Focal and segmental glomerulosclerosis.

An increasing cause of end-stage renal disease is the pathological lesion focal and segmental glomerulosclerosis (FSGS). FSGS is characterized by proteinuria and frequently nephrotic syndrome with ensuing renal failure. The etiology remains unknown in the majority of individuals. The idiopathic form of FSGS is most common; however, secondary forms of FSGS do exist. There is a form of FSGS that is fulminant that frequently recurs after renal transplantation with an estimated frequency of approximately 30%, suggesting that the pathogenesis is not solely a result of intrinsic kidney disease. Recently, hereditary forms of the disease were recognized as well as those associated with other congenital syndromes. Known genetic causes of the hereditary form of this disease have been suggested to account for upwards of 18% of cases. This review will address recent discoveries of the genetic mechanisms of hereditary FSGS and the current interpretations of their interactions at the slit diaphragm.

Symptoms of gastro-oesophageal reflux disease and the severity of obstructive sleep apnoea syndrome are not related in sleep disorders center patients.

BACKGROUND: Studies suggest obstructive sleep apnea syndrome (OSAS) frequently manifests in patients with gastroesophageal reflux disease (GERD) and that there may be a causal relationship. AIM: To determine the relationship between OSAS and symptoms of GERD. METHODS: Consecutive patients referred to the Sleep Disorders Center (SDC) 18 years and older with polysomnographically defined OSAS were evaluated prospectively for GERD using a validated symptoms questionnaire. The GERD and OSAS relationship was assessed by 1) determining frequency of GERD in patients with and without OSAS; 2) ascertaining the relationship between OSAS severity categories and presence of GERD; 3) examining GERD score in relation to those factors that might affect both GERD and OSAS, e.g. obesity. RESULTS: One thousand and twenty-three SDC patients met entry criteria. Amongst participants, GERD was common (29% of women and 17% of males) and OSAS extremely common (58% of women and 80% of males). GERD score did not correlate with OSAS variables. The severity of OSAS did not influence the prevalence of GERD. CONCLUSION: In a large group of patients referred to a sleep disorders center, there was no relationship between OSAS and GERD symptoms. Also, there was no relationship between the severity of OSAS and the likelihood of GERD symptoms.

Evidence for genetic factors in the development and progression of IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is the most common glomerulonephritis in the world among patients undergoing renal biopsy. Once considered a relatively benign condition, longitudinal follow-up studies have revealed that in fact 9 to 50% of patients progress to end-stage renal disease within 20 years of disease onset. In the three decades since its first description by Jean Berger and Nicole Hinglais, clinical, epidemiologic, and immunologic studies of the pathogenesis of primary (idiopathic) mesangial glomerulonephritis with predominant IgA deposits have characterized the features of IgAN as a distinct glomerular disease entity. However, the basic molecular mechanism(s) underlying abnormal IgA deposition in the mesangium with ensuing extracellular matrix expansion and mesangial cell proliferation remains poorly understood. The task of elucidating the molecular basis of IgAN is made especially challenging by the fact that both environmental and genetic components likely contribute to the development and progression of IgAN. METHODS AND RESULTS: We review here the evidence for genetic factors in the development and progression of IgAN, including a reappraisal of earlier conflicting results from small immunogenetic case-control studies, the evidence for racial differences in the prevalence of IgAN, a detailed summary of all reported occurrences of familial IgAN worldwide, and an exhaustive review of new insights gained through the study of two murine models of hereditary IgAN: the ddY and the uteroglobin-deficient mouse. CONCLUSIONS: With the development of powerful molecular genetic approaches to the study of both Mendelian and complex human genetic diseases, and the successful efforts of investigators to identify and clinically characterize large IgAN multiplex families, we propose that genetic analysis of familial IgAN is the most promising approach to the identification of IgAN disease/susceptibility genes. Alternatively, if the case-control study design is employed to identify associations between particular candidate genes or markers and the development of IgAN, spurious associations caused by the effects of population stratification should be ruled out by confirming the findings using powerful and sensitive family-based methodologies such as the transmission/dysequilibrium test (TDT).

Spectrum of disease in familial focal and segmental glomerulosclerosis.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is the underlying pathologic entity in 5% of adults and 20% of children with end-stage renal disease (ESRD). FSGS is generally considered to be sporadic in origin. METHODS: Recently, we identified 60 families involving 190 individuals with familial FSGS, providing evidence for a subset of families in which a genetic form is segregating. Each family had at least one member with renal biopsy-confirmed FSGS and at least one other member with either renal biopsy-confirmed FSGS or ESRD. RESULTS: Twenty-six families had individuals affected in more than one generation [multigeneration (MG)], and the remaining 34 families had only a single generation (SG) affected. There was equal representation of males and females among affected individuals. Ten percent of MG families were African American, and 52% of SG families were African American. The mean age of presentation was significantly higher in the MG families (32.5 +/- 14.6 years) compared with the SG families (20.1 +/- 12.1 years, P = 0.0001). SG cases had higher levels of proteinuria at presentation (7.0 +/- 5.6 g/24 hr, compared with 3.8 +/- 3.4 g/24 hr, for the MG families, P = 0.002). On renal biopsy, tubulointerstitial damage was more severe in patients in the SG families than in the MG families; however, the level of glomerular damage did not differ between these groups. Fifty percent of the patients had progressed to ESRD by the age of 30 years. Variables measured at presentation that were independently associated with poor renal survival were decreased age, increased serum creatinine, and increased urinary protein excretion. Forty-one patients underwent successful renal transplantation, with a 10-year graft survival rate of 62%. One patient developed clinical and biopsy evidence of recurrence of FSGS in the allograft. CONCLUSION: These data confirm the existence of a non-Alport's form of hereditary glomerulonephritis, which has a morphological pattern of FSGS.

Linkage of a gene causing familial focal segmental glomerulosclerosis to chromosome 11 and further evidence of genetic heterogeneity.

Focal segmental glomerulosclerosis (FSGS) is a pathological entity characterized by proteinuria, nephrotic syndrome, and the progressive loss of renal function. It is a common cause of end-stage renal disease (ESRD). Recently, familial forms of FSGS have been identified. Two families with autosomal dominant FSGS were evaluated for linkage using 351 genomic microsatellite markers. Linkage, multipoint analysis, and tests for heterogeneity were performed on the subsequent results. In addition, three small families were used for haplotype analysis. Evidence for linkage was found on chromosome 11q21-q22 for the largest family, with a maximum lod score of 9.89. The gene is currently localized to an 18-cM area between flanking markers D11S2002 and D11S1986. The disease in a second family was not linked to this locus or to a previously described locus on chromosome 19q13. There were no shared haplotypes among affected individuals in the three smaller families. Our findings demonstrate that genetic heterogeneity is prevalent in FSGS in that at least three genes cause the FSGS phenotype. Identification of the genes that cause familial FSGS will provide valuable insights into the molecular basis and pathophysiology of FSGS.

Acute renal failure following cardiac surgery.

BACKGROUND: Acute renal failure requiring dialysis (ARF-D) occurs in 1.5% of patients following cardiac surgery, and remains a cause of major morbidity and mortality. While some preoperative risk factors have been characterized, the influence of preoperative and intraoperative factors on the occurrence of ARF following cardiac surgery is less well understood. METHODS: Preoperative and intraoperative data on 2843 consecutive adult patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) from February 1, 1995 to February 1, 1997 were recorded and entered into a computerized database. Two definitions of renal failure were employed: (i) ARF defined as a rise in serum creatinine (Cr) of 1 mg/dl above baseline; and (ii) ARF-D defined as the development of ARF for which some form of dialytic therapy was required. The association between preoperative and intraoperative variables and the development of ARF was assessed by multivariate logistic regression. RESULTS: A total of 2672 of the 2844 patients underwent isolated coronary artery bypass grafting (CABG) surgery, the remaining 172 underwent valve surgery with or without bypass grafting. Of the CABG patients 7.9% developed ARF and 0.7% developed ARF-D. The mortality for patients who developed ARF was 14% (OR 15, P = 0.0001) compared with 1% among those who did not develop ARF. The mortality for CABG patients who developed ARF-D was 28% (OR 20, P = 0.0001) compared with 1.8% among those who did not require dialysis. Variables that were significantly associated with the development of ARF by multivariate analysis included: increased age, elevated preoperative serum Cr, duration of CPB, presence of a carotid artery bruit, presence of diabetes, reduced cardiac ejection fraction and increased body weight. Variables independently associated with ARF-D included serum Cr, duration of CPB, carotid artery bruit and presence of diabetes. The utility of these models for predicting the development of ARF and ARF-D was confirmed by bootstrapping techniques. Because of the small number of patients who underwent valve surgery, none of these variables were significantly associated with the development of ARF or ARF-D in this group of patients. CONCLUSION: The development of ARF or ARF-D is associated with a high mortality following CABG surgery. We have identified perioperative variables, which may be useful in stratifying risk for the development of ARF.

Clinical and genetic heterogeneity in familial focal segmental glomerulosclerosis. International Collaborative Group for the Study of Familial Focal Segmental Glomerulosclerosis.

BACKGROUND: Familial forms of focal segmental glomerulosclerosis (FFSGS) that exhibit autosomal dominant or recessive patterns of inheritance have been described. The genetic basis of these hereditary forms of FSGS is unknown. One recent study of a kindred from Oklahoma with an autosomal dominant form of FSGS linked this disease to a region of chromosome 19q. In addition, polymorphisms in a gene in this region on chromosome 19q13 have been linked to congenital nephrotic syndrome of the Finnish type. We have ascertained and characterized a large family with autosomal dominant FFSGS (Duke 6530). METHODS: Families were compared for clinical and genetic heterogeneity. To test for linkage of our family to this portion of chromosome 19, genomic DNA was isolated from 102 family members, and polymerase chain reaction was performed using eight microsatellite markers that spanned the area of interest on chromosome 19. Data were evaluated using two-point linkage analysis, multipoint analysis, and an admixture test. RESULTS: Linkage was excluded at a distance of +/- 5 to 10 CM for all markers tested with two-point log10 of the odds of linkage (LOD) scores and from an approximate 60 CM interval in this area of chromosome 19q via multipoint analysis. CONCLUSIONS: FSGS has been called the "final common pathway" of glomerular injury, as it is a frequent pathological manifestation with diverse etiologies. This diversity likely correlates with the genetic heterogeneity that we have established. Thus, our data demonstrate that there are at least two genes responsible for this disease, and there is genetic as well as clinical heterogeneity in autosomal dominant FSGS.

Focal segmental glomerulosclerosis: a need for caution in live-related renal transplantation.

Focal segmental glomerulosclerosis (FSGS) has increasingly been recognized to occur in a familial pattern. We have observed the development of biopsy-confirmed FSGS and subsequent end-stage renal disease (ESRD) in one live related kidney donor and ESRD without biopsy in another. Both donors had family members with ESRD secondary to FSGS. Both donors were apparently healthy by routine physical examination, urinalysis, and serum creatinine at the time of evaluation as live related donors. We believe these cases emphasize the need for great caution when evaluating siblings as potential live related donors.

Orthostatic acute renal failure in a renal transplant.

Complications due to ureteric obstruction are an occasional cause for renal transplant dysfunction. Here we report an unusual case of orthostatic renal failure in a renal transplant recipient. Our patient had the previously reported predisposing risk factors including: female sex, obesity, and lax abdominal musculature. It is important to recognize this unusual complication of renal transplantation early in order to preserve long-term graft function.