Reduce Proteinuria In Patients Research Articles

#2549 Real world data of dapagliflozin effect on proteinuria in primary glomerulopathies in Croatia

Abstract Background and Aims SGLT2 inhibitors, namely dapagliflozin, proved to slow progression of kidney disease in randomized clinical trials. Our aim was to assess real world efficacy of dapagliflozin on proteinuria level in primary glomerulopathies (GN). Method adult patients with biopsy proven glomerulonephritis from all university hospitals in Croatia who started dapagliflozin as a standard of care were enrolled. Data were analyzed if patients had at least six months of follow up. None of the patients were on immunosuppression. Data are shown as N (%) or median with interquartile range (IQR) and accompanied p levels. Results Overall 118 patients, predominantly male 84 (71.8%) of average age of 52 years (min–max 20–76), were enrolled. Most of the patients had IgA nephropathy (IgAN) (N = 55;46.6%), followed by membranous nephropathy (N = 27;22.9%), FSGS (N = 19;16.1%), membranoproliferative GN (N = 8;6.8%), Alport syndrome (N = 8;6.8%). 95.8% of patients were on ACE inhibitors or angiotensin receptor blockers and 10.7% were on mineralocorticoid receptor inhibitors and RAAS blockage was not significantly upscaled during follow up. During the median follow up of 12.2 (7.5-18.6) months, proteinuria was significantly reduced from 1139 (534–2265) to 701 (305-1543) mg/dU; p < 0.001. When divided by glomerulonephritis type, statistically significant reduction of proteinuria was observed in patients with IgAN and Alport syndrome, while trend of reduction of proteinuria was observed in all types of GN. There was a slight reduction in eGFR levels (54 (43-78) vs. 52 (39–73) ml/min/1,73 m²; p < 0.001) and rise in creatinine values (122 (89–149) vs. 128 (91–159) μmol/l; p < 0.001). There was a significant reduction in systolic (130 (120-140) vs.125 (115-134) mmHg; p < 0.001) and diastolic blood pressure (80 (75-90) vs. 80 (70-85) mmHg; p < 0.001). Reduction of uric acid level was noticed (377 (313–460) vs.343 (294–422); p < 0.001), while there was no effect on LDL levels (2.6 (2.12–3.53) vs.2.3 (1.9–3.30); p = 0.073). Dapagliflozin was well tolerated, one patient discontinued the therapy due to intolerance, one due to urinary infection and two due to relapse of GN which needed immunosuppressive therapy. One patient was excluded from analysis due to non-adherence. Conclusion SGLT2 inhibitor dapagliflozin has significant effect on reduction of proteinuria in patients with primary glomerulonephritis. Our data support a growing body of evidence that SGLT2 inhibitors should be used as a standard of care in patients with glomerular kidney diseases, especially IgAN. Future research should address earlier use of SGLT2 inhibitors during the treatment of glomerulonephritis alongside immunosuppressive therapy as well as look into the effect of SGLT2 inhibitors on mesangial cells.

#1392 MEST-C score correlation with proteinuria reduction after SGLT2i treatment in patients with IgA nephropathy

Abstract Background and Aims Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are associated with better cardiovascular outcomes and with nephroprotection independent of diabetes status. Recent data suggest that SGLT2i significantly reduce proteinuria in patients with IgA nephropathy (IgAN). Data available for the use of the MEST-C score to determine if treatment would benefit IgAN patients is scarce. The aim of our study was to assess the degree of proteinuria reduction after SGLT2i treatment in IgAN and its possible association with the MEST-C score. Method 63 adult patients with biopsy-proven IgA nephropathy, eGFR ≥ 30 mL/min/1.73 m2 (CKD-epi), and total urine protein of >0.5 grams/day at screening were included. Patients with secondary IgAN and crescents were excluded. All receiving maximally tolerated RASi for at least 12 weeks. All patients started dapagliflozin 10 mg once per day after baseline data were registered. The total follow-up was 12 months. The main outcome was the decline in eGFR and the reduction in 24-hour proteinuria from SGLT2i initiation to 1,3, 6, 9, 12 months, end-stage renal disease, or kidney or cardiovascular death. Three repeated measurements of proteinuria (mg/24H) were performed, 90 days before SGLT2i treatment initiation, and only patients with stable proteinuria were enrolled in the study. Results 49 patients (35/14 M/F), with mean age of 41,9 ± 19,6 years, completed follow up. 8 patients discontinued treatment due to adverse events attributed to dapagliflozin. At baseline eGFR was 68.21±18,1 ml/min/1.73 m2 and Upr: 2196±1091 mg/24H. The MEST-C scores were correlated with the serum creatinine level, proteinuria, and hematuria. The mean serum creatinine level was higher in M1, E1, S1, and T1 compared with score “0”. It was statistically significant (p = 0.03) only in the T-score. The mean proteinuria level was again higher in M1, S1, and T1 but reached statistical significance (p = 0.037) in only the T1-score. E1 has higher hematuria. The Upr/24H difference for dapagliflozin was −24.7% (95% CI −27.5, −23.2; p < 0.001) at the end of follow-up (month 12). Proteinuria reduction was similar across all eGFRs, age, and baseline proteinuria. Among MEST-C score parameters, T1 had a negative impact on the antiproteinuric effect of dapagliflozin (p = 0.01) No hypoglycemic events were reported and no deaths occurred. Conclusion In the present study, the use of SGLT2i was associated with a significant reduction of proteinuria in patients with IgA nephropathy and maximally tolerated RASi. We analyzed renal outcomes in association with pathologic features. We established that the presence of the T1 score has a negative impact on proteinuria reduction after SGLT2i treatment. Further studies are needed to investigate the impact of the use of the Oxford Classification score for developing individual treatment therapies.

#1679 Relationship between initial eGFR DIP with proteinuria after SGLT2i treatment, in patients with IgA nephropathy. A real-world clinical study

Abstract Background and Aims Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are associated with better cardiovascular outcomes and with nephroprotection independent of diabetes status. Recent data suggest that SGLT2i significantly reduce proteinuria in patients with IgA nephropathy (IgAN). However, they often cause an initial decline in estimated glomerular filtration rate (eGFR). The aim of our study was to assess the degree of proteinuria reduction after SGLT2i treatment in IgAN and its possible association with the initial functional dip in eGFR. Method 63 adult patients with biopsy-proven IgA nephropathy, eGFR ≥ 30 mL/min/1.73 m2 (CKD-epi), and total urine protein of >0.5 grams/day at screening were included. Patients with secondary IgAN were excluded. All receiving maximally tolerated RASi for at least 12 weeks. All patients started dapagliflozin 10 mg once per day after baseline data were registered. The total follow-up was 12 months. The main outcome was the decline in eGFR and the reduction in 24-hour proteinuria from SGLT2i initiation to 1,3, 6, 9, 12 months, end-stage renal disease, or kidney or cardiovascular death. Results 55 patients (38/17 M/F), with mean age of 44,2±18,3 years, completed follow up. 8 patients discontinued treatment due to adverse events attributed to dapagliflozin. At baseline eGFR was 66.17±19,7 ml/min/1.73 m2 and Upr: 2356±1023 mg/24H. There was a transient decline in eGFR, 30 days after initiation of dapagliflozin (66.17±19,7 min/1.73 m2 at baseline to 57 ml/min/1.73 m2) but then, there was an improvement at month 3 from baseline. The Upr/24H difference for dapagliflozin was −25.1% (95% CI −27.5, −23.2; p < 0.001) at the end of follow-up (month 12). Proteinuria reduction was similar across all eGFRs. Notably, a significant correlation was found between the initial eGFR dip and percentage proteinuria reduction in the 12th month. (R = –0.23; p = 0.03). Consistent results of dapagliflozin treatment on proteinuria were found in all analysis subgroups including sex, baseline proteinuria, systolic blood pressure, and body mass index. No hypoglycaemic events were reported and no deaths occurred. Conclusion In the present study, the use of SGLT2i was associated with a significant reduction of proteinuria in patients with IgA nephropathy in patients with maximally tolerated RASi. Higher initial eGFR dip after treatment initiation was a predictor of a significantly higher reduction in proteinuria at the end of follow-up. The correlation between eGFR dip and proteinuria reduction perhaps reflects the intraglomerular pressure reduction, mediated by tubuloglomerular feedback, one of the numerous.

Reduction of proteinuria in patients with diabetes kidney disease and dysautonomia through measures aimed at controlling supine hypertension

ABSTRACT In diabetes kidney disease (DKD), orthostatic hypotension and supine hypertension often coexist, which, when uncontrolled, contributes to the progression of proteinuria and renal dysfunction. Chronotherapy and elevation of the head of the bed during sleep are feasible clinical measures and could contribute to the control of supine hypertension and proteinuria in this group of patients. This study consists of a series of cases, in which nine consecutive patients with DKD, dysautonomia and supine hypertension (intervention group) were instructed to use chronotherapy and inclination of the head of the bed in six degrees during sleep. These patients were compared with a historical control group. The primary outcome was proteinuria behavior. The intervention group had a significant drop in proteinuria levels, while there was an increase in proteinuria in the control group (variation in the proteinuria/creatininuria index in an isolated sample from the intervention group: −6.60 ± 3.90 g/g; variation in the group control: +1.70 ± 7.10 g/g, p = 0.008). Chronotherapy and six-degree inclination of the head of the bed during sleep were associated with a significant decrease in proteinuria in patients in the intervention group, with conversion of nephrotic into non-nephrotic proteinuria in most of these patients.

The Dual Role of Endothelin-1 and Angiotensin II in Disease Progression of Focal Segmental Glomerulosclerosis and IgA Nephropathy

IgA nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS) are rare primary glomerulopathies, though the incidence of IgAN is greater. Endothelin 1 (ET-1) and angiotensin II (Ang II) are implicated in the development and progression of IgAN and FSGS. Both conditions impact health-related quality of life (HRQoL) and may lead to kidney failure. IgAN and FSGS are both evidenced clinically by proteinuria, with a greater degree of such associated with more progressive disease and shorter times to kidney failure. Accordingly, the reduction of proteinuria in patients with these conditions is a key target. Currently, IgAN and FSGS treatments are unsuccessful or only partially successful in a number of patients. Immunosuppressant therapy is first-line for primary FSGS and utilised for patients with IgAN who remain at high risk of progression despite maximal supportive care; however, while effective, there is a significant risk of toxicity and relapse is frequent. A number of clinical trials are ongoing to investigate the use of non-immunosuppressive agents in the management of these conditions. The dual endothelin Type A receptor/Ang II subtype 1 receptor (ETAR/AT1R) antagonist (DEARA) sparsentan is currently being assessed as a means to control kidney disease progression. Interim study results show that sparsentan can lead to greater reductions in proteinuria than AT1R antagonism alone in IgAN and more patients reaching partial remission (PR) in FSGS. Herein, a symposium by leading experts at the European Renal Association (ERA) 59th Congress in Paris, 19th−22nd May 2022, is presented. It highlights IgAN and FSGS and the role of proteinuria in these conditions, and how targeting ET-1 and Ang II can lead to a reduction in proteinuria in IgAN and potential FSGS PR.

MO253A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED DOSE-RANGING STUDY (LUMINA-1 STUDY) TO EVALUATE THE SAFETY AND EFFICACY OF CCX140 IN SUBJECTS WITH FOCAL SEGMENTAL GLOMERULOSCLEROISS (FSGS)*

Abstract Background and Aims Primary Focal Segmental Glomerulosclerosis (FSGS) is the most common primary glomerular disease in patients with end stage renal disease in the United States. Current treatment regimens target reduction in proteinuria, but may have limited response or exhibit disease recurrence. CCX140 is an orally-administered selective small molecule inhibitor of the C-C chemokine receptor 2 (CCR2) under investigation for the treatment reduction of proteinuria in patients with FSGS. The primary objectives of this study were to evaluate the safety and efficacy of CCX140 in patients with FSGS and a urine protein to creatinine ratio (UPCR) of ≥1 g/g. Efficacy was assessed by the change in UPCR. Method Forty-six adult patients with primary or genetic FSGS were randomized into a double-blind, placebo-controlled Phase 2 dose-ranging study designed to evaluate the safety and efficacy of CCX140. Changes of urinary protein excretion estimation (UPCR) from baseline to Week 12 were measured in four blinded treatment groups (three active CCX140 doses of 5 mg once daily, 10 mg and 15 mg twice-daily (BID) vs placebo). Starting at Week 12, all subjects including those in the placebo group received the CCX140, 15 mg BID for an additional 12 weeks, and UPCR changes from Week 12 to Week 24 were assessed. There was a 4-week follow-up period from Week 24 to Week 28 where no CCX140 was administered. Results In the intent to treat (ITT) analysis of UPCR changes at Week 12 relative to baseline, the 15 mg BID CCX140 group exhibited the greatest reduction of UPCR (median reduction from baseline 0.9 g/g or approximately 30%, and approximately 25% reduction from baseline for the geometric mean), but that did not differ significantly from the placebo group (median reduction from baseline 0.45 g/g; or approximately 22%, and approximately 23% reduction from baseline for the geometric mean). Also, after crossover of the blinded portion of the trial to 15 mg BID active dosing, the previous placebo group did not appear to exhibit an additional reduction of UPCR. CCX140 at all doses was well-tolerated, with no serious adverse events (SAEs) during the blinded trial and a numerically lower rate of treatment-emergent adverse events in the CCX140 treatment groups. Conclusion In the study, CCX140 did not demonstrate a therapeutically meaningful reduction in proteinuria relative to the control group after 12 weeks of blinded treatment. The study provides insights into the natural disease progression of patients with primary or genetic FSGS as part of a clinical trial setting.

Assessing the Impact of Losmapimod on Proteinuria in Idiopathic Focal Segmental Glomerulosclerosis

IntroductionIdiopathic focal segmental glomerulosclerosis (FSGS) is a leading cause of nephrotic syndrome and end-stage renal disease. In preclinical models and biopsies of human FSGS kidneys, p38 mitogen-activated protein kinase (MAPK) has demonstrated enhanced activity; and p38 MAPK inhibition has improved disease markers. This proof-of-concept trial aimed to assess efficacy, safety, tolerability, and pharmacokinetics of losmapimod, an oral p38 MAPK inhibitor, in humans with FSGS.MethodsA single-arm, multicenter, open-label, Phase II trial (NCT02000440) was conducted in adults with FSGS; proteinuria ≥2.0 g/d; estimated glomerular filtration rate (eGFR) ≥45 ml/min per 1.73 m2; blood pressure <140/90 mm Hg. Collapsing and genetic forms of FSGS were excluded. The primary endpoint was number of patients with ≥50% proteinuria reduction and eGFR ≥70% of baseline after receiving losmapimod twice-daily for 16 to 24 weeks.ResultsSeventeen patients received ≥1 losmapimod dose. No patients achieved the primary endpoint; therefore, the study was terminated following a prespecified interim analysis. At week 24, proteinuria reductions between 20% and <50% were observed in 4 patients and proteinuria increases >20% in 3 patients. One patient achieved a proteinuria response (≥50% reduction) at week 2 but subsequently relapsed. Losmapimod pharmacokinetics were consistent with prior studies. No serious adverse events (AEs) were reported.Conclusionp38 MAPK inhibition with losmapimod did not result in ≥50% reduction of proteinuria in patients with FSGS. However, study population heterogeneity may have contributed to our negative findings and therefore this does not eliminate the potential to demonstrate benefit in a population more sensitive to p38 MAPK inhibition if identifiable in the future by precision-medicine methods.

Effectivity of Lumbrokinase in Reducing Proteinuria on patients with Diabetic Kidney Disease

Background: Diabetes Mellitus (DM) is currently developing epidemically and diabetic kidney disease is a major complications affecting one-third of patients with DM. Lumbrokinase is an extract from a worm belonging to the class Lumbricus rubellus, containing bioactive proteolytic enzymes, which is considered as an alternative therapy in reducing proteinuria. Aim: This study aims analysing the effect of the administration of Lumbrokinase in reduction of proteinuria in patients with diabetic kidney disease. Materials & Methods: The study design is a prospective observational study in 6 type 2 DM patients with diabetic kidney disease characterised by proteinuria in RSPAD Gatoto Soebroto, Jakarat, Indonesia. The patients were administered with Lumbrokinase 250mg with a dose of 3x2 capsules daily for 12 weeks. Observations: Study shows no significant difference between laboratory parameters before and after Lumbrokinase administration. However, proteinuria seems to improve, which is marked with decreased Urinary Albumin Creatinine Ratio (UACR) level after Lumbrokinase administration Conclusion: Lumbrokinase appears to be able to decrease proteinuria in type 2 DM patients with diabetic kidney disease. However, further research with more samples is needed.

Rituximab as a Therapeutic Option for Steroid-Sensitive Minimal Change Nephrotic Syndrome in Adults.

Minimal change nephrotic syndrome (MCNS) usually responds to steroids but frequently relapses, requiring additional treatment with immunosuppressive agents. Rituximab is a chimeric murine/human monoclonal immunoglobulin G1 antibody that targets CD20, a B-cell differentiation marker. B-cell recovery begins at approximately 6 months following the completion of treatment. Rituximab has a beneficial effect, with the sustained remission or reduction of proteinuria in patients with steroid-dependent MCNS. Relapses are thought to be associated with an increase in CD19 cells. The mean serum half-life of rituximab was reported to be 10-15 days in patients with steroid-dependent MCNS. Only infusion reactions, such as rash and chills, occurred after single-dose rituximab infusion and can be managed by pre-medication or infusion rate adjustments. Even though severe adverse effects of rituximab are not expected, we must be aware of potentially life-threatening adverse effects. Controlled randomized trials that include adult patients with steroid-dependent MCNS are required to prove the efficacy and safety of rituximab and to evaluate the cost-effectiveness of rituximab treatment. In this review, we highlight recent studies and discuss the effects of these studies on the management of patients with MCNS in adults.

Renal Amyloidosis - Tempo of Proteinuria Resolution in Bortezomib Era

IntroductionAL amyloidosis is a systemic disease where the immunoglobin light chains produced by clonal plasma cells accumulate as insoluble fibrils causing end organ damage. In patients with AL amyloidosis, renal involvement is common, and proteinuria is frequently detected. Current treatment for AL amyloidosis aims at reducing production of these pathological immunoglobulin light chains by eliminating the clonal plasma cell population. Following treatment and normalisation of serum free light chains (SFLCs), improvement in end organ function, as demonstrated by reduction of proteinuria in patients with renal AL amyloidosis, occurs at a much slower rate. Although reduction in proteinuria has been linked to improved outcomes, the rate of this reduction has not been documented in detail in the literature. The purpose of this study is to analyse the tempo of proteinuria resolution in patients with renal AL amyloidosis following bortezomib based chemotherapy.MethodsCases were selected by retrospectively reviewing the hospital electronic database. All patients with biopsy confirmed renal AL amyloidosis were included. Induction chemotherapy was a combination of weekly bortezomib (1.6mg/m2), cyclophosphamide (300mg/m2) and dexamethasone (40mg) given in 4-weekly cycles. During the follow-up period, proteinuria was measured by urinary protein / creatinine ratio (PCR) from random urine samples. The results of the PCR over time were plotted on a scatter plot, and a best fit curve was fitted using IBM SPSS Statistics 20 software to determine the trend of PCR over time. Patients who did not complete bortezomib chemotherapy, or did not have follow-up urinary PCR were excluded.ResultsAfter applying the exclusion criteria, seven patients were analysed, and the baseline characteristics are listed in table 1. The median follow-up was 30.9 months (range: 13.2 – 44.1 months). The median age was 68.8 years (range: 52.5 – 80.5 years). Patients received a median of 6 cycles of chemotherapy (range: 2 – 9 cycles), and all patients received full doses of bortezomib based on their body surface area (average dose of 1.6mg/m2, range: 1.53 – 1.64mg/m2). Five of the 7 patients normalised their SFLCs after one cycle of chemotherapy, and the median time to normalisation was 26 days (range: 13 – 185 days).PCR was used to monitor the level of proteinuria following chemotherapy. One patient was excluded in this part of the analysis due to progressive diabetic and hypertensive nephropathy following an initial improvement in PCR after normalisation of SFLCs. Although there was marked fluctuation of PCR (figure 1), the PCRs followed an exponential decay pattern over time (R2 between 0.223 – 0.976). The median half-life of reduction was 6.2 months (range: 3.4 – 18.2 months).ConclusionsPCR from random urine samples is a useful and convenient way of assessing proteinuria in everyday outpatient setting. Although PCR fluctuates over time in patients with renal AL amyloidosis, there is a general downward trend following bortezomib based chemotherapy and normalisation of SFLCs. This downward trend appears to follow an exponential decay pattern, and most patients have a protracted delay between normalisation of SFLCs and improvement in proteinuria. In view of such delay, normalisation of SFLCs should be the goal of initial therapy, rather than reduction in proteinuria when treating patients with renal AL amyloidosis.Table 1Baseline patient characteristicsValue(range)Age (median)68.8 years(52.5 – 80.5 years)Male (%)55.6%Plasma cell burden (median)12.5%(6 – 25%)Kappa/Lambda light chain ratio (median)0.164(0.011 – 37.333)eGFR > 30ml/min (%)88.9%Protein / creatinine ratio at diagnosis (mean)698mg/L(243 – 1636mg/L) [Display omitted] DisclosuresSimpson:Onyx: Honoraria, Research Funding; Celgene: Honoraria; Janssen Cilag: Honoraria.

Oral Calcitriol for Reduction of Proteinuria in Patients With IgA Nephropathy: A Randomized Controlled Trial

Vitamin D has shown efficacy in the reduction of proteinuria in patients with chronic kidney disease. This study aimed to determine the effect of calcitriol on urinary protein excretion in patients with immunoglobulin A (IgA) nephropathy. Open-label, non-placebo-controlled, randomized study. 50 patients with IgA nephropathy were enrolled. The main criterion for inclusion was urinary protein excretion >0.8 g/d after renin-angiotensin system-inhibitor treatment for at least 3 months. Patients were randomly assigned (1:1) to receive 2 doses (0.5 μg) of calcitriol per week or no treatment for 48 weeks. The primary end point was to compare change in 24-hour urinary protein excretion from baseline to last measurement during treatment. Every 8 weeks, there was measurement of 24-hour urinary protein excretion, serum calcium, serum phosphorus, serum creatinine, and intact parathyroid hormone. Measurement of the primary end point showed changes in urinary protein excretion of +21% (from 1.29 to 1.58 g/24 h; 95% CI, -9% to +52%) in the control group and -19% (from 1.60 to 1.30 g/24 h; 95% CI, -42% to +4%) in the calcitriol-treated group. There was a significant decrease in proteinuria in the calcitriol-treated group compared with the control group (difference between groups, 41%; 95% CI, 5%-79%; P = 0.03). The secondary end point of achieving at least a 15% decrease in proteinuria was attained by 7 of 24 (29%) controls and 17 of 26 (65%) of those treated with calcitriol (P = 0.02). No significant differences were observed in decrease in estimated glomerular filtration rate and change in blood pressure between the 2 groups. The incidence of recorded adverse events was similar between the 2 groups. Small and non-placebo-controlled study. The addition of calcitriol to a renin-angiotensin system inhibitor resulted in a safe decrease in proteinuria in patients with IgA nephropathy.

Rituximab and minimal change nephrotic syndrome: a therapeutic option

Minimal change nephrotic syndrome (MCNS) usually responds to steroids but frequently relapses, requiring additional treatment with immunosuppressive agents. Rituximab is a chimeric murine/human monoclonal immunoglobulin G1 antibody that targets CD20, a B-cell differentiation marker. B-cell recovery begins at approximately 6months following the completion of treatment. Rituximab has a beneficial effect, with the sustained remission or reduction of proteinuria in patients with steroid-dependent MCNS. Relapses are thought to be associated with an increase in CD19 cells. The mean serum half-life of rituximab was reported to be 10-15days in patients with steroid-dependent nephrotic syndrome. Only infusion reactions, such as rash and chills, occurred after single-dose rituximab infusion and can be managed by pre-medication or infusion rate adjustments. Even though severe adverse effects of rituximab are not expected, physicians must be aware of potentially life-threatening adverse effects. Controlled randomized trials that include adult patients with steroid-dependent or steroid-resistant MCNS are required to prove the efficacy and safety of rituximab and to evaluate the cost-effectiveness of rituximab treatment.

Efficacy and Safety of Glucocorticoids Therapy for IgA Nephropathy: A Meta-Analysis of Randomized Controlled Trials

Background: Published reports examining the efficacy and safety of glucocorticoids for preserving renal function in immunoglobulin A nephropathy (IgAN) have yielded conflicting results. To systematically evaluate the efficacy and safety of glucocorticoids agents for IgAN, we conducted a meta-analysis of the published randomized controlled trials (RCTs). Methods: MEDLINE, EMBASE, the Cochrane Library and article reference lists were searched for RCTs that compared glucocorticoids with placebo and any other non-immunosuppressive agents for treating IgAN. The quality of the studies was evaluated with the method of the intention-to-treat analysis and allocation concealment, as well as with the Jadad method. Meta-analyses were performed on the outcomes of proteinuria and renal survival and adverse events in patients with IgAN. Results: Seven RCTs involving 386 patients were included in the review. Four RCTs reported renal survival data with Kaplan-Meier survival curves. Overall, glucocorticoid agents had statistically significant effects on improved renal survival (HR 0.20, 95% CI 0.20 to 0.39) and reduction of proteinuria (standardized mean difference SMD, –0.51; 95% CI –0.73 to –0.29) when compared with the control group. Tests for heterogeneity showed no difference in effect among the studies. In general, glucocorticoid agents were well tolerated. Patients receiving glucocorticoids therapy did not have an increased risk of development of type 2 diabetes mellitus, hypertension or Cushingoid adverse effects, while glucocorticoids were associated with a significant increase in the risk of gastrointestinal tract adverse events. Conclusions: The current cumulative evidence suggests that glucocorticoids have statistically significant effects on protecting renal function and reduction of proteinuria in patients with IgAN, but we should be careful for its gastrointestinal tract reaction. In general, glucocorticoids agents are a promising medication and should be investigated further.

ACEI/ARB therapy for IgA nephropathy: a meta analysis of randomised controlled trials

Published reports examining the efficacy of RAS blockers: angiotensin converting-enzyme inhibitor (ACEI) and angiotensin II receptor blocker (ARB) agents for preserving renal function in IgA nephropathy (IgAN) have yielded conflicting results. To evaluate systematically the effects of ACEI/ARB agents on IgAN, we conducted a meta analysis of published randomised controlled trials (RCTs). MEDLINE, EMBASE, the Cochrane Library and article reference lists were searched for RCTs that compared ACEI/ARB with placebo and any other antihypertensive agents or non-immunosuppressive agents for treating IgAN. The quality of the studies was evaluated with the method of intention to treat analysis and allocation concealment, as well as with the Jadad method. Meta analyses were performed on the outcomes of proteinuria and renal function in patients with IgAN. Eleven RCTs involving 585 patients were included in the review. Seven trials used placebo/no treatment as controls. Four trials used other antihypertensive agents as controls. Overall, ACEI/ARB agents had statistically significant effects on protecting renal function(p < 0.00001) and reduction of proteinuria (p < 0.00001) when compared with control group. Tests for heterogeneity showed no difference in effect among the studies. Systolic and diastolic blood pressure, glomerular filtration rate (GFR), age, did not influence treatment response. ACEI/ARB agents were well tolerated. The current cumulative evidence suggests that ACEI/ARB agents had statistically significant effects on protecting renal function and reduction of proteinuria in patients with IgAN when compared with control groups. ACEI/ ARB agents are a promising medication and should be investigated further.

Optimal dosing of renin–angiotensin–aldosterone system blockers for renal protection: a solved issue?

To the Editor: Schjoedt et al. [1] convincingly demonstrated that at group level a daily dose of 40 mg of the ACE inhibitor lisinopril provides maximum reduction of proteinuria in patients with type 1 diabetes and nephropathy. The importance of the issue of dose is widely appreciated, but it is surprising how little effort has been made to find the optimal dose of a single agent, while numerous studies have been performed worldwide to test the additional antiproteinuric benefit of dual renin–angiotensin–aldosterone system (RAAS) blockade (angiotensin converting enzyme inhibitor plus angiotensin receptor blocker [ARB]). The authors must therefore be acknowledged for their contribution. Does, however, a maximal effect at a dose of 40 mg in a group imply that 40 mg has a maximal effect in all individual patients? We would suggest not. In our experience in non-diabetic patients with overt proteinuria, the dose of lisinopril required for maximal anti-proteinuric effect varies between patients [2]. Schjoedt et al. also mention that their patients had considerably impaired renal function. Considering the renal clearance of lisinopril, circulating plasma levels of lisinopril were presumably high. Thus it is possible that in patients with better preserved glomerular filtration rate, higher daily doses of lisinopril would be required for comparable plasma levels of the drug and efficacy. In addition, other patient factors such as type of renal lesion or genetic make-up could influence inter-individual differences in drug response. Therefore, the evidence so far does not exclude the possibility that daily doses of lisinopril higher than 40 mg may be required in some patients. Nevertheless, it would be unrealistic to claim that highdose RAAS blockade alone has the potential to completely reverse proteinuria in the majority of patients, not even when given in combination with ARB. The limits may be set not only by efficacy, but also by side effects, as illustrated in patients with non-diabetic proteinuria on a high dose (300 mg) of the ARB irbesartan [3]. When lisinopril was added in incremental doses up to 40 mg, adverse events (hyperkalaemia, cough, dizziness) occurred in most patients. Since the results of the Combination Treatment of Angiotensin-II Receptor Blocker and Angiotensinconverting-enzyme Inhibitor in Non-diabetic Renal Disease (COOPERATE) trial have been seriously questioned [4], and with the recent results on renal endpoints of the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) in mind [5], the issue of whether dual RAAS blockade leads to improved long-term renal protection should be addressed in a new randomised study, specifically designed for that purpose. We would strongly favour a design in which dual blockade consists of a combination of the optimal antiproteinuric doses in the individual patient. Until such data are available, we propose an individualised approach, with titration of a single drug based on the effect on proteinuria and on blood pressure, and the extent of side effects. If necessary, a second drug could be added and again titrated, with careful monitoring of side effects being essential. Diabetologia (2009) 52:1217–1218 DOI 10.1007/s00125-009-1328-5

Maximizing inhibition of the renin-angiotensin system with high doses of converting enzyme inhibitors or angiotensin receptor blockers

Over the last 20 years, inhibitors of the renin–angiotensin– aldosterone system (RAAS) have become the cornerstone inthetreatmentofhypertension.Likewise,thesedrugshave found an increasing use in patients with underlying renal disease, as numerous lines of evidence have pointed to theirhavingabloodpressureloweringindependent antiproteinuric effect [1]. This effect of renin–angiotensin system (RAS)inhibitorsgainsinsignificanceasseverallargeinterventional studies have uniformly found that proteinuria is a major risk factor for progression of renal disease [2–5]. In fact, in some of these studies [3,4] the reduction of proteinuria in patients with diabetic nephropathy was associated with a decreased risk of reaching a renal endpoint which included doubling of serum creatinine and end-stage renal disease (ESRD). A similar observation has been made in non-diabetic kidney disease with lower levels of baseline proteinuria [5], demonstrating the importance of lowering protein excretion in a variety of renal disorders and across a broad spectrum of protein excretions. In view of the above-described observations, it is not surprising that there have been attempts to determine whether inhibition of the renin–angiotensin system at various levels could produce additive renoprotective effects. With the advent of a direct renin inhibitor (DRI), in addition to converting enzyme inhibitors (ACEs) and angiotensin receptor blockers (ARBs), there are no less than four potential drug combinations. Furthermore, since antagonists of aldosterone have been shown to decrease protein excretion in patients with renal diseases [6,7], the option of also employing aldosterone inhibitors doubles the potential combination of drugs to eight (Table 1). As would be expected, the most frequently used combination is that of an ACE with an ARB. Many of the studies that have been undertaken with this approach suffer from the confounding effect of further blood pressure lowering with the dual treatment, particularly when the doses used in the combination were the same as those employed in the comparator monotherapies [8]. However, when taken together, in a thoroughly and

The effect of aldosterone blockade in patients with Alport syndrome

Recent studies indicate that adding the mineralocorticoid receptor antagonist spironolactone (SP) to angiotensin converting enzyme inhibitors (ACEI) or ACEI and angiotensin receptor blocker (ARB), which is known as a triple blockade, enhances the more beneficial effects on urinary protein excretion of patients with chronic kidney diseases. In this study, we explored the effects of SP on urinary protein excretion in patients with Alport syndrome featuring persistent proteinuria in spite of the long-term use of ACEI (lisinopril) or both ACEI and ARB (candesartan). Five patients with Alport syndrome were enrolled and SP treatment (25 mg/day) was started. At the start of SP administration, all patients showed good renal function and none of them suffered from hypertension. We decided to assess the effect of SP by determining the morning urinary protein/creatinine ratio (U-P/C) and estimated glomerular filtration rate (EGFR). After SP treatment was started, U-P/C was significantly reduced at 3, 6, 12 and 18 months, while EGFR did not change. The drop in systolic and diastolic blood pressure was statistically significant and serum potassium level was slightly elevated. None of the patients showed signs of severe hyperkalemia (>5.0 mEq/l). These results suggest that aldosterone receptor blockade combined with ACEI and ARB therapy offers a valuable adjuvant treatment for the reduction of proteinuria in patients with Alport syndrome as in those with other chronic kidney diseases. SP can thus be expected to constitute a good renoprotective agent for Alport syndrome. These preliminary data indicate that large-scale trials of this therapy should be done.

Solitary pancreas transplantation: preliminary findings about early reduction of proteinuria in incipient or evident diabetic type I nephropathy

ObjectiveOur work was aimed to evaluate the precocious reduction of proteinuria in patients suffering from diabetes mellitus type 1 with incipient and evident nephropathy after isolated pancreas transplantation (PTA). Materials and methodsFrom December 2000 to March 2003, we followed 24 PTA grafts in 24 patients with diabetes mellitus type 1 (mean age 37.8 years; mean duration of diabetes 24.8 years). The pancreas was transplanted with portal-enteric drainage in 23 patients and systemic-enteric in 1 patient. The immunosuppressive therapy used basilixmab induction and tacrolimus, mycophenolate mophetil (MMF), and low dose steroid maintenance therapy. The renal function, proteinuria, and the glucose metabolic parameters were evaluated before and during the following months after transplant. ResultsAll patients are alive and twenty-one have a well-functioning pancreas with three grafts lost. All patients had persistence of normal renal function. Before transplantation 12 patients displayed proteinuria that was clearly reduced in 11 and gone in three patients, all of whom were insulin-independent. ConclusionsTPA seems to reduce, and in some cases to regress, the proteinuria associated with early diabetic nephropathy.