PURPOSE: We report two cases of long-standing, advanced primary hyperparathyroidism with renal failure. After surgery the two patients presented with marked hypocalcemia and deterioration of renal function which required dialysis 2 and 3 months after parathyroidectomy. These two cases lead us to consider that renal function should be studied before and after surgery in patients operated on for primary hyperparathyroidism. METHODS: In 19 patients operated on for hyperparathyroidism with few symptoms and without renal failure or with very moderate renal failure, blood creatinine and creatinine clearance were measured before (T1) and 1 year (T12) parathyroidectomy. RESULTS: No significant overall changes in the following parameters were observed: blood creatinine T1 71 +/- 19 mumol/L, T12 82 +/- 20 mumol/L, CrCl T1 72 +/- 13 mL/min, CrCl T12 70 +/- 19 mL/min. However, in the patient with greatest deterioration of renal function, CrCl decreased from 45 mL/min at T0 to 33 mL/min at T12. CONCLUSION: A review of the literature shows that in certain cases, renal insufficiency present before cervicotomy may worsen after surgery even if hypercalcemia is corrected. The mechanism is still unclear. A sharp decrease in parathormonemia and parathyroid hypertensive factor may play a role via intrarenal hemodynamic changes.

Aged↗

PubMed1998

Cyclosporin nephrotoxicity: pathophysiology and comparison with FK-506.

At the end of an era of almost exclusive use of cyclosporin A, there have been significant advances in the understanding of its immunosuppressive effects, whereas there is still uncertainty about the mechanisms underlying its nephrotoxicity. The recently introduced FK-506, in spite of its undeniable clinical advantages, has subsequently been proved to have rather similar nephrotoxicity. This paper reviews recent data on cyclosporin A and FK-506 nephrotoxicity, with emphasis on: first, the haemodynamic, functional and structural features; second, the potential mediators; and third, the relationship with some immunosuppressive mechanisms involved to give insights into the pathophysiology.

Animals↗

PubMed1998

Serological markers of autoimmunity in renal transplant patients with chronic hepatitis C.

The aims of this prospective study were to assess the frequency of serological markers of autoimmunity and cryoglobulins in renal transplant (RT) patients presenting with chronic hepatitis C, and to correlate them with serum alanine aminotransferase (ALT) levels, hepatitis C virus (HCV) genotypes and viremia, and HLA-DR phenotypes. Three groups of patients were studied: group I comprised 74 HCV + ve RT patients; group II, 33 HCV-ve RT patients, and group III, 13 HCV-ve/hepatitis B virus (HBV)-positive RT patients. The three groups did not differ significantly according to their mean age, sex ratio and baseline immunosuppression. Serum specimens of these patients were tested for complement (hemolytic activity (CH50), C3, C4 and properdin factor B (PFB) components, rheumatoid factor (RF), immunoglobulin patterns, circulating immune complexes, and autoantibodies including antinuclear (ANA), anti-smooth muscle (ASMA), antimitochondrial, antithyroid microsomal (ATM), antithyroglobulin (ATG) and anti-LKM1 autoantibodies. We also looked for the presence of cryoglobulins in groups I and III. Cryoglobulinemia of type II was present in 2 patients of group I (2.7%) which was associated in 1 case with de novo membranoproliferative glomerulonephritis but was not found in any of the patients of group III. RF (> 40U/ml) were more frequently observed in groups I (55.4%) and III (46%) than in group II (20.6%), although the difference was not statistically significant (p = 0.06). Oligoclonal or monoclonal serum immunoglobulin patterns were present in 16.2% of the patients in group I, 15.4% in group III and only 3.3% in group II (p = 0.07). There was no significant difference between the prevalence of at least one autoantibody in the three groups (ranging from 38.5 to 50%), and neither was the frequency of ANA (23-36.6%), even at a high titer i.e. above 1:320, or ASMA (13.5-23%) significantly different. Conversely, tissue-specific autoantibodies, i.e. ATM, ATG and anti-LKM1, were only observed in HCV+ve patients. CH50, C3, C4 and PFB levels were significantly lower in group I than in group II, although values below the normal ranges were observed only for CH50 and C3 and were mostly found in the HCV+ve RT patients. Circulating immune complexes detected by nephelometry were at similar levels in the three groups, within the normal ranges. The occurrence of at least one autoantibody and/or the presence of RF > 40 U/ml did not correlate with either serum ALT levels or a given HLA-DR phenotype in any of the three groups, nor did they correlate with HCV genotype or HCV viremia in group I. In conclusion, this study shows that contrary to HCV+ve immunocompetent patients, HCV+ve RT patients rarely present with cryoglobulinemia and have the same frequency of non-organ-specific autoantibodies as HCV-ve RT patients. Conversely, antithyroid autoantibodies are only observed in the former group. Finally, serological markers of autoimmunity are not related to serum ALT levels, HLA-DR phenotype, HCV viremia or HCV genotype in HCV+ve RT patients.

Adult↗

PubMed1998

Pharmacokinetics of alphaIFN-2b in chronic hepatitis C virus patients undergoing chronic hemodialysis or with normal renal function: clinical implications.

In this prospective controlled study, the pharmacokinetic profiles of alpha-interferon 2b (alphaIFN-2b) were determined by the enzyme-linked immunosorbent assay method in hepatitis C virus-positive (HCV+) dialysis and nonuremic patients, after a single subcutaneous injection of 3 million units. Ten HCV+/RNA+ patients (group A) with a normal renal function (mean serum creatinine: 1.03 +/- 0.26 [SD] mg/dl) and 10 HCV+/RNA+ patients undergoing chronic hemodialysis (group B) were included. The pharmacokinetic profiles of alphaIFN were determined after the very first subcutaneous injection of the drug. Plasma alphaIFN concentrations were determined before the injection and then 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 28, 32, and 36 h after the injection. They were assessed by means of an enzyme-linked immunosorbent assay test. Patients from both groups had a similar body surface area. It was found that in group B: (1) the mean maximum (SD) serum alphaIFN concentration (Cmax) was significantly higher (52 +/- 12 pg/ml) than in group A (39 +/- 12 pg/ml; P = 0.03); (2) the time at which Cmax occurred (Tmax) was significantly higher (10 +/- 3 h) than in group A (7.5 +/- 2 h; P = 0.05); (3) the observed area under the plasma alphaIFN concentration-time curve was about twice as much, i.e., 936 +/- 212 pg x h/ml, as that for group A (485 +/- 184 pg x h/ml; P < 0.0001); and (4) the alphaIFN half-life was significantly longer (9.6 +/- 2.9 h) than in group A (5.3 +/- 1.3 h). As early as 24 h after the alphaIFN injection was given, the drug was no longer detectable in nonuremic patients' sera, whereas it could be detected up to the next injection in all of the dialysis patients' sera. When trough levels of alphaIFN were measured just before the 10th injection, they were always below the threshold level in the 10 patients from group A, i.e., 4.1 pg/ml, whereas in group B they were measurable for four of nine patients (P = 0.05) and ranged between 5.8 and 36.1 pg/ml. Severe neurologic side effects were observed only in group B, i.e., in three patients. Hemoglobin levels did significantly decrease but only in group B patients, and this was significantly correlated with the Cmax (r = 0.67; P = 0.03). This is the first controlled study to demonstrate that the clearance of alphaIFN is about twice as low in dialysis patients as in nonuremic patients. These results might be of relevance when deciding the optimal alphaIFN therapy scheme for HCV+ patients, either with normal renal function or undergoing chronic hemodialysis.

Adult↗

PubMed1998

Improvement of the Cockcroft-Gault equation for predicting glomerular filtration in cancer patients.

In order to determine the morphological and biological covariables which better predict the glomerular filtration rate in cancer patients, we performed the present study in a population of 123 patients (78 men, 45 women) with various tumor types; 55 of these patients had previously received cisplatin, and 12 had undergone unilateral nephrectomy. The 51Cr-EDTA plasma concentration versus time data of 80 patients were analysed according to a population pharmacokinetic approach by using the Nonlinear Mixed Effects Model (Nonmem) program. The best fit for 51Cr-EDTA clearance estimation was given by the following formula: [formula: see text] (with ABW for actual body weight in kg, age in years, sex = 0 if male and sex = 1 if female, and Scr for serum creatinine in mumol/l). Actual body weight was the most predictive morphologic parameter, and the adjustment was not improved by taking into account the ideal body weight. The GFR of patients previously treated with cisplatin was 18% lower than that of untreated patients age for age. However, this covariable was not present in the final model because it was redundant with other covariables, likely Scr. The formula was then prospectively evaluated with the data of 43 other patients. The mean (+/- SD) ratio between GFR predicted according the Nonmem formula and the observed GFR was 0.95 +/- 0.23 which did not differ significantly from unity. Conversely, the mean ratio between creatinine clearance calculated according to the Cockcroft-Gault equation and the observed GFR (0.86 +/- 0.21) differed significantly from unity. This study shows that in cancer patients the formula to calculate GFR drawn from Nonmem analysis is more accurate than the Cockcroft-Gault equation. However, an accurate determination of GFR requires specific techniques as 51Cr-EDTA clearance investigation.

Adult↗

PubMed1997

Efficacy and safety of lamivudine on replication of recurrent hepatitis B after cadaveric renal transplantation.

BACKGROUND: The aim of this pilot study was to evaluate the efficacy and the safety of lamivudine therapy in hepatitis B virus (HBV)-positive/DNA-positive renal transplant recipients. METHODS: Six HBV DNA-positive cadaveric renal transplant recipients ranging in age from 49+/-6 years were administered lamivudine, at 100 mg/day for a period of at least 6 months, on a compassionate-use basis. Lamivudine is the (-) enantiomer of 3'-thiacytidine, which is known to be a potent inhibitor of HBV replication. All of the patients but one were on cyclosporine-based immunosuppression. RESULTS: The mean serum creatinine was 134+/-44 micromol/L. The mean duration of HBV infection was 230+/-54 months (156-288). All of the patients but one had high serum alanine aminotransferase levels (122+/-52 IU/L; range, 45-243). Histological evaluation showed the presence of either chronic active hepatitis (n=4) or cirrhosis (n=2). All of the patients but one were hepatitis B e antigen negative/hepatitis B e antibody positive, but none were coinfected with either hepatitis C virus or hepatitis D virus. CONCLUSIONS: Lamivudine therapy was associated with (i) a normalization of alanine aminotransferase levels in four of five patients when these levels were increased at the beginning (n=5); (ii) a rapid disappearance of HBV DNA from the serum (detected by hybridization) in all of the patients; (iii) the negativity of HBV DNA by polymerase chain reaction in four patients; and (iv) no change in renal function and in proteinuria when present (one patient). Finally, no adverse effects were noted. When lamivudine therapy was stopped for four patients after 6 months, it was associated with a biochemical and virological relapse within the weeks that followed. Lamivudine therapy was therefore resumed for these patients.

Antiviral Agents↗

PubMed1997

[Preparation for transplantation and graft patient management].

Often considered at the end of a long standing chronic disease, organ transplantation requires a preparation and a strict follow up before grafting which are centered upon the prevention of the risks related to the waiting of the graft and the assessment of the risk related to the transplantation itself. Follow up of the patient after transplantation cannot be interrupted. It is a multidisciplinary approach which is focused primarily upon the function of the graft, the tolerance to immunosuppressive drugs, the detection and prevention of their complications.

Follow-Up Studies↗

PubMed1997

Outcome of patients with antineutrophil cytoplasmic autoantibody-associated vasculitis following cadaveric kidney transplantation.

In this retrospective study, we report on the progress of eight patients with biopsy-proven systemic vasculitis following cadaveric renal transplantation. Extrarenal manifestations associated with antineutrophil cytoplasmic autoantibodies (ANCAs) were present in all but one case. All the patients were on cyclosporine A-based immunosuppression, and none of them had active disease at transplantation. The mean time from the last episode of vasculitis to transplantation was 46 months (range, 10 to 132 months). On the day of transplantation, all but one patient had detectable ANCAs, which ranged from 1:100 to 1:2,000 (perinuclear ANCAs [P-ANCAs], four patients; cytoplasmic ANCAs [C-ANCAs], three patients). There were three patients with Wegener's granulomatosis, none of whom relapsed. Of those patients with microscopic polyangiitis (P-ANCAs, three patients; C-ANCAs, two patients), only one presented with relapse episodes after transplantation; the episodes involved the lungs and the kidney graft, and were successfully treated by methylprednisolone pulses. This patient had the highest ANCA titer before (1:2,000) and after (up to 1:10,000) grafting, and received no immunosuppression prior to transplantation since vasculitis was diagnosed after she had developed end-stage renal failure. This study shows that a relapse of ANCA-associated vasculitis following successful cadaveric renal transplantation occurs infrequently in the cyclosporine A era (ie, 12%), despite the persistence of circulating ANCAs in these patients at the time of transplantation, and even afterward in some cases.

Adult↗

PubMed1997

High rate of hepatitis C virus clearance in hemodialysis patients after interferon-alpha therapy.

To gain insight into the long-term effect of interferon-alpha (IFN-alpha) therapy on hepatitis C virus (HCV) RNA-positive hemodialysis patients, 23 subjects were given 3 MU of IFN-alpha 3 times a week for 6 (n = 12) or 12 months (n = 11). They were followed for 19 months after cessation of therapy. Sustained serum HCV RNA clearance occurred in 42% of patients treated for 6 months and in 64% of those treated for 12 months. HCV was eradicated from 6 of 13 patients infected with HCV genotype 1b and from 2 of 6 patients also infected with hepatitis G virus. HCV RNA remained undetectable in both serum and a liver biopsy of 2 patients who were given cadaveric kidney transplants after IFN-alpha treatment. These data suggest that HCV RNA-positive dialysis patients can be considered for treatment while receiving dialysis, particularly those awaiting transplant.

Adult↗

PubMed1997

Prevalence of antibodies to hepatitis C virus and correlation with liver disease in renal transplant patients.

We studied the prevalence of hepatitis C virus (HCV) infection in 350 renal transplant (RT) patients with a functioning graft. The determination of HCV infection was based upon second-generation ELISA tests (ELISA-2, Abbott) confirmed by second-generation RIBA tests (RIBA-2, Chiron), including the proteins C22-3, C100-3, C33-C and 5-11. Three hundred and sixteen of these RT patients were on ciclosporin A (CsA) therapy with or without steroids (CS) and azathioprine (AZA); 34 received conventional immunosuppression. Eighty-seven RT patients were found to be HCV-positive (2.5%) when assessed by ELISA-2 tests; RIBA-2 was positive in 61 cases and 'indeterminate' in 26. Most of the HCV-positive patients had antibodies against C22-3 (94%), whereas antibodies against nonstructural antigens (C100-3, C33-C) were observed in 18 and 70% of cases, respectively. More than 88% of the HCV-positive patients were already HCV-positive before renal transplantation. Risk factors of developing HCV infection included: (i) the time on dialysis; (ii) the number of blood transufsions before transplantation, and (iii) the number of previous graft(s). There were significantly more HCV-positive patients among those on conventional immunosuppressive therapy (16 of 39) than among those on CsA (71 of 311; p < 0.02). Of those who where HCV-positive before transplantation, and for whom liver enzyme (LE) results were available (n = 68), 40 had either a normal or a transient increase in alanine aminotransferase (ALT) levels at that time, whereas 28 had a chronic increase in serum ALT +/- gamma-glutamyltranspeptidase levels. After transplantation, there was biochemical evidence of chronic liver disease in 33 patients (48.5%). Interestingly, 41 and 64% of those with respectively normal and increased LEs before transplantation presented with a biochemical chronic liver disease after RT. Surprisingly, 36% of those with a pretransplantation increase in ALT had normalized aminotransferase after transplantation. The daily doses of AZA, CS (i.e. prednisolone) were not statistically different between HCV-positive RT patients on conventional therapy (group A) and those on CsA (group B). Moreover, within each group, the daily doses of AZA, CS or CsA were not statistically different between those with a chronic increase in LEs and those with normal LEs. The percentage of HCV-positive RT patients with chronic abnormal LEs was not different between groups A and B. Surprisingly, the patients who were treated at least once for acute rejection with methylprednisolone pulses had a significantly lower incidence of chronic increases in LEs. Nine patients seroconverted for HCV after transplantation: 6 experienced a chronic increase in LEs. Finally, 7 of 87 patients were coinfected by HBV, all of them had a chronic increase in LEs. These results emphasize the fact that ALT alone cannot be used as a surrogate marker for chronic HCV infection in transplantation patients, thus a liver biopsy is required before and a few years after RT to assess liver damage in this population.

Adult↗

PubMed1997

Kinetics of HCV viremia in kidney transplant recipients during and after alpha-interferon therapy.

Fifteen kidney transplant recipients with chronic hepatitis C were given 3 million units recombinant alpha2b-interferon for 142+/-35 days. There were significant decreases in hepatitis C virus (HCV) RNA 1 month after the initiation of treatment (p < 0.01), and at the end of treatment (p < 0.05). HCV RNA was undetectable by PCR analysis during treatment in 5 patients. But HCV RNA reappeared in all patients 1 month after the cessation of therapy, and the level of viremia returned to baseline. While all patients had normalized alanine aminotransferase (ALT) activities at the end of therapy, 11 experienced a relapse during the follow-up period (1 year). There was a correlation between the amount of HCV RNA at the end of treatment and the time of relapse. Serum IgM against core protein of HCV were detected in 7/15 patients. Anti-core IgM remained detectable during treatment and afterwards. There was no correlation between IgM status and other virological parameters, or ALT activity.

Adult↗

PubMed1997

CMV prophylaxis in high-risk renal transplant patients (D+/R-) by acyclovir with or without hyperimmune (CMV) immunoglobulins: a prospective study.

In this prospective randomized study including 28 patients, we show that, in cytomegalovirus (CMV)-seronegative renal transplant recipients (R-) receiving a CMV-seropositive graft (D+), high doses of acyclovir (ACV, i.e. 3,200 mg/day) during the first 3 months after transplantation were as efficient as hyperimmune CMV immunoglobulins (CMV Igs) plus high doses of ACV regarding the prophylaxis of CMV primoinfection. Fifty-four percent of the patients in the ACV arm and 50% in the other arm presented at least one episode of viremia (n.s.). The incidence of CMV disease was 31% in the ACV group and 20% in the ACV + CMV Ig group (n.s.). By comparison with historical controls (no prophylaxis), we found that ACV with or without CMV Ig significantly delayed and significantly decreased the rate of CMV disease, although the severity score was not statistically different. Moreover, high doses of ACV were far less expensive than their combination with hyperimmune CMV Igs. Thus, until oral ganciclovir is available for the prophylaxis of primary CMV infection in renal transplant patients, we recommend the use of high doses of ACV for the first 3 months after transplantation in high-risk renal transplant patients, i.e. D+/R-.

Acyclovir↗

PubMed1997

Changes in blood pressure and renal function following subtotal parathyroidectomy in renal transplant patients presenting with persistent hypercalcemic hyperparathyroidism.

The aims of this retrospective study were to assess renal function and blood pressure after subtotal parathyroidectomy (PTx) performed in renal transplant (RT) patients presenting with persistent hypercalcemic hyperparathyroidism. We identified 34 patients (group A) from our records who had undergone PTx between 1981 and 1994. Group A included 18 women and 16 men with a mean age of 45 +/- 12 years and a mean time on dialysis therapy of 102 +/- 59 months. Thirty of the patients received cyclosporine A (CsA) with or without steroids and/or azathioprine (AZA) and the remaining 4 patients received conventional therapy i.e. AZA and steroids. Twenty-three patients were treated for hypertension and 11 were normotensive. PTx was performed in 21 patients within the first year following renal transplantation and in 13 patients after this period. The study was divided into 3 periods: period 1-pre-PTx; period 2-the month following PTx; period 3-six months after PTx. Parameters were assessed for every patient in each of these periods. Results of group A were compared to those observed in 34 matched (control) RT patients (group B) who did not experience secondary hyperparathyroidism. PTx was associated with a significant decrease in parathyroid hormone (PTH) levels (45 +/- 8 pg/ml vs 338 +/- 54 pg/ml; p = 0.0002) and in calcemia (2.32 +/- 0.18 mmol/l vs 2.75 +/- 0.15 mmol/l; p = 0.0003) during period 3. However, we observed a significant increase in serum creatinine (124 +/- 30 mumol/l vs 110 +/- 25 mumol/l, p = 0.0016) in this group during period 3. Nevertheless, an increase in serum creatinine greater than 30% from baseline which still persisted six months after PTx was only observed in 8 patients (23.5%). There were more hypertensive patients in this latter subgroup (7 out of 8 i.e. 87.5%) than in the rest of the group (16 out of 26 i.e. 64.5%). Renal function impairment in group A was not related to pre-PTx SBP, DBP, MBP, calcemia, creatinine, CsA whole blood trough levels or PTH levels. Conversely, we did not observe significant changes in serum creatinine in the control group during the same periods. During period 2 there was a significant decrease in SBP (134 +/- 16 vs 140 +/- 16 mmHg; p = 0.046), DBP (81 +/- 9 vs 85 +/- 9 mmHg; p = 0.03) and MBP (99.5 +/- 10.5 vs 103.5 +/- 11 mmHg; p = 0.03) of group A. These differences persisted in period 3, with the exception of SBP, although they were no longer statistically significant. Following PTx we were able to discontinue (n = 4) or decrease (n = 4) antihypertensive drugs. In the control group baseline SBP, DBP and MBP were lower than in the PTx group, although the difference was statistically significant only for SBP (132.5 +/- 17 vs 140.5 +/- 16 mmHg; p = 0.05). During the study periods there was no significant changes in SBP, DBP or MBP in the control group. This study shows that RT patients with hypercalcemic hyperparathyroidism are often hypertensive (68%). Subtotal PTx is associated with a significant but transient decrease in SBP, DBP and MBP. Surprisingly we observe a significant and persistent increase in serum creatinine levels in 8 patients (23.5%), particularly in those presenting with hypertension before PTx. These results could reflect a dual effect of parathyroid hormone i.e. a balance between a vasodilating and hypertensive effect.

Adult↗

PubMed1997

[Clinical significance of detection and quantification of hepatitis C virus RNA in hemodialysis: proposal for a rational diagnostic strategy].

Viral infections due to hepatitis C virus in hemodialysis patients are frequent and have a potential risk of progression towards chronicity. Biochemical and viral markers of infection, are transaminases level, anti-HCV serology and the detection of HCV RNA, respectively. A rational strategy based on routine use of these three diagnostic tools is proposed in order to avoid unnecessary assays and to increase in the case of health cost control, the cost/efficacy ratio. The latter is set up, in the sero-negative hemodialysed, on the early detection of infection by the hepatitis C virus in order to consider of a therapeutic which is able to cure patients and to avoid the ineluctable passage towards chronicity; in hemodialysed with positive HCV serology, the detection of HCV RNA allows to establish the infectiosity status of these hemodialysis patients. It is therefore very important to evaluate prospectively this diagnosis approach in hemodialysis patients.

Genotype↗