Rutger J. Maas

The soluble urokinase receptor is not a clinical marker for focal segmental glomerulosclerosis

The soluble urokinase receptor (suPAR) promotes proteinuria and induces focal segmental glomerulosclerosis (FSGS)-like lesions in mice. A serum suPAR concentration cutoff of 3000 pg/ml has been proposed as a clinical biomarker for patients with FSGS. Interestingly, several studies in patients with glomerulopathy found an inverse correlation between the estimated glomerular filtration rate (eGFR) and suPAR. As patients with FSGS present at different eGFRs, we studied the relationship between eGFR and suPAR in a cohort of 476 non-FSGS patients and 54 patients with biopsy-proven idiopathic FSGS. In the non-FSGS patients, eGFR was the strongest significant determinant of suPAR. The proposed cutoff for suPAR in FSGS patients was exceeded in 17%, 39%, and 88% in patients with eGFRs of more than 60, 45-60, and 30-45 ml/min per 1.73 m(2), respectively. In patients with eGFR of <30 ml/min per 1.73 m(2), suPAR exceeded the cutoff in 95% of patients. Levels of suPAR in patients with idiopathic FSGS overlapped with non-FSGS controls and for any given eGFR did not discriminate FSGS cases from non-FSGS controls. In the overall cohort, there was a negative association between idiopathic FSGS and suPAR, and idiopathic FSGS was not an independent predictor of FSGS concentration over 3000 pg/ml. Thus, this study does not support an absolute, eGFR-independent, suPAR concentration cutoff as a biomarker for underlying FSGS pathology and questions the validity of relative, eGFR-dependent suPAR cutoff values.

Serum suPAR in patients with FSGS: trash or treasure?

The urokinase-type plasminogen activator receptor (uPAR) has important functions in cell migration. uPAR can be shed from the cell membrane resulting in soluble uPAR (suPAR). Further cleavage gives rise to shorter fragments with largely unknown functions. Recent studies have demonstrated that both overexpression of uPAR on podocytes and the administration of suPAR cause proteinuria in mice. The common pathogenic mechanism involves the activation of podocyte β3-integrin. Increased activation of β3-integrin is also observed in patients with focal and segmental glomerulosclerosis (FSGS). These observations form the basis for the hypothesis that suPAR may be the circulating factor causing FSGS. A recent study fosters this idea by demonstrating increased suPAR levels in the serum of patients with FSGS and reporting an association with recurrence after transplantation and response to plasmapheresis. However, this study was heavily biased, and subsequent studies have given conflicting results. Although the experimental work is very suggestive, at present there is no proof that any known human suPAR fragment causes FSGS in humans. We therefore suggest that the measurement of suPAR using currently available assays has absolutely no value at the present time in decision-making in routine clinical practice.

Permeability factors in idiopathic nephrotic syndrome: historical perspectives and lessons for the future

The term idiopathic nephrotic syndrome (iNS) traditionally covers minimal change disease and primary focal segmental glomerulosclerosis (FSGS), now thought to be separate disease entities. Clinical and experimental evidence suggest that circulating permeability factors are involved in their pathogenesis. In the past four decades, many investigators have searched for the responsible factors, thus far with little success. The recent report of the soluble urokinase plasminogen activator receptor as a causative factor in FSGS has received much attention, but again the initially promising findings were not confirmed. We describe the history of the search for permeability factors, discuss the pitfalls that are likely responsible for the lack of success and propose criteria that should be used in future studies when evaluating candidate permeability factors.

Minimal change disease and idiopathic FSGS: manifestations of the same disease

Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are the key histological findings in patients with idiopathic nephrotic syndrome (INS). Although MCD and idiopathic FSGS are often considered to represent separate entities based on differences in their presenting characteristics, histology and outcomes, little evidence exists for this separation. We propose that MCD and idiopathic FSGS are different manifestations of the same progressive disease. The gradual development of FSGS in patients with non-remitting or relapsing INS has been well documented. Moreover, FSGS is the uniform result of substantial podocyte loss in animal models, and a common feature of virtually all progressive human glomerulopathies. As evidence suggests a common aetiology, the pathogenesis of MCD and idiopathic FSGS should be studied together. In clinical trials, idiopathic FSGS should be considered to represent an advanced stage of disease progression that is less likely to respond to treatment than the earlier stage of disease, which is usually defined as MCD.

A retrospective study of focal segmental glomerulosclerosis: clinical criteria can identify patients at high risk for recurrent disease after first renal transplantation.

BackgroundFocal segmental glomerulosclerosis (FSGS) is a frequent cause of end-stage renal disease. Renal transplantation in patients with FSGS is often complicated by disease recurrence, which is associated with poor outcome. There are no tests that reliably predict recurrence of FSGS after transplantation. The aim of this study was to evaluate if clinical criteria can identify patients at high risk for recurrent disease.MethodsWe retrospectively studied 94 patients who received a first renal transplant at a median age of 37 years (range 5–69 years). Patients were assigned to one of three groups: familial or genetic FSGS (group I; n=18), secondary FSGS (group II; n=10) and idiopathic FSGS (group III; n=66). Pretransplant clinical characteristics were analyzed to determine predictors of a recurrence after transplantation.ResultsFSGS only recurred in patients with idiopathic FSGS (group III; 42%). Patients with a recurrence had a significantly lower serum albumin, higher 24-hour proteinuria and higher estimated glomerular filtration rate at diagnosis. Serum albumin at diagnosis was the only independent predictor of a recurrence in patients with idiopathic FSGS. Patients with recurrent FSGS had more acute rejection episodes (54% vs. 27%, P =0.02) and lower five year graft survival compared to patients without a recurrence (50 vs. 82%, P <0.01).ConclusionsClinical criteria allow identification of patients at high risk of recurrent FSGS after renal transplantation. This information can be used in the counseling and management of patients with FSGS.

Serum suPAR concentrations in patients with focal segmental glomerulosclerosis with end-stage renal disease.

To the Editor: Huang et al.1 recently reported that plasma soluble urokinase receptor (suPAR) levels were significantly elevated in patients with focal segmental glomerulosclerosis (FSGS) compared to controls. This study confirmed that plasma suPAR levels are negatively correlated with estimated glomerular filtration rate (eGFR).2 Pretransplant serum suPAR concentration has been suggested as a predictor for posttransplant proteinuriarecurrence in patients with FSGS.3 However, these results may have been biased because the controls had higher eGFR.3 We questioned whether serum suPAR is a specific marker for FSGS recurrence risk after transplantation in patients on hemodialysis. We measured serum suPAR concentrations in eight chronic hemodialysis patients using a commercially available assay (Quantikine Human suPAR Immunoassay; R&D Diagnostics, Minneapolis, MN). Three patients had a history of biopsy-proven FSGS in their native kidney and recurrent FSGS in one or two kidney allografts, and five controls had non-FSGS chronic kidney disease (CKD). None of the patients had active infection or systemic malignancy. Serum suPAR levels were >3000 pg/ml in all patients, and were not higher in patients with FSGS compared to controls (Figure 1). Another recent study also concluded that serum suPAR concentration is not specific for FSGS and posttransplant recurrence.4 Of note, Huang et al.1 observed no differences in suPAR levels between patients with primary and secondary FSGS. These data indicate that suPAR measurement using the currently available assay is not helpful in the identification of patients with a high risk of posttransplant FSGS recurrence. Further studies are needed to identify potential specific pathogenic suPAR fragments in primary FSGS.

The Clinical Course of Minimal Change Nephrotic Syndrome With Onset in Adulthood or Late Adolescence: A Case Series

BACKGROUND Few studies have examined the treatment and outcome of adult-onset minimal change nephrotic syndrome (MCNS). We retrospectively studied 125 patients who had MCNS with onset in either adulthood or late adolescence. Presenting characteristics, duration of initial treatment and response to treatment, relapse patterns, complications, and long-term outcome were studied. STUDY DESIGN Case series. SETTING & PARTICIPANTS Patients with new-onset nephrotic syndrome 16 years or older and a histologic diagnosis of MCNS in 1985 to 2011 were identified from pathology records of 10 participating centers. OUTCOMES Partial and complete remission, treatment resistance, relapse, complications, renal survival. RESULTS Corticosteroids were given as initial treatment in 105 (84%) patients. After 16 weeks of corticosteroid treatment, 92 (88%) of these patients had reached remission. Median time to remission was 4 (IQR, 2-7) weeks. 7 (6%) patients initially received cyclophosphamide with or without corticosteroids, and all attained remission after a median of 4 (IQR, 3-11) weeks. 13 (10%) patients reached remission without immunosuppressive treatment. One or more relapses were observed in 57 (54%) patients who received initial corticosteroid treatment. Second-line cyclophosphamide resulted in stable remission in 57% of patients with relapsing MCNS. Acute kidney injury was observed in 50 (40%) patients. Recovery of kidney function occurred almost without exception. Arterial or venous thrombosis occurred in 11 (9%) patients. At the last follow-up, 113 (90%) patients were in remission and had preserved kidney function. 3 patients with steroid-resistant MCNS progressed to end-stage renal disease, which was associated with focal segmental glomerulosclerosis lesions on repeat biopsy. LIMITATIONS Retrospective design, variable treatment protocols. CONCLUSIONS The large majority of patients who had MCNS with onset in adulthood or late adolescence were treated with corticosteroids and reached remission, but many had relapses. Cyclophosphamide resulted in stable remission in many patients with relapses. Significant morbidity was observed due to acute kidney injury and other complications. Progression to end-stage renal disease occurred in a few patients and was explained by focal segmental glomerulosclerosis.

Glomerular disease in 2016: New advances in the treatment of glomerular disease

Studies published in 2016 provide insights that bring us closer to achieving the goal of personalized therapy for primary glomerular diseases. Moreover, promising renal outcome data with new classes of glucose-lowering agents — SGLT2 inhibitors and GLP-1 agonists — offer new hope for patients with diabetic nephropathy.

Kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin as prognostic markers in idiopathic membranous nephropathy

Background Urinary excretion of alpha-1-microglobulin and beta-2-microglobulin reflects tubular damage and predicts outcome in patients with idiopathic membranous nephropathy with reasonable accuracy. Urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin are novel biomarkers of tubular damage. We investigated if these markers could improve prediction of outcome in idiopathic membranous nephropathy. Methods We measured kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin in urine samples from patients with idiopathic membranous nephropathy, who had nephrotic proteinuria and normal renal function. Excretion of alpha-1-microglobulin and beta-2-microglobulin had been measured previously. Progression was defined as a serum creatinine rise >30%, a rise in serum creatinine to an absolute value of ≥135 µmol/L, or a clinical decision to start immunosuppressive therapy. Remission was defined as proteinuria <3.5 g/day and >50% reduction from baseline. Results Sixty-nine patients were included. Median follow-up was 35 months (interquartile range 18–63 months). Progression occurred in 30 patients (44%), and spontaneous remission in 36 (52%). Kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin excretion rates were significantly correlated with each other, and with alpha-1-microglobulin and beta-2-microglobulin. The areas under the receiver operating characteristic curves for progression were 0.75 (0.62–0.87) for kidney injury molecule-1 and 0.74 (0.62–0.87) for neutrophil gelatinase-associated lipocalin. In multivariate analysis with either alpha-1-microglobulin and beta-2-microglobulin, kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin did not independently predict outcome. Conclusion Kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin excretion rates correlated with excretion rates of other tubular damage markers and predicted outcome in patients with idiopathic membranous nephropathy. They did not add prognostic value compared to measurement of either alpha-1-microglobulin or beta-2-microglobulin.