Peripheral nerve involvement in Fabry's disease: Which investigations? A case series and review of the literature.

BACKGROUND: Peripheral nerve system (PNS) involvement is common in Fabry's disease (FD), predominantly affecting the small nerve fibers that are difficult to investigate with conventional electrophysiological methods. PATIENTS AND METHODS: Eighteen patients followed for Fabry's disease underwent a prospective series of electroneurophysiological explorations, including a study of the cardiac parasympathetic autonomic nervous system (ANS) and electrochemical skin conductance (ESC) tests. Data were compared with those obtained in 18 matched healthy controls. RESULTS: All patients had at least one clinical sign suggestive of neuropathy: 16 reported an acrosyndrome and 12 had dyshidrosis. Cold hypoesthesia was found in 15 patients and heat hypoesthesia in 13. Electroneurophysiological investigations and study of the cardiac parasympathetic ANS were normal in all patients. The ESC was significantly lower in FD patients compared with controls. CONCLUSION: PNS involvement is common in FD and should be suspected in patients exhibiting an acrosyndrome, dyshidrosis and/or cold hypoesthesia. Conventional electrophysiological investigations are normal. New techniques, such as ESC, provide early diagnosis of small fiber involvement that currently requires more sophisticated tests difficult to apply in routine practice.

Diagnostic performance of [(18)F]fluorodeoxyglucose positron emission tomography-computed tomography in cyst infection in patients with autosomal dominant polycystic kidney disease.

Cyst infection is a common complication of autosomal dominant polycystic kidney disease (ADPKD). Diagnosis is challenging with standard imaging techniques. We aimed to evaluate the diagnostic performance of [(18)F]fluorodeoxyglucose positron emission tomography-computed tomography (18-FDG PET-CT) for the diagnosis of cyst infections among ADPKD patients, in comparison with computed tomography (CT) and magnetic resonance imaging (MRI). All APKD patients who underwent 18-FDG PET-CT for suspected cyst infection between 2006 and 2013 in a French teaching hospital were included. Diagnosis of cyst infection was retained a posteriori on an index of clinical suspicion. 18-FDG PET-CT findings were was considered to be positive in cases of cyst wall hypermetabolism. CT or MRI findings were were considered to be positive in cases of cyst wall thickening (and enhancement if contrast medium was injected) and infiltration of the adjacent fat. A control group of ADPKD patients with 18-FDG PET-CT performed for other reasons was included. Thirty-two 18-FDG PET-CT scans were performed in 24 ADPKD patients with suspected cyst infection. A diagnosis of cyst infection was retained in 18 of 32 cases: 14 with positive 18-FDG PET-CT findings, and four false negatives. There were no false positives and no hypermetabolism of cyst walls in nine ADPKD control patients. 18-FDG PET-CT had a sensitivity of 77%, a specificity of 100%, and a negative predictive value of 77%. 18-FDG PET-CT allowed a differential diagnosis in three patients. In contrast, CT had a sensitivity of 7% and a negative predictive value of 35% (p <0.001 vs. 18-FDG PET-CT). Only eight MRI scans were performed. The diagnostic performance of 18-FDG PET-CT is superior to that of CT in cyst infections, for comparable radiation doses and with no injection of nephrotoxic contrast medium, in ADPKD patients.

Is renal allograft dysfunction a risk factor for severe infection in kidney transplant recipients?

The ANTICIPE study is a cross-sectional, multicenter, French study. The aim of this study was to describe clinical and biological parameters observed in a cohort of 1446 stable renal transplant recipients, according to the stage of chronic kidney disease. Severe infection was defined as an infection necessitating ≥ 7 days of hospital stay. We observed a negative correlation between declining glomerular filtration rate and occurrence of severe infection (P < .0001). In multivariate analysis, severe infection was associated with age, female gender, chronic kidney disease stage (Kidney Disease Outcomes Quality Initiative classification), and number of acute rejection episodes. Our study suggested that renal allograft function is a predictor not only of cardiac death and cardiovascular complications, but also of severe infections.

Cytomegalovirus risk factors in renal transplantation with modern immunosuppression.

BACKGROUND: Immunosuppressive regimens have lowered the rate of kidney rejection, but with increasing immunodeficiency-related complications. New cytomegalovirus (CMV) prophylaxis also has become available. The impact of these 2 developments on CMV diseases has not been well evaluated. We conducted a randomized trial comparing a drug regimen common in the 1980s, cyclosporin A (CsA) with azathioprine (Aza), with a drug combination used most today, tacrolimus (Tac) with mycophenolate mofetil (MMF), and we analyzed CMV risk factors in kidney transplant patients. METHODS: The 300 patients included in the trial underwent the same universal prophylaxis and preemptive therapy. CMV events and risk factors were prospectively recorded. RESULTS: With preventive and preemptive strategies combined for 3 months, CMV replication was detected in 32.6% and CMV disease in 18.1% of patients. Multivariate analysis on risk factors for CMV disease were CMV donor (D)/recipient (R) matching and first month renal function (risk ratio [95% confidence interval]: 1.02 [1.01; 1.04]; P=0.011), but not the immunosuppressive regimen (P=0.35). The D+/R- combination increased the risk of CMV disease by a factor of 9 (P<0.0001) when compared with D-/R- status, and a factor of 3.5 (P<0.0001) when compared with all CMV-positive recipients. Despite the 50% rate of CMV disease in the D+/R- group, no asymptomatic CMV replication was detected with the preemptive strategy. CONCLUSIONS: With modern immunosuppression, a sequential quadritherapy with Tac/MMF, and a 3-month CMV prevention strategy, the risk for CMV disease remains close to that with CsA/Aza. A CMV-negative recipient transplanted from a CMV-positive donor (D+/R-) remains a major risk factor, calling for better CMV prophylaxis or matching in negative recipients. Preemptive strategy thus appeared inefficient for this high-risk group. Transplant recipients with altered renal function should also be considered at risk.

[Kidney involvement in hematologic malignancies. Diagnostic approach]. / Les atteintes rénales au cours des hémopathies malignes. Stratégie diagnostique.

Kidney involvement is frequent in hematologic malignancies. It is associated with adverse outcome and treatment difficulties. It can affect every area of the renal parenchyma (tubules, interstitium, glomerulus, vessels). Various mechanisms could be implicated: deposits of immunoglobulin fractions or crystals, renal infiltration by malignant cells, urinary tract obstruction, paraneoplastic or storage glomerulopathies… Diagnostic strategy relies on the clinical presentation: acute renal failure, chronic kidney disease, glomerular proteinuria with or without nephrotic syndrome, tubular proteinuria, hydroelectrolytic disorders. In this review, we detail the diagnostic tests that are needed for the detection and the follow-up of renal involvement in hematologic malignancies, and clarify the indications of renal biopsy. We propose diagnostic strategies of renal involvement in myeloma, Waldenström's disease, high grade lymphomas and acute leukemias, low grade lymphomas and chronic leukemias. The adverse effects of treatments (chemotherapy, radiotherapy, stem cell graft …) are not addressed in this review.

Geographical prevalence, risk factors and impact of hepatitis B and C after renal transplantation.

BACKGROUND: Hepatitis B (HBV) and hepatitis C (HCV) virus infections are major risk factors affecting long-term morbidity and mortality after renal transplantation. Hepatitis prevalence is subject to geographical variations. OBJECTIVE: To compare and analyze the geographical prevalence, risk factors and impact of HBV and HCV infection in multinational cohorts of renal transplant recipients. METHODS: From 1989 - 2002, data on 12,856 kidney transplant recipients in 37 countries were collected within the prospective MOST (Multinational Observational Study in Transplantation). Subgroup analyses of hepatitis-related prevalence, risk factors and impact were conducted on patients whose HBV and HCV status was available at time of transplantation. Countries were substratified according to population prevalence of > or = 5% HBV or > or = 10% HCV. RESULTS: The prevalence of HBV was 2.9%, of HCV 8.7% and of HBV together with HCV 0.4%. Risk factors for hepatitis infection in renal transplant recipients were long dialysis time, retransplantation and blood transfusions. At each study endpoint up to 5 years after transplantation, no significant differences in graft function were observed, although the 1-year acute rejection rate tended to be lower in HCV+ patients. At 5 years post-transplant, there were no differences between the subgroups and regions regarding infections, post-transplant diabetes mellitus or malignancies including PTLD. CONCLUSIONS: Overall, HCV infections are more prevalent than HBV. Despite large geographical differences in prevalence, HBV and HCV status did not appear to have a significant impact on renal graft function, infections, malignancies and post-transplant diabetes mellitus up to 5 years after renal transplantation throughout the MOST countries.

Lymphoma-associated hemophagocytic syndrome: a rare cause of severe prerenal acute renal failure.

We report on a 79-year-old woman having hemophagocytosis and capillary hyperpermeability syndrome who presented with anuric prerenal acute renal failure. The patient eventually died of a hypovolemic shock. Post-mortem biopsies evidenced a highly aggressive B cell intravascular lymphoma without amyloidosis. Physicians should be aware of the risk of anuric prerenal acute renal failure in the course of lymphoma-associated hemophagocytic syndrome.

Low 1-year cyclosporine microemulsion doses are associated with better 5-year renal graft function: an insight from MOST, a multinational observational study.

BACKGROUND: In earlier registry analyses, cyclosporine at doses of < 3 mg/kg/d at 1 year post-renal transplantation has been associated with significant graft loss or reduction in renal function. Improvements in cyclosporine formulation with increased bioavailability, plus the use of more efficient comedications, may now confer better outcomes. To determine the effect of the 1-year cyclosporine microemulsion (CsA-ME) dose on renal allograft function at 5 years, we analyzed data collected from 2889 patients with documented graft survival to year 5 in a prospective, multinational, observational study-Neoral MOST. RESULTS: Glomerular filtration rate (GFR) at year 1 was 63 +/- 20 mL/min and 59 +/- 22 mL/min at year 5. The multivariate analysis including year 1 CsA-ME dose as factor and GFR at 1 year as covariate revealed the most significant factors affecting GFR at year 5 were 1-year GFR, donor age > 60 years, and CsA-ME dose at 1 year. Risk factors associated with reduction in 5-year GFR (<65 mL/min) included donor or recipient age >60 years, delayed graft function, cadaveric donor, previous graft, and acute rejection. CsA-ME dose <3 mg/kg/d was found to protect GFR. Analysis of GFR at each year posttransplantation (Wilcoxon model) found 1-year CsA-ME (cutoff 3 mg/kg/d) had a significant effect at each time point. CONCLUSIONS: Compared to higher doses, CsA-ME <3 mg/kg/d at year 1 posttransplantation is associated with increased preservation of renal allograft function at year 5.

Impact of mycophenolate mofetil dose posttransplantation on 12-month renal function: analysis of the MOST database.

INTRODUCTION: Mycophenolate mofetil (MMF) has greatly reduced the risk of acute rejection episodes (ARE) after renal transplantation, but dose reductions/withdrawals could jeopardize long-term results. METHODS: The MOST database of "de novo" patients treated with MMF at month 1 and functioning grafts at month 12 were divided into 2 groups: groups 1, 2 g MMF at month 1 and month 12; and group 2, 2 g MMF at month 1 but MMF <2 g at month 12 to evaluate renal function glonerular filtration rate (GFR). RESULTS: In this study, 1136 patients were receiving 2 g MMF at month 1. On month 12, 645 were on 2 g (56.8%, group 1) and 431 were on <2 g (43.2%, group 2). Group 1 included younger recipients of younger donors with fewer patients with delayed graft function (DGF). Group 1 showed more ARE during month 1 and more patients who received induction. Mean Neoral daily doses at month 1/month 12 were 5.3/3.0 and 5.3/3.1 mg/kg in group 1 and group 2, respectively (P = .05 at month 12). GFR in group 1 and group 2 were 59.06 (CI 57.10-60.60) and 53.81 (CI 52-55.7) at month 1 (P < .001); 63.7 (CI 62.1-65.30) and 55.9 (CI 54.1-57.7) mL/min*1.73 m(2) at month 12 (P < .001). The mean increases in GFR between month 1 and month 12 were 4.64 and 1.94 mL/min*1.73 m(2), respectively (P < .05). A multivariate analysis also included 795 patients from the "maintenance" patient database with retrospective detailed information. The following parameters were highly predictive for good renal function at month 12: donor age younger than 60 years, recipient age younger than 60 years, immediate graft function, 12-month MMF dose = 2 g, absence of CMV infection, and 12-month Neoral dose <3 mg/kg/d. CONCLUSIONS: Maintenance of MMF dose at 2 g/d during the first year appears to facilitate the attainment of optimal renal function at 12-months after kidney transplantation.

Delayed graft function: risk factors, consequences and parameters affecting outcome-results from MOST, A Multinational Observational Study.

BACKGROUND: Delayed graft function (DGF) is a common complication after renal transplantation, and may affect graft function. The aim of this analysis was to evaluate risk factors for DGF, as well as parameters and events influencing graft function after DGF. We analyzed data collected in an ongoing international, prospective; observational study, the Neoral-MOST (Multinational Observational Study in renal Transplantation), and included in the analysis all patients with cadaveric kidney transplants for whom renal function at 1 year posttransplantation was documented (N = 8950). Logistic regression was used to evaluate the risk factors for DGF occurrence, and multifactorial analysis of variance (ANCOVA) to assess the relevance of different factors for GFR at 1 year. RESULTS: Higher donor age, longer CIT, male recipients, Caucasian recipients, high recipients body mass index, and PRA were all associated with a higher risk for DGF. Renal function of former DGF kidneys at 1 year was lower in kidneys of elder donors, or which had experienced rejection or CMV infection. Variations of the maintenance regimen at 1 year posttransplantation were not associated with better graft function. Multifactorial analysis showed donor age and acute rejection as significant independent factors. CONCLUSIONS: Most factors increasing the risk for DGF or having a negative impact on renal function at 1 year in grafts with DGF are predetermined. Additional posttransplant damage by acute rejection was associated with further reductions in GFR. Preventing acute rejection is an important step in achieving optimal function of DGF grafts.

Kelley-Seegmiller syndrome due to a new variant of the hypoxanthine-guanine phosphoribosyltransferase (I136T) encoding gene (HPRT Marseille).

A patient with hyperuricaemia and gouty arthritis due to a new variant of hypoxanthine-guanine phosphoribosyltransferase is described. The mutation (I136T, HPRT Marseille) is in the phosphoribosylpyrophosphate-binding region of the gene and leads to almost total loss of enzyme activity in erythrocytes, with 5% in lymphocytes. Nevertheless, the patient showed no neurological abnormality.

One-year posttransplant renal function is a strong predictor of long-term kidney function: results from the Neoral-MOST Observational Study.

BACKGROUND: Peritransplant risk factors influence short-term and long-term graft survival, and 1-year serum creatinine is known to predict long-term graft survival. To examine interrelationships between risk factors, renal function at 1 year, and long-term graft function in patients maintained on cyclosporine, we analyzed data collected from 10,692 de novo or maintenance renal transplant recipients in an ongoing international, prospective, observational study--Neoral-MOST (Multinational Observational Study in renal Transplantation). The effect of donor age, delayed graft function, acute rejection, donor type, panel-reactive antibodies, and previous graft on 1- and 5-year renal function and their relationship to 1-year serum creatinine was assessed. RESULTS: Donor age, delayed graft function, acute rejection, and donor type significantly increased the risk for serum creatinine > 130 micromol/L at 1 year posttransplant, and 1-year serum creatinine was the strongest predictor of 5-year renal function. After adjustment for 1-year serum creatinine, an ongoing influence was observed for donor age, donor type, and previous graft. Delayed graft function and acute rejection had a significant effect on serum creatinine at year 1 but no additional impact on long-term graft function. CONCLUSIONS: Serum creatinine at 1 year is influenced by risk factors known to affect overall graft survival and is predictive of 5-year renal graft function. The effects of delayed graft function and acute rejection appear to be limited to their influence on serum creatinine at 1 year, whereas donor type and previous graft predominantly affect later stages of graft life.

[Review of quality of life instruments used in end-stage renal disease]. / Qualité de vie et insuffisance rénale chronique terminale: le point sur les différents questionnaires existants.

Health related quality of life (HRQOL) indicators take into account the personal perception of health, and are proposed as an alternative for efficacy indicators in medical and therapeutic decision making. They provide, due to elaboration and validation of a questionnaire, a standardised assessment of the health status perception. This paper provides a review of a variety of HRQOL instruments developed for patients suffering end-stage renal disease (ESRD). Generic instruments are designed to be applicable in general population and disease-targeted instrument are potentially more sensitive to the characteristics of a specific population. Among HRQOL instruments, we found 4 generic questionnaires (the Sickness Impact Profile, the SF 36, the Nottingham Health Profile and the EQ-5D), 3 disease-targeted questionnaires developed for ESRD patient undergoing dialysis (the Kidney Disease Quality of Life instrument, the Kidney Disease Questionnaire and the Choice Health Experience Questionnaire), 1 questionnaire specific for ESRD patients (the HRQOL questionnaire), and 2 specific disease-targeted instruments for renal transplant (the Kidney Transplant Questionnaire and the ESRD Symptom Checklist-Transplantation Module). In France, very few studies on the quality of life of ESRD patients were published; no specific questionnaire validated in French is yet published.

Comparative study on two kidney graft rinsing and preservation solutions in terms of the post-transplantation risk of delayed graft function and cost.

OBJECTIVE: To determine whether Belzer solution (Viaspan, Bristol-Myers Squibb, Brussels, Belgium), which is more expensive than Eurocollins solution, was better at preventing delayed graft function (DGF) and whether it was cost-effective as it could potentially reduce post-transplantation complications. METHOD: The risk of occurrence of complications associated with the use of these two rinsing and preserving solutions was estimated from a survey of 106 patients undergoing renal transplantation between 1 January 1993 and 31 March 1998. Both efficacy and adverse outcomes were recorded along with the costs directly associated with the transplantation procedure in the hospital setting: hospitalization, rinsing and preserving solutions, medical and technical interventions and diagnostic tests. RESULTS: For the 45 kidney grafts rinsed and preserved with Eurocollins (strategy S1: n1 = 45) the cost/graft was estimated at 40 euros. With Viaspan (strategy S2: n2 = 61) the corresponding cost/graft was 424 euros. Logistic regression analysis showed that Viaspan was better than Eurocollins solution (ebeta = 0.437; P = 0.05) in preventing DGF. Overall, S2 was less expensive than S1, from the hospital's perspective. The mean difference per patient was 278 euros, which amounts to a saving of 2% of the total cost per renal transplantation. For rinsing and preserving kidney grafts Belzer solution is therefore preferable to Eurocollins solution.

Tubular lesions and tubular cell adhesion molecules for the prognosis of lupus nephritis.

BACKGROUND: To assess the prognostic value of tubular lesions and cell adhesion molecules' expression, a retrospective study with immunohistochemistry was performed on 152 patients presenting lupus nephritis from January 1985 to December 1999. METHODS: The following clinical parameters were recorded: age, sex, race, time of systemic lupus erythematosus (SLE) diagnosis, time of the biopsy, proteinuria, creatininemia, and renal function at the end of follow-up. All biopsies were re-evaluated according to a tubular grading, an inflammatory grading, the percentage of sclerosed glomeruli, the percentage of crescents, and the current WHO classification. Immunohistochemistry was performed with anti-CD40, anti-CD44, and anti-intercellular adhesion molecule-1 (anti-ICAM-1) antibodies. RESULTS: Patients were 136 women (89.5%) and 16 men with a mean age of 31.2 years +/- 12.8 at the time of biopsy. The mean follow-up period was 94.3 months +/- 64.1. Eighty-eight biopsies (58%) showed various degrees of tubular atrophy. Males (P = 0.001) and tubular grading (P = 0.0001) were linked with renal survival in univariate and multivariate analysis. CD40 (P = 0.01) and ICAM-1 (P = 0.001) tubular expressions were linked with renal survival. ICAM-1 tubular expression provided additional information for the prognosis of the patients with biopsies showing tubular atrophy (P = 0.005) or not (P = 0.05). CONCLUSIONS: Our study shows that tubular lesions are good indicator of lupus nephritis outcome. Furthermore, tubular expression of cell adhesion molecules like ICAM-1 and CD40 also serves to predict the outcome.

Human hypertension caused by mutations in WNK kinases.

Hypertension is a major public health problem of largely unknown cause. Here, we identify two genes causing pseudohypoaldosteronism type II, a Mendelian trait featuring hypertension, increased renal salt reabsorption, and impaired K+ and H+ excretion. Both genes encode members of the WNK family of serine-threonine kinases. Disease-causing mutations in WNK1 are large intronic deletions that increase WNK1 expression. The mutations in WNK4 are missense, which cluster in a short, highly conserved segment of the encoded protein. Both proteins localize to the distal nephron, a kidney segment involved in salt, K+, and pH homeostasis. WNK1 is cytoplasmic, whereas WNK4 localizes to tight junctions. The WNK kinases and their associated signaling pathway(s) may offer new targets for the development of antihypertensive drugs.

Cystatin C is not more sensitive than creatinine for detecting early renal impairment in patients with diabetes.

This study evaluated serum cystatin C as a potential new marker of glomerular filtration rate (GFR) in 49 patients who had steady-state diabetes with early renal impairment. We determined the correlation between GFR measured by chromium 51-labeled EDTA and levels of serum cystatin C, serum creatinine, serum beta(2)-microglobulin, endogenous creatinine clearance, and Cockcroft formula. Sensitivity and specificity for the diagnosis of renal failure, defined as a GFR less than either 80 or 60 mL/min/1.73 m(2), were calculated by receiver operating characteristic (ROC) curves for creatinine, cystatin C, and beta(2)-microglobulin. Finally, we compared mean values of these three serum parameters in patients grouped according to GFR using the two definitions of renal failure. Correlation coefficients with GFR were -0.77 for serum creatinine level, -0.65 for serum cystatin C level, -0.71 for serum beta(2)-microglobulin level, +0.56 for endogenous creatinine clearance, and +0.69 for Cockcroft formula (all P < 0.001). With a cutoff value of 60 mL/min/1.73 m(2), areas under the ROC curve were 0.972 for beta(2)-microglobulin, 0.925 for cystatin C, and 0.916 for creatinine levels. With a cutoff value of 80 mL/min/1.73 m(2), these were 0.838 for beta(2)-microglobulin, 0.780 for cystatin C, and 0.905 for creatinine levels (P = not significant between parameters). These results were not altered after the exclusion of patients (n = 8) with a serum creatinine level greater than 1.41 mg/dL. When patients were classified into three groups according to GFR (group 1, >80 mL/min/1.73 m(2); group 2, 60 to 80 mL/min/1.73 m(2); group 3, <60 mL/min/1.73 m(2)), mean values of serum parameters in the three groups were statistically different (P < 0.0001) except between groups 1 and 2 for cystatin C and beta(2)-microglobulin. With patients classified into two groups (GFR > or < 80 mL/min/1.73 m(2)), mean values for each parameter were statistically different (P < 0.001). Sensitivity, specificity, and positive and negative predictive values for serum creatinine and serum cystatin C levels were very close for both definitions of renal failure. Serum cystatin C is not better than serum creatinine or serum beta(2)-microglobulin levels for estimating GFR in patients with steady-state diabetes using ROC curves or other validation tests.