D. Morel

High incidence of anticytomegalovirus drug resistance among D+R- kidney transplant recipients receiving preemptive therapy.

Anti‐cytomegalovirus (CMV) prophylaxis is recommended in D+R− kidney transplant recipients (KTR), but is associated with a theoretical increased risk of developing anti‐CMV drug resistance. This hypothesis was retested in this study by comparing 32 D+R− KTR who received 3 months prophylaxis (valganciclovir) with 80 D+R− KTR who received preemptive treatment. The incidence of CMV infections was higher in the preemptive group than in the prophylactic group (60% vs. 34%, respectively; p = 0.02). Treatment failure (i.e. a positive DNAemia 8 weeks after the initiation of anti‐CMV treatment) was more frequent in the preemptive group (31% vs. 3% in the prophylactic group; p = 0.001). Similarly, anti‐CMV drug resistance (UL97 or UL54 mutations) was also more frequent in the preemptive group (16% vs. 3% in the prophylactic group; p = 0.05). Antiviral treatment failures were associated with anti‐CMV drug resistance (p = 0.0001). Patients with a CMV load over 5.25 log10 copies/mL displayed the highest risk of developing anti‐CMV drug resistance (OR = 16.91, p = 0.0008). Finally, the 1‐year estimated glomerular filtration rate was reduced in patients with anti‐CMV drug resistance (p = 0.02). In summary, preemptive therapy in D+R− KTR with high CMV loads and antiviral treatment failure was associated with a high incidence of anti‐CMV drug resistance.

Granulocyte Activation and Adhesion Molecules During Hemodialysis With Cuprophane and a High-Flux Biocompatible Membrane

Hemodialysis with complement-activating membranes, such as cuprophane, induces neutropenia and expression of the granulocyte adhesion receptor Mac-1 (CD11b/CD18), while hemodialysis with noncomplement-activating membranes does not. Increased expression of CD11b by neutrophils may mediate cuprophane-induced leukopenia. However, the rebound granulocytosis that follows leukopenia is not fully understood. Ten patients on regular hemodialysis were included in a cross-over study. Hemodialysis was performed for 2 weeks with cuprophane and 2 weeks with polyamide, a high-flux noncomplement-activating membrane. At the end of each period, the following parameters were determined during a hemodialysis session: C5a concentration by enzyme immunoassay and the neutrophil expression of CD11b, LFA-1 (CD11a/CD18), and the antigen recognized by MoF11 (MoF11 Ag), a monoclonal antibody that recognizes activated neutrophils, by immunofluorescence flow cytometry. Hemodialysis with cuprophane induced an increase in C5a concentration and in the expression of CD11b and MoF11 Ag, which were maximal after 15 minutes of hemodialysis, at the nadir of neutropenia. CD11b expression was maintained throughout hemodialysis, despite the reversal of neutropenia. Conversely, after peak expression, C5a and MoF11 Ag decreased as the neutrophil count increased to baseline values. Polyamide hemodialysis did not induce variations in C5a concentration, nor in CD11b and MoF11 Ag expression. CD11a/CD18 expression remained stable during hemodialysis with both membrane types. Neutrophil activation, as determined by MoF11 Ag expression, was correlated with the evolution of neutrophil count and C5a concentration during cuprophane hemodialysis, while CD11b expression was not correlated with neutrophil count throughout dialysis. A decrease in neutrophil activation could explain in part the detachment of neutrophils previously bound to endothelium and, therefore, the reversal of neutropenia.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti‐Cw Donor‐specific Alloantibodies Can Lead to Positive Flow Cytometry Crossmatch and Irreversible Acute Antibody‐Mediated Rejection

Figure 1: Identification of class I DSAs in serum (A) and graft eluate (B) using the single antigen bead assay on a Luminex R

Long-Term Control of Hyperparathyroidism in Advanced Renal Failure by Low-Phosphorus Low-Protein Diet Supplemented with Calcium (without Changes in Plasma Calcitriol)

Phosphorus (Pi) retention linked to chronic renal failure (CRF) favors secondary hyperparathyroidism (HPT). Reduction of Pi and protein intake has been shown to prevent the development of HPT in CRF. The aim of the present study was to assess in patients with advanced CRF the long-term effects on phosphate and calcium metabolism of a low-Pi (5-7 mg/kg/day), low-protein (0.4 g/kg/day) diet providing 300 mg/day calcium (Ca) and supplemented with amino acids and ketoacids, Ca carbonate (400-800 mg/day) and vitamin D2 (1,000 IU/day). Twenty-nine patients with advanced CRF (glomerular filtration rate (GFR) 13.7 +/- 4.5 ml/min) were selected for the study, on the basis of a follow-up of a least 2 years and a satisfactory compliance to the prescribed diet. At the start of the study, biological evidence of HPT was present with increased plasma PTH concentration (144 +/- 95 pg/ml), increased plasma Pi (1.57 +/- 0.33 mmol/l), an increase in alkaline phosphatase activity and plasma osteocalcin concentration. Plasma PTH concentration was positively correlated with plasma Pi and inversely with plasma Ca concentrations and GFR. Pi and protein restriction induced a significant correction of HPT within 3 months after starting the diet. After 2 years of diet, despite the diminution of GFR (11.1 +/- 3.7 ml/min, p < 0.0001), plasma PTH was still lower than at the start of the diet (88 +/- 57 pg/ml, p < 0.01), as was plasma Pi (1.32 +/- 0.24 mmol/l, p < 0.001), total plasma Ca being higher (p < 0.01). Plasma PTH levels were correlated only to plasma Ca concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of a low-protein diet on urinary albumin excretion in uremic patients.

Fifteen patients with advanced renal failure (creatinine clearance less than 25 ml/mn) and with severe albuminuria (greater than 1.5 g/24 h) were put on a low-protein (0.3 g/kg body weight), low-phosphorus (5-7 mg/kg body weight) diet supplemented with essential amino acids and ketoanalogues. During the 6-month follow-up, urinary albumin excretion and fractional renal albumin clearance were reduced significantly while serum albumin concentration increased; no nutritional change occurred during the study.

HILDA/LIF urinary excretion during acute kidney rejection

Recently, a new lymphokine called HILDA (human interleukin for DA cells) has been described and cloned. This cytokine, initially described to be produced by alloreactive T lymphocyte clones grown from a rejected human kidney allograft, is identical to other factors termed D-factor, differentiation-inducing factor, differentiation inhibitory activity, hepatocyte-stimulating factor III, and leukemia inhibitory factor. HILDA/LIF induces various effects on neural, hemopoietic, embryonic cells as well as on bone remodeling and acute phase protein synthesis in hepatocyte. In this study we demonstrate the presence of HILDA/LIF in the urine but not in the serum of kidney graft recipients during acute rejection episodes, whereas this lymphokine was detectable neither in the serum nor in the urine of kidney transplanted patients with stable renal function. These data reinforce the notion of a possible role for this lymphokine in the inflammatory and/or the immune response.

Multiple Myeloma and AL Amyloidosis in a Renal Transplant Recipient

Seven years after a cadaver kidney transplantation a 33-year-old man presented with a monoclonal gammopathy secondarily complicated by AL amyloidosis mainly expressed as a sicca syndrome, gammopathy that ultimately developed into multiple myeloma. The mechanisms responsible for the occurrence of monoclonal gammopathy in renal transplant recipients are discussed.

Intravenous immunoglobulins and rituximab therapy for severe transplant glomerulopathy in chronic antibody‐mediated rejection: a pilot study

Outcome of patients with transplant glomerulopathy (TG) is poor. Using B‐cell targeting molecules represent a rational strategy to treat TG during chronic antibody‐mediated rejection. In this pilot study, 21 patients with this diagnosis received four doses of intravenous immunoglobulins and two doses of rituximab (IVIG/RTX group). They were retrospectively compared with a untreated control group of 10 patients. At 24 months post‐biopsy, graft survival was similar and poor between the treated and the untreated group, 47% vs. 40%, respectively, p = 0.69. This absence of response of IVIG/RTX treatment was observed, regardless the phenotype of TG. Baseline estimated glomerular filtration rate (eGFR) and decline in eGFR during the first six months after the treatment were risk factors associated with 24‐month graft survival. The IVIG/RTX therapy had a modest effect on the kinetics of donor‐specific alloantibodies at M24, compared to the untreated group, not associated with an improvement in graft survival. The mean number of adverse events per patient was higher in the IVIG/RTX group than in the control group (p = 0.03). Taken together, IVIG/RTX treatment for severe TG during chronic antibody‐mediated rejection does not seem to change the natural history of TG and is associated with a high incidence of adverse events.

One-year enzyme-linked immunosorbent assay follow-up of human interleukin for Da cells/leukemia inhibitory factor in blood and urine of 22 kidney transplant recipients.

The cytokine human interleukin for Da cells/leukemia inhibitory factor (HILDA/LIF) exerts multiple biological effects in vitro. In mice, high circulating levels of HILDA/LIF induce a wide range of pathophysiological events, some of them closely involved with immunological and inflammatory responses. Using a sandwich ELISA recognizing the natural human HILDA/LIF molecule with a threshold of 50 pg/ml in urine and 150 pg/ml in plasma, we monitored the urine and plasma HILDA/LIF levels of 22 patients in their first year after a kidney transplant. HILDA/LIF urine excretion is increased during acute rejection, and infections also trigger heavy HILDA/LIF plasma concentrations or urine excretion. In addition, this study raises the question of HILDA/LIF involvement in post-kidney-transplant phenomena such as hypercalcemia, osteoporosis, or the reversal of anemia.

Effect of a Low-Protein Diet on Chemiluminescence Production by Leukocytes from Uremic Patients

Chemiluminescence (CL) emission from leukocytes was studied in 20 uremic patients after ingestion of opsonized zymosan. CL production was impaired when compared with control groups. Six months after a low-protein, low-phosphorus diet supplemented with essential amino acids and ketoanalogues (SD) was started, a significant improvement in CL production was observed. SD may be expected to decrease the susceptibility of uremic patients to bacterial infections.