The influence of allopurinol on kidney haemodynamic and excretory responses to renal ischaemia in anaesthetized rats.

1. This study examined the impact of allopurinol on the renal functional responses to a 30 min period of ischaemia in anaesthetized rats. 2. Immediately on reperfusion, blood pressure rose transiently, while renal blood flow remained stable throughout at control values. Glomerular filtration rate was decreased by some 90% over the first and 80% over the sixth hour (P<0.001). 3. Allopurinol, 50 or 100 mg kg-1, had no effect on the blood pressure or renal blood flow responses over the 6 h reperfusion period but glomerular filtration decreased by 60% initially, and to less than 30% of basal at 6 h. 4. Urine flow and absolute sodium excretion increased 2 - 3 fold in the first 2 h but decreased thereafter. Fractional sodium excretion was 30 times higher for the first 2 h but decreased reaching some 10 fold higher at 6 h. In the presence of allopurinol, urine flow and absolute sodium excretion increased by 5 - 6 fold in the first 2 h, and fell by half by 6 h which was greater than in the vehicle group (P<0.01). Fractional sodium excretion increased 20 fold in the allopurinol animals in the first 2 h period, but fell at a faster rate (P<0.01) than in untreated rats. 5. Potassium excretion decreased (P<0.05) by one half for the 6 h reperfusion period but in the allopurinol animals it was minimally altered. 6. Allopurinol largely ameliorated the decrease in kidney haemodynamic and excretory function following an ischeamic period for the initial few hours of reperfusion.

A renal allograft recipient with late recurrence of focal and segmental glomerulosclerosis after switching from cyclosporine to tacrolimus.

BACKGROUND: Focal and segmental glomerulosclerosis (FSGS) is one of the most frequent and severe primary glomerulonephritis that recurs in transplanted kidneys. Although cyclosporine seems to have no effect on the frequency of FSGS recurrence, there is evidence that cyclosporine reduces proteinuria and prolongs graft survival in patients with recurrent glomerulonephritis after renal transplantation. The effect of tacrolimus on nephrotic syndrome after renal transplantation is controversial. METHODS: We describe the case of a 30-year-old man with steroid-resistant nephrotic syndrome due to FSGS who developed nephrotic syndrome 5 years after renal transplantation due to recurrent disease when he was switched from cyclosporine to tacrolimus. RESULTS: He was given pulses of methylprednisolone and returned to cyclosporine. His proteinuria decreased, but he rapidly developed chronic renal failure. CONCLUSIONS: This observation strongly suggests that tacrolimus should be given with considerable care in renal transplant recipients with FSGS.

Lymphoproliferative disorders after renal transplantation: role of medical imaging.

Post-transplantation lymphoproliferative disorders (PTLD) are a complication of immunosuppressed transplant recipients, and their incidence is reported to be 20-120 times greater than the rate in the general population. After kidney transplantation, PTLD more likely arise within the renal transplant fossa. Radiological patterns of these forms are presented and discussed, according to a review of the literature, and illustrated by cases from our institution. Ultrasound plays an essential role in the early diagnosis of PTLD by detecting a urinary obstruction associated with adenopathy or an ill-defined mass not previously seen. However, in the case of an inconclusive US examination, CT or MRI should be performed to confirm the presence of a mass. Both techniques are useful in evaluating the extension of the process within the transplantation fossa; MRI seems more accurate and can be used for the follow-up, especially after reduction in immunosuppressive therapy without transplant removal.

Treatment of end-stage renal failure after heart transplantation.

BACKGROUND: Five to 10% of heart-transplant recipients develop end-stage renal failure (ESRF). Little is known about the outcome of these patients under renal replacement therapy. METHODS: We conducted a retrospective study in 16 men (mean age 52.8+/-7.4 years at heart transplantation) who developed ESRF 5.3+/-2.1 years later. Results. Haemodialysis (HD) was the first-line treatment (mean Kt/V 1.35+/-0.4). Vascular access was unsuccessful in six patients (37.5%) due to peripheral arteriopathy and they were treated with tunnelled catheters for an average 15 months without bacterial infection. Mean weight was 68.4+/-10 kg at onset of HD and 61.7+/-9 kg one month later. Despite this reduction in extracellular overload, one antihypertensive drug was required in 75% of patients and two drugs in 12.5%. One patient tolerated automated peritoneal dialysis (PD) for 16 months (weekly Kt/V 2.1) despite persistent anuria. Renal transplantation (RT) was contraindicated in eight patients because of aortoiliac arteriopathy (n=5), poor general status (n=2), or ischaemic heart disease (n=1). RT was performed in eight patients with no acute episode of heart or renal graft rejection. There were no serious infectious complications. Three months after RT, mean serum creatinine was 115 micromol/l. One patient developed post-transplant lymphoproliferative disorder 3.5 months after RT and was successfully treated with transplant nephrectomy. Sudden death occurred in two patients 18 and 33 months after RT. Overall patient survival was 100, 78, and 59%, 1, 2 and 3 years after HD onset respectively. Using a time-dependent variable, the Cox model analysis demonstrated that heart-transplant recipients with ESRF have a relative risk of death 3.2 times higher than those without ESRF (95% CI = 1.3-7.8). CONCLUSIONS: HD, PD, and RT can be useful for the treatment of ESRF after heart transplantation. After initiating HD, patient survival is nearly the same as that reported in patients in Europe undergoing HD for other causes. But ESRF seems to reduce life expectancy in heart-transplant recipients.

[Renal harvesting from donors in cardiac arrest: report of 3 cases and surgical technique]. / Prélèvement rénal chez le donneur à coeur arrêté: à propos de trois cas et technique chirurgicale.

During periods of transplant organ shortage, techniques designed to "salvage" transplants must be developed. The authors report three cases of renal harvesting from donors in cardiac arrest, in which the use of in situ perfusion-cooling with transfemoral introduction of Gillot's catheter resulted in six good quality transplants. The indications, surgical technique, alternatives and results are discussed.

In-vitro growth patterns of bone marrow erythroid progenitors from patients with post-renal transplant erythrocytosis.

BACKGROUND: Erythrocytosis is relatively common after renal transplantation and is associated with a higher risk of thromboembolism. Its aetiology is unclear and there is still debate about the most frequently suggested causes. The culture in vitro of erythroid progenitors is regarded as a useful tool for the differential diagnosis of patients with unclear erythrocytosis. We studied the growth in vitro of bone marrow erythroid progenitors from renal transplant patients with erythrocytosis and controls without erythrocytosis. SUBJECTS AND METHODS: Thirteen renal transplant patients with erythrocytosis and 12 normocythaemic renal transplant controls were studied. The clinical characteristics of these patients were evaluated and serum erythropoietin (Epo) and ferritin levels were determined. Bone marrow erythroid progenitors were cultured both with and without the addition of Epo to the medium. RESULTS: Samples from six polycythaemic patients and seven controls did not grow spontaneously in the absence of exogenous Epo. Three cases of post-transplant erythrocytosis and five controls produced CFU-E, but not BFU-E. A few CFU-E and BFU-E grew spontaneously in samples from four polycythaemic patients but not in samples from the controls. Addition of 1 unit per millilitre Epo caused similar increases in the number of colonies in both polycythaemic patients and controls. Of the nine patients eligible for follow-up, all four with spontaneous growth of BFU-E had transient erythrocytosis and four of the five patients with no spontaneous growth or spontaneous growth of CFU-E only had persistent erythrocytosis requiring treatment with ACE inhibitors. CONCLUSIONS: Pathophysiology of post-transplant erythrocytosis is heterogeneous. In one-third of the patients, there was unexpected, spontaneous and transient growth of BFU-E which was not predictive of permanent erythrocytosis. The results of stem-cell studies suggest that in these cases erythrocytosis may be caused by defective regulation of erythroid progenitor proliferation, possibly due to particular cellular interactions or the effect of cyclosporin on erythropoiesis.

EPIBACDIAL: a multicenter prospective study of risk factors for bacteremia in chronic hemodialysis patients.

Bacteremic infections are a major cause of mortality and morbidity in chronic hemodialysis patients. New developments in managing these patients (erythropoietin therapy, nasal mupirocin, long-term implanted catheters, and synthetic membranes) may have altered the epidemiologic patterns of bacteremia in dialysis patients. This multicenter prospective cross-sectional study was carried out to determine the current incidence of and risk factors for bacteremia in chronic hemodialysis patients in France. A total of 988 adults on chronic hemodialysis for 1 mo or longer was followed up prospectively for 6 mo in 19 French dialysis units. The factors associated with the development of at least one bacteremic episode over 6 mo were determined using the multivariate Cox proportional hazards model. Staphylococcus aureus (n=20) and coagulase-negative staphylococci (n=15) were responsible for most of the 51 bacteremic episodes recorded. The incidence of bacteremia was 0.93 episode per 100 patient-months. Four risk factors for bacteremia were identified: (1) vascular access (catheter versus fistula: RR=7.6; 95% CI, 3.7 to 15.6); (2) history of bacteremia (> or =2 versus no previous episode: RR=7.3; 95% CI, 3.2 to 16.4); (3) immunosuppressive therapy (current versus no: RR=3.0; 95% CI, 1.0 to 6.1); and (4) corpuscular hemoglobin (per 1 g/dl increment: RR=0.7; 95% CI, 0.6 to 0.9). Catheters, especially long-term implanted catheters, were found to be the leading risk factor of bacteremia in chronic hemodialysis patients. There was a trend toward recurrence of bacteremia that was not associated with chronic staphylococcal nasal carriage. Synthetic membranes were not associated with a lower risk of bacteremia in this population of well dialyzed patients, but anemia linked to resistance to erythropoietin appeared to be a possible risk factor for bacteremia.

Pretransplant hepatitis C virus infection: a predictor of proteinuria after renal transplantation.

BACKGROUND: Reports have suggested that hepatitis C virus (HCV)-infected kidney recipients may develop de novo glomerular lesions caused by the virus. We studied the relationships between pretransplantation anti-HCV antibodies and the occurrence of proteinuria and the link with short- and long-term patient and graft survival. METHODS: A total of 322 consecutive renal recipients treated at a single center from 1989 to 1994 whose sera were routinely assayed for anti-HCV antibodies at the time of transplantation were analyzed. The risks of persistent proteinuria (>1 g/day), graft loss, or death were estimated by Kaplan-Meier analysis. The relationship between clinical variables and each outcome was examined by Cox multivariate regression analysis. RESULTS: Before transplantation, 9.6% of the recipients were anti-HCV antibody positive. Persistent proteinuria developed in 13.6% recipients. The presence of anti-HCV antibodies was strongly associated with proteinuria (relative risk [RR]=5.36, 95% confidence interval [CI]=2.49-11.51). Proteinuria occurred more frequently in second grafts (RR=2.64, 95% CI=1.10-6.29). The number of HLA-A,B mismatches was an independent risk factor (RR=1.55, 95% CI=1.10-2.19). Recipient age (RR=0.80, 95% CI=0.63-1.02) and duration of dialysis (RR=0.86, 95% CI=0.77-0.96) were protective factors. Histology of biopsies from 26/44 recipients with proteinuria showed that de novo glomerular lesions were more frequent in HCV-positive patients, although the difference was not significant. One- and five-year graft survival rates were significantly worse in patients with proteinuria (90.7% and 41.1%) than in patients without it (95.6% and 91.8%) (P<0.00001). Despite the strong association between HCV infection and proteinuria, patient and graft survival rates in anti-HCV-positive and anti-HCV-negative recipients were similar. CONCLUSIONS: The presence of anti-HCV antibodies before renal transplantation seems to be a major risk factor of proteinuria after transplantation. This may be due to glomerular lesions caused by HCV. However, anti-HCV has no impact on 5-year patient and graft survival.

Relationship between blood pressure and renin, angiotensin II and atrial natriuretic factor after renal transplantation.

The objective of the study was to assess the evolution of renin, angiotensin II, atrial natriuretic factor (ANF) and blood pressure (BP) in the first trimester following renal transplantation in man Thirty-two recipients were investigated for 3 months post-transplantation. Twenty had a history of hypertension with moderate cardiac hypertrophy. Thirty-one retained their native kidneys. Five kidney donors had a history of mild hypertension. The recipients were perioperatively volume-expanded with 0.9% saline and diuresis was maintained for 48 h with furosemide and dopamine. The sodium intake was 25 mEq/24 hours. Prophylactic immunosuppressive therapy was antilymphocyteglobulins (25 cases), or anti-LFA1 (7 cases) and maintenance therapy was cyclosporine-prednisone (8 cases), or cyclosporine-prednisone-azathioprine (24 cases). Mean BP, serum creatinine, urinary sodium excretion (UNA) and hormonal (renin, angiotensin II and ANF) parameters were collected every other day for the first week after transplantation and then twice monthly. Twenty (62.5%) patients developed hypertension and hypertension was more frequent in patients with a delayed graft function, than in patients with immediate good graft function (10/20 vs. 4/12, p < 0.05%). Both hypertensive (group HBP) and normotensive (group NBP) patients had similar very low renin and angiotensin II plasma levels, after an initial early peak. Analysis of covariance with multiple regression analysis showed that in the HBP patients, BP was negatively correlated with UNA (p = 0.02) and positively with plasma ANF (p < 0.01). The normal BP patients also showed a correlation between BP and UNA, although it was limit of statistical significance (p = 0.05); there was no correlation between ANF and BP. We conclude that the RAS is rapidly depressed after renal transplantation and does not interfere with BP regulation. The hypertension in the early stage of post-transplantation varies inversely with the urinary sodium excretion. The defective sodium excretion, which dominates the effect of the low sodium diet, results in volume overload, increased ANF and volume-dependent hypertension.

Toxoplasmosis in kidney transplant recipients: report of six cases and review.

Six patients with toxoplasmosis complicating renal transplantation are described, and 25 other reported cases are reviewed. The mean age of the 31 patients was 35.16 years. Most of the recipients (25 of 29) showed signs of toxoplasmosis within 3 months post-transplantation, with fever, neurological disturbances, and pneumonia as the main clinical features. Diagnosis was established at autopsy in 15 cases, by serology in 13 cases, and by direct examination, culture, or polymerase chain reaction of biological samples in 5 cases. Seventeen patients also had concomitant infections. The donor was the likely source of transmission to 10 recipients; reactivation was suspected in two cases. The source of transmission could not be determined for the remaining 19 patients. The mortality rate was 64.5%. Ten of the 11 patients given specific treatment survived, indicating that early diagnosis and therapy are essential.

Potential interest of anti-ischemic agents for limiting cyclosporin A nephrotoxicity.

Chronic administration of cyclosporin A induces nephrotoxicity in humans. This is related to a cyclosporin A-induced constriction of afferent glomerular arterioles and mesangial cells, which leads to a decrease in filtration pressure and creatinine clearance. Afterwards, cellular lesions are observed involving mainly tubular atrophy and interstitial fibrosis, both of which are nonspecific. The initial mechanism of its toxicity is not clearly explained. The current pharmacological approach is symptomatic in order to counteract or minimize the consequences of a prime cause, which still remains to be defined. However, cyclosporin A has a deletereous effect on mitochondrial functions and mainly on ATP synthesis, which occurs when Ca2+ accumulates in matrix mitochondria. The effects of trimetazidine, an antischemic drug used in the treatment of angina pectoris, have been assessed. This drug is effective in experimental models of hypoxia induced by cyclosporin A: it restores ATP synthesis previously decreased by Ca2+ and cyclosporin A, and releases a part of Ca2+ excess accumulated by mitochondria at concentrations reached in humans at usual dosage regimens. At higher concentrations, it reverses the mitochondrial permeability transition previously generated (opened) by Ca2+ and a pro-oxidant such as terbutylperoxide (t-BH). It was also observed that trimetazidine does not modify the immunosuppressive effects of cyclosporin A in various models. These data suggest that nephrotoxicity of cyclosporin A is not irrevocably linked to its immunosuppressive effect but that it may be possible to counteract at least partly its nephrotoxic effects without altering its effectiveness in preventing graft rejection.

IgA nephropathy: prognostic classification of end-stage renal failure. L'Association des Néphrologues de l'Est.

BACKGROUND: As yet, no clinical or morphological prognostic classification of IgA nephropathy (IgAN) has been generally accepted. The objective of our study was to quantify the risk of developing end-stage renal failure (ESRF) in IgAN. METHODS: We report a prospective longitudinal study of 210 patients with IgAN confirmed by biopsy between 1987 and 1991. Thirty-two (15.2%) patients were lost to follow-up. Mean follow-up after renal biopsy was 5.6 (SD = 2.6) years. The variables included age, gender, illnesses prior to discovery of IgAN, clinical features at IgAN discovery, 24-h proteinuria, serum creatinine, IgA level, and antihypertensive drugs taken at the time of renal biopsy. Sixty-six renal biopsies were classified by light-microscopy according to Lee's morphological classification. The end-point was ESRF. Survival was analysed by a backward and forward stepwise procedure using the Cox model. The most accurate determination of relative risk was obtained by assessing collinearity of the variables. RESULTS: Thirty-three patients (15.7%) (31 men) developed ESRF. The five univariately significant variables: gender, gross haematuria, 24-h proteinuria (24-P), serum creatinine (SC), and antihypertensive treatment, were candidates for multivariate analysis. The final model used SC (< or = 100, 100-150, > 150 mumol/l), 24-P (< 1, > or = 1 g/day) and gender (female vs male) as independent variables (relative risk and 95% confidence interval were 3.5 (2.1, 5.9) for SC; 5.1 (1.9, 13.6) for 24-P; and 3.5 (0.9, 15) for gender). These estimates were used to construct a prognostic classification of ERSF for men with IgAN: stage 1 (SC < or = 150 mumol/l and 24-P < 1 g/day), stage 2 ((SC > 150 mumol/l and 24-P < 1 g/day) or (SC < or = 150 mumol/l and 24-P > or = 1 g/day)); stage 3 (SC > 150 mumol/l and 24-P > or = 1 g/day). The ESRF-free survival was estimated with Kaplan-Meier analysis. It was 98.5% for stage 1, 86.6% for stage 2, 21.3% for stage 3 (P < 0.001), 7 years after histological diagnosis. The validity of Lee's prognostic classification was confirmed using an independent sample. CONCLUSIONS: These classifications identify groups at high risk of ESRF. Therapeutic studies should focus on these groups.

Recurrence of immunoglobulin A nephropathy after renal transplantation in the cyclosporine era.

Immunoglobulin A nephropathy (IgAN) frequently recurs in patients after renal transplantation (RT) on a conventional regimen of immunosuppressive therapy, but little is known about the influence of cyclosporine (Cs) on such a recurrence. We studied 84 patients retrospectively who underwent RT for renal failure attributable to IgAN (n = 71) or Henoch-Schönlein purpura nephropathy (HSPN) (n = 13) in two transplantation units, between January 1985 and June 1991 and were treated with Cs. Four patients died 3 months to 8 years after RT. Graft survival was 88% at 1 year, 75.2% at 5 years, and 63% at 8 years. Fifty patients underwent at least one graft biopsy, but studies with immunofluorescence were performed on only 28 (23 IgAN and 5 HSPN). After a mean follow-up of 68.1 +/- 37.2 months, mesangial IgA deposits recurred in 13 of the 28 patients (12 IgAN and 1 HSP) (prevalence, 46.4%). Among the 13 patients with recurrence of IgA deposits, all but 4 had urinary abnormalities. Light microscopy showed mesangial deposits and focal and segmental glomerular changes in 9 cases. Four patients lost their graft function 69 to 119 months after RT, and 2 had severe graft dysfunction. The rates of graft failure and mean serum creatinine at 1, 5, and 8 years were similar in the 13 patients with recurrence and the 15 patients without proven recurrence. In conclusion, Cs did not reduce the incidence or severity of IgAN recurrence. The latter was the cause of graft loss or dysfunction in 46.1 % of the patients with recurrent IgA deposits. Recurrent glomerulonephritis did not influence the 8-year graft survival in patients with IgAN or HSPN, but it may be an important cause of graft loss as evidenced by more extended follow-up.

IgA nephropathy in patients over 50 years of age: a multicentre, prospective study.

BACKGROUND: IgA nephropathy (IgAN) is considered as a disease of young men under 30 years of age. Findings on clinical and histological presentation and outcome in older patients have rarely been published. METHODS: In a prospective cohort of IgAN patients, recruited over 3 years, 33 patients over age 50 were compared to 96 patients under age 50, according to clinical and histological findings. Actuarial renal survival rate was studied after a mean post-biopsy follow-up of 41 months. RESULTS: Both groups of patients were comparable at baseline for frequency of proteinuria, microscopic haematuria and gross haematuria, but older patients had a significantly higher incidence of hypertension (65 vs 24%, P<0.01). Time between onset and diagnosis of IgAN was similar in both groups. Proteinuria/day, systolic blood pressure, and serum IgA levels were significantly higher, and Ccr was significantly lower in older patients at the time renal biopsy was performed, but serum creatinine and albumin were not. No difference was observed between the two groups for the presence of glomerular or tubulointerstitial lesions. Only endarteritis was significantly more common in older patients (75 vs 34%, P<0.01). End-stage renal failure (ESRF) was confirmed in five patients over 50 and 17 under 50. Renal actuarial survival curves did not show any significant difference between the two groups, even though the six patients who died were classified as ESRF. CONCLUSIONS: When the histological diagnosis of IgAN was established, factors that carry a poor prognosis, i.e. proteinuria, high blood pressure, and decreased Ccr were more commonly present in patients over 50 than under 50. However, after the completion of a relatively short follow-up period, renal survival was identical in the two study groups. Prolonged follow-up is necessary to confirm this trend.

Factors predisposing to post-renal transplant erythrocytosis. A prospective matched-pair control study.

We conducted a prospective study on 81 consecutive patients who had a kidney transplant with graft function for over 3 months to evaluate the prevalence of erythrocytosis following renal transplantation (PTE) and its potential risk factors. True PTE was defined as a RBC mass > 120% of the theoretical value allowing for sex, weight and height. 18 patients (22.2%) developed PTE (RBC mass = 157 +/- 21%) with no evidence of polycythemia vera (PV), or secondary polycythemia due to reduced arterial oxygen, kidney or hepatic tumors. PTE was more common in males (p = 0.041) and less common in patients treated with recombinant erythropoietin (rHEPO) prior to transplantation. 18 non-polycythemic patients (Hb 12.6 +/- 1.3 g/dl) matched for sex, age and renal function were used as case controls. Fewer PTE patients were transfused post-transplantation (p = 0.026). At the time of diagnosis, mean serum EPO was normal and similar to that of controls. PTE patients had lower serum ferritin (p = 0.005) and more commonly received iron supplementation when PTE occurred (p = 0.003). Other clinical factors did not differ significantly between the two groups. Two patients had a thrombotic event, 6 recovered spontaneously and 11 were successfully treated with angiotensin-converting enzyme inhibitors (ACEI). The normalization of Hb, hematocrit and RBC mass in ACEI treated patients was accompanied by a decline in serum EPO (p = 0.008). We conclude that true erythrocytosis is prevalent in cyclosporine-treated renal transplant patients. PTE seems to be an idiopathic erythrocytosis. Pretransplant rHEPO treatment may limit PTE by blunting the increased sensitivity of erythroid precursors to EPO and iron supplementation, which stimulates the development of PTE. ACEI treatment is effective and safe.