Diabetic nephropathy: can renoprotection be extrapolated to cardiovascular protection?
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Albuminuria↗
Biomedical subjects
Hans-Henrik Parving
Publications and source records attributed to Hans-Henrik Parving.
Microalbuminuria in type 1 and type 2 diabetes mellitus: evidence with angiotensin converting enzyme inhibitors and angiotensin II receptor blockers for treating early and preventing clinical nephropathy.
A cumulative incidence of diabetic nephropathy of 25% to 40% has been documented after duration of diabetes of at least 25 years in both type 1 and type 2 diabetic patients. Diabetic nephropathy has become the leading cause (25%-44%) of end-stage renal failure in Europe, the United States, and Japan. Until the early 1980s, no renoprotective treatment was available for use in diabetic nephropathy. Death occurred on average 5 to 7 years after the onset of persistent proteinuria. The two main treatment strategies for prevention of diabetic nephropathy are improved glycemic control and blood pressure lowering, particularly using drugs blocking the renin-angiotensin system. Megatrials and meta-analyses have clearly demonstrated the beneficial effect of both the above-mentioned treatment modalities. Secondary prevention, that is, treatment modalities applied to diabetic patients at high risk for developing diabetic nephropathy (eg, those with microalbuminuria) has been documented, applying angiotensin converting enzyme inhibitors and angiotensin II receptor blockade. The renoprotective effects of these drugs are independent of their beneficial reduction in blood pressure.
Angiotensin Receptor Antagonists↗
Cataract surgery on diabetic patients. A prospective evaluation of risk factors and complications.
PURPOSE: This study presents an evaluation of cataract surgery on diabetic patients. One experienced surgeon carried out phaco emulsification on all subjects and the same surface-coated one-piece PMMA-lens-type was implanted. The lens fluorescence and the blood-aqueous barrier (BAB) were then evaluated as experimental preoperative risk indicators. RESULTS: During follow-up, 10 out of 39 diabetic patients progressed unilaterally in diabetic retinopathy or developed macular oedema, a significant relative risk. Neither lens fluorescence, BAB, HbA1c, level of retinopathy, type/duration of diabetes, diabetes treatment or antihypertensive treatment differed significantly between the group of patients with postoperative progression of retinopathy/macular oedema and those without. Results indicated NIDDM (non-insulin-dependent diabetes mellitus/type 2 diabetes) patients might have increased risk of a postoperative macular oedema. CONCLUSION: When diabetic retinopathy (DR) is not in a proliferative phase it should not be regarded as a contraindication to modern cataract surgery. Neither lens fluorescence nor BAB is valuable as a risk indicator for postoperative progression of DR.
Aged↗
Diurnal variations of glomerular filtration rate and albuminuria in diabetic nephropathy.
BACKGROUND: The aim of our study was to evaluate the diurnal variation in glomerular filtration rate (GFR), and the potential mechanisms responsible for such variations in GFR and albuminuria in diabetic nephropathy. METHODS: In three 24-hour urine samples, divided into a night- and daytime portion, diurnal variation in albuminuria (ELISA) was assessed. Furthermore, during recumbency changes in albuminuria, GFR (51Cr-EDTA plasma clearance) and arterial blood pressure (TM2420) from nighttime (00:00 to 05:00 hours) to subsequent daytime (08:00 to 13:00 hours) were examined in 20 type 1 diabetic patients with diabetic nephropathy. RESULTS: The 24-hour urine collections showed an average rise in albuminuria from night- to daytime of 51% (95% CI; 16 to 95; P < 0.01). During recumbency a non-significant rise was recorded from night- to daytime in albuminuria (22%, -8 to 61, P=0.15), simultaneously with an increase in GFR of 9.0% (3.4 to 14.5, P < 0.005) and mean arterial blood pressure (MABP) of 8.0% (4.3 to 11.7, P < 0.0001). No diurnal variation in fractional clearance of albumin was found. Significant associations between MABP and albuminuria were demonstrated during night- (R2=0.50; P < 0.001) and daytime (R2=0.48; P < 0.005). A linear regression analysis between diurnal variations in MABP and GFR showed that an increase in MABP (of 10%) from night- to daytime was associated with a significant increase in GFR (of 8.0%, 0.2 to 4.1, P < 0.02). CONCLUSIONS: Our study revealed diurnal variations in GFR, albuminuria and MABP in diabetic nephropathy, with lowest values during sleep at night. The observed diurnal variation in albuminuria seems to be explained partly by mechanisms related to orthostasis, and partly by the diurnal variation in GFR and serum albumin concentration. The diurnal variation of blood pressure seems to play a role for the diurnal changes in GFR and albuminuria.
Adolescent↗
Renoprotective effects of losartan in diabetic nephropathy: interaction with ACE insertion/deletion genotype?
BACKGROUND: The beneficial short- and long-term renoprotective effects of angiotensin I-converting enzyme (ACE) inhibition are lower in albuminuric diabetic patients homozygous for the deletion compared to the insertion polymorphism of the ACE gene. In an attempt to overcome this interaction, we evaluated the short-term renoprotective effect in diabetic nephropathy of the angiotensin II receptor antagonist losartan in patients homozygous for the insertion or the deletion allele. METHODS: Fifty-four hypertensive type 1 diabetic patients with diabetic nephropathy homozygous for the insertion (I; N = 26) or the deletion (D; N = 28) allele of the ACE/ID polymorphism were included. After four weeks of washout, the patients received losartan 50 mg daily followed by 100 mg in two treatment periods each lasting two months. Patients and investigators were blinded to ACE genotypes. At baseline and in the end of the treatment periods, 24-hour blood pressure, albuminuria and glomerular filtration rate values were determined. RESULTS: At baseline, blood pressure, albuminuria and glomerular filtration rate (GFR) values were similar in the two genotype groups [II vs. DD, 1134 (238 to 5302) vs. 1451 (227 to 8129) mg/24 h, median (range); 156/82 (17/9) vs. 153/80 (17/11) mm Hg, mean (SD); and 86 (22) vs. 88 (24) mL/min/1.73 m2, respectively]. Both doses of losartan significantly lowered blood pressure, albuminuria, and GFR (P < 0.05 vs. baseline). Losartan 100 mg was more effective than 50 mg in reducing albuminuria, 51% (95% CI; 40 to 61) versus 33% (23 to 42), respectively (P < 0.01). No differences in the impact of losartan between the II and DD groups were observed: Losartan 100 mg lowered systolic/diastolic blood pressure by 12/6 and 10/4 mm Hg, whereas albuminuria decreased by 55% (35 to 68) and 46% (28 to 61), in the II and DD groups, respectively (P = NS). CONCLUSION: Our data suggest that losartan offers similar short-term renoprotective and blood pressure lowering effects in albuminuric hypertensive type 1 diabetic patients with the ACE II and DD genotypes. However, the long-term renoprotective effects remain to be evaluated.
Adult↗
Effect of dietary protein restriction on prognosis in patients with diabetic nephropathy.
BACKGROUND: Recent data suggest that dietary protein restriction improves survival and delays the progression to end-stage renal disease (ESRD) in non-diabetic nephropathies. The purpose of our study was to determine the effect of dietary protein restriction on survival and progression to ESRD in diabetic nephropathy. METHODS: A four-year prospective, controlled trial with concealed randomization was performed comparing the effects of a low-protein diet (0.6 g/kg/day) with a usual-protein diet. The study included 82 type 1 diabetic patients with progressive diabetic nephropathy [pre-study mean decline in glomerular filtration rate (GFR) 7.1 mL/min/year (95% CI, 5.8 to 8.5)]. The main outcome measures were decline in GFR and development of ESRD or death. RESULTS: During the follow-up period the usual-protein diet group consumed 1.02 g/kg/day (95% CI; 0.95 to 1.10) as compared with 0.89 (0.83 to 0.95) in the low-protein diet group (P = 0.005). The mean declines in GFR were 3.9 mL/min/year (2.7 to 5.2) in the usual-protein diet group and 3.8 (2.8 to 4.8) in the low-protein diet group. ESRD or death occurred in 27% of patients on a usual-protein diet as compared with 10% on a low-protein diet (log-rank test; P = 0.042). The relative risk of ESRD or death was 0.23 (0.07 to 0.72) for patients assigned to a low-protein diet, after an adjustment at baseline for the presence of cardiovascular disease (P = 0.01). Blood pressure and glycemic control were comparable in the two diet groups during the follow-up period. CONCLUSION: Moderate dietary protein restriction improves prognosis in type 1 diabetic patients with progressive diabetic nephropathy in addition to the beneficial effect of antihypertensive treatment.
Adult↗
Dual blockade of the renin-angiotensin system in type 1 patients with diabetic nephropathy.
BACKGROUND: Albuminuria and hypertension are predictors of poor renal and cardiovascular outcome in patients with diabetes. Approximately 30% of type 1 patients with diabetic nephropathy (DN) have albuminuria >1 g/day, and blood pressure >135 and/or >85 mmHg despite antihypertensive therapy with recommended doses of ACE inhibitor (ACEI) and diuretics. We tested the effect of dual blockade of the renin-angiotensin system (RAS) in these patients. METHODS: We performed a randomised double blind crossover trial with 2 months treatment with Irbesartan 300 mg o.d. and placebo added on top of previous antihypertensive treatment. We included 21 type 1 patients with DN responding insufficiently to ACEI and diuretics, as defined above. At the end of each treatment period, albuminuria, 24-h blood pressure and glomerular filtration rate (GFR) were measured. RESULTS: Addition of 300 mg Irbesartan to the patients' usual antihypertensive therapy induced a mean reduction in albuminuria of 37% (95% CI 20-49, P<0.001); from 1574 mg/24 h (95% CI 1162-2132) to 996 mg/24 h (95% CI 699-1419), a reduction in 24-h blood pressure of 8 mmHg systolic (95% CI -2 to 18) and 5 mmHg diastolic (95% CI 1-9) (P=0.11 and 0.01, respectively) (from placebo, mean (SE) 146 (4)/80 (2) mmHg). GFR remained unchanged. Serum potassium increased (mean 4.3 to 4.6 mmol/l, P=0.02). Intervention to reduce serum potassium was needed in two patients with GFR <35 ml/min/1.73 m(2). Otherwise the dual blockade with Irbesartan was safe and well tolerated. CONCLUSIONS: Dual blockade of the RAS may offer additional renal and cardiovascular protection in type 1 patients with DN responding insufficiently to conventional antihypertensive therapy, including recommended doses of ACEI and diuretics.
Albuminuria↗
PC-1 amino acid variant (K121Q) has no impact on progression of diabetic nephropathy in type 1 diabetic patients.
BACKGROUND: Recently, an amino acid variant (K121Q) in the glycoprotein PC-1 (Q allele) has been associated with faster progression of diabetic nephropathy, as estimated by calculated creatinine clearance. We tested the impact of the PC-1 (K121Q) variant on loss of glomerular filtration rate (GFR) measured by the [(51)Cr]EDTA plasma clearance technique. METHODS: We performed an observational follow-up study of 295 (182 males) type 1 patients with diabetic nephropathy [mean age 37 (SE 0.7) years, mean duration of diabetes 23 (SE 0.5) years]. All patients were followed for at least 3 years, median 8 years (range 3-17), with at least three measurements of GFR using [(51)Cr]EDTA (median 11 measurements (range 3-32)). Two hundred and seventeen patients had the KK genotype and 78 carried the Q allele (71 KQ and 7 QQ). RESULTS: Patients carrying the Q allele had a mean rate of decline in GFR during follow-up of 3.6 ml/min per year (SE 0.4) compared with 4.0 ml/min per year (SE 0.3) in patients with the KK genotype. Other risk factors for progression of diabetic nephropathy were similar in Q carriers and KK carriers. When dividing patients in tertiles based on rate of decline in GFR, we found no difference in distribution of K121Q genotypes. No difference in the number of patients who died or reached end-stage renal disease during follow-up according to K121Q genotype were found. A multiple linear regression analysis revealed that albuminuria, mean arterial blood pressure, haemoglobin A(1C) and serum cholesterol during follow-up predicted a steeper decline in GFR [R(2) (adjusted)=0.27], whereas the PC-1 genotype did not contribute. CONCLUSIONS: Our study did not reveal an association between the PC-1 amino acid variant K121Q and progression of diabetic nephropathy.
Adult↗
Optimal dose of losartan for renoprotection in diabetic nephropathy.
BACKGROUND: Angiotensin II subtype-1 receptor antagonists represent a valuable new class of drugs in the treatment of diabetic nephropathy. The aim of our study was to evaluate the optimal dose of losartan for renoprotection and blood pressure reduction in diabetic nephropathy. METHODS: Fifty consecutive hypertensive type 1 diabetic patients with diabetic nephropathy received increasing doses of losartan, 50, 100, and 150 mg once daily in three periods each lasting 2 months. At baseline and at the end of each treatment period, albuminuria, 24-h blood pressure (TM2420 A&D), and glomerular filtration rate (GFR) ([(51)Cr]EDTA plasma clearance) were determined. RESULTS: Baseline values of albuminuria (geometric mean (95% CI)) and GFR (means+/-SEM) were 1138 (904-1432) mg/24 h and 91+/-3 ml/min/1.73 m(2), respectively. The blood pressure at baseline was 155/81+/-3/2 mmHg. All doses of losartan reduced albuminuria and blood pressure. Albuminuria was reduced by 30% (95% CI (15-41)) on losartan 50 mg, 48% (35-57) by losartan 100 mg, and 44% (32-56) by losartan 150 mg (all P values <0.01 vs baseline). Losartan 100 mg daily was significantly more effective than 50 mg daily in reducing albuminuria (P<0.01) without differences between the two high doses. Losartan 50, 100, and 150 mg daily decreased systolic/diastolic blood pressures by 7/4, 12/6, and 10/5 mmHg, respectively (all P<0.05). Losartan 100 mg daily was more effective than 50 mg daily in reducing systolic, diastolic, and mean arterial blood pressure (P=0.05), without differences between the high doses. Treatment with losartan 100 and 150 mg lowered GFR by 4 ml/min/1.73 m(2) (P<0.05). CONCLUSION: Our study suggests that the optimal dose of losartan is 100 mg daily for renoprotection and blood pressure reduction in type 1 diabetic patients with diabetic nephropathy.
Albuminuria↗
Increased urinary albumin excretion, endothelial dysfunction, and chronic low-grade inflammation in type 2 diabetes: progressive, interrelated, and independently associated with risk of death.
In 328 type 2 diabetic patients followed for 9.0 years (mean), we investigated whether endothelial dysfunction and chronic inflammation (estimated from plasma markers) can explain the association between (micro)albuminuria and mortality. Of the patients, 113 died. Mortality was increased in patients with baseline microalbuminuria or macroalbuminuria (odds ratios as compared with normoalbuminuria, 1.78 [P < 0.05] and 2.86 [P < 0.01]) and in patients with soluble vascular cell adhesion molecule 1 in the third tertile and C-reactive protein in the second and third tertiles (odds ratios as compared with the first tertile, 2.05 [ P < 0.01], and 1.80 [P < 0.05] and 2.92 [ P < 0.01]). These associations were mutually independent. The mean yearly change in urinary albumin excretion was 9.4%; in von Willebrand factor, 8.1%; in tissue-type plasminogen activator, 2.8%; in soluble vascular cell adhesion molecule 1, 5.2%; in soluble E-selectin, -2.3%; in C-reactive protein, 3.8%; and in fibrinogen, 2.3%. The longitudinal development of urinary albumin excretion was significantly and independently determined by baseline levels of and the longitudinal development of BMI, systolic blood pressure, serum creatinine, glycated hemoglobin and plasma von Willebrand factor (baseline only), soluble E-selectin (baseline only), tissue-type plasminogen activator, C-reactive protein, and fibrinogen. The longitudinal developments of markers of endothelial function and inflammation were interrelated. In type 2 diabetes, increased urinary albumin excretion, endothelial dysfunction, and chronic inflammation are interrelated processes that develop in parallel, progress with time, and are strongly and independently associated with risk of death.
Albuminuria↗
Dual blockade of the renin-angiotensin system in diabetic nephropathy: a randomized double-blind crossover study.
OBJECTIVE: Many patients with diabetic nephropathy (DN) have levels of albuminuria > 1 g/day and blood pressure >135/85 mmHg, despite antihypertensive combination therapy, including recommended doses of ACE inhibitors, e.g., lisinopril/enalapril at 20 mg daily. We tested the concept that such patients might benefit from dual blockade of the renin-angiotensin system (RAS). RESEARCH DESIGN AND METHODS: We performed a randomized double-blind crossover study of 2 months treatment with candesartan cilexetil 8 mg once daily and placebo in addition to previous antihypertensive treatment. We included 18 type 2 diabetic patients with DN fulfilling the above-mentioned criteria. All received recommended doses of ACE inhibitor and, in addition, 15 patients received diuretics, 11 received a calcium channel antagonist, and 3 received a beta-blocker. At the end of each treatment period, we measured the glomerular filtration rate (GFR), 24-h blood pressure, albuminuria, and IgGuria. RESULTS: The addition of candesartan to usual antihypertensive therapy induced a mean (95% CI) reduction in albuminuria of 25% (2-58), P = 0.036 (geometric mean [95% CI] from 1,764 mg/24 h [1,225-2,540] to 1,334 mg/24 h [890-1,998]). It also produced a mean reduction of 35% (9-53) in the fractional clearance of albumin (P = 0.016), a reduction of 32% (1-54) in fractional clearance of IgG (P = 0.046), a reduction in 24-h systolic blood pressure of 10 mmHg (2-18) (P = 0.019) (mean +/- +/- SE) from 148 +/- 3 to 138 +/- 5 mmHg, and a mean reduction in GFR of 5 ml. min(-1). 1.73 m(-2) (0.1-9) (P = 0.045). CONCLUSIONS: Dual blockade of the RAS reduces albuminuria and blood pressure in type 2 diabetic patients with DN responding insufficiently to previous antihypertensive therapy, including ACE inhibitors in recommended doses.
Adrenergic beta-Antagonists↗
Risk factors for development of incipient and overt diabetic nephropathy in type 1 diabetic patients: a 10-year prospective observational study.
OBJECTIVE: To evaluate prospectively putative risk factors for development of microalbuminuria and macroalbuminuria in type 1 diabetes. RESEARCH DESIGN AND METHODS: Prospective observational study of a cohort of type 1 diabetic patients followed in the outpatient clinic at Steno Diabetes Center for < or =10 years (median 9 years). We followed 537 patients aged > or =18 years with type 1 diabetes, with duration of diabetes > or =5 years, with normoalbuminuria (urinary albumin excretion rate < or =30 mg/24 h), and who were not taking antihypertensive medication. Risk factors for development of microalbuminuria and macroalbuminuria were evaluated. RESULTS: The mean progression of urinary albumin excretion rate was 7.6% (SE 0.8) per year. During follow-up, 134 patients (25%) progressed to persistent microalbuminuria or macroalbuminuria (>30 mg/24 h in two of three consecutive urine samples). Cox multiple regression analysis using baseline values of putative predictors of progression showed the following significant predictors of progression from normoalbuminuria to microalbuminuria or macroalbuminuria: baseline log urinary albumin excretion rate 2.63 (relative risk; 95% CI 1.65-4.19), HbA(1c) 1.13% (1.04-1.23), presence of any retinopathy 1.90 (1.26-2.88), and smoking 1.61 (1.11-2.33). Sex, duration of diabetes, arterial blood pressure, serum creatinine, height, and social class were not risk factors. CONCLUSIONS: Our study suggests that several potentially modifiable risk factors predict the development of microalbuminuria and macroalbuminuria in type 1 diabetic patients.
Albuminuria↗