Table 1.
Characteristics of included studies
| Intervention details | Study, Authors (Year) | Inclusion Criteria | Intervention Types and Dosage | Control Group | Mean Duration of Follow-up (yr) | Participants (n); ESRD Events (n) | Mean Age (yr) | Men (%) | Mean Baseline SCr (mg/dl); mean eGFR (ml/min per 1.73 m2) | Mean Urine Protein (g/d) | Treatment Effect (RR and 95% CIs) on DSCR and ESRD |
|---|---|---|---|---|---|---|---|---|---|---|---|
| BP lowering; RAS blockade versus placebo | Lewis et al. (1993) | Age 18–49 yr; history of T1DM≥7 yr with onset <30 yr ; DR, UPE≥500 mg/d and SCr≤2.5 mg/dl | ACEI (captopril, 25 mg 3 times daily) | Placebo | 3 (median) | 409; 51 | 34.5 | 53 | 1.3; 81.53 | 2.75 | DSCR 0.57 (0.36 to 0.89); ESRD 0.63 (0.37 to 1.07) |
| GISEN-REIN-Stratum 1 (1999) | As above; stratum 1: proteinuria 1–2.9 g/d) | ACEI (ramipril, 1.25 mg) | Placebo | 2.68 | 186; 27 | 49.7 | 74.7 | 1.99; 46.60 | 1.70 | DSCR not assessed; ESRD 0.43 (0.20 to 0.92) | |
| RENAAL (2001) | Age 31–70 yr; T2DM; nephropathy (UACR≥300 mg/L and SCr 1.3–3.0 mg/dl) | ARB (losartan, 100 mg/d) | Placebo | 3.4 | 1513; 341 | 60 | 63.2 | 1.9; NR | NR | DSCR 0.83 (0.69 to 1.00); ESRD 0.77 (0.64 to 0.93) | |
| IDNT (2001)a | Age 30–70 yr; T2DM; HT (SBP>135 mmHg, DBP>85 mmHg, or documented treatment with antihypertensive); and proteinuria (UPE≥900 mg/d); SCr 1.0–3.0 mg/dl for women and 1.2–3.0 mg/dl for men | ARB (irbesartan, 75–300 mg/d); CCB (amlodipine, 2.5–10 mg/d) | Placebo | 2.6 | 1148; 183 | 58.9 | 66.5 | 1.67; NR | 2.9 | DSCR 0.71 (0.57 to 0.90); ESRD 0.80 (0.61 to 1.04) | |
| DIABHYCAR (2004) | Age ≥50 yr, T2DM; UAE≥20 mg/L | ACEI (ramipril, 1.25 mg/d) | Placebo | 4 (median) | 4912; 14 | 65.1 | 69.9 | 1.01; NR | NR | DSCR 0.81 (0.56 to 1.18); ESRD 0.40 (0.13 to 1.29) | |
| TRANSCEND (2009) | Age ≥55 yr with documented CVD or DM with end-organ damage who could not tolerate ACEIs | ARB (telmisartan, 8 mg/d) | Placebo | 4.7 | 5926; 17 | 66.9 | 57 | 1.0; 71.75 | NR | DSCR 1.57 (1.03 to 2.37); ESRD 0.70 (0.27 to 1.85) | |
| ORIENT (2011) | Age 30–70 yr; T2DM; UACR>300 mg/g; SCr 1.0–2.5 mg/dl in women and 1.2–2.5 mg/dl in men | ARB (olmesartan, 10–40 mg/d) | Placebo | 3.2 | 568; 152 | 59.2 | 69.1 | 1.62; NR | UACR 192.2 mg/mmol | DSCR 0.89 (0.73 to 1.09); ESRD 0.95 (0.72 to 1.25) | |
| ALTITUDE (2012) | Age ≥35 yr; T2DM receiving oral antidiabetic agents and/or insulin or fasting plasma glucose ≥126 mg/dl or 2-hour plasma glucose ≥200 mg/dl; ≥1 of following: persistent macroalbuminuria (UACR≥200 mg/g) and eGFR≥30 ml/min per 1.73 m2; persistent microalbuminuria (UACR≥20 mg/g and <200 mg/g) and mean eGFR≥30 and <60 ml/min per 1.73 m2; history of CVD and mean eGFR≥30 and <60 ml/min per 1.73m2 | Direct renin inhibition (aliskiren, 150–300 mg/d) | Placebo | 2.74 (median) | 8561; 234 | 64.5 | 68.6 | NR; 57.0 | UACR 207 mg/g | DSCR 0.97 (0.81 to 1.17); ESRD 1.07 (0.83 to 1.38) | |
| KVT (2013) | Age ≥20 yr; hypertension (BP>130/85 mmHg); SCr ≥2.0 mg/dl | ARB (valsartan, 40–160 mg/d) | Conventional therapy (lifestyle modification, diet therapy; glucose, lipid, anemia, potassium, calcium, phosphate, and BP control) | 1.98 (median) | 293; 106 | 64.1 | 72.4 | 3.2; 17.3 | 1.64 | DSCR 0.47 (0.31 to 0.73); ESRD 0.74 (0.54 to 1.01) | |
| BP lowering; RAS blockade versus CCB | Zucchelli et al. (1992) | Age 18–70 yr with established CKD (SCr 1.8–5.0 mg/dl) | ACEI (captopril, 25–100 mg/d) | CCB (nifedipine, 20–40 mg/d) | 4 | 121; 21 | 55 | 57.9 | 2.95; 30.50 | 1.78 | DSCR not assessed; ESRD 0.50 (0.22 to 1.17) |
| BP lowering: ARB versus ACEI versus ARB+ACEI | ONTARGET (2008)b | Age ≥55 yr; ≥1 of following: CAD, PAD, cerebrovascular disease, or DM | ARB (telmisartan, 80 mg/d); ACEI (ramipril, 10 mg/d) | ARB+ACEI (telmisartan+ramipril) | 4.67 | 17,118; 64 | 66.4 | 73.3 | 1.06; 62.2 | UACR 0.82 mg/mmol | DSCR 1.11 (0.88 to 1.39); ESRD 0.94 (0.57 to 1.53) |
| PRONEDI (2013)c | Age >35 yr; T2DM; CKD diabetic nephropathy stages 2–3; UPCR 300 mg/g | ACEI (lisinopril, 40 mg/d); ARB (irbesartan, 600 mg/d) | ACEI+ARB (lisinopril, 20 mg/d +irbesartan, 300 mg/d) | 2.67 (median) | 63; 11 | 68.3 | 70% in lisinopril; 75% in irbesartan; 78% in dual | 1.51; 48.6 | Albumin 3.9 g/dl | DSCR not assessed; ESRD 1.04 (0.35 to 3.06) | |
| BP lowering; others | Hannadouche et al. (1994) | Age 18–70 yr with CKD (SCr 2.26–4.52 mg/dl) | ACEI (enalapril– target DBP<90 mmHg; starting dose 5–10 mg/d according to SCr) | BB (target DBP <90 mmHg) | 3 | 100; 12 | 51.0 | 53 | 2.99; NR | 2.84 | DSCR not assessed; ESRD 0.46 (0.14 to 1.43) |
| ACCOMPLISH (2010) | Age ≥55 yr, history of coronary events, MI, revascularization, stroke, CKD, peripheral arterial disease, LVH, DM | ACEI+CCB (benazepril, 20 mg/d, + amlodipine, 5 mg/d) | ACEI+diuretic (benazepril, 20 mg/d +hydrochlorothiazide, 12.5 mg/d) | 2.9 | 11506; 55 | 68.3 | 60.5 | 1.00; 78.95 | UACR in CKD patients=28.8 mg/mmol; UACR in non-CKD patients=8.7 | DSCR 0.51 (0.40 to 0.64); ESRD 0.84 (0.49 to 1.42) | |
| BP lowering; intensive versus standard | AASK (2002)d | Self-identified African Americans, age 18–70 yr, GFR 20–65 ml/min per 1.73 m2, no other identified causes of renal insufficiency | Target arterial pressure <92 mmHg | Target arterial pressure 102–107 mmHg | 4 | 1094; 171 | 54.6 | 61.2 | 2.18 for men, 1.77 for women; 45.65 | 0.61 in men; 0.41 in women | DSCR not assessed; ESRD 0.92 (0.70 to 1.21) |
| REIN-2 (2005) | Age 18–70 yr; proteinuria 1–3 g/d and CrCl <45 ml/min per 1.73 m2; included if proteinuria ≥3 g/d and CrCl<70 ml/min per 1.73 m2 | Target SBP<130 mmHg and DBP<80 mmHg | Target DBP<90 mmHg irrespective of SBP | 1.58 (median) | 335; 72 | 53.9 | 74.9 | 2.70; 34.99 | 2.85 | DSCR not assessed; ESRD 1.12 (0.74 to 1.69) | |
| Lipid lowering | Endo et al. (2006) | T2DM with clinical albuminuria (UAE>300 mg/g) | Antihyperlipidemic drug+protein-restricted diet (probucol , 500 mg/d +protein-restricted diet 0.8 g/kg per day) | Protein-restricted diet (0.8 g/kg per day) | 2.38 | 102; 23 | 59.6 | 55.9 | 1.59; NR | 1.75 | DSCR not assessed; ESRD 0.76 (0.37 to 1.59) |
| FIELD (2011) | Age 50–75 yr; T2DM; baseline plasma TC 116–251 mg/dl, plus TC/HDL-C ratio ≥4.0 or plasma TG 89–354 mg/dl | Fibrate (fenofibrate, 200 mg/d) | Placebo | 5 (median) | 9795; 47 | 62.2 | 62.7 | 0.88; 87.70 | UACR 1.12 mg/mmol | DSCR 1.65 (1.27 to 2.13); ESRD 0.81 (0.46 to 1.43) | |
| SHARP (2011) | Age ≥40 yr; CKD with >1 Cr ≥1.7 mg/dl in men or 1.5 mg/dl in women, whether receiving dialysis or not | Combination lipid-lowering drug (simvastatin, 20 mg/d+ezetimibe, 10 mg/d) | Placebo | 4.9 (median) | 6247; 2141 | 62 | 62.6 | NR; 26.6 | UACR 206.5 mg/g | DSCR 0.77 (0.62 to 0.96); ESRD 0.98 (0.91 to 1.05) | |
| Glucose lowering; intensive versus standard | UKPDS (1998) | T2DM; fasting plasma glucose >6 mmol/L on 2 mornings, 1–3 wk apart | Intensive glucose lowering (FPG<6 mmol/L; in insulin-treated patients, premeal glucose 4–7 mm/L) with sulfonylurea (chlorpropamide, 100–500 mg/d; glibenclamide, 2.5–20 mg/d; glipizide, 2.5–40 mg/d) | Conventional therapy with diet (FPG<15 mmol/L without symptoms of hyperglycemia) | 10 (median) | 3867; 25 | 53.3 | 61 | 0.92; NR | NR | DSCR 0.42 (0.15 to 1.18); ESRD 0.74 (0.33 to 1.67) |
| VADT (2009) | T2DM with inadequate response to maximal doses of an oral agent or insulin therapy | Intensive glucose lowering (absolute reduction of 1.5% in HbA1c compared with standard therapy) | Standard glucose control | 5.6 (median) | 1766; 18 | 60.4 | 97.1 | 1.0; NR | NR | DSCR 1.00 (0.74 to 1.35); ESRD 0.64 (0.25 to 1.64) | |
| ACCORD (2010)e | Age 40–79 yr; T2DM; HbA1c≥7.5%; history of CVD or age 55–79 yr with anatomic evidence of significant atherosclerosis, albuminuria, LVH, or at ≥2 risk factors for CVD | Intensive glucose lowering (HbA1c<6.0%); intensive BP lowering (SBP<120 mmHg in 4733 participants); lipid-lowering therapy (in 5518 participants; fenofibrate) | Standard glucose control (HbA1c 7.0%–7.9%); standard BP lowering (SBP<140 mmHg); placebo in lipid-lowering therapy | 3.7 (intensive; median); 5 (standard; median) | 10,234; 289 | 62.2 | 62 | 0.90; 90 | UACR 1.54 mg/mmol | DSCR 1.10 (0.96 to 1.26); ESRD 0.91 (0.73 to 1.15) | |
| ADVANCE (2013)f | Age ≥55 yr; T2DM at ≥30 yr and a history of major macrovascular or microvascular disease or ≥1 other risk factor for vascular disease | Intensive glucose control (HbA1c≤6.5%); BP control (SBP<145 mmHg; perindopril, 4 mg+indapamide, 1.25 mg) | Standard glucose control (with target glycated hemoglobin levels defined on the basis of local guidelines; placebo for BP group) | 5 (median) | 11140; 27 | 65.7 | 57.5 | 0.98; 78 | UACR 15 (median) | DSCR 1.15 (0.81 to 1.62); ESRD 0.35 (0.15 to 0.83) | |
| Anemia treatment: high versus partial | Gouva et al. (2004) | Predialysis patients with renal impairment resulting from any cause other than DM with SCr 2.0–6.0 mg/dl and hemoglobin 9.0–11.6 g/dl | Early initiation of EPO (immediately started on 50 U/kg per wk EPO-α with appropriate titration aiming for hemoglobin ≥13 g/dl) | Deferred treatment (start EPO only when hemoglobin decreased to <9 g/dl) | 1.88 (median) | 88; 28 | 65.5 | 56.8 | 3.32; 24.04 | 0.62 | DSCR 0.48 (0.20 to 1.16); ESRD 0.53 (0.28 to 1.02) |
| CAPRIT (2012) | Age 18–80 yr; primary or secondary kidney allograft performed at ≥12 mo before, estimated CrCl <50 ml/min per 1.73 m2; SCr variation <20% in previous 3 mo; using standard immunosuppressive | Complete correction of anemia (target hemoglobin 13–15 g/dl) | Partial correction of anemia (hemoglobin 10.5–11.5 g/dl) | 2 | 125; 16 | 48.9 | 48.8 | 2.12; 34.1 | Albumin 41 g/L | DSCR 0.20 (0.04 to 0.86); ESRD 0.23 (0.07 to 0.76) | |
| Other interventions | Facchini and Saylor et al. (2003) | T2DM; various degrees of renal failure (GFR 15–75 ml/min per 1.73 m2) and otherwise unexplained proteinuria (350–12,000 mg/d) | Carbohydrate-restricted, low-iron-available, polyphenol-enriched dietg | Standard protein diet (0.8 g/kg of protein) | 3.9 | 191; 27 | 59.5 | 52.9 | 1.85; 63.05 | 2.47 | DSCR 0.56 (0.34 to 0.92); ESRD 0.54 (0.26 to 1.11) |
| Chen et al. (2012) | Age 30–83 yr; high-normal body lead burden (lead 80–600 µg; SCr ≤3.9 mg/dl) | Chelation therapy (2-hr 1 g calcium disodium EDTA intravenous infusions+saline solution 200 ml until body lead burden was 60 g) | Weekly 2-hr infusions 20 ml of 50% glucose+saline solution 200 ml over 5 wk | 2.25 | 50; 15 | 58.1 | 80 | 2.85; 28.6 | 3.9 | DSCR 0.53 (0.29 to 0.95); ESRD 0.36 (0.13 to 0.99) |
SCr, serum creatinine; RR, relative risk; RAS, renin-angiotensin system; T1DM, type 1 diabetes mellitus; DR, diabetic retinopathy; UPE, urinary protein excretion; ACEI, angiotensin-converting enzyme inhibitor; DSCR, doubling of serum creatinine; GISEN-REIN, Gruppo Italiano di Studi Epidemiologici in Nefrologia–REIN; T2DM, type 2 diabetes mellitus; UACR, urinary albumin-to-creatinine ratio; ARB, angiotensin-receptor blocker; HT, hypertension; SBP, systolic BP; DBP, diastolic BP; CCB, calcium-channel blocker; DIABHYCAR, Non-insulin-dependent diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril study; TRANSCEND, Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease; CVD, cardiovascular disease; DM, diabetes mellitus; ORIENT, Olmesartan Reducing Incidence of Endstage Renal Disease in Diabetic Nephropathy Trial; ALTITUDE, Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints; KVT, Kanagawa Valsartan Trial; CAD, coronary artery disease; PAD, peripheral artery disease; PRONEDI, Progresión de Nefropatía Diabética; UPCR, urinary protein-to-creatinine ratio; ACCOMPLISH, Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension; MI, myocardial infarction; LVH, left ventricular hypertrophy; AASK, African American Study of Kidney Disease and Hypertension; CrCl, creatinine clearance; FIELD, Fenofibrate Intervention and Event Lowering in Diabetes; TC, total cholesterol; HDL-C, HDL cholesterol; TG, triglyceride; SHARP, Study of Heart and Renal Protection; Cr, creatinine; UKPDS, United Kingdom Prospective Diabetes Study; FPG, fasting plasma glucose; VADT, Veterans Affairs Diabetes Trial; HbA1c, hemoglobin A1c; ACCORD, Action to Control Cardiovascular Disease in Diabetes; ADVANCE, Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation; EPO, erythropoietin; CAPRIT, Correction of Anemia and Progression of Renal Insufficiency in Transplant patients.
IDNT had three treatment groups (ARB versus CCB versus placebo). For the purpose of analysis, we used the ARB and placebo groups.
ONTARGET had three treatment groups (ARB versus ACEI versus ARB+ACEI). We used the ARB and ACEI groups.
PRONEDI trial had three treatment groups (ACEI versus ARB versus ACEI+ARB). We used the ARB and ACEI groups.
AASK trial was a 3×2 factorial trial; data presented here represent the BP target intervention.
ACCORD trial was a double 2×2 factorial trial assessing intensive glucose-lowering therapy, intensive BP-lowering therapy, and lipid-lowering therapy;
ADVANCE trial was a 2×2 factorial-design trial assessing intensive glucose-lowering and BP-lowering therapies.
Fifty percent reduction in carbohydrates; substitute iron-enriched red meats with iron-poor white meats and with protein-enriched food items known to inhibit iron absorption; eliminate all beverages other than tea, water, and red wine; milk recommended for breakfast; exclusive use of polyphenol-enriched extra-virgin olive oil.