Paul Landais

Angiotensin-Converting Enzyme Inhibitors and Progression of Nondiabetic Renal Disease: A Meta-Analysis of Patient-Level Data

Chronic renal disease is a major public health problem in the United States. According to the 1999 Annual Data Report of the U.S. Renal Data System, more than 357 000 people have end-stage renal disease (ESRD), and the annual cost of treatment with dialysis and renal transplantation exceeds

Continuous venovenous haemodiafiltration versus intermittent haemodialysis for acute renal failure in patients with multiple-organ dysfunction syndrome: a multicentre randomised trial

15.6 billion (1). Patients undergoing dialysis have reduced quality of life, a high morbidity rate, and an annual mortality rate of 20% to 25% (1). Identification of therapies to prevent ESRD is an important public health goal. Angiotensin-converting enzyme (ACE) inhibitors are highly effective in slowing the progression of renal disease due to type 1 diabetes (26), and evidence of their efficacy in type 2 diabetes is growing (712). However, although 14 randomized, controlled trials have been completed (1325; Brenner BM; Toto R. Personal communications), no consensus exists on the use of ACE inhibitors in nondiabetic renal disease (2628). In a previous meta-analysis of 11 randomized, controlled trials, we found that therapy with ACE inhibitors slowed the progression of nondiabetic renal disease (29). Since our meta-analysis was performed on group data rather than individual-patient data, we could not fully assess the relationship between the effect of ACE inhibitors and blood pressure, urinary protein excretion, or other patient characteristics (30). Thus, we could not determine whether an equal reduction in blood pressure or urinary protein excretion by using other antihypertensive agents would be as effective in slowing the progression of renal disease. Nor could we determine whether the baseline blood pressure, urinary protein excretion, or other patient characteristics modified the response to treatment. In the current report, we used pooled analysis of individual-patient data to answer these questions. We reasoned that the large number of patients in the pooled analysis would provide sufficient statistical power to detect relationships between patient characteristics and risk for progression of renal disease and interactions of patient characteristics with treatment effect. In principle, strong and consistent results from analysis of this large database would clarify the effects of ACE inhibitors for treatment of nondiabetic renal disease. Methods Study Design We obtained individual-patient data from nine published (1322) and two unpublished (Brenner BM; Toto R. Personal communications) randomized, controlled trials assessing the effects of ACE inhibitors on renal disease progression in predominantly nondiabetic patients. Search strategies used to identify clinical trials have been described elsewhere and are reviewed in Appendix 2. We included 11 randomized trials on progression of renal disease that compared the effects of antihypertensive regimens including ACE inhibitors to the effects of regimens without ACE inhibitors, with a follow-up of at least 1 year. In these studies, the institutional review board at each participating center approved the study, and all patients gave informed consent. Patients underwent randomization between March 1986 and April 1996. Hypertension or decreased renal function was required for entry into all studies. Exclusion criteria common to all studies were acute renal failure, treatment with immunosuppressive medications, clinically significant congestive heart failure, obstructive uropathy, renal artery stenosis, active systemic disease, insulin-dependent diabetes mellitus, history of transplantation, history of allergy to ACE inhibitors, and pregnancy. Table 1 shows characteristics of the patients in each study. Table 1. Study and Patient Characteristics in the Randomized, Controlled Trials Included in the Pooled Analysis Before randomization, patients already taking an ACE inhibitor were switched to alternative medications for at least 3 weeks. After randomization, the ACE inhibitor groups received enalapril in seven studies (1419; Brenner BM; Toto R. Personal communications) and captopril (13), benazepril (20), cilazapril (18), and ramipril (21, 22) in one study each. The control groups received placebo in five studies (1922; Brenner BM; Toto R. Personal communications), a specified medication in five studies (nifedipine in two studies [13, 17] and atenolol or acebutolol in three studies [15, 16, 18]), and no specified medication in one study (14). Other antihypertensive medications were used in both groups to reach the target blood pressure, which was less than 140/90 mm Hg in all studies. All patients were followed at least once every 6 months for the first year and at least once yearly thereafter. Blood pressure and laboratory variables were measured at each visit. Table 1 shows outcomes of each study. We pooled the 11 clinical trials on the basis of similarity of study designs and patient characteristics. In addition, the presence of preexisting hypertension and use of antihypertensive agents in most patients in the control groups in each clinical trial justified pooling data from placebo-controlled and active-controlled trials. Thus, the pooled analysis addresses the clinically relevant question of whether antihypertensive regimens including ACE inhibitors are more effective than anti-hypertensive regimens not including ACE inhibitors in slowing the progression of nondiabetic renal disease. Outcomes Two primary outcomes were defined: ESRD, defined as the initiation of long-term dialysis therapy, and a combined outcome of a twofold increase in serum creatinine concentration from baseline values or ESRD. Because ESRD is a clinically important outcome, we believed that definitive results of analyses using this outcome would be clinically relevant. However, because most chronic renal diseases progress slowly, few patients might reach this outcome during the relatively brief follow-up of these clinical trials, resulting in relatively low statistical power for these analyses. Doubling of baseline serum creatinine is a well-accepted surrogate outcome for progression of renal disease in studies of antihypertensive agents (2, 20) and would be expected to occur more frequently than ESRD, providing higher statistical power for analyses using this outcome. Doubling of baseline serum creatinine concentration was confirmed by repeated evaluation in only one study, which used this variable as the primary outcome. Therefore, we did not require confirmation of doubling for our analysis. Other outcomes included death and a composite outcome of ESRD and death. Withdrawal was defined as discontinuation of follow-up before the occurrence of an outcome or study end. Reasons for withdrawal were 1) nonfatal side effects possibly due to ACE inhibitors, including hyperkalemia, cough, angioedema, acute renal failure, or hypotension; 2) nonfatal cardiovascular disease events, including myo-cardial infarction, congestive heart failure, stroke, transient ischemic attack, or claudication; 3) other nonfatal events, such as malignant disease, pneumonia, cellulitis, headache, or gastrointestinal disturbance; and 4) other reasons, including loss to follow-up, protocol violation, or unknown. Statistical Analysis Five investigators participated in data cleaning. Summary tables were compiled from the individual-patient data from each study and checked against tables in published and unpublished reports. Discrepancies were resolved by contacting investigators at the clinical or data coordinating centers whenever possible. Because the studies followed different protocols, we had to standardize the variable definitions, follow-up intervals, and run-in periods; details of our approach are provided in Appendix 2. S-Plus (MathSoft, Inc., Seattle, Washington) and SAS (SAS Institute, Inc., Cary, North Carolina) software programs were used for all statistical analyses (31, 32). Univariate analysis was performed to detect associations between the covariates and outcomes. Baseline patient characteristics were treatment assignment (ACE inhibitor vs. control), age (logarithmic transformation), sex, ethnicity, systolic blood pressure, diastolic blood pressure, mean arterial pressure, serum creatinine concentration (reciprocal transformation), and urinary protein excretion. Study characteristics were blinding, type of antihypertensive regimen in the control group, planned duration of follow-up, whether dietary protein or sodium was restricted, and year of publication. Baseline patient characteristics and study characteristics were introduced as fixed covariates. Since renal biopsy was not performed in most cases and since criteria for classification of cause of renal disease were not defined, the cause of renal disease was not included as a variable in the analysis. Follow-up patient characteristics (blood pressure and urinary protein excretion) were adjusted as time-dependent covariates; the value recorded at the beginning of each time segment was used for that segment. This convention was used so that each outcome would be determined only by previous exposure. The intention-to-treat principle was followed for comparison of randomized groups. Cox proportional-hazards regression models were used to determine the effect of assignment to ACE inhibitors (treatment effect) and other covariates on risk for ESRD and the combined outcome (33, 34). Multivariable models were built by using candidate predictors that were associated with the outcome (P<0.2) in the univariate analysis. Each model was adjusted for study, but since some studies had no events, we could not include a dummy variable for each study. Rather, we adjusted models for studies that differed significantly from the rest (studies 2 [14], 5 [15], 10 [20], and 11 [21, 22]). We also performed tests for interactions between all covariates and treatment effect. All P values were based on two-sided tests, and significance was set at a P value less than 0.05. Results are expressed as relative risks with 95% CIs. Residual diagnostics were performed on these final models (33, 34)

Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of the European experience 1968–99

BACKGROUND Whether continuous renal replacement therapy is better than intermittent haemodialysis for the treatment of acute renal failure in critically ill patients is controversial. In this study, we compare the effect of intermittent haemodialysis and continuous venovenous haemodiafiltration on survival rates in critically ill patients with acute renal failure as part of multiple-organ dysfunction syndrome. METHODS Our prospective, randomised, multicentre study took place between Oct 1, 1999, and March 3, 2003, in 21 medical or multidisciplinary intensive-care units from university or community hospitals in France. Guidelines were provided to achieve optimum haemodynamic tolerance and effectiveness of solute removal in both groups. The two groups were treated with the same polymer membrane and bicarbonate-based buffer. 360 patients were randomised, and the primary endpoint was 60-day survival based on an intention-to-treat analysis. FINDINGS Rate of survival at 60-days did not differ between the groups (32% in the intermittent haemodialysis group versus 33% in the continuous renal replacement therapy group [95 % CI -8.8 to 11.1,]), or at any other time. INTERPRETATION These data suggest that, provided strict guidelines to improve tolerance and metabolic control are used, almost all patients with acute renal failure as part of multiple-organ dysfunction syndrome can be treated with intermittent haemodialysis.

Hepatitis C Virus Type 1b (II) Infection in France and Italy

BACKGROUND Transplantation of allogeneic haemopoietic stem cells can cure several primary immunodeficiencies. This European report focuses on the long-term results of such procedures done between 1968 and December, 1999, for primary immunodeficiencies. METHODS The report includes data from 37 centres in 18 countries, which participated in a European registry for stem-cell transplantation in severe combined immuno deficiencies (SCID) and in other immunodeficiency disorders (non-SCID). 1082 transplants in 919 patients were studied (566 in 475 SCID patients, 512 in 444 non-SCID patients; four procedures excluded owing to insufficient data). Minimum follow-up of 6 months was required. FINDINGS In SCID, 3-year survival with sustained engraftment was significantly better after HLA-identical than after mismatched transplantation (77% vs 54%; p=0.002) and survival improved over time. In HLA-mismatched stem-cell transplantation, B(-) SCID had poorer prognosis than B(+) SCID. However, improvement with time occurred in both SCID phenotypes. In non-SCID, 3-year survival after genotypically HLA-matched, phenotypically HLA-matched, HLA-mismatched related, and unrelated-donor transplantation was 71%, 42%, 42%, and 59%, respectively (p=0.0006). Acute graft versus host disease predicted poor prognosis whatever the donor origin except in related HLA-identical transplantation in SCID. INTERPRETATION The improvement in survival over time indicates more effective prevention and treatment of disease-related and procedure-related complications--eg, infections and graft versus host disease. An important factor is better prevention of graft versus host disease in the HLA-non-identical setting by use of more efficient methods of T-cell depletion. For non-SCID, stem-cell transplantation can provide a cure, and grafts from unrelated donors are almost as beneficial as those from genetically HLA-identical relatives.

Transplantation of hematopoietic stem cells and long-term survival for primary immunodeficiencies in Europe: Entering a new century, do we do better?

Nucleotide sequence analyses of many strains of the hepatitis C virus (HCV) from several geographic areas have shown substantial variability among the different isolates [1-5]. The degree of variability differs markedly throughout the viral genome: High-sequence divergence is found in some nonstructural proteins and in the regions encoding for the putative envelope proteins, and the E2 region contains two hypervariable regions. In contrast, the 5 untranslated and core protein encoding domains show higher conservation among different strains. Numerous classifications have been proposed that, although unconcerted, distinguish among different HCV genotypes. A genotype is defined by the sequence similarity in both coding and noncoding parts of the viral genome: Nucleotide divergence is less than 10% within each genotype and greater than 20% between distinct genotypes [6, 7]. Genotyping can be done by sequencing HCV isolates, but this is time-consuming. Faster procedures have recently been developed, all of which are based on the polymerase chain reaction (PCR), which can be done using either type-specific or conserved primers, followed by hybridization with a specific probe [8, 9]. Additional assays have been developed using restriction fragment length polymorphism analysis in the 5 noncoding region [10, 11] or in the NS5 region [12]. Finally, Okamoto and colleagues [13] have proposed a method that uses type-specific primers located on the capsid domain and allows HCV isolates to be subgrouped into at least five types [14]. Our strategy for genotyping is based on a modification of this approach [13]. Another method has been proposed by Simmonds and colleagues [11] and is based on a phylogenetic study. Recently, a system for the nomenclature of hepatitis C viral genotypes was proposed [15]; types classified as I, II, III, IV, and V by Okamoto and colleagues are classified in this new system as 1a, 1b, 2a, 2b, and 3a, respectively. Although each genotype was initially thought to have a distinct geographic location (HCV type I being the major genotype in the United States and Europe and types II, III, and IV being reported only in Japan), it is now clear that different genotypes are in fact distributed worldwide [16]. In this context, a major issue concerns the actual clinical effect of these different HCV genotypes. Evidence from studies conducted in Japan and, more recently, in Europe, now suggests that the sensitivity of different HCV genotypes to interferon- therapy might vary substantially [17, 18]. In contrast, it is still unclear whether some HCV genotypes lead to a more severe course of viral infection and are thus associated with the development of primary liver cancer. Reports from Japan addressing this question have been inconclusive; a limited study from Italy suggested that Japanese types of HCV (precise genotyping was not yet available) were associated with cirrhosis [19, 20]. In none of these studies, however, was sufficient attention paid to the ages of the patients or the durations of their infections; indeed, given the genetic variability of HCV, it is plausible that the relative proportion of the various HCV genomes has changed over time. Finally, whether the level of HCV viremia differs according to genotype and to severity of liver disease remains debatable. Our intent, therefore, was to study a large group of patients to elucidate the following points: whether the pattern of distribution of HCV genotypes has been changing over time; whether severity of illness (chronic hepatitis, cirrhosis, and hepatocellular carcinoma) and response to interferon- therapy differs with the HCV genotype; and whether the level of HCV viremia varies with severity of liver disease and with the HCV genotype as determined by the recently introduced branched-chain DNA (bDNA) assay [21, 22]. Key terms are defined in Appendix 1. Methods Patients We retrospectively analyzed 220 patients with chronic liver disease positive for antibody to HCV who were living in France and Italy. Inclusion criteria were biopsy-proven chronic hepatitis of any severity and detectable HCV RNA that allowed HCV genotyping; patients were selected from among those referred to three liver units between 1988 and 1992. Two units were located in Paris and one in Milan; all three were large reference centers with national recruitment. One hundred twenty-four patients were French, 74 were Italian, and 22 were from countries in the Mediterranean area. Patients were divided into three groups (Table 1): Group 1 consisted of 35 patients with histologically confirmed hepatocellular carcinoma; group 2 consisted of 71 patients with cirrhosis and no evidence of hepatocellular carcinoma; and group 3 consisted of 114 patients with chronic hepatitis. Diagnosis of hepatitis was based on appropriate biochemical and histopathologic criteria [23]. The mode of infection was nonambiguously known for 60 patients who had had transfusions and for 27 patients who had used intravenous drugs, but no definite causes could be identified for 133 patients. The date of infection was known for 107 patients: For 78 patients, it was considered to be the date of blood transfusion or the date when intravenous drug use began; 29 patients were followed for non-A, non-B hepatitis infection for at least 10 years. Table 1. Prevalence of Hepatitis C Virus Genotypes in Three Groups of Patients* One hundred six patients were treated with recombinant interferon- 2b (3 MU subcutaneously 3 times/wk for 6 months). Inclusion criteria were the absence of hepatocellular carcinoma, elevated levels of alanine aminotransferase, biopsy-proven chronic hepatitis, and informed consent. Patients were divided into two groups, the first of which comprised 62 responders to interferon-. In these patients, alanine aminotransferase levels returned to normal after treatment with interferon-; 33 were considered long-term responders because alanine aminotransferase levels remained in the normal range for at least 6 months after therapy, and 29 were considered relapsers because alanine aminotransferase levels increased after cessation of treatment. The second group comprised 44 nonresponders; their alanine aminotransferase levels did not return to normal during therapy. Studies All serum specimens showed antibody to HCV by second-generation enzyme-linked immunosorbent assay and by RIBA2 (Ortho Diagnostic Systems, Raritan, New Jersey and Monolisa HCV, Diagnostic Pasteur, Marnes la Coquette, France) and contained HCV RNA detected by nested PCR. Extraction of Hepatitis C Virus RNA and Synthesis of Complementary DNA We used the method of Chomczynski and Sacchi [24] to extract RNA from plasma and serum specimens as previously described [25]. For five patients with chronic active hepatitis, RNA was also extracted from liver biopsy specimens [24]. Polymerase Chain Reaction with Universal and Type-Specific Primers Because nested PCR considerably increases the risk for contamination, a modified procedure was developed in which both steps of nested PCR were done in a single tube [25]. In several ongoing studies, the sensitivity of this assay has been found to be similar to that of classic nested PCR. Universal and antisense-specific primers were used according to the method of Okamoto and colleagues [13, 14]. The first PCR was done for 25 cycles with universal primers. Each reaction cycle included denaturation at 94 C for 1 minute, primer annealing at 55 C for 1.5 minutes, and primer extension at 72 C for 1.5 minutes. In the first amplification using external primers, complementary DNA was centrifuged for 1 minute to combine the second PCR mix with the first. The second amplification was done according to the following protocol: denaturation at 94 C for 1 minute, primer annealing at 62 C for 1.5 minutes, and primer extension at 72 C for 1.5 minutes for 25 cycles, using a universal primer and one of the five type-specific primers. The products of the second PCR were subjected to electrophoresis on a composite acrylamide-bisacrylamide gel (19%/1%), and the fragments were detected by ethidium bromide staining and ultraviolet illumination. Subtypes were determined by band position; type 1a (I), type 1b (II), type 2a (III), type 2b (IV), and type 3a (V) show bands at 49, 144, 174, 123, and 88 base pairs, respectively. Precautions were taken to avoid carryover [26]. In addition, a negative control was inserted at the extraction step and run to the end of the test; results were considered valid if they were consistent in at least two tests done on samples derived from two independent extractions [27]. Quantitative Detection of Serum Hepatitis C Virus RNA To quantitatively detect serum HCV RNA, a signal amplification method based on branched oligodeoxyribonucleotides (bDNA) developed by Chiron (Emeryville, California) was used according to the manufacturers instructions [22]. These bDNAs have a unique primary segment and a set of identical secondary fragments covalently attached to the primary sequence through branched points. The primary sequence is designed to hybridize to oligonucleotide target probes bound to HCV RNA. A second set of oligonucleotide target probes mediate capture of the target nucleic acid onto a microwell. The secondary fragments of the bDNA are used to direct the binding of multiple copies of an oligonucleotide labeled with alkaline phosphatase. The latter is detected using an enzyme-triggerable dioxetane substrate, and the visible light output is recorded on a luminometer permitting quantitation of HCV RNA. The detection limit of this test is 350 000 HCV RNA equivalents per milliliter of serum. Only positive results were included in the calculation of the mean HCV viremia level. Serum specimens were available from 183 of 220 patients for quantitative detection of serum HCV RNA by bDNA. Validation of Results Results were validated by exchanging 20 samples between two laboratories (in Paris and Tokyo) and comparin

European experience of bone-marrow transplantation for severe combined immunodeficiency

BACKGROUND Hematopoietic stem cell transplantation remains the only treatment for most patients with severe combined immunodeficiencies (SCIDs) or other primary immunodeficiencies (non-SCID PIDs). OBJECTIVE To analyze the long-term outcome of patients with SCID and non-SCID PID from European centers treated between 1968 and 2005. METHODS The product-limit method estimated cumulative survival; the log-rank test compared survival between groups. A Cox proportional-hazard model evaluated the impact of independent predictors on patient survival. RESULTS In patients with SCID, survival with genoidentical donors (n = 25) from 2000 to 2005 was 90%. Survival using a mismatched relative (n = 96) has improved (66%), similar to that using an unrelated donor (n = 46; 69%; P = .005). Transplantation after year 1995, a younger age, B(+) phenotype, genoidentical and phenoidentical donors, absence of respiratory impairment, or viral infection before transplantation were associated with better prognosis on multivariate analysis. For non-SCID PID, in contrast with patients with SCID, we confirm that, in the 2000 to 2005 period, using an unrelated donor (n = 124) gave a 3-year survival rate similar to a genoidentical donor (n = 73), 79% for both. Survival was 76% in phenoidentical transplants (n = 23) and worse in mismatched related donor transplants (n = 47; 46%; P = .016). CONCLUSION This is the largest cohort study of such patients with the longest follow-up. Specific issues arise for different patient groups. Patients with B-SCID have worse survival than other patients with SCID, despite improvements in each group. For non-SCID PID, survival is worse than SCID, although more conditions are now treated. Individual disease categories now need to be analyzed so that disease-specific prognosis may be better understood and the best treatments planned.

Prognosis of patients with nonmalignant chronic intestinal failure receiving long-term home parenteral nutrition

The outcome of bone-marrow transplantations (BMT) carried out between 1968 and March 1, 1989, in 183 patients with severe combined immunodeficiency (SCID) was analysed. Recipients of HLA-identical BMTs (70) had a 76% probability of survival (median follow-up 73 months). Of the 32 treated since 1983, 97% have been cured (median follow-up 41 months). This good prognosis was associated with rapid development of T and B cell function. HLA-non-identical, T-cell-depleted, BMT (n = 100) gave significantly lower survival (52%; median follow-up 47 months). Factors associated with poor prognosis were the presence of a lung infection before BMT, absence of a protected environment, and use of female donors for male recipients. Use of a conditioning regimen significantly increased the frequency of sustained engraftment (86% vs 50% for non-conditioned BMT) and resulted in more frequent engraftment of donor B lymphocytes and myeloid cells. Donor B-cell chimerism was strongly associated with the development of normal B-cell function.

KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron

BACKGROUND/AIMS Long-term survival of patients with intestinal failure requiring home parenteral nutrition (HPN) has been only partly shown. Therefore, we described the survival of these patients and explored prognosis factors. METHODS Two hundred seventeen noncancer non-acquired immunodeficiency syndrome adult patients presenting with chronic intestinal failure enrolled from January 1980 to December 1989 in approved HPN programs in Belgium and France; prognosis factors of survival were explored using multivariate analysis. Data were updated in March 1991; not one of the patients was lost to follow-up. RESULTS Seventy-three patients died during the survey, and the mortality rate related to HPN complications accounted for 11% of deaths. Probabilities of survival at 1, 3, and 5 years were 91%, 70%, and 62%, respectively. Three independent variables were associated with a decreased risk of death: age of patients younger than 40 years, start of HPN after 1987, and absence of chronic intestinal obstruction. In patients younger than 60 years of age included after 1983 with a very short bowel, who could represent suitable candidates for small bowel transplantation, the 2-year survival rate was 90%, a prognosis that compared favorably with recent reports of survival after small bowel transplantation. CONCLUSIONS HPN prognosis compares favorably with recent reports of survival after small bowel transplantation.

BONE-MARROW TRANSPLANTATION FOR IMMUNODEFICIENCIES AND OSTEOPETROSIS: EUROPEAN SURVEY, 1968-1985

Familial hyperkalemic hypertension (FHHt) is a Mendelian form of arterial hypertension that is partially explained by mutations in WNK1 and WNK4 that lead to increased activity of the Na+-Cl− cotransporter (NCC) in the distal nephron. Using combined linkage analysis and whole-exome sequencing in two families, we identified KLHL3 as a third gene responsible for FHHt. Direct sequencing of 43 other affected individuals revealed 11 additional missense mutations that were associated with heterogeneous phenotypes and diverse modes of inheritance. Polymorphisms at KLHL3 were not associated with blood pressure. The KLHL3 protein belongs to the BTB-BACK-kelch family of actin-binding proteins that recruit substrates for Cullin3-based ubiquitin ligase complexes. KLHL3 is coexpressed with NCC and downregulates NCC expression at the cell surface. Our study establishes a role for KLHL3 as a new member of the complex signaling pathway regulating ion homeostasis in the distal nephron and indirectly blood pressure.

Limited Duration of Remission of Insulin Dependency in Children With Recent Overt Type I Diabetes Treated With Low-Dose Cyclosporin

In this retrospective analysis of allogeneic bone-marrow transplantation (BMT) carried out between 1969 and 1985 at fourteen European centres in 162 patients with sixteen different types of inherited immunodeficiencies and osteopetrosis, the overall survival with functional grafts was 51.7% (85 patients), with a minimum follow-up of 5 months. In patients with severe combined immunodeficiency HLA-matched (n = 41) and T-cell-depleted HLA-mismatched BMT (n = 46) resulted in 68% and 57% disease-free survival, respectively; after HLA-mismatched transplants, older age (greater than 6 months) and adenosine-deaminase deficiency resulted in poorer survival. Eight other lethal immunodeficiencies, including profound T-cell deficiencies, Wiskott-Aldrich syndrome, Kostmann syndrome, LFA-1/CR 3/p150,95 deficiency, and Chediak-Higashi syndrome as well as malignant osteopetrosis, have been successfully treated by BMT. In this group, survival with functional graft was 47% with HLA-matched and 29% with T-cell-depleted HLA-mismatched BMT. Engraftment failure was the major complication in this group. Poorer prognosis was associated with older patients, profound T-cell deficiencies, and the degree of HLA incompatibility.