Renoprotection: one or many therapies?

BACKGROUND: Renal disease that progresses to end-stage renal disease (ESRD) imposes a great burden on the affected individual and on society, which mainly bears the cost of ESRD (currently more than $10 billion to treat about 333,000 patients annually in the U.S.). Thus, there is a great need to identify therapies that arrest the progression mechanisms common to all forms of renal disease. Progress is being made. Perhaps the most visible advance is the randomized controlled trials (RCT) demonstrating the renoprotective effects of angiotensin-converting enzyme (ACE) inhibitors. There are also numerous other promising renoprotective therapies. Unfortunately, testing each therapy in RCT is not feasible. Thus the nephrologist has two choices: restrict renoprotective therapy to those shown to be effective in RCT, or expand the use of renoprotective therapies to include those that, although unproven, are plausibly effective and prudent to use. The goal of this work is to provide the documentation needed for the nephrologist to choose between these strategies. METHODS: This work first describes the mechanisms believed to be involved in the progression of renal disease. Based largely on this information, 18 separate interventions that slow the progression are described. Each intervention is assigned a level of recommendation (Level 1 is the highest and Level 3 the lowest) according to the strength of evidence supporting its renoprotective efficacy. RESULTS: The number of interventions at each level of recommendation are: Level 1, N = 4; Level 2, N = 4; Level 3, N = 10. Our own experience with the multiple-risk-factor intervention is that most patients can achieve the majority of the Level 1 and 2 interventions, and many of the Level 3 interventions. We recommend the expanded renoprotection strategy. CONCLUSION: This work advances the hypothesis that, until better information becomes available, a broad-based, multiple-risk-factor intervention intended to slow the progression of renal disease can be justified in those with progressive nephropathies. This work is intended primarily for clinical nephrologists and thus each recommended intervention is described in substantial practical detail.

Recurrent type I membranoproliferative glomerulonephritis in a renal allograft: successful treatment with plasmapheresis.

Recurrent disease is increasingly recognized as a cause of renal allograft dysfunction and failure. We describe a patient with type I membranoproliferative glomerulonephritis not associated with hepatitis C. The glomerular disease recurred in the renal allograft within 1 month of transplantation, leading to acute allograft dysfunction and nephrotic syndrome. Aggressive treatment with prednisone and plasmapheresis resulted in improvement in kidney function, improvement of the light microscopic picture, and removal of immune complexes from the glomerular subendothelial space.

Obese living kidney donors: short-term results and possible implications.

BACKGROUND: Living kidney donation has increased recently as the shortage of cadaveric organs continues. This increase has occurred in part, due to expanded donor criteria, including obese patients. This is a potential concern because obesity is associated with surgical complications, possibly death, and chronic medical problems. To address this concern, we examined the outcome of a large group of obese (ObD) and nonobese living kidney donors (NObD). METHODS: A total of 107 obese (body mass index> or =27 kg/m2) and 116 nonobese (body mass index<27 kg/m2) living kidney donors donating at a single institution between 1990 and 1996 were studied. Surgical complications, operative duration, and hospital length of stay were assessed. Preoperative blood pressure, serum creatinine, creatinine clearance, protein excretion, fasting glucose, and hemoglobin A1C were measured and first degree relatives with diabetes were identified. RESULTS: Overall complications were significantly more common in ObD, 16.8 vs. 3.4% (P=0.0012). The majority of complications in the entire cohort, 56%, were wound related and were significantly more common in ObD (P=0.016). There was no significant increase in nonwound-related infections, bleeding, or cardiopulmonary events. There were no deaths or major complications. Operative time was significantly longer in ObD 151+/-30 vs. 141+/-29 min (P<0.05) but hospital duration was no different. Predonation, blood pressure in ObD was significantly higher, (P<0.05) and they more often had a family history of diabetes, 46 vs. 30% (P<0.05) than nonobese donors. Renal function, proteinuria, fasting glucose, or hemoglobin A1C were no different. CONCLUSION: With prudent selection, the use of obese living kidney donors appears safe in the short term. They experience more minor complications, usually wound related, and slightly longer operations. Given a higher baseline blood pressure and family history of diabetes, the long-term effect on the remaining solitary kidney in ObD needs to be examined.

Patient survival after renal transplantation: II. The impact of smoking.

Renal transplant recipients have significantly higher mortality than individuals without kidney disease and the excess mortality is mainly due to cardiovascular causes. In this study, we sought to determine the impact of smoking, a major cardiovascular risk factor, on patient and renal graft survival. The study population included all adult recipients of first cadaveric kidney transplants done in our institution from 1984 to 1991. By selection, all patients were alive and had a functioning graft for at least 1 yr after transplantation. Smoking history was gathered prior to transplantation. The follow-up period was 84.3 + 41 months and during this time 28%, of the patients died and 21%, lost their graft. By univariate and multivariate analysis, patient survival, censored at the time of graft loss, correlated with these pre-transplant variables: age (p < 0.0001); diabetes (p = 0.0002); history of cigarette smoking (p = 0.004); time on dialysis prior to the transplant (p = 0.0005); and cardiomegaly by chest X-ray (p = 0.0005). Post-transplant variables did not correlate with patient mortality. By Cox regression, patient survival time was significantly shorter in diabetics (p < 0.0001), smokers (p = 0.0005), and recipients older than 40 yr. However, there were no significant differences between the survival of smokers, non-diabetics, diabetics, and older recipients. Patient death was the most common cause of renal transplant failure in smokers, in patients older than 40 yr, and in diabetics, but these patient characteristics did not correlate with graft survival. The prevalence of different causes of death was not significantly different between smokers and non-smokers. In conclusion, a history of cigarette smoking correlates with decreased patient survival after transplantation, and the magnitude of the negative impact of smoking in renal transplant recipients is quantitatively similar to that of diabetes.

Mycophenolate mofetil therapy in lupus nephritis: clinical observations.

Controlled clinical trials in renal transplantation have demonstrated that mycophenolate mofetil is well tolerated and has lower renal transplant rejection rates than azathioprine regimens. This study reports on the clinical experiences at two institutions with mycophenolate mofetil (MMF) for severe lupus nephritis. Twelve patients with relapsing or resistant nephritis previously treated with cyclophosphamide therapy and one patient who refused cyclophosphamide as initial therapy for diffuse proliferative nephritis but accepted MMF were included. During combined MMF/prednisone therapy, serum creatinine values remained normal or declined from elevated values: mean change in serum creatinine was -0.26+/-0.46 microM/L, P = 0.039. Proteinuria significantly decreased: mean change in urine protein-to-creatinine ratios was -2.53+/-3.76, P = 0.039. Decreased serum complement component C3 and elevated anti-double-stranded DNA antibody levels at baseline improved in some, but not all, patients. The mean initial dose of MMF was 0.92 g/d (range, 0.5 to 2 g/d). The mean duration of therapy was 12.9 mo (range, 3 to 24 mo). Adverse events included herpes simplex stomatitis associated with severe leukopenia (n = 1), asymptomatic leukopenia (n = 2), nausea/ diarrhea (n = 2), thinning of scalp hair (n = 1), pancreatitis (n = 1), and pneumonia without leukopenia (n = 1). Recurrence of the pancreatitis led to discontinuation of MMF in this patient; all other adverse events resolved with dose reduction. It is concluded that MMF is well tolerated and has possible efficacy in controlling major renal manifestations of systemic lupus erythematosus. Controlled clinical trials are needed to define the role of MMF in the management of lupus nephritis.

Combination ACE inhibitor and angiotensin II receptor antagonist therapy in diabetic nephropathy.

The benefit of angiotensin-converting enzyme (ACE) inhibitor (i) therapy in diabetic glomerulosclerosis is thought to be largely the result of attenuation of angiotensin II (AngII) effects on blood pressure, glomerular hemodynamics and hypertrophy, and tissue fibrosis. The present study was undertaken to determine whether the addition of AngII receptor antagonist therapy to ACEi therapy in diabetic nephropathy results in attenuation of AngII effects beyond that achieved by ACEi therapy alone. Seven patients were studied as inpatients on the General Clinical Research Center each for 3 consecutive weeks as follows: week 1, the patients' usual regimen which included daily oral moderate to high dose ACEi therapy; week 2, the patients' usual regimen plus oral losartan (an antagonist (a) of the angiotensin type 1 receptor, AT1) 50 mg (n = 3) or 100 mg (n = 4) daily; week 3, return to the patients' usual regimen. Diet, physical activity, and blood glucose were held as constant as possible during the three weeks of daily testing. We found that plasma renin levels increased significantly during combination therapy and then returned to baseline values with discontinuation of AT1a therapy: mean baseline renin values (week 1) 3.0 ng/ml/min +/- 1.1 SE, mean renin values during combination therapy (week 2) 7.0 ng/ml/min +/- 3.2 (p = 0.0078 by Wilcoxon rank sum test), mean renin values after discontinuation of AT1a therapy (week 3) 3.9 ng/ml/min +/- 2.0 (NS compared to baseline values). In addition, 2 patients developed transient hypotension when losartan therapy was initiated. During this short-term study, 24-hour proteinuria, serum creatinine, serum potassium, and plasma aldosterone were not changed significantly by combination therapy. We conclude that in patients with diabetic nephropathy addition of AT1a therapy to ACEi therapy attenuates AngII effects better than ACEi therapy alone. We suggest that combination therapy for the management of diabetic glomerulosclerosis merits further investigation.

Pathologic classification of chronic allograft nephropathy: pathogenic and prognostic implications.

BACKGROUND: After transplantation renal allografts frequently develop interstitial fibrosis and tubular atrophy, and these pathologic changes are the hallmarks of chronic allograft nephropathy (CN). However, the diagnosis of CN has no specific pathogenic implications. In this study we sought to determined whether a subclassification of CN according to vascular pathology correlates with posttransplant events, particularly acute rejection, and graft survival. METHODS: A total of 419 patients with moderate to severe CN were subdivided into: (1) transplant arteriopathy (TA, n=233, 56%); (2) arteriolar hyalinosis (AH, n=89, 21%); and (3) no characteristic vascular pathology (IFb, n=97, 23%). RESULTS: Patients with AH differed significantly from patients with TA or IFb in the following parameters: (1) AH was diagnosed later after transplantation (P=0.001); (2) fewer patients with AH had acute rejection (AR) before the diagnosis of CN (P<0.0001). For example, 44% of AH and 75% of TA had AR before CN; (3) patients with AH also had fewer AR episodes than the other two groups (P<0.0001); finally, (4) graft survival was better in patients with AH than in patients with TA (P=0.01 by chi2, P=0.001 by Cox). In contrast, there were no significant differences between patients with TA and IFb. By multivariate analysis the survival of grafts with CN correlated with: (1) serum creatinine at diagnosis (P<0.0001), (2) recipient's weight (P=0.004); (3) presence of FGS or level of proteinuria (P=0.03); and (4) the occurrence of AR after the diagnosis of CN (P<0.0001). Regarding the latter, AR were more common (P=0.007) and more numerous (P=0.005) in patients with TA or IFb than in AH. CONCLUSIONS: CN can be classified according to vascular pathology in the majority of cases, and this classification correlates with graft survival. Although some forms of CN are closely associated with the occurrence of AR others are not. This study also uncovered several variables that correlate with the survival of grafts with CN.

Patient survival after renal transplantation: I. The impact of dialysis pre-transplant.

Patients on dialysis and recipients of renal transplants have higher mortality than individuals without kidney disease. In this study we evaluated the possible impact of dialysis therapy before transplantation on patient survival after the transplant. This analysis includes all of the patients who received a cadaveric renal transplant at The Ohio State University from 1984 to 1991 and who remained alive with functioning grafts for at least six months after the transplant (N = 523). After a follow-up of 84 +/- 14 months, 28% of the patients died and 23% lost their grafts. By multivariate analysis, reduced patient survival (censored at the time of graft loss) correlated with these pre-transplant variables: Older age (P < 0.0001), the presence of diabetes (P = 0.0002), smoking (P = 0.009), and the length of time on dialysis (P = 0.0002). Thus, 7% of patients who were never dialyzed, 23% of those dialyzed for less than three years, and 44% of patients dialyzed for > or = three years died post-transplant. By Cox regression, patient survival months correlated with time on dialysis pre-transplant (P = 0.0003). The type of dialysis (CAPD vs. hemodialysis) did not correlate with patient survival. Graft survival, censored for patient death, did not correlate with any of these pre-transplant variables. The relationship between time on dialysis and patient mortality is due to at least two factors: (1) transplant recipients who had dialysis for > or = 3 years had higher mortality due to infections (22%) than those who had dialysis for < 3 years (3%, P = 0.01 by X2); and (2) increasing time on dialysis increases the prevalence of both left ventricular hypertrophy (P = 0.008) and cardiomegaly (P = 0.004), and these relationships are statistically independent of other factors that also correlate with the prevalence of cardiovascular disease. In conclusion, increased time on dialysis prior to renal transplantation is associated with decreased survival of transplant recipients.

Impact of acute rejection and early allograft function on renal allograft survival.

Both acute rejection and the function of a renal allograft early after transplantation correlate with long-term graft survival. In this study we assessed the relationship between these two factors in 843 adult recipients of first cadaveric renal grafts, transplanted at a single institution and followed for a minimum of 3.5 years. Patients were divided into four groups according to (1) history of acute rejection (AR) during the first 6 months after transplantation, and (2) concentration of serum creatinine at 6 months after transplantation (SCr(6mo) < or > or = 2 mg/dl). Death censored allograft survival was not significantly different among patients without AR and with low SCr(6mo) (group 1, n=376), patients without AR but with an elevated SCr(6mo) (group 2, n=117), and patients with AR but low SCr(6mo) (group 3, n=185). In contrast, graft survival was significantly worse in patients with AR and an elevated SCr(6mo) (group 4, n=165) compared with patients in the other three groups (Cox, P<0.0001). The elevated SCr(6mo) in group 4 patients was not necessarily the consequence of AR, as 32% of patients in group 4 had a SCr at 10 days after transplantation (SCr(10d)), before they had AR, that was equal to or higher than the SCr(6mo). Based on this observation we investigated the implications of the SCr(10d) concentration for graft prognosis. The SCr(10d) correlated weakly with graft survival (Cox, P=0.05). However, an elevated SCr(10d) correlated with other potential risk factors for graft survival including: Older donors (P<0.0001), male recipients (P<0.0001), and heavier recipients (P<0.0001, all by multivariate regression); and posttransplant factors such as, increasing numbers of AR (P<0.0001), higher posttransplant blood pressure (P<0.0001), and lower doses of cyclosporine (P<0.0001, all by multivariate regression). In conclusion, graft dysfunction predicts poor graft survival only when associated with AR. Similarly, AR predicts a poor renal allograft survival only when associated with graft dysfunction. The SCr(10d) is an indicator of risk factors from both the donor and recipient, and an elevated SCr(10d) predicts a higher risk of acquiring additional risk factors early after transplantation.

Relationships between arterial hypertension and renal allograft survival in African-American patients.

In previous studies, we showed that in African-American patients arterial hypertension during the first 6 months after transplantation is associated with a high risk of renal allograft loss. In this study, we sought to examine the relationships between pretransplant blood pressure (preBP), blood pressure early after transplantation (postBP), and allograft function and survival. The study included 116 African-American recipients of first cadaveric renal allografts followed for 64 +/- 40 months. Prior to transplantation, 78% of the patients required antihypertensive medications and 59% had poorly controlled BP (average mean arterial pressure, > or =107 mm Hg). Blood pressure levels increased significantly during the first month posttransplant, particularly in patients with poorly controlled preBP. During the first 6 months posttransplant, 95% of patients required antihypertensive drugs; after the transplant, patients required significantly more and higher doses of antihypertensives compared with pretransplant. In 38% of the patients, postBP remained high despite therapy. The level of postBP correlated with the patient's weight pretransplant and with the level of preBP. Pretransplant BP correlated with postBP 1 month after transplantation (r = 0.4, P < 0.0001), and 70% of the patients with poorly controlled postBP had uncontrolled preBP. Patients with poorly controlled preBP had worse graft survival than patients with well-controlled preBP (P = 0.03 by Cox regression). Furthermore, compared with patients with well-controlled postBP, patients with high postBP had higher serum creatinine at 10 days (P = 0.04) and at 6 months (P = 0.0004) posttransplant; these patients had reduced graft survival (P = 0.0006 by Cox). We found no objective evidence of differences in patient compliance between individuals with high postBP and those with well-controlled postBP. This study confirms the association between high postBP and reduced renal allograft survival in African-American patients. In addition, these results show that the level of preBP can be used to identify patients at high risk of developing severe hypertension immediately after transplantation and those at risk for renal allograft failure.

Factors related to the donor organ are major determinants of renal allograft function and survival.

In this study, we analyzed the relative impact of donor and recipient variables on cadaveric renal allograft function and survival. The unique feature of the study population is that each pair of recipients received their allografts from a single donor. The study includes 378 adult patients. In 129 pairs both recipients were Caucasian, and in 60 pairs one recipient was Caucasian and the other was African-American. All transplants were done in one center, thus minimizing differences in preservation time and providing uniform posttransplant management. The initial analysis showed a relationship between the function of the allograft 6 months after transplantation (serum creatinine [SCr]6 mo) and donor variables (P = 0.0004, analysis of variance). Furthermore, it was calculated that 64% of the variability in the SCr 6mo among patients was due to donor factors and 36% was due to recipient factors. An elevated SCr 6 mo was significantly associated with older donors, male recipients, and patients with acute rejection episodes. Furthermore, other unidentified donor factors may have an impact on allograft function. Reflecting the importance of donor factors, there was a significant relationship between SCr 6mo in paired recipients (P < 0.0008 by Spearman). Analysis of racially dissimilar pairs showed that the SCr 6mo and graft survival 6 months after transplantation were not significantly different between Caucasians and African-Americans. However, beyond 6 months, graft survival was worse in African-Americans (P < 0.0001 by Cox). Compared with Caucasians, graft survival was significantly worse in African-Americans with poorly controlled blood pressure (mean arterial pressure > 105 mmHg) (P = 0.002, Cox), but not in those patients with mean arterial pressure < 105 mmHg. In conclusion, donor factors are major determinants of renal allograft function. However, those factors may not be easily identifiable or quantifiable. Donor factors do not contribute to racial differences in allograft survival. However, poorly controlled hypertension correlates with poor renal graft survival in African-Americans.

Prevalence of hepatitis C in patients with idiopathic glomerulopathies in native and transplant kidneys.

Previous studies suggest that there is an association between hepatitis C (HCV) infection and glomerular diseases in native and transplanted kidneys. However, the data are controversial. To reexamine this issue, we determined the prevalence of serum anti-HCV antibodies in patients with glomerulopathies of native kidneys (n = 105) and in patients with acute and chronic transplant glomerulopathy (TxGN) (n = 62). Compared with a control group of patients with diabetic nephropathy (n = 37, 0% HCV+), the prevalence of HCV antibodies was significantly higher in patients with focal glomerulosclerosis (FGS) (4 of 32, 13%, P = 0.04 by chi-square), but not in patients with membranous nephropathy (MGN) (1 of 19, 5%) or in patients with membranoproliferative glomerulonephritis (MPGN) (2 of 17, 12%). All of the patients with positive HCV serology had histories of intravenous (IV) drug use. Thus, HCV serology was negative in all of the patients with native glomerulopathies without histories of IV drug use. Compared with a group of 105 transplant patients without TxGN (1.8% HCV+), the prevalence of HCV antibodies was significantly higher in patients with acute (A)TxGN (12 or 41: 29%. P = 0.0004) and in patients with chronic (C)TxGN (9 of 27: 33%. P = 0.0004). Compared with controls, patients with ATxGN also had a significantly higher prevalence of serum immunoglobulin (Ig) M antibodies to cytomegalovirus (CMV) (3% and 26% of patients, respectively, P = 0.0004). However, there were no statistical associations between HCV and CMV serologies. These results do not support the postulate that HCV infection is associated with idiopathic native glomerulopathies; instead, the data suggest that the presence of HCV positivity in these patients can be explained by the inclusion of patients with a history of IV drug use. In contrast, these studies demonstrate for the first time an association between HCV infection and transplant glomerulopathies.

The high prevalence of severe early posttransplant renal allograft pathology in hepatitis C positive recipients.

In the USA approximately 10% of candidates for renal transplantation have serum antibodies to hepatitis C (HCV). To assess the possible impact of HCV infection on early posttransplant events we assessed allograft complications during the first 6 months following renal transplantation in three groups of adult renal allograft recipients: (1) HCV antibody positive recipients (R-HCV) (n=32); (2) HCV negative recipients who received kidneys from HCV antibody positive donors (D-HCV) (n=48); and (3) HCV negative recipients of HCV negative allografts who were transplanted during the same time period as R-HCV (Ctrl) (n=204). Allograft biopsies were done for evaluation of allograft dysfunction during the first 6 months posttransplant in 58% of Ctrl, 42% of D-HCV, and 63% of R-HCV (not significantly different). The prevalence of acute tubulointerstitial rejection was similar among the 3 groups of patients. In contrast, compared with Ctrl, both R-HCV and D-HCV had a significantly higher prevalence of acute transplant glomerulopathy (Ctrl, 6%; R-HCV, 55%, P<.0001; D-HCV 40%, P=.0004). Acute vascular rejection was more common in R-HCV (60%) than in Ctrl (28%) (P=.009) and the prevalence of chronic vascular rejection was also higher in R-HCV (60%) than in Ctrl (31%) (P=.01). Furthermore, chronic vascular rejection was diagnosed earlier in R-HCV (64% of cases within one month posttransplantation) than in Ctrl (19% within one month) (P=.01). Death censored renal allograft losses occurred in 14% of Ctrl, 17% of D-HCV, and 26% of R-HCV (not significant). In conclusion, R-HCV patients have a high prevalence of severe acute pathologic findings in renal allograft biopsies obtained early after transplantation and develop chronic vascular rejection more often and earlier than HCV negative recipients. These studies also confirm the previously reported association of HCV with acute transplant glomerulopathy.

Nocturnal blood pressure in treated hypertensive African Americans Compared to treated hypertensive European Americans.

Previous studies have shown that African Americans (blacks) tend to have higher nocturnal blood pressure than European Americans (whites). The study presented here was undertaken to determine whether treatment of hypertension influences nocturnal blood pressure differently in blacks than in whites. To answer this question, this study measured nocturnal blood pressure by ambulatory blood pressure monitoring (ABPM) in treated hypertensive blacks and whites whose daytime blood pressures were comparable. Inclusion criteria for this study were: diagnosis of essential hypertension, absence of renal failure, and documentation of antihypertensive therapy, diabetic status, proteinuria status, and body weight. All of the black patients in our programs who underwent ABPM and met the above criteria were included in this study. White patients were included on the basis of having the same inclusion criteria as blacks and showing, by ABPM, daytime mean arterial pressure (MAP) in the same range as that of the blacks selected for this study. The results of nocturnal blood pressure were unknown to the investigators when the patients were selected for this study. In the blacks (N = 62) and whites (N = 72) selected for study, the mean daytime (0600 to 2200 h) MAP was 107 +/- 1 SE mm Hg for both the black and white cohorts. To assess nocturnal blood pressure, the period from 0100 to 0500 h was chosen because it likely encompassed an interval of sleep, which is associated with the nadir of nocturnal blood pressure. This interval was termed 0100 to 0500 h, "middle night." Mean middle night MAP was 97 +/- 12 mm Hg in blacks versus 90 +/- 14 mm Hg in whites (P < 0.006, unpaired t test). The greater middle night MAP in blacks compared with whites was a result of the higher diastolic pressure in blacks (80 +/- 11 mm Hg) versus whites (75 +/- 11 mm Hg) (P = 0.003). Mean middle night systolic blood pressure was numerically higher in blacks than whites (131 +/- 18 mm Hg versus 128 +/- 17 mm Hg), but this difference did not achieve statistical significance. The higher middle night blood pressure in blacks versus whites could not be explained by differences between the groups in daytime MAP, age, gender, body weight, serum creatinine level, proteinuria, diabetic status, or greater use of short-acting antihypertensive agents in blacks versus whites. It was concluded that when treated hypertensive blacks and whites are matched for the same daytime blood pressure, blacks tend to have significantly higher nocturnal blood pressure than whites. The magnitude of this difference suggests that it could contribute importantly to the greater target-organ damage that is seen in hypertensive blacks compared with hypertensive whites.

Progressive histologic injury in kidneys from heart and liver transplant recipients receiving cyclosporine.

Cyclosporine (CsA) causes both acute and chronic nephrotoxicity. The goal of the present studies was to examine the nature of the chronic renal pathologic lesions of CsA nephrotoxicity and to determine whether these lesions progress with prolonged exposure to the drug. With this purpose, we examined large sections of kidneys obtained at autopsy from 15 heart transplant recipients, 7 liver transplant recipients, and 10 nontransplanted controls. Tissue sections were examined blindly by light microscopy, histomorphometry, and color computer image analysis. With increasing time following transplantation, there was a progressive increase in renal arteriolar hyalinosis and in the percentage of glomeruli demonstrating global sclerosis. In addition, there was a statistically significant relationship between arteriolar hyalinosis and global glomerulosclerosis (r=0.61, P<0.003). The percentage of glomeruli with focal glomerulosclerosis was also increased in transplant recipients followed for more than 80 days. The kidneys of heart and liver recipients who died less than 80 days after transplantation, that is, those patients who received no CsA or low doses of CsA, demonstrated significantly more interstitial fibrosis than the kidneys of control individuals. Furthermore, there was no significant increase in the amount of renal interstitial fibrosis in allograft recipients followed for prolonged periods of time. There were no significant relationships between the severity of renal pathologic changes and serum creatinine or systemic blood pressure levels. In conclusion, non-renal transplant recipients demonstrate renal damage that affects primarily the preglomerular arterioles and results in glomerular obliteration. This renal damage increases in relation to the time of exposure to CsA and in relation to the total dose of CsA that the patient receives. These renal structural changes are not reflected initially in changes in glomerular filtration rate, as determined by serum creatinine.

Angiotensin II induction of fibronectin biosynthesis in cultured human mesangial cells: association with CREB transcription factor activation.

We assessed the effect of angiotensin II on fibronectin biosynthesis a nd transcription factor activation in adult human mesangial cells in culture. We found that 10(-5) mol/L angiotensin II tended to increase fibronectin mRNA expression within 1 hour (1.2-fold +/- 0.3-fold of that in controls), with a significant increase after 4 hours (0.3-fold +/- 0.1-fold of that in controls, p < 0.05) and 24 hours (1.9-fold +/- 0.3-fold of that in controls, p < 0.02). In conjunction with increased fibronectin mRNA levels, angiotensin II exposure resulted in a significant elevation in immunoreactive fibronectin concentrations and the incorporation of (35S)-labeled methionine into fibronectin after 2 hours (224% +/- 23% of controls, p < 0.05). Angiotensin II also induced mesangial cell activation of the cyclic adenosine monophosphate response element binding protein (CREB) transcription factor, a DNA binding protein known to recognize specific regulatory elements present on the fibronectin gene promoter. Using the electrophoretic mobility shift assay, we showed that angiotensin II increased mesangial cell expression of the activated form of CREB after 4 hours (1.2-fold +/- 0.04-fold of that in controls, p < 0.05). To determine the importance of the CREB regulatory elements in mediating angiotensin II induction of fibronectin gene transcription, JEG-3 cells were transfected with plasmids containing fibronectin promoter-chloramphenicol acetyltransferase (CAT) reporter gene constructs with (FN510) or without (FN122) the CREB regulatory motifs. Angiotensin II resulted in a significant increase in CAT activity in FN510 transfectants (1.6-fold +/- 0.2-fold of that in controls, p < 0.05), but there was no effect of angiotensin II on FN122 transfected cells. These data demonstrate that angiotensin II stimulates fibronectin biosynthesis in adult human mesangial cells and suggest that the process may be regulated at the transcriptional level.

Racial differences in renal allograft survival: the role of systemic hypertension.

The rate of decline in the number of functioning renal allografts beyond the first year after transplantation has changed little in the last 25 years, and during long-term follow-up most allografts are lost due to chronic transplant rejection or patient death. The recipient race correlates with allograft survival, and African American recipients have a lower allograft survival than Caucasians. The goal of the present study was to identify clinical variables present during the first six months after transplantation that predict the loss of renal allografts beyond six months after transplantation, and in particular to determine the role of systemic hypertension on renal allograft survival in black and white recipients. This study includes 547 recipients of first cadaveric renal allografts performed at The Ohio State University. All patients were treated with a uniform immunosuppressive protocol and had a follow-up of at least three years. By multivariate analysis the following variables correlate with poor allograft survival: an elevated serum creatinine concentration measured six months after transplantation (SCr6mo) (P < 0.0001); black race (P < 0.0001); increasing numbers of acute rejection episodes (ATR) (P = 0.002); and young recipients (P = 0.026). Allograft survival is significantly worse in black (mean allograft half-life of 7.7 +/- 1.3 years) than in white recipients (24 +/- 3 years) (P < 0.0001). Black recipients also have a significantly higher six month average mean arterial blood pressure (MAP) (105 +/- 8 mm Hg) than white recipients (102 +/- 7 mm Hg) (P = 0.002). However, the prevalence of hypertension is not significantly different in black (33%) than in white recipients (26%).(ABSTRACT TRUNCATED AT 250 WORDS)

Renal artery pressure gradients in patients with angiographic evidence of atherosclerotic renal artery stenosis.

From October 1979 to August 1991, 231 patients underwent renal artery balloon angioplasty at The Ohio State University Hospitals. Atherosclerotic renal vascular disease was present in 171 of these patients. From this cohort, 138 patients undergoing their first angioplasty had renal artery pressure gradients performed before and after renal artery angioplasty. The demographics of this group included age 66.9 +/- 10 years (+/- SD), male 51%, white 94%, black 6%, diabetes mellitus 28%, systolic blood pressure 157 +/- 26 mm Hg, diastolic blood pressure 86 +/- 13 mm Hg, standard daily doses of antihypertensive medications 4.2 +/- 3, and serum creatinine 2.6 +/- 2.3 mg/dL. Plasma renin activity was measured in 25 patients and was shown to be elevated in 16. The renal artery stenoses were main renal artery 75%, orificial 22%, distal renal artery 1.4%, and combinations of the above 2.2%. Solitary kidneys were present in six patients (4.3%). Bilateral renal artery stenosis was present in 45% of patients and bilateral angioplasties were performed in one third of these patients. The preangioplasty systolic blood pressure gradient was 109 +/- 50 mm Hg (range, 20 to 230 mm Hg) and the postangioplasty renal artery pressure gradient was 12 +/- 16 mm Hg (range, 0 to 78 mm Hg) (P < 0.001). There were no complications related to measurement of the pressure gradients. The magnitude of the renal artery pressure gradients did not correlate with blood pressure level, number of antihypertensive medications, or serum creatinine level.(ABSTRACT TRUNCATED AT 250 WORDS)