[Failure of microcirculation: diagnosis and therapeutic consequences].
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Diagnostic Imaging↗
Biomedical subjects
M Mauer
Publications and source records attributed to M Mauer.
Remodeling of renal interstitial and tubular lesions in pancreas transplant recipients.
Tubular atrophy and interstitial fibrosis, important in progression of renal diseases, including diabetic (D) and cyclosporine-induced (CSA) nephropathy, have been considered irreversible. Normoglycemia for 10 years following pancreas transplantation alone (PTA) reversed D glomerulopathy lesions. This study quantified tubular, interstitial, and arteriolar parameters in PTA recipients. Kidney function studies and biopsies were performed in eight non-uremic type I D patients (pts) at 5 and 10 years after PTA. Renal biopsies were analyzed by morphometric analysis. All pts were normoglycemic and insulin independent and received CSA during the study. Cortical interstitial volume fraction was increased at 5 years (0.31+/-0.07 vs normal 0.15+/-0.02, P<0.01) and decreased at 10 years post-PTA (0.23+/-0.03, P<0.02 vs 5 years). There was a reduction in the volume fraction of interstitial collagen and cells per cortical tissue, measured using electron microscopy, from 5 (0.126+/-0.061 and 0.103+/-0.026, respectively) to 10 years (0.079+/-0.031, P<0.05, and 0.074+/-0.018, P<0.05, respectively). The volume fraction of tubules which were atrophic (AT) was abnormal at 5 years (0.160+/-0.090) and decreased from 5 to 10 years (0.044+/-0.034, P<0.02), apparently due to AT reabsorption. The index of arteriolar hyalinosis did not change during the study (1.30+/-0.22 and 1.34+/-0.33 at 5 and 10 years, respectively, nonsignificant). This study demonstrates, for the first time in humans, that interstitial expansion is reversible and that atrophic tubules can be reabsorbed. In contrast, there was no improvement in the arteriolar lesions. Whether this is due to long-term normoglycemia, reduction of CSA dose or other mechanisms is unclear.
Adult↗
Cellular basis of diabetic nephropathy: III. In vitro GLUT1 mRNA expression and risk of diabetic nephropathy in type 1 diabetic patients.
AIMS/HYPOTHESIS: Altered glucose transporter expression has been implicated in the pathogenesis of diabetic nephropathy. There is increasing evidence that genetic factors convey risk of, or protection from, diabetic nephropathy and that the behaviour of cultured skin fibroblasts from type 1 diabetic patients may reflect these genetic influences. This study aimed to compare GLUT1 mRNA expression levels in skin fibroblasts from type 1 diabetic patients with either rapid ("fast-track", n=25) or slow ("slow-track", n=25) development of diabetic nephropathy and from non-diabetic normal control subjects (controls, n=25). METHODS: Skin fibroblasts were cultured in Dulbecco's Modified Eagle's Medium with 25 mmol/l glucose for 36 h. Total RNA was isolated, and GLUT1 mRNA levels were estimated by microarray analysis and RT-PCR. RESULTS: Levels of GLUT1 mRNA expression in skin fibroblasts from "slow-track" patients were greater than those from "fast-track" patients (p=0.02), as initially detected by microarray. GLUT1 mRNA expression levels were confirmed by RT-PCR to be higher in skin fibroblasts from "slow-track" patients (4.59+/-2.04) than in those from "fast-track" patients (3.34+/-1.2, p=0.02), and were also higher than in skin fibroblasts from control subjects (3.52+/-1.66, p=0.03). There was no statistically significant difference between levels of expression in the "fast-track" patients and the control subjects. CONCLUSIONS/INTERPRETATION: This finding is consistent with the presence of cellular protection factors against diabetic nephropathy in the "slow-track" patients. These factors could be associated with the regulation of the GLUT1 pathway and may be genetically determined.
Adult↗
Juxtaglomerular apparatus T-cell infiltration affects glomerular structure in Type 1 diabetic patients.
AIMS/HYPOTHESIS: Type 1 diabetes is an autoimmune disorder associated with T-cell mediated injury to multiple endocrine tissues. T-cell infiltration of the juxtaglomerular apparatus could be associated with changes in local renin angiotensin system activity and, thus, with changes in the renal microenvironment. We examined the frequency of juxtaglomerular apparatus T-cell infiltration early in Type 1 diabetes and tested whether this is associated with renal structure and function. METHODS: We classified 89 Type 1 diabetic patients by immunohistochemical analysis as either juxtaglomerular apparatus T-cell positive ( n=37) or T-cell negative ( n=38). Borderline cases ( n=14) were not considered further. RESULTS: T-cell positive patients had a shorter duration of diabetes (6.7+/-2.5 years) than T-cell negative patients (9.2+/-5.0 years, p=0.011) and lower albumin excretion rate, but they had a similar glomerular filtration rate and blood pressure. Renal biopsy morphometric analysis showed similar glomerular basement membrane width and mesangial fractional volume in these two groups. However, glomerular capillary surface density ( p=0.0012) and filtration surface per glomerulus ( p=0.0155) were greater in the T-cell positive patients. CONCLUSION/INTERPRETATION: Increased filtration surface per glomerulus could be associated with glomerular filtration rate preservation in diabetes. Thus, juxtaglomerular apparatus immunologic injury in Type 1 diabetes patients could delay the clinical consequences of diabetic nephropathy.
Adolescent↗
Pharmacological evaluation of the novel thromboxane modulator BM-567 (I/II). Effects of BM-567 on platelet function.
The aim of this work was to evaluate the effects of BM-567 (N-pentyl-N'-[(2-cyclohexylamino-5-nitrobenzene)sulfonyl]urea), a torasemide derivative, on both thromboxane A(2) (TXA(2)) receptors (TP) and thromboxane synthase of human platelets. The drug affinity for TP receptors of human washed platelets has been determined. In this test, BM-567 showed a high affinity (IC(50): 1.1+/-0.1nM) for the TP receptors in comparison with BM-531 (IC(50): 7.8+/-0.7nM) and sulotroban (IC(50): 931+/-85nM), two TXA(2) antagonists. We also demonstrated that BM-567 prevented platelet aggregation induced by arachidonic acid (AA) (600 microM) (ED(100): 0.20+/-0.10 microM), U-46619, a stable TXA(2) agonist (1 microM) (ED(50): 0.30+/-0.04 microM) and collagen (1microgram ml(-1)) (% of inhibition: 44.3+/-4.3% at 10 microM) and inhibited the second wave of ADP (2microM). Moreover, when BM-567 was incubated in whole blood from healthy donors, the closure time measured by the Platelet Function analyzer (PFA-100((R))) was significantly prolonged (closure time: 215+/-21s) by using collagen/epinephrine cartridges. Finally, at the concentration of 1 microM, BM-567 completely reduced the TXB(2) production from human platelets stimulated with AA (600 microM). These results indicate that BM-567 is a novel combined TXA(2) receptor antagonist and thromboxane synthase inhibitor characterized by a powerful antiplatelet potency.
Blood Platelets↗
Alpha-oxoaldehyde metabolism and diabetic complications.
The factors responsible for variable susceptibility to diabetic nephropathy are not clear. According to the non-enzymatic glycation hypothesis, diabetes-related tissue damage occurs due to a complex mixture of toxic products, including alpha-oxoaldehydes, which are inherently toxic as well as serving as precursors for advanced glycation end-products. Protective mechanisms exist to control this unavoidable glycation, and these are determined by genetic or environmental factors that can regulate the concentrations of the reactive sugars or end-products. In diabetes these protective mechanisms become more important, since glycation stress increases, and less efficient defence systems against this stress could lead to diabetic complications. Some of these enzymatic control mechanisms, including those that regulate alpha-oxoaldehydes, have been identified. We have observed significant increases in production of the alpha-oxoaldehydes methylglyoxal and 3-deoxyglucosone in three human populations with biopsy-proven progression of nephropathy. The increase in methylglyoxal could be secondary to defects in downstream glycolytic enzymes (such as glyceraldehyde-3-phosphate dehydrogenase) that regulate its production, or in detoxification mechanisms such as glyoxalase. Other mechanisms, however, appear to be responsible for the observed increase in 3-deoxyglucosone levels. We present results of our studies on the mechanisms responsible for variable production of alpha-oxoaldehydes by measuring the activity and characteristics of these enzymes in cells from complication-prone and -resistant diabetic patients. New therapeutic interventions designed to control these endogenous mechanisms could potentially enhance protection against excessive glycation and prevent or reverse complications of long-term diabetes.
Aldehydes↗
Renal in situ hybridization studies of extracellular matrix related molecules in type 1 diabetes mellitus.
BACKGROUND/AIM: Progressive expansion of mesangial matrix and glomerular basement membrane thickening represent alterations in the balance between synthesis and degradation of glomerular extracellular matrix (ECM) protein and are hallmarks of diabetic nephropathy. In order to elucidate the basis for this imbalance between the synthesis and the degradation of ECM in renal tissues from patients of type 1 diabetes mellitus (type 1D) with diabetic nephropathy (DN), we examined the expression of alpha1 chain of type IV collagen (IV-C), matrix metalloproteinase-2 and -3 (MMP-2, MMP-3), tissue inhibitor of metalloproteinase-1 (TIMP-1) and beta-actin mRNA using a high-resolution in situ hybridization with digoxigenin-labeled oligonucleotide. METHODS: Patients were divided into two groups based on both of degree of mesangial expansion using electron microscopic point counting morphometric methods and duration of type 1D: 7 'fast-track' patients were selected for their very rapid development of DN structural changes and 8 'slow-track' patients for their very slow development of DN structural changes. Seven normal human kidney (NHK) tissues were used as controls. RESULTS: Positive cells for each mRNA were observed in glomerular resident cells, including glomerular mesangial, epithelial and endothelial cells and cells of Bowman's capsule. The percentage of glomerular cells positive for IV-C, MMP-2 and MMP-3 mRNA was significantly greater in the 'slow-track' vs. 'fast-track' patients. No significant differences in percentage positive cells was seen for beta-actin mRNA. Furthermore, to elucidate the total number of positive cells per glomerulus for each mRNA, we estimated total cell number of glomerulus using morphometric techniques on light microscopy tissues. The total cell number per glomerulus was significantly greater in 'fast-track' than that in 'slow-track' patients and NHK. The total number of positive cells per glomerulus for MMP-2 in NHK was significantly greater than that in 'slow-track' and 'fast-track' patients. CONCLUSIONS: Thus, IV-C, MMP-2, MMP-3 and TIMP-1 mRNA are expressed in resident glomerular cells in renal tissues from NHK and type 1D. Glomerular alterations in these in situ mRNA expressions sufficient to explain ECM accumulation and DN risk were not uncovered. These largely negative results could be due to methodologic quantitative imprecision or could indicate that post-translational differences account for ECM imbalance in DN. However, these studies make it clear that unraveling the nature of the ECM production/removal imbalance in DN will require careful consideration of alterations in glomerular cell number.
Adult↗
Kidney transplantation in young children: should there be a minimum age?
The optimal age for transplantation in children with end-stage renal disease remains controversial. Many centers have adopted a policy of waiting until such children reach a certain minimum age or weight, maintaining them on chronic dialysis until then. Their policy is based on historical data showing inferior graft survival in very young children. We feel that with proper donor selection and recipient care, comparable results can be achieved in very young age groups. We herein present our results with kidney transplantation in children <1 year old. Between 1 January 1984 and 31 December 1999, we performed 321 kidney transplants in children < or =13 years at the University of Minnesota. We analyzed our results in three age groups: <1 year (n=30), 1 through 4 years (n=122), and 5 through 13 years (n=169). We found no significant differences in patient or graft survival rates between the three groups. Almost all our infant (<1 year) recipients underwent primary transplants from living donors (LDs). However, even when we compared results only of primary LD transplants between the three groups, we found no significant differences. To date, all our infant recipients are alive and well, 24 (80%) with a functioning original graft. Causes of the 6 graft losses were chronic rejection (n=3), vascular thrombosis (n=2), and recurrent disease (n=1). Infants had significantly lower incidences of acute and chronic rejection compared with older recipients, but a tendency to higher incidences of delayed graft function and vascular thrombosis. Infants had significant increases in weight post transplant: the mean standard deviation score rose from -2.8 pre transplant to -0.2 by age 5 years and to +1.8 by age 10 years. The improvement in height was less marked: the mean standard deviation rose from -3.2 pre transplant to -1.6 by age 5 years and to -1.4 by age 10 years. Kidney transplant results in very young children can be comparable to those in older children. There need be no minimum age for performing a kidney transplant. The timing of the transplant should not be based on age or size alone.
Acute Disease↗
Risk predictors in patients with diabetic nephropathy.
Diabetic nephropathy is currently the most common cause of end-stage renal disease in the Western countries. Only approximately one third of patients with type 1 diabetes develop nephropathy; thus, because it is not feasible to aggressively treat all patients, it becomes very important to find early markers in order to identify patients at high nephropathy risk. To date the best available predictor of overt nephropathy is microalbuminuria. In this article we review the validity of microalbuminuria as a predictor of overt nephropathy and consider other markers of nephropathy risk.
Albuminuria↗
Quantitative immunoelectron microscopy of type VI collagen in glomeruli in type I diabetic patients.
BACKGROUND: The nature of the extracellular matrix (ECM) accumulating in the glomerular basement membrane (GBM) and mesangium (Mes) in diabetes is unknown. Type IV collagen (Col IV) as estimated by quantitative immunoelectron microscopy was reduced in type I diabetic patients (D) with rapid ("fast-track") compared with slow ("slow-track") development of diabetic nephropathy (DN) lesions and controls (C). Col VI is another ECM component suggested to account for Mes matrix (MM) expansion in DN. METHODS: Col VI ECM density was evaluated in eight "slow-track" {Mes fractional volume [Vv(Mes/glom)] <0.32, duration> 20 years} and seven "fast-track" patients [Vv(Mes/glom)> 0.37, duration <20 years diabetes] and in eight C. Quantitative immunoelectron microscopy was performed using polyclonal antibodies to Col VI. Gold particle density (PDG) in MM and the inner layer (IL) of the GBM was measured using stereologic methods. RESULTS: GBM IL PDG was decreased in both fast-track (1.7 +/- 1.6/microm2, mean +/- SD, P < 0.002) and slow-track (3.9 +/- 2.4, P < 0.02) D versus C (10.8 +/- 7.9). GBM IL PDG was also lower in the fast-track versus slow-track D (P < 0.04). Mes matrix PDG/microm2 was decreased in fast-track D (3.2 +/- 3.6) versus C (14.1 +/- 14.6, P < 0.02); a similar trend was seen in slow-track D (5.7 +/- 5.6, P < 0.1). There was no significant difference in MM PDG between the slow-track and fast-track D. CONCLUSION: Col VI density in MM and GBM is decreased in diabetic patients with slowly and rapidly developing renal lesions. This leaves the nature of ECM accumulation in DN unexplained. At least in part, glomerular ECM compositional change is related to diabetes per se and may be independent of the severity of lesions.
Adult↗
Accuracy of methods used to quantify cell hyperplasia.
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Humans↗
Improved growth velocity with intensive dialysis. Consequence or coincidence?
Growth failure in children with end-stage renal disease remains a difficult problem. A 2.5-month-old baby in renal failure due to primary hyperoxaluria type I received intensive dialysis aimed at decreasing oxalate tissue accretion. Over 5.5 months, while awaiting transplantation, his growth velocity was 29 cm/year compared with an average 4 cm/year in infants on hemodialysis and 22 cm/year in normal infants of this age. This remarkable growth rate, which could have represented catch-up growth, is hypothesized to be related to the delivered dialysis dose. It is suggested that this relationship be evaluated in a prospective randomized trial.
Growth↗
Structural characteristics of human substantia nigra neuromelanin and synthetic dopamine melanins.
Neuromelanin (NM) is a complex polymer pigment found primarily in the dopaminergic neurons of the human substantia nigra. The structure of NM is only partially characterized, and its synthesis pathway remains unknown. We used nuclear magnetic and infrared spectroscopy to examine the structure of human NM isolated from the substantia nigra compared with synthetic dopamine melanins. Biochemical analyses were used to investigate proteinaceous and dopaminergic components in these samples. Following acid hydrolysis of NM samples, small amounts of DOPA, dopamine, and a variety of amino acids were measured. These findings suggest a peptide component in NM structure. NM also appears to contain a variety of unidentified structural components possibly derived from the oxidation of dopamine. Human NM differs structurally from synthetic dopamine melanin, but both human and synthetic NM include an aromatic backbone. It is interesting that both human NM and synthetic melanin also contain a large proportion of aliphatic structures. Our results suggest that NM is a more complex pigment than synthetic dopamine melanin formed via dopamine autoxidation alone.
Adult↗
The need for early predictors of diabetic nephropathy risk: is albumin excretion rate sufficient?
Initial studies showing an approximately 80% rate of progression from microalbuminuria (MA) to proteinuria in type 1 diabetic patients led to the broad acceptance of MA as a useful clinical predictor of increased diabetic nephropathy (DN) risk. Some MA patients, however, have quite advanced renal structural changes, and MA may, in these cases, be a marker rather than a predictor of DN. More recent studies have observed only about a 30-45% risk of progression of MA to proteinuria over 10 years, while about 30% of type 1 diabetic patients with MA became normoalbuminuric and the rest remained microalbuminuric. The finding that some MA patients have only mild diabetic renal lesions is consistent with the lower than originally estimated risk of progression from MA to proteinuria and with the notion that some MA patients revert to normoalbuminuria. To increase the complexity of the scenario, some normoalbuminuric long-standing type 1 diabetic patients have well-established DN lesions and approximately 40% of all patients destined to progress to proteinuria are normoalbuminuric at initial screening, despite many years of diabetes. A similar picture is emerging in type 2 diabetic patients, although fewer studies have been conducted. Thus, the predictive precision for MA to progress to overt nephropathy over the subsequent decade or so is considerably less than originally described. It is unclear whether this is due to changes in the natural history of DN resulting from improved glycemia and blood pressure control, or whether there were overestimates of risk in the original studies due to the small sample sizes, post hoc analyses, and variable MA definitions. Albumin excretion rate (AER) remains the best available noninvasive predictor of DN risk and should be regularly measured according to established guidelines. However, AER may be unable to define patients who are safe from or at risk of DN with an accuracy that is adequate for optimal clinical decision making or for the design of certain clinical trials. Investigations into new risk markers or into the combined use of several currently available predictive parameters are needed.
Albuminuria↗
Structural involvement in type 1 and type 2 diabetic nephropathy.
Structural changes underlying diabetic nephropathy in Type 1 diabetes are prodominant in the glomerulus [thickening of glomerular basement membrane (GBM) and mesangial expansion], but also include arteriolar, tubular and interstitial lesions. The structural measure that correlates best with all renal functional parameters in Type 1 diabetes is mesangial fractional volume [Vv(mes/glom)], an estimate of mesangial expansion. Structural-functional relationships in Type 2 diabetes are much less known. These studies investigated renal structure in the early stages of nephropathy [microalbuminuria (MA)] in patients with Type 1 and Type 2 diabetes. Diabetic glomerulopathy was quite advanced in Type 1 diabetic patients with MA, and both Vv (mes/glom) and GBM width were increased as compared to normoalbuminuric (NA) patients when the albumin excretion rate (AER) was > 30 microgram/min. Serial renal biopsies were performed 5 years apart in 11 Type 1 diabetic patients to evaluate whether glomerular and interstitial lesions progress jointly. AER increased significantly in 5 years, while the glomerular filtration rate remained unchanged. All structural parameters were initially abnormal. Vv(mes/glom) and mean glomerular volume increased significantly, whereas GBM width and the interstitial volume fraction were unchanged. Moreover, the change in Vv (mes/glom) was correlated with the change in AER (r =0.64, p <0.05). Thus, at the disease stage during which some patients progress to MA or proteinuria, continuing mesangial expansion is the main variable, whereas further interstitial expansion does not occur. A large number of Type 2 patients were also studied. Early diabetic glomerulopathy was detected by electron microscopy in NA patients and found to be more advanced in those with MA and proteinuria. However, lesions were milder than in Type 1 diabetic patients, and there was considerable overlap between groups. Morphometric results by electron microscopy were similar to those by light microscopy, demonstrating the heterogeneity of renal structure in Type 2 diabetic patients. In fact, only 30% of MA patients had typical diabetic glomerulopathy, while 40% had more advanced tubulo-interstitial and/or vascular lesions and 30% had normal renal structure.
Basement Membrane↗
Insulin-dependent diabetic sibling pairs are concordant for sodium-hydrogen antiport activity.
UNLABELLED: Insulin-dependent diabetic sibling pairs are concordant for sodium-hydrogen antiport activity. BACKGROUND: Recent findings of enhanced Na+/H+ antiport activity in cultured fibroblasts and immortalized lymphoblasts from type 1 diabetic patients with nephropathy support the view that a phenotypic or genotypic factor(s) underlies nephropathy risk. This study evaluated the kinetic properties of Na+/H+ antiporter in cultured fibroblasts from families with two siblings affected by type 1 (insulin-dependent) diabetes. METHODS: Seventeen diabetic sibling pairs were studied. The age was 38 +/- 10 years (mean +/- SD) in probands, the first to develop diabetes, and 39 +/- 7 in siblings; the duration of diabetes was, by definition, longer in probands (24 +/- 12 vs. 17 +/- 8 years in siblings). Na+/H+ antiport activity was determined using a microfluorometric technique with the pH sensitive dye 2', 7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein in skin fibroblasts cultured for at least six passages. RESULTS: There were no significant differences between probands and siblings for the following parameters: glycated hemoglobin, 8.3 +/- 0.8% in probands and 8.6 +/- 1.4% in siblings; creatinine clearance, 103 +/- 24 ml/min/1.73 m2 in probands and 103 +/- 25 in siblings; albumin excretion rate, 6.8 (1 to 860) microgram/min (median and range) in probands and 4.9 (2 to 1334) in siblings. Intracellular pH and buffering capacity were superimposable in the sibling pairs. The Vmax for the antiport was 39.2 +/- 14.7 mmol/liter cell/min in probands and 40.3 +/- 17.6 in siblings. The internal pH for half-maximal activation (Km) and Hill coefficient was also similar in probands and siblings. There were correlations between probands and siblings in values for intracellular pH (r = 0.51, P < 0.04), Vmax (r = 0.84, P < 0.0001), and buffering capacity (r = 0.53, P < 0. 03). Glycated hemoglobin values over five years were not significantly correlated in the sibling pairs (r = 0.3, P > 0.1). Vmax was related with the albumin excretion rate (r = +0.49, P = 0. 005) and glycated hemoglobin (r = +0.41, P = 0.017) in the total cohort of sibling pairs. However, multiple regression analysis, using Vmax as the dependent variable, found no correlations between any of the subjects' clinical and demographic variables. CONCLUSIONS: Familial concordance for Na+/H+ antiport activity in long-term cultured skin fibroblasts from type 1 diabetic siblings suggests that at least some of the in vitro phenotypical characteristics of these cells are likely to be genetically determined and to be, at least in part, independent of in vivo metabolic control.
Adult↗
Is diabetic nephropathy inherited? Studies of glomerular structure in type 1 diabetic sibling pairs.
Only a minority of patients with type 1 diabetes develop diabetic nephropathy (DN). Poor glycemic control cannot fully explain DN risk, and family studies suggest genetic susceptibility factors. To understand familial DN concordance, we evaluated glomerular structure in families with type 1 diabetic sibling pairs. Kidney function and biopsy studies were performed in 21 probands (P) (first to develop diabetes) and 21 siblings (S) (second to develop diabetes), most with normal urinary albumin excretion rates (UAER). Glomerular structure was measured by morphometry. Intrafamilial correlation was estimated by one-way random-effects ANOVA and by mixed-effects ANOVA, adjusting for age and duration of diabetes. Diabetes duration was, by definition, longer in P than in S, while age and sex were similar. HbA1c over 5 years and blood pressure were not different in P and S and were without familial effect. UAER was greater in P than in S (P < 0.05), with strong familial effect (P = 0.03). A strong concordance among siblings for mesangial fractional volume (P < or = 0.01) remained significant after adjustment for diabetes duration and age (P = 0.04). Results were similar for mesangial cell (P = 0.01; adjusted P = 0.04) and mesangial matrix fractional volumes (P < 0.01; adjusted P = 0.06). There was also clustering of the patterns of glomerular lesions. For example, if P had relatively marked glomerular basement membrane thickening compared with mesangial matrix expansion, S had a similar pattern (chi2, P < 0.025). Strong concordance in severity and patterns of glomerular lesions in type 1 diabetic siblings, despite lack of concordance in glycemia, supports an important role for genetic factors in DN risk.
Adult↗
Reversal of lesions of diabetic nephropathy after pancreas transplantation.
BACKGROUND: In patients with type I diabetes mellitus who do not have uremia and have not received a kidney transplant, pancreas transplantation does not ameliorate established lesions of diabetic nephropathy within five years after transplantation, but the effects of longer periods of normoglycemia are unknown. METHODS: We studied kidney function and performed renal biopsies before pancreas transplantation and 5 and 10 years thereafter in eight patients with type I diabetes but without uremia who had mild to advanced lesions of diabetic nephropathy at the time of transplantation. The biopsy samples were analyzed morphometrically. RESULTS: All patients had persistently normal glycosylated hemoglobin values after transplantation. The median urinary albumin excretion rate was 103 mg per day before transplantation, 30 mg per day 5 years after transplantation, and 20 mg per day 10 years after transplantation (P=0.07 for the comparison of values at base line and at 5 years; P=0.11 for the comparison between base line and 10 years). The mean (+/-SD) creatinine clearance rate declined from 108+/-20 ml per minute per 1.73 m2 of body-surface area at base line to 74+/-16 ml per minute per 1.73 m2 at 5 years (P<0.001) and 74+/-14 ml per minute per 1.73 m2 at 10 years (P<0.001). The thickness of the glomerular and tubular basement membranes was similar at 5 years (570+/-64 and 928+/-173 nm, respectively) and at base line (594+/-81 and 911+/-133 nm, respectively) but had decreased by 10 years (to 404+/-38 and 690+/-111 nm, respectively; P<0.001 and P=0.004 for the comparisons with the base-line values). The mesangial fractional volume (the proportion of the glomerulus occupied by the mesangium) increased from base line (0.33+/-0.07) to 5 years (0.39+/-0.10, P=0.02) but had decreased at 10 years (0.27+/-0.02, P=0.05 for the comparison with the baseline value and P=0.006 for the comparison with the value at 5 years), mostly because of a reduction in mesangial matrix. CONCLUSIONS: Pancreas transplantation can reverse the lesions of diabetic nephropathy, but reversal requires more than five years of normoglycemia.
Adult↗