tacrolimus and Hyperkalemia

To determine how well tacrolimus (FK506) and cyclosporin A (CsA) are tolerated after HLA-identical blood stem cell transplantation, we performed a retrospective review of 87 adults transplanted consecutively who received FK506 (n = 40) or CsA (n = 47) in a nonrandomized fashion in combination with methylprednisolone for graft-versus-host disease (GVHD) prophylaxis and compared the incidences of complications potentially related to the immunosuppressive agents. Pre-transplant demographic characteristics, drug compliance and rates of acute GVHD were comparable for the two groups. Following first discharge, fewer patients in the FK506 group required antihypertensive therapy (32 vs 59%, P = 0.022), but more required insulin (34 vs 10%, P = 0.014). There was also a trend for more hyperkalemia and less moderate-to-severe venoocclusive disease in the FK506 group. However, nephrotoxicity, neurotoxicity, hemolytic-uremic syndrome, and cytomegaloviral or fungal infections through the first 100 days post-transplant did not differ significantly between the two groups. We conclude that for allogeneic blood stem cell transplant recipients, the incidence of complications related to FK506 and CsA in equally effective dose schedules in combination with methylprednisolone are similar with the exception of the risks of hypertension and hyperglycemia.

Topics: Acute Kidney Injury; Adolescent; Adult; Chemical and Drug Induced Liver Injury; Cyclosporine; Female; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Hyperglycemia; Hyperkalemia; Hypertension; Immunosuppressive Agents; Incidence; Infections; Male; Methylprednisolone; Middle Aged; Patient Compliance; Retrospective Studies; Seizures; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Whole-Body Irradiation

As corticosteroid-sparing protocols are increasingly utilized in kidney transplant recipients, it is crucial to understand potential drug interactions between tacrolimus (TAC) and the effect of corticosteroid withdrawal as well as to characterize dose adjustments of mycophenolate mofetil (MMF) in this setting. This prospective, multicenter, randomized, double-blind study included 397 patients who were randomized on posttransplant day 8 to receive either placebo (CSWD) or corticosteroid continuance (CCS). TAC trough levels at week two posttransplant were significantly greater in the CSWD group whereas TAC doses were comparable to the CCS group. This interaction was not observed in the African American subgroup. Higher serum creatinine and potassium levels were also observed in the CSWD group. MMF dose was significantly reduced in the CSWD group by the investigators because of decreased WBC counts, mostly outside of study protocol criteria, despite similar incidence of neutropenia and reported cytomegalovirus infection. Understanding TAC and MMF exposure in the context of corticosteroid-sparing protocols should allow for improved dosing of immunosuppressants and better management of posttransplant patients.

Topics: Adrenal Cortex Hormones; Adult; Black or African American; Body Mass Index; Double-Blind Method; Female; Humans; Hyperkalemia; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Renal Insufficiency; Tacrolimus

Alternative measures to trough concentrations [non-trough concentrations and limited area under the concentration-time curve (AUC)] have been shown to better predict tacrolimus AUC. The aim of this study was to determine if these are also better predictors of adverse outcomes in long term liver transplant recipients.. The associations between tacrolimus trough concentrations (C(0)), non-trough concentrations (C(1), C(2), C(4), C(6/8)), and AUC(0-12) and the occurrence of hypertension, hyperkalaemia, hyperglycaemia and nephrotoxicity were assessed in 34 clinically stable liver transplant patients.. The most common adverse outcome was hypertension, prevalence of 36%. Hyperkalaemia and hyperglycaemia had a prevalence of 21% and 13%, respectively. A sequential population pharmacokinetic/pharmacodynamic approach was implemented. No significant association between predicted C(0), C(1), C(2), C(4), C(6/8) or AUC(0-12) and adverse effects could be found. Tacrolimus concentrations and AUC measures were in the same range in patients with and without adverse effects.. Measures reported to provide benefit, preventing graft rejection and minimizing acute adverse effects in the early post-transplant period, were not able to predict adverse effects in stable adult liver recipients whose trough concentrations were maintained in the notional target range.

Topics: Adult; Area Under Curve; Female; Humans; Hyperglycemia; Hyperkalemia; Hypertension; Immunosuppressive Agents; Kidney Diseases; Liver Transplantation; Male; Models, Theoretical; Tacrolimus

Topics: Adolescent; Bilirubin; Child; Child, Preschool; Cyclosporine; Female; Graft Survival; Humans; Hyperkalemia; Immunosuppression Therapy; Infant; Infections; Liver Transplantation; Lymphoproliferative Disorders; Male; Safety; Tacrolimus

The mineralocorticoid aldosterone, secreted by the adrenal zona glomerulosa (ZG), is critical for life, maintaining ion homeostasis and blood pressure. Therapeutic inhibition of protein phosphatase 3 (calcineurin, Cn) results in inappropriately low plasma aldosterone levels despite concomitant hyperkalemia and hyperreninemia. We tested the hypothesis that Cn participates in the signal transduction pathway regulating aldosterone synthesis. Inhibition of Cn with tacrolimus abolished the potassium-stimulated (K+-stimulated) expression of aldosterone synthase, encoded by CYP11B2, in the NCI-H295R human adrenocortical cell line as well as ex vivo in mouse and human adrenal tissue. ZG-specific deletion of the regulatory Cn subunit CnB1 diminished Cyp11b2 expression in vivo and disrupted K+-mediated aldosterone synthesis. Phosphoproteomics analysis identified nuclear factor of activated T cells, cytoplasmic 4 (NFATC4), as a target for Cn-mediated dephosphorylation. Deletion of NFATC4 impaired K+-dependent stimulation of CYP11B2 expression and aldosterone production while expression of a constitutively active form of NFATC4 increased expression of CYP11B2 in NCI-H295R cells. Chromatin immunoprecipitation revealed NFATC4 directly regulated CYP11B2 expression. Thus, Cn controls aldosterone production via the Cn/NFATC4 pathway. Inhibition of Cn/NFATC4 signaling may explain low plasma aldosterone levels and hyperkalemia in patients treated with tacrolimus, and the Cn/NFATC4 pathway may provide novel molecular targets to treat primary aldosteronism.

Topics: Aldosterone; Animals; Calcineurin; Cytochrome P-450 CYP11B2; Humans; Hyperkalemia; Mice; NFATC Transcription Factors; Tacrolimus

Hyperkalaemia with metabolic acidosis is common but under-reported following kidney transplantation. Calcineurin inhibitors, such as tacrolimus, are widely used in the management of transplant patients and are associated with the development of hyperkalaemia. We report on 10 renal transplant patients, treated with fludrocortisone, following identification of hyperkalaemic metabolic acidosis.. All 10 patients were male aged (mean ± SD) 53.0 ± 13.2 years; 7 were Caucasian and 3 South Asian. Before and after fludrocortisone administration, respective (mean ± SD) serum potassium was 6.1 ± 0.4 mmol/L and 5.3 ± 0.3 mmol/L (p = 0.0002); serum bicarbonate 18.5 ± 1.6 mmol/L and 20.5 ± 2.3 mmol/L (p = 0.002); serum sodium 135 ± 4.6 mmol/L and 137 ± 2.2 mmol/L (p = 0.0728); serum creatinine 181 ± 61 μmol/L and 168 ± 64 μmol/L (p = 0.1318); eGFR 42 ± 18 mL/min and 46 ± 18 mL/min (p = 0.0303); blood tacrolimus 10.1 ± 2.9 ng/mL and 10.4 ± 1.4 ng/mL (p = 0.7975); and blood pressure 129 ± 15/79 ± 25 mm Hg and 126 ± 24/75 ± 7 mm Hg. Pre-fludrocortisone, there were 7 episodes of serum potassium ≥6.5 mEq/L, with 4 patients requiring admission for the treatment of hyperkalaemia. Following fludrocortisone, no patients had hyperkalaemia requiring inpatient management.. Treatment of hyperkalaemic metabolic acidosis in transplant patients on tacrolimus with low-dose fludrocortisone resulted in rapid correction of hyperkalaemia and acidosis without significant effects on blood pressure or serum sodium. Fludrocortisone can be an effective short-term option for the treatment of hyperkalaemic metabolic acidosis in kidney transplant recipients on tacrolimus; however, patient selection remains important in order to reduce to risk of potential adverse effects.

Topics: Acidosis; Adult; Aged; Fludrocortisone; Humans; Hyperkalemia; Kidney Transplantation; Male; Middle Aged; Tacrolimus

BACKGROUND Tacrolimus, a calcineurin inhibitor, is the cornerstone of immunosuppressive strategies in transplantation. Other studies have concluded that hyperkalemia correlates with tacrolimus therapy, though the impact is poorly understood. In 2 separate analyses, the aim of this study was to investigate if the presence and/or magnitude of exposure to tacrolimus increased potassium levels in heart or lung transplant recipients. MATERIAL AND METHODS This retrospective study identified allograft recipients who underwent heart or lung transplantation from January 2013 to December 2019 at Ochsner Health in New Orleans, USA. The first analysis (A-1) comprised 103 lung transplant patients' assessed potassium levels and prevalence of hyperkalemia in the absence of tacrolimus before transplant versus 30 days after transplant on tacrolimus. The second analysis (A-2) included 187 heart or lung transplant recipients and compared potassium levels and prevalence of hyperkalemia at day 30 after transplant during higher tacrolimus exposure (High-TAC) vs day 300 during lower tacrolimus exposure (Low-TAC). RESULTS In A-1, patients on tacrolimus had higher median potassium (4.7 mmol/L vs 4.1 mmol/L, P<0.0001) and prevalence of hyperkalemia (32.04% vs 5.83%, P<0.0001). In A-2, patients in the High-TAC group had higher median potassium (4.6 mmol/L vs 4.4 mmol/L, P=0.0005) and prevalence of hyperkalemia (22.46% vs 12.30%, P=0.0056). CONCLUSIONS Our findings support those from previous studies. Presence of and higher levels of tacrolimus were associated with hyperkalemia following heart and lung transplantation. These findings highlight the importance of long-term monitoring of potassium levels in patients treated with tacrolimus.

Topics: Allografts; Graft Rejection; Humans; Hyperkalemia; Immunosuppressive Agents; Lung Transplantation; New Orleans; Potassium; Retrospective Studies; Tacrolimus

Topics: Adult; Cations; Delayed Graft Function; Diabetic Nephropathies; Female; Glomerulonephritis, IGA; Graft Rejection; Humans; Hyperkalemia; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Patient Safety; Polymers; Tacrolimus; Transplant Recipients; Treatment Outcome

Calcineurin is a calcium/calmodulin-regulated phosphatase known for its role in activation of T cells following engagement of the T cell receptor. Calcineurin inhibitors (CNIs) are widely used as immunosuppressive agents; common adverse effects of CNIs are hypertension and hyperkalemia. While previous studies have implicated activation of the Na-Cl cotransporter (NCC) in the renal distal convoluted tubule (DCT) in this toxicity, the molecular mechanism of this effect is unknown. The renal effects of CNIs mimic the hypertension and hyperkalemia that result from germ-line mutations in with-no-lysine (WNK) kinases and the Kelch-like 3 (KLHL3)-CUL3 ubiquitin ligase complex. WNK4 is an activator of NCC and is degraded by binding to KLHL3 followed by WNK4's ubiquitylation and proteasomal degradation. This binding is prevented by phosphorylation of KLHL3 at serine 433 (KLHL3

Topics: Adaptor Proteins, Signal Transducing; Angiotensin II; Animals; Calcineurin; Calcineurin Inhibitors; Carrier Proteins; Cullin Proteins; Gene Expression Regulation; Germ-Line Mutation; Humans; Hyperkalemia; Hypertension; Kidney; Kidney Tubules, Distal; Mice; Microfilament Proteins; Multiprotein Complexes; Phosphorylation; Protein Serine-Threonine Kinases; Renal Insufficiency; T-Lymphocytes; Tacrolimus; Ubiquitination

Topics: Calcineurin Inhibitors; Graft Rejection; Humans; Hyperkalemia; Hypertension; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Polycystic Kidney, Autosomal Dominant; Pseudohypoaldosteronism; Severity of Illness Index; Tacrolimus

Topics: Biomarkers; Chelating Agents; Drug Interactions; Humans; Hyperkalemia; Immunosuppressive Agents; Kidney Transplantation; Patient Safety; Polymers; Potassium; Retrospective Studies; Risk Assessment; Tacrolimus; Treatment Outcome

Voriconazole is an antifungal agent that is commonly used in immunocompromised patients who develop fungal infections. We report a case of severe recurrent hyperkalemia that developed after starting voriconazole for the treatment of histoplasmosis in a kidney transplant patient who was maintained on tacrolimus-based immunosuppression. Hyperkalemia developed despite reducing the tacrolimus dose to maintain levels in a low therapeutic range. Although interactions between azoles and calcineurin inhibitors are widely recognized, this is the 1st report describing new-onset hyperkalemia following initiation of voriconazole in a kidney transplant patient receiving tacrolimus.

Topics: Adult; Antifungal Agents; Histoplasmosis; Humans; Hyperkalemia; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Male; Tacrolimus; Voriconazole

Topics: Acidosis; Adult; Fludrocortisone; Humans; Hyperkalemia; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Tacrolimus; Treatment Outcome

Tacrolimus is the cornerstone of immunosuppression following liver transplantation (OLT). However, this agent may cause hyperkalemia by multiple mechanisms affecting potassium in the distal tubule. The purpose of this study was to evaluate the impact of fludrocortisone for the management of tacrolimus-induced hyperkalemia. Hospitalized adult OLT recipients who received fludrocortisone for tacrolimus-induced hyperkalemia were retrospectively identified. Change in serum potassium within 14 days of initiation was the primary endpoint. Secondary endpoints included serum sodium, blood urea nitrogen, serum creatinine, and tacrolimus concentrations up to 14 days after fludrocortisone initiation. Nine patients were evaluated. Outcomes were analyzed with separate repeated-measures analyses of variance. Mean daily fludrocortisone dose was 0.14 ± 0.08 mg. Serum potassium decreased significantly within the 14-day study period (P < .001). Mean potassium decreased from 5.7 ± 1 to 4.3 ± 0.5 mmol/L within 48 hours of fludrocortisone initiation (P = .002). Sodium concentrations were statistically higher (P = .024), while serum creatinine was not significantly different by day 14. Mean tacrolimus concentration at fludrocortisone initiation was 10.2 ± 5.2 and remained stable to 14 days (10.4 ± 4.7 ng/mL; P = .9). This is the first study in OLT recipients demonstrating fludrocortisone significantly decreases serum potassium in patients with stable tacrolimus concentrations. Larger prospective studies are needed to confirm these results.

Topics: Anti-Inflammatory Agents; Blood Pressure; Creatinine; Female; Fludrocortisone; Humans; Hyperkalemia; Immunosuppressive Agents; Kidney Function Tests; Liver Transplantation; Male; Middle Aged; Tacrolimus

Nephrotoxicity is one of the most common side effects of long-term immunosuppressive therapy with calcineurin inhibitors. We describe a case of distal renal tubular acidosis secondary to tacrolimus administration. A 43-year-old man with end-stage liver disease due to hepatitis C and B virus infections and alcoholic cirrhosis received a liver transplantation under immunosuppressive treatment with tacrolimus and mycophenolate mofetil. In the postoperative period, the patient developed hyperkalemic hyperchloremic metabolic acidosis, with a normal serum anion gap and a positive urinary anion gap, suggesting distal renal tubular acidosis. We excluded other causes of hyperkalemia. Administration of intravenous bicarbonate, loop diuretics, and oral resin exchanger corrected the acidosis and potassium levels. Distal renal tubular acidosis is one of several types of nephrotoxicity induced by tacrolimus treatment, resulting from inhibition of potassium secretion in the collecting duct. Treatment to correct the acidosis and hyperkalemia should be promptly initiated, and the tacrolimus dose adjusted when possible.

Topics: Acidosis, Renal Tubular; Administration, Oral; Adult; Bicarbonates; Cation Exchange Resins; Drug Therapy, Combination; Humans; Hyperkalemia; Immunosuppressive Agents; Liver Cirrhosis, Alcoholic; Liver Transplantation; Male; Mycophenolic Acid; Polystyrenes; Sodium Potassium Chloride Symporter Inhibitors; Tacrolimus; Treatment Outcome

To evaluate the long-term systemic toxicity of tacrolimus (FK-506) administered by various routes, and to assess the effect of dose reduction on toxicity.. The study animals were 120 experimentally naive adult female Wistar rats weighing 200-250 g each. The rats were randomly divided into 10 equal groups (n=12 in each) and treated with tacrolimus administered topically (in drops, 0.3%, q.i.d.), intravitreally (0.5 mg/kg bodyweight/week), intramuscularly (1 mg/kg bodyweight/week), low-dose intravenously (1 mg/kg bodyweight/week) and in high-dose intravenously (2 mg/kg bodyweight/week) for 3 months. The rats in the control groups (one for each different route of administration) were treated with 0.9% NaCl. The blood concentration of tacrolimus, complete blood count and biochemistry parameters were measured each month for the 3-month study period.. The rats in the control groups and experimental groups administered topical and intravitreal tacrolimus did not demonstrate any systemic toxic effects. The rats that developed certain toxic effects (hyperglycaemia, hyperkalaemia and nephrotoxicity) in the groups given low-dose or high-dose i.v. tacrolimus responded well to dose reduction. Following dose reduction, blood glucose concentrations decreased from 247.4 +/- 42.3 mg/dL to 189.6 +/- 37.9 mg/dL (P <0.05), and from 237.4 +/- 41.1 mg/dL to 182.3 +/- 22.7 mg/dL (P <0.05) in the low- and high-dose i.v. tacrolimus-treated rats, respectively. The rats that developed impaired hepatic function after high-dose tacrolimus did not respond to dose reduction. Baseline cholesterol concentrations for the intramuscular and low- and high-dose i.v. tacrolimus-treated groups, demonstrated decreases, respectively, from 87.4 +/- 14.0 mg/dL, 86.4 +/- 14.0 mg/dL and 90.4 +/- 14.3 mg/dL to 53.6 +/- 9.8 mg/dL, 52.1 +/- 12.5 mg/dL and 63.5 +/- 11.7 mg/dL by the end of the second month. The differences were found to be statistically significant (P <0.05 for each result).. Topical or intravitreal administration of tacrolimus seems to be systemically safe whereas parenteral administration can cause some systemic haematological changes such as dose-dependent decreased serum cholesterol concentrations. Dose reduction may prevent such adverse effects.

Topics: Administration, Topical; Animals; Blood Glucose; Dose-Response Relationship, Drug; Drug Administration Routes; Female; Hyperglycemia; Hyperkalemia; Immunosuppressive Agents; Injections, Intramuscular; Injections, Intravenous; Kidney; Liver; Rats; Rats, Wistar; Tacrolimus; Vitreous Body

This study was designed to examine the hypothesis that the nephrotoxicities caused by cyclosporin and tacrolimus might differ in respect of sodium and potassium handling.. 125 patients were studied retrospectively for the first 90 days after renal transplantation. Eighty were treated initially with cyclosporin and 45 with tacrolimus.. A serum sodium level of <135 mmol/l was present for 542/5171 (10.5%) days under tacrolimus treatment compared with 377/5486 (6.9%) days under cyclosporin treatment (P < 0.0001). Severe hyponatraemia, below 120 mmol/l, was also more prevalent under tacrolimus than cyclosporin treatment, P < 0.025. Nine patients, all receiving tacrolimus, were treated with fludrocortisone for fluid depletion and/or hyponatraemia. Serum potassium levels were higher in tacrolimus-treated patients (P < 0.0001), and subjects with hyponatraemia were more likely to experience hyperkalaemia (P < 0.0001).. Hyponatraemia and hyperkalaemia were more frequent in tacrolimus-treated subjects. Taken together with previous work showing that hyperuricaemia is more frequent with cyclosporin treatment, and hypomagnesaemia with tacrolimus treatment, these findings are consistent with qualitative differences between the nephrotoxicities of cyclosporin and tacrolimus.

Topics: Adult; Cyclosporine; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Hyperkalemia; Hyponatremia; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Postoperative Care; Prevalence; Probability; Retrospective Studies; Risk Assessment; Severity of Illness Index; Tacrolimus; Transplantation Immunology; Treatment Outcome

Topics: Acidosis, Renal Tubular; Bicarbonates; Biliary Atresia; Bilirubin; Child, Preschool; Creatinine; Electrolytes; Female; Glomerular Filtration Rate; Humans; Hyperkalemia; Immunosuppressive Agents; Kidney Function Tests; Liver Transplantation; Living Donors; Postoperative Complications; Tacrolimus

This study was designed to (a) estimate the contribution of tacrolimus nephrotoxicity to episodes of renal allograft dysfunction investigated by needle biopsy, (b) describe the temporal evolution of nephrotoxicity and its response to therapy, and (c) ascertain how often renal dysfunction is associated with concurrent extra-renal toxicity. Patients were selected based on a rising serum creatinine, normal ultrasound, and biopsy findings leading to a reduction in the dose of tacrolimus and a fall in serum creatinine. Twenty two (17%) cases of nephrotoxicity were identified amongst 128 consecutive kidney transplant biopsies with sufficient clinical data for analysis. There were 13 males and 9 females, 17-75 yr in age. Tacrolimus was administered initially as a 0.075-0.1 mg/kg/d IV continuous infusion followed by an oral dose of 0.15 mg/kg twice daily. The onset of nephrotoxicity in this study occurred 1-156 wk post-operatively. The mean baseline creatinine was 212.2 +/- 168.0 mumol/l (range 88.4-875.2) and rose 40.6% +/- 14.2% (range 11-66) during episodes of nephrotoxicity (p < 0.001). The highest recorded plasma and whole-blood tacrolimus levels during the toxic episodes were respectively 2.7 +/- 0.8 ng/ml (range 1.1-3.5) and 31.6 +/- 10.6 ng/ml (range 14.5-50.5). The drug levels were considered to be beyond the therapeutic range in 18/22 (82%) patients. The highest tacrolimus level preceeded the rise in serum creatinine in 20 cases by an interval of 1.6 +/- 1.8 d. A mean reduction in tacrolimus dosage of 41% +/- 21% (range 11-89) led to a 86% +/- 18% (range 45-100) fall in the serum creatinine within 1-14 d (p < 0.001). Interactions between tacrolimus and clarithromycin, diltiazem, or itraconazole modified the pharmakokinetic parameters in three cases. Serum potassium > 5.0 mequiv/l was recorded in 9/22 (41%) cases. Three or more elevations in blood glucose > 7.7 mmol/l (140 mg/dl) were recorded in 4/11 (36%) non-diabetic patients. Hand tremors were seen in two (9%) cases and elevated diastolic blood pressure > 90 mmHg in seven (32%) patients. In conclusion, tacrolimus nephrotoxicity accounted for 17% of graft dysfunction episodes investigated by biopsy. Concurrent hyperglycemia, hyperkalemia, or tremors were noted in several patients. Nephrotoxicity responded well to reduction in the drug dosage.

Topics: Acute Disease; Administration, Oral; Adolescent; Adult; Aged; Anti-Bacterial Agents; Antifungal Agents; Biopsy, Needle; Clarithromycin; Creatinine; Diltiazem; Drug Interactions; Female; Humans; Hyperglycemia; Hyperkalemia; Hypertension; Immunosuppressive Agents; Infusions, Intravenous; Itraconazole; Kidney; Kidney Transplantation; Male; Middle Aged; Tacrolimus; Time Factors; Transplantation, Homologous; Tremor; Ultrasonography; Vasodilator Agents

Immunosuppression with FK506 for pediatric heart transplantation has been used in this institution since 1989. This study reports the unique toxicity of this macrolide agent in these heart transplant recipients.. Between October 1989 and August 1994, 49 patients were managed with FK506, which was the initial primary agent in 38 patients. The remaining 11 were switched from cyclosporine A because of persistent rejection or side effects from the cyclosporine A or prednisone. Data were obtained retrospectively from medical records.. Mean duration of follow-up was 29 months (median 37 months, range 3 to 96 months). Twenty-nine patients (59%) were receiving FK506 alone; 20 patients (41%) were receiving additional treatment with azathioprine, prednisone, or methotrexate. There were seven deaths. Twenty patients (41%) had elevated creatinine levels between 1 to 2 mg/dl. Five patients (11%) had levels greater than 2 mg/dl. Two patients with preexisting renal dysfunction while receiving cyclosporine A had chronic renal failure 32 and 36 months after switching to FK506 and required kidney transplantation. Hyperkalemia was a persistent finding in 26 patients. Of eight patients with hypertension, four had preexisting disease while receiving cyclosporine A; two had impaired renal function, and two were receiving prednisone. Severe anemia developed in eight patients (16%), two of whom had parvovirus. Moderate anemia developed in 21 patients (43%). Eosinophilia occurred in 19 patients; 11 of 19 patients (58%) had allergic symptoms. There was one case of diabetes mellitus. There were 12 significant infections with four infection-related deaths. Lymphoproliferative disease was noted in three patients, two of whom survived. Gastrointestinal symptoms, including chronic diarrhea, recurrent abdominal pain, and reflux esophagitis were present in 10 patients.. In our experience, anemia, renal toxicity, hyperkalemia, chronic diarrhea, and allergies were the most common adverse effects of FK506. Unlike cyclosporine A, hypertension, gingival hyperplasia, coarsening of facial features, and hirsutism were not seen.

Topics: Anemia; Case-Control Studies; Child; Cyclosporine; Drug Hypersensitivity; Female; Follow-Up Studies; Gastrointestinal Diseases; Graft Rejection; Heart Transplantation; Humans; Hyperkalemia; Immunosuppressive Agents; Kidney Diseases; Male; Retrospective Studies; Tacrolimus; Time Factors

Hyperkalemia is the most frequent electrolyte abnormality found in whole organ transplant recipients receiving either cyclosporine (CsA) or tacrolimus (FK506). Recipients of a simultaneous pancreas kidney (SPK) transplant with bladder drainage may be particularly susceptible to hyperkalemia secondary to sodium loss from the bladder-drained pancreas, leading to decreased sodium delivery to potassium secretory sites of the kidney. We looked at the incidence of hyperkalemia in 34 type I diabetic SPK recipients transplanted at our center over the period from 1993 to 1995 and compared this with a cohort of 25 type I diabetic recipients of a kidney alone (K(Tx)) transplant. The incidence of hyperkalemia was 73.5% in recipients of an SPK, while it was 44% in K(Tx) recipients (P<0.05). CsA levels were higher, on average, in the SPK group (339 ng/ml+/-62 versus 272 ng/ml+/-58 in the K(Tx) group, P<0.05). However, CsA levels were not different between groups at the time of hyperkalemia, 320+/-74 versus 298+/-49 for SPK and K(Tx), respectively. CsA levels at the time of hyperkalemia were not different from those at the time of normokalemia. Other medications, serum bicarbonate, and renal function were not different in the groups. SPK recipients appear to have a greater incidence of hyperkalemia than kidney alone transplant recipients. This difference cannot be explained by higher acute CsA levels, other medications, or worse renal function. The increased incidence of hyperkalemia may, in part, be secondary to decreased sodium delivery to the transplanted kidney.

Topics: Adult; Cyclosporine; Drainage; Graft Rejection; Humans; Hyperkalemia; Immunosuppressive Agents; Incidence; Kidney Transplantation; Middle Aged; Pancreas Transplantation; Tacrolimus; Urinary Bladder