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Notes: Summary The pathogenesis of diabetic nephropathy remains elusive. A role for renal prostaglandins in antagonizing the hormonal effects of renin-angiotensin II has been postulated as a putative factor leading to hyperfiltration in patients with Type 1 (insulin-dependent) diabetes mellitus. Our aim was to elucidate the effects of angiotensin II on kidney haemodynamics and on blood pressure in eight normal subjects, in nine normotensive, in nine hypertensive with normal sodium-lithium countertransport activity in erythrocytes, in seven hypertensive without and in eight hypertensive Type 1 diabetic patients with microalbuminuria and with high sodium-lithium countertransport activity in erythrocytes. Angiotensin II infusion 4ng·kg−1·min−1 for 60 min) decreased the glomerular filtration rate to a greater extent in normal subjects (−20%), than in normotensive patients (−5% p〈0.01), in hypertensive patients with normal sodium-lithium countertransport activity in erythrocytes (−8% p〈0.01) in hypertensive patients with high sodium-lithium countertransport (−6% p〈0.01) and in hypertensive microalbuminuric patients (−5% p〈0.01) with Type 1 diabetes. The urinary excretion rate of vasodilatory prostaglandins was two-three fold higher in all patients than in normal subjects. Acute indomethacin treatment restored a normal response to angiotensin II infusion in normotensive patients, but did not change the renal haemodynamic response in normal subjects. With regard to hypertensive patients with and without microalbuminuria indomethacin treatment restored a normal response to angiotensin II in some but not all patients. An inverse relation was found between angiotensin II-induced decrease in the glomerular filtration rate and the sodium-lithium countertransport activity in erythrocytes during indomethacin treatment. Hypertensive and microalbuminuric patients with a sodium-lithium countertransport activity higher than 0.41 mmol·l erythrocyte−1·h−1 (the upper limit in normal subjects) also had a greater intimal plus medial thickness of the carotid artery using an ultrasonic imaging technique. Chronic indomethacin administration (30 days) significantly decreased the baseline overnight fasting glomerular filtration rate in normotensive and in hypertensive patients with normal but not in hypertensive and microalbuminuric patients with high sodium-lithium countertransport activity. In conclusion these results demonstrate that: (1) excessive synthesis of vasodilatory prostaglandins antagonizes the regulation of renal haemodynamics by angiotensin II, at least partially accounting for hyperfiltration in Type 1 diabetes, (2) elevated sodium-lithium countertransport activity in erythrocytes identifies a subgroup of patients with Type 1 diabetes and hypertension, with and without microalbuminuria, in whom the normalization of urinary excretion rate of prostaglandins does not restore a normal response to angiotensin II.

Notes: Summary Microalbuminuria predicts overt nephropathy in non-insulin-dependent diabetic (NIDDM) patients; however, the structural basis for this functional abnormality is unknown. In this study we evaluated renal structure and function in a cohort of 34 unselected microalbuminuric NIDDM patients (26 male/8 female, age: 58 ± 7 years, known diabetes duration: 11 ± 6 years, HbA1 c: 8.5 ± 1.6 %). Systemic hypertension was present in all but 3. Glomerular filtration rate (GFR) was 101 ± 27 ml · min–1· 1.73 m–2 and albumin excretion rate (AER) 44 (20–199) μg/min. Light microscopic slides were categorized as: C I) normal or near normal renal structure; C II) changes “typical” of diabetic nephropathology in insulin-dependent diabetes (IDDM) (glomerular, tubulo-interstitial and arteriolar changes occurring in parallel); C III) “atypical” patterns of injury, with absent or only mild diabetic glomerular changes associated with disproportionately severe renal structural changes including: important tubulo-interstitial with or without arteriolar hyalinosis with or without global glomerular sclerosis. Ten patients (29.4 %) were classified as C I, 10 as C II (29.4 %) and 14 as C III (41.2 %); none of these patients had any definable non-diabetic renal disease. GFR, AER and blood pressure were similar in the three groups, while HbA1 c was higher in C II and C III than in C I patients. Diabetic retinopathy was present in all C II patients (background in 50 % and proliferative in 50 %). None of the patients in C I and C III had proliferative retinopathy, while background retinopathy was observed in 50 % of C I and 57 % of C III patients. In summary, microalbuminuric NIDDM patients are structurally heterogeneous with less than one third having “typical” diabetic nephropathology. The presence of both “typical” and “atypical” patterns of renal pathology was associated with worse metabolic control, suggesting that hyperglycaemia may cause different patterns of renal injury in older NIDDM compared to younger IDDM patients. [Diabetologia (1996) 39: 1569–1576]

Notes: Summary Pathogenetic mechanisms other than the quality of metabolic control may play a role in the development of diabetic nephropathy. Some cross-sectional studies have shown that elevated erythrocyte sodium-lithium countertransport (Na + /Li + CT) activity may be linked to incipient or overt nephropathy in insulin-dependent diabetic (IDDM) patients. The aim of the present work was to ascertain if high erythrocyte Na + /Li + CT activity anticipates the development of microalbuminuria in IDDM patients. Evaluation of this cation transport system was carried out in 159 normotensive, normoalbuminuric IDDM patients, who were divided into two groups: those with values above (Group A) and those with values below (Group B) the median level in the overall population (300 μmol/erythrocytes × h). A total of 79 patients in Group A and 80 in Group B underwent periodic examinations over a similar time period (5.2 years, range 3.3–7.4 years and 5.4 years, range 3.4–7.5 years, respectively). Median sodium-lithium countertransport activity was stable when evaluated after 2 and 4 years of follow-up. Only seven patients were excluded from the protocol because changes in their sodium-lithium countertransport activity placed them on the other side of the median value with respect to their baseline measurement. Thus, 152 patients completed the study (76 in Group A and 76 in Group B). Of the 76 patients in Group A, 17 developed persistent microalbuminuria (22.3 %). The number of patients in Group B showing persistent microalbuminuria was significantly lower (4 of 76; 5.2 %; p 〈 0.01). The sensitivity of erythrocyte Na + /Li + CT in predicting the development of microalbuminuria was 85 % and its specificity was 55 %. Seven patients of Group A and five of Group B developed arterial hypertension. Subjects in Group A had significantly higher mean HbA1 c values of twice yearly measurements than those in Group B (9.6 ± 1.7 vs 8.3 ± 1.7 %, p 〈 0.002, mean ± SD) despite similar daily insulin requirements. Systolic and diastolic blood pressure levels were also evaluated every 6 months and were significantly higher in the Group A than in the Group B patients, although on average within the normal range. The odds ratio for developing persistent microalbuminuria in IDDM with elevated baseline erythrocyte Na + /Li + CT activity after adjustment for gender and baseline albumin excretion rate, and mean 6 monthly plasma creatinine, HbA1 c and systolic and diastolic blood pressure levels was 4.2 (95 % confidence intervals 2.0–11.1). It was also found that the percentage of offspring having both parents with Na + /Li + CT activity above the median value was significantly higher in Group A than in Group B (Group A vs Group B: 35 vs 19 %; p 〈 0.01). On the contrary the percentage of offspring whose erythrocyte Na + /Li + CT was lower in both parents was lower in Group A than in Group B: 10 vs 38 %, p 〈 0.01). Parents of Group A offspring had arterial hypertension more frequently than those of Group B. These results indicate that erythrocyte Na + /Li + CT activity is a useful diagnostic tool in identifying normotensive, normoalbuminuric patients who may be predisposed to develop persistent microalbuminuria. This disorder in the cation transport system is associated with poor metabolic control, higher blood pressure, and male sex; it also appears to be, at least partly, genetically transmitted. [Diabetologia (1997) 40: 654–661]

Notes: Summary Proteinuria and nephropathy have been found to cluster in families of non-insulin-dependent diabetic (NIDDM) Pima Indian, and in Caucasian insulin-dependent diabetic (IDDM) patients. No information is at present available for Caucasian NIDDM patients. The aim of the present study was to determine whether micro-macroalbuminuria (AER + ) is associated with albumin excretion rate abnormalities in diabetic and non-diabetic siblings of probands with NIDDM and AER + . We identified 169 Caucasian families with one NIDDM proband (the patient with longest known NIDDM duration) (101 families with only NIDDM siblings, 33 families with both NIDDM and non-NIDDM siblings and 35 families with only non-NIDDM siblings). Of the probands 56 had AER + [Prob-NIDDM-(AER + )], 78 had AER– [Prob-NIDDM-(AER–)], 74 siblings of Prob-NIDDM-(AER + ), and 113 siblings of Prob-NIDDM-(AER–) also had NIDDM. Data on albuminuria and retinopathy from multiple sibling pairs when the size of the sibship was more than two was adjusted according to a weighting factor. The odds ratio for AER + , in siblings of Prob-NIDDM-(AER + ) adjusted for age, hypertension, glycated haemoglobin A1 c and other confounding variables was 3.94 (95 % confidence intervals: 1.93–9.01) as compared to siblings of Prob-NIDDM-(AER–). The 74 siblings of Prob-NIDDM-(AER + ) had higher prevalence of proliferative retinopathy than siblings of Prob-NIDDM-(AER–) (14 vs 2 %; p 〈 0.01). We also identified 66 non-diabetic siblings of 41 NIDDM probands with AER + and 36 non-diabetic siblings of 27 NIDDM probands with AER–. Albumin excretion was two times higher, although still within the normal range, in the non-diabetic siblings of Prob-NIDDM-(AER + ) than in siblings of Prob-NIDDM-(AER–) [median = 13.5 (range 0.5–148) vs 6.6 (range 1–17) μg/min (p 〈 0.05)]. In conclusion higher rates of albumin excretion aggregate in Caucasian families with NIDDM. Proliferative retinopathy is more frequently observed in families showing a clustering of AER + and NIDDM. These findings suggest that familial factors play a role in the pathogenesis of renal and retinal complications in NIDDM. [Diabetologia (1997) 40: 816–823]

Notes: Summary Microalbuminuria (MA) is associated with microangiopathy (renal and retinal lesions) in insulin-dependent diabetic (IDDM) patients. In contrast MA does not reflect microvascular damage in a substantial number of non-insulin-dependent diabetic (NIDDM) patients. MA predicts cardiovascular disease in NIDDM patients with increased von Willebrand factor (vWF) plasma levels which are hypothesized to reflect endothelial dysfunction. However, it is not known whether MA is consequent to generalised endothelial dysfunction or to renal injury. Thus, this study evaluated vWF plasma levels in relation to renal and retinal structural abnormalities in NIDDM patients with MA. Kidney biopsies, fundoscopy and measures of vWF plasma levels were performed in 32 NIDDM patients with MA. These patients were allocated to two renal structural categories: A) Without renal structural abnormalities (C I, n = 10): normal or near-normal renal structure, and B) With renal structural abnormalities (n = 22), further divided into: C II (n = 12) with typical diabetic nephropathology, predominantly glomerulopathy, and C III (n = 10) with atypical patterns of renal injury (more advanced tubulo-interstitial and arteriolar than glomerular changes). vWF plasma levels were significantly higher in category B (C II: 195 ± 49 % and C III: 161 ± 46 %) than in category A (C I: 119 ± 42 %), (chi-square, p 〈 0.05). Diabetic retinopathy was also related to vWF plasma levels (ANOVA, p 〈 0.05). These data suggest that there are two types of MA in NIDDM: one associated with increased vWF levels, established renal injury and frequently retinopathy, and the other characterized by normal vWF levels, normal renal structure and absent or mild diabetic retinopathy. We propose that vWF plasma levels in NIDDM patients with MA may help to identify patients with important renal structural changes, increased retinopathy risk and, perhaps, generalised endothelial dysfunction. Whether vWF plasma levels predict end-stage renal disease and cardiovascular events deserves longitudinal studies. [Diabetologia (1998) 41: 233–236]

Notes: Abstract The effects of the angiotensin-converting enzyme lisinopril were compared with those of the calcium antagonist nifedipine in 162 non-insulin-dependent diabetic hypertensive patients for a 24-week period. In 83 and 79 patients, respectively, lisinopril and slow-release nifedipine produced similar reductions in blood pressure (systolic/diastolic: −16/−13 mmHg supine and −14/−11 mmHg standing after lisinopril; −15/−12 mmHg supine and −14/−11 mmHg standing after nifedipine). Fasting and post-prandial plasma glucose, glycosylated haemoglobin and plasma lipids appeared to be unaffected by either agent. Also, 28% of the patients on lisinopril and 30% of those on nifedipine presented microalbuminuria. Both drugs induced a reduction in the albumin excretion rate (AER). The geometric meanxx: tolerance factor of the reduction in AER among the 23 microalbuminuric patients on lisinopril (−10.0xx:1.3 μg/min) was greater, though not significantly so, than that observed in the 26 on nifedipine (−0.9x:1.2 μg/min). Moreover, lisinopril appeared to be better tolerated than nifedipine in our study population. Microalbuminuria is an important risk factor for cardiovascular mortality in non-insulin-dependent diabetic patients as well as in the general population. To what extent a reduction in the AER could ameliorate the cardiovascular prognosis in non-insulin-dependent diabetic patients is, at present, unknown. Finally, both lisinopril and nifedipine showed a similar antihypertensive effect in these patients which was not associated with significant differences in plasma glucose, insulin or lipid concentrations. The clinical consequences of the insignificant differences in AER remain unclear.