Functional Fc gamma receptor gene polymorphisms and donor-specific antibody-triggered microcirculation inflammation.

Fc-dependent effector mechanisms may contribute to antibody-mediated rejection (ABMR), and distinct gene polymorphisms modifying the function of Fc gamma receptors (FcγRs) may influence the capability of donor-specific antibodies (DSAs) to trigger inflammation. To evaluate the relevance of functional FcγR variants in late ABMR, 85 DSA-positive kidney allograft recipients, who were recruited upon antibody screening of 741 prevalent patients, were genotyped for polymorphisms in FcγRIIA (FCGR2A-H/R131 ; rs1801274), FcγRIIIA (FCGR3A-V/F158 ; rs396991), and FcγRIIIB (FCGR3B-neutrophil antigen 1 ([NA1]/NA2; rs35139848). Individuals with high-affinity FCGR3A-V158 alleles (V/V158 or V/F158 ) showed a higher rate (and extent) of peritubular capillaritis (ptc) in protocol biopsies than homozygous carriers of the lower-affinity allele (ptc score ≥1: 53.6% vs 25.9%; P = .018). Associations were independent of C1q-binding to DSA or capillary C4d. In parallel, there was a trend toward increased macrophage- and injury-repair response-associated transcript subsets. Kidney function over 24 months, however, was not different. In support of a functional role of FcγRIIIA polymorphism, NK92 cells expressing FCGR3A-V158 produced >2 times as much interferon gamma upon incubation with HLA antibody-coated cells as those expressing FCGR3A-F158 . FcγRIIA and FcγRIIIB polymorphisms were not associated with allograft morphology. Our data suggest that the presence of high-affinity FcγRIIIA variants may favor DSA-triggered microcirculation inflammation.

Biomarkers-a potential route for improved diagnosis and management of ongoing renal damage.

Currently, the identification and validation of biomarkers of kidney injury is among the top priorities of many diagnostic biotechnology companies as well as academic research institutes. Specifically, in renal transplantation, validated biomarkers of tissue injury with good discriminatory power between the various renal compartments and the underlying pathophysiology are desired, because sequential allograft biopsies are limited in number and cannot be used as a screening tool. Given the high demands on these markers, it is not surprising that none of those currently under evaluation has been thoroughly validated for a specific entity. Published biomarker candidates for early tubular damage include neutrophil gelatinase-associated lipocalin (NGAL), interleukin (IL)-18, soluble CD30, perforin, and granzyme B. Recently, C4d flow panel reactive antibodies were evaluated as biomarkers for humoral alloimmune responses. Additional biomarkers such as FOXP3 and kidney injury molecule 1 have been studied in the maintenance phase of renal transplantation. Given the complex prerequisites, it is not surprising that no biomarker panel has been sufficiently validated for clinical use. However, in the near future a biomarker for use as an indicator of renal tubule cell injury will be available. Troponin T or transaminase of the kidney may then at least be used to differentiate between functional renal failure (equivalent to a rise in creatinine) and intrinsic kidney injury.

Biocompatibility of haemodialysis membranes determined by gene expression of human leucocytes: a crossover study.

BACKGROUND: Biocompatibility of haemodialysis membranes is the most important quality criteria to enable long-term dialysis without major harmful effects. This study sought to evaluate the differences of genomic signatures derived from peripheral blood mononuclear cells (PBMC) in patients undergoing haemodialysis treatment using two different dialyser membranes: one semi-synthetic and one full-synthetic membrane. DESIGN: Microarray experiments were conducted in PBMCs of four stable haemodialysis patients before and after dialysis comparing semi-synthetic (Hemophan GFS Plus 16) and full-synthetic (Hemoflow FX80) dialysis membranes, respectively. Genes differentially expressed when comparing the two different membranes used were analysed in order to elucidate the underlying molecular mechanisms affecting PBMCs in the course of dialysis treatment. RESULTS: One hundred and seventy-two genes were identified as up-regulated after treatment with semi-synthetic membranes when compared to full-synthetic membranes. These genes could be assigned to processes including immunity and defence, signal transduction, and apoptosis. Dialysis with a full-synthetic membrane, on the other hand, led to an activation of 72 genes that were mainly involved in cell cycle and cell cycle control. CONCLUSION: The over-representation of genes belonging to immunity/defence, signal transduction, and apoptosis as found with semi-synthetic membranes suggests that full-synthetic membranes are more biocompatible than semi-synthetic membranes.

Short-term effects of high-dose zoledronic acid treatment on bone mineralization density distribution after orthotopic liver transplantation.

Patients with "hepatic" bone disease exhibit increased fracture incidence. The effects on bone material properties, their changes due to orthotopic liver transplantation (OLT), as well as zolendronate (ZOL) treatment have not yet been investigated. We studied bone mineralization density distribution (BMDD) in paired transiliacal biopsies (at and 6 months after OLT) from patients (control CON n = 18, treatment group ZOL n = 21, the latter treated with i.v. ZOL at doses of 4 mg/month) for how bone at the material level was affected by the "hepatic" disease in general, as well as by OLT and ZOL in particular. (1) BMDD parameters at baseline reflected disturbed bone matrix mineralization in "hepatic" bone disease combined with low turnover. Trabecular bone displayed a decrease in mean and most frequent calcium concentration (Ca(MEAN) -2.9% and Ca(PEAK) -2.8%, respectively; both P < 0.001), increased heterogeneity of mineralization (Ca(WIDTH) +12.2%, P = 0.01), and increased percentage of bone areas with low mineralization (Ca(LOW) +32.4%, P = 0.02) compared to normal; however, there were no differences compared to cortical bone. (2) Six months after OLT, ZOL-treated trabecular bone displayed reduced Ca(LOW) (-32.0%, P = 0.047), cortical bone increased Ca(MEAN) (+4.2%, P = 0.009), increased Ca(PEAK) (+3.3%, P = 0.040), and decreased Ca(LOW) (-55.7, P = 0.038) compared to CON and increased Ca(MEAN) compared to baseline (+1.9, P = 0.032) without any signs of hyper- or defective mineralization. These changes as consequence of the antiresorptive action of ZOL visible already after 6 months result in beneficial effects on bone matrix mineralization, likely contributing to the significant decrease in fracture incidence observed in these patients 2 years post transplantation.

Prophylactic bisphosphonate treatment prevents bone fractures after liver transplantation.

A randomized controlled prospective open-label single center trial was performed. At the time of transplantation patients were randomly assigned to one of two treatment arms: The study group of 47 patients received zoledronic acid (ZOL, 8 infusions at 4 mg during the first 12 months after LT), calcium (1000 mg/d) and vitamin D (800 IE/d). The control group consisted of 49 patients who received calcium and vitamin D at same doses (CON). The incidence of bone fractures or death was predefined as the primary endpoint. Secondary endpoints included bone mineral density (BMD), serum biochemical markers of bone metabolism, parameters of trabecular bone histomorphometry and mineralization density distribution (BMDD). Patients were followed up for 24 months. Analysis was performed on an intention-to-treat basis. The primary endpoint fracture or death was reached in 26% of patients in the ZOL group and 46% in the CON group (p = 0.047, log rank test). Densitometry results were different between the groups at the femoral neck at 6 months after LT (mean+/-SD BMD ZOL: 0.80 +/- 0.19 g/cm2 vs. CON: 0.73 +/- 0.14 g/cm2, p = 0.036). Mixed linear models of biochemical bone markers showed less increase of osteocalcin in the ZOL group and histomorphometry and BMDD indicated a reduction in bone turnover. Prophylactic treatment with the bisphosphonate zoledronic acid reduces bone turnover and fractures after liver transplantation.

Present status at the Vienna Transplantation Center after four thousand renal transplantations.

The Division of Transplantation at the Medical University of Vienna, Austria was established by Dr Franz Piza, who performed the first deceased donor kidney transplantation in Vienna in 1965. During the next 43 years, 4,849 transplants were performed at this unit. Data were analysed in the time period 1993-2006 for 2,165 deceased donor transplants (1,734 first and 431 regrafts) and 263 living donor transplants. Long-term follow-up was available for more than 95% of all grafts and all recipients had at least 9 months of follow-up. Two- and 6-year graft survival rates were 81.4% and 66.3%, respectively, for first deceased donor grafts, 76.1% and 61.8% for regrafts and 91.5% and 79.1% for living transplants. Appropriate immunosuppression, HLA matching and crossmatching supported by solid basic scientific research have proved successful in achieving good graft survival at our unit.

A "weight-listing" paradox for candidates of renal transplantation?

Research suggests that end-stage renal disease patients with elevated body mass index (BMI) have superior outcomes on dialysis. In contrast, low and high BMI patients represent the highest risk cohorts for kidney transplant recipients. The important question remains concerning how to manage transplant candidates given the potentially incommensurate impact of BMI by treatment modality. We conducted a retrospective analysis of waitlisted and transplanted patients in the United States from 1990 to 2003. We constructed Cox models to evaluate the effect of BMI on mortality of waitlisted candidates and identified risk factors for rapid weight change. We then assessed the impact of weight change during waitlisting on transplant outcomes. Decline in BMI on the waiting list was not protective for posttransplant mortality or graft loss across BMI strata. Substantial weight loss pretransplantation was associated with rapid gain posttransplantation. The highest risk for death was among listed patients with low BMI (13-20 kg/m(2), adjusted hazard ratio = 1.47, p < 0.01). Approximately one-third of candidates had a change in BMI category prior to transplantation. While observed declines in BMI may be volitional or markers of disease processes, there is no evidence that candidates have improved transplant outcomes attributable to weight loss. Prospective trials are needed to evaluate the efficacy of weight loss protocols for candidates of kidney transplantation.

Gene expression profiles of human proximal tubular epithelial cells in proteinuric nephropathies.

In kidney disease renal proximal tubular epithelial cells (RPTEC) actively contribute to the progression of tubulointerstitial fibrosis by mediating both an inflammatory response and via epithelial-to-mesenchymal transition. Using laser capture microdissection we specifically isolated RPTEC from cryosections of the healthy parts of kidneys removed owing to renal cell carcinoma and from kidney biopsies from patients with proteinuric nephropathies. RNA was extracted and hybridized to complementary DNA microarrays after linear RNA amplification. Statistical analysis identified 168 unique genes with known gene ontology association, which separated patients from controls. Besides distinct alterations in signal-transduction pathways (e.g. Wnt signalling), functional annotation revealed a significant upregulation of genes involved in cell proliferation and cell cycle control (like insulin-like growth factor 1 or cell division cycle 34), cell differentiation (e.g. bone morphogenetic protein 7), immune response, intracellular transport and metabolism in RPTEC from patients. On the contrary we found differential expression of a number of genes responsible for cell adhesion (like BH-protocadherin) with a marked downregulation of most of these transcripts. In summary, our results obtained from RPTEC revealed a differential regulation of genes, which are likely to be involved in either pro-fibrotic or tubulo-protective mechanisms in proteinuric patients at an early stage of kidney disease.

Protein biomarkers associated with acute renal failure and chronic kidney disease.

Acute renal failure (ARF) as well as chronic kidney disease (CKD) are currently categorized according to serum creatinine concentrations. Serum creatinine, however, has shortcomings because of its low predictive values. The need for novel markers for the early diagnosis and prognosis of renal diseases is imminent, particularly for markers reflecting intrinsic organ injury in stages when glomerular filtration is not impaired. This review summarizes protein markers discussed in the context of ARF as well as CKD, and provides an overview on currently available discovery results following 'omics' techniques. The identified set of candidate marker proteins is discussed in their cellular and functional context. The systematic review of proteomics and genomics studies revealed 56 genes to be associated with acute or chronic kidney disease. Context analysis, i.e. correlation of biological processes and molecular functions of reported kidney markers, revealed that 15 genes on the candidate list were assigned to the most significant ontology groups: immunity and defence. Other significantly enriched groups were cell communication (14 genes), signal transduction (22 genes) and apoptosis (seven genes). Among 24 candidate protein markers, nine proteins were also identified by gene expression studies. Next generation candidate marker proteins with improved diagnostic and prognostic values for kidney diseases will be derived from whole genome scans and protemics approaches. Prospective validation still remains elusive for all proposed candidates.

Diagnosis of renal osteodystrophy.

The idiom renal osteodystrophy (ROD) represents a heterogeneous pattern of bone disturbances caused by chronic renal insufficiency and concomitant diseases. For the clinical decision of therapy it is most important to differentiate between high and low or adynamic turnover ROD because the therapeutically consequences of these two ends of the ROD spectrum are fundamentally different. Bone histology remains the gold standard for the exact classification of ROD. Serological markers of bone metabolism are not suited for the accurate nomenclature of ROD but are useful for the sequential follow up of ROD after a clear diagnosis has been made. Similarly, radiological diagnosis of ROD using dual energy X-ray absorptiometry (DEXA) or quantitative computer tomography scan (q-CT) is inaccurate and thus more suited for the routine follow up of established disease. Besides mineralization, bone strength and the rate of fractures are strongly determined by the architecture of the bone matrix. This information, however, is also only available on bone biopsy sections and cannot be estimated by non-invasive diagnostic methods. In summary, bone biopsy should be used more liberally for correct classification of bone disease. The sequential follow up and guidance of therapy success can be performed by non-invasive procedures such as biochemical bone marker determination in blood. X-ray imaging and densitometry is suitable only for sequential evaluation of osteoporosis.

Developments in clinical islet, liver thoracic, kidney and pancreas transplantation in the last 5 years.

Although organ transplantation has matured into a proven therapy for end-stage organ failure, the many notable developments of the past 5 years speak to the multitude of remaining challenges. Two new procedures, islet transplantation and adult-to-adult living donor liver transplantation, have emerged to enlarge our therapeutic armamentarium for Type 1 diabetes mellitus and end-stage liver disease, respectively. In cardiac transplantation, the acceptance of ventricular assist devices as destination therapy is a notable event in light of critical shortage of deceased donor organs. Both liver and lung allocation policies have made a dramatic paradigm shift away from waiting time toward the survival benefit of transplantation. Finally, primary threats to post-transplant longevity have gained an increasing share of the spotlight. Recognition of the impact of renal insufficiency for all nonrenal transplant recipients, of recurrent hepatitis C virus for liver recipients, and of accelerated vasculopathy for cardiac have identified novel end points for clinical trials.

Outcome and long-term side effects after synchronous radiochemotherapy for childhood brain stem gliomas.

Between 1993 and 1999, 11 children with histologically confirmed diffuse and exophytic brain stem glioma (BSG) were treated with intensive induction chemotherapy and simultaneous external beam irradiation. Chemotherapy was performed according to the German/Austrian Pediatric Brain Tumor Study HIT '91 and included two cycles of ifosfamide (days 1-3), etoposide (days 4-6), methotrexate (days 15 and 22), cisplatin (days 29-31) and cytarabine (days 29-31), separated by a 3-week interval. Maintenance chemotherapy with carmustine, carboplatin and vincristine (8 cycles over a 1-year period) was given in those patients who responded clinically or radiographically to induction chemotherapy. Six of 11 patients showed an objective reduction in tumor size on magnetic resonance imaging and 4 of 11 are alive in good general condition >22, >22, >90 and >92 months, respectively, after diagnosis without radiographic evidence of tumor progression (1 complete remission, 2 partial remissions, 1 stable disease), but suffer from moderate to severe long-term side effects. Three patients died due to disease progression after having achieved a partial remission which lasted 5, 6 and 18 months, respectively, whereas only short-term stabilization was observed in 4 patients who died within 1 year after diagnosis. Acute hematologic toxicity was severe but manageable. This intensive combined modality treatment was toxic but yielded objective responses in more than 50% and long-term survivors in one third of childhood BSG patients.

Regulation of renal tubular cell apoptosis and proliferation after ischemic injury to a solitary kidney.

The time course and regulation of apoptosis and cellular regeneration after 30 minutes of acute ischemic injury to a single kidney was elucidated in rats at five time points over 20 weeks. The fraction of apoptotic cells was most prominent at 1 day after the insult in the distal tubule (8% +/- 4% vs 0% +/- 0%, acute renal failure [ARF] vs sham, respectively) and was still elevated at 7 days (2% +/- 2% vs 0% +/- 0%). At that time, the whole kidney mRNA expression of the apoptosis inhibitory genes bcl-xL and bcl-2, as well as that of the apoptosis promotor bax, was significantly reduced. Immunohistochemistry of kidney specimen showed suppression of bcl-2 in the distal tubule but up-regulation in the proximal tubule, whereas bax protein was more strongly expressed in the distal tubule. Cellular proliferation started at day 1 and continued over the following 20 weeks, leading to severe tubular dilation and kidney failure. These data indicate that differential regulation of bcl-2 family members contributes to the early apoptotic clearance of lethally injured tubular epithelial cells after ischemic injury to a solitary kidney.

Sirolimus allows early cyclosporine withdrawal in renal transplantation resulting in improved renal function and lower blood pressure.

INTRODUCTION: This study evaluated whether cyclosporine (CsA) could be eliminated from a sirolimus (Rapamune, rapamycin, SRL)-CsA-steroid (ST) regimen at 3 months. METHODS: This was an open-label study conducted in Europe, Australia, and Canada. Upon enrollment, 525 primary (90%) or secondary (10%) renal allograft recipients with cadaveric (89%) or living (11%) donors received 2 mg of sirolimus (troughs>5 ng/ml), CsA, and steroids. At 3 months+/-2 weeks, eligible patients were randomized (1:1) to remain on SRL-CsA-ST or to have CsA withdrawn and therapy continued with SRL (troughs 20-30 ng/ml)-ST. RESULTS: At 12 months, overall graft and patient survival were 89.1% and 94.9%, respectively. In the 430 (82%) randomized patients, there was no difference in graft survival (95.8% vs. 97.2%, SRL-CsA-ST vs. SRL-ST) or patient survival (97.2% vs. 98.1%, respectively). The incidence of biopsy-confirmed primary acute rejection was 13.1% during the prerandomization period. After randomization, the acute rejection rates were 4.2% and 9.8% for SRL-CsA-ST and SRL-ST, respectively (P=0.035). Renal function (calculated glomerular filtration rate, 57 vs. 63 ml/min, P<0.001) and blood pressure significantly improved when CsA was withdrawn. Hypertension, CsA nephrotoxicity, hyperuricemia, and Herpes zoster occurred statistically more frequently in patients remaining on CsA, whereas thrombocytopenia, abnormal liver function tests, and hypokalemia were reported more often for SRL-ST therapy. CONCLUSION: Sirolimus, CsA, and steroids for 3 months posttransplant, followed by elimination of CsA, is a safe and effective alternative to continuous therapy with sirolimus, CsA, and steroids that can result in better renal function and lower blood pressure.

The long-term effect of simultaneous heart and kidney transplantation on native renal function.

BACKGROUND: It is unclear whether patients with heart failure and renal insufficiency should receive a simultaneous heart and kidney transplant or whether a single heart transplantation is sufficient to restore native renal function. METHODS: We analyzed the renal plasma flow and glomerular filtration of the native and transplant kidneys in eight patients long term after simultaneous heart and kidney transplantation using a dynamic MAG3 radioisotope scan and serum creatinine determinations. All subjects had been hemodialysis dependent before transplantation. Seven patients suffered from an intrinsic renal disease that were diabetic nephropathy in three cases, small fibrotic kidneys of undetermined origin in two cases, one lupus nephritis, and cyclosporine nephrotoxicity in one patient who had a previous heart transplant. In one patient renal insufficiency was considered to be solely due to renal hypoperfusion because no intrinsic renal disease could be detected. RESULTS: All patients were on cyclosporine-based triple immunosuppression, transplanted for 4 to 10 years, exhibited cardiac ejection fractions of more than 50% and had normal serum creatinine values. Radioisotopic scan showed no function of the native kidneys in all seven patients with intrinsic renal disease but exhibited normal function of the native kidneys as well as the renal transplant in the patient without intrinsic kidney disease before transplantation. CONCLUSIONS: These data suggest that a simultaneous heart and kidney transplantation is necessary in patients with cardiomyopathy and renal insufficiency due to primary kidney disease, but not in those with hemodynamically mediated renal failure, even if an immunosuppressive regimen with calcineurin inhibitors is used.

The contribution of adhesion molecule expression in donor kidney biopsies to early allograft dysfunction.

BACKGROUND: Renal allograft rejection is associated with the expression of adhesion molecules on vascular endothelial and tubular epithelial cells. METHODS: To assess whether the number of cell adhesion molecules expressed in donor kidneys can predict early rejection or delayed graft function, kidney biopsies from 20 living and 53 cadaveric kidney donors were obtained before engraftment into the recipients and the expression of the cell adhesion molecules intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and endothelial leukocyte adhesion molecule (E-selectin) were determined by immunohistochemistry. RESULTS: All biopsies from living donors showed significantly lower expression of ICAM-1 and VCAM-1 compared to biopsies from cadaveric donors. There was no difference in the expression of adhesion molecules on tubular cells between transplants with primary function compared to allografts with early rejection in living donated kidneys (ICAM-1: 2+/-8 vs. 3+/-8%; VCAM-1: 9+/-7 vs. 1+/-1%), as well as in cadaveric kidneys (ICAM-1: 38+/-29 vs. 39+/-38%; VCAM-1: 55+/-27 vs. 48+/-29%). The expression of ICAM-1 molecules on tubular cells was determined to be a predictor for the occurrence of delayed graft function in cadaveric kidneys (ICAM-1: 65+/-24* vs. 38+/-29% delayed graft versus primary graft function). No delayed graft function occurred in recipients of living donated kidneys. CONCLUSIONS: These data suggest that adhesion molecule expression in donor biopsies is not a predictor for early allograft rejection, but can be used as a marker for the development of postischemic acute renal allograft failure.

Serum proteins modified by neutrophil-derived oxidants as mediators of neutrophil stimulation.

Reactive oxygen intermediates (ROI) released during inflammation may act as important mediators of neutrophil effector functions. The objective of this investigation was to evaluate the influence of ROI generation on neutrophil adhesion molecule regulation and degranulation. Induction of the neutrophil oxidative burst via Fcgamma receptor cross-linking was accompanied by up-regulation of neutrophil surface CD11b, CD35, and CD66b only in the presence of selected serum proteins, such as purified human C4, C5, or human serum albumin (HSA). Scavenging of ROI attenuated protein-dependent receptor regulations. Moreover, exogenous hydrogen peroxide was effective to increase neutrophil CD11b expression in a protein-dependent way. HSA exposed to neutrophil-derived ROI displayed signs of oxidative modification in terms of carbonyl formation. Such modified HSA transferred to resting neutrophils bound readily to the cell surface and effected receptor modulation as well as cellular spreading. In contrast, neither native HSA nor HSA protected against oxidation by the tocopherol analog Trolox exhibited agonistic properties. In conclusion, we demonstrate that neutrophil-derived ROI modify selected serum proteins, which, in turn, act as proinflammatory mediators of neutrophil stimulation.

Complement-dependent acceleration of apoptosis in neutrophils by dialyzer membranes.

Recently, we have shown that cuprophan (CU) causes receptor modulation by a C5-dependent mechanism, which is activated by neutrophil-derived reactive oxygen intermediates. The objective of our study was to evaluate the contribution of dialyzer membranes to the induction of apoptosis in human neutrophils [polymorphonuclear cells (PMNs)]. PMNs harvested from healthy donors were incubated with hollow fibers from a biocompatible membrane polysulfone (PS) and a bioincompatible membrane CU, all in the presence of 25% human serum. After 4, 8, and 12 hours of incubation at 37 degrees C, apoptosis was quantitated by counting the numbers of cells showing features of apoptosis on cytospins by light microscopy and also by flow cytometry using propidium iodide nuclear staining. Compared with PMNs incubated with serum alone, cells cultured with fibers of PS demonstrated a higher percentage of apoptosis. Fibers from CU dialyzers led to a more pronounced induction of apoptosis in PMNs, which was significantly higher compared with PS. This effect was partly mediated by heat-sensitive serum products and depended on the presence of divalent cations. In contrast to the recently described C5-dependent pathway in PMN receptor modulation by CU, this effect seemed to depend on the presence of the complement factor C3. In conclusion, our results indicate that besides the well-known accelerated apoptosis of PMNs in uremia, both biocompatible and bioincompatible dialyzer material itself can accelerate apoptosis in human PMNs.

Impaired phosphate handling of renal allografts is aggravated under rapamycin-based immunosuppression.

BACKGROUND: Impaired phosphate handling of the renal allograft is a common problem and of multifactorial origin. The aim of the study was to elucidate whether a rapamycin- or a mycophenolate-based immunosuppressive therapy aggravates the renal phosphate leak in kidney transplant recipients. METHODS: Renal phosphate handling was determined in thirty-eight cadaveric allograft recipients, with good renal function at 8, 12, 20 and 28 weeks after transplantation. Nineteen patients (group 1) received triple immunosuppression with rapamycin, cyclosporine and prednisolone, nineteen other transplant recipients received mycophenolate mofetil, cyclosporine and prednisolone immunosuppression (group 2), and six healthy subjects (group 3) served as controls. After 12 weeks of stable graft function, group 1 patients were divided further into two subgroups. Ten patients were kept on their immunosuppressive regimen (group 1A), whereas the remaining nine randomly chosen subjects had their cyclosporine withdrawn; they were thus maintained on a dual immunosuppression regimen with prednisolone and a higher dosage of rapamycin (group 1B). RESULTS: Renal phosphate reabsorption was significantly lower in group 1 at 8 and 12 weeks after transplantation as compared with groups 2 and 3. At 20 weeks after transplantation, patients with rapamycin-based immunosuppression (groups 1A and 1B) continued to exhibit hypophosphataemia and impaired renal phosphate handling. Group 1B had the lowest TmP/ GFR compared with all groups. At 28 weeks, renal phosphate reabsorption and plasma phosphate levels were no longer different between patient groups and controls. CONCLUSION: These data suggest that rapamycin-based immunosuppression prolongs the phosphate leak of the allografted kidney, leading to low serum phosphate levels during the first weeks after transplantation.