Syndrome of inappropriate secretion of antidiuretic hormone in traumatic brain injury: when tolvaptan becomes a life saving drug.

OBJECTIVE: To outline the role of a new drug, tolvaptan, in treating severe and chronic hyponatraemia. Tolvaptan decreases aquaporin expression in renal collecting ducts, by inhibiting antidiuretic hormone (ADH)-V2 receptors, to promote free water clearance. Given its mechanism of action, this drug seems the ideal treatment for the syndrome of inappropriate antidiuretic hormone secretion (SIADH) when the osmotic imbalance leads to life threatening complications. DATA SOURCES: A case is described of severe hyponatraemia deriving from SIADH secondary to meningoencephalitis in a patient admitted to hospital for traumatic brain injury. DATA EXTRACTION: Clinical, laboratory and radiological data at presentation and for a 1 year of follow-up were analysed. DATA SYNTHESIS: Tolvaptan ameliorated hyponatraemia, brain oedema and consciousness, and drug withdrawal led to recurrence of hyponatraemia and coma. CONCLUSIONS: In patients with SIADH, which is not self-limited, and is associated with severe cognitive impairment, the use Tolvaptan may prove life saving and should be rigorously evaluated.

Long-term add-on therapy with adefovir in lamivudine-resistant kidney graft recipients with chronic hepatitis B.

BACKGROUND: To assess the long-term effectiveness and safety of adefovir (ADV) plus lamivudine (LMV) in LMV-resistant (R) kidney transplants with chronic hepatitis B, 11 such patients were treated with add-on ADV. METHODS: Serum alanine aminotransferase, renal function and serum hepatitis B virus (HBV) DNA levels were assessed every 3 months; ADV mutations were searched for by INNO-LiPA HBV DR v2 assay. RESULTS: During 36 months (12-48), nine patients cleared serum HBV DNA with a 3-year cumulative virological response rate of 88%, without the emergence of ADV mutations. ADV dose was reduced in six patients (55%) showing a decline of creatinine clearance, in the absence of proximal tubulopathy. CONCLUSIONS: In LMV-R kidney graft recipients, long-term add-on therapy with ADV is efficacious and safe with timely adaptation of ADV dose.

Long-term lamivudine monotherapy in renal-transplant recipients with hepatitis-B-related cirrhosis.

BACKGROUND: Chronic hepatitis B virus (HBV) infection is an important cause of morbidity and mortality in renal-transplant recipients. The aim of the study was to assess the efficacy and safety of long-term lamivudine monotherapy in renal-transplant recipients with HBV-related cirrhosis. METHODS: Seventeen such patients [median age: 45 years; 7 with hepatitis B e antigen (HBeAg)] received daily oral doses of 75-150 mg lamivudine for a median of 48 (range 11-81) months. All patients had baseline serum levels of HBV DNA of over 6 log10 copies per ml and of alanine transaminase (ALT) of over 1.5 times the upper normal limit (UNL). Clinical lamivudine resistance was defined as a rebound of serum HBV DNA above 5.3 log10 copies per ml and of serum ALT of over 1.5 times the UNL in patients who initially responded with HBV DNA levels of less than 5.3 log10 copies per ml and normal ALT values. Controls were 14 renal-transplant patients (median age 44 years; 3 with HBeAg) with HBV-related cirrhosis, naive to any anti-HBV therapy, followed for 58 months (4-135). RESULTS: Thirteen (77%) treated patients had a persistent response throughout the study period, including three (18%) who developed genotypic resistance, compared with none of the untreated controls (77% versus 0%, P < 0.0001). Four (23%) developed clinical resistance. Two of three patients with initially decompensated cirrhosis had a durable response and clinical improvement compared with the transient responder, whose liver function worsened following lamivudine resistance. Two responders developed chronic rejection requiring chronic haemodialysis. Overall, one treated patient developed liver-related complications, compared with eight untreated controls (6% versus 57%, P < 0.01). CONCLUSIONS: Most renal-transplant patients treated with lamivudine achieved a rapid and durable suppression of HBV, which substantially lowered the risk of liver decompensation and death.

Natural history of hepatitis B and C in renal allograft recipients.

BACKGROUND: In renal allograft recipients, most cases of liver dysfunction are caused by hepatitis B virus and hepatitis C virus (HCV). The natural history of hepatitis C and B was studied in 286 renal allograft recipients who received a kidney allograft between 1972 and 1989 when tests for anti-HCV became available. METHODS: In all patients, hepatitis B (HB) surface (s) antigen (Ag) was tested before and anti-HCV (by enzyme-linked immunosorbent assay II) after transplantation. RESULTS: At enrollment in 1989 (5.5+/-4 years after transplantation), 209 patients were anti-HCV positive (C+), 42 patients were HBsAg-positive (B+), and 35 patients were both B+ and C+ (C+B+). One hundred four patients were receiving azathioprine (AZA) and 182 were on cyclosporine A (CsA). Since transplantation, the median follow-up was 18 years in AZA-treated and 13 years in CsA-treated patients. Liver biopsy showed chronic hepatitis in 73 patients, cirrhosis in 20 patients, and fibrosing cholestatic hepatitis in 2 patients. In 34 patients, liver biopsy was repeated, and progression of fibrosis was observed in 24 patients. The 12-year patient survival rate was similar in B+, C+, and B+C+ patients (67%, 78%, and 71%, respectively; P=not significant). Liver-related death was the first cause of death in B+ and B+C+ infected patients (58% and 72%, respectively), whereas cardiovascular disease was the leading cause of death in C+ patients (40%). Multivariate analysis showed that older age (>40 years) (relative risk [RR], 2.8), B+ status (RR, 2.36), and C+ status (RR, 1.65) were independently associated with a worse patient survival. CONCLUSIONS: In the long term, B+ patients had a higher risk of death related to liver disease than C+ patients, and co-infection did not worsen patient survival.

Is cyclosporine in renal-transplant recipients more effective when given twice a day than in a single daily dose?

BACKGROUND: It is still unknown whether it is better to administer cyclosporine (CsA) once or twice a day to renal-transplant patients. METHODS: Fifty-four patients were randomized to receive CsA once a day (OD group, 28 patients) or twice a day (BD group, 26 patients). Clinical parameters and pharmacokinetic studies were regularly monitored over the first year. RESULTS: Two patients lost their grafts because of renal vascular thrombosis. A patient in the BD group died. The other 51 patients were alive with graft functioning after a minimum follow-up of 1 year. Five patients per group had reversible acute rejection. There was a not significant trend toward a lower mean serum creatinine in OD than in BD (1.38 +/- 0.38 and 1.7 +/- 0.80 mg/dL at 1 year posttransplant, respectively). In 47 patients, 319 pharmacokinetic studies were performed. We measured the area under the concentration-time curve during the first 4 hours (AUC0-4) and CsA blood levels at 0, 2, and 4 hours after dosing. C0 was significantly lower in OD than in BD (P=0.0011), whereas C2 (P<0.0001) and C4 (P<0.0001) were significantly higher in OD than in BD. In OD, the AUC was higher than in BD (P<0.0001). OD allows us to reach high levels of C2 and AUC for several hours after dosing, whereas BD showed persistently high levels throughout the whole day. CONCLUSION: No difference in survival and rejection rates were observed between OD and BD groups.

Impact of chronic allograft nephropathy and subsequent modifications of immunosuppressive therapy on late graft outcomes in renal transplantation.

BACKGROUND: Chronic allograft nephropathy (CAN) is the leading cause of organ failure in renal transplant recipients. We retrospectively evaluated the impact of varying immunosuppression in CAN patients on long-term graft survival. METHODS: We retrospectively analysed 158 cyclosporin (CsA)-treated renal transplant recipients with biopsy-proven CAN with follow-up of >1 year. Immunosuppression remained unchanged in 75 (NOVAR) and was modified in 83 patients (VAR). In 36.1% of VAR patients, it was increased; in 63.8%, the addition of other immunosuppressants was associated with a 20% reduction in or withdrawal of CsA. A regression model, for creatinine clearance (CrCl) slope analysis after therapy variation, and Cox's analysis were applied. RESULTS: In VAR patients, two-phase regression did not show a correlation between the inflection point in the CrCl slope and treatment variation. Changing immunosuppression gave a borderline advantage in long-term graft survival compared with NOVAR (P = 0.088). In univariate analysis, severe histological lesions, proteinuria >0.5 g/day and CrCl <25 ml/min at biopsy correlated with poor graft outcome (P = 0.0009). In multivariate analysis, only proteinuria and low CrCl remained significative. Stratifying histological lesions in relation to therapy variation showed that severe lesions significantly decreased survival in both VAR and NOVAR groups; however, the highly negative impact of severe lesions in NOVAR patients on graft survival [relative risk (RR) 3.602] was reduced in VAR patients (RR 1.951), with a 10 year graft survival since biopsy of 0.16 vs 0.34 (P = 0.0001). CONCLUSIONS: In transplant patients with CAN, variation of immunosuppression can reduce the negative impact of severe chronic lesions.

Effect of kidney transplantation on bone mass and body composition in males.

BACKGROUND: Bone loss is a frequent and well-known complication in the first months after renal transplantation, but there are no data considering body composition variables (bone, fat, and lean mass) together in transplant recipients. This prospective study investigated total body bone density, fat mass, and lean mass before and 1, 2, 3, 4, and 6 months after renal transplantation in male patients who underwent hemodialysis. METHODS: Twenty consecutive renal transplant male patients aged 23-64 years (mean, 40 years; median, 41 years) received one of two immunosuppressive therapies (cyclosporine+methylprednisolone, or cyclosporine+methylprednisolone+azathioprine). The bone, fat, and lean mass of the total body and its related subregions were assessed by means of dual X-ray photon absorptiometry. Mixed factorial analysis of variance for repeated measurements was used for the statistical analysis. RESULTS: During the 6 months after transplantation, there was a reduction in trabecular bone mass in the spine, ribs, and pelvis total body subregions; the reduction was statistically significant in the last two subregions. There was no statistically significant difference in the lean mass of the total body or its subregions over time, but there was a statistically significant increase in the fat mass of the total body and all of its subregions; the increase in total and trunk fat mass seemed to be greater in the patients not receiving azathioprine. CONCLUSIONS: Up to 6 months after renal transplantation in male patients who underwent hemodialysis, there is a marked increase in fat mass, a significant loss of trabecular bone mass, and no change in cortical bone and lean mass.