Jan Gossmann

ABCB1 Genotype of the Donor but Not of the Recipient Is a Major Risk Factor for Cyclosporine-Related Nephrotoxicity after Renal Transplantation

Cyclosporine (CsA) nephrotoxicity is a severe complication in organ transplantation because it leads to impaired renal function and chronic allograft nephropathy, which is a major predictor of graft loss. Animal models and in vivo studies indicate that the transmembrane efflux pump P-glycoprotein contributes substantially to CsA nephrotoxicity. It was hypothesized that the TT genotype at the ABCB1 3435C-->T polymorphism, which is associated with decreased expression of P-glycoprotein in renal tissue, is a risk factor for developing CsA nephrotoxicity. In a case-control study, 18 of 97 patients developed CsA nephrotoxicity and showed complete recovery of renal function in all cases when switched to a calcineurin inhibitor-free regimen. Both recipients and donors were genotyped for ABCB1 polymorphisms at the positions 3435C-->T and 2677G-->T/A. For controlling for population stratification, two additional polymorphisms, CYP2D6*4 and CYP3A5*3, with intermediate allelic frequencies were studied. The P-glycoprotein low expressor genotype 3435TT only of renal organ donors but not of the recipients was overrepresented in patients with CsA nephrotoxicity as compared with patients without toxicity (chi2 = 10.5; P = 0.005). CsA dosage, trough levels, and the concentration per dose ratio were not different between the patient groups. In a multivariate model that included several other nongenetic covariates, only the donors ABCB1 3435TT genotype was strongly associated with CsA nephrotoxicity (odds ratio, 13.4; 95% confidence interval, 1.2 to 148; P = 0.034). A dominant role of the donors ABCB1 genotype was identified for development of CsA nephrotoxicity. This suggests that P-glycoprotein is an important factor in CsA nephrotoxicity.

Long‐Term Consequences of Live Kidney Donation Follow‐Up in 93% of Living Kidney Donors in a Single Transplant Center

Live kidney donation is increasing rapidly. Increases of blood pressure and proteinuria but no accelerated loss of renal function in kidney donors have been described. The credibility of this research is hampered by retrieval rates of only 50–70% of donors.

Switch to a Sirolimus‐Based Immunosuppression in Long‐Term Renal Transplant Recipients: Reduced Rate of (Pre‐)Malignancies and Nonmelanoma Skin Cancer in a Prospective, Randomized, Assessor‐Blinded, Controlled Clinical Trial

Renal transplant recipients (RTR) have a 50–200‐fold higher risk for nonmelanoma‐skin cancer (NMSC) causing high rates of morbidity and sometimes mortality. Cohort‐studies gave evidence that a sirolimus‐based immunosuppression may inhibit skin tumor growth. This single‐center, prospective, assessor‐blinded, randomized trial investigated if switching to sirolimus treatment inhibits the progression of premalignancies and moreover how many new NMSC occur compared to continuation of the original immunosuppressive therapy. Forty‐four RTR (mean age 59.9 years, mean duration of immunosuppression 229.5 months) with skin lesions were randomized to sirolimus or continuation of their original immunosuppression. Blinded dermatological assessment at month 6 and 12 by the same dermatologist evaluated the clinical change compared to baseline. Biopsy was performed in suspected malignancy. Already the 6‐month‐assessment showed significant superiority of sirolimus‐therapy: a stop of progression, even regression of preexisting premalignancies (p < 0.0005). This effect was increased at month 12 (p < 0.0001). Nine patients developed histologically confirmed NMSC: one in the sirolimus group, eight in the control group, p = 0.0176. Sirolimus‐based immunosuppression in RTR, even when established many years after transplantation, can delay the development of premalignancies, induce regression of preexisting lesions and decelerate the incidence of new NMSC.

Abrogation of nephrotic proteinuria by rituximab treatment in a renal transplant patient with relapsed focal segmental glomerulosclerosis

Relapse of focal segmental glomerulosclerosis (FSGS) after renal transplantation is 20–40%. Recurrence after a first relapse is 80%. The only current treatment is plasmapheresis and/or cyclophosphamide. We report successful treatment of a second relapse in a 48‐year‐old patient. At age 33, FSGS was diagnosed. The patient began hemodialysis 1 year later. In her first renal transplant, she developed recurrent FSGS and reached terminal transplant failure 3 years later. Eight years later, a second transplant was performed. Immunosuppressive regimen: steroids, mycophenolate mofetil (MMF), tacrolimus (TAC), and rabbit anti‐thymocyte globulin. Proteinuria of 2–6 g/day was detected and a biopsy showed recurrent FSGS. Plasmapheresis was started without success. Another biopsy still showed FSGS. The patient received two doses of rituximab (375 mg/m2 each) i.v. Three weeks later, proteinuria was 350 mg/day (serum‐creatinine 1.6 mg/dl). Twelve months later, proteinuria was at 90 mg/day. Rituximab might be an option for recurrent FSGS after renal transplantation.

Anti-inflammatory effects of clopidogrel intake in renal transplant patients: Effects on platelet-leukocyte interactions, platelet CD40 ligand expression, and proinflammatory biomarkers

Increased platelet activation has been described during treatment with various immunosuppressive agents and may contribute to the high cardiovascular mortality rate in renal transplant patients. Platelets are thought to propagate the inflammatory process of atherosclerosis by interaction with leukocytes.

Anemia in renal transplant recipients caused by concomitant therapy with azathioprine and angiotensin-converting enzyme inhibitors.

Immunosuppression of recipients of renal transplants with azathioprine has been associated with two major side effects: hepatotoxicity and myelotoxicity, mainly in the form of leukopenia. Reports of isolated anemia in these patients have been rare. We now observed the development of severe anemia in 9 out of 11 renal transplant recipients whose immunosuppressive regimen was converted from cyclosporine plus prednisone to azathioprine plus prednisone. A significant (P = 0.001) drop in hematocrit (from 34 +/- 4% to 27 +/- 3%, mean +/- SD) and hemoglobin (from 11.6 +/- 1.3 g/dl to 9.5 +/- 1.0 g/dl) was found. Since a common variable of all these patients was their use of an angiotensin-converting enzyme (ACE) inhibitor as antihypertensive medication, we speculated that the combination of azathioprine and ACE blocker might be the reason for the anemia. We then compared 2 groups of 10 patients each who had been on azathioprine as their regular immunosuppressive agent and who did or did not take an ACE inhibitor. Hematocrit and hemoglobin were significantly (P = 0.01) lower in the group of patients taking ACE inhibitors (33 +/- 6% versus 41 +/- 5% and 11.5 +/- 2.0 g/dl versus 14.0 +/- 1.6 g/dl, respectively). Haptoglobin levels were also significantly (P = 0.05) lower in the ACE inhibitor group (116 +/- 65 mg/dl versus 210 +/- 114 mg/dl). Erythropoietin concentration in the serum and the reticulocyte index were slightly, but not significantly, higher in the ACE inhibitor group but the values were probably too low for their degree of anemia. Comparing hematological parameters of the patients in the ACE inhibitor group before and after beginning of the antihypertensive treatment confirmed a significant reduction of hematocrit and hemoglobin following therapy with an ACE inhibitor. Hematocrit fell from 41 +/- 7% to 36 +/- 6% and hemoglobin from 14.0 +/- 2.3 g/dl to 11.3 +/- 1.5 g/dl (P < 0.05 for both). We conclude that the combination of these two drugs should probably be avoided.

Renal transplantation in the elderly: surgical complications and outcome with special emphasis on the Eurotransplant Senior Programme

BACKGROUND The purpose of this retrospective study was to evaluate the results of the Eurotransplant Senior Programme (ESP) within our centre compared to elderly recipients >or=60 years from the regular Eurotransplant Kidney Allocation System (ETKAS), specifically focusing on surgical aspects. METHODS Data from 73 ESP patients (average donor/recipient age: 71.1/67.1) were compared with those from 51 patients (49.7/63.6) treated within the framework of the ETKAS program between the years 1999 and 2006. The mean follow-up was 39.5 months. RESULTS Cold ischaemic time (ESP versus ETKAS: 10.3 versus 15.0 h), duration of renal replacement therapy (42.2 versus 76.8 months), donor glomerular filtration rate (81.7 versus 109.9 ml/min/1.73 m(2)) and HLA mismatches (4.1 versus 2.4) were significantly different between the two groups (all P < 0.001). Primary graft function was seen in 74% ESP versus 69% of ETKAS patients (P > 0.05). The rate of surgical complications in the ESP versus ETKAS group was 47% versus 28% (P = 0.031) and the revision rate, 33% versus 24% (P = 0.259). Three-year patient and censored graft survival was 84% versus 92% and 85% versus 88% in the ESP and ETKAS group, respectively (all P > 0.05). Ninety-five percent of all deceased patients died with a functioning graft. CONCLUSIONS The donor and recipient pool has been markedly expanded through ESP with similar patient and graft survival compared to elderly recipients grafted according to ETKAS criteria. However, patients and their physicians should be aware of the high surgical complication rate in elderly recipients, particularly when receiving elderly donor kidneys. This might seriously influence postoperative patient management but ultimately does not compromise the transplant outcome.

Pathophysiology of Cyclosporine-Induced Nephrotoxicity in Humans: A Role for Nitric Oxide?

Background: The causes for the nephrotoxicity of cyclosporine A (CsA) have not been fully elucidated. Intrarenal vasoconstriction induced by several different mediators, both in humans and experimental animals, have been proposed. Methods: We studied prostaglandin metabolites, endothelin and nitric oxide in kidney transplant patients receiving their first CsA dose. Prostaglandin metabolites in the urine and endothelin and nitric oxide (NO2/NO3) in urine and plasma were measured in 14 patients before and 3 and 6 h after oral ingestion of CsA (10 mg/kg b.w.). Clearances for inulin and p-aminohippuric acid (PAH) were measured before and in two separate 3-hour periods after CsA. Blood pressure, heart rate, and CsA blood levels were also determined. Results: Clearances of inulin and PAH decreased progressively after CsA dosage while renal vascular resistance increased. Nitric oxide plasma levels decreased in nearly all patients from 21.0 ± 2.8 to 19.1 ± 2.6 (p = 0.003) and then rose slightly to 19.5 ± 2.5 µmol/l (p = 0.1) 3 and 6 h after CsA ingestion, respectively. Urinary excretion of NO2/NO3 decreased nonsignificantly from 269 ± 38.8 to 259 ± 27.7 and 254 ± 41.6 µmol/min (p = 0.5 and 0.5). At the same time, urinary prostaglandin E2 and 6-keto-prostaglandin F1α excretion rate declined significantly [from 1,187 ± 254 to 1,186 ± 351 and 730 ± 148 pg/min (p = 0.27 and 0.02) and from 697 ± 115 to 645 ± 134 and 508 ± 58.2 pg/min (p = 0.34 and 0.05)]. Urinary thromboxane B2 and plasma and urinary endothelin first increased and then decreased nonsignificantly. Mean arterial pressure rose from 107 ± 2.5 to 110 ± 2.6 and 114 ± 3.4 mm Hg (p = 0.1 and 0.05). Conclusion: The pathophysiology of CsA-induced acute renal vasoconstriction involves several different mechanisms including a decrease of the vasodilating prostaglandins E2 and 6-keto-prostaglandin F1α and possibly nitric oxide.

Vascular Endothelial Growth Factor in Diabetic Nephropathy

Background: Vascular endothelial growth factor (VEGF) increases endothelial permeability. VEGF is produced in podocytes and functional receptors are located on endothelial glomerular cells. The aim of the current study in diabetic patients with normal renal function to various degrees of proteinuric nephropathy was therefore to unravel a possible role of the most important isoform VEGF165 for albuminuria and to investigate the impact of therapy with an inhibitor of the renin-angiotensin system on VEGF165 secretion. Subjects and Methods: A cross-sectional study in 72 patients (41 female, 31 male) with long-standing type 1 (n = 35, mean age 43.3 years, range 22–67) or type 2 (n = 37, mean age 66 years, range 53–83) diabetes mellitus was performed; in 19 patients the serum creatinine value was >1.5 mg/dl. Twenty-six healthy volunteers (17 female, 9 male, mean age 34.8 years, range 19–58) with normal renal function served as controls. Serum and urinary VEGF165 was measured by ELISA. Urinary albumin was measured nephelometrically. Mann Whitney U tests were used for comparisons. Results: In type 1 and type 2 diabetics mean urinary VEGF165 concentration amounted to 112 ± 88 (mean ± SD) and 88 ± 85 ng/l, respectively, compared to 101 ± 60 ng/l in the normal volunteers (NS vs. diabetics). The respective mean urinary albumin concentrations were 443 ± 1029, 394 ± 749 and 20 ± 33 mg/l (p < 0.01 vs. diabetics type 2). There was a correlation between urinary VEGF and albumin, but only in patients with type 2 diabetes (R = 0.497; n = 36; p = 0.002). Urinary VEGF165 was similar in patients with (n = 40) and without ACE inhibitor/AT1 antagonist therapy (n = 32) and in normal volunteers, whereas serum VEGF165 was higher in the treated type 1 diabetics. Conclusions: These results may suggest that VEGF165 plays some role in the development of albuminuria in diabetic nephropathy due to type 2 but not type 1 diabetes.

Development of urological cancers in renal transplant recipients: 30‐year experience at the Frankfurt Transplant Center

Fatal post‐transplant malignancies with a high proportion of genitourinary neoplasms represent a serious long‐term challenge. With continuous improvement of the allograft and patient survival, cancer development after renal transplantation may soon turn to the leading morbidity cause. In a retrospective single‐center study of 1990 renal transplant recipients between November 1979 and November 2009, records of patients with urological neoplasms including epidemiological, clinical and survival parameters were accessed. Sixty‐six de novo urological malignancies in 58 recipients were recorded in the study period, being most common after skin cancers (15.6% of enregistered tumors). From these, 29 were renal cell cancers, including five neoplasms of transplanted kidney, 24 transitional cell carcinomas, 11 prostate carcinomas, and two germ cell carcinomas with incidence rates of 1.5%, 1.2%, 0.9% and 0.2%, respectively. The patient follow up was virtually complete. Tumor‐related death was found in 44% of cases. By multivariate analysis, no influence of either duration of dialysis, mode or duration of immunosuppression, gender or age at transplantation on overall patient survival could be demonstrated. This study, documenting a 30‐year single center experience, emphasizes the increased risk for urological neoplasms occuring after renal transplantation. Screening strategies for urological cancers should be optimized. (Cancer Sci 2010; 101: 2430–2435)