albumin concentration or growth significantly. Based on current evidence, no specific dietary advice is necessary for uncomplicated cases of SSNS. Modest salt restriction is beneficial during severe relapses, especially in patients with edema.
Activity
All efforts should be taken to actively mobilize the child; bed rest should be avoided if possible to minimize the risk of thrombosis.
Immunizations
All killed vaccines are generally regarded as safe for administration when a child is in remission. However, relapses are noted to cluster following meningococcal C conjugate vaccination program in the United Kingdom.[20] Caution should be exercised and parents counseled regarding the risk of relapse before administering this vaccine. All live vaccinations should be avoided until children are off daily steroids for at least 6 weeks. Additionally, they should be avoided where cyclophosphamide or cyclosporine A therapy has been initiated.[1]
Complications
Infections
Children with NS are at a higher risk of infection, partly because of the disease itself and partly due to immunosuppressive therapy. They have a strong predilection for pneumococcal infections. Some experts propose that children with NS be administered oral penicillin prophylaxis during a relapse of the disease.[1] It is important to remember that gram-negative bacteria cause a significant proportion of infections in children with NS, and until an organism has been identified in a particular patient, broad-spectrum antibiotics should be prescribed. Patients on immunosuppressive medications, if exposed to varicella infection, should preferably receive the zoster immunoglobulin within 72 hours. Patients who develop varicella should be treated with intravenous acyclovir.[1]
Hypovolemia
Hypovolemia and shock generally occur with the development of edema. Fluid loss during diarrhea, vomiting, sepsis and injudicious diuretic therapy might precipitate development of hypovolemia. Clinical signs and symptoms include severe central abdominal cramps with or without vomiting, reduced urine output, cold extremities, low blood pressure or reactive hypertension. Laboratory findings of low urinary sodium (< 10 mEq/l) and increased hematocrit suggest impending hypovolemic shock. Prompt treatment is essential and colloid infusion is the mainstay of treatment; 4.5% albumin, 20% albumin or plasma should be infused slowly under careful monitoring. If evidence of pulmonary edema develops, the infusion should be stopped and intravenous frusemide (1 mg/kg) administered.
Hypertension
In SSNS, the blood pressure is usually normal. However, hypertension in children with SSNS should be evaluated very carefully. It may reflect hypervolemia or extreme vasoconstriction in response to hypovolemia mediated via the renin-angiotensin system. In the latter, urinary sodium will be very low. If blood pressure exceeds the normal limit, a short course of antihypertensives could be prescribed once hypovolemia is excluded. Commonly used antihypertensive medications are nifedipine, hydralazine or atenolol. Diuretics are useful when hypertension is due to fluid overload.
Thrombosis
Children with NS are prone to develop both arterial and venous thrombosis. The propensity for thrombosis is due to a combination of hemodynamic factors and hypercoagulable state associated with NS. This, along with loss of anti-thrombin[1] in urine, increases the risk of thrombosis in children with NS.[10] The usually affected sites are the deep veins of the legs and pelvis, mesenteric veins and pulmonary vasculature.
Acute renal failure
Acute renal failure rarely complicates SSNS, but a mild degree of prerenal azotemia is seen in association with hypovolemia which responds to volume replacement. Acute renal failure unresponsive to volume replacement with histological appearance of acute tubular necrosis is encountered occasionally with SSNS. Affected individuals usually make complete recovery but dialysis may be required if renal failure persists for a longer duration.
Malnutrition
Children with refractory NS may develop nutritional deficiencies due to poor intake and malabsorption due to gut edema. The effects of poor nutrition may be masked by fluid retention and will be evident only with the resolution of edema.
Hyperlipidemia
One of the cardinal features of NS is hyperlipidemia, characterized by elevated total cholesterol, low-density lipoproteins and very low-density lipoproteins. Whether intermittent hyperlipidemia associated with SSNS increases the risk of future atherosclerosis remains to be determined, and at present, the routine use of lipid lowering drugs is not recommended.
Refractory edema
While awaiting steroid induced diuresis, edema could be controlled by the judicious use of diuretics (frusemide 1-2 mg/kg, spironolactone), once hypovolemia is excluded. In difficult cases 20% albumin or plasma could be infused along with diuretics (frusemide).
Indications for Renal Biopsy
In practice, renal histology is less important than the response to corticosteroid therapy. Renal biopsy is performed only when there are features that suggest histology other than MCD or later when there is steroid resistance.[1]
The indications for renal biopsy are:
Before treatment
1. Onset < 6 months of age
2. Initial macroscopic hematuria
3. Persistent microscopic hematuria with hypertension
4. Acute renal failure not attributable to hypovolemia
5. Low plasma C3 level
A biopsy is discretionary if: (a) onset is between 6-12 months of age, (b) onset above 14-16 years or (c) there is persistent hypertension, microscopic hematuria
Post treatment
A renal biopsy is recommended in all patients with steroid resistance. It is discretionary in frequently relapsing disease before commencing second line drugs (especially CSA).
Specific therapy
Induction of Remission
Corticosteroids
Corticosteroids remain the drug of first choice for induction of remission. While there are no controlled trials that have compared the efficacy of prednisone with prednisolone, both medications are comparable.
The treatment protocol, prednisolone 60 mg/m2 daily in divided doses for 4 weeks followed by 40 mg/m2 / day prednisolone for 3 consecutive days of a week (intermittent) for the next 4 weeks, designed by ISKDC over 35 years ago was empirical.[9] However, current practice is to prescribe alternate day therapy in the second month of treatment in preference to intermittent therapy because it reduces the relapse rate more effectively.[21] In the past 20 years there has been considerable debate regarding the optimization of the initial corticosteroid protocol. Several controlled studies have examined the effects of the duration of prednisolone therapy in relation to long-term outcome. Shorter prednisolone courses are associated with a higher rate of relapse. In contrast, significantly greater sustained remission was achieved by intensifying the initial steroid therapy.[22] Meta-analysis of randomised controlled trials suggests that the total duration of corticosteroid therapy should exceed that used in the ISKDC regimen.[23] The relative risk of relapse at 12-24 months falls by 0.133 (13%) for every month of increase in therapy for seven months.[23] However, the clinical usefulness of this reduction in terms of reducing the incidence of steroid dependent disease and in the use of second-line immunosuppressive agents such as cyclophosphamide and cyclosporine remain unclear. Long-term therapy may also be associated with a higher risk of side effects.
Overall, the optimal initial dose and the duration of corticosteroid therapy that is most beneficial for the induction of sustained remission with minimal side effects remain controversial. Therefore until results of more controlled trials are available, remission should be induced with prednisolone 60 mg/m2/24 hours as a single morning dose and continued for 4-6 weeks, irrespective of the timing of remission, followed by a tapering regimen of alternate day prednisolone for a further 6 weeks in order to achieve sustained remission.[24]
Treatment of Relapses
The characteristic feature of SSNS is tendency to relapse. Intensification of relapse treatment with prednisolone has little effect on the subsequent relapse rate.[25] The response to steroids is much better in relapses when compared to the initial episode.[1] Induction of remission is achieved with prednisolone 60 mg/m2/day as for the initial episode, followed by alternate day prednisolone for a further 4-6 weeks.[24] In spite of the report of induction of remission achieved with prescription of prednisolone,[26] such therapy could lead to difficulties in defining children who develop secondary steroid resistance and therefore is not recommended.
Children with a frequently relapsing disease or steroid dependent disease need individualized treatment.[1], [24] Although there is no data on the merits of long term maintenance, there is prednisolone as opposed to repeated standard relapse treatment, and most pediatric nephrologists favor the former approach.[1], [24] The dose should be titrated to the lowest level possible, sufficient to maintain remission in order to minimize steroid side effects. Most primary school children can tolerate 0.1-0.6 mg/kg/body weight on alternate day while most preschool children will tolerate up to 1mg/kg/body weight on alternate days.[1], [24] The duration should be for a minimum of 3-6 months as alternate day therapy, although a selected group of children may benefit from long-term alternate day treatment.
Steroid toxicity
The side effects of steroids are numerous, well-recognized and of great concern to the patient as well as the family. There was a positive correlation between the side effects and cumulative dose of steroids in children with an initial episode of SSNS.[27] Obesity, hirsutism, arterial hypertension and psychological disturbances are usually reversible after cessation of steroid therapy.[27] However, striae and cataracts are not reversible.[27] Growth failure was observed only in children with prolonged daily steroid therapy, while alternate day steroids were not associated with significant growth impairment.[28], [29] In order to prevent toxicity, patients on long term steroid therapy should be reviewed every 3 months for blood pressure and growth measurements and annually for development of cataracts.[1]
Cytotoxic Therapy
SSNS represents a milder form of the disease and a majority of children could be controlled with corticosteroid therapy.[30], [31] Children with frequently relapsing or steroid dependent disease who show steroid toxicity are the candidates for treatment with alkylating agents or other immunomodulatory drugs.
Cyclophosphamide
Over the past 30 years, CYC has been used for the treatment of childhood NS. It has been effective in inducing sustained remission in frequently relapsing NS (FRNS), steroid dependent NS (SDNS) and inducing remission in SRNS.[14] The initial strategy in cytotoxic treatment using CYC was an increase of daily dosage at biweekly intervals until neutropenia developed and at which point CYC was abruptly discontinued. CYC given orally in a dosage of 3 mg/kg/day for 8 weeks induced sustained remission in 69% at one year and 44% at five years in SSNS.[12] However, in subsequent studies the proportion of sustained remission induced varied considerably.[32] In spite of this, meta-analysis of randomized controlled trials suggests that CYC is useful in inducing sustained remission in SDNS.[32] Although it was reported that prescription of CYC 2 mg/kg/day orally for 12 weeks achieved a higher proportion of sustained remission,[33] subsequent studies failed to confirm this finding.[34] A shorter regimen of CYC for 2 weeks was associated with a higher relapse rate.[35] Intravenous pulsed CYC at 600 mg/m[2] monthly for six months is being increasingly used with variable success for SDNS.[36], [37] Most studies include small number of patients and therefore it is difficult to interpret the advantages over oral therapy. Relapse following CYC is generally treated with steroids. Second course of CYC is effective in inducing long-term remission.[31] As the long-term side effects of CYC are cumulative, such therapy should be reserved for select patients. Response of CYC in SRNS is unpredictable, and the information from literature is limited. Steroid resistant MCNS is usually responsive to CYC and there is a tendency for the subsequent relapses to become steroid responsive.[38]
Chlorambucil
Chlorambucil (CHL) can induce a prolonged steroid free remission in children with FRNS or SDNS and its efficacy is similar or even better than CYC. As with CYC, its long-term toxic effects limit its prolonged or continuous use. The dosage used is 0.2 mg/kg/day for 8-12 weeks.[39] The risk of hematological malignancy is greater with CHL than with CYC.[20]
Cyclosporine A
In SSNS, cyclosporine A (CSA) is generally reserved for children who become steroid dependent following a course of cyclophosphamide.[31], [40], [41] It is now increasingly used in preference to CYC in children approaching puberty, especially boys who are more vulnerable for testicular damage from CYC and in whom the disease does not have a long run.[41] CSA is generally prescribed at a dosage of 3-5 mg/kg/day for a period of one year.[31],[40], [41] Unlike CYC or CHL, CSA loses its protective effectiveness after cessation of treatment.[41] Long lasting remissions were obtained when CSA was prescribed continuously for 5 years.[41] CSA is a difficult drug to use and requires monitoring of blood concentrations and regular measurement of the glomerular filtration rate because of its potential nephrotoxicity.[40], [41]
Other Immunosuppressive Drugs
Nitrogen mustard, azathioprine, tacrolimus, mycophenolate mofetil and vincristine have been tried with variable success but did not gain a great deal of popularity as a result of the initial successful results with CSA. However, success rates and the side effect profile of both vincristine[42] and mycophenolate mofetil[43] are encouraging and they are likely to emerge as attractive steroid sparing agents.
Immunomodulatory Drugs
Levamisole (LEV) is an antihelminthic drug which is an immunostimulant. It has been successfully used at a dosage of 2.5 mg/kg on alternate days alone or in conjunction with alternate day prednisolone for FRNS and SDNS.[16] The major advantage of LEV is its steroid sparing effect, with minimal side effects. LEV is less effective when used alone than in combination with corticosteroids. It is not clear from the literature how prednisolone should be withdrawn during LEV therapy in order to minimize the risk of relapse. Although a controlled trial questioned the early positive findings of LEV therapy,[44] a recent report where LEV therapy was extended to 2-3 years reduced the number of relapses per patient from 5.2 to 0.65 in the first year.[45]
Toxicity of Cytotoxic Drugs
Toxicity of alkylating agents has been well known for many years and includes short term as well as long-term side effects. Bone marrow suppression with neutropenia, lymphopenia and thrombocytopenia, alopecia, nausea, abdominal pain and discomfort, hemorrhagic cystitis and increased risk of malignancy constitute the short term side effects, while long term side effects include increased risk of future malignancy and potential gonadal toxicity.[15] Arterial hypertension, hypertrichosis, gingival hyperplasia, hypomagnesemia, hyperuricemia and nephrotoxicity may be encountered during CSA therapy.[41]
A particular concern regarding the use of cytotoxic drugs is the long-term cancer risk, but this risk has not been quantified in children.[15] There is a general paucity of data regarding cumulative dose toxicity for the various agents mentioned above, and this is an important factor to bear in mind and should be discussed with parents and children before the initiation of therapy. Other potential medium and long-term side effects such as teratogenicity and infertility are also important considerations, but they rarely become major concerns at the doses and durations of cytotoxic immunosuppression employed in the treatment of childhood NS.[15]
Cytotoxic and immunosuppressive drugs undoubtedly play an important role in the treatment of certain forms of childhood NS, even though these drugs in themselves are associated with significant rates of morbidity and even mortality. It is therefore of particular importance that the benefits and risks of these agents are meticulously balanced before considering their use in the treatment of patients with NS. This point is worthy of emphasis since majority of children with SSNS will outgrow the disease around puberty irrespective of therapy.
References
1. Consensus statement on management and audit potential for steroid responsive nephrotic syndrome. Report of a workshop by the British Association for Paediatric Nephrology and Research Unit, Royal College of Physicians. Arch Dis Child 1994; 70: 151-157.
2. Trompeter RS, Lloyd BW, Hicks J, White RH, Cameron JS (1985). Long-term outcome for children with minimal change nephrotic syndrome. Lancet i: 368-370.
3. Shalhoub RJ. Pathogenesis of lipoid nephrosis: a disorder of T-cell function. Lancet 1974; ii: 556-560.
4. Lander HB. Effects of measles on nephrotic syndrome. Am J Dis Child 1949; 78(5): 813-815.
5. Hulton SA, Shah V, Byrne MR, Morgan G, Barratt TM, Dillon MJ. Lymphocyte subpopulations, interleukin-2 and interleukin-2 receptor expression in childhood nephrotic syndrome. Pediatr Nephrol 1994; 8: 135-139.
6. Topaloglu R, Saatci U, Arikan M, Canpinar H, Bakkaloglu A, Kansu E. T-cell subsets, interleukin-2 receptor expression and production of interleukin-2 in minimal change nephrotic syndrome. Pediatr Nephrol 1994; 8: 649-652.
7. Trompeter RS, Layward L, Hayward AR. Primary and secondary abnormalities of T cell sub populations. Clin Exp Immunol 1978; 34: 388-392.
8. Arneil GC. Treatment of nephrosis with prednisolone. Lancet 1956; i: 409-411.
9. The primary nephrotic syndrome in children. Identification of patients with minimal change nephrotic syndrome from initial response to prednisone. A report of the International Study of Kidney Disease in Children. J Pediatr 1981; 98: 561-564.
10. Hoyer PF, Gonda S, Barthels M, Krohn HP, Brodehl J. Thromboembolic complications in children with nephrotic syndrome. Risk and incidence. Acta Paediatr Scand 1986; 75: 804-807.
11. Kresnsky AM, Ingelfinger JR, Grupe WE. Peritonitis in childhood nephrotic syndrome. Am J Dis Child 1982; 136: 732-736.
12. Barratt TM, Soothill JF. Controlled trial of cyclophosphamide in steroid-sensitive relapsing nephrotic syndrome in childhood. Lancet 1970; 2: 479-482.
13. Barratt TM, Bercowsky A, Osofsky SG, Soothill JF. Cyclophosphamide treatment in steroid-sensitive nephrotic syndrome of childhood. Lancet 1975; 1: 55-58.
14. Trompeter RS. Minimal change nephrotic syndrome and cyclophosphamide. Arch Dis Child 1986; 61(8): 727-729.
15. Etteldorf JN, West CD, Pitcock JA, Williams DL. Gonadal function, testicular histology, and meiosis following cyclophosphamide therapy in patients with nephrotic syndrome. J Pediatr 1976; 88: 206-212.
16. Levamisole for corticosteroid-dependent nephrotic syndrome in childhood. British Association for Pediatric Nephrology. Lancet 1991; 337: 1555-17.
17. Bagga A,.Hari P. Levamisole-induced vasculitis. Pediatr Nephrol 2000; 14: 1057-1058.
18. Gassock RJ. Normal physiology and pathophysiology of proteinuria. In Cameron JS, Gassock RJ eds. The nephrotic syndrome. New York; Marcel Dekker, 1988; 219-249.
19. Elises JS,Griffiths PD, Hocking MD et al. Simplified quantification of urinary protein excretion in children. Clin Nephrol 1988; 30: 225-229.
20. Abeyagunawardena A, Goldblatt D, Andrews N, Trompeter RS. Risk of relapse after meningococcal C conjugate vaccine in nephrotic syndrome. Lancet 2003; 9: 362(9382): 449-450.
21. Arbeitsgemeinschaft fr Pδdiatrische Nephrologie. Alternate-day versus intermittent prednisone in frequently relapsing nephrotic syndrome. Lancet 1979; i: 401-403.
22. Bargman JM. Management of minimal lesion glomerulonephritis: Evidence-based recommendations. Kidney Int 1999; 55(S70): S3-S16
23. Hodson EM, Knight JF, Willis NS, Craig JC. Corticosteroid therapy in nephrotic syndrome: a meta-analysis of randomised controlled trials. Arch Dis Child 2000; 83: 45-51.
24. Abeyagunawardena A, Brogan PA, Trompeter RS, Dillon MJ. Immunosuppressive therapy of childhood idiopathic nephrotic syndrome. Expert Opin Pharmacother 2002; 3(5): 513-519.
25. Nephrotic syndrome in children: a randomised controlled trial comparing two prednisone regimens in steroid-responsive patients who relapse early. A report of the International Study of Kidney Disease in Children. J Pediatr 1979; 95: 239-243.
26. Choonara IA, Heney D, Meadow SR. Low dose prednisolone in nephrotic syndrome. Arch Dis Child 1989; 64: 610-611.
27. Ehrich JH, Brodehl J. Long versus standard prednisone therapy for initial treatment of idiopathic nephrotic syndrome in children (Arbeitsgemeinschaft fr Pδdiatrische Nephrologie). European Journal of Pediatrics 1993; 150: 380-387.
28. Rees L, Greene SA, Adlard P, Jones J, Haycock GB, Rigden SP et al. Growth and endocrine function in steroid sensitive nephrotic syndrome. Arch Dis Child 1988; 63: 484-490.
29. Polito C, Oporto MR, Totino SF et al. Normal growth of nephrotic children during long-term alternate day prednisone therapy. Acta Paediatrica Scandinavica 1986; 75: 245-250.
30. Neuhaus TJ, Fay J, Dillon MJ, Trompeter RS, Barratt TM. Alternative treatment to corticosteroids in Steroid sensitive idiopathic nephrotic syndrome. Arch Dis Child 1994; 71: 522-526.
31. Abeyagunawardena A, Dillon MJ, Rees L, van't Hoff W, Trompeter RS. The use of steroid sparing agents in steroid sensitive nephrotic syndrome. Pediatric Nephrol 2003; 18: 919-924.
32. Latta K, von Schnakenburg C, Ehrich JH. A meta-analysis of cytotoxic treatment for frequently relapsing nephrotic syndrome in children. Pediatr Nephrol 2001; 16(3): 271-282.
33. Arbeitsgemeinschaft fr Pδdiatrische Nephrologie. Cyclophosphamide treatment of steroid dependent nephrotic syndrome: comparison with 8 week with 12 week course. Arch Dis Child 1987; 62: 1102-1106.
34. Ueda N, Kuno K, Ito S. Eight and 12 week courses of Cyclophosphamide in nephrotic syndrome. Arch Dis Child 1990; 65: 1147-1150.
35. Barratt TM, Cameron JS, Chantler C, Ogg CS, Soothill JF. Comparative trial of 2 weeks and 8 weeks cyclophosphamide in steroid- sensitive relapsing nephrotic syndrome of childhood. Arch Dis Child 1973; 48: 286-290.
36. Donia AF, Gazareen SH, Ahmed HA, Moustafa FE, Shoeib AA, Ismail AM, Khamis S, Sobh MA. Pulsed cyclophosphamide inadequately suppresses the recurrence of minimal change nephrotic syndrome in corticoid-dependant children. Nephol Dial Transplant 2003; 18(10): 2054-2058.
37. Bircan Z, Kara B. Intravenous cyclophosphamide is the drug of choice for steroid dependant nephrotic syndrome. Pediatr Int 2003; 45(1): 65-67.
38. Abeyagunawardena A, Collins S, Dillon MJ, Rees L, van't Hoff W, Trompeter RS. Alteration of disease course in steroid sensitive nephrotic syndrome following cyclophosphamide. Pediatr Nephrol 2002(
Abstract);17:C67
39. Grupe WE, Makker SP, Ingelfinger JR. Chlorambucil treatment of frequently relapsing nephrotic syndrome. N Engl J Med 1976; 295: 746-749.
40. Hulton SA, Neuhaus TJ, Dillon MJ, Barratt TM. Long-term cyclosporine A treatment of minimal-change nephrotic syndrome of childhood. Pediatr Nephrol 1994; 8: 401-403.
41. Brodehl J. Management of nephrotic syndrome in children. Clinical Immunotherapy 1996; 5: 175-192.
42. Abeyagunawardena AS, Abeysekera CK, Thalgahagoda RS, Dillon MJ. Pulsed vincristine therapy in steroid resistant nephrotic syndrome. Proceedings of the 13th Congress of the International Paediatric Nephrology Association 2004. Pediatr Nephrol 2004 (
Abstract);19:C66
43. Bagga A, Hari P, Moudgil A, Jordan SC. Mycophenolate mofetil and prednisolone therapy in children with steroid-dependant nephrotic syndrome. Am J Kidney Dis 2003; 42(6): 1114-1120.
44. Dayal U, Dayal AK, Shastry JC, Raghupathy P. Use of levamisole in maintaining remission in steroid-sensitive nephrotic syndrome in children. Nephron 1994; 66: 408-412.
45. Ginevri F, Trivelli A, Ciardi MR, Ghiggeri GM, Parfumo F, Gusmano R. Protracted levamisole in children with frequent-relapse nephrotic syndrome. Pediatr Nephrol 1996; 10: 550.(Abeyagunawardena AS)