Delayed acute renal failure in post-transplant period in young children from unexplained etiology.

This report describes six young children (5 male) who developed delayed acute renal failure (DARF) in the early post-kidney-transplant (Tx) period in the absence of acute rejection (AR) or other diagnosable conditions. These young children, aged 16.5 +/- 3.1 (12-21) months [mean +/- SD, (range)] and weighing 8.5 +/- 1.7 (7.1-11.4) kg received a primary renal Tx (5 living-related donor, 1 cadaver) between 1984 and 1992. Immunosuppression included prednisone, azathioprine, and Minnesota antilymphocyte globulin (MALG, n = 5); one patient received cyclosporine and no MALG. Initially, all patients had good urine output (UO). They became systemically ill and abruptly developed diminished UO on post-operative day (POD) 6.5 +/- 1 (4-8). DARF was accompanied by fever (39.1-40.4 degrees C, n = 6), thrombocytopenia (platelets < 100,000/mm3, n = 6), leukocytosis, or leukopenia (white cell count > 20,000/mm3, n = 4 or < 1,000/mm3, n = 1). Four patients had diarrhea. Three had ascites and one was surgically explored for suspected urinary leak. None showed significant urinary obstruction by renal ultrasound. Renograms showed intact blood flow. Renal biopsy showed tubular ectasia (n = 6), vascular congestion (n = 5), focal glomerular endothelial swelling (n = 4), and capillary thrombi (n = 3). None showed AR. Five patients required dialysis for 11 +/- 4 (7-15) days. All patients survived. One patient, treated for suspected AR with the monoclonal antibody OKT3, developed shock and lost her graft on POD 12 due to vascular thrombosis. Renal functional recovery in the remaining five patients took 14 +/- 5 (6-20) days and their serum creatinine at discharge was 0.7 +/- 0.5 (0.3-1.6) mg/dl. We report DARF from undetermined etiology occurring in the first 2 weeks of renal Tx in young children. Treatment is supportive care including dialysis. Recognition of this complication will help avoid risky investigations or unnecessary treatment for rejection.

Does cytomegalovirus cause glomerular injury in renal allograft recipients?

The case of a 16-yr-old woman who received an ABO-incompatible renal allograft for end-stage renal disease due to membranoproliferative glomerulonephritis type I is presented. The patient's posttransplant course was complicated by cytomegalovirus (CMV) infection and the rare finding of glomerular CMV inclusions on renal biopsy. This article focuses on the pathology and pathogenesis of glomerular injury associated with CMV infection in renal allograft recipients and also reviews the epidemiology, clinical implications, diagnosis and management of CMV infection in these patients.

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).

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.

Respiratory syncytial virus infections in pediatric renal transplant recipients.

Immunocompromised patients are considered at increased risk from respiratory syncytial virus (RSV) infection. We examined the incidence and outcome of RSV infection in pediatric renal transplant (Tx) recipients on chronic immunosuppressive therapy. Of 173 recipients transplanted between November 1985 and April 1993, 5 (3%) developed RSV infection (age range 11-39 months). Initial immunosuppression included prednisone, azathioprine, cyclosporine, and polyclonal antibody therapy. Time from Tx to onset of RSV infection was 1 day to 7 months. Symptoms included rhinorrhea, cough, tachypnea, retractions, fever, wheezing, and abnormal chest X-ray. Treatment included bronchodilator therapy, bronchial drainage, ribavirin, and mist tent. Azathioprine was transiently withheld for leukopenia during treatment in 2 recipients. Three recipients developed biopsy-proven acute rejection during (n = 2) or immediately following (n = 1) RSV infection; all responded to corticosteroid treatment. RSV infection is not commonly diagnosed in pediatric renal Tx recipients. The course of RSV infection in our patients did not differ from that reported in normal children. The possible association between RSV and acute rejection warrants further observation. When diagnosed early, RSV infection does not appear to be associated with increased mortality in pediatric renal Tx recipients. Larger numbers of recipients need to be studied to confirm these results.

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.

Causes of kidney allograft loss in a large pediatric population at a single center.

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.

Pediatric renal transplantation at the University of Minnesota: the cyclosporine years.

Overall mortality was low (3.5%) in 199 children who received 217 transplants and quadruple immunosuppression. Graft survival was better in patients on quadruple immunosuppression, compared with historical patients on standard immunosuppression. When censored for deaths with a functioning graft, cumulative graft survival beyond one year was significantly better in patients on quadruple immunosuppression. Acute rejection was more common in CAD recipients and in retransplant recipients. Acute rejection was also more common in patients with FSGS, compared with other causes of ESRD. Preemptive transplants were not associated with a higher incidence of acute rejection. Late acute rejection episodes tended to be associated with a CsA dose < 5 mg/kg/day at one-year posttransplant. Chronic rejection was the major cause of graft loss. Risk factors for graft loss within the first posttransplant year were acute tubular necrosis and an initial CsA dose of < 5 mg/kg/day. Risk factors for graft loss after the first posttransplant year were late onset of the first acute rejection episode and a panel reactivity of > 25% at the time of transplant.

Should there be an expanded role for kidney biopsy in the management of patients with type I diabetes?

Diabetic nephropathy is the single most important cause of end-stage renal disease (ESRD) in the United States. Further, the increased risk of mortality from type I diabetes is almost entirely confined to patients developing clinical diabetic nephropathy. Nonetheless, kidney biopsy has had little role in the clinical assessment of diabetic patients or in the design of clinical research in diabetic nephropathy. The development of dipstick-positive proteinuria in patients with type I diabetes of more than 10 years' duration is regularly associated with advanced structural changes of diabetic nephropathology; in these patients, clinical parameters, especially the rate of decline of glomerular filtration rate (GFR), are accurate monitors of disease progression. Microalbuminuria indicates a very high risk of overt proteinuria and thus ESRD. This increased risk is associated with levels of urinary albumin excretion (UAE; greater than 30 micrograms/min [45 mg/24 h]), which are frequently accompanied by hypertension and reduced or decreasing GFR. At this stage, lesions of diabetic nephropathy are usually already well established. Thus, microalbuminuria is more a marker of early nephropathy than a predictor of later renal injury. Before these clinical stages of nephropathy, there are no accurate predictors of renal risk. Renal biopsy may serve this role by indicating those patients who are developing significant lesions during the "silent" phase of the disease. In large measure, this value of the biopsy derives from evidence that the lesions tend to develop linearly over time and can be measured by techniques that are relatively easily established in standard surgical pathology environments. Renal biopsies can serve to assure the majority of diabetic patients that they are developing serious lesions slowly, if at all.(ABSTRACT TRUNCATED AT 250 WORDS)

De novo hemolytic uremic syndrome following renal transplantation.

We report a case of complete recovery of renal function in a patient with de novo hemolytic uremic syndrome (HUS) following renal transplantation. This 3-year-old girl had none of the factors known to contribute to the development of HUS in transplant recipients. This case illustrates the usefulness of renal biopsy in the accurate diagnosis and management of dysfunction in the allograft following renal transplantation.

Glomerular lesions and urinary albumin excretion in type I diabetes without overt proteinuria.

Since several studies have suggested that a slight increase in urinary albumin excretion (microalbuminuria) is predictive of nephropathy in patients with diabetes mellitus, we studied the relation of albumin excretion to renal structure in patients with insulin-dependent (Type I) diabetes. Renal biopsy specimens were evaluated with light- and electron-microscopical morphometric techniques in 48 patients who had had diabetes for 5 to 40 years and who excreted less than 200 mg of urinary albumin per 24 hours. Patients in Group I (n = 26) had normal urinary albumin excretion, creatinine clearance, and blood pressure; those in Group II (n = 10) had increased urinary albumin excretion but normal creatinine clearance and blood pressure; those in Group III (n = 12) had increased urinary albumin excretion and hypertension, decreased creatinine clearance, or both. Glomerular structure varied similarly, ranging from normal to abnormal in Groups I and II, but was consistently abnormal in Group III. The thickness of the glomerular basement membrane, the fractional volume of the mesangium, and the mesangial volume per glomerulus in Group III exceeded the corresponding values in the other groups significantly. Thus, microalbuminuria, when present with hypertension, decreased creatinine clearance, or both, indicates established abnormalities of glomerular structure. Normal albumin excretion, or microalbuminuria without these other functional abnormalities, does not accurately predict the severity of the underlying glomerular lesions in patients with Type I diabetes.

Results of pediatric kidney transplantation at the University of Minnesota.

In all, 473 renal transplants were performed at the University of Minnesota in 386 children 1-17 years old between August 14, 1963 and December 31, 1988. Standard immunosuppressive protocols, pretransplant blood transfusions, and discontinuation of routine splenectomy have led to improving graft and patient survival rates. Children receiving living-related donor kidneys had better graft and patient survival rates, compared to cadaver kidneys. Graft and patient survival rates were better in children who received primary grafts, compared to retransplants. Children who received DST plus conventional immunosuppression had poorer graft survival, compared to quadruple immunosuppression during the same era. Recently, 1-year graft survival rates with quadruple immunosuppression are equal for children receiving primary, living-related donor or cadaver kidneys. Graft and patient survival rates in children 1-4 years old are identical to those in children 5-17 years old. Age no longer appears to be a risk factor for children undergoing kidney transplantation. Good patient and graft survival rates can be achieved at centers specializing in kidney transplantation for small children. Currently, transplantation is the treatment of choice for all children who are candidates for renal replacement therapy.

The outcome of 304 primary renal transplants in children (1968-1985).

Of 304 children who received primary renal transplants at the University of Minnesota between January 1, 1968, and December 31, 1985, 48 (16%) were under the age of 24 months, 60 (20%) were 2-5 years old, and 196 (64%) were 6-17 years old at transplantation. Currently, 254 (84%) are alive at 2 months to 18 years following their first transplants, 77% with functioning grafts (188 first, 45 retransplants) and 7% on dialysis. Overall, patient and graft survival were not significantly different from the primary graft outcome of nondiabetic adults. The actuarial primary graft function rates at 1, 5, and 10 years were 100, 100, and 90% in 16 HLA-identical sibling kidneys; 84, 64, and 52% in 210 mismatched related kidneys; and 72, 54, and 47% in 78 cadaver kidneys (p less than 0.002). The 1-year patient survival and primary graft function rates in 44 mismatched related recipients under the age of 24 months were 92 and 88%. The use of deliberate, pretransplant random blood transfusion since 1979 has been associated with a decreased rejection rate. Primary graft function of mismatched related kidneys in children receiving standard immunosuppression has significantly improved from 78% at 1 year in the pretransfusion era to 91% (p less than 0.01) in the transfusion era. The overall primary cadaver graft function rate, however, did not improve in the transfusion era. Whether cyclosporine use will improve the cadaver renal allograft function in very young recipients remains to be established. However, with the use of related donors, even very young children can be transplanted safely and with excellent results.

Urinary albumin excretion in renal transplant donors.

Twenty-four hour urinary albumin excretion was measured using sensitive methods in 129 renal transplant donors 1 to 22 years (mean 7.3 years) after kidney donation. The 24 hour urinary albumin excretion values for the donor group was 6 +/- 9.9 mg (mean +/- standard deviation) (range of 0.1 to 65.2 mg) and was 7.7 +/- 4.5 mg for the control group. Five donors (3.9 percent) had 24 hour urinary albumin excretion levels of 25.5 to 65.2 mg 6 to 13 years after donation, values that were greater than a single value from any member of the control group. Elevated diastolic blood pressure (90 mm Hg or greater) was present in these five donors, and in three, labile or established hypertension was present at the time of donation. It is likely that more careful screening of potential donors with labile or fixed hypertension would further reduce the incidence of microalbuminuria in the renal transplant donor. We conclude that urinary albumin excretion values are within the normal range in most renal transplant donors studied several years after renal donation.