[Combined heart and kidney transplantation in Fabry's disease: Long-term outcomes in two patients]. / Transplantation combinée cœur­rein au cours de la maladie de Fabry : suivi à long terme de deux patients.

INTRODUCTION: Fabry disease is a lysosomal storage disorder linked to an alpha-galactosidase A deficiency that can lead to heart and kidney failure. There is little data about the prognosis of patients who undergo a combined heart and kidney transplantation. CASE REPORTS: Two brothers who were diagnosed with Fabry disease after the age of 30 years underwent a combined heart and kidney transplantation at respectively 49 and 42 years of age because of a severe hypertrophic cardiomyopathy with end stage renal failure. They are alive respectively 4 and 9 years after the transplantation. No recurrence of the disease in the transplanted organs has been found. CONCLUSION: Combined heart and kidney transplantation in Fabry disease is an efficient therapy for the cardiomyopathy and kidney failure. Its prognosis can be good when the patients are carefully selected. However, an early diagnosis is critical in order to avoid a procedure associated with a high perioperative mortality.

Outcome of kidney transplantations performed with preformed donor-specific antibodies of unknown etiology.

The detection of preformed donor-specific alloantibodies (DSA) with multiplex-bead arrays has led to the common observation that individuals without a history of pregnancy, transfusion or transplantation can have circulating anti-HLA antibodies of unknown etiology. We retrospectively analyzed the risk of antibody-mediated rejection (AMR) and graft outcome in 41 kidney transplant recipients with DSA of unknown etiology (DSA cause-unk) at the time of transplantation. Twenty-one patients received a posttransplantation desensitization protocol, and 20 received standard immunosuppressive therapy. The mean number of DSA was 1.4 ± 0.8, ranging from 1 to 5. Complement-dependent cytotoxicity crossmatches were negative for all the patients. Flow cytometry crossmatches were positive in 47.6% of cases. The incidence of acute AMR was 14.6% at 1 year, regardless of the immunosuppressive regimen. No patients experienced graft loss following AMR. At month 12, across the entire population of patients with DSA cause-unk, the outcomes were favorable: the measured glomerular filtration rate was 63.8 ± 16.4 mL/min/1.73 m(2), the screening biopsies showed low frequencies of microvascular inflammation and no transplant glomerulopathy, and graft and patient survival were 100%. In conclusion, patients with DSA cause-unk are able to mount AMR but have favorable 1-year outcomes.

Complement genes strongly predict recurrence and graft outcome in adult renal transplant recipients with atypical hemolytic and uremic syndrome.

Atypical hemolytic and uremic syndrome (aHUS) is a severe disease strongly associated with genetic abnormalities in the complement alternative pathway. In renal posttransplantation, few data are available on recurrence risk and graft outcome according to genetic background in aHUS patients. The aim of this study was to identify risk factors for recurrence and transplant outcome and, in particular, the role of complement gene abnormalities. We retrospectively studied 57 aHUS patients who had received 71 renal transplants. A mutation in complement gene was identified in 39 (68%), in factor H (CFH), factor I (CFI), membrane cofactor-protein (MCP), C3 and factor B (CFB). At 5 years, death-censored graft survival was 51%. Disease recurrence was associated with graft loss (p = 0.001). Mutations in complement genes were associated with higher risk of recurrence (p = 0.009). Patients with CFH or gain of function (C3, CFB) mutations had a highest risk of recurrence. M-TOR inhibitor was associated with significant risk of recurrence (p = 0.043) but not calcineurin inhibitor immunosuppressive treatment (p = 0.29). Preemptive plasmatherapy was associated with a trend to decrease recurrence (p = 0.07). Our study highlights that characterization of complement genetic abnormalities predicts the risk of recurrence-related graft loss and paves the way for future genetically based individualized prophylactic therapeutic strategies.

Renal transplantation in patients with AA amyloidosis nephropathy: results from a French multicenter study.

Although end-stage renal disease related to AA amyloidosis nephropathy is well characterized, there are limited data concerning patient and graft outcome after renal transplantation. We performed a multicentric retrospective survey to assess the graft and patient survival in 59 renal recipients with AA amyloidosis. The recurrence rate of AA amyloidosis nephropathy was estimated at 14%. The overall, 5- and 10-year patient survival was significantly lower for the AA amyloidosis patients than for a control group of 177 renal transplant recipients (p = 0.0001, 0.028 and 0.013, respectively). In contrast, we did not observe any statistical differences in the 5- and 10- year graft survival censored for death between two groups. AA amyloidosis-transplanted patients exhibited a high proportion of infectious complications after transplantation (73.2%). Causes of death included both acute cardiovascular events and fatal septic complications. Multivariate analysis demonstrated that the recurrence of AA amyloidosis on the graft (adjusted OR = 14.4, p = 0.01) and older recipient age (adjusted OR for a 1-year increase = 1.06, p = 0.03) were significantly associated with risk of death. Finally, patients with AA amyloidosis nephropathy are eligible for renal transplantation but require careful management of both cardiovascular and infectious complications to reduce the high risk of mortality.

Renal transplantation in HIV-infected patients: the Paris experience.

Kidney transplantation is now considered as a reasonable option for HIV-infected patients with end-stage renal disease. We describe here a retrospective study conducted in five transplantation centers in Paris. Twenty-seven patients were included. Immunosuppressive protocol associated an induction therapy and a long-term treatment combining mycophenolate mofetil, steroids and either tacrolimus or cyclosporine. All the patients had protocol biopsies at 3 months and 1 year. Patient's survival was 100% at 1 year and 98% at 2 years. Graft survival at 1 and 2 years is 98% and 96% at 1 and 2 years, respectively. The mean glomerular filteration rate values at 12 and 24 months were 60.6 mL/min/1.73 m² (range 23-98) and 65.4 mL/min/1.73 m² (range 24-110), respectively. Acute cellular rejection was diagnosed in four cases (15%). Because of high trough levels of calcineurin inhibitor, protease-inhibitor therapies were withdrawn in 11 cases. HIV disease progression was not observed. One patient developed B-cell lymphoma. In conclusion, our study confirms the safety of renal transplantation in HIV-infected patients with few adverse events and a low incidence of acute rejection.

Fumagillin for treatment of intestinal microsporidiosis in renal transplant recipients.

We report 10 cases of intestinal microsporidiosis due to Enterocytozoon bieneusi in renal transplant (RT) recipients who were treated with fumagillin. All patients presented with afebrile subacute diarrhea (median of 2 weeks), associated with abdominal cramps (n = 5), and weight loss (n = 6), a mean of 68 months after RT. The diagnosis was made by the identification of microsporidial spores in stools with the use of appropriate staining and confirmed by a specific polymerase chain reaction assay for E. bieneusi in 7 patients. Median CD4 cell count was 292 cells/mm(3). All patients received a median of 14 days of oral fumagillin (20 mg tid), and four patients also discontinued or tapered their immunosuppressive regimen (mycophenolate mofetil in 3, and azathioprine in 2). Clinical symptoms resolved rapidly with the clearance of microsporidial spores from stools in all patients. A severe but reversible thrombocytopenia was observed in one patient during fumagillin therapy, and another patient presented with abdominal cramps. Trough levels of tacrolimus measured in seven patients dropped below 5 ng/mL in six of them after 7-14 days of fumagillin. Intestinal microsporidiosis can cause subacute diarrhea in RT recipients. Fumagillin is an effective treatment with an acceptable safety profile, but monitoring of tacrolimus levels is warranted.

Donor-estimated GFR as an appropriate criterion for allocation of ECD kidneys into single or dual kidney transplantation.

It has been suggested that dual kidney transplantation (DKT) improves outcomes for expanded criteria donor (ECD) kidneys. However, no criteria for allocation to single or dual transplantation have been assessed prospectively. The strategy of DKT remains underused and potentially eligible kidneys are frequently discarded. We prospectively compared 81 DKT and 70 single kidney transplant (SKT) receiving grafts from ECD donors aged >65 years, allocated according to donor estimated glomerular filtration rate (eGFR): DKT if eGFR between 30 and 60 mL/min, SKT if eGFR greater than 60 mL/min. Patient and graft survival were similar in the two groups. In the DKT group, 13/81 patients lost one of their two kidneys due to hemorrhage, arterial or venous thrombosis. Mean eGFR at month 12 was similar in the DKT and SKT groups (47.8 mL/min and 46.4 mL/min, respectively). Simulated allocation of kidneys according to criteria based on day 0 donor parameters such as those described by Remuzzi et al., Andres et al. and UNOS, did not indicate an improvement in 12-month eGFR compared to our allocation based on donor eGFR.

Safety and efficacy of raltegravir in HIV-infected transplant patients cotreated with immunosuppressive drugs.

Solid organ transplantations (SOT) are performed successfully in selected HIV-infected patients. However, multiple and reciprocal drug-drug interactions are observed between antiretroviral (ARV) drugs and calcineurin inhibitors (CNIs) through CYP450 metabolization. Raltegravir (RAL), a novel HIV-1 integrase inhibitor, is not a substrate of CYP450 enzymes. We retrospectively reviewed the outcomes of 13 HIV-infected transplant patients treated by an RAL + two nucleosidic reverse transcriptase inhibitor (NRTI) regimen, in terms of tolerability, ARV efficacy (plasma viral load, CD4 cell count), drug interactions, RAL pharmacokinetics and transplant outcome. Thirteen patients with liver (n = 8) or kidney (n = 5) transplantation were included. RAL was initiated (400 mg BID) either at time of transplantation (n = 6), or after transplantation (n = 7). Median RAL trough concentration was 507 ng/mL (176-890), which is above the in vitro IC95 for wild type HIV-1 strains (15 ng/mL). Target trough levels of CNIs were promptly obtained with standard dosages of tacrolimus or cyclosporine. RAL tolerability was excellent. There was no episode of acute rejection. HIV infection remained controlled. After a median follow-up of 9 months (range: 6-14), all patients were alive with satisfactory graft function. The use of an RAL + two NRTI-based regimen is a good alternative in HIV-infected patients undergoing SOT.

Combined heart and kidney transplantation in a patient with Fabry disease in the enzyme replacement therapy era.

Fabry disease (FD) is an X-linked genetic disease, resulting from the deficiency of alpha-galactosidase A, a lysosomal enzyme responsible for the cleavage of glycosphingolipids. In absence of enzyme replacement therapy (ERT), globotriaosylceramide (Gb3) accumulates in tissue, leading to progressive organ damage with severe renal, cardiac and central nervous system complications. We herein describe the first case of successful combined and simultaneous heart and kidney transplantation in a young male patient with FD complicated by end-stage renal disease and severe heart failure not responding to late-onset ERT. Combined heart and kidney transplantation can be recommended for Fabry patients with end-stage renal disease and overt hypertrophic cardiomyopathy, severe ischemic or valvular heart disease.

Tolerability of enteric-coated mycophenolate sodium to 1 year in combination with cyclosporine and corticosteroids in renal transplant recipients.

Enteric-coated mycophenolate sodium (EC-MPS) is therapeutically equivalent to mycophenolate mofetil, but delays release of mycophenolic acid until it reaches the small intestine. De novo renal transplant patients taking part in a 12-month, multicenter, randomized study received cyclosporine microemulsion (CsA-ME, early or delayed to day 6), EC-MPS, steroids, and interleukin-2 antagonist induction. Tolerability data relating to EC-MPS are reported. Ninety-seven patients were randomized to early CsA-ME and 100 patients to delayed CsA-ME. Median daily dose of EC-MPS was 1440 mg at all time points throughout the 12-month period. The most frequently reported adverse events were constipation, anemia, urinary tract infection, abdominal pain, leukopenia, and cytomegalovirus infection; there were four malignancies. Fifty patients (24.6%) discontinued EC-MPS prematurely by 12 months, including 42 patients (84%) who discontinued owing to adverse events. No patient discontinued treatment because of gastrointestinal adverse events. Two-thirds of patients (137 [67.5%]) maintained full EC-MPS dose throughout the 12-month study and did not require any dose reduction or dose interruption. EC-MPS is well tolerated in de novo renal transplant recipients when administered in combination with CsA-ME and steroids, with low rates of dose reductions or interruptions. Gastrointestinal adverse events were responsible for dose reduction or interruption in only 5% of patients.

New onset diabetes mellitus incidence and risk factors in kidney transplantation: results of the observational cross-sectional study diapason.

BACKGROUND: New-onset diabetes mellitus (NODM) is a frequent complication of kidney transplantation. Data on NODM are mainly available in the United States. A study was implemented in a French population of kidney transplants. The incidence and risk factors of NODM were analysed. Diabetes was defined according to American Diabetes/World Health Organization guidelines. METHODS: Diapason is an observational cross-sectional study of 527 kidney transplant patients from 17 units based on data collected at a single routine visit 6 to 24 months after kidney transplantation. RESULTS: The mean age of the patients was 47.2 years, and 61.1% were men; 49.5% were receiving cyclosporine microemulsion and 50.5% tacrolimus. NODM developed in 7.0% after a median interval of 1.6 months. Univariate analysis identified six pretransplantation risk factors: advanced age, impaired fasting glucose, at least two cardiovascular risk factors, hepatitis C status, maximums lifetime body mass index above 25, and tacrolimus or cyclosporine therapy. Four independent factors were identified by multivariate analysis: body mass index above 25 (OR = 5.1), pretransplantation impaired fasting glucose (OR = 4.7), hepatitis C status (OR = 4.7), and tacrolimus versus cyclosporine treatment (OR = 3.0). CONCLUSIONS: NODM is associated with risk factors present prior to kidney transplantation and with treatment with tacrolimus as opposed to cyclosporine. Therefore, the choice of calcineurin inhibitor should be based on the patient's overall risk profile.

Intracranial Nocardia recurrence during fluorinated quinolones therapy.

Nocardia infection is a well-recognized complication in renal transplant recipients and other immunocompromised hosts. It is mostly a primary pulmonary infection, which can disseminate to other organs in half of the cases. Nocardiosis is a life-threatening infection. Therefore, an efficient long-lasting treatment must be rapidly administered. We report 1 case of disseminated nocardiosis with pulmonary involvement, brain lesions, and bone lesions in a renal transplant patient, who was treated with stereotactic aspiration in association with high dose of trimethoprim/sulfamethoxazole (TMP/SMX) and imipenem, changed, after 3 weeks to moxifloxacin. First, clinical manifestations decreased after surgical drainage and combination therapy with the 2 antimicrobial agents, but later the patient developed a recurrence of brain lesions during treatment with quinolones. Consequently, the patient was again treated with TMP/SMX and imipenem, after which the patient recovered. It is surprising that moxifloxacin was efficient in vitro and the antimicrobial concentration in the central nervous system was high, yet the nocardial abscess recurred under this therapy.

Nephrotic syndrome associated with hemophagocytic syndrome.

Hemophagocytic syndrome (HPS) is defined by bone marrow and organ infiltration by activated, nonmalignant macrophages, which phagocytose blood cells. The clinical spectrum of HPS is broad, but renal involvement has rarely been investigated. We report a previously unknown renal manifestation of HPS: nephrotic syndrome. This multicentric retrospective study included patients fulfilling the following criteria: (i) no history of nephropathy; (ii) HPS diagnosis with histologic evidence of hemophagocytosis; (iii) occurrence of nephrotic syndrome during HPS; and (iv) available renal histology. Using the same criteria, we also searched the literature for additional cases. We identified nine patients retrospectively and found two additional cases in the literature (five males and six females, whose mean age was 34 +/- 27 years). Black African patients predominated (63.6%). HPS was due to lymphoma (six cases), infectious disease (three cases), and autoimmune disease (one case), and was primary in one patient. Acute renal failure was associated with nephrotic syndrome in 10/11 cases. Renal histology showed acute tubular necrosis associated with collapsing glomerulopathy in five patients (all Africans with negative human immunodeficiency virus serology), minimal change glomerulopathy in four, and thrombotic-microangiopathy with abnormal podocytes in two. Death occurred in seven cases. Nephrotic syndrome should be included among the renal complications of HPS with acute renal failure. We postulate that abnormal T-cell activation and/or high pro-inflammatory cytokine levels during HPS might cause podocyte injuries, especially among African patients with a susceptible genetic background.

TSC2/PKD1 contiguous gene syndrome in an adult.

A 48-year-old woman with a history of autosomal-dominant polycystic kidney disease (ADPKD), was found to have multiple renal angiomyolipomas on a pathological examination after nephrectomy. The clinical and pathological presentation is consistent with the diagnosis of TSC2/PKD1 contiguous gene syndrome, caused by the simultaneous loss of TSC2 and PKD1, the two major genes for tuberous sclerosis complex and ADPKD.

Proteinuria and tubulointerstitial lesions in lupus nephritis.

BACKGROUND: Response of the renal tubules to proteinuria is implicated in progression of renal disease. Experimentally, proteinuria causes increased tubular synthesis of macrophagic and other chemokines, with increased tubular cellular proliferation and apoptosis, leading to interstitial inflammation and fibrosis. Clinically, diminution of proteinuria leads to the slowing of progression, but whether this leads to reduction in tubular lesions has not been directly demonstrated in humans. METHODS: Initial (Bx1) and systematic six-month biopsies (Bx2) from 71 patients with lupus nephritis were studied, with a subset of 34 biopsies also stained for proliferating cell nuclear antigen (PCNA), the macrophage marker PGM1, and cytokeratins (AE1/AE3), and morphometric cell and tubular profile counts performed. RESULTS: Positive correlations were found between increasing levels of proteinuria and the following light microscopic parameters: tubular epithelial pyknosis, tubular epithelial nuclear "activation," tubular lumenal macrophages, interstitial inflammation and fibrosis, but not with tubulointerstitial immunofluorescence. Significant positive correlations also were found with the following immunohistochemical parameters: PCNA in epithelial cells (r = 0.74) and tubular luminal cells (r = 0.47); tubular lumenal macrophages (r = 0.63) and tubular epithelial cells with acquired PGM1 staining (r = 0.36); and pyknotic tubular epithelial cells (r = 0.47). All showed strong correlations with serum creatinine (S(Cr)) as well. All were reduced at Bx2, generally in parallel to the reduction in proteinuria. Tubulointerstitial immune deposits appear to play only a minor role in the development of tubular epithelial lesions and the progression of renal disease in lupus. They show only limited correlation with SCr and no correlation with proteinuria. By multiple regression, they are not associated with tubular epithelial lesions, interstitial inflammation or interstitial fibrosis at either biopsy, whereas tubular epithelial lesions are strongly associated with interstitial inflammation at Bx1 and with interstitial fibrosis at Bx2. Cytokeratin correlated strongly with S(Cr) (r = 0.53, P = 0.002) but not with proteinuria (r = 0.27, NS), and was the sole immunohistochemical parameter to increase at Bx2. It appears to be a sensitive marker for tubular atrophy. CONCLUSIONS: In this study both proteinuria and SCr showed a hierarchy of correlations with morphologic variables: Tubular epithelial cell changes> tubular macrophages> interstitial inflammation> interstitial fibrosis, corresponding to current experimental models, but not previously demonstrated in humans.

Genetic heterogeneity of familial hyperkalaemic hypertension.

BACKGROUND: Familial hyperkalaemic hypertension (FHH) is a Mendelian form of low-renin hypertension characterized by hyperkalaemia and hyperchloraemic acidosis despite a normal glomerular filtration rate. To date, three different loci have been identified, on chromosomes 1, 17 and 12. OBJECTIVE: To test for genetic linkage between the three FHH loci and three new affected kindreds. DESIGN AND METHODS: Clinical, biological and genetic analyses were made of three kindreds, including 11 affected individuals among 25 members. Genotyping was performed using four series of microsatellite markers spanning the chromosomes 1, 17 and 12 loci, and the thiazide-sensitive Na-Cl cotransporter (SLC12A3) gene. RESULTS: Segregation of the trait in each kindred was compatible with an autosomal transmission, the affected individuals displaying reasonably consistent biochemical abnormalities and the expected variability in arterial hypertension. Multipoint linkage analysis excluded linkage with the four candidate loci in kindreds 1 and 2, but not with the chromosome 1 locus in kindred 3. CONCLUSION: These results demonstrate further genetic heterogeneity and that a fourth gene is responsible for FHH in at least two unrelated kindreds. They suggest a variety of molecular defects leading to FHH.

Predictive power of the second renal biopsy in lupus nephritis: significance of macrophages.

BACKGROUND: A new Biopsy Index containing the Glomerular Activity (GAI), Tubulointerstitial Activity (TIAI), Chronic Lesion (CLI), and Immunofluorescence (IFI) indices was developed, showing better correlations with clinical and outcome parameters than the National Institutes of Health Activity and Chronicity Indices (AI and CI) in lupus nephritis. This report examines the ability of these indices and individual morphologic variables to predict doubling of serum creatinine (SCr; CRX2). METHODS: Renal biopsies from 71 patients with lupus nephritis with an initial biopsy (Bx1) and systematic control biopsy (Bx2) after six months of therapy were studied. Kaplan-Meier survival curves were developed for each index and morphologic variable at each biopsy. A subset of 30 biopsies was stained with the macrophage marker PGM1. RESULTS: At Bx1, only the TIAI and the quantity of C3 and vascular staining on IF were predictive of CRX2. At Bx2, particularly predictive of CRX2 were the GAI, IFI, Biopsy Index, and BxInfl, a composite variable comprised of all of the inflammatory variables. Among individual variables, glomerular and tubular macrophages correlated the best with clinical and outcome parameters. Crescents and karyorrhexis/fibrinoid necrosis also correlated with outcome. Neither the NIH CI or our CLI, nor the TIAI correlated with outcome. In 30 biopsies stained with PGM1, PGM1+ cells correlated well with glomerular and tubular macrophages identified on routine stains and showed even better correlations with SCr, proteinuria, and progression to renal insufficiency than the latter. A diffuse membranoproliferative (MPGN) pattern was seen in seven patients at Bx1. In four of the seven patients, MPGN disappeared with therapy, and all finished with normal renal function. However, among the three patients in whom MPGN persisted and eight patients in whom MPGN, focal or diffuse, appeared under therapy, six reached end-stage renal disease, and a seventh died with marked renal insufficiency. CONCLUSIONS: The biopsy index and its components correlate modestly with CRX2 at Bx1, but strongly at Bx2, particularly IFI, BxInfl, and glomerular and tubular macrophages. Stains for macrophage markers form a valuable adjunct in interpretation of renal biopsies in systemic lupus erythematosus (SLE). MPGN features do not have an ominous significance at Bx1, but their persistence or appearance under therapy are associated with poor outcome.

A new morphologic index for the evaluation of renal biopsies in lupus nephritis.

BACKGROUND: Various morphologic indices for the evaluation of renal biopsies in lupus nephritis have been developed, of which the most successful have been the NIH Activity Index (AI) and Chronicity Index (CI). We wished to develop a biopsy index from standard light and immunofluorescence (IF) material that would correlate yet more closely with clinical and outcome parameters than the current indices, and be applicable to both treated and untreated cases. METHODS: A cohort of 71 patients with lupus nephritis who had initial renal biopsies (Bx1) with systematic second biopsies (Bx2) at six months after induction therapy was studied, with a large number of light microscopic and IF variables evaluated. These were examined statistically to choose the combinations of variables with the highest overall correlations with clinical and outcome parameters. RESULTS: The adopted biopsy index comprised four elements: Glomerular Activity Index (GAI), a modification of the standard AI with the addition of glomerular monocytes and elimination of interstitial inflammation; Tubulointerstitial Activity Index (TIAI), evaluating several tubular epithelial and inflammatory components, including interstitial inflammation, but excluding tubular atrophy; Chronic Lesions Index, a modification of the standard CI, with the addition of glomerular scars; IF Index (IFI), a semiquantitative index of IF staining for six standard antisera for glomerular capillary, mesangial, tubulointerstitial, and vascular elements. The Biopsy Index showed a statistically higher correlation with clinical and outcome parameters than the NIH AI (P = 0.0170), the NIH CI (P = 0.0009), or their combination (P = 0.0444). At Bx1, comparisons between correlation coefficients for the appropriate AI or CI value and for the Biopsy Index, were: anti-DNA antibodies (0.30 vs. 045), serum creatinine (SCr; 0.33 vs. 0.48), proteinuria (0.22 vs. 0.36), hemoglobin (-0.21 vs. -0.45), and final renal function (0.22 vs. 0.40). Spearman rank correlations showed similar superiority for outcome parameters: doubling of SCr (0.1810 vs. 0.3018) and end-stage renal disease (0.0529 vs. 0.1925). The same improvement of correlations was seen at Bx2 for most parameters, particularly doubling of SCr (0.2716 vs. 0.4753). CONCLUSIONS: The Biopsy Index and/or its components show better correlations with clinical and outcome parameters than the standard AI and CI and other similar indices.