Manno C

Randomized controlled clinical trial of corticosteroids plus ACE-inhibitors with long-term follow-up in proteinuric IgA nephropathy

BACKGROUND Immunoglobulin A nephropathy (IgAN) is the most common cause of chronic renal failure among primary glomerulonephritis patients. The best treatment for IgAN remains poorly defined. We planned a long-term, prospective, open-label, multicentre, centrally randomized controlled trial to assess whether the combination of prednisone and ramipril was more effective than ramipril alone in patients with proteinuric IgAN. METHODS Ninety-seven biopsy-proven IgAN patients with moderate histologic lesions, 24-h proteinuria > or =1.0 g and estimated glomerular filtration rate (eGFR) > or = 50 ml/min/ 1.73 m(2) were randomly allocated to receive a 6-month course of oral prednisone plus ramipril (combination therapy group) or ramipril alone (monotherapy group) for the total duration of follow-up. The primary outcome was the progression of renal disease defined as the combination of doubling of baseline serum creatinine or end-stage kidney disease (ESKD). The secondary outcomes were the rate of renal function decline defined as the eGFR slope over time, and the reduction of 24-h proteinuria. RESULTS After a follow-up of up to 96 months, 13/49 (26.5%) patients in the monotherapy group reached the primary outcome compared with 2/48 (4.2%) in the combination therapy group. The Kaplan-Meier analysis showed a significantly higher probability of not reaching the combined outcome in the combination therapy group than in the monotherapy group (85.2% versus 52.1%; log-rank test P = 0.003). In the multivariate analysis, baseline serum creatinine and 24-h proteinuria were independent predictors of the risk of primary outcome; treatment with prednisone plus ramipril significantly reduced the risk of renal disease progression (hazard ratio 0.13; 95% confidence interval 0.03-0.61; P = 0.01). The mean rate of eGFR decline was higher in the monotherapy group than in the combination therapy group (-6.17 +/- 13.3 versus -0.56 +/- 7.62 ml/min/ 1.73 m(2)/year; P = 0.013). Moreover, the combined treatment reduced 24-h proteinuria more than ramipril alone during the first 2 years. CONCLUSIONS Our results suggest that the combination of corticosteroids and ramipril may provide additional benefits compared with ramipril alone in preventing the progression of renal disease in proteinuric IgAN patients in the long-term follow-up.

Hemoglobin Targets for the Anemia of Chronic Kidney Disease: A Meta-analysis of Randomized, Controlled Trials

Anemia affects almost all patients with chronic kidney disease (CKD), reduces quality of life, and is a risk factor for early death. Higher hemoglobin (Hb) targets have been widely advocated because of data from observational studies showing that higher Hb is associated with improved survival and quality of life, but higher Hb targets may cause access thrombosis and hypertension and are costly. This study aimed to evaluate the benefits and harms of different Hb targets in CKD on the basis of randomized trial evidence. A comprehensive search of the Cochrane Trials Registry, Medline, Embase, and reference lists was performed. Two independent reviewers assessed studies for inclusion criteria and extracted data on all-cause mortality, cardiovascular disease, strokes, hypertension, seizures, hyperkalemia, access thrombosis, and quality of life. Analysis was by a random-effects model, and results are expressed as relative risk (RR) or weighted mean difference with 95% confidence intervals (CI). Nineteen relevant trials were identified. Twelve trials (638 patients) compared use of erythropoietin versus no erythropoietin treatment, and seven trials (2058 patients) compared higher versus lower Hb targets. Compared with Hb values of >130 g/L or more in the CKD population with cardiovascular disease, Hb values of <120 g/L were associated with lower all-cause mortality (RR, 0.84; 95% CI, 0.71 to 1.00). Hb values of 100 g/L or less reduced the risk of hypertension (RR, 0.50; 95% CI, 0.33 to 0.76) but increased the risk of seizures (RR, 5.25; 95% CI, 1.13 to 24.34). From the available trial evidence, in CKD patients with cardiovascular disease, the benefits associated with higher Hb targets (reduced seizures) are outweighed by the harms (increased risk of hypertension and death). There is insufficient data to guide decisions in patients without cardiovascular disease or in the predialysis population.

A Randomized Pilot Trial Comparing Cyclosporine and Azathioprine for Maintenance Therapy in Diffuse Lupus Nephritis over Four Years

There is not agreement about the best maintenance treatment for patients with diffuse lupus nephritis. This multicenter, randomized trial compared the safety and efficacy of cyclosporine and azathioprine. Seventy-five patients with diffuse proliferative lupus were given three intravenous methylprednisolone pulses followed by prednisone and oral cyclophosphamide for a median of 90 d. Subsequently, patients were randomly assigned either to cyclosporine or to azathioprine for 2 yr (core study). Treatment continued for up to 4 yr (follow-up study). The primary outcome measure was the incidence of disease flares. Secondary end points were proteinuria per day, creatinine clearance, and adverse effects. Seven flares occurred in the cyclosporine group, and eight occurred in the azathioprine group. At the end of the core study, mean proteinuria decreased from 2.8 +/- 3.57 to 0.4 +/- 0.85 g/d (P < 0.0001) in the cyclosporine group and from 2.2 +/- 1.94 to 0.5 +/- 0.78 g/d (P < 0.0002) in the azathioprine group. After 4 yr, mean proteinuria was 0.2 +/- 0.24 and 0.3 +/- 0.33 g/d, respectively. At the core study end and at the follow-up completion, creatinine clearance and BP levels did not change significantly from baseline in either group. Five of 36 patients who were receiving cyclosporine and four of the 33 who were receiving azathioprine stopped the treatment because of adverse effects. For patients with diffuse proliferative lupus nephritis, azathioprine or cyclosporine combined with corticosteroids demonstrated equal efficacy in the prevention of flares.

An evidence-based survey of therapeutic options for IgA nephropathy: Assessment and criticism

BACKGROUND Immunoglobulin A (IgA) nephropathy is a worldwide disease that causes end-stage renal failure in 15% to 20% of patients within 10 years of the apparent onset of disease and in 30% to 40% of individuals within 20 years. Severity of renal lesions, serum creatinine level, and severe proteinuria are adverse prognostic indicators. No specific treatment has been established, but several approaches have been experimented. METHODS We reviewed the literature and evaluated the quality of published randomized trials using standard methods and the quality of their reporting according to the revised version of the Consolidated Standards for Reporting Trials Statement. Meta-analyses of randomized trials on the efficacy of steroid treatment, cytotoxic agents, and fish oils on the outcome of renal function and daily proteinuria in patients with IgA nephropathy were performed. RESULTS Only 10 randomized trials were available and included in the review. Their quality was very poor, and a limited amount of data was reported. Cytotoxic agents seem beneficial on both renal function (relative risk, 0.38; 95% confidence interval [CI], 0.22 to 0.66) and daily proteinuria (weighted mean difference [WMD], -1.16; 95% CI, -2.18 to -0.14) in patients with moderate to severe renal damage, steroids act mainly on proteinuria (WMD, -0.50; 95% CI, -0.78 to -0.21), and fish oils do not imply a particular benefit. This statement is based on the very limited and poor available published evidence. CONCLUSION Only a few randomized trials, of low quality and inadequately reported, are available relating to treatment of IgA nephropathy. More properly designed and reported trials are necessary to reach a definitive assessment of this matter.

Desmopressin Acetate in Percutaneous Ultrasound-Guided Kidney Biopsy: A Randomized Controlled Trial

BACKGROUND Bleeding complications occur in one-third of percutaneous kidney biopsies and increase costs of the hospital stay. The aim of the study was to evaluate the effect of prebiopsy administration of desmopressin acetate versus placebo in the incidence of postbiopsy bleeding complications. STUDY DESIGN Double-blind randomized controlled clinical trial. SETTING & PARTICIPANTS We enrolled all patients with serum creatinine level ≤1.5 mg/dL and/or estimated glomerular filtration rate ≥60 mL/min/1.73 m(2) and normal coagulation parameters undergoing ultrasound-guided biopsy of the native kidney in our unit from August 2008 to December 2009. INTERVENTION We examined prebiopsy subcutaneous administration of desmopressin acetate, 0.3 μg/kg, compared with placebo. OUTCOMES & MEASUREMENTS The primary outcome was incidence of bleeding complications. Secondary outcomes were hematoma size, postbiopsy hemoglobin level, coagulation parameters, glomerular filtration rate, blood pressure, and length of hospital stay. RESULTS 162 adult patients (88 men and 74 women) were enrolled; 80 were allocated to desmopressin treatment, and 82, to the placebo group. Desmopressin compared with placebo significantly decreased the risk of postbiopsy bleeding (11 of 80 [13.7%] vs 25 of 82 [30.5%]; relative risk, 0.45; 95% CI, 0.24-0.85; P = 0.01), hematoma size (median, 208 [25th-75th percentile, 120-300] vs 380 [25th-75th percentile, 270-570] mm(2); P = 0.006] in the 36 patients who experienced bleeding, and mean hospital stay (4.9 ± 1.1 vs 5.9 ± 1.7 days; P = 0.004); postbiopsy hemoglobin levels were not affected significantly in either group. LIMITATION Single-center design of the study. CONCLUSIONS Prebiopsy desmopressin administration decreases the risk of bleeding and hematoma size in patients undergoing percutaneous kidney biopsy without a cost increase.

Alport syndrome and leiomyomatosis: the first deletion extending beyond COL4A6 intron 2.

Alport syndrome (ATS) is a nephropathy characterized by the association of progressive hematuric nephritis with ultrastructural changes of the glomerular basement membrane (thinning, thickening, and splitting), sensorineural deafness, and variable ocular abnormalities (anterior lenticonus, macular flecks, and cataracts). The most common mode of transmission is X-linked inheritance, due to COL4A5 mutations. X-linked ATS is rarely associated with diffuse leiomyomatosis (DL), a benign hypertrophy of the visceral smooth muscle in gastrointestinal, respiratory, and female reproductive tracts. The ATS-DL complex is due to deletions that encompass the 5′ ends of the COL4A5 and COL4A6 genes and include the bidirectional promoter. In this paper, we described 3 ATS-DL cases, 2 familial and 1 sporadic bearing a deletion encompassing the 5′-end of both the COL4A5 and COL4A6 genes, as identified by multiplex ligation-dependent probe amplification (MLPA) analysis. The array-CGH technique allowed a better definition of deletion size, confirming that the proximal breakpoint was within COL4A6 intron 2 in 2 cases. Surprisingly, 1 case had a deletion extending proximally beyond exon 3 of COL4A6, as confirmed by qPCR analysis. This is the largest deletion reported to date that has been associated with ATS-DL and this case should lead us to reconsider the mechanisms that might be involved in the development of diffuse leiomyomatosis.

Long term follow-up of women with hypertension in pregnancy

The reproductive history and the present health status of 66 patients who had had a pregnancy complicated by hypertension during the period 1972–1982 were retrospectively studied. Hypertension in pregnancy is a poor prognostic factor not only for the future development of hypertension but, also, as it is associated to a very poor reproductive history. Such complications are more frequent in pregnant women with very high blood pressure (160/100). In fact, in the case of a previous pregnancy, this group of patients had experienced a high rate of abortions (31.7%), premature deliveries (17.8%) and perinatal mortality (21.4%). Moreover, these women are subject to a higher risk (56.5%) of developing hypertension in successive pregnancies. Risk factors for determining the future development of hypertension are: familiar hypertension, the severity of hypertension during pregnancy and pluriparity.

Beta-Glucans Supplementation Associates with Reduction in P-Cresyl Sulfate Levels and Improved Endothelial Vascular Reactivity in Healthy Individuals

Background Oat and barley beta-glucans are prebiotic fibers known for their cholesterol-lowering activity, but their action on the human gut microbiota metabolism is still under research. Although the induction of short-chain fatty acids (SCFA) following their ingestion has previously been reported, no study has investigated their effects on proteolytic uremic toxins p-cresyl sulfate (pCS) and indoxyl sulfate (IS) levels, while others have failed to demonstrate an effect on the endothelial function measured through flow-mediated dilation (FMD). Objective The aim of our study was to evaluate whether a nutritional intervention with a functional pasta enriched with beta-glucans could promote a saccharolytic shift on the gut microbial metabolism and improve FMD. Methods We carried out a pilot study on 26 healthy volunteers who underwent a 2-month dietary treatment including a daily administration of Granoro “Cuore Mio” pasta enriched with barley beta-glucans (3g/100g). Blood and urine routine parameters, serum pCS/IS and FMD were evaluated before and after the dietary treatment. Results The nutritional treatment significantly reduced LDL and total cholesterol, as expected. Moreover, following beta-glucans supplementation we observed a reduction of serum pCS levels and an increase of FMD, while IS serum levels remained unchanged. Conclusions We demonstrated that a beta-glucans dietary intervention in healthy volunteers correlates with a saccharolytic shift on the gut microbiota metabolism, as suggested by the decrease of pCS and the increase of SCFA, and associates with an improved endothelial reactivity. Our pilot study suggests, in addition to cholesterol, novel pCS-lowering properties of beta-glucans, worthy to be confirmed in large-scale trials and particularly in contexts where the reduction of the microbial-derived uremic toxin pCS is of critical importance, such as in chronic kidney disease.

Chronic Renal Failure for Bilateral Spontaneous Kidney Rupture in a Case of Tuberous Sclerosis

A case of spontaneous, but not contemporary rupture of both kidneys in a 42-year-old man with tuberous sclerosis is described. Despite the high incidence of renal involvement, chronic renal failure due to replacement and compression of renal tissue by hamartomas is rare. We reviewed 25 cases in the literature and found only 1 other case which necessitated maintenance hemodialytic treatment for kidney rupture. It is suggested that early diagnosis and conservative partial nephrectomy could prevent or delay the onset of chronic renal failure, malignant transformation and dramatic rupture of hamartomas.

Cryoglobulinemic membranoproliferative glomerulonephritis: beyond conventional therapy.

Membranoproliferative glomerulonephritis associated with Type II cryoglobulinemia is the predominant type of HCV-related glomerulonephritis. Immunosuppressive and anti-viral therapy is alternately used to treat it, but the results are not always satisfactory or lasting. In this paper we report 3 cases of cryoglobulinemic membranoproliferative glomerulonephritis, treated with different and personalized therapeutic approaches by using conventional therapy and new drugs such as mycophenolate mofetil and rituximab. Our case series report emphasizes the importance of choosing the treatment for each patient, taking into account many factors: age, severity of liver and renal involvement, extra-renal manifestations, any previous treatment, contraindications or adverse events and last but not least the balance between immunosuppression and virus activity.