Atypical Plasmacytic Proliferation in a Case of C3 Glomerulopathy: Pathophysiology Demystified.

An 11-year-old Hispanic female underwent evaluation of asymptomatic proteinuria and hematuria. The patient denied fever, edema, and gross hematuria. Urinalysis showed mild proteinuria, and a urine microscopic examination revealed red blood cells. Screening tests for glomerulonephritis revealed a low C3 and negative ANA, ASO, DNAse-B, and ANCA. Histological examination of a renal biopsy specimen showed glomeruli with endocapillary proliferation, a predominant C3 deposition in the capillary loops by immunofluorescence, and electron dense deposits in the mesangium, paramesangium, and capillary walls by electron microscopy consistent with a diagnosis of C3 glomerulopathy. An interstitial plasmacytosis was also present with focal clustering of plasma cells, which were found to be kappa light chain restricted by in situ hybridization suggestive of a clonal proliferation. One can speculate that these plasma cells may be directly responsible for the renal pathology that was seen.

A 13-Month-Old With Xanthogranulomatous Pyelonephritis With Features of Renal Malakoplakia.

Xanthogranulomatous pyelonephritis is an uncommon chronic inflammatory renal disorder caused by chronic infection with gram-negative bacteria leading to destruction of the renal parenchyma and replacement with foamy lipid-laden macrophages. Renal malakoplakia is another rare form of chronic inflammatory granulomatous disease in the kidney associated with infection usually occurring in adults with immunocompromised status or debilitating disease. It is hallmarked by the finding of foamy histiocytes with distinctive basophilic inclusions (Michaelis-Gutmann bodies). We present a case of a 13-month-old male with history of congenital hydronephrosis who presented with clinical and radiologic findings suggestive of xanthogranulomatous pyelonephritis. However, further pathologic studies revealed the presence of Michaelis-Gutmann bodies, which are pathognomonic for renal malakoplakia. With this case we hope to bring further evidence to support that these two conditions are not mutually exclusive but rather represent two pathologic processes on the same disease spectrum.

Approach to Pediatric Patients with UTI in the PICU.

Urosepsis and UTI are common causes and comorbidities in children admitted to the pediatric intensive care unit (PICU). Risk factors for morbidity and mortality in pediatric patients include young age (< 2 years old), presence of congenital renal anomalies of the urinary tract, and immunosuppression from transplant (kidney, liver, heart, and bone marrow). Workup of urosepsis focuses on identification of renal anomalies of the urinary tract through ultrasound, X-ray cystourethrogram, urodynamic studies, and CT/MRI. Management consists of appropriate choice in antibiotics, hemodynamic instability, and prevention of acute kidney injury (AKI) with particular recognition that chronic renal failure can be present in all chronically ill children, which is not limited to pediatric patients with congenital anomalies of the kidney urinary tract. This review includes a review of the workup and management of pediatric patients with UTI and urosepsis in both healthy patients and patients with known anomalies of the urinary tract.

NGAL distinguishes steroid sensitivity in idiopathic nephrotic syndrome.

BACKGROUND: Idiopathic nephrotic syndrome (NS) is the most common glomerular disorder of childhood. Invasive biopsy remains the diagnostic method of choice for NS. Prognosis correlates with steroid responsiveness, from sensitive (SSNS) to resistant (SRNS). Neutrophil gelatinase-associated lipocalin (NGAL) has been demonstrated to be a powerful risk marker of chronic kidney disease progression. We set out to determine if urine NGAL can distinguish between patients with SRNS, SSNS, and healthy controls. METHODS: Urine and clinical data were collected from patients at Cincinnati Children's Hospital who were recently diagnosed with active nephrotic syndrome as well as healthy controls. Participants included SRNS (n = 15), SSNS (n = 14), and healthy controls (n = 10). Urinary NGAL was measured by ELISA and normalized to creatinine. RESULTS: Median NGAL was significantly (p < 0.001) higher in SRNS (172.3 ng/ml, IQR 18.8-789) than both SSNS (6.3 ng/ml, IQR 4.9-9.9) and healthy controls (6.5 ng/ml, IQR 4.2-9.1). The area under the curve (AUC) for NGAL to distinguish SRNS from SSNS was 0.91 (p < 0.0001). NGAL levels demonstrated a significant negative correlation with glomerular filtration rate (r = -0.5, p < 0.001). Results did not change with NGAL corrected for urine creatinine and were independent of the degree of proteinuria. CONCLUSIONS: NGAL levels differentiate SSNS from SRNS and correlate with disease severity in SRNS.

Distinct metalloproteinase excretion patterns in focal segmental glomerulosclerosis.

Metalloproteinase-2 (MMP-2) and metalloproteinase-9 (MMP-9) degrade type IV collagen, and represent important tissue remodeling enzymes in several kidney disorders. In this study, we measured urinary levels of MMP-2, MMP-9, and the tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) in patients with steroid-sensitive nephrotic syndrome (SSNS, n = 18, median age 5) and focal segmental glomerulosclerosis (FSGS, n = 16, median age 15). We found that urinary concentrations of MMP-2, MMP-9, TIMP-1, and TIMP-2 were significantly elevated in FSGS patients as compared to SSNS in both relapse and remission (p < 0.002). Furthermore, urinary levels of these enzymes are increased early on in the FSGS disease process (chronic kidney disease stages 1 and 2). The findings from this pilot study suggest that MMPs and TIMPs have the potential to represent candidate, early non-invasive biomarkers for diagnosis and/or response to therapy. In addition, they may represent therapeutic targets for preventing chronic kidney disease progression in FSGS.

Discovery and initial validation of α 1-B glycoprotein fragmentation as a differential urinary biomarker in pediatric steroid-resistant nephrotic syndrome.

PURPOSE: In this cross-sectional pilot study we set out to discover a non-invasive biomarker that could distinguish steroid-resistant nephrotic syndrome (SRNS) from steroid-sensitive nephrotic syndrome (SSNS). EXPERIMENTAL DESIGN: Urine and clinical data were collected from patients with idiopathic nephrotic syndrome and healthy controls. Using SELDI-TOF-MS, we identified an 11-fold upregulated 13.8 kDa fragment of α 1-B glycoprotein (A1BG) in urine in SRNS. To validate our findings, A1BG was detected by Western blot. Creatinine was measured and transformed to glomerular filtration rate (GFR) by the new Schwartz formula and classified to chronic kidney disease (CKD) stage. p-Values were determined by unpaired t-test and Mann-Whitney rank sum test. Microalbumin was also measured to determine albumin/creatinine ratios. RESULTS: The 13.8 kDa A1BG was present in 7 of 19 patients with SRNS; but absent in all SSNS (n=15) and controls (n=10). The A1BG(+) patients had lower GFR than A1BG(-) patients (p<0.009) and tended to have higher CKD stage. CONCLUSION AND CLINICAL RELEVANCE: The 13.8 kDa A1BG fragment had a high discriminatory power for steroid resistance in pediatric nephrotic syndrome, but is only present in a subset of patients. Additional longitudinal studies are required to determine the usefulness of this biomarker as a non-invasive predictive marker of therapeutic response.

Laser capture microdissection-microarray analysis of focal segmental glomerulosclerosis glomeruli.

Focal segmental glomerulosclerosis (FSGS) is a major cause of end-stage renal disease. In this report we used laser capture microdissection to purify diseased glomeruli, and microarrays to provide universal gene expression profiles. The results provide a deeper understanding of the molecular mechanisms of the disease process and suggest novel therapeutic strategies. Consistent with earlier studies, molecular markers of the differentiated podocyte, including WT1, nephrin, and VEGF, were dramatically downregulated in the diseased glomerulus. We also observed multiple changes consistent with increased TGF-beta signaling, including elevated expression of TGF-beta(2), TGF-beta(3), SMAD2, TGF-beta(1) receptor, and thrombospondin. In addition, there was relatively low level expression of Csf1r, a marker of macrophages, but elevated expression of the chemokines CXCL1, CXCL2, CCL3, and CXCL14. We also observed strongly upregulated expression of Sox9, a transcription factor that can drive a genetic program of chondrogenesis and fibrosis. Further, the gene with the greatest fold increase in expression in the diseased glomerulus was osteopontin, which has been previously strongly implicated in kidney fibrosis in the unilateral ureteral obstruction mouse model. These results confirm old findings, and indicate the involvement of new genetic pathways in the cause and progression of FSGS.

Autonomic dysreflexia manifested by severe hypertension.

BACKGROUND: Autonomic dysreflexia (AD) is a sudden and exaggerated autonomic response to stimuli in patients with spinal cord injuries or dysfunction above the splanchnic sympathetic outflow (T5-T6). Hypertension is a relatively common manifestation of AD. CASE REPORT: We describe a case of a young man with T4-T6 spinal cord tumor who developed severe hypertension before any other clinical feature of AD, leading to a subsequent clinical evaluation and the correct diagnosis. Treatment with labetalol was only partially successful in controlling the elevated blood pressure. Hypertension resolved immediately after bladder decompression. CONCLUSIONS: AD manifested by severe hypertension is uncommon. Bladder decompression appears to be safe and effective for management of hypertension in patients with AD.