Clinical Practice Audit on the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis in the Netherlands.

INTRODUCTION: Managing complex and rare systemic autoimmune diseases such as antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) can be challenging and is often accompanied by undesirable variations in clinical practice. Adequate understanding of clinical practice can help identify essential issues to improve the care for AAV patients. Therefore, we studied the real-life management and outcomes of AAV patients in the Netherlands. METHODS: In this cohort study, we investigated clinical practice in university and nonuniversity teaching hospitals with respect to patients with a clinical diagnosis of AAV. We retrospectively collected clinical data encompassing clinical variables, medication details, and outcome parameters. RESULTS: Data of 230 AAV patients were collected in 9 Dutch hospitals. Of these, 167 patients (73%) were diagnosed with granulomatosis with polyangiitis, 54 (24%) with microscopic polyangiitis and 9 (4%) with eosinophilic granulomatosis with polyangiitis. One hundred sixty-six patients (72%) had generalized disease. The median year of diagnosis was 2013 (range 1987-2018). Besides steroids, oral cyclophosphamide was the most used drug (50%) for induction therapy and azathioprine (68%) for maintenance therapy. Adverse outcomes were major infections in 35%, major relapses in 23%, malignancy in 10%, major cardiovascular events in 8%, and end-stage renal disease in 7%. CONCLUSION: Oral cyclophosphamide was the most frequently used induction therapy, azathioprine for maintenance therapy; over time, the use of rituximab is increasingly employed. Major infection and relapses are the most prevalent adverse outcomes. This audit resulted in important indicators for treatment of AAV patients that can be implemented for future, national audits to improve the outcomes of AAV patients.

Nephrin Loss Can Be Used to Predict Remission and Long-term Renal Outcome in Patients With Minimal Change Disease.

INTRODUCTION: Minimal change disease is a common cause of nephrotic syndrome. In general, patients with minimal change disease respond to corticosteroids and have excellent long-term renal survival. However, some patients have less favorable outcome. These patients are often thought to have progressed to focal segmental glomerulosclerosis. We previously reported that a segmental loss of podocyte markers is present before the development of focal segmental glomerulosclerosis in a rat model. Here, we investigated whether loss of podocyte marker nephrin can serve as a biomarker for predicting poor outcome in patients with minimal change disease. METHODS: We obtained 47 kidney biopsy samples from patients diagnosed with minimal change disease and stained sections with periodic acid-Schiff and for nephrin. Nephrin loss was scored by 2 independent researchers who were blinded to clinical outcome. Clinical data were collected retrospectively, and nephrin loss was correlated with clinical follow-up data. RESULTS: Nephrin loss was present in 34% of the biopsy samples. During follow-up, patients with nephrin loss achieved remission less frequently (61%) compared to patients without (96%) (P = 0.002). Moreover, 5-year eGFR was lower in the patients with renal nephrin loss. The risk of eGFR decreasing to < 60 ml/min per 1.73m2 increased with each percentage of glomeruli with nephrin loss (hazard ratio = 1.044, 95% confidence interval = 1.02-1.07). CONCLUSION: These results indicate that nephrin loss in patients with minimal change disease can help predict both remission and long-term renal outcome.

Systemic Monocyte Chemotactic Protein-1 Inhibition Modifies Renal Macrophages and Restores Glomerular Endothelial Glycocalyx and Barrier Function in Diabetic Nephropathy.

Inhibition of monocyte chemotactic protein-1 (MCP-1) with the Spiegelmer emapticap pegol (NOX-E36) shows long-lasting albuminuria-reducing effects in diabetic nephropathy. MCP-1 regulates inflammatory cell recruitment and differentiation of macrophages. Because the endothelial glycocalyx is also reduced in diabetic nephropathy, we hypothesized that MCP-1 inhibition restores glomerular barrier function through influencing macrophage cathepsin L secretion, thus reducing activation of the glycocalyx-degrading enzyme heparanase. Four weeks of treatment of diabetic Apoe knockout mice with the mouse-specific NOX-E36 attenuated albuminuria without any change in systemic hemodynamics, despite persistent loss of podocyte function. MCP-1 inhibition, however, increased glomerular endothelial glycocalyx coverage, with preservation of heparan sulfate. Mechanistically, both glomerular cathepsin L and heparanase expression were reduced. MCP-1 inhibition resulted in reduced CCR2-expressing Ly6Chi monocytes in the peripheral blood, without affecting overall number of kidney macrophages at the tissue level. However, the CD206+/Mac3+ cell ratio, as an index of presence of anti-inflammatory macrophages, increased in diabetic mice after treatment. Functional analysis of isolated renal macrophages showed increased release of IL-10, whereas tumor necrosis factor and cathepsin L release was reduced, further confirming polarization of tissue macrophages toward an anti-inflammatory phenotype during mouse-specific NOX-E36 treatment. We show that MCP-1 inhibition restores glomerular endothelial glycocalyx and barrier function and reduces tissue inflammation in the presence of ongoing diabetic injury, suggesting a therapeutic potential for NOX-E36 in diabetic nephropathy.

Macrophages in diabetic nephropathy in patients with type 2 diabetes.

BACKGROUND: Inflammation plays a role in the development of diabetic nephropathy (DN) in type 2 diabetes. Although macrophages have been found in experimental models of DN, little is known regarding the presence of macrophages in patients with DN. Therefore, we investigated the presence and phenotype of glomerular and interstitial macrophages in relation to clinical and histopathological parameters in patients with DN. METHODS: Renal autopsy samples were obtained from 88 type 2 diabetic patients with histologically proven DN and stained for CD68 and CD163 as general and M2/anti-inflammatory markers of macrophages. Renal damage was scored based on histopathological classification of DN. Control renal autopsy samples were obtained from patients without renal abnormalities and from diabetic patients without DN. Positive cells per glomerulus were counted. Interstitial macrophages were counted semi-quantitatively. RESULTS: Macrophages were present in all groups. In the DN group, the mean number of CD68+ cells per glomerulus and CD163+ cells per glomerulus was 4.2 (range 0-19) and 2.1 (range 0-14.47), respectively. The distribution was similar between all histopathological classes. Glomerular CD163+ macrophages were positively associated with DN class, interstitial fibrosis and tubular atrophy, and glomerulosclerosis. Interstitial CD68+ macrophages were correlated with glomerular filtration rate stage and albuminuria. CONCLUSIONS: Our results demonstrate that macrophages are present in the glomeruli and interstitium of type 2 diabetic patients with DN and of controls. Although patients and controls had similar numbers of glomerular macrophages, glomerular anti-inflammatory CD163+ macrophages were associated with pathological lesions in DN. Taken together with the correlation between interstitial macrophages and interstitial fibrosis and tubular atrophy, DN class, and renal function, this finding suggests that macrophages may play a role in DN progression. Therefore, targeting macrophages may be a promising new therapy for inhibiting the progression of DN.

Fidelity and evolution of recurrent FSGS in renal allografts.

Five pathologic variants of FSGS were recently defined ("Columbia classification"), but the stability of these phenotypes in renal allografts remains unknown. We hypothesized that if the variants represent distinct diseases, then the pattern of recurrent FSGS in renal allografts will mimic the original disease in the native kidney. This multicenter study included 21 cases of recurrent FSGS from 19 patients who had both native and transplant biopsy samples available for analysis. These results support the Columbia classification, because 81% recurred in the same pattern as the original disease, but three variants manifested plasticity from native to allograft kidneys or in the pattern of recurrence (four FSGS, not otherwise specified [NOS] to collapsing variant, two collapsing variant to FSGS NOS, and one cellular variant to FSGS NOS). No transitions between the cellular and the collapsing variants were observed, supporting the view that these are separate entities. Three categories of recurrence were observed: Type I, recurrence of the same variant of FSGS; type II, recurrence of the same FSGS variant, preceded by a minimal change-like lesion; and type III, recurrence of a different FSGS variant in the allograft. Thus, potential evolution of the pathologic phenotype should be considered in pathologic interpretation and clinical trials.

The use of extracellular matrix probes and extracellular matrix-related probes for assessing diagnosis and prognosis in renal diseases.

PURPOSE OF REVIEW: Scarring in the kidney results from excessive local synthesis and exogenous accumulation of extracellular matrix components. Once chronic damage is present in the biopsy, therapeutic intervention for the renal patient encounters severe limitations. It is therefore essential to determine clinical outcome preferably at a time point before the development of overt scarring. Clinical parameters and morphologic alterations in the biopsy are currently used as tools for the diagnosis of the renal disease entity and for assessment of the patient's prognosis. Expression levels of extracellular matrix and matrix-related components may serve as additive and even superior prognostic indicators to conventional parameters. We will elaborate on studies supporting this concept. RECENT FINDINGS: Several investigators have shown in experimental models for renal disease that extracellular matrix probes and related probes reflect disease progression and predict outcome. In this review, we will provide an update on the most recent studies of human renal biopsies showing that expression of extracellular matrix components, regulators of matrix degradation, and cytokines affecting matrix deposition may be employed for discrimination of diagnostic groups and predicting prognosis. SUMMARY: Molecular techniques are expected to be used more and more for diagnostic and prognostic purposes in nephrological practice to supplement the histopathological analysis of the renal biopsy. Assessment of expression of matrix molecules, matrix-regulating cytokines, and metalloproteinases in renal kidney biopsies is helpful to distinguish patients who are at risk of developing progressive renal failure from patients who are likely to recover from renal tissue injury by natural remodeling mechanisms.