NEFROLOGÍA. Vol. XXV. Número 2. 2005 Study of biopsied nephrotic syndrome for 20 years in the Cadiz bay area: histological correspondence, renal prognosis and clinical prognostic factors P. L. Quirós, M. Ceballos*, C. Remón, A. Lozano, R. del Castillo, E. Aznar*, M. A. Pérez Pérez-Ruilópez*, M. Rivero* and E. Fernández Ruiz Nephrology Department. Puerto Real Univesity Hospital. *Nephrology Department. Puerta del Mar University Hospital. Cadiz. SUMMARY Aims: To analyse the histological correspondence, the renal survival and the clinical prognostic factors in the nephrotic syndrome for more than 20 years in our environment as well as the influence of the nephrotic proteinuria in the renal survival in the different histological particular types of glomerulonephritis. Patients and methods: Among the 542 primary and secondary glomerulonephritis diagnosed by kidney biopsy for two decades in the Cadiz Bay Area, we selected 242 patients whose clinical presentation and the biopsy indication was the nephrotic syndrome. Statistics methods: means ± typical deviation, percentiles, percentages, Kaplan-Meier curves, long-rank test, student's t-test, chi-square analysis and Cox proportional hazards model test. Results: 242 patients with nephrotic syndrome (44.66% out of the total of glomerulonephritis), average age of 39.15 ± 18 years old. Average proteinuria 6.75 ± 4,53 g/day. Etiology: membranous nephropathy (33.85%), lupus nephritis (14.46%), minimal change disease (11.57%), focal segmental glomerulosclerosis (10.33%), renal amyloidosis (9.95%). 33%, 45%, 63% and 72% of the patients with nephrotic syndrome developed to the End-stage Renal Disease and starting point of dialysis in 5, 10, 15 and 20 years respectively. After the multivariate model, the age older than 60 years old, the high levels of proteinuria and the coexistence with hypertension or renal failure, in the moment of diagnosis, showed to be independents clinical prognostic factors. The nephrotic proteinuria had a negative influence in the prognosis in the different histological types, especially in the IgA nephropathy and the lupus nephritis. Conclusions: The nephrotic syndrome is the main indication of the renal biopsy in our environment. In general, as an independent group, its development is slowly progressive to the End-stage Renal Disease, having the possibility of being also conditioned by certain clinical factors present in the moment of the biopsy. The Correspondence: Pedro Luis Quirós Ganga Avda. de la Libertad, 32, 4º, 1º C 11500 El Puerto de Santa María (Cádiz) E-mail: pedroquiros@ono.com nefrologia.hupr.sspa@juntadeandalucia.es 147 P. L. QUIRÓS y cols. presence of nephrotic proteinuria is also a negative factor in the progression in many of the glomerulonephritis. Key words: Nephrotic syndrome. Glomerulonephritis. Renal survival. Prognostic factors. ESTUDIO DEL SÍNDROME NEFRÓTICO BIOPSIADO DURANTE 20 AÑOS EN LA BAHÍA DE CÁDIZ: CORRESPONDENCIA HISTOLÓGICA, PRONÓSTICO RENAL Y FACTORES CLÍNICOS QUE INFLUYEN EN EL MISMO RESUMEN Objetivos: Analizar la correspondencia histológica, la supervivencia renal y los factores pronósticos clínicos en el síndrome nefrótico, a la vez que estudiar la influencia de la proteinuria nefrótica en la supervivencia renal de los distintos tipos histológicos de glomerulonefritis crónicas. Pacientes y métodos: 542 pacientes diagnosticados de glomerulonefritis primarias o secundarias mediante biopsia renal durante dos décadas en la Bahía de Cádiz, de los que en 242 la presentación clínica e indicación de biopsia fue el síndrome nefrótico. Estadística: Medias, medianas, percentiles, porcentajes, curvas de Kaplan-Meier, test de long-rank, t de student, chi-cuadrado, modelo de riesgo proporcional de Cox. Resultados: De los 542 pacientes con glomerulonefritis 242 presentaban síndrome nefrótico (44,66%). Edad media 39,15 ± 18 años. Proteinuria media 6,75 ± 4,53 g/día. Etiología: nefropatía membranosa (33,85%), lúpica (14,46%), cambios mínimos (11,57%), focal y segmentaria (10,33%), amiloidosis renal (9,95%). El 33%, 45%, 63% y 72% de los pacientes con síndrome nefrótico evolucionaron a la IRCT a los 5, 10, 15 y 20 años respectivamente (media de supervivencia renal de 10,6 años). Mediante análisis multivariante, los factores pronósticos clínicos independientes fueron la edad mayor de 60 años, los niveles elevados de proteinuria y la presencia de HTA o insuficiencia renal en el momento del diagnóstico. La proteinuria nefrótica condicionó negativamente el pronóstico en las distintas formas histológicas, fundamentalmente en las nefropatías IgA y lúpica. Conclusiones: El síndrome nefrótico es la principal indicación de biopsia renal en nuestro medio. En general, y como grupo único, independiente de su etiología concreta, su evolución es lentamente progresiva hacia la IRCT, pudiendo ser condicionada además por determinados factores clínicos presentes en el momento de la biopsia. La proteinuria nefrótica es, además, un factor de progresión en muchas de las glomerulonefritis. Palabras clave: Síndrome nefrótico. Glomerulonefritis. Supervivencia renal. Factores pronósticos. INTRODUCTION Nephrotic syndrome (NS) comprises a group of symptoms and signs that appear in conditions of glomerular impairment in which serious proteinuria is the main feature. Bradley and Tyson1 already described it in detail in the mid 20th Century. It is characterized by the presence of massive proteinuria (higher than 3.5 g/24 h/1.73 m2 in adults or 40 mg/h/m2 in children)2, hyponatremia and hypoalbu148 minemia2,3, hypercholesterolemia, hypertriglyceridemia and lipiduria, and edemas2. Other possible complications are infectious deseases5 and vascular thrombosis6. Any glomerular disease, primary or secondary, may produce NS at some stage of its course. Among these conditions, the ones that stand out for their frequency are minimal changes disease in children, and in the adult, membranous nephropathy and focal and segmentary glomerulosclerosis among primary glo- NEPHROTIC SYNDROME IN CADIZ AREA merulonephritis (GN) and diabetic nephropathy among secondary GN7-9. The course and prognosis of NS is varied, and it depends on several factors: on the one hand, the etiology itself, so that currently it is the main and less controversial indication for renal biopsy10,11 because of the persistence and severity of proteinuria per se12-15 that induces the progressive development of glomerular sclerosis, tubular damage, and interstitial fibrosis, which promote renal disease progression independently of the particular histological type16; other factors include male gender17, advanced age18, and the presence of renal failure18,19 and arterial hypertension (AHT)13 at the time of the biopsy. The main goals of the present work are the study of the causes of biopsied nephrotic syndrome, of its progression to dialysis, as well as clinical risk factors that when present at the time of the biopsy may have en effect on the later, and the influence of nephrotic proteinuria on the renal course of the main glomerular nephropathies. MATERIAL AND METHODS We retrospectively studied 542 adult patients (older than 15 years), diagnosed with some type of primary (PGN) or secondary (SGN) glomerulonephritis by means of renal biopsy at the Puerto Real and Puerta del Mar University Hospital of the province of Cadiz, a joint area that we have designated as «Cadiz Bay Area», in the time frame between January 1st 1982 and June 30th 2003. Biopsies from renal grafts and from renal transplantation-related glomerular pathologies were excluded. Further, we have selected 242 (44.66%) patients that had NS, considered as those with proteinuria greater than 3.5 g/24 h at the time of biopsying. In all patients basal data were gathered on particulars, age, gender, biopsy date, blood pressure numbers, plasma creatinine level (Crp) proteinuria, and the anatomopathological diagnosis obtained from biopsy (nomenclature according to the Spanish Registry on GN7,8). Prognostic variables. From those recorded at the time of renal biopsy the following were taken for analysis as prognostic factors of renal function: male gender, presence of AHT (we consider hypertension in patients with blood pressure levels greater than 140/90 mmHg20 or those treated with antihypertensive drugs), proteinuria and its quantification, and renal function measured by Crp. Final variable: renal function status at the end of the study, and renal function survival time, computed as the time elapsed from renal biopsy date to date of renal function final failure, as defined by the first dialysis session after definitive loss of renal function. For that, each patient situation at the end of the study period related to their inclusion in dialysis programs has been recorded. Statistical methods · Descriptive statistics using arithmetic mean, standard deviation (SD) and percentiles for quantitative parameters. For qualitative variables, frequency distributions have been used. · Chi-squared test for comparison of qualitative variables. · Student's t test for comparison of two means and variance analysis to compare multiple means. · Kaplan-Meier's actuarial survival curves and log-rank test for curves comparison. · Mean renal life expectancy by the formula: t1/2 = Ln2 / mean annual loss rate (where t1/2: mean renal life expectancy. Ln2: natural logarithm of 2). · Cox proportional regression model for survival multivariance analysis with selected variables showing significance in univariate analyses (log-rank, Student' t test o chi-squared test). · A p value < 0.05 was considered significant. RSIGMA software from HORUS has been used for statistical analyses. RESULTS Of the 542 biopsied patients, 291 are men (53.7%) and 251 are women (46.3%). The mean age is 36.4 ± 17.6 years. Of them, 242 (44.66%) had nephrotic proteinuria at the time of diagnosis, being the main indication for renal biopsy in our setting. The main causes for NS (Fig. 1) were, among PGN, MN, MC and FSG, and in SGN diagnosed through renal biopsy, LN and AMYL. NS was a bit more frequent in men (men/women ratio 1.2), with a mean age of 39.15 ± 18 years. The vast majority of patients (70%) had renal failure (considered as Crp higher than 1.5 mg/dL) at the time of diagnosis, with a mean Crp of 1.49 ± 1.12 mg/dL. Mean proteinuria of NS patients was 6.75 ± 4.53 g/24 h. At the time of renal biopsy, 40.7% of patients had AHT. NS progression (Fig. 2), considered as a whole group independently of its etiology, was slowly progressing to end-stage renal failure (ESRF) and dialysis, being in this condition 33%, 45%, 63%, and 72% of patients at 5, 10, 15, and 20 years, respectively (SVR of 67%, 55%, 37%, and 28%, at the 149 P. L. QUIRÓS y cols. % 40 35 30 25 20 15 10 5 0 14.46 n = 82 33.88 NS: morphological substrate Table I. Univariate analysis (Student's test and Chi2) of clinical prognostic factors in NS ESRF (dialysis) Non-ESRF 1.1 39.9 ± 17.01 1.2 ± 0.8 4.24 ± 2.04 37% 35% p NS NS < 0.05 < 0.05 < 0.01 < 0.05 % 11.57 n = 35 n = 28 10.33 9.91 n = 25 n = 24 6.21 5.58 Gender (M/F ratio) Age (mean ± SD) Crp (mg/dL). (Mean ± SD) Proteinuria (g/24 h). (Mean ± SD) Patients with Crp > 1.5 (%) Patients with AHT (%) 3.85 3.17 0.5 0.5 1.28 37.53 ± 20 2.2 ± 1.44 8.83 ± 4.8 63% 65% NS = Not significant. C M DIA es B no N nIg A VA Ex SC tra cG N AM PG M FS M M Ig AN N LN G YL P Abbreviations according to REGN7,8: NM: membranous nephropathy; LN: lupus nephropathy; MC: minimal changes disease; FSG: focal and segmentary glomerulosclerosis; AMYL: renal amyloidosis; MPGP: membranous proliferative GN; IgAN: IgA nephropathy; DIABN: diabetic nephropathy; Mes non-IgA: non-IgA mesangial GN; VASC: renal vasculitis; ExtracGN: proliferative extracapillary GN. Fig. 1.--NS morphological substrate (histological correlation). same time intervals). Mean renal life expectancy has been estimated to be 10.6 years. Moreover, this course may be conditioned and aggravated if other factors coexist at the time of biopsying: by comparing survival curves (log-rank test; Fig. 3), both age greater than 60 years (p < 0.01) and renal failure presence (p < 0.001) (Crp > 1.5 mg/dL) or AHT (p < 0.01) from diagnosis had a significant effect on renal function prognosis. % SVR 100 90 80 70 60 50 40 30 20 10 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 NS 100 93 87 82 74 67 63 59 56 55 55 49 49 47 41 37 30 30 28 28 28 Gender was not a significant variable related to this prognosis. We have also performed, as part of the prognostic univariate analysis, a study of the means differences (Student's t test) and proportions (Chi2) of prognostic factors analyzed in two groups of NS patients: those who progressed to dialysis and those who did not at the end of the study (Table I). On the one hand, we could observed that, at the time of biopsy, the former presented higher creatinine (p <0 05 and proteinuria p < 0.05) means; on the other hand, the proportion of hypertensive patients that did not progressed to dialysis was significantly higher in the later group. All variables but patient gender (the only one that did not show any significance in univariate analyses) were included in Cox multivariate regression analysis. The results (Table II) show us that, at the time of renal biopsy, age grater than 60 years, raised proteinuria levels, and the coexistence of AHT or renal failure were the independent clinical prognostic factors of progression to dialysis in our NS patients. The third important goal in our study was to analyze the impact of nephrotic proteinuria on renal function survival in all patients diagnosed with GN by biopsy (n = 542 patients). Thus, on the one hand, comparing renal function survival curves in patients with proteinuria lower and hig- t 1/2 = 10.6 years Table II. Cox multivariate analysis of clinical prognostic factors Relative risk AGE > 60 years AHT CREATININE Crp > 1.5 PROTEINURIA 2.64 2.87 3.97 4.17 2.82 95% CI 1.34-3.26 1.87-3.75 2.39-4.88 2.6-5.31 1.41-3.68 p < 0.05 < 0.05 < 0.001 < 0.001 < 0.05 Years SVR: cumulative renal survival rate Fig. 2.--Renal survival curve in NS. 150 NEPHROTIC SYNDROME IN CADIZ AREA % SVR 100 90 80 70 60 50 40 30 20 10 0 0 1 2 3 4 5 1. GENDER 100 90 80 Woman 70 60 50 % SVR 2. AGE < 20 p = NS 40 Man 30 20 10 0 6 7 8 9 10 11 12 13 14 15 0 p < 0.01* > 60 40-60 20-40 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Years Years % SVR 100 90 80 70 60 50 40 30 20 10 0 0 1 2 3 4 3. Crp > 1.5 100 90 80 Crp < 1.5 70 60 50 Crp < 1.5 p < 0.001 40 30 20 10 0 5 6 7 8 9 10 11 12 13 14 15 % SVR 4. AHT No AHT p < 0.01* AHT 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Years NS = not significant. (*) Comparison of patients > 60 with the remaining. Years Fig. 3.--Univariate prognostic study (log-rank) of clinical prognostic factors in NS. Table III. Percentage of patients with NS that progressed to ESRF and those that did not, in all GN in particular histological types (Chi squared) ESRF (dialysis) In In In In In In In all GN in total the primary GN subgroup the secondary GN subgroup IgAN FSG MPGN LN 64% 59% 60% 59.9% 60.4 57% 67% No ESRF 36% 41% 40% 40.1% 39,6 43% 33% p < 0.001 < 0.05 < 0.05 < 0.05 < 0.05 NS < 0.001 Note: It is not possible to evaluate MN because most patients (94.5%) had nephrotic proteinuria at the time of biopsy. her than 3.5 g/24 h (Fig. 4), we have observed a marked worse course for the later, statistically significant in PGN and SGN global subgroups, in IgA and lupus nephropathy, and almost significant in focal and segmentary glomerulosclerosis (p < 0.1). On the other hand, when we have compared the proportion of patients with nephrotic range proteinuria that progressed to dialysis and those that did not in each of these histological subtypes (Table III), we have also observed similar results. These analyses could not be performed in membranous nephropathy due to the low percentage of patients without nephrotic proteinuria (5.5%), which hindered the comparative study with those that presented that proteinuria level (94.5%). 151 P. L. QUIRÓS y cols. In IgAN % SVR % SVR In LN 100 100 Prot. < 3.5 90 Prot. < 3.5 90 80 80 70 70 60 60 50 50 40 40 Prot. > 3.5 30 Prot. > 3.5 30 p < 0.05 p < 0.05 20 20 10 Patients with nephrotic proteinuria: 12.2% 10 Patients with nephrotic proteinuria: 52.9% 0 0 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 Years In FSG Years In MPGN % SVR % SVR 100 100 90 90 Prot. < 3.5 80 80 Prot. < 3,5 70 70 60 60 50 50 40 40 30 30 Prot. > 3,5 Prot. > 3.5 p < 0.1 p = NS 20 20 10 Patients with nephrotic proteinuria: 55% 10 Patients with nephrotic proteinuria: 49% 0 0 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 Years Years In total PGN In total SGN % SVR % SVR 100 100 Prot. < 3.5 90 90 Prot. < 3.5 80 80 70 70 60 60 50 50 40 40 Prot. > 3.5 30 30 Prot. > 3.5 p < 0.05 p < 0.05 20 20 10 Patients with nephrotic proteinuria: 44.4% 10 Patients with nephrotic proteinuria: 47% 0 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Years Proteinuria < 3.5 g/24 h NS = not significant. Note: It is not possible to represent MN because most patients (94.5%) had nephrotic proteinuria at the time of biopsy. Years Proteinuria > 3.5 g/24 h Fig. 4.­ Effect of nephrotic range proteinuria in SVR in the primary and secondary GN subgroups and in some particular histological types (log-rank). DISCUSSION Currently, NS represents the main and less controversial10,11 indication for renal biopsy, additionally being the most frequent consultation reason of patients that will further be diagnosed with any type of glomerulopathy7-9. In primary GN, the most frequent etiologies are membranous nephropathy, minimal changes disease, and focal and segmentary glomerulosclerosis. Lupus nephropathy and renal amyloidosis are, by far, the most frequent causes of NS in biopsied secondary GN. Logically the frequency of other important causes of NS not usually biopsied, mainly diabetic nephropathy, is not well represented in this study, which deals only with glomerulopathies histologically confirmed. This clinical-histological correspondence is in agreement with most of published series in this field7-9. 152 NS progression in each of the main histological GN types is well documented in the literature. However, the works that study NS renal function survival independently of the anatomopathological diagnosis, as the one published by Hunt et al.21, are scant. In the same way, we have tried to analyze renal progression and prognosis in NS from the time when biopsy is indicated, independently of its etiology and histological findings or response to possible later treatments not recorded in our study, focusing on the influence that certain clinical prognostic factors may have on NS. The disease course was slowly progressing to dialysis (33%, 45%, 63%, and 72% of the patients at 5,10, 15, and 20 years, respectively, from renal biopsy), with a mean renal life expectancy of 10.6 years. Hunt el al.21 show in their results a renal survival a little bit higher than ours, of 85% and 79% at 5 and 10 years, respectively, although basal creatinine plasma levels in their patients were lower than those in our patients, which might have led to a better outcome. Moreover, this better prognosis of NS is conditioned, to a variable extent, by certain clinical factors. Thus, after the univariate analysis and Cox regression analysis, age greater than 60 years, proteinuria levels, and the coexistence of AHT or renal failure at the time of renal biopsy, have shown to be independent clinical factors for a worse renal function course. In Hunt et al.21 series, only raised proteinuria levels at the time of diagnosis, and creatinine plasma level and severe proteinuria one year later were considered as such. Nor male gender, as in our case, nor age or the presence of AHT reached statistical significance with the multivariate analysis. On the other hand, nephrotic proteinuria presence at the time of diagnosis was a poor prognostic factor for the disease course of most of GN, which implicated a worse renal survival as compared with that of patients with lower proteinuria. We have observed it in this way in our experience, with statistical evidence, for the whole PGN and SGN, in IgAN and LN, and with less significance in FSG. Due to the variable and uncertain progression of some of these glomerulopathies, it is essential being able to define, from diagnosis, what factors or clinical circumstances, as nephrotic proteinuria, may have an influence on prognosis. This is the case for IgAN since, although its renal survival is lengthy, it is not a benign disease, having a variable percentage of patients that progress to dialysis (between 20-40% according to some series22,23). Other authors have demonstrated this correlation between nephrotic proteinuria and renal prognosis in IgAN24,25, LN26,27, and other glomerular diseases28,29. NEPHROTIC SYNDROME IN CADIZ AREA In order to prevent or slowing this progression, some measures have thus to be taken in any patient diagnosed with NS. Among them we highlight as widely endorsed in the literature protein restriction diet, already proposed by the MDRD study30 and other authors31,32, blood pressure control13 (even for these patients, systolic pressure less than 125-130mmHg and diastolic pressure less than 75-80 mmHg according to current recommendations20,33,34), and lowering proteinuria13,14. Currently, it is admitted that the mainstay of this antiproteinuric, antihypertensive and renoprotective treatment for renal diseases is comprised by those drugs that block the renin-angiotensin system, such as ACE inhibitors13,34-37, and ARA-II13,34,38,39. Besides, specific treatments with corticosteroides and/or immunosuppressants may be added to these antiproteinuric treatments, if indicated and according to NS etiology. 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