NEW THERAPIES IN LOWERING PROTEINURIA: IMPACT ON KIDNEY AND CARDIOVASCULAR OUTCOMES Piero Ruggenenti MD (Bergamo – Italy)
ABSTRACT Chronic kidney disease is the strongest risk factor for cardiovascular disease. Randomized, multicenter studies in diabetic and nondiabetic patients with chronic proteinuric nephropathies clearly demonstrated that renin-angiotensin system (RAS) inhibitors, such as angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) used alone or in combination effectively retard renal disease progression. Renoprotection, in turn, translates into significant cardioprotection. The Ramipril efficacy in Nephropathy (REIN) study showed that proteinuria reduction, in addition to arterial blood pressure control, largely mediates the nephroprotective effect of RAS inhibitor therapy. Despite RAS inhibition, however, most patients with chronic kidney disease (CKD) continue to progress to end stage renal disease (ESRD). This highlighted the importance of innovative therapeutic approaches aimed to halt or revert CKD progression in those at risk. Along this line, a multimodal strategy targeting urinary proteins by dual RAS inhibition with ACE inhibitors and ARBs uptitrated to maximum tolerated doses, intensified blood pressure control, amelioration of dyslipidemia by HmGCoA reductase inhibitors (statins), smoking cessation and healthy lifestyle implementation – the Remission Clinic approaach - was applied in day-by-day clinical practice at our outpatient clinic to normalize urinary proteins and prevent renal function loss in patients predicted to rapidly progress to ESRD because of nephrotic range proteinuria refractory to standard antihypertensive dosages of an ACE inhibitor. The efficay and safety of this approach was tested in a matched-cohort study comparing the outcome of 56 patients referred to our Remission Clinic with that of historical 56 reference- patients identifyed from patients randomized to the ramipril arm of the REIN study who were matched with patients by age, gender and severity of proteinuria and were on standard doses of remipril (5 mg per day) recommended for blood pressure control. Data showed that the multi-drug treatment titrated to urinary proteins – the Remission Clinic program – compared to a conventional regimen titrated to blood pressure, significantly slowed GFR decline and reduced the risk of terminal kidney failure by 8.5 folds. During 7-year observation, only 2 patients treated according to the Remission Clinic protocol progressed to ESRD – these patients were affected by Idiopathic Membranous Nephropathy, a disease that now we know may fully recover with lymphocytolic therapy with rituximab - , compared to 17 reference-patients on conventional therapy. Moreover, on the basis of individual GFRs at inclusion and rates of GFR decline observed on follow-up, no other patient was projected to progress to ESRD within expected life-time, while 3 additional reference-patients were projected to need renal replacement therapy within 14, 22 and 34 years after the end of the active observation period, respectively. The above effects were associated with more effective BP, serum cholesterol and urinary proteins reduction in patients treated according to the Remission Clinic approach compared to reference-patients on conventional therapy. Twenty-six patients achieved disease regression or remission [24-h proteinuria <0.3 g or ≥0.3 g and <1 g, with improving or stable GFR]20. On the contrary, only a small minority of reference-patients achieved disease remission or regression and were therefore protected from eventual progression to ESRD. Of note, no patient or reference patient with 24-h proteinuria <1 g died, had cardiovascular events or progressed to ESRD. All these events were confined to those with residual 24-h proteinuria ≥1 g. Serum potassium was similar in the two cohorts and no patient withdrew from the Remission Clinic because of refractory hyperkalemia or other serious adverse events. We concluded that: i. a standardized, multidrug, sequential treatment targeting urinary proteins can be safely and effectively applied in every-day clinical practice. ii. by this approach, heavy proteinuria can be normalized, even in cases resistant to standard therapy. iii. reduction of
proteinuria to normal range translates into stabilization of kidney function and in effective prevention of ESRD. We decided not to test the Remission Clinic protocol in the setting of a randomized clinical trial since results of the above matched-cohort study were so strong and convincing that we found unethical to prospectically allocate controls to a conventional treatment regimen based on single drug RAS inhibitor therapy titrated just to blood pressure control. We rather decided to test the Remission Clinic protocol, in a multicenter observational study, including a network of Nephrology Centers and that will be progressively extended to nephrology units from several developing countries worldwide. The use of an on-line database will allow easily monitoring compliance to protocol and the safety/efficacy profile of the Remission Clinic strategy in a large patient population. Early intervention will allow preventing onset and progression of renal disease in subjects at risk and to limit the related cardiovascular morbidity and mortality. Prevention strategies at population levels might be life savings, in particular in developing countries where renal replacement therapy is not available for all patients in need.
OVERDOSE… MA NON CERTO DI ETICA Una critica ragionata alle strategie di lobby del e multinazionali del farmaco di Luca Poma (*) Quando ho deciso di scrivere questa recensione, in risposta all’intervento di un collega che si spendeva lodando lo scrittore americano Richard Epstein ed il suo saggio “Overdose – Come una regolamentazione eccessiva mette a rischio le medicin
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