Gene/Protein Disease Symptom Drug Enzyme Compound
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Glomerular diseases, including diabetes and various forms of glomerulonephritis, account for more than 70% of patients undergoing renal transplantation. Among these patients, more than 40% develop significant proteinuria, and around 15% develop persistent nephrotic syndrome. The most common cause of posttransplantation proteinuria is chronic allograft nephropathy (60%), followed by recurrent (15%) and de novo (10%) glomerulonephritis. Persistent proteinuria is associated with a significantly reduced rate of graft survival but often can be controlled with non-disease-specific therapy including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers with favorable effects on long-term prognosis. Recurrent or de novo glomerulonephritis occurs in 6%-20% of patients overall and is more common in patients transplanted with glomerulonephritic organs. Glomerulonephritis in the allograft is also associated with a reduction in long-term (5-year) graft survival (40% vs 70%). The most common diseases associated with allograft glomerulonephritis and their recurrence rates in transplantation patients are idiopathic focal glomerular sclerosis (20%-30%), IgA nephropathy (25%), membranoproliferative glomerulonephritis (type 1, 25%; type 2, 80%), membranous nephropathy (30%), and hemolytic-uremic syndrome (classic, 10%; atypical, 40%; familial, 60%). This article reviews new developments in the understanding of 3 of these diseases-focal glomerular sclerosis, membranous nephropathy, and hemolytic-uremic syndrome-as they relate to the incidence of recurrence, the effects of recurrence on graft survival, risk factors for recurrence, and management issues for nephrologists caring for patients with renal allografts. Proper donor selection, early diagnosis in high-risk patients, and appropriate management can prolong graft survival and improve long-term outcomes.
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PMID:Recurrent glomerulonephritis in the renal allograft: an update of selected areas. 1598 71

Glomerular injury and proteinuria in diabetes (types 1 and 2) and IgA nephropathy is related to the degree of podocyte depletion in humans. For determining the causal relationship between podocyte depletion and glomerulosclerosis, a transgenic rat strain in which the human diphtheria toxin receptor is specifically expressed in podocytes was developed. The rodent homologue does not act as a diphtheria toxin (DT) receptor, thereby making rodents resistant to DT. Injection of DT into transgenic rats but not wild-type rats resulted in dose-dependent podocyte depletion from glomeruli. Three stages of glomerular injury caused by podocyte depletion were identified: Stage 1, 0 to 20% depletion showed mesangial expansion, transient proteinuria and normal renal function; stage 2, 21 to 40% depletion showed mesangial expansion, capsular adhesions (synechiae), focal segmental glomerulosclerosis, mild persistent proteinuria, and normal renal function; and stage 3, >40% podocyte depletion showed segmental to global glomerulosclerosis with sustained high-grade proteinuria and reduced renal function. These pathophysiologic consequences of podocyte depletion parallel similar degrees of podocyte depletion, glomerulosclerosis, and proteinuria seen in diabetic glomerulosclerosis. This model system provides strong support for the concept that podocyte depletion could be a major mechanism driving glomerulosclerosis and progressive loss of renal function in human glomerular diseases.
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PMID:Podocyte depletion causes glomerulosclerosis: diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene. 1614 37

We have identified several eye muscle antigens and studied the significance of the corresponding serum autoantibodies in patients with Graves' disease. Of these antigens, only calsequestrin is expressed more in eye muscle than other skeletal muscles, which could explain at least partly the specific involvement of eye muscle in patients with Graves' disease. Earlier, we found a modest relationship between anti-calsequestrin antibodies and ophthalmopathy, but in that study we used calsequestrin prepared from rabbit heart muscle and measured antibodies by immunoblotting. We have reinvestigated the prevalences of anti-calsequestrin antibodies in larger groups of well-characterized patients with thyroid autoimmunity with and without ophthalmopathy and control patients and healthy subjects, using standard enzyme-linked immunosorbent assay incorporating highly purified rabbit skeletal muscle calsequestrin, which has a 97% homology with human calsequestrin, as antigen. Anti-calsequestrin antibodies were detected in 78% of patients with active congestive ophthalmopathy, in 92% of those with active inflammation and eye muscle involvement, but in only 22% of patients with chronic, 'burnt out' disease. Tests were also positive in 5% of patients with Graves' hyperthyroidism without evident ophthalmopathy (two patients) and one patient with 'watery eyes' but no other clear signs of congestive ophthalmopathy and IgA nephropathy and no known thyroid disease, but in no patient with Hashimoto's thyroiditis, toxic nodular goitre, non-toxic multi-nodular goitre or diabetes, or age- and sex-matched healthy subjects. In serial studies of all 11 patients with Graves' hyperthyroidism who had active ophthalmopathy at the time of the first clinic visit, or developed eye signs during the first 6 months, and positive anti-calsequestrin antibodies in at least one sample, anti-calsequestrin antibodies correlated with the onset of ocular myopathy in six patients. Antibodies targeting calsequestrin appear to be specific markers for ophthalmopathy and sensitive indicators of the ocular myopathy subtype of ophthalmopathy in patients with thyroid autoimmunity. However, these results must be considered preliminary until a large prospective study of patients with newly diagnosed Graves' hyperthyroidism, in which serum levels of calsequestrin antibodies are correlated with clinical changes and orbital eye muscle and connective tissue/fat volumes, has been carried out.
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PMID:Antibodies targeting the calcium binding skeletal muscle protein calsequestrin are specific markers of ophthalmopathy and sensitive indicators of ocular myopathy in patients with Graves' disease. 1679 74

We reported a case of a 38-year-old woman with both massive proteinuria and severe obesity. We diagnosed her as metabolic syndrome from her waist size of over 90 cm around her umbilicus, hyperlipidemia (high TG level) and hypertension. The urinary protein was more than 3.5 g/day and body mass index was 38.7 at admission. The renal biopsy specimen revealed IgA nephropathy. According to Clinical guidelines of IgA nephropathy 2nd version, Committee of IgA Nephropathy-the Special Study Group on Progressive Glomerular Disease, the Ministry of Health, Labor and Welfare of Japan-, her prognosis belonged to a rather poor group. We planed to administer steroid treatment first, however considering the adverse effects of steroid therapy, such as hyperlipidemia and diabetes mellitus, we tried to decrease her body weight as much as possible, and then treated her with both angiotensin converting enzyme inhibitor and anti-platelet drug. After her body mass index (body weight) was approximately 30.1 % (30 kg) less than that on admission, a parallel reduction of urinary protein was observed, and the final level was approximately 0.18 g/day. Decline in the body weight, diet and exercise were the chief measures that reduced the urinary protein without corticosteroid therapy.
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PMID:[An IgA nephropathy case with highly reduced urinary protein concomitant with reduced obesity]. 1712 85

The transforming growth factor (TGF)-beta-inducible integrin alpha v beta6 is preferentially expressed at sites of epithelial remodeling and has been shown to bind and activate latent precursor TGF-beta. Herein, we show that alpha v beta6 is overexpressed in human kidney epithelium in membranous glomerulonephritis, diabetes mellitus, IgA nephropathy, Goodpasture's syndrome, and Alport syndrome renal epithelium. To assess the potential regulatory role of alpha v beta6 in renal disease, we studied the effects of function-blocking alpha v beta6 monoclonal antibodies (mAbs) and genetic ablation of the beta6 subunit on kidney fibrosis in Col4A3-/- mice, a mouse model of Alport syndrome. Expression of alpha v beta6 in Alport mouse kidneys was observed primarily in cortical tubular epithelial cells and in correlation with the progression of fibrosis. Treatment with alpha v beta6-blocking mAbs inhibited accumulation of activated fibroblasts and deposition of interstitial collagen matrix. Similar inhibition of renal fibrosis was observed in beta6-deficient Alport mice. Transcript profiling of kidney tissues showed that alpha v beta6-blocking mAbs significantly inhibited disease-associated changes in expression of fibrotic and inflammatory mediators. Similar patterns of transcript modulation were produced with recombinant soluble TGF-beta RII treatment, suggesting shared regulatory functions of alpha v beta6 and TGF-beta. These findings demonstrate that alpha v beta6 can contribute to the regulation of renal fibrosis and suggest this integrin as a potential therapeutic target.
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PMID:Alphav beta6 integrin regulates renal fibrosis and inflammation in Alport mouse. 1720 Jan 87

Amylin (islet amyloid peptide) plays a critical role in islet amyloidosis and in the development of beta-cell dysfunction in patients with diabetes; however, the involvement of amylin in renal amyloidosis has not been studied. For this reason, we surveyed 149 patients with biopsy-proven diabetic nephropathy (DN). The results were compared to 95 renal disease control patients, which included membranoproliferative glomerulonephritis, light-chain deposition, IgA nephropathy, and obesity-related glomerulopathy (ORG). Seventy-two of the 149 patients with DN showed amylin deposition in their renal tissue. Amylin was mainly distributed in the expanded mesangial area, Kimmelstiel-Wilson nodules, Bowman's capsule, and in blood vessels. The frequencies of mesangial proliferation, glomerular nodule lesions, and glomerular sclerosis were higher in DN patients with amylin deposits. Furthermore, the tubular interstitial lesions were more severe in these patients. Of the 95 disease-control patients, four with ORG were positive for renal amylin deposits. Our study has found renal amylin deposition in patients with DN and that the deposition was associated with disease severity. We suggest that strict metabolic control and reversing insulin resistance in patients with diabetes may blunt the process of amylin deposition in the kidney and possibly protect renal function in these patients.
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PMID:Amylin deposition in the kidney of patients with diabetic nephropathy. 1749 60

The incidence and prevalence of end-stage renal disease (ESRD) is increasing. Diabetic nephropathy has increased in absolute numbers and as a proportion of patients with ESRD. This is almost totally accounted for by the explosive outbreak of Type 2 diabetes mellitus (DM). The world is in the midst of an epidemic of Type 2 DM and hence this trend is likely to continue for some more time. The contribution of glomerulonephritis as a proportion of patients with chronic renal failure (CRF) has declined due to increase in other causes such as diabetes. The annual incidence of IgA nephropathy, which is also a very common cause of renal insufficiency, has not changed. The incidence of focal segmental glomerulosclerosis is increasing while that of membranoproliferative glomerulonephritis is decreasing. Peak incidence of ESRD due to hypertension has shifted to a higher age-group. The proportion of renovascular disease as a cause of ESRD is also increasing. Human immunodeficiency virus associated nephropathy is the third leading cause of ESRD in African-Americans aged 20-64 years. Other diseases such as analgesic nephropathy and lead nephropathy are slowly disappearing. The significance of elevated body lead in patients with varying degrees of renal insufficiency requires further evaluation. The incidence of CRF is significantly higher in the elderly and hence there is a "graying" of CRF population. Census projections show that this trend will continue into the foreseeable future. The incidence and prevalence of ESRD vary between different populations, countries and within countries. The reason for the variations requires further study.
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PMID:Changing profile of causes of chronic renal failure. 1765 16

Elevated serum uric acid level is associated with obesity, insulin resistance, diabetes, nephropathy, and hypertension. Epidemiologic studies suggest that serum uric acid levels are heritable. We sought to identify chromosomal regions harboring quantitative trait loci that influence serum uric acid in Mexican Americans using data from 644 participants in the San Antonio Family Heart Study. Serum uric acid was found to exhibit significant heritability (0.42) in this population (P = 2 x 10(-7)) after accounting for covariate effects. In addition, genetic correlations between serum uric acid and other cardiovascular risk factors, such as body mass index, waist circumference, systolic BP, and pulse pressure, were identified, suggesting that the genes associated with uric acid level are also associated with these phenotypes. Multipoint linkage analysis identified quantitative trait loci with measurable effects on serum uric acid variability. The highest multipoint logarithm of odds score of 3.3 was found at 133 cM on chromosome 6q22-23, a region that also contains genes that seem to influence familial IgA nephropathy, obesity, BP, insulin resistance, and type 2 diabetes. Given the relationship between uric acid level and these conditions, future studies should investigate potential candidate susceptibility genes found in this region.
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PMID:Genome scan for determinants of serum uric acid variability. 1797 10

There are racial differences in primary renal diseases for end-stage renal disease (ESRD) and the incidence and prevalence of cardiovascular disease (CVD). To reduce the number of patients with both ESRD and CVD, an effective screening method for CKD should be established. In Japan, screening with the urine dip-stick test for proteinuria has been used since 1972 targeting every child and worker and since 1983 for every resident over 40 years old. There are several reasons for continuing this screening program. First, the positive rate of proteinuria is high in the Japanese general population, especially subjects with neither hypertension nor diabetes. Most of these subjects have no symptoms, and the only sign of renal disease is asymptomatic urinary abnormalities. Second, the prevalence and incidence of glomerulonephritis, especially IgA nephropathy, are high in the Japanese and Asian races, and urinalysis is the only method for early detection of chronic glomerulonephritis. Third, 10-year survival of the ESRD patients due to glomerulonephritis was approximately twice that of ESRD patients due to diabetes and nephrosclerosis. Consequently, reducing the incidence of ESRD due to glomerulonephritis is one of the best ways to reduce the prevalence of ESRD. Furthermore, higher incidence of ESRD in Asian races than in Caucasians was reported. Proteinuria is known to be the best predictor for reducing renal function, and the urine dip-stick test for proteinuria is less expensive and is cost-effective. For an effective screening strategy to reduce the ESRD population in Japanese and Asians, universal screening with the urine dip-stick test for proteinuria could be one solution.
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PMID:Chronic kidney disease perspectives in Japan and the importance of urinalysis screening. 1817 65

Gene polymorphisms, in particular single nucleotide polymorphisms (SNPs), have been associated to multifactorial diseases such as cancer, inflammation and autoimmunity. Indeed for some autoimmune diseases, it has been possible to identify critical residues that play a major role in susceptibility to diseases. The association of a common T/C polymorphism in the promoter region of the beta 2 constant chain of the T-cell receptor with autoimmune diseases, such as insulin-dependent diabetes, autoimmune hepatitis, IgA nephropathy, membranous nephropathy, Graves' disease and Hashimoto's thyroiditis, was described in the 1990 s. These reports have not been confirmed in the last few years. We also failed in a previous study to detect any difference between 70 normal subjects and 70 patients with primary biliary cirrhosis; however, we found a difference in allelic frequency between males and females. This finding led us to make an allele frequency study of this single nucleotide polymorphism between sexes in a new series of patients. We studied 165 subjects, 80 males and 85 females, and we found a significant difference between sexes especially for the CC homozygous genotype: 34% of females vs. 14% of males (P = 0.008). If the higher frequency of CC homozygous genotype (that is associated with an increased risk of autoimmune diseases) in females would be confirmed in normal population, this could be an explanation of the controversial results obtained by association studies made between this SNP and autoimmune diseases.
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PMID:A possible mechanism for non-replication of allelic association between a single nucleotide polymorphism of the human beta T-cell receptor and autoimmune diseases. 1827 72


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