The Model for End-stage Liver Disease score is potentially a useful predictor of hyperkalemia occurrence among hospitalized angiotensin receptor blocker users.

WHAT IS KNOWN AND OBJECTIVE: Angiotensin receptor blockers (ARBs) are medications commonly used for treating conditions such as hypertension. However, ARBs are frequently associated with hyperkalemia, a potentially critical adverse event, in high-risk patients. Although both the liver and the kidney are major elimination routes of ARBs, the relationship between hepatorenal function and ARB-related hyperkalemia has not yet been investigated. The purpose of this study was to evaluate the risk of hyperkalemia, in terms of various hepatorenal functions, for hospitalized patients newly initiated on ARB treatment. METHODS: We evaluated ARB-related hyperkalemia in a cohort of 5530 hospitalized patients, who had not previously used ARBs, between 12 April 2004 and 31 May 2012. Hepatorenal function was assessed by the Model for End-stage Liver Disease (MELD) score. Hyperkalemia risk was assessed by hepatorenal function, risks were categorized into the four MELD scoring groups, and the groups were compared with one another. RESULTS AND DISCUSSION: The MELD score was significantly different between the hyperkalemic and non-hyperkalemic groups (independent t-test, P < 0.001). The MELD score 10-14, 15-19 and ≥ 20 groups showed higher risks of hyperkalemia than the lowest MELD score group {log-rank test, P < 0.001; multiple Cox proportional hazard model, hazard ratios 1.478 (P = 0.003), 2.285 (P < 0.001) and 3.024 (P < 0.001), respectively}. WHAT IS NEW AND CONCLUSION: The MELD score showed a stronger predictive performance for hyperkalemia than either serum creatinine or estimated glomerular filtration rate alone. Furthermore, the MELD score showed good predictive performance for ARB-related hyperkalemia among hospitalized patients. The clinical implications and reasons for these findings merit future investigation.

Onset time of hyperkalaemia after angiotensin receptor blocker initiation: when should we start serum potassium monitoring?

WHAT IS KNOWN AND OBJECTIVE: Angiotensin receptor blockers (ARBs) frequently induce hyperkalaemia in high-risk patients. Early detection of hyperkalaemia can reduce the subsequent harmful effects. This study was performed to examine the onset time of hyperkalaemia after ARB therapy. METHODS: We carried out a retrospective analysis to determine the onset time of hyperkalaemia (serum potassium >5·5 mm) among hospitalized patients newly starting ARB therapy between 2004 and 2012, in a tertiary teaching hospital. Predefined possible risk factors and concomitant medications were evaluated. RESULTS AND DISCUSSION: During the 97-month study period, a total of 4267 hospitalized patients started ARBs as new drugs and 225 patients showed hyperkalaemia. A significantly increased risk of hyperkalaemia was detected among patients with a high baseline potassium [odds ratio (OR) 6·0] and those who took non-potassium-sparing diuretics (OR 2·2) or potassium supplements (OR 1·6). A high glomerular filtration rate (GFR) was associated with a lower risk of hyperkalaemia (OR 0·992). Fifty-two percentage of hyperkalaemic events occurred within the first week after initiation of ARB therapy. The highest frequency of hyperkalaemia occurred on the first day after initiation of ARBs. Hyperkalaemia occurred earlier in patients with a high baseline serum potassium level, reduced GFR, diabetes and in those without heart failure. WHAT IS NEW AND CONCLUSION: Hyperkalaemia occurs most frequently at the beginning of ARB therapy in hospitalized patients. Monitoring of serum potassium and estimated GFR after initiation of ARBs should be started within a few days or not later than 1 week, especially in patients with risk factors.

Upregulation and function of GADD45gamma in unilateral ureteral obstruction.

We performed differential display analysis to determine transcriptional activity in the rat kidney, following unilateral ureteral obstruction and found a 12-fold increase in the expression of Growth Arrest and DNA Damage-45gamma (GADD45gamma), a stress-responsive molecule that interacts with cell-cycle proteins. GADD45gamma was strongly expressed in as little as 6 h following ureteric obstruction in the renal tubules, and was also found in kidney tissue of patients with chronic glomerulonephritis. Adenovirus-mediated expression of GADD45gamma in cultured renal tubular cells activated p38 along with a significant upregulation of C-C and C-X3-C chemokine ligands and fibrosis-related factors such as several matrix metalloproteinases, transforming growth factor-beta1, decorin, and bone morphogenetic protein 2. Silencing of GADD45gamma expression significantly blunted the upregulation of these inflammatory and fibrogenic mediators and monocyte infiltration in the ureteral obstructed rat kidney. Our study shows that GADD45gamma is quickly upregulated in the kidney with an obstructed ureter, enhancing the production of factors regulating the pathogenesis of kidney disease.

Beneficial effects on the renal function of both recipients and donors in living donor kidney transplantation.

In living donor kidney transplantation, initial function of the donor kidneys is split into the remnant kidney and the recipient's implanted kidney. We addressed the questions whether the donor's remnant kidney function increases or decreases after donation and whether the donor's donated kidney is greater or less than that of the recipient's implanted kidney after transplantation. We measured and calculated the functional ratio of each kidney using technetium-99m diethylenetriaminepentaacetic acid (99mTcDTPA) as well as serum creatinine (Scr; mg/dL) and creatinine clearance (Ccr; mL/min/1.73 m2) using 24-hour urines from 100 donors. The Ccr was also calculated using the Cockcroft-Gault formula (Ccr-CG; mL/min/1.73 m2). Within 7 days postnephrectomy, we measured Scr, Ccr, and Ccr-CG of the remnant kidney. For recipients, the Scr, Ccr, and Ccr-CG of the implanted kidney with 24-hour urine were obtained within 7 days posttransplantation. The average Scr, Ccr, and Ccr-CG of the donors were 0.85 +/- 0.17 mg/dL, 110.4 +/- 20.8 mL/min/1.73 m2, and 82.8 +/- 17.3 mL/min/1.73 m2, respectively. After donation, the Ccr and Ccr-CG of remnant kidney increased from 54.5 +/- 11.4 and 40.8 +/- 9.3 mL/min/1.73 m2 to 68.0 +/- 14.3 and 53.6 +/- 11.6 mL/min/1.73 m2, respectively. The recipient Ccr and Ccr-CG of donated kidney also increased from 55.9 +/- 11.8 and 42.0 +/- 9.9 mL/min/1.73 m2 to 78.4 +/- 18.0 and 53.4 +/- 16.4 mL/min/1.73 m2, respectively. Kidney transplantation from a living donor should be encouraged with total functional benefit for both donors and recipients.

Routine screening for the functional asymmetry of potential kidney donors.

The functional capacity of each kidney of a healthy donor may change under the influence of genetic and environmental factors. An assumption that the donor kidneys show equal function is not always true. As part of the pre-nephrectomy evaluation of potential donors, radioisotope renal scintigraphy using technetium-99m diethylenetriaminepentaacetic acid (99mTcDTPA) was routinely included to evaluate renal functional asymmetry of undetermined etiology. The functional ratios of each kidney using 99mTcDTPA as well as serum creatinine (Scr) and creatinine clearance (Ccr) in a 24-hour urine were measured and calculated from a hundred donors. The left kidneys showed greater function (51.67%-53.35% under 95% confidence interval [CI]) and the average left versus right ratio was 52.5 versus 47.5. The average fraction of Ccr of left kidneys was 57.8 mL/min/1.73 m +/- 10.99 compared with right kidneys at 52.6 mL/min/1.73 m +/- 11.63. Seventy-three healthy volunteers donated their left kidneys, and 27, their right kidney. The average fraction of Ccr of the donated kidneys was 55.9 mL/min/1.73 m +/- 11.78 compared with that of the remnant kidneys (54.5 mL/min/1.73 m +/- 11.39). After kidney donation, the Scr of the donors increased from 0.85 mg/dL +/- 0.17 to 1.33 mg/dL +/- 0.27. The average postnephrectomy Ccr was 68.0 mL/min/1.73 m +/- 14.29. Even though the Ccr after kidney donation was higher than that of the remnant kidney estimated before the donation, one must pay attention to possible functional kidney asymmetry to select the nephrectomy site.

Fractional creatinine clearance of the donated kidney using Cockcroft-Gault formula as a predictor of graft function after living donor transplantation.

To prevent hyperfiltration of the renal allograft, it is important to initially provide adequate functioning nephrons to meet the metabolic demands of a recipient. During the preoperative evaluation of a potential kidney donor, it is necessary to estimate the renal function of donated kidney compared with the metabolic needs of the recipient. The functional ratio of each kidney was measured using technetium-99m diethylenetriaminepentaacetic acid. The serum creatinine (Scr, mg/dL) and estimated creatinine clearance (Ccr, mL/min/1.73 m(2)) using the Cockcroft-Gault formula were measured and calculated in 82 donors. We excluded recipients who had an episode of rejection, and followed all recipients for more than 6 months posttransplantation. The average functional proportion of the donated kidney was 50.5% +/- 4.7% of the total Ccr 83.4 +/- 18.3 of donors. The Scr of recipients at 1, 3, 6, and 9 months posttransplantation were significantly (P < .05) correlated with the fractional Ccr of the donated kidney; however, Scr at 1 year was not correlated (P = .307). Furthermore, the Ccr of the recipient at 1, 3, and 6 months posttransplantation were significantly (P < .05) correlated with the fractional Ccr of the donated kidney; however, the Ccr at 9 months and 1 year were not correlated (P = .094 and .141, respectively). The Scr and Ccr of recipients within 6 months after transplantation may depend on the functional mass of the donated kidney, which should be estimated prior to kidney donation and compared with the metabolic demands of the potential recipient.

Effect of basiliximab on renal allograft rejection within 1 year after transplantation.

Basiliximab is widely used in clinical practice for initial immunosuppressive treatment of renal transplant recipients, seeking to reduce the incidence of acute rejection episodes without adverse events. This retrospective study included 123 renal allograft recipients transplanted at a single center. All were followed for longer than 1 year after transplantation and treated with calcineurin inhibitor and steroid (methylprednisolone) for prophylactic immunosuppression, but basiliximab and mycophenolate mofetil were optional. We compared the outcomes of renal transplant recipients who were versus treated were not with basiliximab as initial immunosuppressive therapy. Basiliximab was used for initial immunosuppression in 42 patients. Their maintenance immunosuppressive treatment included triple (n = 44) or double (n = 79) regimens, including a calcineurin inhibitor (cyclosporine [n = 87] or tacrolimus [n = 36]), methylprednisolone with or without mycophenolate mofetil. Twenty-six (21.1%) patients had a rejection episode within 1 year after transplantation and 22 (17.9%) had infections. Within the first year after transplantation the patients who were treated with basiliximab showed fewer rejection episodes (n = 6, 14.3%) than the patients without this therapy (n = 20, 24.7%), which was not statistically significant (P = .245). However, basiliximab significantly affected the occurrence of rejection episodes among the double immunosuppressive regimen group (P = .006), but not the triple regimen group (P = .098) without an impact on infection episodes (P value of double, triple = .291, .414) within 1 year after transplantation. We concluded that basiliximab was more useful for the recipients treated with double immunosuppression with a calcineurin inhibitor and steroid than for those on a triple regimen including mycophenolate mofetil.

In vivo expression of transforming growth factor-beta1 in humans: stimulation by cyclosporine.

BACKGROUND: Transforming growth factor-beta1 (TGF-beta1) is an immunoregulatory and fibrogenic cytokine. In an earlier in vitro study, we demonstrated that cyclosporine (CsA) increases TGF-beta1 transcription rate in human T lymphocytes. Herein, we explored whether CsA augments the in vivo expression of TGF-beta1 in humans. METHODS: The inherent difficulty in studying the in vivo effect of CsA in humans was circumvented by investigating stable end-stage renal disease patients who were preconditioned with CsA before their living donor renal transplantation. Sera and peripheral blood mononuclear cells were obtained from CsA-preconditioned patients and quantified for TGF-beta1 expression at the mRNA (by competitive polymerase chain reaction) and protein (sandwich enzyme-linked immunosorbent assay) levels. RESULTS: Our studies demonstrated a significant increase in TGF-beta1 expression after CsA therapy. The stimulatory effect was unique to TGF-beta1, and CsA did not increase interleukin (IL)-10, IL-6, IL-2, or tumor necrosis factor-alpha expression. CONCLUSIONS: Our first-time demonstration of a TGF-beta1-selective in vivo stimulatory effect of CsA in humans: (1) advances a TGF-beta1-centered hypothesis for the beneficial (immunosuppression) and detrimental (fibrosis, hypertension) effects of CsA use, and (2) broadens the mechanism of immunosuppressive action of CsA to include heightened expression of an endogenous immunosuppressive cytokine.

ACE inhibitors attenuate expression of renal transforming growth factor-beta1 in humans.

Progressive nephropathies are characterized by the enhanced accumulation of extracellular matrix in the kidney. Overproduction of transforming growth factor-beta (TGF-beta) was shown to result in pathological tissue fibrosis through the accumulation of extracellular matrix proteins. It has been proposed that angiotensin II stimulates TGF-beta production. Despite accumulating data supporting the effects of angiotensin-converting enzyme (ACE) inhibitors on the attenuation of TGF-beta in vitro and in rats, such studies in humans are lacking. The present study sought to determine the effects of ACE inhibitors on TGF-beta1 in patients with glomerulonephritis. Using competitive polymerase chain reaction and the sandwich enzyme-linked immunosorbent assay, TGF-beta1 messenger RNA (mRNA) abundance and TGF-beta1 protein levels were measured. Patients with immunoglobulin A nephropathy administered ACE inhibitors showed significantly lower renal TGF-beta1 gene expression than patients not administered these medications (mean ratios of TGF-beta1/beta-actin, 4.27 +/- 0.62 [SEM] versus 14.81 +/- 3.87; P < 0.05), whereas no difference was noted between patients administered ACE inhibitors and healthy controls (4.27 +/- 0.62 versus 2.78 +/- 0.71). ACE inhibitor therapy did not affect TGF-beta1 mRNA expression in freshly isolated mononuclear cells. Urine and serum TGF-beta1 protein levels were not affected by the administration of ACE inhibitors. However, possibly a longer duration of treatment would decrease TGF-beta1 levels in urine or blood. In conclusion, we observed a significant reduction in TGF-beta1 expression in the kidney by ACE inhibitors, and this suggests that the effects of ACE inhibitors observed in animals can be extrapolated to patients with chronic renal disease.

Effect of nifedipine on renal allograft function and survival beyond one year.

We previously reported that a calcium channel blocker supplemented immunosuppression produced excellent patient and graft survival rates in cadaveric kidney transplantation. We report here the long term outcome of patients treated with nifedipine-supplemented triple immunosuppression as compared with those of historical controls who were treated similarly without nifedipine. Study subjects included 111 patients transplanted in 1990-1994, treated with nifedipine and triple immunosuppression and with functioning grafts for more than one year (Nifedipine group). The results of cyclosporine (CyA) dose, blood pressure (BP), serum creatinine (Cr), and actuarial graft survival rate (GSR) up to 5 years posttransplant in these patients were compared with those of 52 patients transplanted in 1985-1990, treated similarly without calcium channel blockers (Control group). Donor sources, gender ratio, age distribution, causes of end stage renal disease, incidence of hypertension prior to transplantation and incidence of rejection in the first year between the groups were comparable. Throughout the study period the Nifedipine group had significantly lower serum Cr (1.5 +/- 0.7 vs. 1.8 +/- 0.7 mg/dl) and higher GSR (93.8% vs. 88% at 5 years) than the Control group. BP was comparable despite higher CyA doses in the Nifedipine group (4.3 +/- 1.1 vs. 3.3 +/- 1.1 mg/kg/day). We conclude that nifedipine is beneficial in improving long-term graft function and survival in kidney transplant recipients by mitigating CyA associated renal injury.

Influence of donor and recipient gender on early graft function after living donor kidney transplantation.

Long-term effects of donor and recipient gender on the outcome of living donor kidney transplantation have been examined but the impact on early graft function is less certain. In this study, we analyzed age, gender, body weight, height, body surface area (BSA), and lean body weight (LBW) of both donors and recipients. Preoperatively we collected 24-hour urine samples to measure creatinine excretion from donor and postoperatively we determined when the recipient serum creatinine (Scr) reached baseline levels. Variables included were ischemic times, kidney graft weight, duration of dialysis, cause of end-stage renal disease (ESRD), degree of HLA match, and mismatch, types of immunosuppression (cyclosporine or FK506, dual or triple), and episodes of acute rejection. The variables were analyzed by independent sample t tests and chi-square statistics using SPSS. Values of P < .05 were considered significant. Male patients of both donors and recipients were significantly taller and heavier (higher BSA and LBW) than female. Urinary 24-hour creatinine excretion was greater in male patients whether donors or recipients. There were no statistical differences in graft weight or creatinine clearance based on the gender of the donor or recipient. The creatinine of male donors or recipients was higher than that of females. The other variables were not significantly different. In conclusion, the effect of donor or recipient gender on early graft function depends on the metabolic demands, which are higher in male recipients.

A case of nephrogenic diabetes insipidus caused by obstructive uropathy due to prostate cancer.

Nephrogenic diabetes insipidus (DI) secondary to chronic urinary tract obstruction is a rare disease. The exact cause is unknown but it is likely that increased collecting duct pressures cause damage to the tubular epithelium, resulting in insensitivity to the action of arginine-vasopressin (AVP). A 77-year-old man complaining of polyuria and polydipsia was treated with alpha glucosidase inhibitor under the impression of polyuria due to diabetes mellitus. But his symptoms did not improve. Water deprivation and AVP administration study revealed that the patient had nephrogenic DI. Urinary tract obstruction due to an enlarged prostate was suggested as a principal cause of nephrogenic DI. The patient underwent transurethral resection of the prostate and bilateral subcapsular orchiectomy. After surgery, the urine osmolarity was normalized and the patient became symptom-free. We report a case of nephrogenic DI due to obstructive uropathy which was cured by surgery eliminating obstruction.

Age matching improves graft survival after living donor kidney transplantation.

BACKGROUND: Donor and recipient age in kidney transplantation are known to affect graft and patient survival. To address the question of whether the age difference between donor and recipient impacts on graft survival and death-censored graft survival after transplantation, we examined the impact of age matching (less than 10-year age difference) on the survivals after living donor kidney transplantation. METHODS: Two hundred one cases of the primary living donor kidney transplantation were performed and were divided into two groups, age-matched (n = 123) versus age-discrepant (n = 78). Variables included in this study were age, gender, body weight, height, kidney disease, type and duration of dialysis before transplantation, degree of human leukocyte antigen mismatch, ischemic time, graft weight, episode of rejection, type of immunosuppression, recipient serum creatinine after transplantation, and causes of patient death and graft loss. RESULTS: We observed the disparities of graft survival (P = .008) and death-censored graft survival (P = .003) between the groups. One-, 3-, and 5-year death-censored graft survival was 100%, 100%, and 97% in the age-matched group, respectively; and 97%, 90%, and 88% in the age-discrepant group, respectively. By Cox regression multivariate analysis, the variable of age-matching was an independent predictor for both graft survival (ß = 1.325, P = .017) and death-censored graft survival (ß = 2.217, P = .021). CONCLUSION: During living donor and recipient matching, age difference between donor and recipient should be minimized.

Clinical significance of prophylactic antibiotics in renal transplantation.

INTRODUCTION: The use of new selective immunosuppressants as well as the emergence of new antimicrobial resistances raise the use of prophylactic antibiotics as a matter of controversy. The purpose of this study was to retrospectively analyze the clinical significance of prophylactic antibiotics in kidney transplantation. METHODS: This retrospective study included 174 renal allograft recipients who were divided into two groups: group A including patients who received perioperative prophylactic antibiotics and group B, who did not receive them. We analyzed who the incidence of infectious complications as well as the causative micro-organisms and their antimicrobial resistance within 1 month after kidney transplantation. RESULTS: Overall bacterial infections were observed during the first postoperative month in 13 cases (7.4%): 6 (3.4%) surgical site 4 (2.3%) urinary tract, 2 (1.1%) bacteremic, and 1 (0.6%) central catheter infections. There was no respiratory infection. The incidence of bacterial infection was not significantly different between the two groups. The major micro-organisms isolated after kidney transplantation, were Staphylococcus aureus and Escherichia coli; both of which had already shown multidrug resistance at the initial time of infection. CONCLUSION: Not only did use of prophylactic antibiotics have little impact to prevent bacterial infections after kidney transplantation, but also it may induce antimicrobial resistance against the antibiotics used for prophylaxis. Moreover, the increased antibiotic resistance prior to kidney transplantation hampers the effectiveness of prophylactic antimicrobial agents. Guidelines for perioperative antibiotic prophylaxis should be therefore revised.

Cytokine gene expression in peripheral blood mononuclear cells during acute renal allograft rejection.

Many studies have explored the participation of cytokines and their genes in renal allograft rejection by using biopsy tissues. To screen for rejection, a biopsy is too invasive to perform without a clinical clue. Therefore, we studied the expression of cytokines that contribute to the early phase of allograft rejection by analyzing mRNA transcripts in sequential blood samples of peripheral blood mononuclear cells (PBMCs) 120 of 6 among patients transplanted before diagnosis of rejection. for comparison with 6 control recipients. The relative expression amount of cytokine genes encoding interleukin (IL) 2, IL-4, IL-10, IL-15, and interferon-γ were assessed using real-time reverse-transcription polymerase chain reactions. IL-2, IL-4, and IL-15 mRNA expressions in clinically stable prerejection phase of the rejection group were significantly higher than those of the control group. In the prerejection samples, the expression of mRNA encoding IL-10 negatively correlated with the expressions of IL-2, IL-4, and IL-15 mRNAs, which were not different from the positive correlations in the postoperative samples from the control group. The expression patterns of IL-2, IL-4, IL-10, and IL-15 genes in PBMCs after transplantation may help to identify acute rejection episodes before clinical deterioration to monitor the efficacy of immunosuppressive treatment.

Rectal culture screening for vancomycin-resistant enterococcus in chronic haemodialysis patients: false-negative rates and duration of colonisation.

Infection or colonisation with vancomycin-resistant enterococci (VRE) is common in chronic haemodialysis (HD) patients. However, there is limited information on the duration of VRE colonisation or on the reliability of consecutive negative rectal cultures to determine the clearance of VRE in chronic HD patients. Chronic HD patients from whom VRE was isolated were examined retrospectively. Rectal cultures were collected more than three times, at least one week apart, between 1 June 2003 and 1 March 2010. The results of the sequential VRE cultures and patients' data were analysed. Among 812 patients from whom VRE was isolated, 89 were chronic HD patients and 92 had three consecutive negative cultures. It took 60.7 ± 183.9 and 111.4 ± 155.4 days to collect three consecutive negative cultures in the 83 non-chronic haemodialysis patients and nine chronic HD patients, respectively (P = 0.011). The independent risk factors for more than three negative sequential rectal cultures were glycopeptide usage [odds ratio (OR): 2.155; P = 0.003] and length of hospital stay (OR: 1.009; P = 0.001). After three consecutive negative rectal cultures, two of six chronic HD patients and 10 of 36 non-HD patients were culture positive again. In conclusion, a significant proportion of patients colonised with VRE cannot be detected by three-weekly rectal cultures, and the duration of VRE colonisation in chronic haemodialysis patients tends to be prolonged. These results may be contributing to the continued increase in the prevalence of VRE.

Does hepatorenal syndrome affect the result of liver transplantation? Clinical observations.

Hepatorenal syndrome (HRS) is a reversible, functional renal failure that occurs in patients with advanced hepatic failure. However, the reported rates of complete recovery of renal function and patient survivals after orthotopic liver transplantation (OLT) are variable. The aim of this study was to compare the outcomes after OLT between patients with HRS and those without HRS (no-HRS). We established exclusion criteria to select study patients who underwent OLT in a single center between January 2005 and October 2008. The exclusion criteria included the following: (1) malignancy, (2) <18 years of age, (3) other than primary OLT, (4) ABO mismatch or hemophilia, (5) no liver cirrhosis, and (6) survival >1 month after OLT. We selected 71 subjects, including 8 HRS and 63 no-HRS patients. No significant differences were observed in the estimated glomerular filtration rate (eGFR) between the 2 groups except for a lower eGFR on the day of and 1 month after OLT in the HRS group: 108.3 ± 40.5 versus 31.4 ± 14.1 mL/min and 85.4 ± 15.0 versus 57.3 ± 12.1 mL/min (P = .000 and P = .014, respectively). The renal function of 6/7 HRS patients who survived >1 year improved. The 1-year patient survival rate after OLT in HRS patients was similar to that without HRS: 95% versus 86% (P = .37). We concluded that HRS had minimal effects on patient survival and return of acceptable renal function.