Manuel Praga

Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis

Objectives To develop recommendations for the management of adult and paediatric lupus nephritis (LN). Methods The available evidence was systematically reviewed using the PubMed database. A modified Delphi method was used to compile questions, elicit expert opinions and reach consensus. Results Immunosuppressive treatment should be guided by renal biopsy, and aiming for complete renal response (proteinuria <0.5 g/24 h with normal or near-normal renal function). Hydroxychloroquine is recommended for all patients with LN. Because of a more favourable efficacy/toxicity ratio, as initial treatment for patients with class III–IVA or A/C (±V) LN according to the International Society of Nephrology/Renal Pathology Society 2003 classification, mycophenolic acid (MPA) or low-dose intravenous cyclophosphamide (CY) in combination with glucocorticoids is recommended. In patients with adverse clinical or histological features, CY can be prescribed at higher doses, while azathioprine is an alternative for milder cases. For pure class V LN with nephrotic-range proteinuria, MPA in combination with oral glucocorticoids is recommended as initial treatment. In patients improving after initial treatment, subsequent immunosuppression with MPA or azathioprine is recommended for at least 3 years; in such cases, initial treatment with MPA should be followed by MPA. For MPA or CY failures, switching to the other agent, or to rituximab, is the suggested course of action. In anticipation of pregnancy, patients should be switched to appropriate medications without reducing the intensity of treatment. There is no evidence to suggest that management of LN should differ in children versus adults. Conclusions Recommendations for the management of LN were developed using an evidence-based approach followed by expert consensus.

Treatment of IgA Nephropathy with ACE Inhibitors: A Randomized and Controlled Trial

Some retrospective studies have suggested a beneficial influence of angiotensin-converting enzyme (ACE) inhibitors on the progression of IgA nephropathy (IgAN), but prospective and controlled studies demonstrating this effect are lacking. Forty-four patients with biopsy-proven IgAN, proteinuria > or = 0.5 g/d, and serum creatinine (SCr) < or = 1.5 mg/dl were randomly assigned either to receive enalapril (n = 23) or to a control group (n = 21) in whom BP was controlled with antihypertensives other than ACE inhibitors. Primary outcome was renal survival estimated by a 50% increase in baseline SCr. Secondary outcomes were the presence of a SCr > 1.5 mg/dl at the last visit and the evolution of proteinuria. Baseline clinical findings were similar at baseline between enalapril-treated and control group, and there were no differences in BP control during follow-up. Mean follow-up was 78 +/- 37 mo in the enalapril group and 74 +/- 36 mo in the control group. Three patients (13%) in the enalapril group and 12 (57%) in the control group reached the primary end point (P < 0.05). Kaplan-Meier renal survival was significantly better in enalapril group than in control group: 100% versus 70% after 4 yr and 92% versus 55% after 7 yr (P < 0.05). Three patients in the enalapril group (13%) and 11 (52%) in the control group showed SCr > 1.5 mg/dl at the last visit (P < 0.05). Proteinuria significantly decreased in the enalapril group, whereas it tended to increase in the control group (P < 0.001 between groups). In conclusion, ACE inhibitors significantly improve renal survival in proteinuric IgAN with normal or moderately reduced renal function.

Acute interstitial nephritis

Acute interstitial nephritis (AIN) represents a frequent cause of acute kidney injury, accounting for 15-27% of renal biopsies performed because of this condition. By and large, drug-induced AIN is currently the commonest etiology of AIN, with antimicrobials and nonsteroidal anti-inflammatory drugs being the most frequent offending agents. Pathogenesis is based on an immunologic reaction against endogenous nephritogenic antigens or exogenous antigens processed by tubular cells, with cell-mediated immunity having a major pathogenic role. The characteristic interstitial infiltrates, mostly composed of lymphocytes, macrophages, eosinophils, and plasma cells, experience a rapid transformation into areas of interstitial fibrosis. A significant proportion of AIN has nowadays an oligosymptomatic presentation, although the presence of specific extrarenal symptoms such as fever, skin rash, arthralgias, and peripheral eosinophilia has an important role to orientate clinical diagnosis. Identification and removal of the offending drug are the mainstay of the treatment, but recent studies strongly suggest that early steroid administration (within 7 days after diagnosis) improves the recovery of renal function, decreasing the risk of chronic renal impairment. Delayed steroid treatment, when interstitial fibrosis has taken place, would have a less pronounced or nule therapeutic benefit.

Spontaneous Remission of Nephrotic Syndrome in Idiopathic Membranous Nephropathy

Spontaneous remission is a well known characteristic of idiopathic membranous nephropathy, but contemporary studies describing predictors of remission and long-term outcomes are lacking. We conducted a retrospective, multicenter cohort study of 328 patients with nephrotic syndrome resulting from idiopathic membranous nephropathy that initially received conservative therapy. Spontaneous remission occurred in 104 (32%) patients: proteinuria progressively declined after diagnosis until remission of disease at 14.7 +/- 11.4 months. Although spontaneous remission was more frequent with lower levels of baseline proteinuria, it also frequently occurred in patients with massive proteinuria: 26% among those with baseline proteinuria 8 to 12 g/24 h and 22% among those with proteinuria >12 g/24 h. Baseline serum creatinine and proteinuria, treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists, and a >50% decline of proteinuria from baseline during the first year of follow-up were significant independent predictors for spontaneous remission. Only six patients (5.7%) experienced a relapse of nephrotic syndrome. The incidence of death and ESRD were significantly lower among patients with spontaneous remission. In conclusion, spontaneous remission is common among patients with nephrotic syndrome resulting from membranous nephropathy and carries a favorable long-term outcome with a low incidence of relapse. A decrease in proteinuria >50% from baseline during the first year predicts spontaneous remission.

Validation of the Oxford classification of IgA nephropathy in cohorts with different presentations and treatments

The Oxford Classification of IgA Nephropathy (IgAN) identified mesangial hypercellularity (M), endocapillary proliferation (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T) as independent predictors of outcome. Whether it applies to individuals excluded from the original study and how therapy influences the predictive value of pathology remain uncertain. The VALIGA study examined 1147 patients from 13 European countries that encompassed the whole spectrum of IgAN. Over a median follow-up of 4.7 years, 86% received renin–angiotensin system blockade and 42% glucocorticoid/immunosuppressive drugs. M, S, and T lesions independently predicted the loss of estimated glomerular filtration rate (eGFR) and a lower renal survival. Their value was also assessed in patients not represented in the Oxford cohort. In individuals with eGFR less than 30 ml/min per 1.73 m2, the M and T lesions independently predicted a poor survival. In those with proteinuria under 0.5 g/day, both M and E lesions were associated with a rise in proteinuria to 1 or 2 g/day or more. The addition of M, S, and T lesions to clinical variables significantly enhanced the ability to predict progression only in those who did not receive immunosuppression (net reclassification index 11.5%). The VALIGA study provides a validation of the Oxford classification in a large European cohort of IgAN patients across the whole spectrum of the disease. The independent predictive value of pathology MEST score is reduced by glucocorticoid/immunosuppressive therapy.

Effects of body-weight loss and captopril treatment on proteinuria associated with obesity.

We have identified 17 obese patients (body mass index, BMI, 37.9 +/- 4.1) with proteinuria > 1 g/day (1.3-6.4 g/24 h, mean 3.1 +/- 1.7). Their age was 34-70 years (48.3 +/- 10); 11 were females and 6 males. Six patients had only one functioning kidney and a sleep apnea syndrome had been diagnosed in 5. Renal biopsies, obtained in 5 cases, showed focal glomerulosclerosis in 2 cases, minimal changes in 2 and mesangial proliferation in 1. Nine patients (group 1) were treated with hypocaloric diets; body weight significantly decreased (BMI 37.1 +/- 3, 34 +/- 3.5 and 32.6 +/- 3.2 at 0, 6 and 12 months, respectively) as well as proteinuria (2.9 +/- 1.7, 1.2 +/- 1 and 0.4 +/- 0.6 g/24 h). There was a significant correlation between body weight loss and decrease in proteinuria (r = 0.69, p < 0.05). Eight patients (group 2) were treated with captopril, without dietary changes. BMI remained stable but proteinuria showed a dramatic decrease, similar to that in group 1 (3.4 +/- 1.7, 1.2 +/- 0.9 and 0.7 +/- 1 g/24 h, respectively). Renal function remained stable in both groups. In summary, both body weight loss and captopril treatment can induce a sharp decrease in obesity-related proteinuria.

Obesity, proteinuria and progression of renal failure

Purpose of reviewRecent studies have reported an alarming increase in the incidence of obesity-related glomerulopathy, in a context of a worldwide spread of obesity. Recent findingsSeveral epidemiological investigations have confirmed that obesity is a significant risk factor for the appearance of proteinuria and end-stage renal disease in a normal population. Obesity-induced hemodynamic changes and glomerular deposition of lipids (partly mediated by sterol regulatory element-binding proteins) play an important role in the pathogenesis of obesity-related renal disease. In addition, the renin-angiotensin-aldosterone system is markedly activated in obesity, adipocytes being an important source of these hormones. Weight loss induces a marked reduction in all renin-angiotensin-aldosterone system components. Patients with reduced renal mass of any origin appeared to be particularly susceptible to the detrimental influence of obesity: body mass index was the most important risk factor for the development of proteinuria and renal insufficiency in patients with unilateral renal agenesis, unilateral nephrectomy and remnant kidneys. Weight loss induces a very important reduction in proteinuria in chronic proteinuric nephropathies of different etiologies. SummaryPrevention and treatment of obesity should be a first-line objective in the therapeutic approach of patients with diabetic and nondiabetic chronic renal diseases.

Long-Term Beneficial Effects of Angiotensin-Converting Enzyme Inhibition in Patients With Nephrotic Proteinuria

Angiotensin-converting enzyme inhibitors (ACEI) can reduce proteinuria in diabetic and nondiabetic nephropathy. However, no studies have determined whether this antiproteinuric effect modifies the progression of renal insufficiency. We studied the evolution of 46 nondiabetic patients with nephrotic proteinuria treated with captopril for a minimum of 12 months. The follow-up period before captopril treatment was 12 to 18 months. At the end of follow-up, after captopril introduction (24.4 +/- 7.6 months), proteinuria had decreased from 6.3 +/- 2.5 to 3.9 +/- 3.1 g/24 h (P less than 0.001), with a mean decrease of 45% +/- 28%. The proteinuria decrease was higher in patients with reflux nephropathy, proteinuria associated with reduction of renal mass, inactive crescentic glomerulonephritis, nephroangiosclerosis, and IgA nephropathy, whereas patients with membranous glomerulonephritis and idiopathic focal glomerulosclerosis showed a poorer response. Patients were separated according to a proteinuria reduction greater (group A, 23 patients) or lower (group B, 23 patients) than 45% of the initial value. At the end of follow-up, renal function had not significantly changed in group A with respect to values at the start of treatment: serum creatinine (SCr) was 229 +/- 167 mumol/L (2.6 +/- 1.9 mg/dL) versus 203 +/- 97 mumol/L (2.3 +/- 1.1 mg/dL), and creatinine clearance (CrCl) was 0.80 +/- 0.52 mL/s (48 +/- 31 mL/min) versus 0.87 +/- 0.47 mL/s (52 +/- 28 mL/min). The slope of the reciprocal of Scr (1/SCr) showed a significantly beneficial change after captopril introduction.(ABSTRACT TRUNCATED AT 250 WORDS)

Membranous glomerulonephritis associated with hepatitis C virus infection in renal transplant patients

BACKGROUND Hepatitis C virus (HCV) infection has been described in association with various types of glomerular diseases, usually type I membranoproliferative glomerulonephritis and rarely membranous glomerulonephritis (MGN). In this article, we describe the first series of MGN exhibited in renal transplant patients and associated with HCV infection. METHODS From January 1980 to December 1994, 2045 kidney transplantations were performed in our renal transplant units. A retrospective analysis demonstrated an overall 20% prevalence of HCV virus-positive patients; 409 transplanted patients were HCV positive (ELISA and RIBA). RESULTS Fifteen patients developed an allograft MGN (3.66%) 24 months after renal transplantation. MGN appeared in the form of significant proteinuria (>1.5 g/24 h) with stable renal function. In all cases, graft biopsy demonstrated a thickening of the capillary wall, subepithelial electron-dense deposits, and IgG and C3 diffuse granular deposits along the basal membrane. Ten cases were considered de novo, two cases were considered recurrent MGN, and three cases were considered undetermined because the primary renal disease was chronic glomerulonephritis. All patients showed negative antinuclear antibodies and cryoglobulins, normal complement, and negative rheumatoid factors. During follow-up (an average of 2 years), 12 patients developed a progressive worsening of renal function, with increased serum creatinine and persistent proteinuria; 8 of the 12 patients returned to dialysis. Of the remaining three cases, two patients showed partial remission of nephrotic syndrome after high doses of steroids, and one patient persisted with stable renal function and proteinuria (<2 g/24 h.). CONCLUSIONS In summary, HCV is preferentially associated with MGN in renal transplant patients, rather than with membranoproliferative glomerulonephritis as in the normal adult population. MGN associated with HCV infection has a similar clinical picture and outcome to posttransplant idiopathic de novo MGN, with persistent massive proteinuria and progressive deterioration of renal function.

Double versus single renal allografts from aged donors

BACKGROUND The age limit of the cadaver kidney donors is increasing in response to the growing demand for renal transplantation. Simultaneous double kidney transplantation (SDKT) with kidneys obtained from elderly adults has been proposed to increase the transplantation number and improve its results. However, if SDKT is performed when there are no clear indications, a negative effect could be produced on the total number of transplanted patients as both kidneys would be used for only one recipient. MATERIAL AND METHODS In December 1996 we designed a transplantation protocol to be able to extend the selection of cadaver kidney donors with normal serum creatinine levels without establishing any age limit. A pregraft renal biopsy was always performed to analyze the glomerulosclerosis (GE) percentage whenever the donors were 60 years of age or older. A SDKT was performed in a single recipient when the donor age was 75 years or older or when the donors between 60 and 74 years old had a GE rate of more than 15%. On the contrary, a single kidney transplantation was performed in two different recipients for kidneys from donors between 60 and 74 years of age with a GE rate of less than 15%. Kidneys having GE rates of more than 50% were discarded for transplantation. Donor kidneys from subjects younger than 60 years of age were always used for a single kidney transplantation. RESULTS Based on the above mentioned protocol, from December 1996 to May 1998, 181 patients received a kidney transplantation in our hospital. These patients were divided into three groups: group I which included the SDKT recipients (n=21), group II or single kidney recipients from 60- to 74-year-old donors (n=40), and group III or recipients from <60-year-old donors (n=120). The mean follow-up time was 15+/-5 months (range 6-24). Mean donor age was 75+/-7 years in group I, this was significantly higher than in group II (67+/-4, P<0.001) and group III (37+/-15, P<0.001). The primary nonfunction rate was low in the three groups, there being no statistically significant differences (5, 5, and 4%, respectively). A significantly greater percentage of patients from group I (76%) presented immediate renal graft function as compared with group II (43%, P<0.01) and III (50%, P<0.05). The acute rejections rate was very low in all three groups (9.5, 7.5, and 22%, respectively) with significant differences between groups II and III (P<0.05). No significant differences between the different groups were observed for one year actuarial patient survival (100, 95, and 98%, respectively) or graft survival rates (95, 90, and 93%, respectively). The 6-month serum creatinine levels were excellent in the three groups, although there were significant differences between groups I and II (1.6+/-0.3 vs. 1.9+/-0.6 mg/dl, P<0.05), II and III (1.9+/-0.6 vs. 1.4+/-0.4 mg/dl, P<0.001), and I and III (P<0.05). CONCLUSIONS Simultaneous double kidney transplantations make it possible to use kidneys from extremely elderly donors (>75 years) or those whose GE>15%. In addition, kidneys from donor 60-74 years old in which the GE<15% can be used for single kidney transplantations in two different recipients with excellent results.