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Despite mounting experimental evidence that cyclosporine inhibits pancreatic islet cell function, clinical data on posttransplant diabetes mellitus (PTDM) in renal allograft recipients in the cyclosporine era are scarce. Between June 1983 and December 1988, 39 of 337 (11.6%) cyclosporine-treated adult renal transplant recipient whose grafts survived longer than 1 year developed PTDM. Of these, 43.6% and 74.4% were diagnosed by 3 and 12 months posttransplant, respectively, and 51.3% were insulin-dependent. Incidence of PTDM was highest in blacks (19.8%) and Hispanics (21.3%) and in those with HLA-A 30 and Bw 42 antigens. Older recipients and those that received cadaveric kidneys were more likely to develop diabetes than those who received living related allografts (14% vs. 5.3%, P less than 0.05). The rate of PTDM appeared to be independent of the type of induction, immunosuppressant therapy, incidence of rejection, total steroid and cyclosporine dose, percentage of body weight gain in the first posttransplant year, and serum creatinine concentration. Actuarial 5-year, decaying from 100% at 1 year, patient and graft survival rates were 87% and 70%, respectively, in the PTDM group compared with 93% and 90%, respectively, in controls. Causes of graft failure among the diabetics included chronic rejection (6), patient death (3), noncompliance with immunosuppressants (2), and sepsis (1). The incidence of infectious complications was significantly higher in the PTDM group compared with the control group (53% vs. 16%, P less than 0.05), with all 5 deaths among the diabetics being sepsis-related.

In order to evaluate the impact of ciclosporin in patients with adult onset polycystic kidney disease (ADPKD) following renal transplantation, we performed a single-center study of all (n = 65) patients with this disorder since 1978, 43 of whom received CSA (PC-CSA) with the remaining 22 treated with azathioprine (PC-AZA). An additional group of 45 age- and time-matched group of non-polycystic CSA-treated patients (nonPC-CSA) were used as a separate control group. Patient and graft survivals at 1 and 5 years were similar in PC-CSA when compared to nonPC-CSA. The commonest causes of death in both groups were cardiovascular related. The incidence of posttransplant hypertension and acute rejection were also similar. Urinary tract infections (UTIs) were, however, more frequent among PC-CSA (11 and 33% pre- and posttransplant respectively) when compared to the nonPC-CSA (2 and 17% pre- and posttransplant respectively). The PC-CSA cohort showed improved 1-year patient and graft survivals when compared to PC-AZA (94 and 70% vs. 72 and 34%) with less rejection episodes (42 vs. 88%) during the first year posttransplant but a higher mean serum creatinine at the end of the first year (2.0 vs. 1.6 mg/dl, 176.6 vs. 141.3 mumol/l). Posttransplant hypertension (67 vs. 70%) and UTIs (33 vs. 33%) were, however, similar in both groups. In summary, renal transplantation in ADPKD in the CSA era is associated with equal patient and graft survivals when compared with nonpolycystic patients of comparable age, but superior results when compared with the earlier azathioprine era.

Seventy-two and 34 consecutive HLA-identical sibling renal transplant recipients were treated with azathioprine/prednisone (AZA; follow-up, 5.0 years) and cyclosporine/prednisone (CSA; mean follow-up, 2.9 years), respectively. Both groups were similar in age, sex, race, and number of transplants, but there were more diabetics in the CSA group (34% v 8%). Actual patient survival at 1 year and actuarial patient survival at 5 years were 100% and 96%, respectively in the CSA group compared with an actual patient survival of 91% and 82% at 1 and 5 years, respectively, in the AZA group. Actual graft survival at 1 year improved from 85% in the AZA group to 97% in the CSA-treated recipients (P less than 0.05). Mean serum creatinine at 5 years remained stable in the AZA group at a mean of 123 mumol/L (1.4 mg/dL) compared with a progressive increase in this parameter to a mean of 212 mumol/L (2.4 mg/dL) after the same time interval in the CSA patients. Furthermore, the slopes of the serum creatinine against time were significantly different between the two groups (P less than 0.01). Mean daily CSA dose averaged 4 mg/kg 12 months following transplantation, with a decrease to 2.4 mg/kg by the fifth year. Causes of death in the AZA group were cardiovascular (eight), sepsis (three), cancer (one); and in the CSA group, Kaposi's sarcoma (one). Causes of graft failure in the AZA group were immunological (six), sepsis (three), technical (two), recurrence of disease (one), and patient death with a functioning graft (five). Technical (one), noncompliance (two), recurrence of disease (one), and patient death with a functioning kidney (one) caused graft failure in the CSA group. No difference in posttransplantation serum cholesterol or incidence of new onset diabetes was observed between the two groups, but hypertension was significantly more frequent (51% v 21%, P less than 0.01) when CSA was used. In conclusion, intermediate-term results of CSA-treated HLA-identical transplant recipients showed improved patient and graft survival with less complications apart from hypertension. However, the slow, but relentless, increase in serum creatinine in the CSA-treated patients compared with those treated with AZA is of concern.

Despite increasing referrals for organ donation in metropolitan New York, procurement has remained essentially unchanged from 1983 through 1988 at 9 to 13 per million population, falling far short of increasing demand. This is not due to delay in the diagnosis of brain death, higher discard rates, or increased medical unsuitability, although exclusion because of human immunodeficiency virus (HIV) disease, or risk thereof, has increased and now accounts for 38% of exclusions. Consent for organ donation remains consistently low among blacks (24%), has increased among Hispanics from 17% in 1984 to 47% in 1988, and remains the highest, but without improvement, among whites. Causes for the observed stagnation and potential corrective factors include poorly focused educational efforts, lack of sensitivity to the grieving family by hospital personnel, physician frustration at the increasingly prominent role of government and its regulations in the practice of medicine, and eradication of competition between local organ procurement agencies.

We evaluated the ability of three enzymes--N-acetyl-beta-D-glucosaminidase (NAG; EC 3.2.1.30), alanine aminopeptidase (AAP; microsomal aminopeptidase, EC 3.4.11.2), and gamma-glutamyltransferase (GGT; EC 2.3.2.2)--and adenosine deaminase binding protein (ABP) in urine to predict or confirm renal-transplant rejection in patients treated with cyclosporine. We measured the enzymes daily during the early post-transplant hospital stay of 104 renal-transplant recipients (72 men and 32 women). We also measured ABP in 32 of these patients. We analyzed the data by calculating the activity ratio of each day's test value to the previous day's result and optimized the sensitivity (SN) and specificity (SP) to determine the optimal ratio for each test. The results indicate that cyclosporine treatment reduces the optimal sensitivity and specificity of these tests. Three comparable tests (ABP, GGT, and AAP) yield the best optimal values (SN = 0.77, 0.69, 0.77; and SP = 0.71, 0.74, 0.63, respectively), and the NAG test yields the lowest combination of sensitivity and specificity (SN = 0.62, SP = 0.66). All four tests were less sensitive and specific than the plasma creatinine test (optimal day-to-day difference = 5 mg/L). However, the ABP and AAP tests gave indications of rejection at least 24 h before clinical diagnosis for 50% of the patients experiencing rejection, while early plasma creatinine increases of 5 mg/L occurred in only 19% of this group.

In the dog kidney in vivo, malonate augmented ammoniagenesis from both amide and nonamide nitrogen sources, similar to previous in vitro investigations using incubating canine renal tubules. This was highly significant in alkalotic dogs, where it was accompanied by decreased renal tissue concentrations of glutamate. Changes in renal ammonia metabolism were less evident in acidotic dogs where a markedly decreased glomerular filtration rate was noted following malonate administration. Under conditions of complete ureteric obstruction which effectively abolished glomerular filtration, malonate significantly augmented ammoniagenesis above baseline in acidotic dogs. These in vivo results with malonate have similarities to those seen in dogs subjected to an acid challenge alone and suggest that the adaptation in renal ammoniagenesis under both circumstances occurs via enhanced deamination of glutamate pools.

Juvenile nephronophthisis has been recognized recently as an important cause of chronic renal failure in childhood and adolescence. This report describes clinical and morphological findings in monozygotic twins in whom the triad of juvenile nephronophthisis, congenital hepatic fibrosis and retinal hypoplasia coexisted. The findings are discussed in relation to previous reports of nephronophthisis associated with either retinal abnormalities or congenital hepatic fibrosis. The occurrence of similar ocular and hepatic anomalies with the other cystic kidney diseases, polycystic disease and medullary sponge kidney disease is reviewed. A spectrum of oculo-hepato-renal syndromes is identified with many interrelated features which suggest a shared basic aetiology.

Six interrelated abnormalities of Bartter's syndrome are analyzed-juxtaglomerular hyperplasia, angiotensin resistance, altered kallikrein-kinin system, hyperprostaglandinuria, hypokalemia, and chloride-losing nephropathy. Arguments are advanced that any one of these could be the proximate cause and result in all the others. By the same token, each abnormality could be a consequence of any of the others and, furthermore, modulate the others by negative or positive feedback. Despite many recent insights, available data do not permit a definitive conclusion as to the locus of the primary abnormality. Rather, the syndrome presents as a remarkable biological counterpart to an electronic integrated circuit. The altered physiology of Bartter's syndrome is reviewed and the pathogenesis of the syndrome analyzed in the light of recent literature.

Fifty-six MR studies were obtained in 32 renal transplant patients, by using T1-weighted, spin-echo, and inversion-recovery pulse sequences. The findings, particularly the loss of corticomedullary differentiation, and the extent of vascular penetration into the renal parenchyma, were compared with the clinical and histologic diagnosis of transplant rejection. Thirteen MR studies on 11 patients with clinically normal renal transplants demonstrated normal corticomedullary differentiation. Renal vessels extended into the parenchyma in all 11 patients and to the cortex in 38%. In 37 MR studies on 22 patients with a clinical or histologic diagnosis of acute and/or chronic transplant rejection, the corticomedullary differentiation was normal in 8%, faint in 24%, and absent in 68%. Renal parenchymal vessels were visualized in 32%, but extended to the level of the cortex in only 8%. In 68% of the studies with transplant rejection, no parenchymal vessels were seen. When the corticomedullary differentiation was either faint or absent, the vascular pattern was normal in 6%; in 68% of cases no parenchymal vessels could be identified. We conclude the corticomedullary differentiation and the renal vascular pattern are useful parameters in the evaluation of renal transplant rejection.

To evaluate the effect of aggressive intrapartum and early neonatal resuscitation on perinatal mortality, neonatal morbidity, and long-term outcome, we evaluated two groups of low-birth-weight infants who received different intrapartum and early neonatal care. One group of infants was delivered at a university-based regional perinatal center offering both high-risk obstetric and tertiary neonatal care. The second population consisted of infants from five community hospitals with level I nurseries. These two groups were selected because they differed in the ability to provide intrapartum and early neonatal care and because a total base population could be evaluated. During the 4-year study period, 174 infants with birth weights of 500 to 1499 gm were delivered at the university center and 297 infants were delivered at the community hospitals. At the university center, there was a significant reduction in fetal deaths, a delay in the time of neonatal deaths, and a reduction in hyaline membrane disease. Neonatal mortality rates at the university center were not reduced, and the incidence of sequelae was not affected. These data suggest that for the smallest infant, intrapartum and immediate neonatal care at a tertiary center may decrease fetal mortality and neonatal morbidity rates. Neonatal mortality and long-term outcome, however, may be less affected.

Renal hemodynamics and solute and water handling were evaluated in 19 sickle cell patients and 8 matched normal subjects during water diuresis, before and after acute oral administration of a nonsteroidal antiinflammatory drug (NSAID). Baseline GFR and RPF were higher in the patients compared to the normals. In contrast to normals, indomethacin and sulindac induced a 16% and 14% decrease in GFR, respectively. Indomethacin resulted in a slight increase in UOsm in normals, but a substantially greater rise in the patients. Following indomethacin a greater fall in FENa, fractional solute delivery to the diluting segment of the nephron [(CH2O + CNa + K)/GFR], fractional solute reabsorption in the diluting segment [CH2O/GFR] and the fraction of distally delivered solute reabsorbed [CH2O/(CH2O + CNa + K)] was observed in the sickle cell patients than in the normal subjects. A similar trend, but of significantly lesser magnitude than that induced by indomethacin, was observed following sulindac in the sickle cell patient. The data imply that the supranormal GFR observed in the sickle cell patients was prostaglandin-mediated. The effects of NSAID's on renal solute and water handling in the sickle cell patients are compatible with a prostaglandin-dependent decreased salt reabsorption in the medullary thick ascending limb of Henle, together with a hyperfunctioning proximal tubule. The data also imply an additional indomethacin-sensitive antinatriuretic effect in the diluting segment in these patients. Moreover, the results suggest that in sickle cell anemia sulindac may not have a "renal sparing" advantage over other NSAID's.

The mode of inheritance of Bartter syndrome is unclear; however, autosomal recessive inheritance seems likely. A consistent genetic marker of the carrier state likewise remains elusive. HLA typing was done in a family in whom six of 12 sibs have the syndrome. No significant HLA-syndrome linkage was found. This is in contrast to another familial hypokalemic syndrome in which a significant HLA association was found.

A 14-year-old female patient with metastatic carcinoid developed streptozocin-induced glomerular, proximal, and distal tubular dysfunction. The latter was in the form of nephrogenic diabetes insipidus, with urine volumes in excess of 11 L/24 h. The prostaglandin synthetase inhibitor, indomethacin, rapidly corrected the polyuria both initially and on rechallenge, independent of change in glomerular filtration rate.

Postnatal transfer of high-risk infants to a neonatal intensive care unit has been an accepted medical practice for more than two decades. More recently, antepartum maternal referral for the smallest infants has been recommended to reduce infant mortality, morbidity, and long-term handicaps. The limited data available to compare in utero and postnatal transfer suggest that maternal risk factors may also influence antenatal referral. We evaluated antepartum maternal and postnatal infant referrals from five metropolitan Denver hospitals with level I facilities. Mothers who were referred to the tertiary perinatal center before delivery were more likely to have one or more high-risk conditions. The presence of a maternal risk factor (preeclampsia, antepartum bleeding, prolonged rupture of the membranes, or chorioamnionitis) was significantly more common in the maternal transfer group (p less than 0.002). Neonatal weight was higher for the maternal referrals compared with neonatal referrals. Neonatal survival was independently improved by transport of mother or infant, increasing birth weight, and higher Apgar scores. We suggest that maternal risk factors were an important determinant in the choice of antenatal referral to our perinatal center for both the community and regional hospitals during this study period. Studies that compare outcome of infants after maternal and infant transfer must control for potentially inherent differences between the antenatally and postnatally transferred infants.

The possible role of gamma-glutamyltransferase (gamma-GT) in renal ammonia production from glutamine remains controversial, prompting the current investigation. In rat proximal tubules, compounds known to activate the enzyme including the endogenously produced organic anion, hippurate, induced a significant increase in glutamine-ammoniagenesis both in nonacidosis and chronic metabolic acidosis although in absolute terms the increase was not more marked under the latter conditions. AT-125, which irreversibly inactivates gamma-GT, but not phosphate-dependent glutaminase, reduced the production of ammonia from glutamine in both acid-base states. In absolute terms, again, this reduction was similar under both acid-base conditions, implying an unimportant role for gamma-GT in vitro in the augmentation in renal ammoniagenesis induced by chronic metabolic acidosis. Maleate-stimulated glutamine-ammoniagenesis recently attributed to its intramitochondrial inhibitory effect in the dog is substantially due to the activation of gamma-GT in rat proximal tubules.

A longitudinal study was conducted to determine whether the early neurologic and motor impairment observed in children with neonatal polycythemia and hyperviscosity persisted into school age. Forty-nine children who had neonatal polycythemia and hyperviscosity were evaluated at a mean age of 7 years. Of these, 21 (group 1) received a partial plasma exchange transfusion, whereas 28 (group 2) received symptomatic care. Forty control children (group 3) with a normal neonatal hematocrit were also evaluated. Testing consisted of a battery of measures to evaluate IQ, achievement, neuromotor function, and gross and fine motor skills. Maternal education and IQ were also assessed to avoid potential confounding by differences in the home environment. The neonatal course of the children with polycythemia and hyperviscosity was characterized by an increased number of problems, including hypoglycemia and cyanosis. At 7 years of age, the 49 children who had hyperviscosity (groups 1 and 2) had significantly lower "spelling" and arithmetic achievement test results and gross motor skill scores. Scores for reading, visual motor integration, and neurologic signs did not differ significantly from group 3. Maternal IQ scores were similar for both groups. Left-hand preference was seen in 14% of group 1 and 2 children and 7% of group 3 children (not significant). The scores for IQ, achievement, neuromotor function, and visual motor integration were compared for the hyperviscosity group (groups 1 and 2) and the control group (group 3) by multivariate analysis of variance with sex and hyperviscous group as independent variables and maternal education and maternal IQ as covariates (P = .040).(ABSTRACT TRUNCATED AT 250 WORDS)