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Concept: Nephrotic syndrome


Abatacept (cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin fusion protein [CTLA-4-Ig]) is a costimulatory inhibitor that targets B7-1 (CD80). The present report describes five patients who had focal segmental glomerulosclerosis (FSGS) (four with recurrent FSGS after transplantation and one with primary FSGS) and proteinuria with B7-1 immunostaining of podocytes in kidney-biopsy specimens. Abatacept induced partial or complete remissions of proteinuria in these patients, suggesting that B7-1 may be a useful biomarker for the treatment of some glomerulopathies. Our data indicate that abatacept may stabilize β1-integrin activation in podocytes and reduce proteinuria in patients with B7-1-positive glomerular disease.

Concepts: Protein, Glomerulus, Nephron, Nephrotic syndrome, Proteinuria, Focal segmental glomerulosclerosis, Glomerulosclerosis, CTLA-4


Kawasaki disease (KD) is a systemic vasculitis and affects many organ systems. It often presents sterile pyuria, microscopic hematuria, and proteinuria due to renal involvement. The aims of this study were to define clinical characteristics of acute KD patients with pyuria and to analyze meaning of pyuria in KD.

Concepts: Nephrology, Vasculitis, Nephrotic syndrome, Arthralgia, Glomerulonephritis, Kawasaki disease, Urinalysis, IgA nephropathy


Alendronate is a widely used bisphosphonate in the treatment of osteoporosis. Although it has been proven to be a very useful drug, it has some side effects as well. In this paper, we describe a case of nephrotic syndrome due to alendronate administration. A 36-year-old man was admitted to the nephrology outpatient clinic with widespread edema 4 months after initiation of alendronate. He had a 13-kg weight gain within a 2-week period. He had no clinical or laboratory problems apart from osteoporosis, which was the indication for initiation of the drug. Physical examination at admission was unremarkable, but for nephrotic edema. Laboratory studies revealed nephrotic range proteinuria (13.5 g/day), normal renal function, hypoalbuminemia (1.7 g/dl), and also hypercholesterolemia (400 mg/dl). A kidney biopsy was performed. Light microscopic evaluation revealed a slight increase in mesangial cells and matrix; however, no abnormalities in the tubules or interstitium were noted. Alendronate was withdrawn and diuretic therapy was initiated. Patient’s weight gradually decreased from 84 to 67 kg within a 1-week period. No other drugs for the treatment of nephrotic syndrome were administered. During the clinical course, serum creatinine remained stable, and proteinuria gradually decreased and disappeared 40 days after stopping alendronate. It was noted that alendronate administration can give rise to nephrotic syndrome, while discontinuation of this drug may improve the pathology without any specific treatment.

Concepts: Bisphosphonate, Renal failure, Kidney, Nephrology, Renal physiology, Nephrotic syndrome, Proteinuria, Nephritic syndrome


Mutations in the inverted formin 2 gene (INF2) have recently been identified as the most common cause of autosomal dominant focal and segmental glomerulosclerosis (FSGS). To quantify the contribution of various genes contributing to FSGS, we sequenced INF2 where all mutations have previously been described (exons 2 to 5) in a total of 215 probands and 281 sporadic individuals with FSGS, along with other known genes accounting for autosomal dominant FSGS (ACTN4, TRPC6, and CD2AP) in 213 probands. Variants were classified as disease-causing if they altered the amino acid sequence and if they were not found in control samples and in families segregated with disease. Mutations in INF2 were found in a total of 20 of the 215 families (including those previously reported) in our cohort of autosomal dominant familial nephrotic syndrome or FSGS, thereby explaining disease in 9%. INF2 mutations were found in 2 of 281 individuals with sporadic FSGS. In contrast, ACTN4- and TRPC6-related diseases accounted for 3 and 2% of our familial cohort, respectively. INF2-related disease showed variable penetrance, with onset of disease ranging widely from childhood to adulthood, and commonly leading to end-stage renal disease in the third and fourth decade of life. Thus, mutations in INF2 are a more common, although still a minor, monogenic cause of familial FSGS when compared with other known autosomal dominant genes associated with FSGS.

Concepts: DNA, Protein, Kidney, Genetics, Amino acid, Nephrotic syndrome, Sequence, Focal segmental glomerulosclerosis


AIMS: In diseases with proteinuria, e.g. nephrotic syndrome and preeclampsia, there often is suppression of plasma renin-angiotensin-aldosterone system components, expansion of extracellular volume and avid renal sodium retention. Mechanisms of sodium retention in proteinuria are reviewed. METHODS AND RESULTS: In animal models of nephrotic syndrome, the amiloride-sensitive epithelial sodium channel ENaC is activated while more proximal renal Na(+) transporters are down-regulated. With suppressed plasma aldosterone concentration and little change in ENaC abundance in nephrotic syndrome, the alternative modality of proteolytic activation of ENaC has been explored. Proteolysis leads to putative release of an inhibitory peptide from the extracellular domain of the gamma ENaC subunit. This leads to full activation of the channel. Plasminogen has been demonstrated in urine from patients with nephrotic syndrome and preeclampsia. Urine plasminogen correlates with urine albumin and is activated to plasmin within the urinary space by uPA. This agrees with aberrant filtration across an injured glomerular barrier independent of the primary disease. Pure plasmin and urine samples containing plasmin activate inward current in single murine collecting duct cells. In the present paper, it is shown that human lymphocytes may be used to uncover the effect of urine-plasmin on amiloride- and aprotinin-sensititve inward currents. Data from hypertensive rat models show that protease inhibitors may attenuate blood pressure. CONCLUSION: Aberrant filtration of plasminogen and conversion within the urinary space to plasmin may activate gamma ENaC proteolytically and contribute to inappropriate NaCl retention and edema in acute proteinuric conditions and to hypertension in diseases with chronic microalbuminuria/proteinuria. © 2012 The Authors Acta Physiologica © 2012 Scandinavian Physiological Society.

Concepts: Kidney, Hypertension, Blood pressure, Nephrotic syndrome, Aldosterone, Sodium, Potassium, Epithelial sodium channel


Minimal change disease (MCD), the most common idiopathic nephrotic syndrome in children, is characterized by proteinuria and loss of glomerular visceral epithelial cell (podocyte) ultrastructure. Lipopolysaccharide (LPS) and puromycin aminonucleoside (PAN) are used to study podocyte injury in models of MCD in vivo and in vitro. We hypothesized that LPS and PAN influence components of the innate immune system in podocytes such as the Toll-Like Receptor (TLRs), TLR adapter molecules, and associated cytokines. Our results show that cultured human podocytes constitutively express TLRs 1-6 and TLR-10, but not TLRs 7-9. LPS (25 μg/ml) or PAN (60 μg/ml) caused comparable derangement of the actin cytoskeleton in podocytes. Quantitative RT-PCR analysis show that LPS differentially up-regulated the expression of genes for TLRs (1 > 4 ≥ 2 > 3 > 6 > 5), the adapter molecule, MyD88, and transcription factor NF-κB within one hour. LPS also caused increased levels of IL-6, IL-8 and MCP1 without exerting any effect on TNF-α, IFN-α or TGF-β1 at 24 h. Immunofluorescence intensity analysis of confocal microscopy images showed that LPS induced a significant increase in nuclear translocation of NF-κB by 6 h. In contrast, PAN-induced only small changes in the expression of TLRs 2-6 that included a persistent increase in TLRs 2 and 5, a transient increase in TLR-4, and a gradual increase in TLRs 3 and 6 between 1 and 6 h. Correspondingly, it did not alter pro-inflammatory cytokine levels in podocytes. However, PAN induced a low but significant increase in NF-κB nuclear translocation within one hour that remained unchanged up to 6 h. In summary, these novel findings show that LPS, a known TLR-4 ligand, induced the gene expression of multiple TLRs with maximum effect on the expression of TLR-1 suggesting a loss of receptor selectivity and induction of receptor interactions in podocytes. A comparable derangement of the podocyte cytoskeleton and significant increase in the nuclear translocation of NF-κB by PAN suggest that disparate but complementary mechanisms may contribute to the development of podocytopathy in MCD.

Concepts: Immune system, DNA, Gene, Gene expression, Innate immune system, Toll-like receptor, Nephrotic syndrome, Minimal change disease


Overexpression of soluble urokinase receptor (suPAR) causes pathology in animal models similar to primary FSGS, and one recent study demonstrated elevated levels of serum suPAR in patients with the disease. Here, we analyzed circulating suPAR levels in two cohorts of children and adults with biopsy-proven primary FSGS: 70 patients from the North America-based FSGS clinical trial (CT) and 94 patients from PodoNet, the Europe-based consortium studying steroid-resistant nephrotic syndrome. Circulating suPAR levels were elevated in 84.3% and 55.3% of patients with FSGS patients in the CT and PodoNet cohorts, respectively, compared with 6% of controls (P<0.0001); inflammation did not account for this difference. Multiple regression analysis suggested that lower suPAR levels associated with higher estimated GFR, male sex, and treatment with mycophenolate mofetil. In the CT cohort, there was a positive association between the relative reduction of suPAR after 26 weeks of treatment and reduction of proteinuria, with higher odds for complete remission (P=0.04). In the PodoNet cohort, patients with an NPHS2 mutation had higher suPAR levels than those without a mutation. In conclusion, suPAR levels are elevated in geographically and ethnically diverse patients with FSGS and do not reflect a nonspecific proinflammatory milieu. The associations between a change in circulating suPAR with different therapeutic regimens and with remission support the role of suPAR in the pathogenesis of FSGS.

Concepts: Immune system, Regression analysis, Clinical trial, Pathology, Nephrotic syndrome, Proteinuria, Mycophenolic acid, Focal segmental glomerulosclerosis


Relapses or flares of systemic lupus erythematosus (SLE) are frequent and observed in 27-66% of patients. SLE flares are defined as an increase in disease activity, in general, requiring alternative treatment or intensification of therapy. A renal flare is indicated by an increase in proteinuria and/or serum creatinine concentration, abnormal urine sediment or a reduction in creatinine clearance rate as a result of active disease. The morbidity associated with renal flares is derived from both the kidney damage due to lupus nephritis and treatment-related toxic effects. Current induction treatment protocols achieve remission in the majority of patients with lupus nephritis; however, few studies focus on treatment interventions for renal flares in these patients. The available data, however, suggest that remission can be induced again in a substantial percentage of patients experiencing a lupus nephritis flare. Lupus nephritis flares are independently associated with an increased risk of deterioration in renal function; prevention of renal flares might, therefore, also decrease long-term morbidity and mortality. Appropriate immunosuppressive maintenance therapy might lead to a decrease in the occurrence of renal and extrarenal flares in patients with SLE, and monitoring for the early detection and treatment of renal flares could improve their outcomes.

Concepts: Nephrology, Renal physiology, Rheumatology, Nephrotic syndrome, Systemic lupus erythematosus, Lupus erythematosus, Glomerulonephritis, Lupus nephritis


Rituximab could be an effective treatment for childhood-onset, complicated, frequently relapsing nephrotic syndrome (FRNS) and steroid-dependent nephrotic syndrome (SDNS). We investigated the efficacy and safety of rituximab in patients with high disease activity.

Concepts: Nephrotic syndrome


BACKGROUND: Idiopathic nephrotic syndrome (NS) in children is classified as steroid sensitive or steroid resistant. Steroid sensitivity typically portends a low risk of permanent renal failure. However, some initially steroid-sensitive patients later develop steroid resistance. These patients with late steroid resistance (LSR) are often treated with immunosuppressant medications, but the effect of these additional drugs on the long-term prognosis of LSR is still unknown. METHODS: A retrospective chart review was performed on patients diagnosed with idiopathic NS and subsequent LSR during the 8-year study period from 2002 up to and including 2009, with a minimum of 2 years of follow-up. Primary outcome measures were proteinuria and renal function. RESULTS: A total of 29 patients were classified as having LSRNS. The majority of patients received treatment with calcineurin inhibitors and/or mycophenolate mofetil. Seven patients received three or more non-steroid immunosuppressant medications. Sustained complete or partial remission was achieved in 69 % of patients. Three developed end-stage renal disease, and all others maintained normal renal function. There were 13 episodes of serious adverse events, none of which were fatal or irreversible. CONCLUSION: Most patients with LSRNS responded to immunosuppressive therapy by reduction or resolution of proteinuria and preservation of renal function. The results suggest that immunosuppressive treatment is a viable option in NS patients who develop LSR.

Concepts: Renal failure, Chronic kidney disease, Kidney, Nephrology, Nephrotic syndrome, Immunosuppressive drug, Nephritic syndrome, Minimal change disease