Glomerular hyperfiltration in experimental diabetes mellitus: potential role of tubular reabsorption

An increase in Na+/glucose cotransport upstream to the macula densa might contribute to the increase in single nephron GFR (SNGFR) in early diabetes mellitus by lowering the signal of the tubuloglomerular feedback, i.e., the luminal Na+, Cl-, and K+ concentration sensed by the macula densa. To examine this issue, micropuncture experiments were performed in nephrons with superficial glomeruli of streptozotocin-induced diabetes mellitus in rats. First, in nondiabetic control rats, ambient early distal tubular concentrations of Na+, Cl-, and K+ were about 21, 20, and 1.2 mM, respectively, suggesting collection sites relatively close to the macula densa. Second, glomerular hyperfiltration in diabetic rats was associated with a reduction in ambient early distal tubular concentrations of Na+, Cl-, and K+ by 20 to 28%, reflecting an increase in fractional reabsorption of these ions up to the early distal tubule. Third, in diabetic rats, early proximal tubular application of phlorizin, an inhibitor of Na+/glucose cotransport, elicited (1) a greater reduction in absolute and fractional reabsorption of Na+, Cl-, and K+ up to the early distal tubule, and (2) a greater increase in early distal tubular concentration of these ions, which was associated with a more pronounced reduction in SNGFR. These findings support the concept that stimulation of tubular Na+/glucose cotransport by reducing the tubuloglomerular feedback signal at the macula densa may contribute to glomerular hyperfiltration in diabetic rats. Glomerular hyperfiltration in diabetic rats serves to compensate for the rise in fractional tubular reabsorption to partly restore the electrolyte load to the distal nephron.     

Glomerular hemodynamics and the renin-angiotensin system in patients with type 1 diabetes mellitus

BACKGROUND: Many studies have reported that blocking the renin-angiotensin-system (RAS) with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker in the patient with diabetes mellitus leads to an increase in renal plasma flow (RPF), no change in glomerular filtration rate (GFR), and a fall in filtration fraction. This constellation is generally attributed to predominant efferent arteriolar dilation. METHODS: This study examined the renal hemodynamic response to blocking the RAS with both captopril and candesartan on separate days in 31 patients with type 1 diabetes mellitus. RESULTS: There was a wide range of changes in RPF and GFR in response to the two agents, each administered at the top of its dose-response range. The RPF response to the two agents was strongly concordant (r = 0.65; P < 0.001), as was the GFR response (r = 0.81; P < 0.001). Moreover, there was a strong correlation between the RPF response and the change in GFR with each agent (r = 0.83 and 0.66; P < 0.01). A significant rise in RPF was followed by a rise in GFR. The RPF dependency of GFR in the type 1 diabetics suggests strongly that glomerular filtration equilibrium exists in the glomeruli of the diabetic kidney: Simple notions of local control based on afferent:efferent arteriolar resistance ratios are too simplistic. CONCLUSION: Our data suggest that the intrarenal RAS is activated in over 80% of patients with type 1 diabetes mellitus. Abundant evidence suggests that this activation predisposes to diabetic nephropathy.     

Oxidant/antioxidant status and hyperfiltration in young patients with type 1 diabetes mellitus

Diabetic nephropathy (DN), a major cause of morbidity and mortality in diabetes, will develop within a subset of type 1 diabetes mellitus (T1DM) patients, and oxidative stress has been implicated in its pathogenesis. To investigate the relationship between indicators of early DN stages (hyperfiltration estimated by creatinine clearance ≥150 ml/min per 1.73 m², microalbuminuria) and oxidative stress, a prospective study was conducted in 29 T1DM patients (age 13.89 ± 4.61 years) and 18 control subjects (age 13.23 ± 3.99 years). Blood samples were collected to assay for biomarkers of oxidative stress (malondialdehyde and carbonyl groups) and antioxidants (glutathione peroxidase, reduced glutathione, α-tocopherol, and β-carotene). With respect to control subjects, in T1DM patients, an increase was found in biomarkers of oxidative stress (p < 0.05), mainly due to the group of subjects with hyperfiltration, and a decrease in the ratio α-tocopherol/lipids (p < 0.05). In multiple regression analyses, age at disease onset, glycated hemoglobin, microalbuminuria, and oxidative stress biomarkers remained as explicative variables of hyperfiltration (R ² adjusted = 0.731, p = 0.000). These findings support the importance of the oxidative damage to lipids and proteins, which is linked to hyperfiltration and which could contribute to the development of DN in patients with T1DM.     

Glomerular filtration surface in type I diabetes mellitus

Previously we have shown that relative glomerular mesangial expansion was an important correlate of renal dysfunction in diabetes. To extend the understanding of structural functional relationships, 37 patients with type I diabetes mellitus for 5 to 33 years were studied with multiple creatinine clearance (Ccr), urinary albumin excretion, and blood pressure measurements, and percutaneous renal biopsies. Glomerular volume and percent sclerosed glomeruli were determined; quantitative stereology was performed to determine relative glomerular structural parameters. Per glomerulus we calculated mesangial volume and capillary filtration surface and per patient we estimated capillary filtration surface. Capillary filtration surface per glomerulus or per patient were highly predictive of Ccr (r = +0.78, r = +0.79, P less than 0.001). There was a significant but weak relationship between Ccr and mesangial volume. However, mesangial volume and glomerular volume together were highly predictive of both Ccr and filtration surface. Mesangial volume was increased and filtration surface decreased in the hypertensive patients and the patients with urinary albumin excretion less than 250 mg/24 hr. Thus, it appears that mesangial expansion within a relatively large glomerulus has less influence on filtration than does a similar increase in mesangial volume within a smaller glomerulus. There is a striking relationship between glomerular filtration rate and filtration surface in diabetes throughout the range from hyperfiltration to significant hypofiltration.     

Glomerular permselectivity at the onset of nephropathy in type 2 diabetes mellitus

The development of microalbuminuria in individuals with type 2 diabetes mellitus is associated with a 10-fold increase in the risk of progression to overt nephropathy and eventual end-stage renal failure. The present study reports long-term (up to 8 yr) follow-up of 43 Pima Indians with type 2 diabetes detected on screening to have microalbuminuria. The natural history of albuminuria in these individuals included progression to overt proteinuria (urinary albumin excretion > or = 300 mg/d) in half of the participants by 7 yr of follow-up. The size selectivity of the glomerular barrier was also investigated using dextran sieving and pore theory. Whereas a comparison group of macroalbuminuric Pima Indians had an excess of large pores that served as a macromolecular "shunt," individuals with microalbuminuria had a shunt size no different from long-term diabetic, normoalbuminuric control subjects. An abrupt transition from little or no relationship to a highly significant and positive relationship between increasing albuminuria and shunt size occurred at an albumin-to-creatinine ratio of approximately 3000 mg/g. Shunt size in macroalbuminuric individuals correlated with the extent of foot process broadening. Podocyte foot processes in microalbuminuric participants were not different from those in control subjects. In conclusion, although microalbuminuria in type 2 diabetic Pima Indians often heralds progressive glomerular injury, it is not the result of defects in the size permselectivity of the glomerular barrier but rather of changes in either glomerular charge selectivity or tubular handling of filtered proteins or of a combination of these two factors.     

Glomerular hyperfiltration predicts the development of microalbuminuria in stage 1 hypertension: the HARVEST

Factors related to the development of microalbuminuria in hypertension are not well known. We did a prospective study to investigate whether glomerular hyperfiltration precedes the development of microalbuminuria in hypertension. We assessed 502 never-treated subjects screened for stage 1 hypertension without microalbuminuria at baseline and followed up for 7.8 years. Creatinine clearance was measured at entry. Urinary albumin and ambulatory blood pressure were measured at entry and during the follow-up until subjects developed sustained hypertension needing antihypertensive treatment. Subjects with hyperfiltration (creatinine clearance >150 ml/min/1.73 m2, top quintile of the distribution) were younger and heavier than the rest of the group and had a greater follow-up increase in urinary albumin than subjects with normal filtration (P<0.001). In multivariable linear regression, creatinine clearance adjusted for confounders was a strong independent predictor of final urinary albumin (P<0.001). In multivariable Cox regression, patients with hyperfiltration had an adjusted hazard ratio for the development of microalbuminuria based on at least one positive measurement of 4.0 (95% confidence interval (CI), 2.1-7.4, P<0.001) and an adjusted hazard ratio for the development of microalbuminuria based on two consecutive positive measurements of 4.4 (95% CI, 2.1-9.2, P<0.001), as compared with patients with normal filtration. Age, female gender, and 24 h systolic blood pressure were other significant predictors of microalbuminuria. In conclusion, stage 1 hypertensive subjects with glomerular hyperfiltration are at increased risk of developing microalbuminuria. Early intervention with medical therapy may be beneficial in these subjects even if their blood pressure falls below normal limits during follow-up.     

Glomerular hyperfiltration and increased glomerular filtration surface are associated with renal function decline in normo- and microalbuminuric type 2 diabetes

The prevalence of glomerular hyperfiltration in type 2 diabetic patients varies widely. Here we studied whether glomerular hyperfiltration in diabetic nephropathy in type 2 patients is related to renal structural changes and predicts the functional development of diabetic nephropathy. Thirty normo- or microalbuminuric type 2 diabetic patients having a renal biopsy were followed every 6 months for a mean of 6.2 years. The glomerular filtration rate (GFR) at the time of biopsy, determined by iohexol clearance, correlated with filtration surface per glomerulus, but no other quantitative microscopic morphometric parameter. The filtration surface was positively associated with the decrease in GFR during the first year but not associated in subsequent years following the renal biopsy. The GFR showed a statistically significant linear decrease in 9 of the 30 patients; however, slopes of the regression lines were almost zero in 11 patients. The GFR increased and decreased in a parabolic manner in two patients. Seven of the nine patients with a statistically significant decline in renal function did not show any appreciable worsening of albuminuria, while two patients developed persistent proteinuria. Thus, in renal biopsy-proven normo- or microalbuminuric type 2 diabetic patients, glomerular hyperfiltration is closely associated with an increased glomerular filtration surface. An elevated GFR predicts its subsequent decline, which may occur without worsening of albuminuria.     

Glomerular mesangial fibrillary deposits in a patient with diabetes mellitus

Various systemic or primary glomerular diseases can result in deposition of fibrillary material in the glomerular tuft and may cause an important diagnostic challenge for the pathologists. Biopsy findings of a patient with type 2 diabetes is presented here in which striking fibrillary structures were identified in the mesangium by ultrastructural examination. The distinction between diabetic fibrillosis and fibrillary glomerulonephritis accompanying diabetic nephropathy is discussed in the setting of a literature review.     

Renal hyperfiltration related to diabetes mellitus and obesity in human disease

High intraglomerular pressure is associated with renal hyperf iltration, leading to the initiation and progression of kidney disease in experimental models of diabetes mellitus (DM). In humans, hyperf iltration is observed in patients with type 1 and type 2 DM, and is also seen in patients with pre-diabetic conditions, such as the metabolic syndrome. From a mechanistic perspective, both vascular and tubular factors likely contribute to the pathogenesis of hyperf iltration. Until now, human studies have primarily focused on the use of medications that inhibit the renin angiotensin system to reduce efferent vasoconstriction and thereby improve hyperfiltration. More recent advances in the development of investigational adenosine antagonists and inhibitors of sodium glucose cotransport may help to elucidate tubular factors that contribute to afferent vasodilatation. In this review, we summarize available data from experimental and human studies of type 1 and type 2 DM and obesity to provide an overview of factors that contribute to the hyperf iltration state. We have focused on the renin angiotensin system, cyclooxygenase-2 system, nitric oxide, protein kinase C and endothelin as vascular determinants of hyperfiltration. We also dis-cuss relevant tubular factors, since experimental models have suggested that inhibition of sodium-glucose cotransport may be renoprotective.     

Impact of renin angiotensin system modulation on the hyperfiltration state in type 1 diabetes

The initial stages of diabetic nephropathy are characterized by glomerular hyperfiltration and hypertension, processes that have been linked to initiation and progression of renal disease. Renin angiotensin system (RAS) blockade is commonly used to modify the hyperfiltration state and delay progression of renal disease. Despite this therapy, many patients progress to ESRD, suggesting heterogeneity in the response to RAS modulation. The role of the RAS in the hyperfiltration state in adolescents with uncomplicated type 1 diabetes was examined, segregated on the basis of the presence of hyperfiltration. Baseline renal hemodynamic function was characterized in 22 patients. Eleven patients exhibited glomerular hyperfiltration (GFR>or=135 ml/min), and in the remaining 11 patients, the GFR was <130 ml/min. Renal hemodynamic function was assessed in response to a graded angiotensin II (AngII) infusion during euglycemic conditions and again after 21 d of angiotensin-converting enzyme (ACE) inhibition with enalapril. AngII infusion under euglycemic conditions resulted in a significant decline in GFR and renal plasma flow in the hyperfiltration group but not in the normofiltration group. After ACE inhibition, GFR fell but did not normalize in the hyperfiltration group; the normofiltration group showed no change. These data show significant differences in renal hemodynamic function between hyperfiltering and normofiltering adolescents with type 1 diabetes at baseline, after AngII infusion and ACE inhibition. The response to ACE inhibition and AngII in hyperfiltering patients suggests that vasodilation may complement RAS activation in causing the hyperfiltration state. The interaction between glomerular vasoconstrictors and vasodilators requires examination in future studies.     

Glomerular size and charge selectivity in insulin-dependent diabetes mellitus

The pathogenesis of clinical nephropathy in Type 1 (insulin-dependent) diabetes was investigated by measuring renal fractional clearances of albumin, total IgG, IgG4 and beta 2-microglobulin, four plasma proteins which differ in size and charge. Seventy patients and eleven control subjects were studied. In diabetic patients with normal urinary albumin excretion (less than 30 mg/24 hr), fractional IgG clearance was two to three times higher than in control subjects, whereas fractional clearance of the anionic plasma proteins IgG4 and albumin was similar to that of control subjects. These alterations indicate an increase in anionic pore charge within the glomerular basement membrane concomitant with an increase in either pore size or impairment of tubular reabsorption. Diabetic patients, whose urinary albumin excretion has started to rise (30 to 100 mg/24 hr), had unchanged fractional IgG compared to patients with normal albumin excretion, while fractional IgG4 and albumin clearances were increased three- to fourfold; indicating unchanged glomerular pore size, but a decrease in anionic pore charge. In patients demonstrating urinary albumin excretion of greater than 100 mg/24 hr fractional IgG clearance increased to the same extent as fractional albumin clearance, indicating an increase in large pore area. Fractional beta 2-microglobulin clearances were similar to that of control subjects in the different patient groups indicating unchanged tubular reabsorption of proteins. Thus, the increase in large pore area seen in patients with clinical nephropathy is preceded by loss of anionic charge in the glomerular basement membrane. It is likely that this loss of anionic charge is due to loss of heparan sulphate-proteoglycan.     

Acute postoperative mononeuropathy in a patient with type II diabetes mellitus]

Diabetes mellitus is an endocrinologic illness that affects multiple systems. One of then is the nervous system. It has been attempted to establish a relationship between metabolic abnormalities associated with diabetes and the degree of nervous system affectation. We present a case of mononeuritis involving the left peroneal nerve which occurred suddenly during the postoperative phase of a thoracoplasty in a patient with type II diabetes mellitus. The clinical picture was associated with a hyperglycemic nonketotic decompensation. We analyze the precipitating factors and their possible prevention.     

Advances in management of type 1 diabetes mellitus

Treatment of type 1 diabetes mellitus has always posed a challenge to balance hyperglycemia control with hypoglycemia episodes. The quest for newer therapies is continuing and this review attempts to outline the recent developments. The insulin molecule itself has got moulded into different analogues by minor changes in its structure to ensure well controlled delivery, stable half-lives and lesser side effects. Insulin delivery systems have also consistently undergone advances from subcutaneous injections to continuous infusion to trials of inhalational delivery. Continuous glucose monitoring systems are also becoming more accurate and user friendly. Smartphones have also made their entry into therapy of diabetes by integrating blood glucose levels and food intake with calculated adequate insulin required. Artificial pancreas has enabled to a certain extent to close the loop between blood glucose level and insulin delivery with devices armed with meal and exercise announcements, dual hormone delivery and pramlintide infusion. Islet, pancreas-kidney and stem cells transplants are also being attempted though complete success is still a far way off. Incorporating insulin gene and secretary apparatus is another ambitious leap to achieve insulin independence though the search for the ideal vector and target cell is still continuing. Finally to stand up to the statement, prevention is better than cure, immunological methods are being investigated to be used as vaccine to prevent the onset of diabetes mellitus.     

Impact of hyperglycemia on the renin angiotensin system in early human type 1 diabetes mellitus.

It has been demonstrated previously that moderate hyperglycemia without glucosuria can increase plasma renin activity and mean arterial pressure in young healthy males with early uncomplicated type 1 diabetes mellitus. This study was conducted to extend these observations by testing the hypothesis that mild to moderate hyperglycemia can affect renal function by increasing renin angiotensin system (RAS) activity in diabetic humans. The study included 10 men and women with early, uncomplicated type 1 diabetes (duration <5 yr), all ingesting a controlled sodium and protein diet. They were studied on four separate occasions, during a subdepressor dose of the angiotensin II (AngII) receptor blocker losartan, and during graded AngII infusion, 1.5 and 2.5 ng/kg per min, while euglycemic (blood glucose 4 to 6 mmol/L) and again while hyperglycemic without glucosuria (blood glucose 9 to 11 mmol/L), according to a randomized crossover design. Outcome measures included mean arterial pressure (MAP), GFR, effective renal plasma flow (ERPF), renal vascular resistance (RVR), filtration fraction (FF), and urine sodium excretion (UNaV) at baseline and in response to the above maneuvers. During hyperglycemic conditions, MAP was significantly higher compared with euglycemia, as were RVR and FF. After the administration of losartan, a significant renal and peripheral depressor effect was noted, with decreases in MAP, RVR, and FF, whereas during euglycemia the responses to losartan were minimal. AngII infusion resulted in elevations in MAP, RVR, and FF and a decline in UNaV during both glycemic phases, but the responses during hyperglycemia, most significantly at the 1.5 ng/kg per min infusion rate, were blunted. These data support the hypothesis that hyperglycemia affects renal function by activating the RAS. The mechanism remains obscure, but these contrasting responses may provide a link between the observations that maintenance of euglycemia and blockade of the RAS prevent or delay diabetic kidney disease, and furthermore, may clarify the mechanism whereby high glucose promotes renal disease progression in diabetes.     

Glomerular filtration rate and its influential factors in type 2 diabetes mellitus at different stages of albuminuria

Objective To study the characteristics of glomerular filtration rate (GFR) and its influential factors in type 2 diabetes mellitus at different stages of albuminuria. Method GFR was measured in 630 cases of type 2 diabetes mellitus between 2002 and 2005 by plasma disappearance of 99m-techmetium-diethylene- triamine- penta-acetic acid (99mTc-DTPA). Body mass index (BMI), blood pressure, plasma glucose, HbA1c, Scr, BUN, uric acid (UA), profile of plasma lipid and 24 h-urinary albumin excretion (24 h-UAE) were also measured. All the patients were divided into 3 groups according to their 24 h-UAE: normoalbuminuric group (group A, 24 h-UAE<30 mg), microalbuminuric group (group B, 24 h-UAE from 30 mg to 300 mg) and macroalbuminuric group (group C, 24 h-UAE>300 mg). Results (1) The mean GFR was (99.8±26.3) ml/min, (96.1±31.2) ml/min and (69.7±29.8) ml/min in A, B and C groups respectively. The GFR in group C was significantly lower than that in group A and group B(P<0.01). (2) Negative correlations were found between GFR and age in all these groups (group A r= -0.533, group B r=-0.612 and group C r=-0.412，respectively, P<0.01）. (3) In each group, GFR of patients with hypertension was significantly lower than that of patients without hypertension（P<0.05）. (4) The Pearson correlation analysis adjusted by age showed that GFR was negatively correlated with 24 h-UAE in group B and group C (r=-0.283 and -0.24 respectively, all P<0.05). The multiple stepwise regression analysis showed that 24 h-UAE was the major influential factor of GFR in these 2 groups. Conclusions Measurement of both GFR performed by non-traumatic plasma disappearance of 99mTc-DTPA method and UAE provides a more precise evaluation on the the development and progression of diabetic nephropathy. Albuminuria should be controlled, especially in microalbuminuric stage.     

2型糖尿病患者不同蛋白尿期肾小球滤过率的变化及影响因素

目的 研究2型糖尿病（DM）患者不同蛋白尿期的肾小球滤过率并探讨其影响因素。 方法 根据尿白蛋白量（24 h）把630例2型糖尿病住院患者分成正常白蛋白尿组（A组）、微量白蛋白尿组（B组）及大量白蛋白尿组（C组），用放射性核素(99m Tc-DTPA)肾动态显像测定肾小球滤过率(GFR), 同时测定其体质量指数、血压、血糖、糖化血红蛋白、肾功能、血脂及尿白蛋白量（24 h）。 结果 （1）A组GFR值平均为（99.8±26.3） ml/min；B组为（96.1±31.2） ml/min；C组为（69.7±29.8） ml/min。C组的GFR显著低于A组和B组（P < 0.01）。（2）3组患者的GFR均与年龄呈负相关（A组r = -0.533，B组r = -0.612，C组r = -0.412，均P < 0.01）。（3）有高血压史者的GFR平均值均低于同组无高血压史者（P均< 0.05）。（4）控制年龄后的偏相关分析结果显示，在B组及C组，GFR与尿白蛋白量（24 h）呈负相关（r = -0.283 及-0.240，均P < 0.05）。多元逐步回归分析结果显示，尿白蛋白量（24 h）是影响异常蛋白尿组患者GFR的主要因素。 结论 放射性核素肾动态显像法测定GFR，同时联合尿白蛋白量检测，能更全面准确地评估糖尿病肾病的进展。应积极控制蛋白尿，尤其在微量白蛋白尿期。     

Co-occurrence of type 1 diabetes mellitus and celiac disease

The co-occurrence of celiac disease(CD) and type 1 diabetes(T1DM) has been reported as 5-7 times more prevalent than CD alone.The clinical presentation and natural history of CD in patients with T1 DM may vary considerably.Less than 10% of patients with T1 DM and CD show gastrointestinal symptoms.Therefore,experts support screening for CD in T1 DM patients,though there is no consensus as to the recommended frequency of screening.When stratified by time since CD diagnosis,longer follow-up and coexistence of CD are associated with significant increased risk of diabetic associated morbidity and mortality.Early CD diagnosis and treatment with a gluten-free diet are essential.