Blood pressure control in kidney transplantation: therapeutic implications.

Post-transplant hypertension remains a significant risk factor for graft loss, but whether or not specific blood pressure (BP) medications affect graft outcome is still unknown. We assessed the interaction between BP control and antihypertensive drugs on graft outcome. We retrospectively examined clinic BP data for 1662 renal transplant (RTx) patients, transplanted between 1994 and 2000 at our centre. The analysis examined all patients who received central alpha-agonists and peripheral alpha-antagonists, beta-blockers, calcium channel blockers (CCBs), angiotensin-converting enzyme (ACE) inhibition (ACEI), angiotensin receptor blockers (ARBs). BP recordings during treatment were categorized for each agent. Thus, a particular BP could be categorized for multiple medications. A total of 1462 patients (pts) (88%) were Caucasian and 800 pts (46%) received cadaveric RTx. There were 10.6+/-6.8 BP measurements for each patient post-RTx. CCBs, alone among the classes of antihypertensive drugs evaluated, reduced the risk for graft loss (RR: 0.736; P=0.035) in the overall analysis. Interestingly, stratifying levels of BP control unmasked a beneficial effect on graft survival of ACEI/ARB therapy in individuals with higher levels of systolic (>152 mmHg) and diastolic blood pressure (>98 mmHg) treated with ACEI/ARBs compared to individuals treated with CCBs (P<0.01 for each). Thus, stabilizing BP is important post-RTx. CCBs are associated with improved rates of graft survival. Their role in a compromised RTx, however, deserves further study. ACEI/ARBs have clear benefits, improving graft survival in individuals with elevated systolic blood pressure and proteinuria. CCBs are not as efficacious in this setting.

Type 2 angiotensin II receptor expression in human renal allografts: an association with chronic allograft nephropathy.

AIMS: The renin-angiotensin system (RAS) has been implicated in renal fibrosis through activation of the type I angiotensin II (Ang II) receptor (AT1R). Whether the other predominant Ang II receptor, the type 2 Ang II receptor (AT2R), has a fibrotic or sparing role in adult human renal tissue is unknown. MATERIALS AND METHODS: We used the reverse-transcription polymerase chain reaction (RT-PCR) to assess intragraft AT2R mRNA expression in biopsy samples from 23 renal transplant recipients. Potential correlations between intragraft AT2R mRNA. matrix-modulating genes and histologic evidence of chronic rejection were assessed. RESULTS: AT2R mRNA was confirmed by sequence analysis of the RT-PCR product. AT2R mRNA expression directly correlated with angiotensinogen (Spearman correlation coefficient (r(s)) 0.72; p = 0.0011) mRNA expression, and interestingly, AT2R mRNA inversely correlated with inflammatory gene expression in the biopsy samples. However, AT2R mRNA directly correlated with transforming growth factor-beta (TGF-beta) (r(s) 0.59: p = 0.044), matrix metalloproteinase-1 (MMP-1) (r(s) 0.83; p = 0.001), tissue inhibitor of metalloproteinase-2 (TIMP-2) (r(s) 0.74; p = 0.001) and TIMP-3 (r(s) 0.80; p = 0.001) mRNA expression. Moreover, AT2R mRNA and protein expression was significantly greater in the patients with biopsy-proven chronic allograft nephropathy (n = 9; p = 0.045 vs. no chronic allograft nephropathy and donor biopsy samples for mRNA analyses). CONCLUSIONS: These data demonstrate that AT2R mRNA is expressed in adult human renal tissue in the setting of renal transplantation. Its apparent association with matrix-modulating genes raises the hypothesis that AT2R mRNA expression may be linked with extracellular matrix regulation in the setting of chronic allograft nephropathy.

Simultaneous pancreas-kidney transplantation reduces excess mortality in type 1 diabetic patients with end-stage renal disease.

BACKGROUND: Diabetic renal disease continues to be the most significant cause of end-stage renal disease (ESRD) in the United States. Renal transplantation improves diabetic ESRD patient survival; however, the diabetic state remains associated with poor patient survival. Simultaneous pancreas-kidney (SPK) transplantation can restore normoglycemia and thus may improve outcomes. METHODS: We assessed the impact of SPK on age-range-matched type 1 diabetic patients who underwent renal transplantation at a single center. The observed/expected life span and annual mortality rates (AMRs) were used as measures of survival. A Cox proportional hazards analysis was used to analyze the impact of potential variables on mortality in SPK recipients. RESULTS: SPK transplantation (N = 335) increased the observed/expected life span compared with diabetic cadaveric (DM-Cad, N = 147) and live-donor (DM-Live, N = 160) transplant recipients (P = 0.004) and significantly reduced the AMRs (SPK, 1. 5%; DM-Cad, 6.27%; DM-Live, 3.65%, P = 0.008, SPK vs. other DM). Moreover, the SPK observed/expected life span and AMR were not significantly different from that of age-range-matched nondiabetic transplant recipients (N = 492). The only variable that was significantly associated with patient survival was discharge serum creatinine (relative risk 1.16, P < or = 0.0154). CONCLUSION: These data demonstrate that SPK improves the ability for type 1 diabetic patients to live more of their expected life span. This suggests that glycemic control, even as a late intervention in a diabetic patient's lifetime, may beneficially affect survival.

Renin-angiotensin system gene expression in post-transplant hypertension predicts allograft function.

BACKGROUND: Registry analyses and single-center studies have demonstrated that hypertension significantly increases the risk for chronic graft loss. The graft itself may contribute to posttransplant hypertension, and intragraft vasoactive hormones therefore, may be dysregulated in posttransplant hypertension. METHODS: We used the reverse-transcription polymerase chain reaction to assess the intragraft regulation of renin-angiotensin system transcripts in biopsy samples from 42 stable renal transplant patients with posttransplant hypertension. We also examined mRNA expression of inducible nitric oxide synthase, transforming growth factor-beta (TGF-beta), select cytokines, and metalloproteinase transcripts in biopsy tissue. Polymerase chain reaction products were quantitated using high performance liquid chromatography and normalized to beta-actin mRNA expression. Serum creatinine, glomerular filtration rate or creatinine clearance and tubular atrophy on biopsy were concurrently assessed. RESULTS: Renin and select Thl cytokine mRNA expression correlated with blood pressure. Type 1 angiotensin II receptor mRNA expression significantly correlated with glomerular filtration rate or creatinine clearance (P = 0.034) and inversely correlated with Th1 cytokines, inducible nitric oxide synthase, and cyclooxygenase-1 mRNA expression (P< or =0.013 for each). Type 1 angiotensin II receptor mRNA also approached a significant inverse correlation with TGF-beta mRNA expression (P = 0.09). Conversely, angiotensin-converting enzyme mRNA expression directly correlated with Thl cytokine (P< or =0.008 for each) and TGF-beta mRNA expression (P = 0.006). Type 1 angiotensin II receptor mRNA expression also correlated with matrix metalloproteinase-1 promoter region, tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) and tissue inhibitor of matrix metalloproteinase-3 mRNA expression. Notably, matrix metalloproteinase-1 promoter region, tissue inhibitor of matrix metalloproteinase-2, and tissue inhibitor of matrix metalloproteinase-3 inversely correlated with TGF-beta mRNA expression (P< or =0.0027 for each). Type 1 angiotensin II receptor mRNA expression at biopsy directly correlated with glomerular filtration rate at 2 year's follow-up. However, angiotensin-converting enzyme mRNA expression at biopsy inversely correlated with glomerular filtration rate at 2 year's follow-up. CONCLUSIONS: These data suggest that allograft-level RAS gene expression may be predictive of future graft function in the setting of diastolic hypertension.

Using renal transplantation to evaluate a simple approach for predicting the impact of end-stage renal disease therapies on patient survival: observed/expected life span.

The effectiveness of therapy for a chronic disease can be assessed by evaluating the length of time that a patient survives after receiving treatment. We used a novel means for measuring the effectiveness of renal replacement therapy for patients with end-stage renal disease (ESRD): the ratio of observed life span divided by expected life span. This ratio incorporated observed life span for patients from the time of ESRD and expected life span based on state-specific life-table analyses. A total of 3,782 individuals with ESRD were analyzed (average follow-up, 14.2 +/- 4.9 years); 3, 192 patients in that group received a kidney transplant at some point during their course of ESRD. For each patient, we determined a curve of observed/expected life span. Separate patient groups were analyzed to determine the median population observed/expected life span or the percentage of patients who reached 0.5 observed/expected life span. Younger transplant recipients (<21 years) had a median observed/expected life span of 67%, significantly greater than the median observed/expected life span for those aged 21 to 40 years (49%; P = 0.01) and 41 to 60 years (47%; P = 0.01). Surprisingly, 57% of the patients aged older than 60 years reached their median observed/expected life span (P = 0.02 versus <21 years; P = not significant against all others). A Cox proportional hazards model identified era of immunosuppression (hazards ratio, 0.32) and atherosclerotic vascular disease-related ESRD (hazards ratio, 2.07) as significant variables influencing patient survival and observed/expected life span. This simple ratio is easy to use and may be a helpful tool for assessing the survival benefits of risk-factor modifications and therapeutic advances in transplantation and ESRD care.

The 10-year incidence of renal insufficiency in people with type 1 diabetes.

OBJECTIVE: To describe the 10-year decrease in estimated creatinine clearance and the incidence of renal insufficiency and end-stage renal disease in a cohort of people with type 1 diabetes. RESEARCH DESIGN AND METHODS: A population-based cohort of individuals with younger-onset diabetes (diagnosed at < 30 years old and taking insulin) participated in an examination during 1984-1986 (n = 891), a 6-year follow-up examination during 1990-1992 (n = 765), and a 10-year follow-up examination during 1995-1996 (n = 634). Serum creatinine and risk factors were measured during standardized protocols at each examination. Estimated adjusted creatinine clearance was computed by a modification of the Cockroft-Gault formula. A clinically meaningful change was defined as a decrease in the estimated annual creatinine clearance of > or = 3 ml.min-1.1.73 m-2.year-1. Renal insufficiency was defined by the development of a serum creatinine of 2.0 mg/dl or greater after the 1984-1986 examination. RESULTS: The 10-year estimated incidence of an annual decrease in the creatinine clearance of > or = 3 ml.min-1.1.73 m-2 for the cohort was 52.5%, and the cumulative 10-year incidence of renal insufficiency and end-stage renal failure was 14.4%. In univariate analyses, incidence of a decrease in the estimated creatinine clearance of > or = 3 ml.min-1.1.73 m-2.year-1 and the incidence of renal insufficiency were both related to higher glycosylated hemoglobin; higher diastolic blood pressure; the presence of microalbuminuria and gross proteinuria; more severe retinopathy; and a history of loss of tactile sensation or temperature sensitivity at baseline. In logistic regression analysis, after adjusting for the presence of microalbuminuria and gross proteinuria at baseline, higher glycosylated hemoglobin and higher diastolic blood pressure were associated with decreasing estimated creatinine clearance. In logistic regression analyses, after adjusting for the presence of microalbuminuria and gross proteinuria at baseline, the incidence of renal insufficiency was independently associated with age, glycosylated hemoglobin, hypertension, and serum HDL cholesterol. CONCLUSIONS: These data suggest that a public health approach aimed at controlling glycemia, blood pressure, and serum lipids might result in reducing the rate of decline in renal function and development of renal insufficiency in people with type 1 diabetes.

Rapid in vivo measurement of single-kidney extraction fraction and glomerular filtration rate with MR imaging.

PURPOSE: To compare the accuracy of a noninvasive magnetic resonance (MR) imaging method to rapidly determine single-kidney glomerular filtration rate (GFR) relative to findings with an accepted standard of reference. MATERIALS AND METHODS: Simultaneous inulin and MR imaging measurements of renal excretory function were performed in six small swine. Renal extraction fraction of gadopentetate dimeglumine was determined with T1 measurements of flowing blood in the renal vein and in a systemic vessel 10-300 minutes after administration. These data were correlated with standard inulin-derived measurements of single-kidney GFR obtained during the same intervals as the MR imaging measurements. Gradient-echo (GRE) and echo-planar imaging were investigated for in vivo measurement of extraction fraction. RESULTS: The MR imaging-derived measurements of extraction fraction and single-kidney GFR were not significantly different from the inulin-determined measures (P > .18). The MR imaging extraction fraction and single-kidney GFR measurements correlated with inulin-derived measurements of the same parameters (r = .74 to .89, P < .0007). CONCLUSION: T1 measurement methods with GRE and echo-planar imaging are acceptable techniques with which to measure renal excretory function in a rapid and noninvasive manner in this model. Rapid measurements of single-kidney GFR should enable studies of the response of renal hemodynamics to pharmaceutical manipulation.

Rapid measurement of Gd-DTPA extraction fraction in a dialysis system using echo-planar imaging.

Gd-DTPA (Magnevist, Berlex, Wayne, NJ) extraction fractions (EF) have been measured for three dialysis filter types using an echo-planar imaging (EPI) Look-Locker T1 measurement technique under conditions of fast and slow flow. The mean EF measured in Fresenius (Bad Homburg, Germany) F3, F6, and F8 dialysis filters were 0.015 +/- 0.005, 0.053 +/- 0.004, and 0.084 +/- 0.003, respectively, under conditions of fast flow which provided complete refreshment of spins in the intervals between read-out pulse samples of the T1 relaxation recovery. Data acquisition and post-processing techniques were developed to extend the accuracy of the LL technique to systems with slow flow which did not provide complete refreshment of spins between samples of the T1 recovery. A multi-shot EPI LL interleaved acquisition of relaxation recovery space (IRRS) provided T1 measurement accuracy comparable to the refreshed system, +/- 10, but at the expense of increased scan times (factor of 2 or 3). Discarding the first few non-equilibrium relaxation recovery samples from the T1 fit allowed accurate T1 estimation (+/- 10) with a single-shot EPI LL method under conditions of slow flow. These EPI LL EF measurement methods may provide useful techniques for evaluating renal function in vivo.

Measurement of Gd-DTPA dialysis clearance rates by using a look-locker imaging technique.

The exponential clearance rate constant, (kappa), and filtration fraction (FF) have been measured for dialysis of Gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) (Magnevist, Berlex, Wayne, NJ) solutions by using a Look-Locker imaging technique under conditions of flow. The measured values of kappa for the Baxter CA-50, CA-110, and CA-210 filters were 0.0037 +/- 0.0003, 0.0057 +/- 0.0017, and 0.0092 +/- 0.0018 min-1, respectively, for dialysis of 4.0 liters of aqueous Gd-DTPA solutions. The measured values of FF for the Baxter CA-110 and CA-210 filters were 0.060 +/- 0.013 and 0.089 +/- 0.015, respectively, for dialysis of aqueous Gd-DTPA at 350 ml/min. The kappa and FF measurements agree with values that use inversion recovery (IR) on static samples obtained by drawing aliquots of solution during the course of dialysis. This in vitro experiment suggests that accurate in vivo measurements of filtration fraction and glomerular filtration rate (GFR) may be possible.

Magnetic resonance angiography in progressive renal failure: a technology assessment.

The objective of this study was to assess the cost-effectiveness of magnetic resonance angiography (MRA) imaging for renal artery stenosis (RAS) in people with progressive renal failure (PRF). We created a simulation model to determine the incremental cost-effectiveness of MRA screening in PRF compared with the fallback strategy of not screening. Costs, probabilities, and utilities were estimated from the literature and from institutional data. A three-state Markov model was used to simulate the progression from PRF to end-stage renal disease and death. In our baseline analysis, assuming a sensitivity of 0.85 and a specificity of 0.8 of MRA for RAS, we obtained an incremental cost-effectiveness of MRA screening compared with no screening of $2,214 per quality-adjusted life year saved, which is less than many commonly performed procedures. Under our baseline assumptions, if the receiver-operating characteristic curve of MRA for RAS is better than the chance curve, then MRA screening would be cost-effective. The analysis was most sensitive to assumptions about renal function after correction of RAS and prevalence of RAS, although the results show that MRA remains cost-effective for reasonable ranges of these assumptions. The use of MRA in PRF would be a worthwhile investment of resources in comparison with many currently funded procedures. The expense and morbidity associated with end-stage renal disease make any reasonable way of delaying or preventing the disease worth examining in detail.

An NMR study of cellular phosphates and membrane transport in renal proximal tubules.

Technical limitations in the measurement of cellular phosphates have hindered studies of interrelationships between cellular Pi, its transport, and its metabolism in renal proximal tubule (PT) cells. We have developed a noninvasive 31P-nuclear magnetic resonance (NMR) probe-perifusion system to measure cellular Pi and have utilized this system to investigate relationships in canine PT cells between the membrane transport and the cellular content of Pi. With 1.2 mM Pi in the extracellular medium, the cellular Pi content of PT averaged 4.94 +/- 0.55 nmol/mg protein. Inhibition of Pi uptake by removal of extracellular Pi rapidly decreased all cellular phosphate compounds to values that were between 55 and 85% of control. Partial replacement of extracellular Pi (0.4 mM) increased cellular phosphates up to 84-100% of control values. Inhibition of Na(+)-K(+)-adenosinetriphosphatase uptake by the addition of ouabain failed to change either cellular Pi or organic phosphates. Reducing the basolateral membrane potential with the addition of barium chloride increased cellular Pi content by nearly 30%. Maximal contents of cellular Pi and ATP were achieved at 0.4 mM Pi in the presence of an inwardly directed Na+ gradient and at 0.8 mM Pi in its absence. These data indicate that cellular Pi content in canine PT is regulated by Na(+)-dependent and -independent transport mechanisms and by the membrane potential across the basolateral membrane. Lastly, cellular ATP content was found to be directly proportional to the cellular Pi content over a physiological range.

Kidney disease and hypertension in blacks.

Black Americans have relatively more hypertension and hypertensive renal disease than white Americans. The reasons for these differences are not clear and are under investigation. The genetic basis of hypertension may be different between blacks and whites. The response to systemic hypertension may also be different. Hypertensive black patients appear to develop renal arterial fibroplasia and renal insufficiency at an earlier age than white patients. Adequate control of blood pressure appears to be more effective in slowing the rate of decline in renal function among whites than among blacks. However, the available data are not sufficient. More information is needed to identify risk factors for the development of end-stage renal disease and to guide the management of hypertension in blacks.

Isolation and characterization of renal cortical membranes using an aqueous two-phase partition technique.

The aqueous two-phase partition technique is a simple, rapid and inexpensive method for the fractionation of membrane preparations. Aqueous two-phase partitioning separates according to surface properties such as charge and hydrophobicity, making it complementary to established centrifugation techniques, which separate on the basis of density. Although aqueous two-phase partitioning has been successfully applied to animal tissues, there are limited data on the functional properties of the isolated membranes. We have applied the aqueous two-phase partition technique to rat renal brush-border membrane vesicles and sheets. Our aim was to remove organelle contamination while maintaining the functional properties of the membranes. Evidence from marker enzyme analysis and electron microscopy supports the conclusion that renal brush-border membranes are fractionated separate from the mitochondria and endoplasmic reticulum. This separation procedure did not alter the Na(+)-dependent transport of brush-border membrane vesicles. Na(+)-D-glucose symporter and Na(+)-H+ antiporter activity in the fractionated preparation increased to the same extent as did the enrichment of enzyme markers for brush-border membranes.

Epidemiology and prevention of renal disease.

More than 40,000 new patients begin treatment for end-stage renal disease in the United States each year. The most frequent causes are diabetes and hypertension. The incidence rates for blacks and Native Americans are six- to sevenfold in excess of those for whites. Studies are seeking to determine the roles of atherosclerotic vascular disease, renal ischemia, and the amount of renal mass on the rate of progressive renal disease. Other studies seek to identify the factors that predict the development of nephropathy in patients with diabetes mellitus. Treatment of hypertension slows the rate of progressive renal disease by 40% to 50%. Meta-analysis of several European studies suggests that dietary protein restriction appears to delay the onset of end-stage renal disease.

Disruption of mitochondrial function by suramin measured by rhodamine 123 retention and oxygen consumption in intact DU145 prostate carcinoma cells.

Suramin, an antiparasitic drug, has shown antitumor activity in humans. This may occur in part through disruption of energy balance, which is believed to be part of its antiparasitic action. Suramin disrupts mitochondrial function in intact DU145 prostate carcinoma cell monolayers as seen by its causing the release of rhodamine 123 from prestained cells beginning at about 10 microM in 96-well microtiter plates measured with a fluorescent plate scanner. This effect was similar to the ionophore carbonyl cyanide m-chlorophenylhydrazone, dissolved in ethanol at 0.01 N and indicates that suramin acts as a respiratory poison or an ionophore. This effect was confirmed by studies of oxygen consumption with a Clark oxygen electrode and cellular ATP content which demonstrated uncoupling of oxidative phosphorylation by 100 microM suramin, a clinically achievable plasma drug level.

Factors affecting renal allograft function in long-term recipients.

The natural history of renal allograft function in long-term recipients is not known. To characterize renal allograft function and the factors that affect it, we reviewed the records of all patients who received a renal allograft at the University of Wisconsin between 1965 and 1981 and selected those who had annual data on renal function for at least 10 years. We identified 155 patients--78 with living-related donors and 77 with cadaveric donors. All patients were adults receiving azathioprine and prednisone. Renal function was estimated by calculated creatinine clearances (Ccr), which correlated well with measured 24-hour creatinine clearances. The creatinine clearance data for each patient were plotted versus time. In 73% of patients, the creatinine clearance increased for several years before reaching a peak value. After the peak, the creatinine clearance declined in a linear manner. Stepwise regression analyses indicated that allografts from cadaveric donors had a greater increase in creatinine clearance from the value at year 1 to the peak than allografts from living-related donors (0.35 +/- 0.25 v 0.21 +/- 0.23 mL/s [21.4 +/- 15.0 v 12.7 +/- 13.8 mL/min]; P less than 0.001). The average time to reach the peak value of creatinine clearance was longer in cadaveric allografts (6.8 +/- 3.5 v 4.6 +/- 4.0 years; P less than 0.001). Postpeak, the rate of decline in creatinine clearance was faster in cadaveric allografts than in living-related ones (0.06 +/- 0.05 v 0.04 +/- 0.04 mL/s/yr [3.50 +/- 2.99 v 2.55 +/- 2.16 mL/min/yr]; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Growth hormone regulates ammoniagenesis in canine renal proximal tubule segments.

To determine whether growth hormone (GH) directly affects ammoniagenesis in the renal proximal tubule, ammonia production was measured in suspensions of isolated canine renal proximal tubule segments (IPTs) incubated with 2.5 mM L-glutamine and varying concentrations of human growth hormone (hGH). Ammonia production from IPTs significantly increased by nearly threefold in the presence of hGH (10(-6) M) at 60 min. This increase was dose dependent, with as little as 10(-9) M hGH significantly stimulating ammonia production. In addition, hGH enhanced glucose production when lactate, alanine, and succinate replaced L-glutamine as substrate. hGH significantly stimulated ammonia production when IPTs were incubated at alkalotic and neutral pH. The effect of hGH was lost at acidic pH. When hGH was added to IPTs incubated under Na(+)-equilibrated conditions, ammonia production was not different from control. hGH stimulated ouabain-sensitive Na(+)-K(+)-adenosinetriphosphatase (ATPase) activity by 8.1 +/- 1.1% in basolateral membranes isolated from IPTs. hGH stimulation of proximal tubule ammonia production from L-glutamine occurs at physiological concentrations of hGH and when the extracellular-to-intracellular Na+ gradient favors L-glutamine transport. This effect is associated with an increase in basolateral Na(+)-K(+)-ATPase activity. The data suggest a role for hGH in the regulation of renal acid-base metabolism under physiological conditions in which increased net acid excretion is important.