Stephen M. Korbet

MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis

The increased burden of chronic kidney and end-stage kidney diseases (ESKD) in populations of African ancestry has been largely unexplained. To identify genetic variants predisposing to idiopathic and HIV-1–associated focal segmental glomerulosclerosis (FSGS), we carried out an admixture-mapping linkage-disequilibrium genome scan on 190 African American individuals with FSGS and 222 controls. We identified a chromosome 22 region with a genome-wide logarithm of the odds (lod) score of 9.2 and a peak lod of 12.4 centered on MYH9, a functional candidate gene expressed in kidney podocytes. Multiple MYH9 SNPs and haplotypes were recessively associated with FSGS, most strongly a haplotype spanning exons 14 through 23 (OR = 5.0, 95% CI = 3.5–7.1; P = 4 × 10−23, n = 852). This association extended to hypertensive ESKD (OR = 2.2, 95% CI = 1.5–3.4; n = 433), but not type 2 diabetic ESKD (n = 476). Genetic variation at the MYH9 locus substantially explains the increased burden of FSGS and hypertensive ESKD among African Americans.

APOL1 Genetic Variants in Focal Segmental Glomerulosclerosis and HIV-Associated Nephropathy

Trypanolytic variants in APOL1, which encodes apolipoprotein L1, associate with kidney disease in African Americans, but whether APOL1-associated glomerular disease has a distinct clinical phenotype is unknown. Here we determined APOL1 genotypes for 271 African American cases, 168 European American cases, and 939 control subjects. In a recessive model, APOL1 variants conferred seventeenfold higher odds (95% CI 11 to 26) for focal segmental glomerulosclerosis (FSGS) and twenty-nine-fold higher odds (95% CI 13 to 68) for HIV-associated nephropathy (HIVAN). FSGS associated with two APOL1 risk alleles associated with earlier age of onset (P = 0.01) and faster progression to ESRD (P < 0.01) but similar sensitivity to steroids compared with other subjects. Individuals with two APOL1 risk alleles have an estimated 4% lifetime risk for developing FSGS, and untreated HIV-infected individuals have a 50% risk for developing HIVAN. The effect of carrying two APOL1 risk alleles explains 18% of FSGS and 35% of HIVAN; alternatively, eliminating this effect would reduce FSGS and HIVAN by 67%. A survey of world populations indicated that the APOL1 kidney risk alleles are present only on African chromosomes. In summary, African Americans carrying two APOL1 risk alleles have a greatly increased risk for glomerular disease, and APOL1-associated FSGS occurs earlier and progresses to ESRD more rapidly. These data add to the evidence base required to determine whether genetic testing for APOL1 has a use in clinical practice.

Reactive glycosylation endproducts in diabetic uraemia and treatment of renal failure.

In diabetes and ageing, glucose-derived advanced glycosylation endproducts (AGEs) cross-link proteins and cause vascular tissue damage. Elimination of circulating low-molecular weight AGE-modified molecules (LMW-AGEs) by the kidney is impaired in diabetic patients with end-stage renal disease, a group subject to accelerated atherosclerosis. We determined the effectiveness of current renal replacement treatments on elimination of serum LMW-AGEs in diabetic and non-diabetic patients with end-stage renal disease. Although diabetic patients receiving high-flux haemodialysis achieved 33% lower steady-state serum LMW-AGE than did those in conventional haemodialysis (p < 0.005), LMW-AGE concentrations remained 3.5-6 fold above normal, whether high-flux dialysis, conventional haemodialysis, or chronic ambulatory peritoneal dialysis were used. High-flux haemodialysis markedly reduced AGE during each treatment session (47.9% in the diabetic, p < 0.001 and 60.6% in the non-diabetic group, p < 0.001) but concentrations returned to pre-treatment range within 3 hours. In contrast, normal LMW-AGE concentrations were maintained in patients with functioning renal transplants. We found that LMW-AGEs with an apparent molecular weight of 2000-6000 circulate and retain strong inherent chemical reactivity--when exposed to collagen in vitro, up to 77% attached covalently to form AGE-collagen, and the AGE-crosslink inhibitor aminoguanidine completely inhibited this reaction. The results suggest that LMW-AGEs comprise a set of chemically-reactive molecules that are refractory to removal by current dialysis treatments. Through covalent reattachment onto vascular matrix or serum components, LMW-AGEs may exacerbate vascular pathology associated with end-stage renal disease.

Factors predictive of outcome in severe lupus nephritis

In 1992, we published the results of a prospective, controlled trial of aggressive therapy (high-dose prednisone plus oral cyclophosphamide alone or with plasmapheresis) in 86 patients with severe lupus nephritis. During this study, remission (serum creatinine < or =1.4 mg/dL [< or =123 micromol/L] and proteinuria < or =330 mg/d of protein) in renal disease occurred in 37 patients (43%). To assess the long-term effect of remission on patient and renal survival, we now report the results of our extended follow-up of these patients. After an average of 10 years of follow-up in the 86 patients, patient survival rates at both 5 and 10 years were 95% in the group that had a remission and 69% at 5 years and 60% at 10 years in the no-remission group (P < 0.001). Renal survival rates were 94% at both 5 and 10 years in the remission group compared with 46% at 5 years and 31% at 10 years in the no-remission group (P < 0. 0001). Features predictive of remission included stable renal function after 4 weeks on therapy, category IV lesion, lower chronicity index, white race, lower urine protein excretion level at baseline, and lower baseline serum creatinine level. The features predictive of end-stage renal disease were higher baseline serum creatinine level, presence of anti-Ro antibodies, and failure to attain a remission. Thus, in patients with the most severe forms of lupus nephritis, a remission of clinical renal abnormalities is associated with dramatic improvement in long-term patient and renal survival.

Timing of complications in percutaneous renal biopsy.

Percutaneous renal biopsy (PRB) is a safe and effective tool in the diagnosis and management of renal disease; however, the optimal timing of observation after biopsy is not clearly established. With the use of real-time ultrasound guidance, PRB of native kidneys was performed in 750 adult patients at an academic institution by an attending nephrologist or fellow between June 1983 and June 2002. All patients were observed for 23 to 24 h after biopsy for the presence, severity, and timing of complications. Biopsy-related complications occurred in 98 (13%) patients; minor complications occurred in 50 (6.6%) patients, and major complications occurred in 48 (6.4%) patients. One (0.1%) patient died as a result of the biopsy. Multivariate analysis using logistic regression found only serum creatinine at baseline predictive of a complication. Patients with a serum creatinine > or = 5.0 mg/dl were 2.3 times as likely to have a complication (odds ratio, 2.3; 95% confidence interval, 1.3 to 4.1; P < 0.005). Complications were identified in 38 (42%) patients by < or = 4 h, in 61 (67%) patients by < or = 8 h, in 77 (85%) patients by < or = 12 h, and in 81 (89%) patients at < or = 24 h. The PRB remains a safe procedure, but the risk of complication is higher in patients with advanced renal insufficiency. After biopsy, an observation time of up to 24 h remains optimal as an observation period of < or = 8 h risks missing > or = 33% of complications.

Focal segmental glomerular sclerosis in adults: Presentation, course, and response to treatment

The authors performed a retrospective clinicopathologic study in 81 patients with primary focal segmental glomerular sclerosis (FSGS) to determine whether they could identify clinical or histologic features at presentation that could be predictive of outcome and response to therapy. Males constituted 58% of patients, and 53% were black. At biopsy the patients were 40 +/- 17 years old; 74% were nephrotic, and renal insufficiency was present in 62%. The average time from presentation to biopsy was 16 months, and the average total follow-up was 62 months. Nephrotic patients had a significantly poorer prognosis as compared with nonnephrotic patients (5- and 10-year survivals of 76% and 57% v 92% and 92%; P < 0.05). A multivariate analysis was done on histologic and clinical features at biopsy, assessing for risk factors leading to end-stage renal disease, showing only the serum creatinine and the degree of interstitial fibrosis to have a significant correlation. Thirty nephrotic patients received prednisone, with a treatment time of 5.5 +/- 4 months and a total dose of 5.9 +/- 2.9 g per course of treatment. Fifteen of these patients (50%) achieved a remission by 3.7 +/- 2 months (10 complete remission and 5 partial remissions), with all patients responding within 9 months. Only two patients had spontaneous remissions (both partial). The 5- and 10-year survival for patients in remission were both 100% as compared with 66% and 41% (P < 0.01), respectively, for nephrotic patients not in remission. No clinical feature at presentation of biopsy was predictive of response to therapy when a multivariate analysis was performed.(ABSTRACT TRUNCATED AT 250 WORDS)

Focal Segmental Glomerulosclerosis in Nephrotic Adults: Presentation, Prognosis, and Response to Therapy of the Histologic Variants

The histopathologic diagnosis of primary focal segmental glomerulosclerosis (FSGS) has come to include a number of histologic lesions (variants), but the prognostic significance of these discrete lesions is controversial because published information regarding the presentation, course, and response to treatment is limited. A retrospective analysis was conducted of 87 nephrotic adult patients with biopsy-proven primary FSGS. Patients were categorized on the basis of histologic criteria into those with a classic scar (36 patients), the cellular or collapsing lesion (40 patients), or the tip lesion (11 patients) of FSGS to evaluate differences in presentation, response to therapy, and clinical outcomes. The clinical features at biopsy were similar among the three groups with the exception that patients with the tip lesion were older and patients with the collapsing lesion had more severe proteinuria. Over the course of follow-up, 63% of patients treated attained remission and the response to steroid therapy was similar among the groups (classic scar 53% versus collapsing lesion 64% versus tip lesion 78%; P = 0.45). The overall renal survival was significantly better for patients who entered remission compared with patients who did not enter remission (92% versus 33% at 10 yr; P < 0.0001). The renal survival at 10 yr for patients who entered remission was similar among the three groups (classic scar 100% versus tip lesion 100% versus collapsing lesion 80%; P = 0.61). In patients who did not enter remission, the renal survival at 10 yr was significantly worse for patients with collapsing lesion and tip lesion (classic scar 49% versus tip lesion 25% versus collapsing lesion 21%; P = 0.002). In conclusion, the prognosis for nephrotic FSGS patients who enter remission is excellent regardless of the histologic lesion. Because the remission rate after treatment is similar among patients with the histologic variants, response to therapy cannot be predicted on the basis of histology alone. Thus, nephrotic patients with primary FSGS should receive a trial of therapy irrespective of the histologic lesion when not contraindicated.

Severe Lupus Nephritis: Racial Differences in Presentation and Outcome

This study assessed whether certain clinicopathologic variables could explain the impact of race on outcome in 86 patients who had severe lupus nephritis and were available for long-term follow-up after participating in a prospective, controlled, clinical trial. Fifty-four (63%) patients were white, 21 (24%) were black, and 11 (13%) were categorized as other. The proportion of patients with anti-Ro, anti-nRNP, and anti-Sm was significantly greater among black patients. Biopsies with segmental active proliferative and necrotizing lesions that involved >or=50% of glomeruli +/- membranous glomerulonephritis (class III >or=50%+/-V) were significantly more common (white 44%, black 76%, other 36%; P < 0.05) and diffuse proliferative glomerulonephritis +/- membranous glomerulonephritis (class IV+/-V) was less common (white 54%, black 24%, other 64%) among black patients. Attainment of a remission was greatest among white patients (white 52%, black 29%, other 27%; P = 0.09). Features that were predictive of a remission were white race, baseline serum creatinine, and class IV+/-V lesions. Patient survival at 10 yr (white 81%, black 59%, other 73%; P = 0.029) and renal survival at 10 yr (white 68%, black 38%, other 61%; P = 0.015) were significantly poorer in black patients. Predictors of ESRD were serum creatinine, the presence of anti-Ro antibodies, class III >or=50%+/-V lesions, and failure to achieve a remission. In conclusion, racial differences were observed in the serologic and histologic features at presentation, response to treatment, and outcome of patients with severe lupus nephritis. In a population of patients with severe lupus nephritis, black patients were significantly more likely to have a serologic profile and renal lesions that were associated with more aggressive renal disease and resulted in worse outcomes than white patients.

The racial prevalence of glomerular lesions in nephrotic adults

We retrospectively evaluated the prevalence of primary glomerular lesions in adults who had a renal biopsy for nephrotic proteinuria. From July 1975 to May 1994, 340 patients undergoing renal biopsies evaluated at Rush-Presbyterian-St Lukes Medical Center had the primary glomerular lesions of minimal-change disease, focal segmental glomerular sclerosis (FSGS), membranous glomerulonephritis (MGN), membranoproliferative glomerulonephropathy, immunoglobulin A nephropathy, and immunotactoid glomerulopathy. The patients had a mean age of 43 +/- 17 years, 57% were male, and 50% were white, 36% were black, 7% were of other race, and 7% were of unknown race. The distribution of lesions for black patients was minimal-change disease 14%, FSGS 57%, MGN 24%, membranoproliferative glomerulonephritis 2%, immunoglobulin A 2%, and immunotactoid glomerulopathy 1%; for white patients, the distribution of lesions was minimal-change disease 20%, FSGS 23%, MGN 36%, membranoproliferative glomerulonephropathy 6%, immunoglobulin A 8%, and immunotactoid glomerulopathy 6%. The prevalence of FSGS was significantly greater (P < 0.0001) and that for MGN, immunoglobulin A, and immunotactoid glomerulopathy was significantly less (P < 0.05) for black patients compared with white patients. In a logistic regression analysis, race remained the only significant predictor of FSGS (P = 0.0001), with black patients four times as likely to have FSGS as white patients. The distribution of lesions among white patients was similar based on gender, age, and biopsy period. For black patients the distribution was also similar based on gender and age, but over 20 years the incidence of FSGS increased from 39% (1975 to 1984) to 64% (1985 to 1994) (P < 0.01). Thus, significant racial differences in the distribution of primary glomerular lesions exists. This has important prognostic and therapeutic implications for nephrotic adults.

Membranous Glomerulonephritis and Malignancy

The purpose of this review is to enhance the clinical awareness of the association between membranous glomerulonephritis and neoplasia. Controversy has persisted that has tended to minimize this association, therefore, we report our experience to shed some light on this controversy as well as to make diagnostic recommendations. One hundred seven adult patients with biopsy-proven membranous glomerulonephritis were selected for review. Twenty of these patients had a known secondary cause of membranous glomerulonephritis other than malignancy. Data were collected retrospectively on all these patients and nine were found who had or developed malignancy associated with membranous glomerulonephritis. Clinical data were analyzed to ascertain the onset of renal disease in relation to the malignancy as well as to determine the ultimate patient and renal outcome after treatment of the neoplasm. Of the 87 patients with presumed idiopathic membranous glomerulonephritis, nine (10.3%) had or developed a malignancy associated with their renal disease. The membranous glomerulonephritis was seen in patients with various solid tumors as well as hematologic malignancies. All patients presented with nephrotic-range proteinuria. Proteinuria manifested itself prior to or concomitantly with the diagnosis of the neoplasm in approximately 80% of cases. Follow-up data were available on seven patients: complete remission of proteinuria was seen in two patients associated with treatment of their tumors, one patient developed end-stage renal disease, and the remaining four patients had persistent proteinuria associated with tumor recurrence or metastasis. There appears to be a clear association between membranous glomerulonephritis and neoplasia.(ABSTRACT TRUNCATED AT 250 WORDS)