Low Pre-Transplant Caveolin-1 Serum Concentrations Are Associated with Acute Cellular Tubulointerstitial Rejection in Kidney Transplantation.

Acute and chronic transplant rejections due to alloreactivity are essential contributors to graft loss. However, the strength of alloreactivity is biased by non-immunological factors such as ischemia reperfusion injury (IRI). Accordingly, protection from IRI could be favorable in terms of limiting graft rejection. Caveolin-1 (Cav-1) is part of the cell membrane and an important regulator of intracellular signaling. Cav-1 has been demonstrated to limit IRI and to promote the survival of a variety of cell types including renal cells under stress conditions. Accordingly, Cav-1 could also play a role in limiting anti-graft immune responses. Here, we evaluated a possible association between pre-transplant serum concentrations of Cav-1 and the occurrence of rejection during follow-up in a pilot study. Therefore, Cav-1-serum concentrations were analyzed in 91 patients at the time of kidney transplantation and compared to the incidence of acute and chronic rejection. Higher Cav-1 levels were associated with lower occurrence of acute cellular tubulointerstitial rejection episodes.

Renal involvement in primary Sjögren's syndrome: A retrospective study of 103 biopsy-proven cases from a single center in China.

AIM: To retrospectively investigate the features of renal involvements in patients with primary Sjögren's syndrome (pSS) with biopsy results. METHODS: A total of 2096 pSS inpatients at Peking Union Medical College Hospital in China from 2005 to 2015 were identified. Patients with biopsy-proven renal involvement (SS-renal) and matched controls (SS-only) were recruited. The clinical and pathologic features as well as treatments and outcomes were systematically analyzed. RESULTS: One hundred and three pSS nephritis (inpatients had biopsy-proven renal involvement. Tubulointerstitial 53, 51.5%) was the prominent pathologic pattern with glomerulonephritis (GN) present in 50 (48.5%) of the renal lesions. The patterns of GN lesions included membranous nephropathy (37, 35.9%), mesangial proliferative glomerulonephritis (six, 5.8%) or immunoglobulin A nephropathy (three, 2.9%), minimal change disease (four, 3.9%) and focal segmental glomerulosclerosis (three, 2.9%). Compared to SS-only patients, SS-renal patients had fewer dry eyes and positive objective xerostomia (P < 0.05). They presented with a significantly lower incidence of interstitial lung disease (ILD), leukocytopenia and elevated immunoglobulin G levels (P < 0.05). They received a larger initial dosage of corticosteroid and had a higher mortality rate (P < 0.05). CONCLUSION: This Chinese SS-renal population with biopsy results has diverse pathologic patterns and distinct clinical features. They are characterized with prominent renal-associated and mild SS-associated features. They received more vigorous treatment but had poorer prognosis.

Proton pump inhibitors are associated with increased risk of development of chronic kidney disease.

BACKGROUND: Acute interstitial nephritis secondary to proton pump inhibitors (PPIs) frequently goes undiagnosed due to its subacute clinical presentation, which may later present as chronic kidney disease (CKD). We investigated the association of PPI use with the development of CKD and death. METHODS: Two separate retrospective case-control study designs were employed with a prospective logistic regression analysis of data to evaluate the association of development of CKD and death with PPI use. The population included 99,269 patients who were seen in primary care VISN2 clinics from 4/2001 until 4/2008. For evaluation of the CKD outcome, 22,807 with preexisting CKD at the first observation in Veterans Affairs Health Care Upstate New York (VISN2) network data system were excluded. Data obtained included use of PPI (Yes/No), demographics, laboratory data, pre-PPI comorbidity variables. RESULTS: A total of 19,311/76,462 patients developed CKD. Of those who developed CKD 24.4 % were on PPI. Patients receiving PPI were less likely to have vascular disease, COPD, cancer and diabetes. Of the total of 99,269 patients analyzed for mortality outcome, 11,758 died. A prospective logistic analysis of case-control data showed higher odds for development of CKD (OR 1.10 95 % CI 1.05-1.16) and mortality (OR 1.76, 95 % CI 1.67-1.84) among patients taking PPIs versus those not on PPIs. CONCLUSIONS: Use of proton pump inhibitors is associated with increased risk of development of CKD and death. With the large number of patients being treated with proton pump inhibitors, healthcare providers need to be better educated about the potential side effects of these medications.

Gene Expression in Biopsies of Acute Rejection and Interstitial Fibrosis/Tubular Atrophy Reveals Highly Shared Mechanisms That Correlate With Worse Long-Term Outcomes.

Interstitial fibrosis and tubular atrophy (IFTA) is found in approximately 25% of 1-year biopsies posttransplant. It is known that IFTA correlates with decreased graft survival when histological evidence of inflammation is present. Identifying the mechanistic etiology of IFTA is important to understanding why long-term graft survival has not changed as expected despite improved immunosuppression and dramatically reduced rates of clinical acute rejection (AR) (Services UDoHaH. http://www.ustransplant.org/annual_reports/current/509a_ki.htm). Gene expression profiles of 234 graft biopsy samples were obtained with matching clinical and outcome data. Eighty-one IFTA biopsies were divided into subphenotypes by degree of histological inflammation: IFTA with AR, IFTA with inflammation, and IFTA without inflammation. Samples with AR (n = 54) and normally functioning transplants (TX; n = 99) were used in comparisons. A novel analysis using gene coexpression networks revealed that all IFTA phenotypes were strongly enriched for dysregulated gene pathways and these were shared with the biopsy profiles of AR, including IFTA samples without histological evidence of inflammation. Thus, by molecular profiling we demonstrate that most IFTA samples have ongoing immune-mediated injury or chronic rejection that is more sensitively detected by gene expression profiling. These molecular biopsy profiles correlated with future graft loss in IFTA samples without inflammation.

Kidney biopsy findings in primary Sjögren syndrome.

BACKGROUND: Renal involvement is rare in primary Sjögren syndrome (PSS). In this study, we examined renal biopsy findings in patients with PSS and correlated them with their clinical and renal findings. METHODS: Twenty-five patients with PSS who underwent renal biopsies from two renal units in Scotland between 1978 and 2013 were identified from renal biopsy database. We examined the renal morphologic, clinical and renal findings at the time of renal biopsy, renal and patient outcomes. RESULTS: The diagnosis of PSS preceded renal biopsy in 18/25 patients. In this group, the median duration of the disease was 5.5 years. Significant proteinuria, combined microscopic haematuria and proteinuria and reduced renal excretory function were found in 76, 56 and 84% of patients, respectively. The 3-year actuarial patient survival was significantly lower in patients with glomerulonephritis as compared with tubulointerstitial nephritis (66 versus 100%, P = 0.02). There was no difference in 3-year actuarial renal survival between these two groups (92 versus 92%, P = 1.0). CONCLUSIONS: Renal biopsy is rare in PSS and often reveals diverse pathological findings. Glomerulonephritis, as compared with tubulointerstitial nephritis, is associated with higher early mortality. Further studies are needed to evaluate the utility of renal biopsy and its impact on disease management.

Designation of T-cell-mediated rejection type Ib and IIa reflects the type of rejection rather than the severity in the Banff classification.

OBJECTIVES: Whether T-cell-mediated rejection Banff classification type Ib (severe tubulointerstitial rejection) and type IIa (mild vascular rejection) are associated with responses to antirejection therapy and long-term graft survival are unclear. MATERIALS AND METHODS: One hundred ten patients were enrolled who had at least 1 episode of T-cell-mediated rejection and whose highest T-cell-mediated rejection severity was T-cell-mediated rejection type Ib or IIa. RESULTS: T-cell-mediated rejection Ib occurred significantly later than T-cell-mediated rejection IIa (P < .001). The proportion of partial/no response to antirejection therapy was comparable between the 2 groups (P = .83). Up to 8-year posttransplant, death-censored graft survival rate of the T-cell-mediated rejection Ib group was similar to that of the T-cell-mediated rejection IIa group (P = .51). Early T-cell-mediated rejection IIa had a statistically higher death-censored graft survival rate than did late T-cell-mediated rejection IIa (P < .001), while no significant difference in the death-censored graft survival was found between early and late T-cell-mediated rejection Ib (P = .11) or between early T-cell-mediated rejection Ib and early T-cell-mediated rejection IIa (P = .11) or between late T-cell-mediated rejection Ib and late T-cell-mediated rejection IIa (P = .07). Furthermore, the T-cell-mediated rejection IIa with isolated v1 lesion (v1, i0-1, t0-1) showed a similar death-censored graft survival rate compared to T-cell-mediated rejection IIa with intensive tubulointerstitial inflammation (v1, i2-3, t2-3). The timing of rejection, graft number, the number of indicated biopsies and the presence of ci/ct lesions were associated with long-term graft loss. CONCLUSIONS: The designation of T-cell-mediated rejection type Ib and IIa reflects the different type rather than the distinct severity of rejection and has no independent prognostic significance.

A nationwide nested case-control study indicates an increased risk of acute interstitial nephritis with proton pump inhibitor use.

The magnitude of the suspected increase in risk of acute interstitial nephritis among proton pump inhibitor users is uncertain. Here, we conducted a nested case-control study using routinely collected national health and drug dispensing data in New Zealand to estimate the relative and absolute risks of acute interstitial nephritis resulting in hospitalization or death in users of proton pump inhibitors. The cohort included 572,661 patients without a history of interstitial nephritis or other renal diseases who started a new episode of proton pump inhibitor use between 2005 and 2009. Cases had a first diagnosis after cohort entry of acute interstitial nephritis confirmed by hospital discharge letter or death record, and renal histology (definite, 46 patients), or discharge letter or death record only (probable, 26 patients). Ten controls, matched by birth year and sex, were randomly selected for each case. In the case-control analysis based on definite cases and their controls, the unadjusted matched odds ratio (95% confidence interval) for current versus past use of proton pump inhibitors was 5.16 (2.21-12.05). The estimate was similar when all cases (definite and probable) and their corresponding controls were analyzed, and when potential confounders were added to the models. The crude incidence rates and confidence intervals per 100,000 person-years were 11.98 (9.11-15.47) and 1.68 (0.91-2.86) for current and past use, respectively. Thus, current use of a proton pump inhibitor was associated with a significantly increased risk of acute interstitial nephritis, relative to past use.

Clinically significant renal involvement in primary Sjögren's syndrome: clinical presentation and outcome.

OBJECTIVE: To estimate the prevalence and investigate the clinical features and the outcome of clinically significant renal involvement in a large cohort of patients with primary Sjögren's syndrome (SS). METHODS: Among 715 patients who met the American-European Consensus Group criteria for primary SS, those with clinically significant renal involvement were identified and their clinical and immunologic features were recorded. The prognosis in patients with primary SS with renal involvement was assessed by the clinical appearance of any of the following major outcomes: death, hemodialysis, chronic renal failure (CRF), and lymphoma. Kaplan-Meier analysis was applied to compare death rates between patients without and those with renal involvement. RESULTS: Thirty-five patients with primary SS (4.9%) had clinically significant renal involvement, representing a total followup time after renal diagnosis of 252.2 person-years. Thirteen patients (37.1%) had interstitial nephritis alone, 17 patients (48.6%) had glomerulonephritis (GN) alone, and 5 patients (14.3%) had both entities. Nine patients died (25.7%), 11 developed CRF (including 4 requiring chronic hemodialysis) (31.4%), and 9 developed lymphoma (25.7%). The overall 5-year survival rate was 85%. Kaplan-Meier analysis showed statistically significant reduced survival for patients with primary SS with renal involvement compared to those without renal involvement (P < 0.0001 by log rank test), with GN patients displaying increased mortality. Eight of 9 reported deaths (89%) and 8 of 9 lymphomas (89%) were observed among patients with GN. CONCLUSION: The long-term prognosis varies for patients with primary SS who have clinically significant renal involvement. Patients with interstitial nephritis display a favorable prognosis, while patients with GN are at high risk of developing lymphoma and have poor survival.

Measuring urinary tubular biomarkers in type 2 diabetes does not add prognostic value beyond established risk factors.

Tubulointerstitial disease plays an important role in the pathophysiology of diabetic kidney disease. To determine whether biomarkers of tubular injury could predict renal outcome and mortality in patients with type 2 diabetes, we measured urinary levels of kidney injury molecule-1 (KIM-1) and glycoprotein non-metastatic melanoma B (Gpnmb), both normalized to the urinary creatinine, in 978 individuals from the Edinburgh Type 2 Diabetes Study. At baseline, 238 patients had an estimated glomerular filtration rate (eGFR) below 60 ml/min/1.73 m2 while 147 and 15 patients had microalbuminuria or overt proteinuria, respectively. Both the urine KIM-1 and Gpnmb to creatinine ratios correlated with the urinary albumin to creatinine ratio, the duration of diabetes, and the stringency of glycemic control but not with blood pressure or baseline eGFR. Higher ratios of each marker were associated with a faster decline in kidney function during 4 years of follow-up; however, this was not independent of the urinary albumin to creatinine ratio. Higher KIM-1, but not Gpnmb ratios were associated with an increased risk of mortality, but this association was no longer significant after adjustment for other risk factors, in particular albuminuria. Thus, tubular injury in persons with type 2 diabetes may contribute to the decline in kidney function; however, measuring the urinary concentration of these two tubular biomarkers does not confer additional prognostic information beyond established risk factors.

[Characteristics of chronic renal failure in black adult patients hospitalized in the Internal Medicine department of Treichville University Hospital]. / Particularités de l'insuffisance rénale chronique chez des patients adultes noirs hospitalisés dans le service de médecine interne du CHU de Treichville.

OBJECTIVE: To describe the epidemiological, clinical, biological aspects, treatment and outcome of chronic renal failure. METHODS: A retrospective study was conducted on medical data of 301 inpatients with chronic renal failure from January 1, 2004 to December 31, 2008 in the internal medicine department of Treichville university hospital. RESULTS: The hospital prevalence of chronic renal failure was 7.5%. The average patient age was 44±10 years [range : 16-86 years] and sex ratio was 1.3. The main medical histories were self-medication (38.5%) and hypertension (33.5%). In 82.4% cases, it was the end-stage renal disease. Biological abnormalities were important. The causes were dominated by nephroangiosclerosis noted in 25.3%, followed by HIV-associated nephropathy in 17% and chronic interstitial nephritis in 10.3%. Treatment consisted of transfusion in 71% and dialysis in 16%. Lethality was 54%. CONCLUSION: The chronic renal failure is a fairly common cause of hospitalization in our department. His prognosis is terrible. The main causes are nephroangiosclerosis and HIV-associated nephropathy. Accent should be placed on preventive measures of hypertension and AIDS.

Urinary kidney injury molecule-1 in patients with IgA nephropathy is closely associated with disease severity.

BACKGROUND: The pathological characteristics of IgA nephropathy (IgAN) are highly variable. Urinary kidney injury molecule-1 (KIM-1) is a sensitive biomarker for proximal tubule injury. The aim of the study is to investigate the value of KIM-1 as a biomarker for assessing the renal injury in IgAN. METHODS: The levels of urinary KIM-1 in 202 patients with IgAN, 46 patients with other renal diseases as disease controls and 60 healthy blood donors as normal controls were measured. Correlations with clinical and histopathological features of patients with IgAN were evaluated. RESULTS: The levels of urinary KIM-1 were significantly higher in patients with IgAN than in normal controls (P < 0.001) and in patients with non-IgAN (P = 0.011). Urinary levels of KIM-1 in IgAN positively correlated with levels of serum creatinine and proteinuria and negatively with creatinine clearance. The more severe the tubulointerstitial injury was, the higher the levels of urinary KIM-1. Patients with severe mesangial proliferation, crescents formation or endocapillary proliferation had higher levels of urinary KIM-1 than those without. The levels of tubular KIM-1 expression in immunohistochemistry closely correlated with the levels of urinary KIM-1 (r = 0.553, P = 0.032). Renal survival was significantly worse in patients with elevated urinary KIM-1 (P = 0.020). CONCLUSION: Urinary KIM-1 may be a useful biomarker to evaluate kidney injury in IgAN.

Histopathology and histomorphometry of the urogenital tract in 15-month old male and female rats treated neonatally with SERMs and estrogens.

In this study, two selective estrogen receptor modulators (SERMs), tamoxifen (TAM) and toremifene (TOR) or two estrogens, ethinylestradiol (EE) and diethylstilbestrol (DES) were administered to newborn male and female Sprague-Dawley rats (days 1-5) to investigate the occurrence of developmental abnormalities in the adulthood. The compounds were dosed (s.c.) at an equimolar dose of 24.9 micromol/kg. During the follow-up period, mortality occurred mainly in DES-treated male rats (3/4), associated with obstructive urinary calculi and suppurative renal inflammation in 2/3 rats. Similar lesions were not evident in other groups. At the age of 15 months, the animals were necropsied and organs were collected for histopathology and histomorphometry. Treatment-related abnormalities were restricted to the reproductive organs. Chronic prostatitis and epithelial abnormalities in the vas deferens were observed in all treatment groups. The columnar epithelium of vas deferens showed hyperplasia and development of subepithelial glandular structures resembling epididymal cysts reported in humans exposed in utero to DES. Testicular atrophy was observed especially in estrogen-treated rats. Mainly in SERM-treated female rats, the uterus showed luminal dilation or obstruction, loss of endometrial glands and myometrium disorganization including foci of muscular disruption. TOR-treated female rats showed polyp-like nodules (incidence 4/15) and a high incidence (9/15) of a simple cuboidal epithelium in cervical regions normally occupied by multilayered epithelia. In conclusion, the vas deferens is a main target organ following neonatal administration of SERMs and estrogens. In addition, female rats were significantly more susceptible to SERM treatment than to treatment with estrogens.

Susceptibility of three genetic lines of chicks to infection with a nephropathogenic T strain of avian infectious bronchitis virus.

Mortality rates were compared in three genetic lines of specific pathogen-free chicks inoculated with one of two doses of a nephropathogenic strain of avian infectious bronchitis (IB) virus. The mortality rates were influenced primarily by the chick strain, but also by age and dose of virus. Chicks of the inbred S line were highly susceptible. After inoculation with a low dose of virus at 2 and 4 weeks of age, mortality was 90 and 45%, respectively. Chicks of the HWL non-inbred line were also susceptible, with mortality rates after inoculation at 2 and 4 weeks of age of 70 and 25%, respectively. Chicks of the inbred W line were resistant and non-significant mortality of 10% occurred only in 2-week-old chicks inoculated with a high dose of virus. Viral distribution in tissues of susceptible S and resistant W chicks did not differ, and virus was present in the trachea, lung and kidney of chicks from both lines throughout the acute phase (between days 3 and 7) of infection. Viral titres in the trachea and kidney in susceptible S chicks were slightly but not significantly higher than in the other chicks during the acute phase of infection. Histopathological assessment indicated an earlier onset of a regenerative phase in the trachea of W chicks than in S chicks. S chicks, in contrast to W chicks, showed no signs of renal regeneration. Additionally, the kidneys of S chicks differed from those of W chicks in showing more severe nephritis, more tubular necrosis and less heterophil infiltration and lymphocytic response throughout the acute phase of infection. The results indicate that chicken lines may differ greatly in their susceptibility to fatal IB nephritis and that resistance is likely to be under the control of immune responses to viral infection.

Chronic cholestatic liver disease with associated tubulointerstitial nephropathy in early childhood.

We report the clinical and morphological features of an unusual hepatorenal disorder in 2 patients. The main clinical features were early onset of cholestatic liver disease and progressive tubulointerstitial nephritis, leading to renal death in early childhood. Renal histology showed interstitial fibrosis, tubular atrophy and dilatation, glomerular cysts in the cortex and periglomerular fibrosis; liver histology was characterized by portal fibrosis and bile duct abnormalities. Evaluating the 12 patients published in the literature, the long-term prognosis of the liver function appears bad, suggesting the possibility of a combined liver and kidney transplantation.

Time course of effects of tetraethoxysilane (TEOS) on the kidney and blood silicon concentration in mice.

To clarify the time course of toxicological effects of tetraethoxysaline [Si(OC2H5)4, TEOS] on the kidney and the relationship between blood silicon levels (Si-B) and the effects, 250 mg/kg or 500 mg/kg TEOS was intraperitoneally administered to ten 5-week-old male ICR mice (SPF grade) in each group, and morphological and functional changes of the kidney were assessed at 12 h, 24 h, 3 days and 2 weeks after administration of TEOS. Injury to tubular epithelial cells was observed in mice killed 12 and 24 h after administration, and its severity increased with increasing dosage. The mean values of blood urea nitrogen exhibited dose-related increase in mice sacrificed 24 h after the administration. The concentrations of Si-B increased in order of the administered doses of TEOS, and then decreased steadily. The results of Si-B were consistent with the concept that renal toxicity of TEOS is mediated by siliceous compounds. The kidney was recovering from injury 3 days after administration, and had developed tubulointerstitial nephritis, which could be regarded as repaired lesion of acute injury, by 2 weeks after administration.

Outcome of renal transplantation in different primary diseases.

1. Graft survival rates increased about 3-5 percentage points for patients with all primary diseases in 1989-1990. 2. Patients with different diseases had 1-year graft survival rates that varied from 73% for noninsulin-dependent diabetes (NIDDM) to 83% for IgA nephropathy (IgAN). Five-year graft survival varied from 40% for NIDDM to 66% for IgAN. 3. Our findings in Clinical Transplants 1990 that IgAN patients have a high graft survival was confirmed and 1-year graft survival improved by 5% in the last 2 years. 4. There was a 20 percentage point increase in full-time work status of patients after transplantation; 68% of patients with polycystic kidney disease (PKD) and chronic glomerulonephritis (CGN) had full-time work status after 3 years whereas patients with diabetes mellitus (DM) and atheronephrosclerosis (NS) had about 50%. 5. Good early graft function (urine output during the first 24 hours posttransplant, no dialysis within the first-week posttransplant, and no rejection episodes before discharge), predicted good 1-year graft survival for patients with different diseases but patients with NS and DM had a poorer graft survival beyond the first year posttransplant. Patients who had poor early function had 20% lower graft survival than those who had good function. However, in patients with IgAN, no urine at day 1 still resulted in graft survival comparable to those that produced urine. 6. More patients with DM were transplanted within 1 year after going into ESRD than those with other diseases. Conversely, 46% of those with NS did not get transplanted until more than 2 years after developing ESRD. 7. Only 77% of NS patients had functioning grafts at discharge compared to DM (84%), PKD (81%), IgAN (81%), and CGN (80%). 8. Black patients had a statistically significant higher incidence of anuria on the first day compared with Whites. They also had a higher incidence of dialysis and rejection during the first hospitalization. This was true for CGN, DM, PKD, and NS patients. Following excellent early function, Black CGN and DM patients had a higher incidence of rejection than White CGN and DM patients.

Tubulointerstitial renal disease in systemic lupus erythematosus.

Tubulointerstitial renal disease is found frequently in patients with systemic lupus erythematosus. Despite the frequency of this entity, little is known about the prognostic significance of this biopsy finding. We reviewed 46 consecutive renal biopsy specimens from patients with systemic lupus erythematosus who were followed up for a mean of 5.4 years. Tubulointerstitial abnormalities were present in 39% of the entire group of patients and in 51% of the patients who had clinical evidence of renal abnormalities. Tubulointerstitial inflammation was closely associated with diffuse proliferative glomerulonephritis, with elevation of serum creatinine (SCr) concentration at biopsy, and with increased frequency of proteinuria both at biopsy and at follow-up. Additionally, active interstitial inflammation was associated with an increased risk of doubling the entry SCr concentration. The presence or absence of tubulointerstitial disease, however, did not add additional prognostic information to the predictive power of the entry SCr concentration or the glomerular histologic features.

Balkan nephropathy and malignant tumors.

The question of whether the cancer death risk is higher in Balkan nephropathy (BN) foci has been approached by a comparison of 25 BN endemic municipalities with the same number of the group matched ones. It came out that the total cancer mortality was considerably higher, and mortality of nonurinary cancer slightly higher in BN endemic municipalities. The absence of a significant difference for the non-urinary cancer sites the authors explain by the fact that in municipalities designated as endemic only a part of the population lived in actual BN foci. They re-evaluated data published for Bulgarian BN endemic foci and concluded that, apart of a higher total cancer mortality, there was a significantly higher (although unrecognized) risk of nonurinary deaths in BN endemic settlements.

[Possibility for studying the life expectancy of patients with Balkan endemic nephropathy by dispensary observation]. / Vuzmozhnost za prouchvane produlzhitelnostta na zhiveene na bolnite ot balkanska endemichna nefropatiia chrez dispanserno nabliudenie.

The follow-up cards of 1100 patients that died of Balkan endemic nephropathy (BEN) within the period 1962-1981 were studied with a view to establishing the incidence of the disease in Vratza district, affection of sex and age and chiefly--the duration of the disease. The authors established that the disease was found in 47 settlements of Vratza district, that the females were more often affected as compared with the males and that the subjects aged from 30 to 70 were most frequently affected. More that the half of the patients with BEN was established by the authors, to die with--in the first 5 years since the onset of the disease, whereas the rest--live longer, in single cases, over 20 years.