Annalisa Perna

Renal function and requirement for dialysis in chronic nephropathy patients on long-term ramipril : REIN follow-up trial

BACKGROUND The Ramipril Efficacy In Nephropathy (REIN) study found that in patients with chronic nephropathies and proteinuria of 3 g or more per 24 h, ramipril safely reduced the rate of decline of the glomerular filtration rate (GFR) and halved the combined risk of doubling of serum creatinine or end-stage renal failure (ESRF), as compared with placebo plus conventional antihypertensive drugs at the same level of blood pressure control. At the end of the core study patients continued on or shifted to ramipril and were formally enrolled into the REIN follow-up study. METHODS 97 patients entered the follow-up study. Patients originally randomised to ramipril continued with the same daily dose (n=51), whereas those originally on placebo plus conventional antihypertensive drugs switched to ramipril after the first visit of the follow-up study (n=46). Ramipril (1.25 to 5.00 mg/day) and conventional antihypertensive therapy were targeted at achieving diastolic blood pressure under 90 mm Hg. The main efficacy variables were GFR decline and ESRF (need for dialysis). Analysis was by intention to treat. FINDINGS During the follow-up study the mean rate of GFR decline per month decreased from 0.44 (SD 0.54) mL/min per 1.73 m2 in the core study to 0.10 (0.50) mL/min per 1.73 m2 in patients originally randomised to ramipril (p=0.017), and from 0.81 (1.12) to 0.14 (0.87) mL/min per 1.73 m2 in those originally randomised to placebo plus conventional antihypertensive therapy (p=0.017). At the final visit, mean absolute GFR values were 12 mL/min per 1.73 m2 higher (33% better) in patients randomised to ramipril than in those assigned placebo (n=26 and 17, respectively: 35.5 [19.0] vs 23.8 [9.4] mL/min per 1.73 m2, p=0.01). 19 of the patients originally on ramipril versus 35 switched from placebo to ramipril progressed to ESRF (p=0.027) during the whole observation period; of these, six (8%) versus 14 (16%) reached that endpoint during the follow-up study; and the risk ratios were 1.86 (95% CI 1.07-3.26) over the whole observation period and 2.95 (1.13-7.68) during follow-up. Beyond follow-up at month 36, the incidence of ESRF was zero in patients originally randomised to ramipril but 30% in patients on placebo plus conventional antihypertensive therapy. INTERPRETATION In patients with chronic nephropathy and high risk of rapid progression to ESRF, ramipril reversed the tendency of GFR to decline with time. Moreover, a treatment period of sufficient duration (> or =36 months) eliminated the need for dialysis. Even patients previously treated with antihypertensive drugs other than angiotensin-converting-enzyme inhibitors benefited from shifting to ramipril.

Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts

We studied here the independent associations of estimated glomerular filtration rate (eGFR) and albuminuria with mortality and end-stage renal disease (ESRD) in individuals with chronic kidney disease (CKD). We performed a collaborative meta-analysis of 13 studies totaling 21,688 patients selected for CKD of diverse etiology. After adjustment for potential confounders and albuminuria, we found that a 15 ml/min per 1.73 m² lower eGFR below a threshold of 45 ml/min per 1.73 m² was significantly associated with mortality and ESRD (pooled hazard ratios (HRs) of 1.47 and 6.24, respectively). There was significant heterogeneity between studies for both HR estimates. After adjustment for risk factors and eGFR, an eightfold higher albumin- or protein-to-creatinine ratio was significantly associated with mortality (pooled HR 1.40) without evidence of significant heterogeneity and with ESRD (pooled HR 3.04), with significant heterogeneity between HR estimates. Lower eGFR and more severe albuminuria independently predict mortality and ESRD among individuals selected for CKD, with the associations stronger for ESRD than for mortality. Thus, these relationships are consistent with CKD stage classifications based on eGFR and suggest that albuminuria provides additional prognostic information among individuals with CKD.

Prognosis of Untreated Patients with Idiopathic Membranous Nephropathy

Background Defining the most appropriate treatment for patients with idiopathic membranous nephropathy is a matter of controversy. The course of the disorder is often benign, and the immunosuppressive regimens used in some patients have uncertain benefits and substantial risks. We studied the natural history of idiopathic membranous nephropathy in patients who received only symptomatic therapy. Methods We prospectively studied 100 consecutive patients (68 men and 32 women; mean [±SD] age, 51 ±17 years) with biopsy-proved idiopathic membranous nephropathy. The patients received diuretic or antihypertensive drugs as needed, but no glucocorticoid or immunosuppressive drugs. We examined the patients and measured their urinary protein excretion and serum creatinine concentrations every 6 months for a mean of 52 months. Results Twenty-four (65 percent) of the 37 patients followed for at least five years had complete or partial remission of proteinuria; in 6 others (16 percent), end-stage renal disease developed...

Cross sectional longitudinal study of spot morning urine protein:creatinine ratio, 24 hour urine protein excretion rate, glomerular filtration rate, and end stage renal failure in chronic renal disease in patients without diabetes

abstract Objective: To evaluate whether the protein:creatinine ratio in spot morning urine samples is a reliable indicator of 24 hour urinary protein excretion and predicts the rate of decline of glomerular filtration rate and progression to end stage renal failure in non-diabetic patients with chronic nephropathy. Design: Cross sectional correlation between the ratio and urinary protein excretion rate. Univariate and multivariate analysis of baseline predictors, including the ratio and 24 hour urinary protein, of decline in glomerular filtration rate and end stage renal failure in the long term. Setting: Research centre in Italy. Subjects: 177 non-diabetic outpatients with chronic renal disease screened for participation in the ramipril efficacy in nephropathy study. Main outcome measures: Rate of decline in filtration rate evaluated by repeated measurements of unlabelled iohexol plasma clearance and rate of progression to renal failure. Results: Protein:creatinine ratio was significantly correlated with absolute and log transformed 24 hour urinary protein values (P=0.0001 and P<0.0001, respectively.) Ratios also had high predictive value for rate of decline of the glomerular filtration rate (univariate P=0.0003, multivariate P=0.004) and end stage renal failure (P=0.002 and P=0.04). Baseline protein:creatinine ratios and rate of decline of the glomerular filtration rate were also significantly correlated (P<0.0005). In the lowest third of the protein:creatinine ratio (<1.7) there was 3% renal failure compared with 21.2% in the highest third (>2.7) (P<0.05). Conclusions: Protein:creatinine ratio in spot morning urine samples is a precise indicator of proteinuria and a reliable predictor of progression of disease in non-diabetic patients with chronic nephropathies and represents a simple and inexpensive procedure in establishing severity of renal disease and prognosis. Key messages The protein:creatinine ratio measured in spot morning urine samples is a simple and reliable indicator of 24 hour urinary protein excretion rate and can therefore be used to quantify proteinuria without the need for timed urine collection Spot morning urinary protein:creatinine ratio is the strongest baseline predictor of progression of renal disease in non-diabetic patients with chronic nephropathies Compared with 24 hour urinary protein excretion rate, the spot morning ratio is an even more reliable predictor of decline in glomerular filtration rate and progression to end stage renal failure and represents a simple and inexpensive procedure in the determination of severity of renal disease and prognosis

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.

Sodium Intake, ACE Inhibition, and Progression to ESRD

High sodium intake limits the antihypertensive and antiproteinuric effects of angiotensin-converting enzyme (ACE) inhibitors in patients with CKD; however, whether dietary sodium also associates with progression to ESRD is unknown. We conducted a post hoc analysis of the first and second Ramipril Efficacy in Nephropathy trials to evaluate the association of sodium intake with proteinuria and progression to ESRD among 500 CKD patients without diabetes who were treated with ramipril (5 mg/d) and monitored with serial 24-hour urinary sodium and creatinine measurements. Urinary sodium/creatinine excretion defined low (<100 mEq/g), medium (100 to <200 mEq/g), and high (≥200 mEq/g) sodium intake. During a follow-up of >4.25 years, 92 individuals (18.4%) developed ESRD. Among those with low, medium, and high sodium intakes, the incidence of ESRD was 6.1 (95% confidence interval [95% CI], 3.8-9.7), 7.9 (95% CI, 6.1-10.2), and 18.2 (95% CI, 11.3-29.3) per 100 patient-years, respectively (P<0.001). Patients with high dietary sodium exhibited a blunted antiproteinuric effect of ACE inhibition despite similar BP among groups. Each 100-mEq/g increase in urinary sodium/creatinine excretion associated with a 1.61-fold (95% CI, 1.15-2.24) higher risk for ESRD; adjusting for baseline proteinuria attenuated this association to 1.38-fold (95% CI, 0.95-2.00). This association was independent from BP but was lost after adjusting for changes in proteinuria. In summary, among patients with CKD but without diabetes, high dietary salt (>14 g daily) seems to blunt the antiproteinuric effect of ACE inhibitor therapy and increase the risk for ESRD, independent of BP control.

Chronic proteinuric nephropathies: Outcomes and response to treatment in a prospective cohort of 352 patients with different patterns of renal injury

The Ramipril Efficacy in Nephropathy (REIN) study found that angiotensin-converting enzyme (ACE) inhibitors effectively decreased proteinuria, glomerular filtration rate (GFR) decline (DeltaGFR), and incidence of end-stage renal disease (ESRD) in patients with proteinuric chronic nephropathies. In this study, we prospectively investigated the main clinical determinants of progression and response to treatment in the 352 patients enrolled into the REIN study. Mean DeltaGFR (0.56 +/- 0.05 [SEM] versus 0.21 +/- 0.05 mL/min/1.73 m(2)/mo; P = 0.0001) and incidence of ESRD (30% and 10%; P = 0.0001) were more than twice that in patients with proteinuria of 2 g/24 h or greater of protein compared with those with protein less than 2 g/24 h (relative risk [RR], 4.07; 95% confidence interval [CI], 2.20 to 7.52), as well as in patients with hypertension compared with normotension (mean DeltaGFR, 0.48 +/- 0. 05 versus 0.22 +/- 0.05 mL/min/1.73 m(2)/mon; P = 0.0006; ESRD, 25% versus 10%; P = 0.004; RR, 3.18; 95% CI, 1.38 to 7.32). Hypertension at study entry (P = 0.038), greater mean blood pressure on follow-up (P = 0.002), and urinary protein excretion rate (P = 0.0001) were independent predictors of faster DeltaGFR. DeltaGFR was approximately twofold faster in patients with type 2 diabetes than in those with primary glomerular disease (P = 0.002; including immunoglobulin A [IgA] nephropathy, P = 0.009); nephrosclerosis (P = 0.03), adult polycystic kidney disease (APKD), or chronic interstitial nephritis (P = 0.006). Diabetes at study entry (P = 0. 02) and greater mean blood pressure (P = 0.0001) and urinary protein excretion rate (P = 0.0001) on follow-up were independent predictors of faster DeltaGFR. After correction for baseline covariates, diabetes was also associated with an increased risk for progression to ESRD (RR, 2.39; 95% CI, 1.01 to 5.68; P < 0.05). At multivariate analyses, ramipril significantly decreased DeltaGFR (regression coefficient,-0.23 +/- 0.11 [SEM]; P = 0.036) and ESRD (RR, 2.08; 95% CI, 1.21 to 3.57; P = 0.008) in patients with baseline proteinuria of 2 g/24 h or greater of protein, and the renoprotective effect increased for increasing levels of proteinuria. Ramipril decreased DeltaGFR to a similar extent in normotensive and hypertensive patients (-0.14 +/- 0.11 versus -0.14 +/- 0.09) and significantly limited ESRD in hypertensive patients (RR, 2.03; 95% CI, 1.26 to 3. 26; P = 0.004). DeltaGFR was decreased by 42% in primary glomerular disease (P = 0.017), by 35% in IgA nephropathy, and by 37% in nephrosclerosis, but was not improved in type 2 diabetes, APKD, or interstitial nephritis. At multivariate analyses, ramipril significantly slowed DeltaGFR (-0.24 +/-0.08; P = 0.004) and progression to ESRD (RR, 2.32; 95% CI, 1.36 to 3.96; P = 0.002) in patients without diabetes, but not in patients with diabetes, who tended to have a faster DeltaGFR (+0.62 +/- 0.44) on ramipril therapy. In summary, patients with proteinuria of 2 g/24 h or greater of protein, preexisting hypertension, or type 2 diabetes were faster progressors. Greater blood pressure and degree of proteinuria were the strongest determinants of faster GFR decline. The renoprotective effect of ramipril was similar in patients with normotension and hypertension. Hypertensive patients and those with proteinuria of 2 g/24 h or greater of protein, primary glomerular disease, or nephrosclerosis gained the most from ACE inhibitor treatment. During the study period, those with proteinuria less than 2 g/24 h of protein, type 2 diabetes, or polycystic kidney disease did not benefit by treatment to an appreciable extent.

Role of Remission Clinics in the Longitudinal Treatment of CKD

Heavy proteinuria is a major determinant of progression to ESRD for patients with chronic nephropathies and reducing proteinuria should be a key target for renoprotective therapy. In the Remission Clinic, we applied a multimodal intervention to target urinary proteins in 56 consecutive patients who had >3 g proteinuria/d despite angiotensin-converting enzyme inhibitor therapy. We compared the rate of GFR decline and incidence of ESRD in this cohort with 56 matched historical reference subjects who had received conventional therapy titrated to a target BP. During a median follow-up of 4 yr, the monthly rate of GFR decline was significantly lower in the Remission Clinic cohort (median -0.17 versus -0.56 ml/min per 1.73 m2; P < 0.0001), and ESRD events were significantly reduced (3.6 versus 30.4% reached ESRD). Follow-up BP, cholesterol, and proteinuria were lower in Remission Clinic patients than in reference subjects, such that disease remission or regression was achieved in up to 50% of patients who would have been otherwise expected to progress rapidly to ESRD on conventional therapy. Proteinuria reduction independently predicted a slower rate of GFR decline and ESRD incidence, but response to treatment differed depending on the underlying disease. Regarding safety, no patient was with drawn because of hyperkalemia. In summary, multidrug treatment titrated to urinary protein level can be safely and effectively applied to normalize proteinuria and to slow the loss of renal function significantly,especially among patients without type 2 diabetes and with otherwise rapidly progressing chronic nephropathies.

Phosphate May Promote CKD Progression and Attenuate Renoprotective Effect of ACE Inhibition

Phosphate may promote the onset and progression of chronic nephropathies. Here we evaluated the relationships between baseline serum phosphate levels, disease progression, and response to ACE inhibition in 331 patients with proteinuric nephropathies in the prospective Ramipril Efficacy In Nephropathy (REIN) trial. Independent of treatment, patients with phosphate levels in the highest two quartiles progressed significantly faster either to ESRD or to a composite endpoint of doubling of serum creatinine or ESRD compared with patients with phosphate levels below the median (P < 0.001). Results were similar when we analyzed phosphate as a continuous variable (P ≤ 0.004). The renoprotective effect of ramipril decreased as serum phosphate increased (P ≤ 0.008 for interaction); this modification of the treatment effect by phosphate persisted despite adjusting for potential confounders such as GFR and urinary protein. In summary, these data suggest that phosphate is an independent risk factor for progression of renal disease among patients with proteinuric CKD, and high levels of phosphate may even attenuate the renoprotective effect of ACE inhibitors. Future trials should test whether reducing serum phosphate improves renal outcomes and optimizes the renoprotective effect of ACE inhibition.

Effect of longacting somatostatin analogue on kidney and cyst growth in autosomal dominant polycystic kidney disease (ALADIN): a randomised, placebo-controlled, multicentre trial

BACKGROUND Autosomal dominant polycystic kidney disease slowly progresses to end-stage renal disease and has no effective therapy. A pilot study suggested that the somatostatin analogue octreotide longacting release (LAR) could be nephroprotective in this context. We aimed to assess the effect of 3 years of octreotide-LAR treatment on kidney and cyst growth and renal function decline in participants with this disorder. METHODS We did an academic, multicentre, randomised, single-blind, placebo-controlled, parallel-group trial in five hospitals in Italy. Adult (>18 years) patients with estimated glomerular filtration rate (GFR) of 40 mL/min per 1·73 m(2) or higher were randomly assigned (central allocation by phone with a computerised list, 1:1 ratio, stratified by centre, block size four and eight) to 3 year treatment with two 20 mg intramuscular injections of octreotide-LAR (n=40) or 0·9% sodium chloride solution (n=39) every 28 days. Study physicians and nurses were aware of the allocated group; participants and outcome assessors were masked to allocation. The primary endpoint was change in total kidney volume (TKV), measured by MRI, at 1 year and 3 year follow-up. Analyses were by modified intention to treat. This study is registered with ClinicalTrials.gov, NCT00309283. FINDINGS Recruitment was between April 27, 2006, and May 12, 2008. 38 patients in the octreotide-LAR group and 37 patients in the placebo group had evaluable MRI scans at 1 year follow-up, at this timepoint, mean TKV increased significantly less in the octreotide-LAR group (46·2 mL, SE 18·2) compared with the placebo group (143·7 mL, 26·0; p=0·032). 35 patients in each group had evaluable MRI scans at 3 year follow-up, at this timepoint, mean TKV increase in the octreotide-LAR group (220·1 mL, 49·1) was numerically smaller than in the placebo group (454·3 mL, 80·8), but the difference was not significant (p=0·25). 37 (92·5%) participants in the octreotide-LAR group and 32 (82·1%) in the placebo group had at least one adverse event (p=0·16). Participants with serious adverse events were similarly distributed in the two treatment groups. However, four cases of cholelithiasis or acute cholecystitis occurred in the octreotide-LAR group and were probably treatment-related. INTERPRETATION These findings provide the background for large randomised controlled trials to test the protective effect of somatostatin analogues against renal function loss and progression to end-stage kidney disease. FUNDING Polycystic Kidney Disease Foundation.