K.V. Johny

Hypercoagulability, a serious problem in patients with ESRD on maintenance hemodialysis, and its correction after kidney transplantation

BACKGROUND Recurrent vascular access thrombosis (VAT) resulting in failure to continue maintenance hemodialysis (HD) therapy is not an uncommon event. The cause of VAT in these circumstances remains uncertain. We describe results of our studies to identify changes in hemostatic balance in patients on maintenance HD therapy that probably contributed to a hypercoagulable state. METHODS We studied 82 patients with end-stage renal disease on maintenance HD therapy who underwent HD for 11 to 52 months (39.3 +/- 27.4 months). Forty-nine episodes of VAT occurred in 22 patients; a single episode occurred in 12 patients; and 2 or more episodes, in 10 patients. Blood coagulation studies, including assays of inhibitors and activated protein C (PC) resistance (APCR), were performed using standard techniques. RESULTS Investigations showed the presence of lupus anticoagulant (LA) in 5.6%, anticardiolipin antibody immunoglobulin G (IgG) in 3.9% and IgM in 5.3%, APCR in 20.5%, and deficiencies in protein S (PS), PC, and antithrombin III (ATIII) in 32.1%, 24.4%, and 19.2%, respectively. When parameters were compared between patients with and without VAT episodes, LA, PC, PS, and APCR levels were significantly abnormal in those who experienced VAT. Sixteen subjects with hypercoagulable states on HD therapy underwent renal transplantation and were evaluated 9.3 +/- 4.2 months posttransplantation. Deficiencies in PC (P = 0.014), PS (P = 0.001), ATIII (P = 0.017), and APCR (P = 0.0001) were completely corrected in all subjects. CONCLUSION Hypercoagulability is a risk factor for recurrent VAT in HD patients, and renal transplantation successfully corrects these abnormalities.

Safety and efficacy of infliximab in a patient with active WHO class IV lupus nephritis

Because disease activity in systemic lupus erythematosus correlates well with increased serum levels and activity of the cytokine tumor necrosis factor alpha (TNF-α), we report on the safety and efficacy of infliximab, a chimeric monoclonal antibody directed against TNF-α, given to a patient with active lupus with diffuse proliferative nephritis (WHO Class IV). This patient who failed to remit with a combination of full-dose steroids, mycophenolate mofetil, and cyclosporine, went into sustained remission with the addition of infliximab infusions.

Does Parathyroid Hormone Affect Erythropoietin Therapy in Dialysis Patients

Objective: The objective of this study was to assess the response to recombinant human erythropoietin (rHuEPO) during treatment of anemia in dialysis patients with hyperparathyroidism. Subjects and Methods: A total of 118 patients with stage 5 renal failure on dialysis therapy were selected for this study. Anemia was treated with rHuEPO. Laboratory data for each patient included intact parathyroid hormone (iPTH), hemoglobin (Hb), hematocrit (Hct), blood urea nitrogen, serum creatinine, calcium, phosphate, and alkaline phosphatase. Patients with iPTH >32 pmol/l were considered hyperparathyroid. Erythropoietin resistance index (ERI) was expressed as the ratio of weekly rHuEPO dose/Hct level. Results: Of the 118 patients, 83 (70.3%) were on hemodialysis (HD) and 35 (29.7%) were on continuous ambulatory peritoneal dialysis (CAPD). Sixty-three patients (64.3%) with iPTH >32 pmol/l had Hb <11 g/dl, while 34 (54.8%) with iPTH <32 had Hb >11 g/dl (p = 04). Thirty-three (56%) patients with iPTH >32 pmol/l had hemocrit <33%, while 38 (61.3%) with iPTH <32 had hemocrit <33% (p = 0.4). The median value of weekly rHuEPO dose in HD patients (12,000 units) was significantly higher in comparison with CAPD patients (6,000 units; p < 0.0001). ERI was significantly higher in HD than CAPD patients with iPTH <16 pmol/l (p = 0002) as well as with patients with 16–32 pmol/l (p = 0.012). Conclusions: CAPD patients showed a reduced requirement for rHuEPO and better control of anemia compared with HD patients. ERI was also lower in CAPD than in HD patients. Hyperparathyroidism is a parameter predictive of rHuEPO hyporesponsiveness in dialysis patients.

Xanthomonas maltophilia infection in chronic peritoneal dialysis patients

Xanthomonas maltophilia infection has only been occasionally reported in patients receiving chronic peritoneal dialysis. We describe four cases of Xanthomonas maltophilia infection associated with chronic peritoneal dialysis. Two patients presented with peritonitis and two with exit site infection. All patients were diabetics, who immediately prior to the study had not received antibiotic therapy. Failure to respond to multiple antibiotic therapy resulted in catheter removal in both patients with peritonitis. In those patients with only exit site infections, dialysis could be continued following antibiotic therapy and catheter replacement in one. Catheter loss in our patients was directly attributed to peritonitis with Xanthomonas maltophilia infection.

Association of low heart rate variability with atherosclerotic cardiovascular disease in hemodialysis patients

Objective: The aim of this study was to investigate the left-ventricular (LV) mass-adjusted association between low heart rate variability (HRV) and atherosclerotic cardiovascular disease (ASCVD) among hemodialysis patients in Kuwait. Subjects and Methods: One hundred and eight patients were enrolled in the study. HRV time domain measures were obtained by 48-hour Holter monitoring, including the standard deviation of all R-wave-to-R-wave (RR) intervals (SDNN), standard deviation of all 5-min averaged intervals (SDANN), HRV triangular index (HRV-TI), percent of adjacent RR intervals differing by >50 ms (pNN50), and root mean square of sums of squares of all differences (rMSSD). Left ventricular ejection fraction (LVEF) and LV mass index (LVMI) were measured by M-mode echocardiography. Comorbidity was assessed using medical record review. Prevalent ASCVD was defined as coronary artery, cerebrovascular, or peripheral vascular disease. Results: Prevalence of ASCVD, LV hypertrophy, and LVEF <40% were 56, 59, and 10%, respectively. The SDANN was negatively associated with ASCVD (–20 ms; p = 0.003), LV systolic dysfunction (–20 ms; p = 0.001), elevated LVMI (–20 ms; p = 0.002), hypertension (–34 ms; p = 0.01), and diabetes (–20 ms; p = 0.001). After adjustment for hypertension and LVMI using logistic regression, ASCVD was associated with the lowest quartile of SDANN (OR = 4.3, p = 0.009), HRV-TI (OR = 3.3, p = 0.03), and SDNN (OR = 2.3, p = 0.10). These associations persisted after adjusting for LVEF. Conclusion: In dialysis patients, low HRV indices were strongly associated with prevalent ASCVD, independent of LVMI and LVEF. The interrelationships among HRV, diabetes, hypertension, and LVMI should be addressed in studies of HRV and ASCVD.

High incidence of post-transplant diabetes mellitus in Kuwait

Post-transplant diabetes mellitus (PTDM) has been reported to occur in 5-15% of non-diabetic renal transplant recipients. During a 15-year period (January 1983-January 1998), 631 renal transplant recipients (TxR) were followed-up in our Centre of whom 79 (12.5%) had pre-transplant diabetes mellitus. Among the 552 TxR who were non-diabetic at pre-transplantation, 117 (21.2%) developed PTDM. The gender, native renal disease and the mode of pre-transplant dialysis did not differ in those with and without PTDM. Of the 117 TxR who developed PTDM, 63 (53.8%) were above the age of 45 years where as only 90 (20.7%) of the 435 who remained non-diabetic (NDM) were above this age (P<0.05). PTDM occurred in 115 (29.6%) recipients of Arab origin (Kuwaitis and non-Kuwaitis) where as only two (1.7%) non-Arabs developed it. There was no difference in the incidence of PTDM when prednisone and azathioprine (two drug regime) were used or with cyclosporine (triple drug regime). The incidence of acute rejection episodes did not differ among PTDM and NDM groups. The over all incidence of infections requiring hospitalisation was higher in PTDM group (1.8 episodes per patient) compared to NDM group (one episode per patient) during the study period (P<0.001). Coronary heart disease was also more frequent in PTDM (15 vs. 6%, P<0.05). The cumulative graft survival at 1, 5, 10 and 14 years in the PTDM (97, 92, 74 and 67%, respectively) and NDM groups (97, 91, 80 and 73%, respectively) was similar. However, an important cause of graft loss was death of the recipient in PTDM compared to NDM (10.7 vs. 3.6%). Similarly, the patient survival up to 14 years did not differ between PTDM and NDM groups (80 and 82%, respectively), although infection related deaths were more frequent in the PTDM group (65 vs. 49%) although not statistically significant. In conclusion, there is a high incidence of PTDM in Kuwait; age and race being the two important contributory factors. The overall patient and graft survival are not adversely affected by PTDM although infections and coronary heart disease are more frequently encountered in this group.

Cytomegalovirus infection in kidney transplant recipients: early diagnosis and monitoring of antiviral therapy by the antigenemia assay.

CYTOMEGALOVIRUS (CMV) is one of the most frequent infections in renal transplant recipients. After primary infection the virus remains dormant in various cells/organs for years. There are many factors that may reactivate virus replication; among them, organ transplantation certainly is the most important one, often causing serious disease and often associated with decreased graft survival. Though treatment is available, its timing and dosage should be tailored according to the ongoing CMV disease. There are different approaches for the diagnosis of CMV infections. The “gold standard” is cell culture in which the virus can be isolated. However, it is a timeconsuming and expensive procedure. Though combining virus isolation with immunofluorescence technique reduces the time from weeks to days, it is still not enough to meet the demand of a rapid diagnosis. Polymerase chain reaction (PCR) may have a strong impact on the diagnosis of CMV infection, but there is a need for further standardization and simplification. Many of the kidney transplant recipients fail to produce antibodies due to immunosuppressive therapy, making serological diagnosis undependable in CMV infections. Recently, detection of a specific CMV replication-related antigen (CMV antigen pp65) directly in leukocytes of patients has shown a good correlation with the clinical condition of the patient. This, CMV antigenemia assay (AA) seems to provide not only a reliable, specific, and sensitive diagnostic tool, but also facilitates monitoring the effectiveness of antiviral therapy.

Inferior Long-Term Outcome of Renal Transplantation in Patients with Diabetes mellitus

Objective: To retrospectively review the long-term outcome of renal transplant in diabetics at Mubarak Al-Kabeer Hospital and Hamad Al-Essa Organ Transplant Center, Kuwait from 1983 to 1998. Methods: There were 631 renal transplant patients, comprising 79 (12.5%) patients with pretransplant diabetes mellitus (pre-TDM), 117 (18.5%) patients with post-transplant diabetes mellitus and 435 (69%) nondiabetics (ND). Subjects with post-transplant diabetes mellitus were excluded from the comparative analysis. Distribution of sex, source of donors and mode of immunosuppression were similar in pre-TDM and ND groups. Results: Fifty-three (67%) recipients in pre-TDM and 90 (20.5%) in the ND group (p < 0.01) were above 45 years of age. However, 26 (33.3%) pre-TDM and 345 (79.5%) ND were below age 45. Among those who died, coronary artery disease led to death in 36% of pre-TDM and 27% in ND. Hyperlipidemia requiring drug therapy was observed in 37% pre-TDM and 6% ND. The incidence of severe infections was nearly twice in pre-TDM over ND recipients (1.9 vs. 1.0 per patient, p < 0.001). Acute rejection episodes were more frequently seen in pre-TDM (43%) than ND (33%), however the difference was not statistically significant. The patient survivals at 1, 5, 10, 14 years were significantly lower in pre-TDM (84, 65, 58 and 58%, respectively) than in ND (97, 93, 86 and 82%, respectively). The major contributory factors were severe infections and coronary artery disease. The cumulative graft survival showed a similar pattern (52% in pre-TDM, 73% in ND at 10 years). However, when death is excluded, the 10-year pure graft survival probability was similar for the pre-TDM and ND groups (76% vs. 80%). Conclusion: Our study indicates poor patient survival in pre-TDM due to coronary artery disease and infections, whereas the pure long-term graft survival was equally good in pre-TDM and ND transplant recipients.

Long-Term Follow-up of 100 High-Risk Renal Transplant Recipients Converted From Calcineurin Inhibitors to Sirolimus: A Single Center Experience

While conversion of stable renal transplant recipients (RTR) from calcineurin inhibitors (CNI) to sirolimus (SRL) is safe and effective, it is still under investigation for recent, high-risk cases. We studied the long-term effects of conversion of high-risk subjects maintained on a CNI, mycophenolate mofetil, plus steroid regimen to SRL, mycophenolate mofetil, plus steroid on graft and patient outcomes. We retrospectively reviewed the first 100 RTR converted to SRL treatment over approximately 5 years. The main indications for conversion were biopsy-proven acute rejection (BPAR), CNI toxicity, CNI elimination, and acute-tubular necrosis (ATN). Exclusion criteria were limited to bone marrow suppression. The overall mean +/- SD age was 38.5 +/- 15.6 years, including pediatric and geriatric age groups. Mean +/- SD body mass index (BMI) was 28.99 +/- 8.0 and 40% had a BMI > 30. There were 40% RTR from deceased donors and 60% showed 4 to 6 HLA mismatches. Preconversion total BPAR and steroid-resistant rejection incidences were 35% and 14%, respectively. Mean +/- SD time to start of SRL was 11.9 +/- 22.8 months posttransplantation. Proteinuria > 2 g/d, leukopenia, and hyperlipidemia increased significantly after conversion (P = .001, P = .0003, and P = .0001, respectively). Patient and graft survivals were 95% and 90%, respectively. There was significant improvement in graft function postconversion (P < .0001). There was a high incidence of side effects and cases of SRL discontinuation. Multivariate analysis demonstrated the influence of bone marrow suppression, obesity, hyperlipidemia, nutritional status, proteinuria, and graft function on graft and patient outcomes. We concluded that conversion from CNI to SRL was effective among high-risk RTR, but with a high incidence of adverse events during long-term follow-up.

Renal Artery Stenosis in Patients with Peripheral Vascular Disease in Kuwait

Objective: The aim of this study was to identify the incidence of atherosclerotic renal artery stenosis (RAS) in patients with peripheral vascular disease (PVD) and its relation to any known risk factors. Subjects and Methods: This prospective study was conducted on 212 patients who were subjected to peripheral angiography for symptoms of PVD over a 3-year period from 1995 to 1998 at the Mubarak Al-Kabeer Hospital, Kuwait. Angiographic evidence of atherosclerotic disease and its severity was recorded in renal, abdominal aorta, iliac, femoral, popliteal and below-knee arteries. In addition, a detailed search of identifiable risk factors was done using history, clinical examination and laboratory studies. Results: The incidence of significant atherosclerotic RAS (more than 50% diameter stenosis) in patients with PVD was 15/212 (7.07%) with no significant difference in ratio between males and females (p = 0.3) compared to that of PVD alone. Patients with common iliac and femoral artery lesions had a high incidence of RAS (93.3 and 86.7%, respectively) with more than 80% probability in RAS patients with involvement of these vessels. There was significant renal impairment (p < 0.005), as assessed by serum creatinine levels, in patients with RAS compared to those who did not have it. There was a high incidence of smoking in patients with RAS (p = 0.02), and smoking was the only risk factor identified in these subjects. Conclusions: Patients with iliac or femoral atherosclerotic disease have a high probability of associated RAS. Presence of renal impairment in patients with PVD is highly indicative of RAS. Smoking is the only identified risk factor for RAS in association with PVD in our population.