R. Kohli

Digoxin pharmacokinetics: Role of renal failure in dosage regimen design

Radioimmunoassayed serum concentration and urinary excretion data for digoxin from azotemic patients were characterized using a 2‐compartment open model. Urinary excretion rates of digoxin as well as serum concentration data are needed to accurately characterize the disposition of the drug. Seven patients with renal failure showed highly variable steady‐state volumes of distribution (VSSD = 195 to 489 liters/1.73 m2) and tÛβ values (1.5 to 5.2 days). This variability is a major limiting factor in the use of dosage regimen nomograms that assume a constant VSSD and a rigorous relationship between tÛβ and creatinine clearance (ClCR). Body clearance (ClB) is a parameter that is affected by both elimination and distribution of drugs. A linear relationship between ClB and renal clearance of digoxin or ClCR was found and was used to develop a model‐independent approach to calculation of maintenance doses of digoxin. Several methods for calculating steady‐state serum concentrations of digoxin (CSSD) were compared with actual measurements obtained in 16 chronically medicated patients. Optimum computation of CSSD is obtained by use of digoxin renal and body clearances. Variability in the digoxin: creatinine renal clearance ratio is the major limiting factor in prediction of digoxin dosage regimens.

Circulating concentrations of di(2-ethylhexyl) phthalate and its de-esterified phthalic acid products following plasticizer exposure in patients receiving hemodialysis

The degree of exposure to the plasticizer di(2-ethylhexyl) phthalate (DEHP) was assessed in 11 patients undergoing maintenance hemodialysis for the treatment of renal failure. The amount of DEHP leached from the dialyzer during a 4-hr dialysis session was estimated by monitoring the DEHP blood concentration gradient across the dialyzer. Circulating concentrations of the biologically active products of DEHP de-esterification, viz., mono(2-ethylhexyl) phthalate (MEHP) and phthalic acid, were also determined during the dialysis session. On the average, an estimated 105 mg of DEHP was extracted from the dialyzer during a single dialysis session, with a range of 23.8 to 360 mg. The rate of extraction of DEHP from the dialyzer was correlated with serum lipid content as expressed by the sum of serum cholesterol and triglyceride concentrations (r = +0.65, p less than 0.05). Time-averaged circulating concentrations of MEHP during dialysis (1.33 +/- 0.58 micrograms/ml) were similar to those of DEHP (1.91 +/- 2.11 micrograms/ml). Blood concentrations of phthalic acid (5.22 +/- 3.94 micrograms/ml) were higher than those of the esters. The length of time patients had been receiving regular dialysis treatment was not a determinant of circulating concentrations of DEHP or MEHP. In contrast, time-averaged circulating concentrations of phthalic acid correlated strongly with the duration (in years) of dialysis treatment (r = +0.92, p less than 0.001). The results indicated substantial exposure to DEHP during hemodialysis and that the de-esterified products of DEHP are present in significant concentrations in the systemic circulation. Further study is needed to assess the contribution of these metabolites to the biological actions of DEHP in man.

Early and severe hyperparathyroidism associated with hypercalcemia after renal transplant treated with cinacalcet.

Bone disease is a common clinical problem following renal transplantation. In renal transplant recipients, multiple underlying factors determine the extent of bone loss and the subsequent risk of fractures. In addition to the well‐recognized risk to bone disease posed by steroids, calcineurin inhibitors and pre‐existing bone disease, persistent hyperparathyroidism (HPT) contributes to post‐transplant bone loss. HPT is usually treated with vitamin D supplements combined with calcium. Patients whose HPT is associated with hypercalcemia pose a difficult therapeutic dilemma which often requires parathyroidectomy. Cinacalcet, a calcium mimetic agent, offers a unique pharmacologic approach to the treatment of patients with post‐transplant hypercalcemia and HPT. In this paper, we describe the clinical course and biochemical changes in 10 renal transplant recipients with hypercalcemia and severe HPT early after renal transplantation treated with cinacalcet. Cinacalcet therapy corrected hypercalcemia and decreased parathyroid hormone (PTH) levels in all cases. A transient rise in the level of alkaline phosphatase was noted following initiation of cinacalcet therapy. In this patient population, correction of HPT was not permanent as discontinuing cinacalcet therapy led to a rapid rise in PTH level.

The occurrence of IgA-nephropathy in patients with diabetes mellitus may not be coincidental: a report of five cases.

We describe five patients with IgA-nephropathy complicating diabetes mellitus. In four cases, diabetic glomerulosclerosis was present at the same time. One patient suffered from dermatitis herpetiformis. The observation of the present five cases together with the notion of an increased prevalence in diabetes mellitus of celiac disease and dermatitis herpetiformis suggests that the occurrence of IgA-nephropathy in diabetic patients is not mere coincidence.

Prognostic Utility of Hypothermic Machine Perfusion in Deceased Donor Renal Transplantation

UNLABELLED Pulsatile pump perfusion of kidney transplants is known to decrease delayed graft function (DGF) and improve 1 year graft survival when compared to static cold preservation. Kidneys with better flow and resistance parameters on perfusion are likely to have a better post transplant function. These parameters are commonly used to evaluate kidneys being considered for transplantation. This study assesses the time frame for a kidney within which it reaches optimal perfusion parameters. All kidneys pumped between 5/2006 and 9/2009 on a Lifeport© kidney transporter at our local organ procurement agency were studied. 190 kidneys were evaluated and then divided into two groups based on whether terminal flows increased or declined after prolonged perfusion. All kidneys were assessed for changes in flow (F), resistance (R) and temperature at 15 minute intervals. Discards, DGF and one year graft survival were noted. The Student paired t test and Chi-square analysis were used to compare data. A multiple logistic regression analysis was performed to study independent predictors of DGF on pump perfusion. RESULTS For all kidneys, the mean initial flow was 59 ± 35 mL/min which improved to an average flow of 128 ± 38 mL/min with continued perfusion. The maximal flow and terminal flows were 148 ± 51 and 135 ± 38 mL/min respectively. The flows at 2, 4, and 6 hours was 125 ± 41, 128 ± 42 and 130 ± 39 mL/min respectively. Kidneys that improved on continued perfusion had a significantly lower discard rate (20 vs 34% p < 0.05), but a higher incidence of DGF (64 vs 39%, P < .05). One year graft loss (death censored) was comparable in the two groups. (4/42 vs. 3/33, P = .94). Resistance at 2, 4, and 6 hours was predictive of DGF, as was donor anoxia and cerebrovascular accident (CVA) as the cause of death. CONCLUSIONS Kidneys on pulsatile pump perfusion tend to show improved flows and decreased resistance over time. The average flow for a kidney is reached by 2 hours. Those kidneys that start with lower flow rates that improve after 2 hours with continued perfusion are less likely to be discarded but are still associated with a greater incidence of delayed graft function. Resistance at 2 hours predicts DGF while initial resistance predicts one year graft survival.

Low-Dose Rabbit Antithymocyte Globulin Versus Basiliximab Induction Therapy in Low-Risk Renal Transplant Recipients: 8-Year Follow-Up

Antibody induction is effective in preventing acute rejection, but its effects on long-term renal allograft function and survival remain controversial. Moreover, given the risks of antibody induction, full-dose lymphocyte-depleting therapy for low-risk patients is usually avoided. However, the benefit and risks associated with low-dose (Lo) rabbit antithymocyte globulin (rATG; 3-5 mg/kg total) induction in a low-risk population have not been explored. We now report the long-term outcomes in this patient population. We defined low risk as white, panel-reactive antibody<30%, and non-Donor with Cardiac Death (DCD) recipients. We compared the risk of acute rejection and graft survival for both living donor (LD) and deceased donor (DD) recipients. The average dose of rATG was 3.1±1.2 mg/kg. Forty DD recipients received basiliximab (BSX) and 145 patients were induced with Lo rATG. Twenty LD recipients received BSX and 64 received Lo rATG. The groups did not differ in demographics, donor characteristics, and maintenance immunosuppression. At 8 years, patient survival was higher for LD patients compared to DD recipients (91% vs 45%, P=.004). In recipients of LD kidneys, 8-year patient survivals were not different comparing Lo rATG and BSX groups (92% vs 91%, respectively, P=.55). In LD, 8-year graft survival was excellent irrespective of induction (Lo rATG 100% vs BSX 98%); however, Lo rATG was associated with a lower rate of acute rejection (7.8% vs 35% BSX, P<.01) and better mean serum creatinine at 3 and 5 years (1.2 vs 1.5, P=.02 and 1.18 vs 1.54, P=.04, respectively). For DD, Lo rATG was associated with a better long-term graft survival (86% vs 76% BSX, P=.02). Viral infections and cancer rates were similar for Lo rATG and BSX. Thus, we conclude that Lo rATG induction may add long-term benefit in low-risk patients compared to anti-interleukin-2 receptor therapy without incurring additional risks of infectious or malignant diseases.

Dual Kidney Transplants From Very Old or Very Young Donors: Long-Term Outcomes and Complications

The disparity between donors and the demand for organ transplants grows steadily. Annually, 4700 patients die on the kidney transplant waiting list in the United States. To increase utilization of deceased donor organs, we expanded our acceptable criteria to include very old (VO) or very young (VY) donors. We transplanted both such kidneys (dual transplant) into a single recipient and evaluated the long-term outcomes and complications. From July 2001 to December 2005, 16 patients (mean age 68, range 60-78) received dual kidneys from VO (mean age 72, range 60-79) donors and 6 patients (mean age 47, range 27-72) were transplanted from VY (mean age 17 months, range 2-36) donors. Seventy-four percent of these kidneys were imported after rejection by their local center due to low glomerular filtration rate (GFR) and extreme age. One- and 5-year patient survival rates were 100% and 88%, respectively. Death-censored 1- and 5-year graft survival rates for recipient of VO kidneys were 95% and 93%, and 66% and 50% for recipients of VY kidneys, respectively. Five-year graft survival rate for recipients of VO donor kidneys was 93% and was equal to the survival of standard deceased donor (SCD) kidney transplants (87%). The 5-year survival of dual transplants from VO donors was higher than expanded criteria deceased donor (ECD; P=.05). Over a mean follow-up of 66±28 months, rejection rates were 10%, not statistically different than other groups. Of 22 dual transplants, four patients experienced urinary tract infections; three developed incisional subcutaneous seromas, and there were more urinary leaks compared to SCD (13.6% vs 2%, P=.002). The average 1- and 5-year estimated GFR (Cockcroft-Gault) was 57.4 and 54.6 mL/min, respectively. When properly placed in a single patient, such marginal organs are a valuable resource that offer comparable outcomes to SCD transplants and superior outcomes to ECD organs.

African American renal transplant recipients (RTR) require higher tacrolimus doses to achieve target levels compared to white RTR: does clotrimazole help?

The number of African Americans (AAs) on the kidney waiting list is increasing in the United States. Several studies showed that AAs are at higher risk for rejection and graft loss. Because of genetic polymorphisms, AAs may metabolize calcineurin inhibitors faster than Caucasian (C) individuals. The goal of this study is to evaluate the tacrolimus (TAC) dose required to reach therapeutic levels and to assess the impact of clotrimazole on TAC metabolism in AAs compared to C patients. One hundred forty-two AA renal transplant recipients (RTRs) were compared to 309 C RTRs. Demographics were similar in both groups. Induction therapy and maintenance immunosuppression were similar in both groups and included TAC, mycophenolate acid (MPA), and steroids. The goal in all RTRs was to maintain a 12-hour trough level of 10 to 15 ng/mL in the first 3 months, 8 to 10 ng/mL for the first year, and 5 to 8 ng/mL thereafter. To achieve these levels, AA RTRs require a significantly higher dosage of TAC compared to C patients (5.9 ± 2.9 vs 3.6 ± 2 mg/d, respectively, P < .0001). By multivariate analysis, TAC dose requirements were not affected by age, gender, MPA or prednisone dose, diabetes, and renal function. Adding clotrimazole (CTM) to the RTR regimen significantly reduced the TAC dose requirements in all RTRs. When CTM was used, the TAC dose requirement was not statistically significantly different between AA and C patients (2.6 ± 1.2 mg/d vs 1.8 ± 1.5 mg/d, P = .07). We conclude that AAs required a higher TAC dose to reach the desired trough level in RTRs compared to C RTRs. The use of CTM eliminates the need for higher doses of TAC in AA RTRs. Thus, CTM may aid AA RTRs in achieving therapeutic TAC levels while reducing drug costs.

The Pharmacokinetics and Pharmacodynamics of Methylprednisolone in Chronic Renal Failure.

Methylprednisolone (MP) pharmacokinetics and its directly suppressive effects on cortisol secretion, circulating T-cells, and basophils in blood were compared in six chronic renal failure (CRF) subjects and six healthy controls after an IV administration of MP 0.6 mg kg-1 as the sodium succinate ester. The CRF subjects were studied between hemodialysis treatments. The total clearance of methylprednisolone sodium succinate (the prodrug) was reduced by 40% in CRF; however, the pharmacokinetics of methylprednisolone remained unchanged. Methylprednisolone clearance was approximately 280 ml h-1 kg-1 and volume of distribution was about 1.1 L kg-1. Physiological pharmacodynamic models were applied for the immediate effects of MP, based on the premise that receptor binding is followed by rapid suppression of the secretion of cortisol and recirculation of basophils, T-helper cells, and T-suppressor cells, which persist until inhibitory concentrations (IC50) of methylprednisolone disappear. The difference in (IC50) for each pharmacodynamic parameter was not statistically significant, suggesting no difference in the responsiveness of these factors to methylprednisolone in CRF. As the pharmacokinetics of other corticosteroids are altered in CRF, the lack of pharmacokinetic and pharmacodynamic changes of methylprednisolone may engender a therapeutic advantage for this corticosteroid in CRF.

Universal perioperative antimicrobial prophylaxis is not necessary in kidney transplantation.

Laftavi MR, Rostami R, Patel S, Kohli R, Laftavi H, Feng L, Said M, Dayton M, Pankewycz O. Universal perioperative antimicrobial prophylaxis is not necessary in kidney transplantation. 
Clin Transplant 2011 DOI: 10.1111/j.1399‐0012.2011.01531.x. 
© 2011 John Wiley & Sons A/S.