Noncollapsing Focal Segmental Glomerulosclerosis Research Articles

Kidney Histopathology of Patients with Hepatitis C Infection and Diabetes Mellitus before and after Availability of Direct-Acting Antiviral Therapy

Introduction: Type 2 diabetes mellitus (DM) and diabetic kidney disease are increasing. Hepatitis C infection (HCV) occurs in 1% of the world population and can induce several kidney diseases. DM prevalence is increased in individuals with HCV; however, kidney diseases in those with both DM and HCV have not been assessed. Direct-acting antiviral agents (DAAs) became available for HCV treatment in 2014; it is unknown if DAAs altered the spectrum of kidney disease in patients with DM and HCV. Methods: Case review identifying patients with kidney biopsy and clinical history of DM and HCV between 2009–2013 (pre-DAA) and 2016–2020 (post-DAA), excluding kidney transplant, hepatitis B, HIV, and inadequate biopsy, identified 245 biopsies. Biopsies were evaluated for diabetic glomerulosclerosis (DGS) class, global and focal segmental glomerulosclerosis (FSGS), other glomerular diseases, interstitial fibrosis/tubular atrophy (IFTA), interstitial nephritis, acute tubular injury and degree of arterial and arteriolar sclerosis. Kidney disease differences in pre-DAA versus post-DAA eras and in mild versus severe DGS were assessed by χ2 and Fisher’s exact tests. Results: The most common non-DGS lesions were non-collapsing FSGS (41%), HCV-related IgM dominant immune complex glomerulonephritis (IgM-ICGN, 18%), IgA nephropathy (9%), and membranoproliferative glomerulonephritis (MPGN, 7%). Collapsing FSGS was more common pre-DAA versus post-DAA (8% vs. 1%, p = 0.03). Biopsies from patients with HCV and DM were reduced in post-DAA (0.7%) versus pre-DAA (1.3%) (p < 0.0001). Post-DAA there were less MPGN (2% vs. 10%, p = 0.02) and more advanced DGS (85% vs. 61%, p = 0.0002), non-collapsing FSGS (57% vs. 31%, p < 0.0001), IFTA (2.0 vs. 1.6, p = 0.0002), and vascular sclerosis (2.1 vs. 1.6, p < 0.0001). Conclusion: Post-DAA there were reduced biopsies and MPGN, with more severe DGS class, non-collapsing FSGS, IFTA, and chronic vascular changes. This suggests a modulating effect of DAAs on HCV-related kidney pathology with DM and chronic changes driving indications for kidney biopsy.

Nephrotic syndrome in the elderly: epidemiological aspects, clinical data, and renal biopsy findings.

Nephrotic syndrome is the most common clinical presentation of glomerular disease in elderly patients, and renal biopsy is an important diagnostic resource. The aim of this study was to describe nephrotic syndrome among elderly patients in Brazil, focusing on tubulointerstitial and vascular involvement. This was a retrospective study of patients over 65 years of age with nephrotic syndrome who underwent renal biopsy between January 2012 and December 2019. Of the 123 renal biopsies that occurred during the study period, 44 (35.8%) were performed for the investigation of nephrotic syndrome. Among those 44 cases, the main etiologies were membranous nephropathy in 13 cases (29.5%), amyloidosis in ten (22.7%), non-collapsing focal segmental glomerulosclerosis (FSGS) in four (9.1%), and collapsing FSGS in four (9.1%). Patients with minimal change disease (MCD) had the lowest degree of interstitial fibrosis compared with the other glomerulopathies, and histological signs of acute tubular necrosis (ATN) were less common among those with amyloidosis than among those with membranous nephropathy, FSGS, or MCD (P=0.0077). Of the patients with ATN, the frequency of acute kidney injury (AKI) was highest in those with MCD (P<0.001). All patients had some degree of vascular involvement, regardless of the type of glomerulopathy. In conclusion, the second most common cause of nephrotic syndrome in this population was amyloidosis, and acute interstitial tubule involvement was more marked in MCD. Vascular involvement is something that cannot be dissociated from the age of the patient and is not only due to the underlying glomerulopathy.

The effects of add-on corticosteroids on renal outcomes in patients with biopsy proven HIV associated nephropathy: a single centre study from South Africa

BackgroundThe aim of this study was to assess, the efficacy and safety of add-on corticosteroids to antiretroviral therapy [ART] in patients with biopsy proven HIV associated nephropathy.MethodsAll included patients had histological evidence of either collapsing or non-collapsing focal segmental glomerulosclerosis (FSGS) or podocyte and/or parietal cell hypertrophy or hyperplasia. All patients had evidence of tubulointerstitial inflammation with microcysts. Patients were randomized to ART with the addition of 1 mg/kg of corticosteroids [ART+C] or remained in the group [ART Alone] and followed for 2 years. A repeat biopsy was performed at 6 months.ResultsTwenty-one patients were randomized to [ART+C] and 17 to [ART Alone]. The baseline estimated glomerular filtration rate (eGFR) was significantly lower in the [ART+C] vs. [ART Alone] group [35mls/min/1.73m2 vs. 47 mls/min/1.73m2, p = 0.015]. The [ART+C] cohort had a statistically significant improvement in median (eGFR) from baseline to last follow up compared with [ART Alone] i.e. [Δ = 25mls/min (IQR: 15;51) vs 9 mls/min (IQR: 0–24), p = 0.008].There were no statistically significant differences between the groups when proteinuria and histology were analyzed. There were 8 deaths during the trial period, 7 from [ART+C] (Log rank p = 0.071).ConclusionsIn the [ART+C] cohort there was a significant improvement in eGFR over 2-years with increased mortality. Routine corticosteroid use cannot currently be recommended. Further investigation to define which subgroup of this cohort would safely benefit from the positive effects is required.Trial registrationISRCTN study ID (56112439] was retrospectively registered on the 5 September 2018.

KIDNEY DISEASE IN THE SETTING OF HIV INFECTION: CONCLUSIONS FROM A KIDNEY DISEASE: IMPROVING GLOBAL OUTCOMES (KDIGO) CONTROVERSIES CONFERENCE

HIV-positive individuals are at increased risk for kidney disease, including HIV-associated nephropathy, noncollapsing focal segmental glomerulosclerosis, immune-complex kidney disease, and comorbid kidney disease, as well as kidney injury resulting from prolonged exposure to antiretroviral therapy or from opportunistic infections. Clinical guidelines for kidney disease prevention and treatment in HIV-positive individuals are largely extrapolated from studies in the general population, and do not fully incorporate existing knowledge o f the unique HIV-related pathways and genetic factors that contribute to the risk of kidney disease in this population. We convened an international panel of experts in nephrology, renal pathology, and infectious diseases to define the pathology of kidney disease in the setting of HIV infection; describe the role of genetics in the natural history, diagnosis, and treatment of kidney disease in HIV-positive individuals; characterize the renal risk-benefit of antiretroviral therapy for HIV treatment and prevention; and define best practices for the prevention and management of kidney disease in HIV-positive individuals.

Cancer drugs and the glomerulus

Several chemotherapeutics including novel immunotherapies and targeted therapies have recently been approved for the treatment of various cancers. Several nephrotoxicities secondary to treatment with chemotherapeutics have been described in patients with cancer. Acute kidney injury from acute tubular necrosis and acute interstitial nephritis is commonly reported nephrotoxicities following treatment with cancer drugs. Although less common, several glomerular lesions include minimal change disease, collapsing and non-collapsing focal segmental glomerulosclerosis secondary to chemotherapy-related podocyte injury have been reported in the literature. In addition to conventional chemotherapeutics, several novel cancer drugs including immune point check inhibitors, anti-vascular endothelial growth factor inhibitors, and tyrosine kinase inhibitors have also been associated with various glomerular lesions. While the occurrence of glomerular toxicities related to cancer drugs is less common than tubular injury, failure to recognize these associations may lead to poor renal outcome. In this article, we review several chemotherapy-related glomerular diseases including thrombotic microangiopathy.

A prospective study of collapsing focal segmental glomerulosclerosis

Collapsing focal segmental glomerulosclerosis (cFSGS) is characterized by rapid progression to end-stage renal disease (ESRD). We evaluated the clinicopathological spectrum of cFSGS and compared its clinical behavior to steroid and tacrolimus (TAC)-resistant noncollapsing focal segmental glomerulosclerosis (FSGS). All patients (>14 years) diagnosed with cFSGS were enrolled in the study. Staining for differentiated podocyte markers such as WT 1, PAX and KI67 were performed in all patients. The outcome and histological features of cFSGS was compared with a prospectively followed cohort of steroid and TAC-resistant noncollapsing FSGS. The study included 22 cFSGS patients and 19 cases of steroid and TAC-resistant FSGS. Complete remission, partial remission, steroid resistance, progression to ESRD and death were observed in 13.6%, 4.5%, 27.3%, 36.4% and 18.2% patients, respectively. Patients with cFSGS had higher serum creatinine and more advanced tubulointerstitial changes compared to resistant FSGS. Twenty-six percent of therapy resistant noncollapsing FSGS progressed to ESRD after two years of stopping TAC. However, there was no difference in progression to ESRD between cFSGS and therapy-resistant noncollapsing FSGS at the end of two years. Glomerular collapse in the setting of FSGS is poorly responsive to treatment and has a high rate of progression to ESRD. The long-term prognosis of cFSGS and steroid and TAC-resistant FSGS are similar.

Collapsing FSGS: a clinicopathologic study of 10 cases from Pakistan

Idiopathic collapsing focal segmental glomerulosclerosis (FSGS), a rare variant of FSGS, is of interest because of its increasing incidence, frequent association with black race, HIV-1 infection, and intravenous (IV) drug abuse. This lesion has not been reported from Pakistan until now. We reviewed our 14-year native renal biopsies record and identified 10 cases of this entity (July 1995-July 2009). Patients' demographic and clinicopathologic data were collected from case files. Renal biopsies were studied by light microscopy, immunofluorescence microscopy, and electron microscopy. A control group of 124 patients with noncollapsing FSGS was selected for comparison of clinical, laboratory, and outcome parameters. All the patients were young adults (mean age: 22.4 +/- 4.6 years). The majority were males (9 vs. 1 female). All presented with nephrotic syndrome (24-h urinary protein: 6.7 +/- 9.22 g). In addition, 8 had mild to moderate renal failure (serum creatinine: 4.12 +/- 4.6 mg/dl). No history of heroin or IV drug abuse was elicited and all tested negative for HIV. Only two patients (20%) responded to steroid treatment, while eight (80%) did not. Five of the patients (50%) developed endstage renal disease after a mean interval of 18 months. Idiopathic collapsing FSGS is increasingly being reported in patients who have no HIV infection or history of IV drug abuse. There is a need for increased awareness among pathologists all over the world to diagnose this condition to guide nephrologists and patients regarding the poor prognosis of this form of FSGS.

Glomerular lesions in HIV-positive patients: a 20-year biopsy experience from Northern Italy

Glomerular involvement in HIV-positive patients is quite heterogeneous. In the present paper we reviewed 73 renal biopsies performed during a period of more than 20 years in a single Nephrology Unit, Milan, Northern Italy, in order to evaluate the aspects of single types of glomerular lesions (including HIV associated nephropathy-HIVAN), grouped according to histological patterns and clinical presentation. Moreover, in the group of non-HIVAN patients, the possible differences in histological characteristics from non-HIV lesions were investigated. Renal tissues were obtained by percutaneous biopsies and were studied by light microscopy, immunofluorescence and electron microscopy. For the histological description three histological groups were identified: HIVAN, immune complex glomerulonephritis (GN) and glomerulopathies not related to immune-mediated mechanisms (so-called "various" glomerulopathies). HIVAN was observed in 9 cases, immune complex GNs in 40 cases (10 mesangial proliferative GN, 8 membranoproliferative GN, 5 lupus-like GN, 4 "acute" GN, 2 crescentic GN, 4 IgA nephropathy, 4 membranous GN and 3 immunotactoid GN) and "various" glomerulopathies in 24 cases (13 non-collapsing focal segmental glomerulosclerosis, 3 minimal changes, 3 end-stage renal disease, 4 diabetic nephropathy and one amyloidosis). Our 20-year biopsy series of HIV-related glomerular involvement confirmed the heterogeneity of lesions. In our series, the vast majority of HIV-related GN are the so-called immune complex GNs, with some peculiar aspects, as multiple site location of deposits and a frequent tendency towards sclerosis, in agreement with experimental data regarding HIV and fibrosis.

Acute Human Parvovirus B19 Infection and Nephrotic Syndrome in Patients with Sickle Cell Disease

Human Parvovirus B19 (HPV B19) infection has previously been thought to be a trigger of nephrotic syndrome. The virus is associated with significant morbidity in patients with sickle cell disease (SCD) and a major cause of transient red cell aplasia (TRCA). We report three patients with SCD who presented with TRCA secondary to acute HPV B19 infection who subsequently developed significant proteinuria and nephrotic syndrome (NS) on outpatient follow up. There were 37 cases of acute HPV B19 infection in SCD patients admitted to King's College Hospital between November 2002 and July 2008. 29 cases were in children below the age of 16 years, eight in patients over the age of 16 years. The average age of the cohort was just over 11 years at diagnosis. Three patients developed NS within 4 months of acute HPV B19 infection and TRCA. Two of these patients were aged 17 and 26 years at diagnosis (patient 1 and 2 respectively), whereas the third was a child aged 11 (patient 3). Renal histology demonstrated the collapsing variant of focal segmental glomerulosclerosis (FSGS) in the acute phase of NS in patient 1, a characteristic finding associated with HPV B19-associated nephrotic syndrome. A subsequent biopsy in the same patient two years later demonstrated non-collapsing FSGS and marked interstitial fibrosis. Patient 2 had a renal biopsy performed 4 months after the onset of NS. This demonstrated non-collapsing FSGS, acute sickle nephropathy and significant chronic tubular atrophy. Patient 3 also had a renal biopsy 1 year after her acute HPV B19 infection which demonstrated the cellular variant of FSGS. Patient 1 was treated with immunosuppression and although the NS has improved slowly he continues to have significant proteinuria and progressive renal impairment. Patient 2 has not received immunosuppressive therapy and has also slowly improved from her NS but continues to have significant proteinuria; her estimated GFR has fallen from 169 ml/min to 104 ml/min six months after the acute HPV B19 infection. Patient 3 was treated with corticosteroids with subsequent improvement in serum albumin and symptoms but proteinuria persists with normal renal function. Consistent with previous reports, we observe that NS is a relatively rare complication of HPV B19 infection in young children with SCD (one case in 29 in our cohort). However, two out of eight patients older than 16 years developed this complication. Proteinuria in patients with SCD is common and gradual in onset, and eventually may progress to NS. Nephrotic syndrome of acute onset in adults with SCD is rare, only two cases were observed during a 6-year period among our cohort of over 400 adult patients with SCD. In both cases, they were associated with recent HPV B19 infection. It has previously been noted that acute HPV B19 infection in older patients with HbSC SCD have a more severe clinical course than younger children (Smith-Whitley et al., 2004). Our data, though limited by small numbers in the cohort, suggest that older SCD patients with acute HPV B19 infection may be more susceptible to chronic complications including the development of NS and progressive renal fibrosis. A correct diagnosis of the aetiology of NS is vitally important as the HPV B19-associated condition may not be responsive to corticosteroids, unlike other aetiologies of NS in this age group. It is possible that antiviral therapy may be of benefit in the acute setting but this needs further investigation. Furthermore, immunisation of older children and young adults who are HPV B19-naïve may be effective in preventing an important contributor of chronic renal disease in SCD patients.

Observations on a Cohort of HIV-Infected Patients Undergoing Native Renal Biopsy

Aims: This study aims to explore the spectrum of renal disease in HIV-infected patients, identify clinical predictors of HIV-associated nephropathy (HIVAN), and investigate the performance of renal biopsy in HIV-infected patients. Method: Of 263 HIV-infected patients with renal disease evaluated between 1995 and 2004, 152 had a renal biopsy, while 111 had not. A group comparison was performed. Results: The leading biopsy diagnoses were HIVAN (35%), noncollapsing focal segmental glomerulosclerosis (22%), and acute interstitial nephritis (7.9%), amongst over a dozen others. There was a trend of decreasing yearly incidence of HIVAN diagnoses, paralleling the use of antiretroviral therapy. By multivariate logistic regression, CD4 counts >200 cells/mm³ and higher estimated glomerular filtration rate were strong negative predictors of HIVAN. HIVAN patients were more likely to require dialysis (p < 0.0001) and had worse overall survival (p = 0.02). Younger age and lower estimated glomerular filtration rate were significant predictors of renal biopsy in multivariate regression analysis. More biopsied patients progressed to dialysis (51 vs. 25%, p = 0.001) and death (15 vs. 5.4%, p = 0.001), despite more frequent corticosteroid treatment (29 vs. 3.6%, p = 0.001). Conclusion: These findings may reflect more severe acute and/or chronic disease at the time of biopsy and suggests that earlier renal biopsy may be warranted in HIV-infected patients, especially in light of the changing spectrum of renal disease in this group.

Idiopathic collapsing focal segmental glomerulosclerosis in pediatric patients.

The aim of this study was to evaluate the clinical outcome of our patients with idiopathic collapsing focal segmental glomerulosclerosis (FSGS) as compared to those with non-collapsing FSGS. The study included a total of 39 patients with idiopathic FSGS. Of these, 11 had collapsing FSGS and the remaining 28 were collectively grouped as non-collapsing FSGS. The mean ages, gender ratio (M:F), and percentage of African-American patients in collapsing versus non-collapsing FSGS groups were 12.7+/-3.1 and 8.9+/-5.1 years, 1.2:1 and 4.6:1, and 90.9 and 53.6%, respectively. After a mean followup period of 31.5+/-22.3 months, 8 patients (73%) with collapsing FSGS had chronic renal impairment as compared to 8 (29%) patients with non-collapsing FSGS group after a mean follow-up period of 18.7+/-12.9 months. However, the cumulated renal survival at 30 months did not reveal a significant difference. In comparison to non-collapsing FSGS, collapsing FSGS in our study was equally common in females as in males and occurred predominantly in African Americans. The outcome of our patients with collapsing FSGS at 30 months was better than in previous reports.

Proteinuria in rats induced by serum from patients with collapsing glomerulopathy

Primary collapsing glomerulopathy recurs postransplant, raising the possibility of circulating factors implicated in the pathogenesis of the disease. To determine the presence of circulating factors in collapsing glomerulopathy patients, we tested serum from those patients in an in vivo assay. Eleven groups of rats received serum from collapsing glomerulopathy patients, idiopathic focal segmental glomerulosclerosis (FSGS) or healthy subjects in its native form, isolated IgG, or serum without IgG. The presence of proteinuria and creatinine clearance were determined. Histopathologic analysis included light, immunofluorescence, and electron microscopy. Collapsing glomerulopathy rats developed proteinuria while rats injected with serum from FSGS and healthy subjects did not. Rats injected with serum of collapsing glomerulopathy in its native form developed marked proteinuria (99.2 +/- 42 mg/24 hours at day 5, P= 0.0001, compared to the baseline), and decreased in creatinine clearance. Rats receiving isolated IgG or serum without IgG from collapsing glomerulopathy developed mild proteinuria (46.5 +/- 8.4 mg/24 hours and 30.9 +/- 11 mg/24 hours, respectively, at day 5 (P= 0.0001). Glomerular tuft retraction and podocyte damage were seen only in collapsing glomerulapthy rats. No abnormalities were found in rats injected with serum from FSGS or healthy subjects. Circulating factors in the serum of collapsing glomerulopathy patients produce podocyte damage, whereas such factors are not present in noncollapsing FSGS. IgG eluates from collapsing glomerulopathy produce proteinuria when injected into the rat. Such factors remain in the circulation when serum of patients is adsorbed into protein A, raising the possibility that there are more than one circulating factor present in patients with collapsing glomerulopathy.

Collapsing glomerulopathy: A clinically and pathologically distinct variant of focal segmental glomerulosclerosis

Sixteen patients with renal biopsy findings of extensive focal glomerular capillary collapse, visceral epithelial cell hypertrophy and hyperplasia, and variable degrees of tubulointerstitial injury in the absence of evidence for human immunodeficiency virus (HIV) infection or intravenous drug abuse were prospectively identified by renal biopsy. The pathologic process was designated collapsing glomerulopathy to distinguish it from other patterns of focal glomerular sclerosis. The clinical and pathologic characteristics of these 16 patients were analyzed and compared to a group of 25 patients with noncollapsing focal segmental glomerulosclerosis (FSGS). Thirteen of 16 patients with collapsing glomerulopathy were black as compared with 11 of 25 with FSGS (P = 0.018). The most common findings at presentation were hypertension and manifestations of the nephrotic syndrome. Although the duration of symptoms prior to presentation was no longer in the collapsing glomerulopathy group, the presenting mean serum creatinine was higher in patients with collapsing glomerulopathy than in those with noncollapsing FSGS (3.5 +/- 3.4 mg/dl vs. 1.3 0.6 mg/dl, P = 0.001). Twenty-four-hour urine protein excretion was also higher in the collapsing glomerulopathy group (13.2 +/- 7.7 g/day vs. 4.6 +/- 4.5 g/day FSGS, P = 0.005). The collapsing glomerulopathy patients had a mean age of 41.4 +/- 19.1 (range 19 to 81), a male-to-female ratio of 11:5 and a black-to-white ratio of 13:3. Renal survival, evaluated by life-table analysis, was markedly worse in collapsing glomerulopathy patients than in FSGS patients (P = 0.0004). It is proposed that collapsing glomerulopathy is a distinct entity characterized by black racial predominance, massive proteinuria, relatively rapidly progressive renal insufficiency, and distinctive pathologic findings.(ABSTRACT TRUNCATED AT 250 WORDS)