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To determine outcome in diabetic pancreas transplant recipients according to risk factors and the surgical techniques and immunosuppressive protocols that evolved during a 33-year period at a single institution.Insulin-dependent diabetes mellitus is associated with a high incidence of management problems and secondary complications. Clinical pancreas transplantation began at the University of Minnesota in 1966, initially with a high failure rate, but outcome improved in parallel with other organ transplants. The authors retrospectively analyzed the factors associated with the increased success rate of pancreas transplants.From December 16, 1966, to March 31, 2000, the authors performed 1,194 pancreas transplants (111 from living donors; 191 retransplants): 498 simultaneous pancreas-kidney (SPK) and 1 simultaneous pancreas-liver transplant; 404 pancreas after kidney (PAK) transplants; and 291 pancreas transplants alone (PTA). The analyses were divided into five eras: era 0, 1966 to 1973 (n = 14), historical; era 1, 1978 to 1986 (n = 148), transition to cyclosporine for immunosuppression, multiple duct management techniques, and only solitary (PAK and PTA) transplants; era 2, 1986 to 1994 (n = 461), all categories (SPK, PAK, and PTA), predominantly bladder drainage for graft duct management, and primarily triple therapy (cyclosporine, azathioprine, and prednisone) for maintenance immunosuppression; era 3, 1994 to 1998 (n = 286), tacrolimus and mycophenolate mofetil used; and era 4, 1998 to 2000 (n = 275), use of daclizumab for induction immunosuppression, primarily enteric drainage for SPK transplants, pretransplant immunosuppression in candidates awaiting PTA.Patient and primary cadaver pancreas graft functional (insulin-independence) survival rates at 1 year by category and era were as follows: SPK, era 2 (n = 214) versus eras 3 and 4 combined (n = 212), 85% and 64% versus 92% and 79%, respectively; PAK, era 1 (n = 36) versus 2 (n = 61) versus 3 (n = 84) versus 4 (n = 92), 86% and 17%, 98% and 59%, 98% and 76%, and 98% and 81%, respectively; in PTA, era 1 (n = 36) versus 2 (n = 72) versus 3 (n = 30) versus 4 (n = 40), 77% and 31%, 99% and 50%, 90% and 67%, and 100% and 88%, respectively. In eras 3 and 4 combined for primary cadaver SPK transplants, pancreas graft survival rates were significantly higher with bladder drainage (n = 136) than enteric drainage (n = 70), 82% versus 74% at 1 year (P =.03). Increasing recipient age had an adverse effect on outcome only in SPK recipients. Vascular disease was common (in eras 3 and 4, 27% of SPK recipients had a pretransplant myocardial infarction and 40% had a coronary artery bypass); those with no vascular disease had significantly higher patient and graft survival rates in the SPK and PAK categories. Living donor segmental pancreas transplants were associated with higher technically successful graft survival rates in each era, predominately solitary (PAK and PTA) in eras 1 and 2 and SPK in eras 3 and 4. Diabetic secondary complications were ameliorated in some recipients, and quality of life studies showed significant gains after the transplant in all recipient categories.Patient and graft survival rates have significantly improved over time as surgical techniques and immunosuppressive protocols have evolved. Eventually, islet transplants will replace pancreas transplants for suitable candidates, but currently pancreas transplants can be applied and should be an option at all stages of diabetes. Early transplants are preferable for labile diabetes, but even patients with advanced complications can benefit.

Chronic rejection (CR) is the most common cause of graft loss beyond the 1st posttransplant year. The aim of this analysis was to identify the risk factors for the development of CR in pediatric renal transplant recipients. Between June 1984 and March 1994, 217 renal transplants were performed in children at our center. Immunosuppression included prednisone, azathioprine, cyclosporine (CsA), and prophylactic antibody. Using multivariate analysis, we studied the impact of the following variables on the development of biopsy-proven CR: age at transplant (or = 5 years,5 years), gender, race, transplant number (primary, retransplant), donor source (cadaver, living donor), donor age (20 years, 20-49 years,49 years), number of ABDR mismatches (0, 1-2, 3-4, 5-6), number of DR mismatches (0, 1, 2), percentage peak panel reactive antibody (PRA) (or = 50%,50%), percentage PRA at transplantation (or = 50%,50%), dialysis pretransplant, preservation time24 h, acute tubular necrosis requiring dialysis, initial CsA dosage (or = 5 mg/kg per day,5 mg/kg per day), CsA dosage at 1 year posttransplant (or = 5 mg/kg per day,5 mg/kg per day), acute rejection (AR), number of AR episodes (ARE) (1,1), timing of AR (or = 6 months,6 months), reversibility of AR (complete, partial), and infection [cytomegalovirus (CMV), non-CMV viral, bacterial]. Risk factors for the development of CR in pediatric renal transplant recipients were: AR (P0.0001, odds ratio 19.4), multiple ARE (1 vs. 1) (P0.0001, odds ratio 30.1), and high percentage peak PRA (50%) (P0.03, odds ratio 3.6).

Renal morphometric analysis was performed in 15 (13 male) Alport syndrome patients ages 4 to 26 years, along with 10 controls ages 3 to 26 years, to better understand the structural basis of renal dysfunction in Alport syndrome. The glomerular basement membrane (GBM) width class frequencies of controls were normally distributed; those of Alport syndrome patients were slightly skewed, especially toward thicker classes, although there was also an increase in the proportion of thinner classes. Mesangial volume fraction was not different between Alport syndrome patients (0.21 +/- 0.09) and controls (0.19 +/- 0.04). There was an inverse correlation between mesangial volume fraction and creatinine clearance in Alport syndrome patients (r = -0.72, P < 0.01); however, the creatinine clearances in Alport syndrome patients were far less than in insulin-dependent diabetic patients with similar mesangial volume fraction. Similarly, there was no significant difference in the surface density of the peripheral GBM (in square micrometers per cubic micrometer) in Alport syndrome patients (0.12 +/- 0.04) versus controls (0.13 +/- 0.02). The surface density of the peripheral GBM correlated with creatinine clearance in Alport syndrome patients (r = 0.71, P < 0.01). However, there was a greater reduction in creatinine clearance as related to declining the surface density of the peripheral GBM in Alport syndrome than in diabetic patients. The cortical interstitial volume fraction was highly inversely correlated with creatinine clearance in Alport syndrome patients (r = -0.85, P < 0.01). Global glomerular sclerosis was 0% in five and 5 to 61% in nine Alport syndrome patients and correlated inversely with creatinine clearance (r = -0.74, P < 0.01). However, the creatinine clearance was lower in Alport syndrome than in diabetic patients with similar cortical interstitial volume fraction and percent glomerular sclerosis. There was no significant difference in an index of glomerular number between Alport syndrome patients and controls. Thus, changes in mesangial volume fraction, cortical interstitial volume fraction, percent glomerular sclerosis, and surface density of the peripheral GBM in Alport syndrome patients only partially account for the reduction in creatinine clearance. It was speculated that decreased glomerular capillary wall hydraulic conductivity in Alport syndrome could explain many of these observations.

Thickening of the glomerular basement membrane (GBM) and expansion of the mesangial matrix are hallmarks of human diabetic nephropathy. Renal tissues from 15 patients with type II (non-insulin-dependent) diabetes (NIDDM) were studied by immunofluorescence (IF) and immunogold electron microscopy (IEM) for the distribution of 2 type IV collagen peptides [alpha 3(IV) noncollagenous (NC) domain and alpha 4(IV) NC domain] and 2 classical type IV collagen chains [alpha 1(IV) NC domain and alpha 2(IV) domain]. There was intense staining for alpha 3(IV) NC and alpha 4(IV) NC domain in the GBM but not in the mesangial matrix of patients with overt diabetic nephropathy. In contrast, staining with antibodies to alpha 1(IV) NC and alpha 2(IV) NC domain reacted with mesangial matrix but was significantly decreased in the GBM in the patients with overt diabetic nephropathy. IEM confirmed the IF findings. These data suggest that expansion of the mesangial matrix and thickening of GBM in NIDDM involves separate and distinct type IV collagen components and that the site-specific matrix alterations in NIDDM and type I (insulin-dependent) diabetes are parallel.

Current knowledge regarding the concordance and discordance of the eye and kidney complications of diabetes is based on observations by ophthalmoscopy of retinal structural changes, which may be present at early stages of the disorder, and renal functional changes, which only become apparent at the later stages of the disease. For this reason we investigated the relationship between retinal structural lesions and quantitative measures of glomerular structure in patients with insulin-dependent diabetes mellitus (IDDM). Renal biopsies were evaluated using morphometric techniques, and retinopathy classification was determined by retinal fundus photography in 86 patients with IDDM: age 30.4 ± 7.3 years and duration of IDDM 18.9 ± 6.3 years (mean ± SD). Retinopathy score correlated with glomerular basement membrane width (r = 0.39, P = 0.0002), mesangial volume fraction (VvMes/Glom) (r = 0.35, P = 0.0009), surface density of the peripheral capillary wall (SvPGBM/Glom) (r = 0.34, P = 0.0013), and index of arteriolar hyalinosis (r = 0.36, P = 0.0008). Abnormalities in VvMes/Glom and SvPGBM/Glom were more pronounced in patients with both retinopathy and hypertension. Four of the 15 patients (27%) with either normal urinary albumin excretion (UAE) or low-level microalbuminuria had advanced retinopathy but normal VvMes/Glom. In conclusion, the presence of advanced retinal disease with or without hypertension in patients with IDDM indicates a greater likelihood of advanced nephropathy as evidenced by increased VvMes/Glom and decreased SvPGBM/Glom. However, marked discordance between retinopathy and nephropathy occurs, as illustrated by patients with normal UAE or low-level microalbuminuria, normal glomerular structural measures, and advanced retinopathy.

At our institution, 521 kidney transplants were performed in 429 children (mean age 8.7 +/- 5.6-years) between 1969 and 1991. Of these transplants, 408 were primary, 113 were retransplants, 347 were living related, 171 were cadaver, and 3 were living nonrelated. Immunosuppression consisted of prednisone, azathioprine, and Minnesota antilymphocyte globulin (non-CSA) in 339 patients, total lymphoid irradiation in 8, and, more recently, cyclosporine (CSA) in addition in 168 patients. Average follow-up was 8.8 +/- 6.0 years. Actuarial graft survival in the non-CSA versus CSA groups at 1 year was 77.0% versus 85.7%; at 5 years, 59.6% versus 71.9%. Of 136 non-CSA patients, causes of graft loss at 5 years included: chronic rejection in 55 (40.4%), acute rejection in 27 (19.9%), recurrent disease in 16 (11.8%), technical complications in 8 (5.9%), infectious complications in 4 (2.9%), other causes in 5 (3.7%), and death with a functioning graft in 21 (15.4%). Of 40 CSA patients, causes of graft loss at 5 years included: chronic rejection in 16 (40.0%), acute rejection in 8 (20.0%), recurrent disease in 6 (15.0%), technical complications in 3 (7.5%), other causes in 2 (5.0%), and death with a functioning graft in 5 (12.5%). The causes of graft loss did not significantly differ in the non-CSA and CSA groups. Chronic rejection was the most common cause of graft loss in both groups. Research focusing on chronic rejection is needed to improve graft outcome in pediatric kidney transplantation.

Although 4000 pancreas transplants have now been done, alone or in combination with a kidney transplant, the risk/benefit profile of the procedure has not been established by controlled studies. A solo pancreas transplant abolishes the need for daily insulin but requires chronic immunosuppression, has high failure rates, and is not proved to lessen the chronic complications of diabetes. Thus, it is probably justified only in those diabetic patients with incapacitating disease. For uraemic diabetic patients, combined pancreas and kidney transplantation often removes dependence on both insulin and dialysis, and has lower rejection rates than pancreas transplant alone. However, it needs more immunosuppression than kidney transplant alone, has no proven benefit on chronic complications of diabetes, and carries an increased risk of rejection, infection, and cancer. Living-related-donor kidney transplantation followed by cadaver pancreas transplantation is a possible alternative. Transplantation of pancreatic islets could offer the advantages of strict metabolic control without the drawbacks of immunosuppressive therapy. Thus, research efforts should concentrate on immune-protected islet transplantation. An alternative approach to avoiding long-term immunosuppression is the promotion of allograft tolerance.

In a cross-sectional study, glomerular basement membrane (GBM) width, the volume fractions of the mesangium (VvMes), its cell (VvCell) and matrix (VvMatx) components, and surface density of the peripheral capillary surface (SvPGBM) were measured in renal biopsies from 187 nondiabetic living related and cadaveric donors of kidneys for transplantation and from 150 patients with insulin-dependent (type I) diabetes mellitus of 1–41 yr duration. In the diabetic patients, the matrix was the major factor in the expansion of the mesangium. However, both VvCell (0.11 ± 0.04) and VvMatx (0.20 ± 10) in diabetic patients exceeded the same measurements in nondiabetic subjects (0.07 ± 0.02 for each component) (P < 0.001 in each case). Linear regression analysis demonstrated significant correlations (P < 0.001 for all) between GBM width, VvMes, VvCell, VvMatx, or SvPGBM and either urinary albumin excretion and creatinine clearance, with the higher correlation coefficients in all cases with albuminuria. Of the structural parameters, VvMatx correlated best with either functional measure by stepwise regression, with GBM as an added factor only with albuminuria. Therefore, although models of diabetic glomerulopathy must consider enlargement of both mesangial cells and matrix, the predominant factor in the progression of structural and functional renal disease is mesangial matrix expansion.

The evaluation of renal biopsies from diabetic patients rests upon measurements of many structures in glomeruli, the tubules and the interstitium. These individual values can also be expressed as an index of renal structure. To assess the validity of the individual values versus a published index of renal structure, we evaluated glomerular basement membrane width, mesangial volume fraction, other measures of glomerular structure, and percentage glomerulosclerosis in type 1 diabetic subjects with renal function ranging from normal to marked albuminuria, hypertension, and a falling glomerular filtration rate. For all measured structural parameters and for the index, all groups of diabetic patients, even those who had completely normal renal function, had values different from non-diabetic subjects (P

In examining the pathophysiology underlying the development of hypertension in diabetes mellitus, it is important to draw clear distinctions between Type I and Type II diabetes. In patients with Type I diabetes, with a peak onset of disease early in the second decade of life, hypertension clearly represents the sequelae to the development of substantial renal lesions, especially in the glomerulus. Thus the prevalence of hypertension in those patients without substantial glomerular lesions approximates the incidence of hypertension in the general population (approximately 4%). In patients with Type II diabetes mellitus and onset generally later in adult life, an increase in blood pressure can often be demonstrated early after or even before diagnosis of the disease (most readily demonstrated in the Pima Indians). Furthermore, clear familial tendencies towards the development of nephropathic complications of diabetes can be shown. In patients with Type I disease, the fall in glomerular filtration rate parallels the fall in glomerular capillary surface available for filtration. This reduction in the peripheral glomerular capillary surface correlates well with the expansion of the mesangium, strongly implicating the mesangial expansion in the demise in renal function. For both Type I and Type II diabetes mellitus, the increase in albuminuria may reflect an opening of large pores in the glomerular basement membrane, thereby allowing serum proteins to cross into the filtration space.

Two female siblings were treated for acute neonatal hyperammonaemia due to complete carbamyl phosphate synthetase I deficiency. The first child was detected clinically at 65 hours of age and therapy started at 79 hours. The second child was followed from birth and therapy started at 5 hours of age. The extrapolated rate of increase of blood ammonia, in the first hours of life before therapy started, was 19 mumol L-1 h-1 in both babies. Peak blood ammonia level was 2235 mumol/L in the first (clinically detected) child and 271 mumol/L in the second (prospectively followed) child. The second child became symptomatic at 3 hours of age when blood ammonia level was as low as 90 mumol/L, whereas blood ammonia levels above 100 mumol/L caused no symptoms during recovery. The child detected clinically required haemodialysis and peritoneal dialysis to treat the hyperammonaemia. In the prospectively treated child, early therapy with intravenous sodium benzoate and sodium phenylacetate slowed the rate of increase in blood ammonia level, but this therapy did not prevent the need for peritoneal dialysis.

The pediatric nephrologist has traditionally not been involved in the care of the diabetic child since diabetic nephropathy presents in adulthood. Recent studies suggest that diabetic kidney disease develops silently during childhood. Measurement of urinary albumin excretion (UAE) allows earlier detection of patients at risk of nephropathy, often in adolescence. In addition to diabetic nephropathy, diabetic children are at risk of urinary tract infections, renal papillary necrosis, and various forms of glomerulonephritis. The role of the pediatric nephrologist in the care of the child with diabetes might include advising on the administration and interpretation of screening for UAE and the measurement and interpretation of glomerular filtration rate, and blood pressure. Children with evidence of renal dysfunction should be evaluated and treated by the pediatric nephrologist. Frequently, renal biopsy will be necessary in these patients. Future research may allow the detection of diabetic kidney disease earlier in childhood, further expanding the role of the pediatric nephrologist. In particular, early renal biopsy may eventually be used to select those patients at risk of diabetic nephropathy for specific treatment alterations.

The role of cadaver kidney transplantation in the management of end-stage renal disease in young children is controversial. To assess the current risk-benefit ratio of cadaver first and second kidney transplants in recipients under 6 years of age, we compared the outcome of 19 transplants performed between 1984 and 1989 using a quadruple-drug regimen (Minnesota antilymphocyte globulin, azathioprine, prednisone, cyclosporine) with the outcome of 25 transplants performed prior to 1984 without the use of cyclosporine at a single institution. Twenty-five transplants were in children under the age of 3 years. In the last decade patient survival has significantly improved. One-year patient survival improved from 53% before 1979 to 90% since 1979 (P less than 0.05). The use of the quadruple-drug regimen since 1984 was associated with a significant improvement in one-year cadaver graft function from 40% before 1979 to 78% in recipients under 6 years of age, and from 22% to 82% in recipients under 3 years of age (P less than 0.05). With the quadruple-drug regimen, one-year and four-year graft function rates for children under 6 years of age were 83% for first cadaver transplants and 72% for second cadaver transplants, which were essentially the same results as in older children and adults. Children who received kidneys from donors over 4 years of age achieved the best result, with 87% one-year graft function compared with 50% for kidneys from donors under 4 years old. In 15 children with successful transplants, 8 (53%) showed accelerated growth, 5 (33%) had normal-velocity growth, and only 2 children (14%) with suboptimal renal function had poor growth following transplantation. Therefore, we believe that with a quadruple-drug immunosuppressive protocol, cadaver renal transplantation using kidneys from adults or pediatric donors over 4 years old is an acceptable form of treatment in young children with end-stage renal disease for whom there are no suitable living-related donors.

The timing of renal transplantation in infants is controversial. Between 1965 and 1989, 79 transplants in 75 infants less than 2 years old were performed: 23 who were 12 months or younger, 52 who were older than 12 months; 63 donors were living related, 1 was living unrelated, and 15 were cadaver donors; 75 were primary transplants and 4 were retransplants. Infants were considered for transplantation when they were on, or about to begin, dialysis. All had intra-abdominal transplants with arterial anastomosis to the distal aorta. Sixty-four per cent are alive with functioning grafts. The most frequent etiologies of renal failure were hypoplasia (32%) and obstructive uropathy (20%); oxalosis was the etiology in 11%. Since 1983 patient survival has been 95% and 91% at 1 and 5 years; graft survival has been 86% and 73% at 1 and 5 years. For cyclosporine immunosuppressed patients, patient survival is 100% at 1 and 5 years; graft survival is 96% and 82% at 1 and 5 years. There was no difference in outcome between infants who were 12 months or younger versus those who were aged 12 to 24 months; similarly there was no difference between infants and older children. Sixteen (21%) patients died: 5 after operation from coagulopathy (1) and infection (4); and 11 late from postsplenectomy sepsis (4), recurrent oxalosis (3), infection (2), and other causes (2). Routine splenectomy is no longer done. There has not been a death from infection in patients transplanted since 1983. Rejection was the most common cause of graft loss (in 15 patients); other causes included death (with function) (7), recurrent oxalosis (3), and technical complications (3). Overall 52% of patients have not had a rejection episode; mean creatinine level in patients with functioning grafts is 0.8 +/- 0.2 mg/dL. Common postoperative problems include fever, atelectasis, and ileus. At the time of their transplants, the infants were small for age; but with a successful transplant, their growth, head circumference, and development have improved. Transplantation in infants requires an intensive multidisciplinary approach but yields excellent short- and long-term survival rates that are no different from those seen in older children or adults. Living donors should be used whenever possible. Patients with a successful transplantation experience improved growth and development, with excellent rehabilitation.

The effect of cyclosporin (CsA) on the endotoxin-induced generalized Shwartzman reaction (GSR) was studied in diabetic and nondiabetic rats. After 4.5 wk of diabetes, CsA (20 mg/kg) or intralipid as a control substance was given intraperitoneally daily for 10 days. Next, diabetic rats were given either high-dose (2 mg/kg) or low-dose (0.1 mg/kg) endotoxin (Escherichia coli 026 :B6 lipopolysaccharide B) as a single injection. The rats were killed at intervals of 1, 4, 8, and 24 h. No significant glomerular thrombi were seen in the nondiabetic control animals, whereas the severity of glomerular thrombi in the diabetic animals was dependent on the presence or absence of CsA, endotoxin dose, and degree of glycemic control. In the diabetic rats, glomerular thrombi occurred maximally at 4 h but were no longer present at 24 h. The CsA/high-dose–endotoxin rats had fewer glomerular thrombi than rats receiving the intralipid/high–dose endotoxin, but this difference was not statistically significant. The CsA/low-dose–endotoxin rats had increased glomerular thrombi compared with the intralipid/low-dose–endotoxin rats (P < 0.01). Insulin treatment reduced the glomerular capillary thrombi in the CsA/low-dose–endotoxin diabetic animals. Thus, CsA aggravates the GSR with low-dose endotoxin but has no significant effect when high-dose endotoxin is given. Improved glycemic control reduces the GSR in CsA-treated rats. Thus, the interrelationships of diabetes, endotoxin, and CsA on the GSR are complex, and the pathogenesis of these events is unclear.

The expression of mRNA and distribution of alpha 1(IV), alpha 3(IV) chains of type IV collagen, matrix metalloproteinase 2 (MMP-2), and tissue inhibitor of metalloproteinase 1 (TIMP-1) were examined in kidneys from streptozotocin-diabetic rats, 2.5 months after administration of the drug, an early time point when specific diabetic glomerular changes were still minimal. Ten age-matched Sprague-Dawley rats were assigned to control and diabetic groups. Compared to the controls, the diabetic rats had a significantly lower body weight, higher kidney weight and serum glucose levels, but no significant changes of glomerular surface area and urine albumin were observed. Northern blot analysis, using whole kidney mRNA, revealed that diabetic rat kidneys expressed 113.5% more alpha 1(IV), 46.5% more alpha 3(IV), 54.8% less MMP-2 and 246% more TIMP-1 (in all instances: p0.05). These results were corroborated by in situ hybridization for RNA expression. A quantitative analysis of the data indicated the following changes in glomeruli: (1) 74.6% more alpha 1(IV), (2) 103.8% more alpha 3(IV), (3) 40.7% less MMP-2 and (4) 80.9% more TIMP-1. Similar changes were observed in tubular (proximal and distal) cells. We conclude that an increased synthesis and decreased degradation of renal extracellular matrix components occur early after induction of experimental diabetes, before the onset of typical structural changes in the kidneys, and represent changes of specific gene expression at the transcriptional level. All the cell types in the glomerulus as well as the proximal and distal tubules appear to be involved in this alteration of expression, and this is a novel finding.

We studied the impact of early cyclosporine (CSA) levels on the incidence of rejection in pediatric transplant recipients. Between 1 January 1984 and 31 December 1994, a total of 234 pediatric patients underwent kidney transplants and received CSA immunosuppression. We analyzed the impact of CSA levels (at 1 wk, 2 wk, 1 month, 2 months, and 3 months) on the incidence of rejection in the first 3 and the first 6 months post-transplant. We found that CSA levels at all timepoints correlated, i.e. recipients with low levels in the early post-transplant period tended to have low levels throughout the first 12 months. Multivariate analysis for risk factors by biopsy-proven rejection in the first 3 months revealed that the CSA trough level was the critical factor (p0.05). Recipients with CSA trough levels100 ng/ml had 2.24 times the risk of rejections vs. those with blood levels100 ng/ml. Similarly, the CSA trough level at 1 month was the critical risk factor for biopsy-proven rejection within the first 6 months (p0.05). The major risk factor for graft loss within the first 12 months was a biopsy-proven rejection episode. We conclude that in pediatric kidney transplant recipients, early CSA trough levels100 ng/ml are associated with a significantly increased incidence of rejection in the first 6 months post-transplant.

At the University of Minnesota, outcome of renal transplants for infants and young children is the same as outcome for older children and adults. We reviewed our decision-making process in the pre-, peri-, and postoperative care of these recipients.

Between May 1, 1986 and May 31, 1992 at the University of Minnesota, we interpreted 129 renal allograft biopsy specimens (done in 48 grafts during the first 6 months posttransplant) as showing changes consistent with chronic rejection. For this retrospective analysis, we reexamined these biopsies together with clinical information to determine: (a) whether a diagnosis other than chronic rejection would have been more appropriate, (b) how early posttransplant any chronic rejection changes occurred, and (c) if the diagnosis correlated with outcome. We found that (1) chronic rejection is uncommon in the first 6 months posttransplant; it was documented in only 27 (2.4%) of 1117 renal allografts and was preceded by acute rejection in all but 3 recipients (for these 3, the first biopsy specimen showed both acute and chronic rejection). (2) Chronic vascular rejection was seen in 1 recipient as early as 1 month posttransplant; the incidence increased over time and was associated with an actual graft survival rate of only 35%. (3) The most frequent cause of arterial intimal fibrosis in the first 6 months posttransplant was arteriosclerotic nephrosclerosis (ASNS) of donor origin. Long-term graft function for recipients with ASNS was 67%. (4) Early-onset ischemia or thrombosis was seen in 14 recipients and predicted poor outcome: only 35.7% of these recipients had long-term graft function. (5) Cyclosporine (CsA) toxicity was implicated in only 3 recipients, who had mild diffuse interstitial fibrosis in association with elevated CsA levels. Other variables (including systemic hypertension, urinary tract infection, obstructive uropathy, neurogenic bladder, cobalt therapy, and recurrent disease) were not significantly associated with chronic renal lesions in the first 6 months posttransplant. A significant number of biopsies were originally interpreted as showing chronic rejection, but the diagnosis was changed upon reevaluation in conjunction with clinical data. We conclude that many factors coexist to produce chronic lesions in biopsies during the first 6 months posttransplant, so clinical correlation is needed before establishing a diagnosis of chronic rejection.

Acute renal insufficiency in the setting of hemolysis and thrombocytopenia, a triad that constitutes adult or pediatric hemolytic uremic syndrome, can be associated with or triggered by diverse conditions such as verocytotoxin-producing Escherichia coli, viral infections, pregnancy, malignant hypertension, scleroderma, renal radiation, allograft rejection, lupus erythematosus, and assorted medications such as mitomycin C, cyclosporine, and oral contraceptives. Recurrent and de novo hemolytic uremic syndrome occur after renal transplantation. Relapses are also common and probably reflect incomplete resolution of the initial episode. The major differential diagnoses of hemolytic uremic syndrome in the renal allograft include acute vascular rejection, cyclosporine, FK506 or antilymphocyte antibody nephrotoxicity, and malignant hypertension, all of which may display overlapping clinical and histologic features with primary hemolytic uremic syndrome; in such instances, the exact diagnosis may be quite difficult. It is possible that the risk of recurrence may be reduced by proper timing of transplantation and suitable choice of immunosuppressive agents. Intensive plasmapheresis in conjunction with fresh frozen plasma and supportive management of renal failure may lessen mortality and morbidity even in recurrent hemolytic uremic syndrome after transplantation.

We have previously characterized the evolution of renal cortical interstitial fibrosis in the rabbit model of unilateral ureteral obstruction (UUO). In our earlier report, we examined the extracellular matrix protein composition of the interstitial space. Of note, UUO was associated with the acquisition of prominent interstitial collagen IV immunoreactivity. Interstitial collagens I and III were also increased. In situ hybridization localized increased expression of collagens I and IV to cells of the interstitial space. In the current study, we examine metalloproteinase and metalloproteinase inhibitor expression in the obstructed renal cortex. Matrix metalloproteinase-2 is a metalloproteinase with activity against both collagen IV and denatured collagen I. At day 3 of UUO, both transcripts were significantly increased, although expression of these mRNAs was not different from controls after 7 and 16 days of UUO. Expression of mRNA of tissue inhibitor of the metalloproteinases (TIMP) was significantly increased in the UUO samples at all times, although it was maximal at day 3. Immunohistochemically, increased TIMP reactivity localized to the interstitial space, and TIMP mRNA expression was seen to parallel the interstitial macrophage infiltration that accompanies ureteteral obstruction. In contrast, TIMP-2 mRNA expression appeared to be biphasic, with peaks at both day 3 and day 16 of UUO. At day 7, expression was not different from controls. These data suggest a role for impaired matrix degradation in the development of interstitial fibrosis in the obstructed kidney, particularly at late times when collagen mRNA expression has returned to control values.

To determine whether optimized glycemic control in type I diabetic recipients of renal allografts will prevent or delay diabetic renal lesions in the allograft.Prospective, controlled, and randomized trial of glycemic control in an inception cohort of type I diabetic renal allograft recipients. The experimental group underwent maximized glycemic control, and the standard group was treated in the same way as other patients in the transplant clinic. Patients underwent baseline (before transplant) and 5-year posttransplant allograft biopsies.University of Minnesota Hospital and Clinic and the Clinical Research Center and Hennepin County Medical Center, Minneapolis.Type I diabetics with terminal diabetic renal failure undergoing renal transplantation. Forty-eight patients randomized to maximized or standard control completed the trial.Subcutaneous insulin given several times a day or continuously (maximized group) and once or twice each day (standard group) was used throughout the trial. A significant difference for hemoglobin A1 level was maintained (mean +/- SD: standard, 0.117 +/- 0.013; maximized, 0.096 +/- 0.016; P0.001).The primary end point of this trial was the difference between the groups in renal glomerular mesangial expansion as determined by electron microscopy.There was a more than twofold increase in the volume fraction of mesangial matrix per glomerulus in the standard group (mean +/- SD, 0.043 +/- 0.034) compared with the maximized group (0.019 +/- 0.038; P = .024). The threefold increase in arteriolar hyalinosis, the greater widening of the glomerular basement membrane, and increase of volume fraction of the total mesangium in the patients who received standard treatment all approached significance (P = .10 or less). The incidence of severe hypoglycemic episodes was greater in the maximized group (1.7 per patient per year) than in the standard treatment group (0.1 per patient per year; P.001).This trial indicates a causal relationship between hyperglycemia and an important lesion of diabetic nephropathy, mesangial matrix expansion, in renal allografts transplanted into diabetic recipients. In addition, the results with other lesions central to the development of diabetic nephropathy support the major conclusion.

We used immunogold electron microscopic (IEM) techniques with periodate-lysine-paraformaldehyde-fixed and Lowicryl-embedded or cryopreserved tissues to study the distribution of alpha 1(IV) and alpha 3(IV) chains of Types IV and VI collagen in glomerular basement membrane (GBM) and mesangial matrix of glomeruli in normal human kidneys. Monoclonal antibodies to alpha 1(IV) and alpha 3(IV) collagen chains and Type VI collagen could be detected only with cryoultramicrotomy, whereas polyclonal anti-Type IV collagen antibody was detectable in Lowicryl-embedded tissue. Ultrastructural detail was better preserved in the Lowicryl-embedded tissue. IEM labeling provided more detailed information as to the site-specific array of these extracellular matrix molecules in glomeruli than did immunofluorescent microscopy. The labeling of alpha 1(IV) collagen chain was distributed mainly along the endothelial side of glomerular basement membrane and the mesangial matrix. Mesangial GBM was relatively poorly labeled compared with that of mesangial matrix. In contrast, the alpha 3(IV) chain was detected throughout the thickness of the GBM, but there was no labeling of mesangial matrix. Type VI collagen distribution was identical to that of the alpha 1(IV) chain within the glomerulus but was also associated with interstitial collagen fibrils. This study documents and details the heterogeneous distribution of Type IV and VI collagen chains within the normal human glomerulus and provides the framework for the study of these matrix components in human glomerular diseases.

We have reviewed the clinical course of 30 pediatric bone marrow transplant (BMT) recipients requiring dialysis for acute renal failure early after BMT. Patients requiring dialysis were not significantly different from the general pediatric BMT population except for: (1) a greater proportion of neuroblastoma patients in the dialysis group, and (2) fewer autologous and more unrelated BMT donors in the dialysis group. Twenty-three patients (77%) died without recovering renal function 1-72 days (mean 12 days) after dialysis was begun. Sepsis was the most commonly cited cause of renal failure and death in these patients. Seven patients (23%) recovered sufficient renal function to stop dialysis; all long-term survivors were in this group. Factors at the onset of dialysis associated with persistent renal failure were weight gain ofor = 10% of baseline body weight, requirement of three or more drugs for blood pressure support and hyperbilirubinemia. Although acute renal failure requiring dialysis is an ominous development following BMT, recovery of renal function is possible with aggressive supportive care.

Diabetic rats manifest abnormal renal hemodynamic responses, with persistent renal vasodilation at reduced renal perfusion pressures. We hypothesized that in diabetes, renal hemodynamics are modulated by increased activity of the endogenous vasodilator, NO. In anesthetized Munich-Wistar rats, after 6 wk of streptozotocin-induced, insulin-treated diabetes, and in age-matched, nondiabetic littermates (n = 7-8), basal renal hemodynamics and responses to graded reductions in renal perfusion pressure were determined before and after intrarenal arterial infusion of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). An identical protocol was followed in a second cohort of rats pretreated with indomethacin (4 mg/kg iv). Diabetic rats demonstrated hyperglycemia, renal enlargement, hyperfiltration, and increased urinary excretion of the stable NO metabolites, NO2 and NO3. L-NAME eliminated basal hyperfiltration in diabetic rats, and L-NAME, but not indomethacin, also eliminated persistent renal vasodilation at reduced renal perfusion pressure. We conclude that in a rat model of diabetes, increased endogenous NO activity may play a role in basal hyperfiltration and in the persistent renal vasodilatation manifested at reduced renal perfusion pressures.

Pancreas transplantation prevents or retards development of early diabetic glomerular lesions in renal allografts transplanted to patients with insulin-dependent diabetes mellitus (IDDM), but its effect on established renal lesions in native kidneys of such patients is unknown. Renal biopsy samples were taken before and 5 years after pancreas transplantation from 13 non-uraemic IDDM patients and compared with baseline and 5-year biopsy samples from 10 persistently hyperglycaemic IDDM patients who did not undergo transplantation. The two groups were similar in age, duration of diabetes, metabolic control, renal function, and blood pressure. Glomerular structures were measured by standard morphometric techniques. Haemoglobin A1 concentrations fell to within the normal range after pancreas transplantation but did not change in the comparison group. Glomerular basement membrane width did not significantly change in either group. Glomerular volume decreased and mesangial fractional volume increased in the pancreas transplant recipients but there was no significant change in total mesangial volume over 5 years. By contrast, both glomerular volume and mesangial fractional volume increased in the comparison patients, resulting in increased total mesangial volume. Diabetic glomerular lesions in patients with their own kidneys were not ameliorated by pancreas transplantation, despite 5 years of normoglycaemia. Pancreas transplantation can correct severe metabolic instability and thus improve quality of life, but it cannot yet be recommended for the treatment of established lesions of diabetic nephropathy.

Eight women with insulin-dependent diabetes mellitus (IDDM) with low creatinine clearance rate (CCR) and normal urinary albumin excretion (UAE) were compared with three other groups of diabetic women: 19 with normal creatinine clearance rate (CCR) and UAE, 7 with normal CCR and microalbuminuria, and 7 with low CCR and microalbuminuria. The four groups were similar in age, duration of diabetes, HbA1, incidence of urinary tract infection, prevalence of bladder neuropathy, and urinary urea nitrogen excretion rate. The prevalence of hypertension was similar among the groups, although mean arterial pressure was higher in the low CCR and microalbuminuria group. Renal area index was lower in the low CCR and normal UAE groups than in the other groups of diabetic patients, but was not different from normal. Morphometric measures of mesangial expansion and estimates of arteriolar hyalinosis and global glomerulosclerosis were increased to a similar degree in the low CCR and normal UAE, normal CCR and microalbuminuria, and low CCR and microalbuminuria groups compared with the group without abnormalities of renal function. Therefore, it is likely that diabetic glomerulopathy is, at least in part, responsible for the loss of glomerular filtration rate seen in the low CCR and normal UAE patients. Thus, the definition of incipient nephropathy may have to be expanded beyond the concept of microalbuminuria if longitudinal study of such patients reveals an increased risk of the subsequent development of overt nephropathy. Finally, screening for diabetic kidney disease among IDDM patients should include determination of glomerular filtration rate and measurement of UAE and blood pressure, especially among women.

Purpose To review renal pathological changes in diabetes, which include thickening of all renal extracellular basement membranes and the mesangial matrix and, to a lesser extent, mesangial cell expansion. Critical renal lesions in diabetic nephropathy Two renal lesions appear critical in diabetic nephropathy. Mesangial expansion out of proportion to the size of the glomerulus is inversely related to proteinuria, hypertension and a declining glomerular filtration rate. Arteriolar hyalinosis is related to global glomerulosclerosis and both are correlated with the clinical features of nephropathy. By the time renal dysfunction is clinically detectable, these lesions tend to be advanced. Interstitial volume may be increased in insulin-dependent diabetes mellitus, particularly in areas containing sclerotic glomeruli or marked tubular atrophy. Future research Longitudinal studies of renal structure and function and a simultaneous study of potential risk factors and pathways of injury are necessary to develop more refined predictors and clearer pathogenic concepts of this important diabetic complication.

The natural history of focal segmental glomerulosclerosis in patients retransplanted after loss of a primary allograft is not well established. We studied 14 patients with FSGS who were retransplanted between April 1964 and September 1990 to determine if recurrence in a second or subsequent allograft could be predicted. In this group, 8 of the primary allografts were lost to recurrent disease and 6 to rejection. None of the 6 patients who lost their primary allograft to rejection without evidence of recurrent FSGS suffered recurrent disease after retransplantation. In contrast, 3 of the 8 patients who lost their primary allograft rapidly to FSGS suffered recurrent disease and loss of function in all subsequent allografts. The remaining 5 patients had prolonged function of the primary allograft ranging between 4 and 10.5 years, despite recurrence of FSGS. Of these 5 patients, 2 have excellent renal function after retransplantation without recurrence of FSGS in the secondary allograft at 9 and 10.5 years posttransplant; 2 have lost their secondary allograft to recurrent FSGS, but are free of recurrence in the third allograft at 0.5 and 5.8 years postoperatively; 1 maintains a serum creatinine level of 1.9 mg% despite recurrence of FSGS in the secondary allograft at 1 year postoperatively. Our data show that, without recurrence of FSGS in the primary allograft, further renal transplants will be free of recurrent disease. Based on this finding, we advocate use of living-related donors for second transplants in these patients. With rapid recurrence of FSGS and subsequent accelerated loss of the primary allograft, further renal transplants carry a high likelihood of recurrent FSGS and graft loss. A substantial proportion of patients with recurrent FSGS in the primary allograft will have prolonged renal function, and are likely to have excellent results with subsequent allografts.

Renal pathological changes of diabetes include thickening of all renal extracellular basement membranes and the mesangial matrix and, to a lesser extent, mesangial cell expansion. Two renal lesions appear critical in diabetic nephropathy. Mesangial expansion out of proportion to the size of the glomerulus is related to proteinuria, hypertension, and declining GFR. Arteriolar hyalinosis is related to global glomerulosclerosis, and both are correlated with the clinical features of nephropathy. By the time renal dysfunction is clinically detectable, these lesions tend to be advanced. Interstitial volume may be increased in insulin-dependent diabetes mellitus, particularly in areas containing sclerotic glomeruli or marked tubular atrophy. Parallel findings were documented for type I membranoproliferative glomerulonephritis in which the increased mesangial volume fraction was related to decreased GFR, increased glomerular permeability to protein, and hypertension. As in diabetes, the cortical interstitial volume fraction is correlated with functional abnormalities in type I membranoproliferative glomerulonephritis. Thus, in both of these chronic glomerular disorders, mesangial expansion and interstitial expansion are associated with disordered renal function. Thus, it is not true that glomerular structural changes correlate poorly with glomerular function. Whether it is the glomerular or interstitial pathology or both that is causally responsible for the dysfunction requires further study.

In examining the pathophysiology underlying the development of hypertension in diabetes mellitus, it is important to draw clear distinctions between Type I and Type II diabetes. In patients with Type I diabetes, with a peak onset of disease early in the second decade of life, hypertension clearly represents the sequelae to the development of substantial renal lesions, especially in the glomerulus. Thus the prevalence of hypertension in those patients without substantial glomerular lesions approximates the incidence of hypertension in the general population (approximately 4%). In patients with Type II diabetes mellitus and onset generally later in adult life, an increase in blood pressure can often be demonstrated early after or even before diagnosis of the disease (most readily demonstrated in the Pima Indians). Furthermore, clear familial tendencies towards the development of nephropathic complications of diabetes can be shown. In patients with Type I disease, the fall in glomerular filtration rate parallels the fall in glomerular capillary surface available for filtration. This reduction in the peripheral glomerular capillary surface correlates well with the expansion of the mesangium, strongly implicating the mesangial expansion in the demise in renal function. For both Type I and Type II diabetes mellitus, the increase in albuminuria may reflect an opening of large pores in the glomerular basement membrane, thereby allowing serum proteins to cross into the filtration space.

Transplantation is the treatment of choice for children with end-stage renal disease. However, the long-term quality of life and socioprofessional outcome for those with successful transplants have not previously been reported. We studied these factors in patients transplanted when less than 18 years old who currently have greater than or equal to 10 years of graft function. A total of 57 questionnaires were sent out; 57 (100%) responded [24 female and 33 male patients; average (+/- SD) age at tx = 10 +/- 5 years (0.9-17.7); average f/u = 15.6 +/- 3 years (10-26); current age = 26 +/- 5 years (12-38); 26 had greater than 1 transplant]. Of the 57 respondents, 9 are less than 18 (all are in school); 48 are greater than or equal to 18 (7 in school, 37 employed, 4 unemployed); 12 are married, 1 engaged, and 2 divorced; and 9 have children. While in school, 43 (75%) had participated in sports, 37 (65%) in other extracurricular activities; 7 (12%) were A and 33 (58%) B students; 15 (26%) received awards or scholarships. For those working, the range of occupations is broad (average work week = 41 +/- 5 hr). Health-related absence from work has been nonexistent for 93%. Health is rated as good to excellent by 91% and fair by 9%. The future is regarded as hopeful or promising by 80%. Similarly, 89% are satisfied with life in general; 95% said health never or seldom interferes with family life; 95% feel health and drug side effects are of no or minor concern in sexual relationships. Only 3% feel health is a problem in maintaining a sexual relationship (41% are not sexually active). Only 4% stated that health often interferes with social life; 98% meet with friends on a regular basis; 76% are satisfied with personal relationships and 8% dissatisfied; 91% are satisfied with their ability to perform at work or school and 5% dissatisfied. Of note, 32% are dissatisfied with body appearance. Major concerns are short stature and brittle bones. Major suggestions include education/support groups to deal with teasing at school and peer problems. We conclude that transplanted children with long-term graft function have a favorable social and professional outcome. Overall, quality of life seems excellent.

The glomerular filtration barrier consists of complex matrix constituents interposed between the glomerular endothelial and epithelial cells, which constitute the lining of the glomerular capillaries. The matrix components include collagen and noncollagenous molecules such as laminin and proteoglycans. This review describes herein the metabolic consequences of diabetes mellitus to which increased permeability of the filtration barrier may be attributed by altering matrix molecules.

We were concerned that clinical manifestations of rejection (R) might be subtle in small children transplanted with adult kidneys. We retrospectively analyzed the first rejection episode (biopsy proven) in 22 children (R group) under age 4 years [mean age, 23.7 +/- 2.2 months (+/- SEM); mean weight, 9.4 +/- 0.4 kg] receiving an adult-related donor kidney. We matched these patients for age, date of transplant, donor source and immunosuppression with 36 children without R (control or C group). We compared both groups at similar intervals from transplantation, based on the time of R (5.38 +/- 1.2 months) in the R group and analyzed the immediate 8-week period prior to R and the corresponding interval in the C group. Hypertension occurred in 82% (18/22) of the R versus 8% (3/36) of the C group (P less than 0.01). Fever longer than 7 days occurred in 45% (10/22) of the R versus 0% (0/36) of the C group (P less than 0.01). Increased creatinine occurred in only 45% (10/22) of the R versus 3% (1/30) of the C group (P less than 0.01). Cyclosporine did not influence these manifestations of R. The clinical manifestations did not predict the R grades on biopsy, which were moderate to severe in 13 and mild in 9 of the R patients. Graft survival was higher at 3 years in the C (95%) than in the R patients (65%), (P less than 0.004). Thus, clinical manifestations of acute R can be subtle in small children with adult renal allografts. Renal biopsy should not be delayed until the creatinine is elevated in these patients.

Duplex Doppler sonography recently has been used to evaluate renal transplants. Some authors have stated that high resistive indexes (RIs) occur in the presence of acute renal transplant rejection. RIs less than 0.7 are considered as probably excluding acute transplant rejection. We performed a prospective study of duplex sonographic examinations of pediatric patients (mean age, 8 years; 13 boys, two girls) with renal allografts and clinically suspected transplant disease. The results of 22 duplex studies were correlated with histopathologic data obtained between July 1987 and June 1988. RIs of the arcuate arteries in patients with acute rejection (n = 14) averaged 0.62 (range, 0.50-0.80). The RI in patients with chronic rejection (n = 1) was 0.59. RIs in patients with acute tubular necrosis (n = 3) averaged 0.66 (range, 0.59-0.72). RIs in patients with cyclosporine A toxicity (n = 4) averaged 0.66 (range, 0.58-0.79). Tubulointerstitial rejection was predominant, with only two patients showing minimal acute vascular rejection. Thirteen of 14 pediatric patients with histologically proved renal transplant rejection had a resistive index of less than 0.70. This study refutes the concept that resistive indexes of less than 0.7 exclude acute rejection.

Renal biopsies in 45 patients with insulin-dependent diabetes mellitus (IDDM) were examined by semiquantitative light microscopy and quantitative electron microscopic stereologic morphometry. In these 14 males and 31 females, aged 13-52 yr, who had had IDDM for 2.5-29 yr there was no strong relationship between either glomerular basement membrane (GBM) thickness or mesangial expansion and duration of IDDM. There was only a weak relationship between the thickness of the GBM and expansion of the mesangium. Thus, GBM thickening and mesangial expansion in IDDM occur at rates that often differ from one another and that vary greatly among patients. The clinical manifestations of diabetic nephropathy, albuminuria, hypertension, and decreased glomerular filtration rate related poorly or not at all to GBM thickening. In contrast, all light and electron microscopic measures of mesangial expansion were strongly related to the clinical manifestations of diabetic nephropathy, although in the absence of these clinical findings, it was not possible to predict the severity of any of the diabetic glomerular lesions. Mesangial expansion had strong inverse correlations with capillary filtering surface area density. It is hypothesized that mesangial expansion could lead to glomerular functional deterioration in IDDM by restricting the glomerular capillary vasculature and its filtering surface. However, capillary closure, glomerular sclerosis, and interstitial fibrosis could also contribute to the clinical manifestations of this disorder.