Effect of long-term near-normoglycemia on the progression of diabetic nephropathy

The effect of prolonged restoration of near-normoglycemia on the progression of diabetic nephropathy was evaluated in a controlled study in which 10 insulin-dependent (type 1) diabetic patients with clinical proteinuria were randomized to continue with conventional insulin treatment (CIT) or to undertake more intensive diabetic therapy using continuous subcutaneous insulin infusion (CSII). The patients, mean age 33 +/- 8 yr, mean duration of diabetes 15 +/- 4 yr, were studied before and during 12 months of either CIT or CSII therapy. Glycemic control was assessed by means of mean blood glucose (MBG) +/- Standard deviation (SD), urinary glucose excretion and glycosylated hemoglobin, while renal function was assessed by albumin, IgG and beta-2-microglobulin urinary excretion rates, serum creatinine and creatinine clearance. Blood glucose level, urinary glucose excretion and glycosylated hemoglobin fell significantly in the CSII group, while no differences were found in the CIT group after the 12 months observation period. Both groups showed a deterioration in all indices of renal function, as illustrated by an increase of protein excretion rates and of serum creatinine, and by a decline in creatinine clearance. Comparison of the rate of increase of urinary albumin and IgG excretion and of serum creatinine and of the rate of fall in creatinine clearance between CIT and CSII groups demonstrated that the rate of progression of diabetic nephropathy may be slowed by correction of hyperglycemia. Our study, with due reservations because of the small number of examined patients and differences in kidney function at the beginning of the trial shows that intensive diabetic care may play a role in the proteinuric stage of diabetes in slowing further destruction of residual glomerular structure and in delaying end stage renal failure.     

Effect of vitamin E therapy on progression of diabetic nephropathy

Pathogenesis of diabetic nephropathy, which belongs to most serious microangiopathic complications of diabetes, is still not completely clear. Thromboxan A2 and increased oxidation stress are new factors apparently associated with pathogenesis of diabetic nephropathy. It was the aim of the contribution to verify the participation of thromboxan A2 and oxidation stress in the pathogenesis of diabetic nephropathy, as well as to follow the effects of treatment with vitamin E on its progression. In 19 diabetic subjects with microalbuminemia (MA) (age 55.2 +/- 7.6 years), 10 diabetic subjects with normoalbuminemia (NA) (age 54.4 +/- 6.1 years) and in 10 healthy subjects (age 53.6 +/- 9.4) the authors examined the level of malondialdehyde (MLDA) in serum, metabolites of thromboxan A2 (thromboxan B2-TXB2) and prostacyclin PGI2 (6-keto-PGF1 alpha) in urine by means of an RIA method (Isotop, Hungary). The diabetic patients with microalbuminemia were subsequently administered natural vitamin E (EVIT, Rodisna, FRG) at the daily dose of 1200 IU for the period of four months. After two and four months, respectively, MA, MLDA, TXB2 and 6-keto-PGF1 alpha) were examined. The age of the subjects in the two groups was not significantly different. In diabetic subjects with MA, the authors observed significantly higher MLDA levels in serum than in the control individuals (0.55 +/- 0.26 vs. 0.22 +/- 0.02 mumol/l, P < 0.001) and a significant difference occurred also in TBX2 in urine (134.7 +/- 113.8 vs. 27.7 +/- 10.1 ng/12 h, P < 0.001). Increased levels of TXB2 in urine were already present in diabetic subjects with NA as compared with healthy individuals (69.1 +/- 38.8 vs. 27.7 +/- 10.1 ng/12 h, P < 0.05). The treatment with vitamin E caused a significant decrease of MA (93.8 +/- 45.6 vs. 67.95 +/- 28.4 micrograms/min, P < 0.05), MLDA in serum (0.55 +/- 0.26 vs. 0.32 +/- 0.16 mumol/l, P < 0.001). On the basis of our results it is possible to suppose the role of oxidation stress and increased level of thromboxan A2 in the pathogenesis of diabetic nephropathy. The authors also confirmed that the treatment with vitamin E favorably decreases microalbuminemia, while the nephroprotective effect is apparently mediated not only by the antioxidant action, but also the decrease of thromboxan A2 production.     

The role of the diet as a risk factor for the development and progression of diabetic nephropathy

Diabetic nephropathy (DN) is the leading cause of kidney disease in patients starting renal replacement therapy, and affects up to 40% of type 1 and type 2 diabetic patients. Diet seems to play an important role in the development of the disease. There are evidences supporting the concept that not only the amount but also the origin of dietary protein are associated with DN. Few studies analyzed the role of dietary lipids. A low-protein diet slows down the decline of renal function and ameliorates the DN prognosis and death in patients with type 1 diabetes with micro- and macroalbuminuria. Studies in type 2 diabetic patients are scanty but short-term studies suggest that this approach decreases albuminuria. However, the use of low-protein diet for long periods is compromised by poor compliance and its long-term safety is not firmly established. Enthusiastic results come up when comparing the effect of different sources of animal protein on renal function and lipid profile in patients with DN, which may represent an alternative strategy for low-protein diet on medical nutritional therapy in patients with DN and in cardiovascular risk factors and endothelial function.     

Probucol delays progression of diabetic nephropathy

Probucol has antioxidant and cholesterol-lowering effects. This study examined the effect of probucol on progression of diabetic nephropathy. We performed a randomized, open trial on 102 type 2 diabetes patients with clinical albuminuria (urinary albumin excretion >300 mg/g Cr). Fifty-one patients were assigned to probucol treatment (500 mg/day) and 51 to no probucol treatment. Among all patients, 40 who had serum creatinine >or=2mg/dl at baseline were defined as advanced cases. All patients were followed for a maximum 3 years. HbA1c levels were not different between two groups. High-density lipoprotein cholesterol decreased significantly in probucol group. Increase in urinary protein (g/day/month) was significantly greater in non-probucol than in probucol group. Hemodialysis was initiated in 23 patients (10 in probucol group and 13 in non-probucol group). The mean interval to initiation of hemodialysis was significantly longer in probucol group (20.7+/-8.2 months) than in non-probucol group (11.3+/-7.4 months). In advanced cases, increases of both serum creatinine and urinary protein were significantly suppressed in probucol group. In advanced cases, the hemodialysis-free rate was significantly higher in probucol group than in non-probucol group. These results suggest that probucol may suppress the progression of diabetic nephropathy.     

Pregnancy and progression of diabetic nephropathy

Aims/hypothesis: Pregnancy could damage kidney function in diabetic nephropathy. We investigated the long-term impact of pregnancy on the progression of diabetic nephropathy. Methods: Our observational follow-up study included all women patients with Type I (insulin-dependent) diabetes mellitus who developed diabetic nephropathy between 1970 and 1989 at Steno Diabetes Center (n = 93). Follow-up lasted 16 years (range 3–28) from the onset of diabetic nephropathy until death or the year 2000. A total of 26 women became pregnant after the onset of diabetic nephropathy (group A). The remaining 67 served as control subjects (group B). All patients received aggressive antihypertensive treatment (blood pressure goal < 140/90 mmHg). Results: The two groups were comparable at onset of diabetic nephropathy regarding blood pressure, albuminuria, s-cholesterol, smoking, retinopathy and s-creatinine (mean 79(SD 23) μmol/l). The slopes of 1/s-creatinine (1000 · l ·μmol^–1· year^–1) during the whole observation period were –0.39(0.40) compared with –0.41(0.70) (group A vs B – NS). The slopes of 1/s-creatinine before and after pregnancy were similar. Decline in creatinine clearance (ml/min/yr) was 3.2 (3.4) compared with 3.2 (5.1) (group A vs B -NS). At the end of follow-up, 35 % (95 %-CI:17–53) of the pregnant women had died and 19 % (7–39) had reached end stage renal disease compared to 34 % (23–45) and 24 %(14–34) of the control subjects, respectively(NS). Group A and B had similar blood pressure levels during the whole observation period: 136(13)/83(7) vs 139 (14)/85(7) mmHg (NS). Conclusion/interpretation: Pregnancy has no adverse long-term impact on kidney function and survival in Type I diabetic patients with well-preserved kidney function (normal serum creatinine) suffering from diabetic nephropathy. [Diabetologia (2002) 45: 36–41] Received: 20 June 2001 and in revised form: 21 September 2001     

Smoking: a factor promoting onset and progression of diabetic nephropathy

Although smoking was identified two decades ago as a factor promoting the onset and progression of nephropathy in Type 1 and then in Type 2 diabetes, its role has been largely neglected. More recently, it has been shown that smoking adversely affects renal haemodynamics and protein excretion even in subjects without renal disease. In addition, it impairs the prognosis for renal function in patients with non-diabetic renal disease. Recent studies have suggested the involvement of sympathetic activation, increased endothelin production, and impaired endothelial cell-dependent vasodilatation in the genesis of smoking-induced renal function impairement. Cessation of smoking apparently slows progression to renal failure, but the decision to stop smoking is difficult because of the high addictive potential of the habit. The challenge remains for diabetologists and nephrologists to motivate patients to stop smoking.     

Effects of pregnancy on the onset and progression of diabetic nephropathy and of diabetic nephropathy on pregnancy outcomes

Controversy exists regarding the effect of pregnancy on the development and course of diabetic nephropathy. This study followed 43 pregnant women with previous diabetes mellitus, 32 without nephropathy (Group I) and 11 with nephropathy (Group II). Urinary albumin excretion (UAE), serum creatinine (Cr) and creatinine clearance (CCr) in the pre-pregnancy (Pre-P), first trimester (1T), third trimester (3T) and 1 year postpartum (PP) were evaluated. In both groups there were an increase in 3T compared to Pre-P of CCr (137 vs. 98 ml/min and 110 vs. 81 ml/min, p = 0.0001, respectively) and UAE (7.78 vs. 3.15 mg/24 h and 592 vs. 119 mg/24 h, p = 0.0001, respectively). Increase of Cr in the PP compared to 1T in Group II (0.88 vs. 0.70 mg/dL, p = 0.031) was observed. There were no difference in UAE, CCr and Cr in the PP when compared to pre-P as well variance over time between groups. Group II showed higher prevalence of chronic hypertension (72.7 vs. 21.9%, p = 0.004), preeclampsia (63.6 vs. 6.3%, p = 0.0003) and lower gestational age at birth (36 vs. 38 weeks, p = 0.003). We conclude that pregnancy was not associated with development and progression of diabetic nephropathy in women with or without mild renal dysfunction. The presence of diabetic nephropathy was associated with increased risk of perinatal complications.     

Dietary factors and progression of diabetic nephropathy

The role of dietary factors in patients with type 1 (insulin-dependent) diabetes is reviewed by examining three different aspects: the effect of an acute protein load, the effect of dietary protein restriction on the progression of nephropathy and the metabolic effects of low-protein diets. After an acute protein load some impairment of the renal functional reserve may be observed only in patients with type 1 diabetes and overt nephropathy. However, the renal functional reserve is not able to give useful indications of the extent of renal damage and the prognosis of the disease. Both short-term and long-term dietary protein restriction are followed by a significant decrease in glomerular filtration rate (GFR) and albuminuria in type 1 diabetics with incipient nephropathy. In patients with overt nephropathy the long-term administration of a low-protein diet is followed by significant reductions in the rate of decline of GFR and in urinary protein excretion only when started at GFR values higher than 45 ml/min. The rate of functional deterioration when dietary treatment is prescribed seems critical in modulating the effects of a low-protein diet. In addition, low-protein diets may exert important metabolic and clinical effects beyond their supposed effect on progression. Clearly, an adequate dietary regimen is only part of the medical treatment in patients with diabetic nephropathy.     

Cholesterol-lowering therapy may retard the progression of diabetic nephropathy

Summary There is experimental evidence to suggest that hypercholesterolaemia may play a pathogenetic role in progressive glomerular injury. We investigated the effect of cholesterol-lowering therapy on the progression of diabetic nephropathy in 34 patients with non-insulin-dependent diabetes mellitus. Patients were randomly assigned in a single-blind fashion to treatment with either lovastatin, an HMG CoA reductase inhibitor (n=16; mean dose 30.0±12.6 mg/day) or placebo (n=18) for 2 years. Renal function was assessed by serially measuring the serum creatinine, glomerular filtration rate (using Cr⁵¹-EDTA), and 24-h urinary protein excretion. Lovastatin treatment was associated with significant reductions in total cholesterol (p<0.001), LDL-cholesterol (p<0.001) and apo B (p<0.01), the reductions at 24 months being 26, 30 and 18%, respectively. Beneficial effects on serum triglyceride, HDL-cholesterol and apo A1 levels were also observed. Lp(a) showed no significant change in both groups. Glomerular filtration rate deteriorated significantly in the placebo group after 24 months (p<0.025) but showed no significant change in the lovastatin-treated patients. The increase in serum creatinine was statistically significant (p<0.02) in placebo-treated patients at 12 and 24 months, and in the lovastatin group after 24 months. Twenty-four hour urinary protein excretion increased in both groups (p<0.05). Lovastatin treatment was not associated with significant elevations in liver or muscle enzymes. We conclude that effective normalisation of hypercholesterolaemia may retard the progression of diabetic nephropathy.Abbreviations NIDDM Non-insulin-dependent diabetes mellitus - GFR glomerular filtration rate - Lp(a) lipoprotein(a) - apo apolipoprotein - LDL low-density lipoprotein - VLDL very low density lipoprotein - HDL high-density lipoprotein     

Management of diabetic nephropathy: epidemiology, pathogenesis of nephropathy and factors influencing progression

Diabetes mellitus is a major scourge of the modern world and the complications of this disease are important causes of morbidity and mortality. It is expected that the prevalence of this disease will increase several fold in all regions of the world over the coming decades. The prevalence of type 2 diabetes (initial resistance to endogenous insulin, usually found in obese adults) is about nine times greater than that of type 1 diabetes (absence of insulin, usually found in children and young adults) and thus the burden of this disease is mainly of patients with type 2 diabetes. The many complications of diabetes mellitus include cardiovascular disease, retinopathy, nephropathy, peripheral neuropathy and peripheral vascular disease. These complications appear in patients with either type of diabetes. This monograph will be devoted to the discussion of diabetic nephropathy (DN).     

Environmental tobacco smoke furthers progression of diabetic nephropathy

Clinical studies suggest that smoking is a risk factor in the progression of chronic kidney disease, including diabetic nephropathy. The mechanisms involved are not completely understood. We have previously demonstrated that nicotine, one of the compounds present in large amounts in tobacco, promotes mesangial cell proliferation and fibronectin production. In this study, we hypothesized that exposure to environmental tobacco smoke (ETS) promotes the progression of diabetic nephropathy by increasing the expression of profibrotic cytokines such as transforming growth factor-beta (TGF-β) and the extracellular matrix proteins fibronectin and collagen IV. Six-week-old diabetic (db/db) mice were divided into 2 groups. The experimental group (n = 12) was exposed to ETS at a concentration of 30 mg/m for 6 hr/d, 5 d/wk for 8 weeks. The control group (n = 8) was exposed to room air. Urine was collected before euthanasia for albumin (enzyme-linked immunosorbent assay) and creatinine measurements (mass spectrometry). After euthanasia, the kidneys were harvested for morphometric analysis and Western blot analysis. Serum was saved for cotinine measurements by enzyme-linked immunosorbent assay. ETS exposure resulted in serum levels of cotinine similar to those found in human smokers. ETS exposure for 8 weeks induced significant mesangial expansion (approximately 50% increase) that was accompanied by concomitant increases in TGF-β and fibronectin expression (approximately 20%). However, ETS did not modify results in significant changes in urinary albumin excretion. These studies demonstrate that ETS exposure worsens the progression of diabetic nephropathy by increasing the amount of mesangial expansion and that these effects are likely mediated by increased expression of profibrotic cytokines such as TGF-β.     

Effects of pulsatile intravenous insulin therapy on the progression of diabetic nephropathy

The purpose of this study was to assess the effects of pulsatile intravenous insulin therapy (PIVIT) on the progression of diabetic nephropathy in patients with type 1 diabetes mellitus (DM). This 18-month multicenter, prospective, controlled study involved 49 type 1 DM patients with nephropathy who were following the Diabetes Control and Complications Trial (DCCT) intensive therapy (IT) regimen. Of these, 26 patients formed the control group (C), which continued on IT, while 23 patients formed the treatment group (T) and underwent, in addition to IT, weekly PIVIT. Blood pressure in all patients was maintained below 140/90 mm Hg on antihypertensive medication, preferentially using angiotensin-converting enzyme (ACE) inhibitors. All study patients were seen in the clinic weekly for 18 months, had monthly glycohemoglobin (HbA1c), and every 3 months, 24-hour urinary protein excretion and creatinine clearance (CrCl) determinations. The HbA1c levels declined from 8.61% +/- 0.33% to 7.68% +/- 0.31% (P = .0028) in the T group and from 9.13% +/- 0.36% to 8.19% +/- 0.33% (P = .0015) in the C group during the study period. CrCl declined significantly in both groups, as expected, but the rate of CrCl decline in the T group (2.21 +/- 1.62 mL/min/yr) was significantly less than in the C group (7.69 +/- 1.88 mL/min/yr, P = .0343). We conclude that when PIVIT is added to IT in type 1 DM patients with overt nephropathy, it appears to markedly reduce the progression of diabetic nephropathy. The effect appears independent of ACE inhibitor therapy, blood pressure, or glycemic control.     

Effects of cicaprost and fosinopril on the progression of rat diabetic nephropathy

We have studied the effects of chronic therapy with cicaprost (a PGI₂ analog), fosinopril (a converting enzyme inhibitor), and the combination of both drugs on the progression of experimental diabetic nephropathy. Uninephrectomized streptozotocin-induced diabetic rats were maintained for 8 months with plasma glucose between 13.7 and 22.0 mmol/L to hasten renal damage. Systemic and renal parameters were measured periodically, and at sacrifice structural and morphometrical renal studies were performed to evaluate diabetic injury.Control rats exhibited characteristic features of this model, such as high blood pressure and plasma creatinine and urinary albumin excretion, together with prominent alterations in the kidney (renal and glomerular hypertrophies, mesangial matrix expansion, and tubular alterations). The three therapies attenuated equivalently the progression of diabetic renal injury, as estimated by lower urinary albumin excretion, renal and glomerular hypertrophies, and a better renal architectural preservation. No synergistic action was appreciated with the combined therapy. However, renal preservation achieved with cicaprost was not linked to reductions in systemic blood pressure, whereas in the groups treated with fosinopril the hypotensive effect of this drug could have contributed to the positive outcome of the therapy. Therefore, nephroprotection exerted by this PGI₂ analog in this model seems more related to the derangement of renal local mechanisms than to systemic blood pressure control. Finally, the possibility that an impaired prostacyclin synthesis or bioavailability is involved in the pathogenesis of the diabetic nephropathy in this model underlies our results.     

Slowing the progression of diabetic nephropathy and its cardiovascular consequences

This paper incorporates the findings from a multidisciplinary meeting on diabetic nephropathy and its renal and cardiovascular complications into a review article. The epidemic of obesity and the growing elderly population in the United States are primary drivers of a secondary epidemic of incipient type 2 diabetes mellitus and diabetic nephropathy. Current therapies aim to treat blood pressure, particularly with agents that block the renin-angiotensin system, to a target of 130/80 mm Hg. However, even lower blood pressure targets may be optimal. Control of hyperglycemia and dyslipidemia, smoking cessation, exercise, and weight loss all compliment blood pressure control and are achieved most effectively when the patient, provider, and health system are aligned with these goals. Once end-stage renal disease (ESRD) is reached, patients enter the highest cardiovascular risk-state appreciated in human medicine. Because of uniform access to care in the United States, advanced data systems, and circulatory system (intravascular) access in most patients, the ESRD population should be the future sampling frame for newer treatments tested in both prospective cohort and randomized trials. Cardiorenal risk, or the degree of excess cardiovascular risk incurred by patients with chronic kidney disease and ESRD, is a state offering considerable research opportunities for novel cardiovascular risk factors. Future studies should fully consider the possibility that improved outcomes would be achieved at a greater cost; thus, cost-effectiveness studies are essential for understanding the economic aspects of implementation. The goal of an ideal clinical trial would be ESRD prevention; however, pragmatic objectives such as a greater understanding of therapeutic toxicities should also be explored in this population.     

A case report of a diabetic nephropathy patient with cirrhotic ascites treated by peritoneal dialysis

A 64-year-old man was admitted because of abdominal fullness, edema and anorexia. He had come to our hospital for treatment of liver cirrhosis and diabetic nephropathy for 1 year. We started diuretics and human albumin intravenous administration. Although the edema disappeared and abdominal fullness improved a little, blood urea nitrogen (BUN) and serum creatinine became elevated, hepatic function deteriorated and he lost his appetite. We consequently started continuous ambulatory peritoneal dialysis (CAPD) in order to control ascites and uremia. Abdominal fullness, appetite and BUN and serum creatinine improved without hepatic function deterioration. It might be important to start CAPD to control ascites although serum creatinine levels might be slightly elevated.     

High-fat diet in low-dose-streptozotocin-treated heminephrectomized rats induces all features of human type 2 diabetic nephropathy: a new rat model of diabetic nephropathy

Background and aimWe have developed a new rat model that mimics the natural course of diabetic nephropathy seen in type 2 diabetes.MethodsNine days after intravenous injection of streptozotocin (STZ) (40 mg/kg) or vehicle to 8-week-old male Sprague–Dawley rats, the animals’ right kidneys were surgically removed. Two weeks after surgery, the STZ-injected rats were fed on either a high-fat (ST + HF) or a normal (ST) diet, while the vehicle-injected rats were fed on the high-fat diet (HF).ResultsBaseline biochemical markers did not differ between the three groups. Only the ST + HF group showed a significant increase in plasma glucose levels after 15 weeks, and simultaneously plasma insulin levels started to decrease, followed by an increase in plasma total cholesterol and triglyceride levels at 25 weeks and slightly later by an increase in blood pressure. In the ST + HF group, significant microalbuminuria was detected at 15 weeks followed by overt proteinuria, both of which were absent in the other two groups. Also in ST + HF, the creatinine clearance rate increased until week 15, and then gradually decreased. Histologically, ST + HF rats showed mesangial expansion at week 25, and diffuse glomerular sclerosis at the end of the experiments.ConclusionThe chronological changes in biochemical, physiological and histological markers in ST + HF rats are reminiscent of human type 2 diabetes and nephropathy. Our new model of type 2 diabetic nephropathy should help us to understand the pathophysiology of the disease and serve to explore measures to prevent and treat diabetic nephropathy.