Lessons learned from more than 1,000 pancreas transplants at a single institution.

OBJECTIVE: 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. SUMMARY BACKGROUND DATA: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Risk factors for chronic rejection in pediatric renal transplant recipients--a single-center experience.

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 time > 24 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 (P < 0.0001, odds ratio 19.4), multiple ARE (> 1 vs. 1) (P < 0.0001, odds ratio 30.1), and high percentage peak PRA (> 50%) (P < 0.03, odds ratio 3.6).

Altered kidney matrix gene expression in early stages of experimental diabetes.

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: p < 0.05). 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.

Outcome of chickenpox in 66 pediatric renal transplant recipients.

Although chickenpox can cause severe morbidity and mortality in pediatric renal transplant recipients, published reports describing treatment of these patients are few, especially in the cyclosporine era. Sixty-nine episodes of chickenpox occurring in 66 patients were diagnosed in our transplant population between January 1984 and May 1996. Immunosuppression consisted of prednisone and azathioprine (30 cases); prednisone, azathioprine, and cyclosporine (38 cases); or prednisone alone (1 case). Azathioprine was temporarily discontinued in 66 of 68 cases. Cyclosporine was continued at the preexisting dose in 36 of 38 cases. Acyclovir was administered parenterally in 62 of 69 cases. Sixty-five of 66 patients survived. Cyclosporine use did not increase the incidence of severe disease (p > 0.1). Acute allograft rejection occurred in three patients and responded to prednisone. Chickenpox in children with renal transplants can be successfully treated with intravenous acyclovir and temporary withdrawal of azathioprine. Allograft rejection is uncommon with this approach. Patients receiving cyclosporine do not appear to experience increased morbidity or mortality with chickenpox.

The importance of early cyclosporine levels in pediatric kidney transplantation.

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 (p < 0.05). Recipients with CSA trough levels < 100 ng/ml had 2.24 times the risk of rejections vs. those with blood levels > 100 ng/ml. Similarly, the CSA trough level at 1 month was the critical risk factor for biopsy-proven rejection within the first 6 months (p < 0.05). 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 levels < 100 ng/ml are associated with a significantly increased incidence of rejection in the first 6 months post-transplant.

Impact of age on renal graft survival in children after the first rejection episode.

Infants are thought to be more immunoreactive and at a greater risk for developing irreversible rejection compared with older children. We investigated this by analyzing patient and graft survival rates, incidence of acute rejection, reversibility of acute rejection, development of a subsequent acute rejection, and incidence of graft loss due to rejection in 154 children (< 18 years of age) after primary renal transplantation. Most patients (n = 139) were treated with quadruple immunosuppression (antibody, azathioprine, prednisone, cyclosporine). Treatment of the first acute rejection episode (ARE) consisted of antibody and increased prednisone (68%) or increased prednisone alone (30%), and was not significantly different between the age groups. Transplants were from living donors (LRD) in 80% of cases. Patients were followed for at least 1 year (mean 58 +/- 30 months); 68% (105/154) of recipients experienced 1 or more ARE. The incidence of ARE was significantly lower in patients < 2 years of age (45%) compared with patients 2-5 (76%, P = 0.01), 6-12 (78%, P = 0.005), and 13-17 (76%, P = 0.009) years of age. There was no significant difference in the 1-, 2- and 5-year patient or graft survival rates, the development of a subsequent acute rejection, or the incidence of graft loss due to acute rejection when analyzed by age group. These data suggest that the impact of an ARE is similar for younger and older children in our population receiving predominantly LRD transplants and quadruple immuno-suppression.

Recipient evaluation, preparation, and care in pediatric transplantation: the University of Minnesota protocols.

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.

Chronic renal allograft rejection in the first 6 months posttransplant.

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.

Recurrent hemolytic uremic syndrome in an adult renal allograft recipient: current concepts and management.

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.

Altered expression of matrix metalloproteinase-2, TIMP, and TIMP-2 in obstructive nephropathy.

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.

Structural-functional relationships in Alport syndrome.

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.

Differential distribution of type IV collagen chains in patients with diabetic nephropathy in non-insulin-dependent diabetes mellitus.

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.

Effect of glycemic control on early diabetic renal lesions. A 5-year randomized controlled clinical trial of insulin-dependent diabetic kidney transplant recipients.

OBJECTIVE: To determine whether optimized glycemic control in type I diabetic recipients of renal allografts will prevent or delay diabetic renal lesions in the allograft. DESIGN: 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. SETTING: University of Minnesota Hospital and Clinic and the Clinical Research Center and Hennepin County Medical Center, Minneapolis. PATIENTS: Type I diabetics with terminal diabetic renal failure undergoing renal transplantation. Forty-eight patients randomized to maximized or standard control completed the trial. INTERVENTION: 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; P < 0.001). MAIN OUTCOME: The primary end point of this trial was the difference between the groups in renal glomerular mesangial expansion as determined by electron microscopy. RESULTS: 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). CONCLUSIONS: 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.

Estimating glomerular number in situ using magnetic resonance imaging and biopsy.

In the past researchers have used an estimate of one million as the number of glomeruli in each human kidney. However, recent work on excised kidneys has demonstrated a large variation in glomerular number from one person to another (330,000 to 1,400,000) per kidney. Theoretically an in situ estimate of glomerular number could be obtained if renal cortical volume, volume density of glomeruli per cortex [Vv(glom/cortex)] and mean glomerular volume are known. We used a dog model to demonstrate that an accurate estimate of cortical volume could be obtained in situ using magnetic resonance imaging (MRI). Vv(glom/cortex) and mean glomerular volume were obtained from needle biopsies. An independent and more direct method (the fractionator) was used to validate the estimate of glomerular number obtained using MRI and renal biopsy. On average there was very good agreement between the fractionator method (379,000 +/- 40,000) and the MRI/renal biopsy method (376,000 +/- 108,000) for the 10 dog kidneys measured; however we found up to a 36% difference between the two methods in an individual kidney. Nonetheless, the estimate from the MRI/renal biopsy method has more precision than the assumption that there are one million glomeruli per human kidney.

Application of electron microscopic immunocytochemistry to the human kidney: distribution of type IV and type VI collagen in normal human kidney.

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.

Recurrence of steroid-resistant nephrotic syndrome in kidney transplants is associated with increased acute renal failure and acute rejection.

We performed 73 kidney transplants in 51 patients with steroid-resistant nephrotic syndrome (SRNS) with focal segmental glomerular sclerosis (FSG) ages 18.4 +/- 12.8 (mean +/- SD) years. Recurrence of SRNS, defined by rapid onset of proteinuria, hypoalbuminemia and/or > 95% epithelial cell foot process effacement with or without the presence of FSG, occurred in 26 grafts in 16 patients. Acute renal failure (ARF) occurred in 16 of 26 (61.5%) grafts with recurrence versus 7 of 47 (14.9%) grafts without recurrence (P < 0.0001). ARF occurred in 4 of 9 (44.4%) living-related donor (LRD) recipients with recurrence and 3 of 21 (12.5%) LRD recipients without recurrence (NS). ARF in cadaver donor (CAD) recipients with recurrence was 12 of 17 (70.5%) versus 4 of 23 (17.4%) without recurrence (P < 0.0001). ARF was also higher in LRD or CAD with recurrence than in a control group of non-SRNS patients matched for age, sex and time of transplantation. Graft survival at one year was lower in patients with recurrence and ARF [4 of 16 (25%)] compared to patients with recurrence and no ARF [9 of 11 (82%), P < 0.01]. There was no difference in graft survival in patients without recurrence who did or did not have ARF. One or more acute rejection episodes occurred in all 16 patients with ARF and recurrence, in all 7 patients with ARF without recurrence, and in 7 of 10 patients with recurrence without ARF compared with only 11 of 40 (28%) of patients with neither recurrence nor ARF (P < 0.0001, < 0.001 and < 0.04, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Outcome of dialysis for acute renal failure in pediatric bone marrow transplant patients.

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 of > or = 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.

The effects of normalization of dietary protein intake and carotid artery ligation on the renal autoregulatory abnormalities of streptozotocin diabetic rats.

We studied renal autoregulation in nondiabetic and streptozotocin diabetic Münich-Wistar rats 6 weeks after diabetes induction. We had previously shown that diabetic rats had greater preservation of renal blood flow (RBF) at reduced renal perfusion pressures (RPP) than control rats and speculated that this could be due to higher protein intake in the diabetic rats. Because of hyperphagia, the diabetic rats in the present study on a 24% protein diet (D-24) had 70% or greater increase in dietary protein intake compared to controls on the same diet (C-24). Diabetic rats on a 14% protein diet (D-14) had a dietary protein intake similar to C-24 and less than that of D-24 animals. Baseline glomerular filtration rate (GFR) and renal blood flow were lower and renal vascular resistance (RVR) was higher in the D-14 compared to the C-24 or D-24 rats. Nonetheless, at markedly reduced RPP both diabetic groups had better sustained RBFs and lower RVRs than the controls. Thus, increased dietary protein intake cannot explain the autoregulatory abnormalities in diabetes. Bilateral carotid artery ligation increased systemic blood pressure similarly in the C-24, D-24, and D-14 rats. All three groups responded with increased RVR to carotid artery ligation. Following carotid artery ligation, differences were no longer seen between diabetic and control rats for RBF at reduced RPPs. These studies indicate that diabetic rats are capable of generating increased RVR, ruling out impaired vascular constrictive capacity as an explanation of these hemodynamic abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship between retinal and glomerular lesions in IDDM patients.

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.