Donor kidney volume and outcomes following live donor kidney transplantation.

Pre-donation kidney volume and function may be crucial factors in determining graft outcomes in kidney transplant recipients. We measured living donor kidney volumes by 3D helical computed tomography scanning and glomerular filtration rate (GFR) by (125)I-iothalamate clearances in 119 donors, and correlated these values with graft function and incidence of acute rejection at 2 years post-transplantation. Kidney volume strongly correlated with GFR (Pearson r= 0.71, p < 0.001). Body size and male gender were independent correlates of larger kidney volumes, and body size and age were predictors of kidney function. The effects of transplanted kidney volume on graft outcome were studied in 104 donor-recipient pairs. A transplanted kidney volume greater than 120 cc/1.73 m(2) was independently associated with better estimated GFR at 2 years post-transplant when compared to recipients of lower transplanted kidney volumes (64 +/- 19 vs. 48 +/- 14 mL/min/1.73 m(2), p < 0.001). Moreover, recipients of lower volumes had a higher incidence of acute cellular rejection (16% vs. 3.7%, p = 0.046). In conclusion, kidney volume strongly correlates with function in living kidney donors and is an independent determinant of post-transplant graft outcome. The findings suggest that (1) transplantation of larger kidneys confers an outcome advantage and (2) larger kidneys should be preferred when selecting from otherwise similar living donors.

Assessing glomerular filtration rate by estimation equations in kidney transplant recipients.

Surveillance of glomerular filtration rate (GFR) is crucial in the management of kidney transplant recipients. With special emphasis on serum creatinine (SCr) calibration assay, we assessed the performance of estimation equations as compared to iothalamate GFR (iGFR) in 209 patients using the modification of diet in renal disease (MDRD), Nankivell and Cockcroft-Gault methods. Fifty-five percent of patients were treated with a calcineurin inhibitor (CNI) and all were taken trimethroprim-sulfametoxazole at the time of SCr measurement. The mean iGFR was 44 +/- 26 mL/min/1.73 m2. The MDRD equation showed a median difference of 0.9 mL/min/1.73 m2 with 53% of estimated GFR within 20% of iGFR. Median differences were 7.5 and 7.0 mL/min/1.73 m2 for Nankivell and Cockcroft-Gault formulas, respectively. The accuracy of the Nankivell and Cockcroft-Gault formulas was such that only 38% and 37% of estimations, respectively, fell within 20% of iGFR. The performance of all equations was not uniform throughout the whole range of GFR, with some deterioration at the extremes of GFR levels. In addition, good performance of the MDRD equation was seen in subjects taking CNI. In conclusion, the overall performance of the MDRD equation was superior to the Nankivell and Cockcroft-Gault formulas in renal transplant recipients including subjects treated with CNI.

Pancreas transplantation in type 1 diabetes: hope vs reality.

Pancreas transplantation can improve quality of life for patients with type 1 diabetes by eliminating hypoglycemic and hyperglycemic episodes, the need for insulin injections, frequent self-monitoring of blood glucose levels, and dietary restrictions. Increasing evidence suggests that it may slow the progression of long-term diabetic complications. On the other hand, patients risk the adverse effects of lifelong immunosuppression.

Prevalence and determinants of hyperhomocysteinemia in hemodialysis and peritoneal dialysis.

BACKGROUND: Hyperhomocysteinemia is an independent risk factor for atherosclerotic complications in patients with end-stage renal disease, although the mechanisms remain unclear. The major determinants of plasma homocysteine concentration are usually folate, vitamin B12, pyridoxal 5'-phosphate (vitamin B6), and glomerular filtration rate. METHODS: We measured factors, including plasma folate, vitamin B12, vitamin B6, creatinine, as well as the dose and duration of dialysis, that might affect plasma homocysteine concentrations in 130 patients on hemodialysis (HD) and compared these observations with those in 46 patients on peritoneal dialysis (PD). Independent determinants of total homocysteine were identified using a multiple logistical regression analysis. RESULTS: Total homocysteine values averaged 29.8 mumol/liter in HD patients, significantly higher than the mean value of 19.9 mumol/liter observed in patients on PD (P < 0.001). The prevalence of hyperhomocysteinemia was 90.8% among HD patients, significantly higher than the prevalence of 67.4% among PD patients. Folate values in HD patients averaged 45.5 nmol/liter and were significantly lower than in PD patients (104.2 nmol/liter, P < 0.001). For patients on HD, the only determinant of total homocysteine concentration was plasma folate (r = -0.31, P < 0.001). In contrast, for PD patients, total homocysteine did not correlate with plasma folate, vitamin B12, or vitamin B6. CONCLUSIONS: Hyperhomocysteinemia is more prevalent and intense in HD patients compared with those on PD. The homocysteine response may become refractory to excess folate supplementation in PD patients.

Prospective study of hyperhomocysteinemia as an adverse cardiovascular risk factor in end-stage renal disease.

BACKGROUND: Retrospective and case-control studies show that hyperhomocysteinemia is an independent risk factor for atherosclerosis in patients with end-stage renal disease. We studied prospectively the association between total homocysteine and cardiovascular outcomes. METHODS AND RESULTS: In all, 167 patients (93 men, 74 women; mean age, 56.3+/-14.7 years) were followed for a mean duration of 17.4+/-6.4 months. Cardiovascular events and causes of mortality were related to total homocysteine values and other cardiovascular risk factors. Cox regression analysis was used to identify the independent predictors for cardiovascular events and mortality. Fifty-five patients (33%) developed cardiovascular events and 31 (19%) died, 12 (8%) of cardiovascular causes. Total plasma homocysteine values ranged between 7.9 and 315.0 micromol/L. Levels were higher in patients who had cardiovascular events or died of cardiovascular causes (43.0+/-48.6 versus 26.9+/-14.9 micromol/L, P=.02). The relative risk (RR) for cardiovascular events, including death, increased 1% per micromol/L increase in total homocysteine concentration (RR, 1.01; CI, 1.00 to 1.01; P=.01). CONCLUSIONS: These prospective observations confirm that hyperhomocysteinemia is an independent risk factor for cardiovascular morbidity and mortality in end-stage renal disease, with an increased RR of 1% per micromol/L increase in total homocysteine concentration. Interventional studies are needed to evaluate the possible effects of modifying this risk factor in these patients.

Hyperhomocysteinemia: detection, risk assessment, and treatment.

Homocysteine is formed by the demethylation of methionine in the course of its normal metabolism. Hyperhomocysteinemia is an independent risk factor for vascular disease. It develops most commonly from folate deficiency, genetic abnormalities, and chronic renal failure. Current models favor direct angiotoxicity involving endothelial and vascular smooth muscle cells, and impaired thrombolysis. Folic acid reduces hyperhomocysteinemia and thus provides an opportunity for risk-factor modification.

Homocysteinemia and vascular disease in end-stage renal disease.

Homocysteine is an intermediate amino acid formed during the metabolism of methionine, a sulfur-containing essential amino acid, and cleared by the kidneys. The two major acquired causes of increased homocysteine values are chronic renal failure and absolute or relative deficiencies of folate, vitamin B12 or vitamin B6, three vitamins involved in the normal metabolism of methionine. We studied 176 patients (97 men and 79 women with mean age 56.3 +/- 14.8 years) with end-stage renal disease on peritoneal or hemodialysis. Homocysteine concentrations averaged 26.6 +/- 1.5 mumol/liter in patients with renal failure as compared to 10.1 +/- 1.7 mumol/liter in normals. Abnormal values exceeded the 95th percentile for normal controls in 149 patients, giving an overall prevalence of homocysteinemia of 85%. There was preservation of the negative correlation between homocysteine and folate (r = -0.48), suggesting responsiveness in spite of impairment. Increased homocysteine concentrations were associated with an increased odds ration for atherosclerotic and thrombotic complications independent of other traditional risk factors and the length of time on dialysis. The odds ratio for vascular events with homocysteine levels was 2.9 (CI 1.4 to 5.8) for the upper two quintiles of homocysteine values compared to the lower three quintiles adjusted for age, gender, hypertension, diabetes, hypercholesterolemia, smoking and time on dialysis. These data indicate that plasma homocysteine values represent an independent risk factor for vascular events in patients on peritoneal and hemodialysis. The mechanism by which high homocysteine concentrations might cause vascular damage in patients with renal failure remains unclear.

Dietary protein restriction, blood pressure control, and the progression of polycystic kidney disease. Modification of Diet in Renal Disease Study Group.

In the Modification of Diet in Renal Disease Study, a follow-up (mean, 2.2 yr) of 200 study participants with autosomal dominant polycystic kidney disease (ADPKD) was conducted to determine the effect of lowering protein intake and blood pressure on the rate of decline in GFR. The rate of decline was faster in participants with ADPKD than in persons with other diagnoses, reflecting, in part, faster disease progression in the ADPKD group. Baseline characteristics that predicted a faster rate of decline in GFR in persons with ADPKD were greater serum creatinine (independent of GFR), greater urinary protein excretion, higher mean arterial pressure (MAP), and younger age. In patients with initial GFR values between 25 and 55 mL/min per 1.73 m2, neither assignment to a low-protein diet group nor assignment to a low blood pressure group significantly reduced the rate of decline of GFR in ADPKD participants. Similarly, the decline in GFR was not related to achieved protein intake or MAP. In participants with GFR values between 13 and 24 mL/min per 1.73 m2, assignment to the low MAP group led to a somewhat more rapid decline in GFR. However, the more rapid decline in GFR did not appear to be due to a detrimental effect of low blood pressure or the antihypertensive agents used to reach the low blood pressure goal. Lower protein intake, but not prescription of the keto acid-amino acid supplement, was marginally associated with a slower progression of renal disease.

Changing demographics in renal transplant recipients: the 30 year Cleveland Clinic experience.

While it does appear that the most recent era of transplantation has not resulted in significant improvement in long-term allograft function, this appears to be due, at least in part, to the transplantation of increasing numbers of high-risk patients. It is noted that the improved results accomplished over prior eras of transplantation have been maintained despite the inclusion of these high-risk patients. Patients currently undergoing transplantation are more likely to be older, diabetic, obese or African American. All of these subgroups have poorer patient survival in the most recent transplant era and thus, death with a functioning graft has become a significant contributor to graft loss. Recipients were more likely to receive kidneys from cadaveric donors in the most recent era and within the live-donor groups, sibling donation has decreased. Hopefully, the recent trend of increased live-donor transplants (especially living, unrelated transplants) will continue. Cadaveric recipients were at higher risk for posttransplant ATN which, for the first time in the current era, had a significant adverse impact on graft survival. Long-term survival appeared to be associated with particular characteristics (optimal age at transplantation, optimal donor age, live donor, etc.), and can be achieved despite known risk factors, such as rejection or delayed graft function.

Performance of four computer-based diagnostic systems.

BACKGROUND: Computer-based diagnostic systems are available commercially, but there has been limited evaluation of their performance. We assessed the diagnostic capabilities of four internal medicine diagnostic systems: Dxplain, Iliad, Meditel, and QMR. METHODS: Ten expert clinicians created a set of 105 diagnostically challenging clinical case summaries involving actual patients. Clinical data were entered into each program with the vocabulary provided by the program's developer. Each of the systems produced a ranked list of possible diagnoses for each patient, as did the group of experts. We calculated scores on several performance measures for each computer program. RESULTS: No single computer program scored better than the others on all performance measures. Among all cases and all programs, the proportion of correct diagnoses ranged from 0.52 to 0.71, and the mean proportion of relevant diagnoses ranged from 0.19 to 0.37. On average, less than half the diagnoses on the experts' original list of reasonable diagnoses were suggested by any of the programs. However, each program suggested an average of approximately two additional diagnoses per case that the experts found relevant but had not originally considered. CONCLUSIONS: The results provide a profile of the strengths and limitations of these computer programs. The programs should be used by physicians who can identify and use the relevant information and ignore the irrelevant information that can be produced.

Racial differences in the incidence and progression of renal diseases.

There is an excess incidence of ESRD treatment among non-White North Americans that is not completely explained by the racial prevalences of the underlying diseases, including hypertension, which can potentially cause renal disease. The racial difference is particularly striking for presumed nephrosclerosis from hypertension and for nephropathy from Type II diabetes, but is not yet substantiated for ESRD attributed to polycystic kidney disease or Type I diabetes. The existing data are insufficient to support the notion that poorer blood pressure control alone is responsible for the racial differences in incident ESRD. Black race (and possibly Mexican or Native American heritage) may be a specific risk factor for ESRD, independent of hypertension and its treatment.

5-HT1A and histamine H1 receptors in HeLa cells stimulate phosphoinositide hydrolysis and phosphate uptake via distinct G protein pools.

Regulation of phosphate uptake was studied in a HeLa cell line after transfection with DNA encoding the human 5-HT1A receptor. In these cells, 5-HT stimulates sodium-dependent phosphate uptake via protein kinase C activation. Endogenous histamine H1 receptors (739 +/- 20 fmol/mg protein) were identified with [3H]pyrilamine. Histamine (i) stimulated phosphoinositide hydrolysis (EC50 = 8.6 +/- 4.1 microM), (ii) activated protein kinase C (2.4-fold increase in activity), and (iii) increased phosphate uptake (EC50 = 3.2 +/- 1.8 microM) by increasing maximal transport (Vmax(basal) = 6.2 +/- 0.3 versus Vmax(histamine) = 9.1 +/- 0.4) without changing the affinity of the transport process for phosphate. Prolonged treatment with 16 microM phorbol 12-myristate 13-acetate completely blocked protein kinase C activation and markedly attenuated the stimulation of phosphate uptake induced by histamine, establishing that 5-HT and histamine stimulate phosphate uptake through the common pathway of protein kinase C activation. The linkages of the histamine H1 and 5-HT1A receptors to G protein pools were assessed in two ways. (i) The stimulation of phosphoinositide hydrolysis, protein kinase C activity, and phosphate uptake associated with histamine were insensitive to pertussis toxin, whereas those associated with 5-HT were very sensitive to pertussis toxin. (ii) The stimulation of phosphoinositide hydrolysis, protein kinase C activity, and phosphate uptake induced by histamine and 5-HT were additive. These findings suggest that distinct receptor types can stimulate phosphoinositide hydrolysis, protein kinase C, and phosphate uptake in an additive fashion through distinct pools of G proteins in a single cell type.

Short-term regulation of Na+/K+ adenosine triphosphatase by recombinant human serotonin 5-HT1A receptor expressed in HeLa cells.

Agonist occupancy of the cloned human serotonin (5-HT)1A receptor expressed in HeLa cells stimulates Na+/K+ ATPase activity as assessed by rubidium uptake. The purpose of the study was to determine which of the receptor-associated signaling mechanisms was responsible for this effect. 5-HT stimulated Na+/K+ ATPase 38% at 2 mM extracellular potassium, an effect characterized by a decrease in apparent K0.5 from 2.8 +/- 0.3 to 1.8 +/- 0.3 mM potassium without a significant change in apparent Vmax. The EC50 for the transport effect was approximately 3 microM 5-HT. The response was pertussis toxin-sensitive but did not involve inhibition of adenylate cyclase, as stimulation of Na+/K+ ATPase by 5-HT was observed in the presence of excess dibutyryl cAMP. Protein kinase C was not required for the response since short-term incubation with the phorbol esters phorbol 12 myristate, 13 acetate (PMA) and phorbol 12,13-dibutyrate (PDBu) did not mimic the 5-HT effect. Moreover, 5-HT increased Na+/K+ ATPase activity after inactivation of protein kinase C by overnight incubation with PMA. 5-HT and the sesquiterpene lactone thapsigargin increased cytosolic calcium in this cell model, and the EC50 for 5-HT corresponded with that for stimulation of Na+/K+ ATPase. Both thapsigargin and A23187, a calcium ionophore, also increased Na+/K+ ATPase activity in a dose-responsive fashion. The response to 5-HT, thapsigargin, and A23187 was blocked by conditions that removed the cytosolic calcium response. By two-dimensional gel electrophoresis, we established evidence for a calcium-sensitive but protein kinase C-independent signaling pathway. We conclude that the 5-HT1A receptor, which we have previously shown to stimulate phosphate uptake via protein kinase C, stimulates Na+/K+ ATPase via a calcium-dependent mechanism. This provides evidence for regulation of two separate transport processes by a single receptor subtype via different signaling mechanisms.

Thapsigargin demonstrates calcium-dependent regulation of phosphate uptake in HeLa cells.

We used thapsigargin, a sesquiterpene lactone that mobilizes intracellular Ca without increases in inositol phosphates or major activation of protein kinase C (PKC), to test the specific effects of increasing cytosolic Ca on Na-dependent phosphate uptake in HeLa cells. Thapsigargin increased the Vmax for phosphate uptake from 5.40 +/- 0.26 to 7.86 +/- 0.43 nmol.mg protein-1.3 min-1 (n = 7, P less than 0.001) without change in the apparent Km for phosphate, which averaged 0.15 +/- 0.02 mM. The effect of thapsigargin was dependent on concentration and time. Inactivation of PKC by overnight exposure to 16 microM phorbol 12,13-dibutyrate did not eliminate the effect of thapsigargin, although it completely abolished the effects of phorbol ester on phosphate uptake. Thus thapsigargin are not dependent on PKC. As in other cell systems, thapsigargin increased cytosolic Ca concentration. Removal of extracellular Ca diminished the increase in cytosolic Ca and eliminated the effect of thapsigargin on phosphate uptake. Collectively, our data indicate that Na-dependent phosphate uptake in HeLa cells can be regulated by at least three specific signaling pathways: protein kinase A, PKC, and increased cytosolic Ca.