Pathology spectrum of kidney damage in Hodgkin’s lymphoma, non-Hodgkin lymphoma/leukemia, and lymphoplasmacytic lymphoma in the real practice

Background: Kidney damage in lymphomas/leukemia’s presents with either acute kidney injury (AKI), chronic kidney disease (CKD), or both; and whilst AKI leads to evaluation often based on the clinical data, in some AKI and in almost all CKD cases kidney biopsy gives a clue to the diagnosis. Methods: A single center non-interventional retrospective study identified 36 patients with biopsy-proven kidney damage: 6 with Hodgkin’s lymphoma (HL), 18 with non-Hodgkin’s lymphoma/leukemia (NHL/CLL), and 12 with lymphoplasmacytic lymphoma (LPL). Results: Fifty-eight percent males and 42% females mean age 56.2 ± 17.4 years, presented with nephrotic syndrome in 47.2%, and with AKI in 11.1% of cases; 75% of patients diagnosed with CKD; in 13.9% AKI was superimposed on CKD. Patients with NHL/CLL presented with AKI significantly more often compared to HL and LPL—44% versus 16.6% versus 0 respectively. Monoclonal immunoglobulin (MIg) related glomerulopathies (GP) were found in 83.3% versus 16.6% cases in the LPL and NHL/CLL sub-groups, respectively ( p = 0.013). Patterns of damage included intracapillary monoclonal deposition disease, light and heavy chain amyloidosis, monotypic membranous nephropathy (MN), cryoglobulinemic glomerulonephritis (GN) and C3-GN in the LPL; and monotypic MN and proliferative GN with MIg deposits in the NHL/CLL sub-groups respectively. Paraneoplastic GPs were found in 83.3%, 38.8%, and 16.6% of patients with HL, NHL/CLL, LPL, respectively (HL vs LPL, p < 0.001), and included minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and IgA-nephropathy in the HL; membranoproliferative GN, MN, and MCD in NHL/CLL; and FSGS in the LPL sub-groups. Tubulointerstitial damage revealed in NHL/CLL sub-group only, and found in every other case with 80% of lymphoid infiltration. Conclusions: Pattern glomerular damage depends on lymphoma type: paraneoplastic GPs are typical for HL, MIg-related GPs dominate in LPL, NHL/CLL presents mainly as paraneoplastic with single MIg-related patterns. Tubulointerstitial damage due to specific kidney infiltration attributable to NHL/CLL.

Identifying Therapeutic Strategies in IgA Nephropathy through Comprehensive Transcriptomic Characterization

IgA nephropathy (IgAN) is an autoimmune disease and the most common primary glomerulonephritis. The four-hit hypothesis describes mechanism of the disease, from synthesis of galactose deficient IgA (GD-IgA), to recognition of GD-IgA by anti-glycan antibodies and deposition of the formed immune complex in the mesangium. Complement and coagulation cascade activation ensues, resulting in mesangial activation and cytokine release, podocyte injury, mesangial sclerosis and tubulointerstitial damage. Currently, there is no disease cure, and 30-40% of patients progress to end stage renal disease.Using complementary bioinformatic approaches, we demonstrate different levels of deviation of the transcriptome of the glomerulus in IgAN from normal, with the aim of identifying therapeutic targets. Approaches used herein include, deconvolution of the transcriptome to estimate immune constitution, co-regulation-based functional analysis of differentially expressed genes, modular co-expression analysis, network analysis of metabolic pathways and differential gene correlation analysis.We describe the immune composition in IgAN and the relatively low fold changes of the abundance of different immune cells and strength of immune signatures compared with control. Additionally, we identify enrichment of the intestinal network for IgA synthesis, repression of expression and dysregulation of networks of amino acid metabolism and PPAR signaling pathways in IgAN glomeruli. We also find loss of correlation between expression of matrix synthesizing and matrix degrading genes in IgAN.We conclude by discussing how therapies based on some nodes in these altered pathways described have been shown to be efficacious in IgAN and/or other inflammatory diseases and the potential of others in effective treatment.

Long-Term Protection of CHBP Against Combinational Renal Injury Induced by Both Ischemia–Reperfusion and Cyclosporine A in Mice

Renal ischemia–reperfusion (IR) injury and cyclosporine A (CsA) nephrotoxicity affect allograft function and survival. The prolonged effects and underlying mechanisms of erythropoietin derived cyclic helix B peptide (CHBP) and/or caspase-3 small interfering RNA (CASP-3siRNA) were investigated in mouse kidneys, as well as kidney epithelial cells (TCMK-1), subjected to transplant-related injuries. Bilateral renal pedicles were clamped for 30 min followed by reperfusion for 2 and 8 weeks, with/without 35 mg/kg CsA gavage daily and/or 24 nmol/kg CHBP intraperitoneal injection every 3 days. The ratio of urinary albumin to creatinine was raised by IR injury, further increased by CsA and lowered by CHBP at 2, 4, 6 and 8 weeks, whereas the level of SCr was not significantly affected. Similar change trends were revealed in tubulointerstitial damage and fibrosis, HMGB1 and active CASP-3 protein. Increased apoptotic cells in IR kidneys were decreased by CsA and CHBP at 2 and/or 8 weeks. p70 S6 kinase and mTOR were reduced by CsA with/without CHBP at 2 weeks, so were S6 ribosomal protein and GSK-3β at 8 weeks, with reduced CASP-3 at both time points. CASP-3 was further decreased by CHBP in IR or IR + CsA kidneys at 2 or 8 weeks. Furthermore, in TCMK-1 cells CsA induced apoptosis was decreased by CHBP and/or CASP-3siRNA treatment. Taken together, CHBP predominantly protects kidneys against IR injury at 2 weeks and/or CsA nephrotoxicity at 8 weeks, with different underlying mechanisms. Urinary albumin/creatinine is a good biomarker in monitoring the progression of transplant-related injuries. CsA divergently affects apoptosis in kidneys and cultured kidney epithelial cells, in which CHBP and/or CASP-3siRNA reduces inflammation and apoptosis.

Tubular cell damage may be the earliest sign of renal extrahepatic manifestation caused by Hepatitis C

Chronic kidney disease (CKD) is one of the most well-known extrahepatic manifestations caused by hepatitis C infection (HCV). CKD is typically discovered at a late stage. HCV-nephropathy may show different histopathologic patterns, as both glomerular and tubulointerstitial damage have been described. Identification of patients with early renal manifestations would be beneficial to provide treatment and avoid progression to CKD. The observational prospective single-center HCVKID study assessed the prevalence of early renal manifestations in patients with chronic HCV and compared these patients with HCV-negative healthy controls cross-sectionally. HCV-positive patients with and without renal manifestations were also compared to define biomarkers suitable for identifying early manifestations in standard clinical practice. Tubular proteinuria as judged by urine α 1-microglobulin was the most common early renal manifestation found in 11% in HCV-positive patients, followed by hematuria in 8%. Kidney filtration was statistically significantly lower among HCV-positive patients with renal manifestation according to any calculation method. There were no significant differences in duration of infection or stage of liver fibrosis between patients with or without renal manifestations. Tubular cell damage may be the earliest sign of renal dysfunction caused by HCV. Complement activation also correlates with the dysfunction, indicating of contribution to HCV-induced renal manifestations even in their early phase.

MO1026MICROALBUMIN LEVEL IN URINE DEPENDING ON ACE GENE POLYMORPHISM IN PATIENTS WITH VUR

Background and Aims reflux nephropathy (RN) is the most serious complication of vesicoureteral reflux (VUR). The aim of the study was to assess the urinary level of MA (microalbumin) as an expression of tubulointerstitial damage depending of ACE genotype polymorphisms in children with VUR. Method 94 patients, with VUR at the age from 3 year to 16 years (average age of 6.72 ± 0.68 years), including 65 girls (69,1%) were enrolled. As a control population to compare the distribution of genotypes and alleles of ACE gene used a sample of 100 healthy children (82girls), indigenous ethnic groups, mean age of 11.3 ± 5.4 years. To determine the gene polymorphism of ACE we used the method of polymerase chain reaction. Renal scar in DMSA scan was performed at least six months after urine tract infection (UTI). According to DMSA scan results, children were divided into 2 groups: gr. 1 - 12p. (VUR without RN), gr. 2 – 82 p. (VUR with RN). Urinary excretion of MA was measured by ELISA method. Results In gr. 1 is the frequency of genotype I/I amounted to 58%, I/D is 42% and D/D – is not detected. In the scar group (gr.2) frequency of genotype I/I is 12% (p1,2&lt;0,05), I/D is 63% and (p&gt;0.05), and D/D is 25% (p&lt;0.05), respectively. In the distribution of I and D allele in children with VUR (71,3% of children with RN has got D allele). In RN groups with genotype D/D, the level of MA/Cr in the urine was 1,5 times higher than in children with genotype I/D (p&lt;0.05) and 3-3,5 times higher than in patients with genotype I/I (р=0.0001). Significant difference in urinary levels of MA/Cr in the non scar group with genotype I/I and I/D is not revealed. Conclusion D/D-genotype of ACE may be a genetic susceptibility factor contributing to adverse renal prognosis – reflux nephropathy and presenting as risk factor for scar formation. A high urinary level of MA/Cr and positive correlation with genotype D/D is a significant and sensible marker of tubulointerstitial damage

Role of Human Mesangial-Tubular Crosstalk in Secretory IgA-Induced IgA Nephropathy

<b><i>Background:</i></b> IgA nephropathy (IgAN) is characterized by the mesangial deposition of pathogenic IgA. We previously detected the deposition of pathogenic secretory IgA (SIgA) in the mesangium of about one-third of IgAN patients. Tubulointerstitial injury has an important role in the development of IgAN. However, the relationship between SIgA and tubulointerstitial damage is currently unclear. In this work, the role of the mesangial-tubular crosstalk was explored in the tubulointerstitial damage in SIgA-induced IgAN. <b><i>Methods:</i></b> SIgA deposition in renal tissues of IgAN patients was detected by immunofluorescence. Flow cytometry was used to assess the binding of SIgA to human renal mesangial cells (HRMC) and human proximal tubule epithelial (HK-2) cells. HK-2 was co-cultured with HRMC added with SIgA isolated from patients or normal volunteers. Protein synthesis and gene expressions of TNF-α, TGF-β1, and MCP-1 were determined by ELISA and PCR, respectively. The expressions of the above cytokines in renal tissues of patients and normal controls were detected by immunohistochemistry. <b><i>Results:</i></b> Twenty-nine of 96 patients had SIgA deposition in the mesangium, but SIgA was rarely detected in the tubulointerstitium. The binding rate of SIgA to HK-2 (2.79%) was significantly lower than that of HRMC (81.6%) (<i>p</i> &#x3c; 0.001). The expressions of TNF-α, TGF-β1, and MCP-1 in HRMC were significantly higher than in SIgA-stimulated HK-2 (<i>p</i> &#x3c; 0.05), and their expressions were significantly higher in the SIgA-stimulated co-culture group compared with SIgA-stimulated HRMC (<i>p</i> &#x3c; 0.05). The expressions of the above cytokines were mainly detected in tubulointerstitium of IgAN patients with positive and negative SIgA deposition, without significant difference between the 2 groups, but to a significantly higher level than that in normal controls, and their expressions positively correlated with tubulointerstitial injury. <b><i>Conclusion:</i></b> Inflammatory factors released from the mesangium after SIgA deposition might mediate tubulointerstitial damage via mesangial-tubular crosstalk in IgAN.

MAMs Protect Against Ectopic Fat Deposition and Lipid-Related Kidney Damage in DN Patients

Ectopic fat deposition (EFD) in the kidney plays a key role in the development of diabetic nephropathy (DN). Mitochondria-associated ER membranes (MAMs) are structures that connect to the endoplasmic reticulum (ER) and are involved in lipid metabolism. However, there are few studies on MAMs in the field of kidney disease, and the relationship between EFD and MAMs in DN is still unclear. In this study, increased EFD in the kidneys of DN patients was observed, and analysis showed that the degree of EFD was positively correlated with renal damage. Then, the MAMs were quantified by an in situ proximity ligation assay (PLA). The MAMs in the kidneys were found to gradually decrease through the different stages of DN, while the expression of ADRP (a marker of lipid droplets) and tubulointerstitial damage increased. Moreover, correlation analysis showed that the MAMs were negatively correlated with serum lipid levels, the EFD in the kidney and renal damage. Finally, we observed decreased expression of MAM-control proteins (DsbA-L, PACS-2, and MFN-2) in different stages of DN and they were associated with lipid deposition and renal damage. These data showed that the destruction of MAMs in DN might be the cause of EFD and interstitial damage in the kidney.

Fucoidan Ameliorates Renal Injury-Related Calcium-Phosphorus Metabolic Disorder and Bone Abnormality in the CKD–MBD Model Rats by Targeting FGF23-Klotho Signaling Axis

Background: Recently, chronic kidney disease (CKD)-mineral and bone disorder (MBD) has become one of common complications occurring in CKD patients. Therefore, development of a new treatment for CKD–MBD is very important in the clinic. In China, Fucoidan (FPS), a natural compound of Laminaria japonica has been frequently used to improve renal dysfunction in CKD. However, it remains elusive whether FPS can ameliorate CKD–MBD. FGF23-Klotho signaling axis is reported to be useful for regulating mineral and bone metabolic disorder in CKD–MBD. This study thereby aimed to clarify therapeutic effects of FPS in the CKD–MBD model rats and its underlying mechanisms in vivo and in vitro, compared to Calcitriol (CTR).Methods: All male rats were divided into four groups: Sham, CKD–MBD, FPS and CTR. The CKD–MBD rat models were induced by adenine administration and uninephrectomy, and received either FPS or CTR or vehicle after induction of renal injury for 21 days. The changes in parameters related to renal dysfunction and renal tubulointerstitial damage, calcium-phosphorus metabolic disorder and bone lesion were analyzed, respectively. Furthermore, at sacrifice, the kidneys and bone were isolated for histomorphometry, immunohistochemistry and Western blot. In vitro, the murine NRK-52E cells were used to investigate regulative actions of FPS or CTR on FGF23-Klotho signaling axis, ERK1/2-SGK1-NHERF-1-NaPi-2a pathway and Klotho deficiency.Results: Using the modified CKD–MBD rat model and the cultured NRK-52E cells, we indicated that FPS and CTR alleviated renal dysfunction and renal tubulointerstitial damage, improved calcium-phosphorus metabolic disorder and bone lesion, and regulated FGF23-Klotho signaling axis and ERK1/2-SGK1-NHERF-1-NaPi-2a pathway in the kidney. In addition, using the shRNA-Klotho plasmid-transfected cells, we also detected, FPS accurately activated ERK1/2-SGK1-NHERF-1-NaPi-2a pathway through Klotho loss reversal.Conclusion: In this study, we emphatically demonstrated that FPS, a natural anti-renal dysfunction drug, similar to CTR, improves renal injury-related calcium-phosphorus metabolic disorder and bone abnormality in the CKD–MBD model rats. More importantly, we firstly found that beneficial effects in vivo and in vitro of FPS on phosphorus reabsorption are closely associated with regulation of FGF23-Klotho signaling axis and ERK1/2-SGK1-NHERF-1-NaPi-2a pathway in the kidney. This study provided pharmacological evidences that FPS directly contributes to the treatment of CKD–MBD.

Angiotensin II type 1a receptor loss ameliorates chronic tubulointerstitial damage after renal ischemia reperfusion

We investigate whether suppressing the activation of the angiotensin II type 1a receptor (AT1a) can ameliorate severe chronic tubulointerstitial damage (TID) after renal ischemia reperfusion (IR) using AT1a knockout homozygous (AT1a−/−) male mice. To induce severe chronic TID after renal IR, unilateral renal ischemia was performed via clamping of the right renal pedicle in both AT1a−/− and wild-type (AT1a+/+) mice for 45 min. While marked renal atrophy and severe TID at 70 days postischemia was induced in the AT1a+/+ mice, such a development was not provoked in the AT1a−/− mice. Although the AT1a+/+ mice were administered hydralazine to maintain the same systolic blood pressure (SBP) levels as the AT1a−/− mice with lower SBP levels, hydralazine did not reproduce the renoprotective effects observed in the AT1a−/− mice. Acute tubular injury at 3 days postischemia was similar between the AT1a−/− mice and the AT1a+/+ mice. From our investigations using IR kidneys at 3, 14, and 28 days postischemia, the multiple molecular mechanisms may be related to prevention of severe chronic TID postischemia in the AT1a−/− mice. In conclusion, inactivation of the AT1 receptor may be useful in preventing the transition of acute kidney injury to chronic kidney disease.