Carlos Chiurchiu

Rituximab for idiopathic membranous nephropathy

Treatments for idiopathic membranous nephropathy, a common cause of nephrotic syndrome, can be very toxic. In view of the pathogenic potential of B cells in this disease, we studied the effects of four weekly infusions of rituximab (375 mg/m(2)-- the monoclonal antibody to B-cell antigen CD20--in eight patients who had idiopathic membranous nephropathy with persistent nephrotic syndrome. At weeks 4 and 20, urinary protein decreased from mean (SE) 8.6 g/24 h (1.4) to 3.8 (0.8) and 3.7 (0.9), respectively (p<0.0001). At week 20, albuminuria and albumin fractional clearance decreased by 70% and 65%, and serum albumin increased by 31%. CD20 B lymphocytes fell below normal ranges up to study end. The short-term risk-benefit profile of rituximab seems more favourable to that of any other immunosuppressive drug used to treat idiopathic membranous nephropathy.

Rituximab in Idiopathic Membranous Nephropathy: A One-Year Prospective Study

Currently available monoclonal antibodies against the B cell surface antigen CD20 have been employed to explore whether specific inhibition of B cells may help improve the outcome of idiopathic membranous nephropathy (IMN) and may avoid the side effects of steroids and immunosuppressants. This prospective, observational study evaluated the 1-yr outcome of eight IMN patients with persistent (>6 mo) urinary protein excretion > 3.5 g/24 h given four weekly infusions of the anti-CD20 antibody rituximab (375 mg/m(2)). At 3 and 12 mo, proteinuria significantly decreased from mean (+/- SD) 8.6 +/- 4.2 to 4.3 +/- 3.3 (-51%, P < 0.005) and 3.0 +/- 2.5 (-66%, P < 0.005) g/24 h, albumin fractional clearance from 2.3 +/- 2.1 to 1.2 +/- 1.7 (-47%, P < 0.05) and 0.5 +/- 0.6 (-76%, P < 0.003), and serum albumin concentration increased from 2.7 +/- 0.5 to 3.1 +/- 0.3 (+21%, P < 0.05) and 3.5 +/- 0.4 (+41%, P < 0.05) mg/dl. At 12 mo, proteinuria decreased to < or =0.5 g/24 h or < or =3.5 g/24 h in two and three patients, respectively. Proteinuria decreased in the remaining patients by 74%, 44%, and 41%, respectively. Body weight, diastolic BP, and serum cholesterol progressively decreased in parallel with an improvement of edema in all patients. Renal function stabilized (Delta1/creatinine: +0.002 +/- 0.007). CD20 B lymphocytes fell below normal ranges up to study-end. No patient had major drug-related events or major changes in other laboratory parameters. Rituximab thus promotes sustained disease remission in patients otherwise predicted to progress to ESRD, and it is safe. The long-term risk/benefit profile of this novel, disease-specific approach seems much more favorable to that of commonly employed immunosuppressive drugs.

Angiotensin-converting enzyme inhibition and renal protection in nondiabetic patients : The data of the meta- analyses

ESRD represents a major health problem. The number of patients who enter kidney replacement programs has increased at an average of 7% per year in the past 10 yr. A large number of experimental and clinical studies have demonstrated that chronic nephropathies share common pathogenic mechanisms that contribute to renal disease progression, even independent of the original cause. Clinical studies found a significant correlation between the extent of urinary protein excretion and the rate of GFR decline in both diabetic and nondiabetic chronic nephropathies. Randomized trials, in particular the Ramipril Efficacy In Nephropathy (REIN) study, also showed that treatments that reduce proteinuria (namely angiotensin-converting enzyme [ACE] inhibitors) are renoprotective and limit progression to ESRD. Meta-analyses of randomized clinical trials also evaluated the role of proteinuria and of ACE inhibition therapy in chronic renal disease progression. Their findings were consistent with those of the REIN study and confirmed in larger series of patients the predictive value of proteinuria and the renoprotective effect of proteinuria reduction by ACE inhibition therapy. Thus, the meta-analyses may confirm and extend previous findings generated by randomized clinical trials. Conceivably, well-designed studies in properly selected and carefully monitored patients who are at increased risk continue to be the best approach to test novel hypotheses. The meta-analyses, however, represent a valuable tool to evaluate the consistency and generalizability of trial results to larger cohorts of patients.

Rituximab for Idiopathic Membranous Nephropathy: Who Can Benefit?

Rituximab effectively reduces proteinuria in patients with idiopathic membranous nephropathy (IMN), but response to treatment may vary from patient to patient. The association between baseline clinical, laboratory, and histology covariates and proteinuria reduction was evaluated retrospectively by multiple linear regression analysis at 3 mo after rituximab therapy in 14 patients with IMN with proteinuria > 3.5 g/24 h while on angiotensin-converting enzyme inhibition for at least 6 mo and no previous remissions. The association strength was expressed by standardized beta coefficients (SbetaC). Glomerular (SbetaC = 0.48, P = 0.049) and tubulointerstitial (TI) scores (SbetaC = 0.61, P = 0.003) predicted the outcome. Among glomerular and TI score components, tubular atrophy (SbetaC = 0.59, P = 0.003) and interstitial fibrosis (SbetaC = 0.60, P = 0.001) were significantly associated with 3-mo proteinuria. Urinary protein excretion decreased from 9.1 +/- 4.0 to 4.6 +/- 3.5 g/24 h (P < 0.001) in eight patients with TI score 1.7 but did not change in six with a score > or = 1.7. Nine additional patients with IMN then were allocated prospectively to rituximab treatment on the basis of a TI score < 1.7. Three-month proteinuria decreased in all patients from 8.9 +/- 5.3 to 4.9 +/- 3.9 g/24 h (P < 0.001) and serum albumin increased from 2.2 +/- 0.6 to 2.8 +/- 0.5 mg/dl (P < 0.01). Changes in serum albumin and cholesterol were inversely correlated (P < 0.02, r = -0.44). Rituximab achieved CD20 and CD19 depletion in all patients. In patients with IMN and nephrotic proteinuria despite angiotensin-converting enzyme inhibition therapy, renal biopsy findings may help in predicting response to rituximab and defining selection criteria for randomized trials that aim to assess the risk/benefit profile of B cell target therapy as compared with aspecific immunosuppressants and/or conservative therapy alone.

Effects of verapamil added-on trandolapril therapy in hypertensive type 2 diabetes patients with microalbuminuria: The BENEDICT-B randomized trial

Objectives To address whether nondihydropyridine calcium-channel blocker added-on angiotensin-converting-enzyme inhibitor therapy ameliorates albuminuria and cardiovascular outcomes in type 2 diabetes patients. Design The Bergamo Nephrologic Diabetes Complications Trial-B was a multicentre, prospective, double-blind, parallel-group trial comparing renal and cardiovascular outcomes in 281 hypertensive type 2 diabetes patients with microalbuminuria randomized to at least 2-year VeraTran (verapamil/trandolapril 180 mg/2 mg daily) or trandolapril (2 mg daily, identical image) treatment. Main outcome was persistent macroalbuminuria (albuminuria >200 μg/min in two consecutive visits). Treatment targets were SBP/DBP less than 120/80 mmHg and HbA1C less than 7%. Results Over a median follow-up of 4.5 years, 18 patients (13%) on VeraTran vs. 15 (10.5%) on trandolapril [unadjusted hazard ratio (95% confidence interval [CI]) 1.07 (0.54–2.12), P = 0.852] progressed to macroalbuminuria, respectively; 62 (44.9%) vs. 71 (49.7%) [0.80 (0.57–1.12), P = 0.198] regressed to normoalbuminuria (urinary albumin excretion <20 μg/min), and 20 (14.5%) vs. 21 (14.7%) [hazard ratio 0.93 (0.50–1.72), P = 0.816] had major cardiovascular events. BP and metabolic control were similar between groups. Patients with cardiovascular events were significantly less [13 (9.8%) vs. 28 (18.9%), hazard ratio: 0.37 (0.19–0.71), P = 0.003] among those regressing to normoalbuminuria than those without regression. Difference was independent of treatment allocation and was significant also after adjusting for baseline characteristics [0.40 (0.20–0.79), P = 0.009], follow-up SBP [0.40 (0.20–0.80), P = 0.010] or DBP [0.36 (0.18–0.73), P = 0.004] BP or HbA1C [0.43 (0.21–0.88), P = 0.021]. Conclusion In hypertensive type 2 diabetes patients with microalbuminuria, verapamil added-on trandolapril did not improve renal or cardiovascular outcomes. Independent of verapamil, trandolapril normalized albuminuria in half of patients and this translated into significant cardioprotection.

Effects of Manidipine and Delapril in Hypertensive Patients With Type 2 Diabetes Mellitus The Delapril and Manidipine for Nephroprotection in Diabetes (DEMAND) Randomized Clinical Trial

To assess whether angiotensin-converting enzyme inhibitors and third-generation dihydropyridine calcium channel blockers ameliorate diabetic complications, we compared glomerular filtration rate (GFR; primary outcome), cardiovascular events, retinopathy, and neuropathy in 380 hypertensive type 2 diabetics with albuminuria <200 mg/min included in a multicenter, double-blind, placebo-controlled trial (DEMAND [Delapril and Manidipine for Nephroprotection in Diabetes]) and randomized to 3-year treatment with manidipine/delapril combination (10/30 mg/d; n=126), delapril (30 mg/d; n=127), or placebo (n=127). GFR was centrally measured by iohexol plasma clearance. Median monthly GFR decline (interquartile range [IQR]) was 0.32 mL/min per 1.73 m2 (IQR: 0.16–0.50 mL/min per 1.73 m2) on combined therapy, 0.36 mL/min per 1.73 m2 (IQR: 0.18–0.53 mL/min per 1.73 m2) on delapril, and 0.30 mL/min per 1.73 m2 (IQR: 0.12–0.50 mL/min per 1.73 m2) on placebo (P=0.87 and P=0.53 versus combined therapy or delapril, respectively). Similar findings were observed when baseline GFR values were not considered for slope analyses. Albuminuria was stable in the 3 treatment groups. The hazard ratio (95% CI) for major cardiovascular events between combined therapy and placebo was 0.17 (0.04–0.78; P=0.023). Among 192 subjects without retinopathy at inclusion, the hazard ratio for developing retinopathy between combined therapy and placebo was 0.27 (0.07–0.99; P=0.048). Among 200 subjects with centralized neurological evaluation, the odds ratios for peripheral neuropathy at 3 years between combined therapy or delapril and placebo were 0.45 (0.24–0.87; P=0.017) and 0.52 (0.27–0.99; P=0.048), respectively. Glucose disposal rate decreased from 5.8±2.4 to 5.3±1.9 mg/kg per min on placebo (P=0.03) but did not change on combined or delapril therapy. Treatment was well tolerated. In hypertensive type 2 diabetic patients, combined manidipine and delapril therapy failed to slow GFR decline but safely ameliorated cardiovascular disease, retinopathy, and neuropathy and stabilized insulin sensitivity.

Effect of the Urotensin Receptor Antagonist Palosuran in Hypertensive Patients With Type 2 Diabetic Nephropathy

The urotensin system has been hypothesized to play an important role in the pathophysiology of diabetic nephropathy. In this multicenter, randomized, double-blind, placebo-controlled, 2-period crossover study, the effects of the urotensin receptor antagonist palosuran on urinary albumin excretion and blood pressure in hypertensive patients with type 2 diabetic nephropathy treated with a single blocker of the renin-angiotensin-aldosterone system were assessed. Patients with 24-hour albuminuria >0.5 and <3.0 g, systolic blood pressure >135 and <170 mm Hg, and/or diastolic blood pressure >85 and <110 mm Hg received both palosuran 125 mg BID and placebo for 4 weeks each. Fifty-four patients (20% women; mean age: 61.6 years, blood pressure: 155/84 mm Hg, and albuminuria: 1016 mg per 24 hours) were included in the per-protocol analysis. Palosuran did not affect albuminuria, blood pressure, glomerular filtration rate, or renal plasma flow significantly. These results question whether urotensin receptor antagonism represents a new treatment strategy in this high-risk patient population.

Elevada prevalencia de hiperparatiroidismo secundario en pacientes con enfermedad renal crónica en diálisis en Argentina

BACKGROUND There are few data in Argentina on the prevalence and management of bone and mineral metabolism (BMM) in patients with chronic kidney disease (CKD). OBJECTIVES AND METHODS A survey was carried out in dialysis units in 2010 to measure the prevalence of and types of treatments for BMM disorders in Argentina. The data obtained was then compared to the published results from other large population studies. We recorded characteristics of dialysis centres and participating patients, the frequency of measurements and individual results for BMM biochemical markers, as well as the type of management used to control hyperphosphataemia and secondary hyperparathyroidism. RESULTS 1210 patients from 25 dialysis centres in Argentina participated in the study (representing 4.7% of the country’s prevalent dialysis population in 2010). The mean patient age was 55.3±17.6 years, 60.8% were male, 3.3% were on peritoneal dialysis and 29.1% suffered diabetes. In all centres, phosphataemia and calcaemia were measured on a monthly basis, 60% of centres measured intact parathyroid hormone (iPTH) every 6 months, 36% every 3 to 4 months, and 4% annually. As recommended by K/DOQI, 51.6% of patients had adequate levels of calcium (8.4-9.5 mg/dl), 51.6% had adequate phosphorus (3.5-5.5 mg/dl) and 21.1% displayed acceptable iPTH levels (150-300 pg/ml). 24% had iPTH <150 pg/ml and 54.5% >300 pg/ml. iPTH ≥600 pg/ml was present in 28.3%, and 13.3% had values ≥1000 pg/ml. These figures differed from those published by the DOPPS II study, in which 51.1% of patients had iPTH <150 pg/ml, and only 26.7% had iPTH ≥300 pg/ml. Calcium-based phosphate binders were used in 83.6% of the patients, 5.6% used sevelamer and 4.0% used aluminium-containing compounds. To achieve control of hyperparathyroidism, oral or intravenous calcitriol was predominantly used (50.5%) with a small percentage of patients receiving paricalcitol or doxercalciferol. CONCLUSIONS The present study shows a high prevalence of secondary hyperparathyroidism, which differs from that published by other large population studies. There was a high proportion of patients with BMM markers outside the ranges suggested by K/DOQI. Mainly phosphate binders based on calcium and calcitriol continue to be used for the management of hyperphosphatemia and hyperparathyroidism respectively.

Inhibition of the renin-angiotensin system and cardio-renal protection: focus on losartan and angiotensin receptor blockade

Angiotensin II plays a central role in the pathogenesis and progression of proteinuric nephropathies and related cardiovascular complications. Losartan is a selective non-peptide angiotensin Type 1-receptor blocker (ARB) with unique uricosuric effect, not shared by other ARBs. Losartan has demonstrated renoprotective effects in animals and humans with diabetic and non-diabetic renal diseases similar to those of angiotensin-converting enzyme inhibitors, with a lower incidence of dry cough and angioneurotic oedema. A reduced incidence of cerebrovascular events and diabetes has been reported in hypertensive patients with left ventricular hypertrophy on losartan therapy compared with patients treated with atenolol. Whether ARBs have superior cardioprotective effects, compared with other blood pressure medications, is still unknown. Combined angiotensin-converting enzyme inhibitor and ARB therapy improves renal outcomes in non-diabetic nephropathies more than single drug renin-angiotensin system inhibition. Whether this also applies to diabetic nephropathy and related cardiovascular outcomes is still unknown.

Reporte de caso: Trasplante Renal en un paciente con Epidermolisis Bullosa

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genodermatosis characterized by abnormalities in the anchoring fibrils which attach the basal cell layer of the epidermis to the underlying structures. A characteristic feature of this disorder is the presence of recurrent blistering or erosions, the result of even minor traction to these tissues. Patients with RDEB frequently develop chronic renal failure, and require renal replacement therapy being a major cause of morbidity and mortality. The role of renal transplantation in these patients is scarcely known. We present the case of an end-stage renal disease patient with RDEB treated by renal transplantation and his follow-up during a period of 83 months after the transplant. In this period, there were very low frequency of serious infections as well as the absence of skin tumors. Renal transplantation could be an alternative to renal replacement therapy in epidermolysis bullosa patients with end-stage renal disease, reducing the comorbidities associated with this treatment.Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genodermatosis characterized by abnormalities in the anchoring fibrils which attach the basal cell layer of the epidermis to the underlying structures. A characteristic feature of this disorder is the presence of recurrent blistering or erosions, the result of even minor traction to these tissues. Patients with RDEB frequently develop chronic renal failure, and require renal replacement therapy being a major cause of morbidity and mortality. The role of renal transplantation in these patients is scarcely known. We present the case of an end-stage renal disease patient with RDEB treated by renal transplantation and his follow-up during a period of 83 months after the transplant. In this period, there were very low frequency of serious infections as well as the absence of skin tumors. Renal transplantation could be an alternative to renal replacement therapy in epidermolysis bullosa patients with end-stage renal disease, reducing the comorbidities associated with this treatment.