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                                                A few minimal change nephrotic syndrome

ping the initial prednisolone therapy. It is      group will reveal itself as (i) frequent
obvious from this s...
INDIAN PEDIATRICS                                                 VOLUME 31-SEPTEMBER 1994

dose used is 2.5 mg/kg on alt...

    Desperate diseases are treated with        common complications like severe life
desperate measures such a...
INDIAN PEDIATRICS                                                          VOLUME 31-SEPTEMBER 1994

thromboembolic episo...
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  1. 1. Editorial A few minimal change nephrotic syndrome (MCNS) cases do not respond to steroids and a few steroid responders have histology other than MCNS like focal segmental glomerulosclerosis (FSGS) or membrano- Recent Concepts in Management proliferative (MPGN) or mesangioprolifera- of Nephrotic Syndrome tive glomerulonephritis (mesprolif GN)- It is not clear whether MCNS and FSGS are two extremes of same disease with diffuse This is the third editorial on nephrotic mesangial proliferative stage in between syndrome in this journal in last 4 years. The in those nephrotics who end in renal previous 2 editorials were addressed to failure(4,6). problems of frequent relapses(l) and review of literature on pathogenesis of nephrotic Though a single best plan is yet to be syndrome(2). In a recent article, analysis of established, prednisolone therapy is the 111 nephrotic children for appropriateness mainstay of the treatment and other drugs of therapy revealed inappropriate dosage are used only if the patient does not respond and duration of prednisolone and cyclo- to steroids or develops toxicity to steroids phosphamide therapy advised by 39.4% pe- and needs alternative treatment(4-7). The diatricians, 59% internists and 80% general second objective in those who respond to practitioners(3). Hence, this editorial aims prednisolone is to prevent subsequent re- to review conventional therapy and recent lapses. More than 50% of nephrotics relapse advances in management of nephrotic and in some series more than 40% of MCNS syndrome. are frequent relapsers (more than 3 relapses in 1 year after initial response) or steroid The main objectives in management of dependent (relapse while tapering steroids nephrotic syndrome are to induce quick re- or within 2 weeks of stopping). There is not mission to ensure freedom from edema and a single clinical, biochemical, immunologi- consequences of persistent nephrotic state cal or histological test to predict frequent such as hyperlipidemia, protein malnutri- relapsers, but occurrence of first relapse tion, thromboembolic episodes, severe in- soon after the initial attack predicts frequent fections, etc. This is achieved by adminis- future relapses requiring multiple courses of tration of oral prednisolone in a dosage of 2 prednisolone therapy which escalates the mg/kg/day in 2-3 divided doses for the-ini- risk of steroid toxicity. tial attack and is effective in ameliorating proteinuria in 93-98% of minimal change Recent data published by German Col- nephrotic syndrome and 75-77% of cases of laborative Study showed that when longer idiopathic nephrotic syndrome which con- and more intensive course of prednisolone stitutes 90% of total nephrotic population in was administered for the initial attack (12 children. Hence, steroid responsive nephro- weeks instead of 8 weeks course of ISKDC tic syndrome and minimal change nephrotic regime), the subsequent relapse rate was re- syndrome are used interchangeably loosely. duced significantly, 18 months after stop-
  2. 2. EDITORIAL ping the initial prednisolone therapy. It is group will reveal itself as (i) frequent obvious from this study that intensive initial relapsers, (ii) steroid dependent, (iii) infre- treatment has a decisive influence on subse- quent relapsers, or (iv) no relapse after the quent relapse and produced longer remis- first attack. For this, strict definitions should sion^). The longer course may result in be used otherwise future management higher incidence of steroid toxicity, hence cannot be planned. the third issue of avoidance of steroid toxi- The management of frequent relapses or city needs to be considered. steroid dependent nephrotic syndrome It is evident that side effects of steroids should be individualized and some of the such as cushingoid appearance, hyperten- options are as follows: (i) single low dose sion, striae, osteoporosis, cataracts, growth alternate day prednisolone treatment for retardation, infections and psychosocial dis- 3-12 months to keep proteinuria under turbances adds to the morbidity and mortal- control; (ii) use of cytotoxic drugs like ity of nephrotic syndrome. Although the cyclophosphamide or chlorambucil for 8 Germany study showed no difference in the weeks in frequent relapsers and for 12 steroid toxicity with a 12 week course of weeks for steroid dependent cases keeping prednisolone when compared with an 8 in mind short term and long term toxic week course of ISKDC, a close monitoring effects on bone marrow, gonadal functions of these patients with weekly BP, weight and oncogenic potentials. The cumulative record and clinical evaluation for presence dose of cyclophosphamide of 200 mg/kg of covert infection is mandatory(4-7). and of chlorambucil of 10 mg/kg is consid- ered safe. A single course of cytotoxic drugs Regular follow up in Outpatient Depart- when used with tapering dose of predniso- ment to detect relapse at early stage before lone results in long remissions of 24-30 edema starts (urine albumin 3+ on 3 conse- months in 40-60% of children with MCNS. cutive days) is sufficient to start treatment. Steroid responsiveness is associated with Recently, 24 hour urinary protein excretion better outcome even in the non minimal is replaced by urine protein/creatinine change nephrotics diagnosed by histologic ratio in early morning spot sample of urine. criteria. Children who relapse soon after A ratio of 3.5 or more correlates with cyclophosphamide treatment pose major nephrotic range of proteinuria as observed therapeutic problems for clinicians. Cur- in our institution (unpublished data) and rently, two new drugs are used for their confirmed by others(9,10). steroid sparing effects in steroid dependent/ frequent relapsing/steroid and cyclophos- The treatment of relapse should be less phamide resistant nephrotic syndrome. intensive and aimed at inducing urinary remission (protein free 3 consecutive early (i) Levamisole, a non-specific immu- morning urine samples) followed by 4 nostimulant of T cell function in immuno- weeks of alternate day prednistflone (1.5 comprised individuals, has been used in a mg/kg/48 h) as a single morning dose every multicentric double blind placebo con- other day. The intensity of treatment of re- trolled trial by the British Association for lapse has no further influence on subsequent Pediatric Nephrology in 61 children with relapse rate. With this regime, at the end of frequently relapsing and dependent cortico- 1 year of follow up, the steroid responsive steroid sensitive nephrotic syndrome. The 1034
  3. 3. INDIAN PEDIATRICS VOLUME 31-SEPTEMBER 1994 dose used is 2.5 mg/kg on alternate day In Western countries like Germany and orally for 112 days along with tapering dose USA it is advocated in steroid dependent of prednisolone on alternate day for first 56 and steroid resistant nephrotic syndrome in days of levamisole treatment. On follow up children around pubertal age when cyclo- 14/31 on levamisole and 4/30 on placebo phosphamide and chlorambucil are contra- were in remission for more than 3 months indicated or in cases who do not respond to and this result was statistically significant. cyclophosphamide. Levamisole is not avail- Review of literature reveals 83 out of a total able for clinical use in many western coun- of 109 children and adults treated with tries. Cyclosporin A is not available or levamisole showed complete or partial re- affordable in our country. mission and steroid sparing effect. Hence, With this treatment, majority of MCNS this study recommends levamisole in select- will stop relapsing over 5-15 years, if they ed cases of frequent relapsing and steroid do not succumb to infections, steroid toxi- dependent steroid responsive nephrotic city or unrelated conditions. Growth retar- syndrome without severe nephrotic state, dation is a major problem with prolonged thromboembolic episodes, severe hypo- steroid therapy or persistent nephrotic state. volemic or shock. The side effects of this drug are minimal and cost benefit ratio The picture is not rosy for nephrotics favorable. Long term treatment free remis- with steroid resistant FSGS MPGN or sions are less with levamisole when com- diffuse mesangioproliferative GN as many pared to cytotoxic drugs(ll,12). We have relentlessly progress to end stage renal used this drug with good results in 50 disease, hypertension or remain persistently frequent relapsers. in a nephrotic state(4-8). . (ii) Cyclosporin A is a recent addition to In steroid non-responsive nephrotic the armametarium of drugs for steroid syndrome kidney biopsy is mandatory to dependent or steroid resistant nephrotic separate minimal lesions from non-minimal syndrome. It inhibits cell mediated immune lesion nephrotic syndrome with the help of responses by reducing production of inter- light, electron and immunofluorescent leukin-2 by activated T-lymphocytes. The microscopy to decide about the choice of dose recommended is 4-5 mg/kg/day for 6- the drug and to predict long term 12 months. It was highly effective in 87% prognosis(4-8). steroid dependent nephrotic syndrome It has been widely believed that hematu- allowing cessation of prednisolone therapy, ria, hypertension and reduced renal function but most patients relapse while tapering at onset are bad prognostic signs and predict Cyclosporin A. Thus, a steroid dependent a lesion other than minimal change. But patient is converted to cyclosporin depen- from ISKDC study it emerged that amongst dent nephrotic syndrome. It is less effective patients with MCNS, diastolic hypertension in steroid resistant cases. Nephrotoxicity is was present in 13.5%, hematuria in 22.7% a known side effect with cyclosporin hence and elevated serum creatinine in 32.5%, but serial renal biopsies and monitoring of drug low C3 levels in an occasional case. Hence levels are recommended during cyclosporin if more than 2 atypical features or low therapy(13,14). Its bioavailability is vari- serum C3 is encountered in a nephrotic able and cost is prohibitive for our country. child, biopsy is indicated. 1035
  4. 4. EDITORIAL Desperate diseases are treated with common complications like severe life desperate measures such as high dose IV threatening infections, hypertension, hyper- pulse methylprednisolone, IV cyclophos- lipidemia and thromboembolic episodes phamide, or IV vincristin with controversial during the course of the disease. One should results(15,16). These new modalities of look for these complications and treat them therapy should be used by pediatricians or promptly to reduce the morbidity and mor- pediatric nephrologists conversant with tality. Currently, high protein diet and re- these modalities with a team approach as peated IV albumin infusions are thought to the treatment can be more hazardous than be responsible for hyperfiltration, so dietary the disease. protein intake to meet with requirement for growth is advised. In those patients who have not yet progressed to renal failure but exhibit ne- A small number of nephrotic children phrotic proteinuria, nephrotic syndrome or will need renal replacement therapy over a hypertension, use of ACE inhibitors, such as period of time. Renal transplant is not well enalapril may be tried which reduces established except in few centres in India. proteinuria, controls hypertension, reduces Transplant associated problems such as intraglomerular hypertension and hyperfil- rejection, severe infections and recurrence tration leading to glomerulosclerosis. We of disease in transplanted kidney will be have used this drug in the dose of 0.15-0.3 additional problems for future. mg/kg per day for 6-18 months in steroid To conclude, the current trend in mana- resistant, cyclophosphamide resistant cases. gement of nephrotic syndrome is to treat the Periodic monitoring with estimation of patients with intensive prednisolone therapy serum potassium, serum cr-eatinine, blood for the initial attack which is known to count is necessary to evaluate the side reduce the incidence of subsequent relapse effects(17). in steroid responsive nephrotic syndrome. Frequent relapsers and steroid dependent Use of antiplatelet agents like dipyri- should be treated with levamisole (if damole and low dose aspirin with or without nephrotic state is not serious) or cyclophos- anticoagulants like warfarin can prevent phamide (if the patient is not pubertal). progression of renal damage due to second- Cyclosporin can be used if the patient ary mechanisms like platelet aggregation can afford 6-12 month treatment. Long and intracapillary coagulopathy. The sur- remissions are induced by cytotoxic agents. vival and reduction in nephrotic syndrome Kidney biopsy is indicated in steroid non- is better in MPGN and FSGS when these responsive cases before a decision is made drugs are combined with cytotoxic drugs to use cyclophosphamide (or cyclosporin) and prednisolone. In the non-minimal for minimal lesion or focal segmental glo- change nephrotic syndrome, collection of merulosclerosis. Long term steroid therapy sufficient number of cases in each with dipyridamole and low dose aspirin may histopathologic category are difficult for be useful in membranoproliferative glome- randomized double blind controlled rulonephritis, whilst membranous glomeru- trials(15,16). lonephropathy should be left alone. At any Clinical and chemical alterations in stage of the long course of this disease, nephrotic syndrome are responsible for serious infections, hypovolemic shock or 1036
  5. 5. INDIAN PEDIATRICS VOLUME 31-SEPTEMBER 1994 thromboembolic episodes can occur even in 8. Srivastava RN, Govel S, Bagga A. Non- minimal change nephrotic syndrome. In: MCNS, whilst many non-minimal change Proceedings of First National Symposium nephrotics progress ultimately to end stage on Glomerular Diseases in Children. Eds renal failure. Mehta KP. Bombay, Vakil and Sons, 1993, pp 27-29. Kumud P. Mehta, 9. Iyer RS, Shailaja SN, Bhaskaranand N, Professor of Pediatrics and Head of Baliga M, Venkatesh A. Quantitation of Department, Pediatric Medicine, proteinuria using protein/creatinine ratio Chief, Nephrology Department and in random urine sample.' Indian Pediatr Honorary Assistant Director of Research 1991, 28: 463-467. Department, Bai Jerbai Wadia Hospital for 10. Shastri NJ, Shendurnikar N, Nayak U, Children and Research and Kotecha PV. Quantification of proteinuria Consultant Pediatrician, by urine protein/creatinine ratio. Indian Jaslok Hospital and Research Centre, Pediatr 1994, 31: 334-337. Bombay. 11. British Association for Pediatric Nephro- logy. Levamisole for corticosteroid de- REFERENCES pendent nephrotic syndrome in childhood. Lancet 1991, 337: 1555-1557. 1. Phadke M, Bhave S. Idiopathic nephrotic 12. Mehta KP, Ali U, Kutty M, Kolhatkar U. syndrome. The frequent relapsers. Indian Immunoregulatory treatment for minimal Pediatr 1990, 27: 1035-1038. change nephrotic syndrome. Arch Dis 2. Srivastava RN. Nephrotic Syndrome: Child 1986, 61: 153-158. Present status II. Indian Pediatr 1993, 30: 13. Niaudet P, Broyer M, Habib R. Treatment 313-317. of idiopathfc nephrotic syndrome with 3. Gulati S, Kher V, Elhence R, Kumar P, cyclosporin A in children. Clin Nephrol Sharma RK, Gupta A. Treatment of 1991, 35: S 31-36. nephrotic syndrome. Indian Pediatr 1994, 14. Tanaka R, Yoshikawa N, Kitano Y, Ito H, 31: 165-170. Nakamura H. Long term cyclosporin 4. Kim MS, Grupe WE. The management of treatment in children with steroid depen- primary glomerular disease. In: Pediatric dent nephrotic syndrome. Pediatr Nephrol Kidney Disease, 2nd edn. Ed Edelmann 1993, 7: 249-252. CM, Boston, Little Brown and Co., 1992, 15. Trompeter RS. Immunosuppressive thera- pp 1355-1380. py in the nephrotic syndrome in children. 5. Barratt M, Clark G. Minimal change Pediatr Nephrol 1989, 3: 194-200. nephrotic syndrome and focal segmental 16. Mendonza SA, Reznik VM, Griswold glomerulosclerosis. In: Pediatric Nephro- WR, Krensky AM. Treatment of steroid logy, 3rd edn. Eds Holiday, Barratt, resistant, focal segmental glomeruloscle- Avner. Baltimore, William and Wilkins, rosis with pulse methyl prednisolone and 1994, pp 767-787. alkylating agents. Pediatr Nephrol 1990, 6. Kher KK, Makker SP, Sweet M. Modern 4:303-307. management of nephrotic syndrome. 17. Mehta KP, Ali U. Enalapril in the man- Indian J Pediatr 1988, 55: 527-540. agement of resistant nephrotic syndrome of childhood. Abstracts 5th Asian Pacific 7. Brodehl J. Conventional therapy for idio- pathic nephrotic syndrome. Clin Nephrol Congress of Nephrology, New Delhi, 1991, 35: S 8-15. 1992, p 72. 1037