tacrolimus and Uremia

Uremic itch is a frequent and sometimes very tormenting symptom in patients with advanced or end-stage renal failure, with a strong negative impact on the quality of life. According to a representative study, the point prevalence of chronic itch is 25% in hemodialysis patients but may reach more than 50% in single cohorts depending on the country and dialysis efficacy. Not much is known regarding the pathogenesis of uremic itch. Besides parathyroid hormone, histamine, tryptase, and alteration of the calcium-phosphate metabolism have been suspected. More recently, derangements in the opioid system and an inflammatory condition have been investigated as suspected players in the pathogenesis of uremic itch, but remain unproven so far. Treatment of chronic itch in dialysis patients remains difficult. Besides topical application of rehydrating or immunomodulating compounds, such as γ-linolenic acid or tacrolimus treatment with nalfurafine may be helpful. Apart from that, gabapentin and pregabalin are promising drugs to alleviate uremic itch. In many cases, UVB phototherapy is effective in reducing the intensity of itch. When treating patients, one should take into account that most of the drugs available are not licensed for the treatment of itch. Therefore, a deliberate use of therapeutic options aiming for a good risk-benefit relation should be adopted. In very severe and refractory cases, patients suitable for renal transplantation might be switched to 'high urgency' status, as successful renal transplantation cures uremic pruritus in most of the cases.

Topics: Acupuncture Therapy; Amines; Analgesics, Opioid; Anticonvulsants; Calcineurin Inhibitors; Cyclohexanecarboxylic Acids; Gabapentin; gamma-Aminobutyric Acid; gamma-Linolenic Acid; Humans; Kidney Failure, Chronic; Morphinans; Narcotic Antagonists; Pregabalin; Pruritus; Receptors, Opioid, kappa; Receptors, Opioid, mu; Renal Dialysis; Spiro Compounds; Tacrolimus; Ultraviolet Therapy; Uremia

Uremic pruritus or chronic kidney disease-associated pruritus (CKD-aP) remains a frequent and compromising symptom in patients with advanced or end-stage renal disease, strongly reducing the patient's quality of life. More than 40% of patients undergoing hemodialysis suffer from chronic pruritus; half of them complain about generalized pruritus. The pathogenesis of CKD-aP remains obscure. Parathormone and histamine as well as calcium and magnesium salts have been suspected as pathogenetic factors. Newer hypotheses are focusing on opioid-receptor derangements and microinflammation as possible causes of CKD-aP, although until now this could not be proven. Pruritus may be extremely difficult to control, as therapeutic options are limited. The most consequential approaches to treatment are: topical treatment with or without anti-inflammatory compounds or systemic treatment with (a) gabapentin, (b) μ-opioid receptor antagonists and κ-agonists, (c) drugs with an anti-inflammatory action, (d) phototherapy, or (e) acupuncture. A stepwise approach is suggested starting with emollients and gabapentin or phototherapy as first-line treatments. In refractory cases, more experimental options as μ-opioid-receptor-antagonists (i.e., naltrexone) or κ-opioid-receptor agonist (nalfurafine) may be chosen. In desperate cases, patients suitable for transplantation might be set on 'high urgency'-status, as successful kidney transplantation will relieve patients from CKD-aP.

Topics: Acupuncture Therapy; Amines; Anti-Inflammatory Agents; Calcium Channel Blockers; Cyclohexanecarboxylic Acids; Gabapentin; gamma-Aminobutyric Acid; gamma-Linolenic Acid; Humans; Morphinans; Naltrexone; Narcotic Antagonists; Pentoxifylline; Phototherapy; Pregabalin; Pruritus; Receptors, Opioid, kappa; Renal Insufficiency, Chronic; Spiro Compounds; Tacrolimus; Thalidomide; Uremia

The immunosuppressive drugs used for solid organ transplantation all have a narrow therapeutic index with wide variation between individuals in the blood concentration achieved by a given dose. Therapeutic drug monitoring is employed routinely but may not allow optimisation of drug exposure during the critical period two to three days following transplantation. A key factor in the inter-individual variability for tacrolimus, and probably sirolimus, is whether an individual is genetically predicted to express the drug metabolising enzyme cytochrome P450 3A5 (CYP3A5). Individuals predicted to express CYP3A5 by possession of at least one wild-type CYP3A5*1 allele require 1.5-2 times higher doses of tacrolimus to achieve target blood concentrations than individuals homozygous for the CYP3A5*3 allele who are functional non-expressers of CYP3A5. Planning the initial tacrolimus dose based on the CYP3A5 genotype has been shown to allow more rapid achievement of target blood concentrations after transplantation than a standard dose given to all patients. However, it remains to be demonstrated that use of this approach as an adjunct to therapeutic drug monitoring can reduce either efficacy failure (transplant rejection) or toxicity. Use of a pharmacogenetic approach to dosing sirolimus awaits testing and it is unlikely to be useful for ciclosporin or everolimus.

Topics: Alleles; Biomarkers, Pharmacological; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Humans; Immunosuppressive Agents; Organ Transplantation; Tacrolimus; Uremia

The uremic pruritus is a very painful symptom suffered by chronic haemodialysis patients and is observed in 22 to 74% of the subjects. The causes of uremic pruritus have not yet been clarified. During the last 20 to 30 years it has been focused on altogether 5 different pathophysiological hypotheses: stimulating influences (e.g. calcium phosphate deposits in the epidermis), stimuli (e.g. secondary hyperparathyroidism), neuropathic injuries (e.g. disturbance of the cutaneous innervation in patients with uremic peripheral neuropathy), and central nervous changes (e.g. accumulation of endorphins in uremic patients which is associated with increasing pruritus), and immunologic conditions. The last mentioned immunological hypothesis has increasing importance, not at least based on the fact that the application of a topical calcineurin inhibitor (tacrolimus) improves the uremic pruritus. However, this fact could not be confirmed in a recent prospective placebo-controlled study from the USA. Only after kidney transplantation with a functioning transplant the uremic pruritus is stopped. That is why no causal therapy exists so far. Actually, the uremic pruritus has to be treated by topical and systemic means in a symptomatic and polypragmatic way only. Urea represents one of the most important "natural moisturizing factors" which are responsible for the hydration of the skin. It has been demonstrated that older patients have decreased urea levels within the stratum corneum of the epidermis, whereas in patients with terminal kidney insufficiency - despite dryness of the skin - as a paradox finding elevated levels of urea have been assessed in the stratum corneum. Because of this reason, the meaning of urea as part of the "natural moisturizing factors" system is not understood, until now. However, there are very promising results of clinical phase II studies showing a significant effect of topical application of 2.5% L-arginine hydrochlorid ointment - a semi-essential amino acid - on improvement of dryness and, in particular, on improvement of pruritus in haemodialysis patients.

Topics: Antipruritics; Arginine; Calcineurin Inhibitors; Capsaicin; Controlled Clinical Trials as Topic; Humans; Ichthyosis; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Ointments; Prospective Studies; Pruritus; Renal Dialysis; Skin; Tacrolimus; Urea; Uremia

Topical tacrolimus is an immunosuppressant that acts through the inhibition of calcineurin and thus of the T cells. This causes a decrease in the production of interleukins, the granulocyte colony stimulating factor, alpha interferon and tumor necrosis factor. Although the use of topical tacrolimus is only indicated for the treatment of moderate or severe atopic dermatitis, its immunosuppressant effect and fewer side effects regarding topical corticosteroids have lead to the increase of its use in other types of inflammatory skin diseases. The purpose of this article is to review the use of tacrolimus in this group of diseases other than atopic dermatitis, this use not being authorized within the data sheet of the drug.

Topics: Adult; Autoimmune Diseases; Child; Clinical Trials as Topic; Dermatitis; Graft vs Host Disease; Humans; Immunosuppressive Agents; Lichenoid Eruptions; Multicenter Studies as Topic; Off-Label Use; Pruritus; Psoriasis; Pyoderma Gangrenosum; Skin Diseases; Tacrolimus; Uremia; Vitiligo

Topics: Humans; Naltrexone; Peritoneal Dialysis, Continuous Ambulatory; Prevalence; Pruritus; Renal Dialysis; Tacrolimus; Uremia

Topics: Administration, Topical; Adult; Calcineurin Inhibitors; Double-Blind Method; Humans; Immunosuppressive Agents; Pruritus; Severity of Illness Index; Tacrolimus; Treatment Outcome; Uremia

Pruritus is a common and disabling symptom for patients undergoing hemodialysis. Many topical and systemic treatments have been used for uremic pruritus, mostly in anecdotal reports. A recent case series demonstrated that topical tacrolimus ointment 0.03% had a significant antipruritic effect for patients with uremia. In an attempt to confirm these findings, we conducted a randomized, double-blind, vehicle-controlled study to assess the efficacy of tacrolimus ointment 0.1% for the treatment of hemodialysis-related pruritus. The results of this study do not demonstrate that tacrolimus ointment 0.1% is more effective than vehicle in relieving uremic pruritus.

Topics: Administration, Topical; Aged; Double-Blind Method; Humans; Immunosuppressive Agents; Middle Aged; Ointments; Pruritus; Renal Dialysis; Tacrolimus; Uremia

Uremia is proposed to increase sympathetic nerve activity (SNA) in hemodialysis patients. The aims of the present study were to determine whether reversal of uremia by successful kidney transplantation (RTX) eliminates the increased SNA and whether signals arising in the diseased kidneys contribute to the increased SNA in renal failure.. We compared muscle sympathetic nerve activity (MSNA) in 13 hemodialysis patients wait-listed for RTX and in renal transplantation patients with excellent graft function treated with cyclosporine (RTX-CSA, n=13), tacrolimus (RTX-FK, n=13), or without calcineurin inhibitors (RTX-Phi, n=6), as well as in healthy volunteers (CON, n=15). In addition to the above patients with present diseased native kidneys, we studied 16 RTX patients who had undergone bilateral nephrectomy (RTX-NE). Data are mean+/-SEM. MSNA was significantly elevated in hemodialysis patients (43+/-4 bursts/min), RTX-CSA (44+/-5 bursts/min), RTX-FK (34+/-3 bursts/min), and RTX-Phi (44+/-5 bursts/min) as compared with CON (21+/-3 bursts/min), despite excellent graft function after RTX. RTX-NE had significantly reduced MSNA (20+/-3 bursts/min) when compared with RTX patients. MSNA did not change significantly with RTX in 4 hemodialysis patients studied before and after RTX (44+/-6 versus 43+/-5 bursts/min, P=NS). In contrast, nephrectomy resulted in reduced MSNA in all 6 RTX patients studied before and after removal of the second native kidney.. Despite correction of uremia, increased SNA is observed in renal transplant recipients with diseased native kidneys at a level not significantly different from chronic hemodialysis patients. The increased SNA seems to be mediated by signals arising in the native kidneys that are independent of circulating uremia related toxins.

Topics: Calcineurin Inhibitors; Cyclosporine; Female; Hemodynamics; Humans; Hypertension; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Muscle, Skeletal; Nephrectomy; Renal Dialysis; Sympathetic Nervous System; Tacrolimus; Uremia

Simultaneous pancreas-kidney transplantation has become a widely accepted treatment option for selected uremic patients with insulin-dependent diabetes mellitus (IDDM). Patient survival rates at 1 year exceed 90%, and rates of pancreas graft survival, 70%. However, solitary pancreas transplantation for nonuremic patients with IDDM has been controversial because of the less favorable outcome and the need for long-term immunosuppression with its associated morbidity and mortality.. We studied the outcome of 225 solitary pancreas transplants during three immunosuppressive eras: the precyclosporine (CsA) era (n=83), the CsA era (n=118), and the tacrolimus era (n=24). Only patients with labile IDDM (e.g., hypoglycemic unawareness, insulin reactions, > or = 2 failed attempts at intensified insulin therapy for metabolic control) underwent solitary pancreas transplantation. Using univariate and multivariate analyses, we looked at patient and graft survival, the risk of surgical complications, and native kidney function during these three eras.. Pancreas graft survival improved significantly over time: 34% at 1 year after transplantation in the pre-CsA era, 52% in the CsA era, and 80% in the tacrolimus era (P=0.002). Pancreas graft loss due to rejection decreased from 50% at 1 year in the pre-CsA era, to 34% in the CsA era, to 9% in the tacrolimus era (P=0.008). The rate of technical failures (i.e., the risk of surgical complications) decreased from 30% in the pre-CsA era, to 14% in the CsA era, to 0% in the tacrolimus era (P=0.001). Patient survival rates at 1 year have ranged between 88% and 95% in the three eras (P=NS). Matching for at least one antigen on each HLA locus and avoiding HLA-B mismatches significantly decreased the incidence of rejection. The incidence of native kidney failure due to drug-induced toxicity decreased significantly over time, in part because only recipients with pretransplant creatinine clearance > or = 80 ml/min received transplants.. Solitary pancreas transplantation has become a viable alternative for nonuremic patients with labile IDDM. The risks of surgical complications and drug-induced nephrotoxicity have significantly decreased over time. Using tacrolimus as the mainstay immunosuppressant, patient and graft survival rates now no longer trail those of simultaneous pancreas-kidney transplantation.

Topics: Adolescent; Adult; Azathioprine; Cyclosporine; Diabetes Mellitus, Type 1; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Pancreas Transplantation; Prednisone; Tacrolimus; Uremia

Topics: Adolescent; Adult; Anti-Bacterial Agents; Child; Child, Preschool; Creatinine; Diabetes Mellitus, Type 1; Female; Heart Transplantation; Humans; Hypertension; Immunosuppression Therapy; Infant; Infant, Newborn; Kidney; Male; Middle Aged; Oliguria; Prospective Studies; Tacrolimus; Uremia

Topics: Adult; Aminoisobutyric Acids; Antiviral Agents; Benzimidazoles; Cyclopropanes; Drug Combinations; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Leucine; Liver Transplantation; Living Donors; Proline; Pyrrolidines; Quinoxalines; Sulfonamides; Tacrolimus; Uremia

Topics: Adult; Aminoisobutyric Acids; Benzimidazoles; Cyclopropanes; Drug Combinations; Hepacivirus; Humans; Lactams, Macrocyclic; Leucine; Liver Transplantation; Living Donors; Proline; Pyrrolidines; Quinoxalines; Sulfonamides; Tacrolimus; Uremia

Simultaneous pancreas and kidney transplantation (SPK) from cadaveric donors has become a widely accepted therapeutic option for insulin-dependent uremic patients. In 1996 the first SPK from a live donor was performed. This procedure offers the advantage of a better immunologic match, reduced cold ischemia injury, and decreased waiting time. As such, it is an attractive alternative treatment for diabetic patients with end-stage nephropathy with an available living donor.. We performed six SPKs from living-related donors. There were four men and two women among the recipients; median age was 34 (range, 29-39) years. All donors were recipients' siblings with excellent HLA matching. Donors underwent standardized metabolic workup, anti-insulin and anti-islet antibody assays, and computed tomography of the abdomen. Both donors and recipients were treated with octreotide for 5 days perioperatively. After transplantation, the patients were maintained on tacrolimus-based immunosuppression, with the exception of one recipient of SPK from an identical twin, who received cyclosporine monotherapy.. All the donors are doing well and have normal renal function and blood glucose levels. One-year patient, renal, and pancreatic graft survival rates were 100%, 100%, and 83%, respectively. Acute kidney rejection was documented in two patients, and both recovered completely after OKT3 therapy. No rejection of pancreatic graft has been documented. Except for one patient who lost the graft because of hemorrhagic pancreatitis, all recipients maintained serum glucose levels at less than 130 mg/dL without insulin therapy. No major surgical complications such as graft thrombosis, intra-abdominal infection, or abscess were reported.. Living donor SPK can represent a successful alternative to cadaveric donor SPK. The procedure can be performed safely in the donor and with low morbidity in the recipient.

Topics: Adult; Blood Glucose; Cadaver; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Muromonab-CD3; Pancreas Transplantation; Tacrolimus; Tissue Donors; Treatment Outcome; Uremia

The aim of this study was to investigate the mechanism of hypertension and thromboembolic events induced by cyclosporin (CyA) and tacrolimus (FK506) in respect to their action on the serotonergic blood system. The study was carried out on healthy rats and those with experimental chronic renal failure. CyA injected into healthy and uremic rats caused an increase in serotonin (5-HT) concentration levels in whole blood and platelets. Concomitantly a rise in systolic blood pressure was observed. Platelet aggregation values were significantly higher in uremic rats given CyA. FK506 had no influence on 5-HT blood content, blood pressure or platelet aggregation values. It is concluded that 5-HT may play a role in the development of hypertension and thrombotic events caused by CyA. Furthermore, lower incidence of these complications during FK506 treatment could be the result of this drug's limited effect on the serotonergic blood system.

Topics: Animals; Cyclosporine; Hypertension; Immunosuppressive Agents; Male; Rats; Rats, Wistar; Serotonin; Tacrolimus; Thrombosis; Uremia

In vitro inhibition of human peripheral blood mononuclear cell (PBMC) proliferation by immunosuppressive drugs has been shown to correlate with clinical outcomes in kidney transplant patients. The aim of our study was to analyse the degree of variability of in vitro interactions of FK506 (FK) with combinations of cyclosporin A (CyA), methylprednisolone (MP), 6-mercaptopurine (6ME), and mycophenolic acid (MPA) using phytohaemagglutinin (PHA) stimulated PBMCs. Our hypotheses were: that a wide range of interindividual variation would be detected; and that certain combinations of drugs would have a synergistic inhibitory effect on PHA stimulated PBMCs. Cells were cultured in supplemented RPMI 1640 for 65 hours at 37 degrees C in humidified 5% CO2 - 95% air and proliferative responses measured by 3H-thymidine incorporation over a further 24 hours. Inhibition of PBMC proliferation was assessed over 10 FK concentrations ranging from 1 x 10(-8) to 10 micrograms/ml using both volunteer controls (n = 51) and dialysis patients (n = 23). A wide range of interindividual variability of FK inhibition occurred throughout the range of FK concentrations tested, becoming less variable at the higher concentrations. The interactions of FK with CyA, MP, 6ME and MPA were assessed using PBMCs from 12 volunteer controls. For FK at 1 x 10(-8) micrograms/ml; CyA, MP, 6ME and MPA were used at 0.01 microgram/ml. For FK at 1 x 10(-7) micrograms/ml; CyA, MP, 6ME and MPA were used at 0.1 microgram/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Cyclosporine; Drug Synergism; Humans; In Vitro Techniques; Kidney Transplantation; Lymphocyte Activation; Mercaptopurine; Methylprednisolone; Mycophenolic Acid; Phytohemagglutinins; Tacrolimus; Uremia