Michael E. Falkenhain

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.

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.

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.

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.

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 patients 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.

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.

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.

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.