The nephrotic syndrome (a follow up study of 32 cases)Mahrukh K Joshi, Pravina W Kandoth, Suman M Sant, MP Bhagat
Department of Pediatrics, Seth G.S. M. College and K.E.M. Hospital, Parel, Bombay-400 012, India
32 cases of nephrotic syndrome treated with steroids and followed up for upto 8 years have been analysed. The series consisted of 17 boys and 15 girls. Nineteen cases had an onset of the disease below 6 years of age, the rest after this age. Biochemical studies were done in all cases, and renal biopsies were performed in 18 cases and repeated in 2 cases. Minimal changes were present in 3 cases and structural changes in 15 cases. Three patients were declared cured, 17 were declared to be in remission, 8 were relapsing and 4 expired. The correlation of age at onset, sex, biochemical findings, histopathologic findings and time of relapse with the final outcome has been discussed. Prognosis was better in boys and in cases having onset of the disease after 6 years of age. Hypertension and hematuria were associated with structural changes in biopsy. Absence of relapses or their cessation after the first two years of the disease signified a good prognosis.
Follow up studies of the nephrotic syndrome are being reported in the literature with increasing frequency. Of late, renal biopsy has been given special importance, and the relation of the histopathological changes to steroid responsiveness, biochemical changes and final prognosis has been reported by many workers. The following is an analysis of 32 steroid treated cases studied by us and followed up for a period upto 8 years.
A detailed history with special reference to age at onset of the disease, the number of relapses prior to admission and the possible cause for the initial attack and the relapses was obtained in each case. The urine was examined and cultured in all cases. Serum proteins, serum cholesterol, BUN and serum electrolytes were estimated on admission and repeated periodically until the time of remission. These investigations were also repeated with each relapse. A fortnightly follow up was instituted, and this included a complete physical check up and urine examination. Renal biopsies were obtained successfully in 18 patients, and repeated successfully in 2 patients.
All patients received prednisolone in dose of 2 mg/kg/day for 3 weeks. The disappearance of oedema, proteinuria, hypercholesterolemia constituted complete remission. The persistence of either proteinuria or hypercholesterolemia with disappearance of oedema was termed ,partial remission. Partial or complete remission was observed with this therapy in all cases except one, who was later found to be suffering from amyloidosis; prednisolone therapy was discontinued in this case. Patients were then kept on a maintenance dose of 10 to 20 mg of prednisolone on alternate days. The maintenance dose was gradually decreased and later discontinued after remission had persisted for 2 years. The same regime was repeated with each relapse. Symptomatic treatment for hypertension and infection was given wherever necessary.
Patients were declared cured if remission persisted for more than 5 years. They were said to be in remission if proteinuria was absent and serum cholesterol was within normal limits at the time of writing this paper and for atleast 9 months prior to this date. Patients were termed as relapsing if there was reappearance of proteinuria and/or the serum cholesterol was raised above normal levels any time during the 9 months prior to writing of this paper.
The minimum period of follow up was 9 months and the maximum was 8 years. 13 patients were followed up for more than 5 years, and 7 patients for 3 to 5 years.
The histopathological classification adopted was that recommended by Churg et al (1970) of the International Study Group, and the renal changes were classified as (1) minimal, (2) proliferative, (3) membranous glomerulonephropathy, (4) focal glomerulosclerosis (5) chronic disease and (6) miscellaneous including amyloidosis, and pyelonephritis.
An attempt was made to correlate the final outcome of the disease with the age at onset, sex, hypertension, hematuria, serum protein and cholesterol levels and the histopathological changes.
The results in the present study are shown in [Table 1],[Table 2] and [Table 3].
There were 17 males and 15 females in our series. Out of these, 9 males and 10 females were below 6 years of age at the time of onset of the disease, and 8 females and 5 males were above this age [Table 1].
The overall prognosis was significantly poorer in the age group with onset below 6 years (p <0.01). In this group 4 cases expired, 7 cases were relapsing, another 7 cases were in remission and only 1 case was declared cured, whereas in the group with onset at a later age there were no deaths, only 1 case was relapsing, 10 cases were in remission and 2 cases were cured [Table 1].
Hematuria (>5 r.b.c./h.p.f.) was present in 12 cases of which 8 were females. This preponderance of females is statistically not significant. Presence of hematuria had no significant correlation with the final outcome of the disease [Table 1].
Hypertension was present on admission in 8 cases; 5 of these were females having an onset of the disease below 6 years of age. Hypertension responded to treatment in all cases except one female who later expired. These figures are also not statistically significant. Hypertension also did not seem to have any effect on the final outcome of the disease [Table 1]. Scattergrams were prepared to show the correlation of serum chemistry (serum protein and cholesterol levels) with the histopathology as well as the final outcome. No significant correlation could be established.
Initial renal biopsy revealed minimal changes in 3 cases (2 males and 1 female), proliferative changes in 8 cases (2 males and 6 females), membranous glomerulonephropathy in 2 females, pyelonephritis in 1 female, amyloidosis in 1 male, focal glomerulo-sclerosis in 1 male and chronic nephritis in 2 females [Table 2] and [Figure 1],[Figure 2],[Figure 3],[Figure 4],[Figure 5],[Figure 6]. See [Figure 1],[Figure 2],[Figure 3],[Figure 4],[Figure 5],[Figure 6] on page 31A & 31B. Of the 8 cases having proliferative changes, 4 had membranoproliferative disease, 3 had mesangioendothelial proliferation and 1 showed diffuse proliferation. Repeat biopsies were successfully carried out in 2 cases. One male patient with membranous glomerulonephropathy changes on initial biopsy showed minimal changes on repeat biopsy after 4 years; this patient is declared cured. The second case who initially showed membrano-proliferative changes did not show any changes when biopsy was repeated after 5 years; this patient is clinically classified as relapsing. The total number of biopsies performed are too small to be statistically significant if the histopathological changes were to be correlated with the age of onset or the final outcome of the disease.
Biopsies were available in 10 cases with hypertension and/or hematuria. All these cases showed gross structural changes.
Twenty cases were followed up for more than 3 years, and in this group the period during which the relapses occurred could be significantly correlated with the final outcome. Of 3 cases who were declared cured, two had no relapses and one continued to have relapses for only 2 years after the onset of the disease. Out of 9 cases who were in remission, only 1 case continued to have relapses upto the third year. Seven out of eight relapsing cases continued to have relapses even 3 years after onset [Table 3]. Thus, persistence of relapses after the third year has significant effect on the final outcome (p <0.01).
A number of studies have shown that the incidence of nephrosis is significantly higher in males than in females (Dayal et at, 1968; Heymann et al, 1972; Heymann and Starzman, 1946; Kark and Muehroke, 1954; Schwartz et at, 1970; Siegel et al, 1972; Todd & Bouton, 1965; White et al, 1970). Opinion is however divided as to the difference in prognosis between males and females (Siegel et al, 1912; White et al, 1970). In our series, the incidence was marginally higher amongst males who also appeared to have a better prognosis. The results are however not statistically significant.
When the age of onset of the disease is considered, the incidence has been reported to be greater under the age of 6 years (Schwartz et at, 1970; Todd & Bouton, 1965; White et al, 1970) and the prognosis has also been considered to be better in this group (Kark & Muehroke, 1954; Schwartz et at. 1970; White et al, 1970) although Siegel et al (1972), state that the age at onset has no effect on the prognosis. However in our series, although the group with onset below 0 years had a higher incidence, the prognosis was significantly poor.
The incidence of hypertension, hematuria and azotemia has been reported to be higher in females with onset of the disease after 6 years (White et al, 1970) and these cases are said to have a poor prognosis (Barnes et al, 1950; Cornfeld & Schwartz. 1966; Dayal et al, 1968; Kark & Muechroke, 1954; Srivastava et al, 1973; Vernier et al, 1961; White et al, 1970). Schwartz et at (1970) however claim that none of these features alter the prognosis. The presence of hypertension, hematuria and/or azotemia is also reported to be directly related to gross structural changes on renal biopsy (Kark & Muehrcke, 1965; Srivastava et al, 1973; Vernier et al, 1961) ; and is indicative of poor response to steroids (Barnes et al, 1950; Cornfeld et at, 1966; Kark & Muehrcke, 1954). In our series, hypertension and hematuria were more frequent in females, particularly those with an onset of the disease below 6 years. Although our series is too small and our follow up too short to correlate these findings with the final outcome, the presence of gross structural changes on biopsy in all 10 females with hypertension and/or hematuria appears to be important in the consideration of the final prognosis. Azotemia was not present in any case of the present series at any time.
Alterations in serum proteins and serum cholesterol have been reported to be closely related to the structural histopathological changes (Todd & Bouton, 1965). Scattergrams prepared by us did not reveal any such correlation.
The occurrence and reappearance of moderate to severe proteinuria during the course of the disease is a reliable indicator of relapse but we agree with Todd & Bouton (1965) that the severity of proteinuria is of no prognostic significance.
The value of renal biopsy in predicting steroid response (Arneil & Lam, 1966; Cameron, 1968; Chandra et al, 1970; Schwartz et al, 1970; Todd & Bouton, 1965; Vernier et at, 1961), and the final prognosis (Chandra et al, 1970; Todd & Bouton, 1965; White et al, 1970) cannot be denied. All studies show that minimal changes carry a good prognosis (Cameron, 1968; Vernier et al, 1961). Minimal changes have been reported to be more frequent in boys and when the onset of the disease is below 6 years. Structural changes, particularly in girls with an onset of the disease after 6 years, are said to have a poor prognosis (White et al, 1970). Todd & Bouton (1965) state that although structural changes have a poor prognosis, the final outcome is better in cases with proliferative changes than with membranous changes. In our series, minimal changes were observed in only 3 cases as we were more particular about obtaining kidney biopsies in frequent relapsers. Though our series is small, the results are in agreement with the above findings.
Seigal et al (1972) have reported good prognosis in patients who did not have any relapses in the first 3 years after onset of the disease. He also states that a trend towards a decreasing number of relapses per case was not evident until after the tenth year of the disease. We have found a significantly better prognosis in cases who had no relapses at all, or did not have relapses after the first 2 years of the disease. Two females who showed structural histopathological changes on biopsy had frequent relapses during the first 3 years after onset of the disease. Subsequently they had a prolonged remission for three and a half years, after which they relapsed again Thus even prolonged remission in case: who show structural changes on biopsy do not necessarily signify a good prognonsis.
Acknowledgements are due to (1) the Dean, K. E. M. Hospital for permission to publish this series, (2) Mr. Ravindran for help in the statistical analysis of the data and (3) Dr. Bharati Chandan, M.D. Pediatric Tutor, and the past and present resident medical staff of our unit for their continued help in running the nephrotic clinic.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3]