Corrigendum: Delphi: A Democratic and Cost-Effective Method of Consensus Generation in Transplantation.

[This corrects the article DOI: 10.3389/ti.2023.11589.].

Corrigendum: Thrombotic Microangiopathy in the Renal Allograft: Results of the TMA Banff Working Group Consensus on Pathologic Diagnostic Criteria.

[This corrects the article DOI: 10.3389/ti.2023.11590.].

Delphi: A Democratic and Cost-Effective Method of Consensus Generation in Transplantation.

The Thrombotic Microangiopathy Banff Working Group (TMA-BWG) was formed in 2015 to survey current practices and develop minimum diagnostic criteria (MDC) for renal transplant TMA (Tx-TMA). To generate consensus among pathologists and nephrologists, the TMA BWG designed a 3-Phase study. Phase I of the study is presented here. Using the Delphi methodology, 23 panelists with >3 years of diagnostic experience with Tx-TMA pathology listed their MDC suggesting light, immunofluorescence, and electron microscopy lesions, clinical and laboratory information, and differential diagnoses. Nine rounds (R) of consensus resulted in MDC validated during two Rs using online evaluation of whole slide digital images of 37 biopsies (28 TMA, 9 non-TMA). Starting with 338 criteria the process resulted in 24 criteria and 8 differential diagnoses including 18 pathologic, 2 clinical, and 4 laboratory criteria. Results show that 3/4 of the panelists agreed on the diagnosis of 3/4 of cases. The process also allowed definition refinement for 4 light and 4 electron microscopy lesions. For the first time in Banff classification, the Delphi methodology was used to generate consensus. The study shows that Delphi is a democratic and cost-effective method allowing rapid consensus generation among numerous physicians dealing with large number of criteria in transplantation.

Thrombotic Microangiopathy in the Renal Allograft: Results of the TMA Banff Working Group Consensus on Pathologic Diagnostic Criteria.

The Banff community summoned the TMA Banff Working Group to develop minimum diagnostic criteria (MDC) and recommendations for renal transplant TMA (Tx-TMA) diagnosis, which currently lacks standardized criteria. Using the Delphi method for consensus generation, 23 nephropathologists (panelists) with >3 years of diagnostic experience with Tx-TMA were asked to list light, immunofluorescence, and electron microscopic, clinical and laboratory criteria and differential diagnoses for Tx-TMA. Delphi was modified to include 2 validations rounds with histological evaluation of whole slide images of 37 transplant biopsies (28 TMA and 9 non-TMA). Starting with 338 criteria in R1, MDC were narrowed down to 24 in R8 generating 18 pathological, 2 clinical, 4 laboratory criteria, and 8 differential diagnoses. The panelists reached a good level of agreement (70%) on 76% of the validated cases. For the first time in Banff classification, Delphi was used to reach consensus on MDC for Tx-TMA. Phase I of the study (pathology phase) will be used as a model for Phase II (nephrology phase) for consensus regarding clinical and laboratory criteria. Eventually in Phase III (consensus of the consensus groups) and the final MDC for Tx-TMA will be reported to the transplantation community.

Parietal Epithelial Cell Behavior and Its Modulation by microRNA-193a.

Glomerular parietal epithelial cells (PECs) have been increasingly recognized to have crucial functions. Lineage tracking in animal models showed the expression of a podocyte phenotype by PECs during normal glomerular growth and after acute podocyte injury, suggesting a reparative role of PECs. Conversely, activated PECs are speculated to be pathogenic and comprise extracapillary proliferation in focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (CrescGN). The reparative and pathogenic roles of PECs seem to represent two sides of PEC behavior directed by the local milieu and mediators. Recent studies suggest microRNA-193a (miR193a) is involved in the pathogenesis of FSGS and CrescGN. In a mouse model of primary FSGS, the induction of miR193a caused the downregulation of Wilms' tumor protein, leading to the dedifferentiation of podocytes. On the other hand, the inhibition of miR193a resulted in reduced crescent lesions in a mouse model of CrescGN. Interestingly, in vitro studies report that the downregulation of miR193a induces trans-differentiation of PECs into a podocyte phenotype. This narrative review highlights the critical role of PEC behavior in health and during disease and its modulation by miR193a.

Disruption of APOL1-miR193a Axis Induces Disorganization of Podocyte Actin Cytoskeleton.

APOL1-miR193a axis participates in the preservation of molecular phenotype of differentiated podocytes (DPDs). We examined the hypothesis that APOL1 (G0) preserves, but APOL1 risk alleles (G1 and G2) disrupt APOL1-miR193a axis in DPDs. DPDG0s displayed down-regulation of miR193a, but upregulation of nephrin expression. DPDG1s/G2s exhibited an increase in miR193a and down-regulation of the expression of adherens complex's constituents (CD2AP, nephrin, and dendrin). DPDG0s showed decreased Cathepsin L, enhanced dynamin expressions, and the intact actin cytoskeleton. On the contrary, DPDG1s/G2s displayed an increase in Cathepsin L, but down-regulation of dynamin expressions and disorganization of the actin cytoskeleton. APOL1 silencing enhanced miR193a and Cathepsin L, but down-regulated dynamin expressions. DPDG1s/G2s displayed nuclear import of dendrin, indicating an occurrence of destabilization of adherens complexes in APOL1 risk milieu. These findings suggest that DPDG1s and DPDG2s developed disorganized actin cytoskeleton as a consequence of disrupted APOL1-miR193a axis. Interestingly, docking and co-labeling studies suggested an interaction between APOL1 and CD2AP. APOL1G1/G1 and APOL1G1/G2 transgenic mice displayed nuclear import of dendrin indicating destabilization of adherens complexes in podocytes; moreover, these mice showed a four-fold increase in urinary albumin to creatinine ratio and development of focal segmental glomerular lesions.

Role of Apolipoprotein L1 in Human Parietal Epithelial Cell Transition.

Human parietal epithelial cells (PECs) are progenitor cells that sustain podocyte homeostasis. We hypothesized that the lack of apolipoprotein (APO) L1 ensures the PEC phenotype, but its induction initiates PEC transition (expression of podocyte markers). APOL1 expression and down-regulation of miR193a coincided with the expression of podocyte markers during the transition. The induction of APOL1 also stimulated transition markers in human embryonic kidney cells (cells with undetectable APOL1 protein expression). APOL1 silencing in PECs up-regulated miR193a expression, suggesting the possibility of a reciprocal feedback relationship between APOL1 and miR193a. HIV, interferon-γ, and vitamin D receptor agonist down-regulated miR193a expression and induced APOL1 expression along with transition markers in PECs. Luciferase assay suggested a putative interaction between miR193a and APOL1. Since silencing of APOL1 attenuated HIV-, vitamin D receptor agonist-, miR193a inhibitor-, and interferon-γ-induced expression of transition markers, APOL1 appears to be a critical functional constituent of the miR193a- APOL1 axis in PECs. This notion was confirmed by further enhanced expression of PEC markers in APOL1 mRNA-silenced PECs. In vivo studies, glomeruli in patients with HIV, and HIV/APOL1 transgenic mice had foci of PECs expressing synaptopodin, a transition marker. APOL1 likely regulates PEC molecular phenotype through modulation of miR193a expression, and APOL1 and miR193a share a reciprocal feedback relationship.

Thrombotic microangiopathy associated with synthetic cannabinoid receptor agonists.

Marijuana is one of the most commonly used recreational drugs in the United States. As marijuana is illegal in the majority of countries, the use of readily available and unregulated synthetic cannabinoids (SCBs) has increased. Little is known about the potential adverse effects of SCBs especially in regards to their nephrotoxicity. Case reports of acute kidney injury (AKI) from acute tubular injury secondary to their use have been reported. However, the exact pathology, mechanism, and extent of renal injury remain unknown. We report the first case of biopsy proven thrombotic microangiopathy (TMA) associated with SCBs resulting in AKI. The patient suffered significant morbidity with loss of renal function eventually requiring renal replacement therapy.

HIV Promotes NLRP3 Inflammasome Complex Activation in Murine HIV-Associated Nephropathy.

Dysregulated growth and loss of podocytes are important features of HIV-associated nephropathy. Recently, HIV was reported to induce a new type of programed cell death, pyroptosis, in T lymphocytes through induction of Nod-like receptor protein 3 (NLRP3) inflammasome complexes. We evaluated the role of HIV in podocyte NLRP3 inflammasome formation both in vivo and in vitro. Renal cortical sections of HIV-transgenic mice (Tg26) displayed increased expression of NLRP3, ASC (a CARD protein), caspase-1, and IL-1ß proteins, confirming NLRP3 inflammasome complex formation in podocytes of Tg26 mice. Renal tissues of Tg26 mice also displayed enhanced mRNA levels and protein expressions of inflammasome markers (NLRP3, ASC, and caspase-1, and IL-1ß). Serum of Tg26 mice also showed elevated concentrations of IL-1ß cytokine compared with FVBN mice. HIV induced pyroptosis in a dose- and time-dependent manner within podocytes, a phenotype of inflammasome activation. Caspase-1 inhibitor not only attenuated podocyte expression of caspase-1 and IL-1ß but also provided protection against pyroptosis, suggesting that HIV-induced podocyte injury was mediated by caspase-1 activation. Interestingly, HIV-induced podocyte pyroptosis could be partially inhibited by Tempol (a superoxide dismutase-mimetic agent) and by glyburide (an inhibitor of potassium efflux). These findings suggest that generation of reactive oxygen species and potassium efflux contribute to HIV-induced pyroptosis and NLRP3 inflammasome activation in podocytes.

Epigenetic Modulation of Human Podocyte Vitamin D Receptor in HIV Milieu.

HIV (human immunodeficiency virus) has been reported to induce podocyte injury through down regulation of vitamin D receptor (VDR) and activation of renin angiotensin system; however, the involved mechanism is not clear. Since HIV has been reported to modulate gene expression via epigenetic phenomena, we asked whether epigenetic factors contribute to down regulation of VDR. Kidney cells in HIV transgenic mice and HIV-infected podocytes (HIV/HPs) displayed enhanced expression of SNAIL, a repressor of VDR. To elucidate the mechanism, we studied the effect of HIV on expression of molecules involved in SNAIL repressor complex formation and demonstrated that HIV enhances expression of the histone deacetylase HDAC1 and DNA methyl transferases DNMT3b and DNMT1. 293T cells, when stably transfected with SNAIL (SNAIL/293T), displayed suppressed transcription and translation of VDR. In SNAIL/293T cells, co-immunoprecipitation studies revealed the association of HDAC1, DNMT3b, DNMT1, and mSin3A with SNAIL. Chromatin immunoprecipitation experiments confirmed the presence of the SNAIL repressor complex at the VDR promoter. Consistent with the enhanced DNA methyl transferase expression in HIV/HPs, there was an increased CpG methylation at the VDR promoter. Chromatin immunoprecipitation assay confirmed occurrence of H3K4 trimethylation on SNAIL promoter. Neither a VDR agonist (VDA) nor an HDAC inhibitor (HDACI) nor a demethylating agent (DAC) individually could optimally up regulate VDR in HIV milieu. However, VDA and HDACI when combined were successful in de-repressing VDR expression. Our findings demonstrate that SNAIL recruits multiple chromatin enzymes to form a repressor complex in HIV milieu that down regulates VDR expression.

Apolipoprotein L1 (APOL1) Variants (Vs) a possible link between Heroin-associated Nephropathy (HAN) and HIV-associated Nephropathy (HIVAN).

In 1970s, Heroin-associated Nephropathy (HAN), one form of focal and segmental glomerulosclerosis (FSGS), was a predominant cause of End-stage Kidney Disease (ESKD) in African-Americans (AAs). In 1980s, with the surge of Acquired Immune Deficiency Syndrome (AIDS) in AAs, HAN more or less disappeared, and the incidence of Human Immunodeficiency Virus associated Nephropathy (HIVAN) markedly increased. Recent studies in AAs have identified APOL1 variants (Vs) as a major risk factor for the development and progression of non-diabetic kidney diseases including idiopathic FSGS and hypertension-attributed nephrosclerosis. These observations have also offered partial insights into the mechanisms of development, and higher rate of occurrence of both HAN and HIVAN in AAs. AAs with APOL1Vs develop idiopathic FSGS at four-fold higher rate compared to European Americans (EAs). Similarly, HIV infected AAs with APOL1Vs (if not on antiviral therapy), risk a 50% (10-fold greater) chance of developing HIVAN. It has been suggested that APOL1Vs expression may render podocytes more vulnerable to various types of injury: bacterial, viral, and others. However, in addition to genetic variants, additional factors such as persistence of a second hit may determine the nature and severity of glomerular disease. In patients with HAN, heroin or contaminants may have been the offending second insult(s) which caused renal disease in susceptible AA patients. In the 80's, since heroin-induced second hit was neither consistent nor sustained (depending on drug availability in the street), the disease was masked or replaced HIV infected patients (especially in untreated subjects), by an overwhelming second hit by the virus which was both intense as well as persistent. It appears that APOL1Vs may be one of the links between the disappearance of HAN and emergence of HIVAN in AA patients.

AT1R blockade in adverse milieus: role of SMRT and corepressor complexes.

ANG II type 1 receptor blockade (AT1R-BLK) is used extensively to slow down the progression of proteinuric kidney diseases. We hypothesized that AT1R-BLK provides podocyte protection through regulation of silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) and vitamin D receptor (VDR) expression under adverse milieus such as high glucose and human immunodeficiency virus infection. Both AT1R-BLK and VDR agonists (VDAs) stimulated VDR complex formation that differed not only in their composition but also in their functionality. AT1R-BLK-induced VDR complexes contained predominantly unliganded VDR, SMRT, and phosphorylated histone deacetylase 3, whereas VDA-VDR complexes were constituted by liganded VDR and CREB-binding protein/p300. AT1R-BLK-induced complexes attenuated podocyte acetyl-histone 3 levels as well as cytochrome P-450 family 24A1 expression, thus indicating their deacetylating and repressive properties. On the other hand, VDA-VDR complexes not only increased podocyte acetyl-histone 3 levels but also enhanced cytochrome P-450 family 24A1 expression, thus suggesting their acetylating and gene activation properties. AT1R-BLK- induced podocyte SMRT inhibited expression of the proapoptotic gene BAX through downregulation of Wip1 and phosphorylation of checkpoint kinase 2 in high-glucose milieu. Since SMRT-depleted podocytes lacked AT1R-BLK-mediated protection against DNA damage, it appears that SMRT is necessary for DNA repairs during AT1R-BLK. We conclude that AT1R-BLK provides podocyte protection in adverse milieus predominantly through SMRT expression and partly through unliganded VDR expression in 1,25(OH)2D-deficient states; on the other hand, AT1R-BLK contributes to liganded VDR expression in 1,25(OH)2D-sufficient states.

Curtailing endothelial TGF-ß signaling is sufficient to reduce endothelial-mesenchymal transition and fibrosis in CKD.

Excessive TGF-ß signaling in epithelial cells, pericytes, or fibroblasts has been implicated in CKD. This list has recently been joined by endothelial cells (ECs) undergoing mesenchymal transition. Although several studies focused on the effects of ablating epithelial or fibroblast TGF-ß signaling on development of fibrosis, there is a lack of information on ablating TGF-ß signaling in the endothelium because this ablation causes embryonic lethality. We generated endothelium-specific heterozygous TGF-ß receptor knockout (TßRII(endo+/-)) mice to explore whether curtailed TGF-ß signaling significantly modifies nephrosclerosis. These mice developed normally, but showed enhanced angiogenic potential compared with TßRII(endo+/+) mice under basal conditions. After induction of folic acid nephropathy or unilateral ureteral obstruction, TßRII(endo+/-) mice exhibited less tubulointerstitial fibrosis, enhanced preservation of renal microvasculature, improvement in renal blood flow, and less tissue hypoxia than TßRII(endo+/+) counterparts. In addition, partial deletion of TßRII in the endothelium reduced endothelial-to-mesenchymal transition (EndoMT). TGF-ß-induced canonical Smad2 signaling was reduced in TßRII(+/-) ECs; however, activin receptor-like kinase 1 (ALK1)-mediated Smad1/5 phosphorylation in TßRII(+/-) ECs remained unaffected. Furthermore, the S-endoglin/L-endoglin mRNA expression ratio was significantly lower in TßRII(+/-) ECs compared with TßRII(+/+) ECs. These observations support the hypothesis that EndoMT contributes to renal fibrosis and curtailing endothelial TGF-ß signals favors Smad1/5 proangiogenic programs and dictates increased angiogenic responses. Our data implicate endothelial TGF-ß signaling and EndoMT in regulating angiogenic and fibrotic responses to injury.

Azilsartan is associated with increased circulating angiotensin-(1-7) levels and reduced renovascular 20-HETE levels.

BACKGROUND: Activation of angiotensin (ANG) II type 1 receptors (AT1R) promotes vasoconstriction, inflammation, and renal dysfunction. In this study, we addressed the ability of azilsartan (AZL), a new AT1R antagonist, to modulate levels of plasma ANG-(1-7) and renal epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE). METHODS: Sprague-Dawley rats were infused with ANG II (125 ng/min) or vehicle (VEH). AZL (3 mg/kg/day) or VEH was administered starting 1 day prior to ANG II or VEH infusion. On day 10, plasma was obtained for measurement of ANG-(1-7) and kidneys for isolation of microvessels for EET and 20-HETE determination and histological evaluation. RESULTS: Mean 24-hour blood pressure (BP) was not different between VEH and AZL treatment groups, whereas the BP elevation with ANG II infusion (121 ± 5 mm Hg) was completely normalized with AZL cotreatment (86 ± 3 mm Hg). The ANG II-induced renal damage was attenuated and cardiac hypertrophy prevented with AZL cotreatment. Plasma ANG-(1-7) levels (pg/ml) were increased with AZL treatment (219 ± 22) and AZL + ANG II infusion (264 ± 93) compared to VEH controls (74.62 ± 8). AZL treatment increased the ratio of EETs to their dihydroxyeicosatrienoic acid (DHET) metabolites and reduced 20-HETE levels. CONCLUSIONS: Treatment with AZL completely antagonized the elevation of BP induced by ANG II, prevented cardiac hypertrophy, attenuated renal damage, and increased ANG-(1-7) and EET/DHET ratio while diminishing 20-HETE levels. Increased ANG-(1-7) and EETs levels may emerge as novel therapeutic mechanisms contributing to the antihypertensive and antihypertrophic actions of AZL treatment and their relative role compared to AT1R blockade may depend on the etiology of the hypertension.

Pharmacological manipulation of arachidonic acid-epoxygenase results in divergent effects on renal damage.

Kidney damage is markedly accelerated by high-salt (HS) intake in stroke-prone spontaneously hypertensive rats (SHRSP). Epoxyeicosatrienoic acids (EETs) are epoxygenase products of arachidonic acid which possess vasodepressor, natriuretic, and anti-inflammatory activities. We examined whether up-regulation (clofibrate) or inhibition [N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH)] of epoxygenase would alter systolic blood pressure (SBP) and/or renal pathology in SHRSP on HS intake (1% NaCl drinking solution). Three weeks of treatment with clofibrate induced renal cortical protein expression of CYP2C23 and increased urinary excretion of EETs compared with vehicle-treated SHRSP. SBP and urinary protein excretion (UPE) were significantly lowered with clofibrate treatment. Kidneys from vehicle-treated SHRSP, which were on HS intake for 3 weeks, demonstrated focal lesions of vascular fibrinoid degeneration, which were markedly attenuated with clofibrate treatment. In contrast, 2 weeks of treatment with the selective epoxygenase inhibitor, MS-PPOH, increased UPE without significantly altering neither urinary EET levels nor SBP. Kidneys from vehicle-treated SHRSP, which were on HS intake for 11 days, demonstrated occasional mild damage whereas kidneys from MS-PPOH-treated rats exhibited widespread malignant nephrosclerosis. These results suggest that pharmacological manipulation of epoxygenase results in divergent effects on renal damage and that interventions to increase EET levels may provide therapeutic strategies for treating salt-sensitive hypertension and renal damage.

Modulation of renin angiotensin system predominantly alters sclerotic phenotype of glomeruli in HIVAN.

HIV-associated nephropathy (HIVAN) is a common complication of HIV-1 infection in patients with African ancestry in general and with APOL1 gene risk variants in particular. Although collapsing glomerulopathy is considered a hallmark of HIVAN, significant numbers of glomeruli in patients with HIVAN also display other variants of focal segmental glomerulosclerosis (FSGS). We propose that collapsed glomeruli as well as glomeruli with other variants of FSGS are manifestations of HIVAN and their prevalence depends on associated host factors. We explored the role of the renin-angiotensin system (RAS) in the manifestation of any specific glomerular phenotype in HIVAN. To evaluate the role of the RAS we have used a genetically engineered mouse model of HIVAN (Tg26) with two and four copies of angiotensinogen (Agt) gene (Tg26/Agt2 and Tg26/Agt4). In Tg26/Agt2, 1 out of 6 glomeruli exhibited sclerosed phenotype, whereas 1 out of 25 glomeruli displayed collapsed phenotype; on the other hand, in Tg26/Agt4, 1 out of 3 glomeruli exhibited sclerotic phenotype and only 1 out of 7 glomeruli showed collapsed phenotype. To inhibit the effect of RAS, Tg26/Agt2 were administered captopril, aliskiren, aliskiren plus captopril or aliskiren plus telmisartan by miniosmotic pumps for 4 weeks. In all experimental groups there was a significant reduction in percentage of sclerosed glomeruli and only minimal reduction in collapsed glomeruli compared to normal saline receiving Tg26/Agt2. These findings suggest that the manifestation of the sclerosed phenotype in HIVAN is predominantly dependent on activation of the RAS.

mTOR plays a critical role in p53-induced oxidative kidney cell injury in HIVAN.

Oxidative stress has been implicated to contribute to HIV-induced kidney cell injury; however, the role of p53, a modulator of oxidative stress, has not been evaluated in the development of HIV-associated nephropathy (HIVAN). We hypothesized that mammalian target of rapamycin (mTOR) may be critical for the induction of p53-mediated oxidative kidney cell injury in HIVAN. To test our hypothesis, we evaluated the effect of an mTOR inhibitor, rapamycin, on kidney cell p53 expression, downstream signaling, and kidney cell injury in both in vivo and in vitro studies. Inhibition of the mTOR pathway resulted in downregulation of renal tissue p53 expression, associated downstream signaling, and decreased number of sclerosed glomeruli, tubular microcysts, and apoptosed and 8-hydroxy deoxyguanosine (8-OHdG)-positive (+ve) cells in Tg26 mice. mTOR inhibition not only attenuated kidney cell expression of p66ShcA and phospho-p66ShcA but also reactivated the redox-sensitive stress response program in the form of enhanced expression of manganese superoxide dismutase (MnSOD) and catalase. In in vitro studies, the mTOR inhibitor also provided protection against HIV-induced podocyte apoptosis. Moreover, mTOR inhibition downregulated HIV-induced podocyte (HP/HIV) p53 expression. Since HP/HIV silenced for mTOR displayed a lack of expression of p53 as well as attenuated podocyte apoptosis, this suggests that mTOR is critical for kidney cell p53 activation and associated oxidative kidney cell injury in the HIV milieu.

Collapsing glomerulopathy in 19 patients with systemic lupus erythematosus or lupus-like disease.

BACKGROUND AND OBJECTIVES: Collapsing glomerulopathy is a podocytopathy with segmental or global wrinkling and collapse of capillary walls and overlying epithelial cell proliferation. Idiopathic collapsing glomerulopathy is a distinct clinicopathologic entity with significant proteinuria, poor response to immunosuppressive therapy, and rapid progression to renal failure. Collapsing glomerulopathy is associated with viral infections, autoimmune disease, and drugs. This work presents the largest group of collapsing glomerulopathy in patients with SLE. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Clinicopathological features were retrospectively studied in 19 patients with SLE (16 patients) or SLE-like (3 patients) disease with collapsing glomerulopathy. RESULTS: Initially, 95% of patients had nephrotic syndrome with proteinuria of 3-12 g per 24 hours, creatinine levels of 0.6-9.6 mg/dl, positive lupus serologies, and normal complement levels in 63%. Segmental and/or global collapsing glomerulopathy was seen in 11%-77% of glomeruli. Tubular atrophy with focal microcystic changes and interstitial fibrosis was seen in 35% of patients. Minimal glomerular mesangial deposits were noted in 63% of patients, and extensive foot process effacement was seen in 82% of patients. Initial treatment was with pulse/oral steroids. Follow-up from 13 patients revealed that 7 patients progressed to ESRD at the time of biopsy up to 21 months later, 1 patient returned to normal creatinine (1.1 mg/dl) without proteinuria, and 5 patients had creatinine of 1.2-3.6 mg/dl with proteinuria of 0.37-4 g per 24 hours. CONCLUSIONS: Collapsing glomerulopathy may be seen in SLE patients presenting with massive proteinuria with or without lupus nephritis, which may have prognostic significance.