Genetic background determines renal response to chronic lithium treatment in female mice

Author(s):  
Theun de Groot ◽  
Rosalinda Doty ◽  
Lars Damen ◽  
Ruben Baumgarten ◽  
Steffi Bressers ◽  
...  

Background Chronic lithium treatment for bipolar disease causes mainly side effects in the kidney. A subset of lithium users develops nephrogenic diabetes insipidus (NDI), a urinary concentrating disorder, and chronic kidney disease (CKD). Age, lithium dose and duration of treatment are important risk factors, while genetic background might also play an important role. Methods In order to investigate the role of genetics, female mice of 29 different inbred strains were treated for one year with control or lithium chow and urine, blood and kidneys were analysed. Results Chronic lithium treatment increased urine production and/or reduced urine osmolality in 21 strains. Renal histology showed that lithium increased interstitial fibrosis and/or tubular atrophy in eight strains, while in none of the strains glomerular injury was induced. Interestingly, lithium did not elevate urinary albumin-creatinine ratio (ACR) in any strain, while eight strains even demonstrated a lowered ACR. The protective effect on ACR coincided with a similar decrease in urinary IgG levels, a marker of glomerular function, while the adverse effect of lithium on interstitial fibrosis/tubular atrophy coincided with a severe increase in urinary β2-microglobulin (B2M) levels, an indicator of proximal tubule damage. Conclusion Genetic background plays an important role in the development of lithium-induced NDI and chronic renal pathology in female mice. The strong correlation of renal pathology with urinary B2M levels indicates B2M as a promising biomarker for chronic renal damage induced by lithium.

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Emmanuelle Charrin ◽  
Dina Dabaghie ◽  
Rik Mencke ◽  
Ilke Sen ◽  
Katja Möller-Hackbarth ◽  
...  

Abstract Background and Aims Podocyte integrity is crucial for the maintenance of glomerular function in health and disease. Numerous studies have reported that Klotho overexpression, or treatment with recombinant Klotho, reduces glomerular and tubular damage in mouse models of renal disease. However, the mechanism(s) of action are not fully understood. Several recent studies have also reported that Klotho is expressed in podocytes, where it protects against various types of injury. These findings conflict with previous studies, which have shown that renal Klotho expression is exclusively confined to proximal and distal tubular cells. Method To address this discrepancy and enhance our understanding of the putative glomeruloprotective effects mediated by Klotho, we examined the expression pattern of Klotho in human and mouse kidney by several different methods, and explored its protective effects by overexpressing full-length human Klotho directly in podocytes or in a distant organ (i.e. liver). Results Data at the mRNA and protein levels all converged towards an absence or very low expression of Klotho in podocytes. The generation of a podocyte-specific Klotho knockout mouse further demonstrated that its deletion did not affect glomerular structure or function. Moreover, Klotho deficiency did not worsen glomerular injury in an experimental model of glomerulonephritis (anti-GBM). However, when Klotho was overexpressed in hepatocytes (Alb-cre;hKlothofl/+ - Alb-hKL), serum Klotho increased drastically with no changes in Fgf23 or phosphate metabolism. In mice challenged with anti-GBM, renal histology and ultrastructure of the filtration barrier was less severely affected in Alb-hKL compared to WT mice. There were also significantly less albuminuria, podocyte loss and interstitial fibrosis in Alb-hKL mice compared to their WT littermates. In contrast, mice which overexpressed Klotho in podocytes (Pod-hKL) were not protected from renal injury. Conclusion Taken together, these results strongly suggest that Klotho is not expressed in any substantial amounts in human or mouse podocytes, and that membrane-bound Klotho does not play a role in podocyte biology. Importantly, our results confirm a beneficial role for soluble Klotho in protecting podocytes against injury, and in maintaining glomerular integrity and function.


Author(s):  
Yu Ho Lee ◽  
Ki Pyo Kim ◽  
Sun-Hwa Park ◽  
Dong-Jin Kim ◽  
Yang-Gyun Kim ◽  
...  

Abstract Background Interstitial fibrosis and tubular atrophy (IFTA) is a well-recognized risk factor for poor renal outcome in patients with diabetic kidney disease (DKD). However, a noninvasive biomarker for IFTA is currently lacking. The purpose of this study was to identify urinary markers of IFTA and to determine their clinical relevance as predictors of renal prognosis. Methods Seventy patients with biopsy-proven isolated DKD were enrolled in this study. We measured multiple urinary inflammatory cytokines and chemokines by multiplex enzyme-linked immunosorbent assay in these patients and evaluated their association with various pathologic features and renal outcomes. Results Patients enrolled in this study exhibited advanced DKD at the time of renal biopsy, characterized by moderate to severe renal dysfunction [mean estimated glomerular filtration rate (eGFR) 36.1 mL/min/1.73 m2] and heavy proteinuria (mean urinary protein:creatinine ratio 7.8 g/g creatinine). Clinicopathologic analysis revealed that higher IFTA scores were associated with worse baseline eGFR (P < 0.001) and poor renal outcome (P = 0.002), whereas glomerular injury scores were not. Among measured urinary inflammatory markers, C-X-C motif ligand 16 (CXCL16) and endostatin showed strong correlations with IFTA scores (P = 0.001 and P < 0.001, respectively), and patients with higher levels of urinary CXCL16 and/or endostatin experienced significantly rapid renal progression compared with other patients (P < 0.001). Finally, increased urinary CXCL16 and endostatin were independent risk factors for poor renal outcome after multivariate adjustments (95% confidence interval 1.070–3.455, P = 0.029). Conclusions Urinary CXCL16 and endostatin could reflect the degree of IFTA and serve as biomarkers of renal outcome in patients with advanced DKD.


2020 ◽  
Vol 51 (6) ◽  
pp. 483-492 ◽  
Author(s):  
Juan Tao ◽  
Hui Wang ◽  
Xiao-Juan Yu ◽  
Ying Tan ◽  
Feng Yu ◽  
...  

Background: A revision of the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification for lupus nephritis has been published in 2018. The current study aimed to verify the utility of this system. Materials and Methods: A total of 101 lupus nephritis patients from a large Chinese cohort who underwent renal biopsy in Peking University First Hospital were reevaluated by 2 renal pathologists, who had no knowledge of the clinical findings. The association between clinical data at the time of initial renal biopsy and follow-up and pathological features were further analyzed on all patients selected. Results: The mean age of the cohort was 33 years with a male/female ratio of 1:9, and a median follow-up period of 128 months. The presence and extent of mesangial hypercellularity, endocapillary hypercellularity, global and segmental glomerulosclerosis, neutrophil exudation/karyorrhexis, glomerular hyaline deposits, extracapillary proliferation (crescents), tubular atrophy/interstitial fibrosis, and interstitial inflammation were significantly correlated with several clinical renal injury indices (systemic lupus erythematosus disease activity index, serum creatinine value, proteinuria, and C3 level) at the time of biopsy. By multivariable Cox hazard analysis, fibrous crescents, tubular atrophy/interstitial fibrosis, and the modified National Institutes of Health chronicity index were independent risk factors for patients’ composite renal outcomes (hazard ratio [HR] 4.100 [95% CI 1.544–10.890], p = 0.005; HR 8.584 [95% CI 2.509–29.367], p = 0.001; and HR 3.218 [95% CI 1.138–9.099], p = 0.028; respectively). Conclusions: The 2018 revision of the ISN/RPS classification for lupus nephritis has utility for prediction of clinical renal outcomes.


2017 ◽  
Vol 69 (5) ◽  
pp. e23-e24
Author(s):  
Agnes B. Fogo ◽  
Mark A. Lusco ◽  
Behzad Najafian ◽  
Charles E. Alpers

2021 ◽  
Vol 8 ◽  
Author(s):  
Shuo-Ming Ou ◽  
Ming-Tsun Tsai ◽  
Huan-Yuan Chen ◽  
Fu-An Li ◽  
Wei-Cheng Tseng ◽  
...  

Background: Galectin-3 (Gal-3) is a multifunctional glycan-binding protein shown to be linked to chronic inflammation and fibrogenesis. Plasma Gal-3 is associated with proteinuria and renal dysfunction, but its role has never been confirmed with kidney biopsy results. In our study, we aimed to explore the expression of Gal-3 in biopsy-proven patients, and we tested the hypothesis that chronic kidney disease (CKD) leads to upregulation of plasma Gal-3 expression in corresponding biopsy findings and RNA sequencing analysis.Method: In 249 patients (male/female: 155/94, age: 57.2 ± 16.3 years) who underwent kidney biopsy, plasma levels of Gal-3 were measured to estimate the association of renal fibrosis. Relationships between plasma Gal-3 levels, estimated glomerular filtration rate (eGFR) and renal histology findings were also assessed. We further examined the gene expression of Gal-3 in RNA-sequencing analysis in biopsy-proven patients.Results: Compared to patients without CKD, CKD patients had higher levels of plasma Gal-3 (1,016.3 ± 628.1 pg/mL vs. 811.6 ± 369.6 pg/ml; P = 0.010). Plasma Gal-3 was inversely correlated with eGFR (P = 0.005) but not with proteinuria. Higher Gal-3 levels were associated with interstitial fibrosis, tubular atrophy and vascular intimal fibrosis. RNA-sequencing analysis showed the upregulation of Gal-3 in fibrotic kidney biopsy samples, and the differentially expressed genes were mainly enhanced in immune cell activation and the regulation of cell-cell adhesion.Conclusions: Plasma Gal-3 levels are inverse correlated with eGFR but positively correlated with renal fibrosis, which may be involved in the immune response and associated pathways. These findings support the role of Gal-3 as a predictive marker of renal fibrosis.


2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Helene Lazareth ◽  
Nicolas Delanoy ◽  
COHEN Raphaël ◽  
Emilie Boissier ◽  
KARRAS Alexandre ◽  
...  

Abstract Background and Aims Inhibitors of poly-ADP-ribose-polymerase-1 (PARP) are prescribed for the treatment of metastatic breast and ovarian cancers. Clinical data trials suggest that niraparib may not have adverse effects on the kidney. Method We present a descriptive case series of renal function parameters of all the patients who received niraparib for maintenance treatment of recurrent ovarian cancer in a tertiary care center. Twenty patients received niraparib for the first time between april 2018 and march 2019 in the Georges Pompidou European Hospital, Paris, France. Four patients were excluded from the analysis because of lack of repeated serum creatinine (Scr) measurements during the first 4 months following niraparib introduction. Results The patients ranged in age from 51 to 82 years. All patients were women with high grade serous ovarian carcinoma. Personal medical history of hypertension was present in 68% and diabetes in 18% of patients. All patients received carboplatin and 90% received bevacizumab as maintenance treatment after first-line chemotherapy. Niraparib was introduced on average 3 years (range 2 to 9 years) after the diagnosis of cancer, at a dosage of 200 mg/day in all patients. The median Scr at baseline was 84 μmol/l (range 62 to 114 µmol/l). All patients experienced an increase in Scr level over the 3 months following niraparib introduction. The average max Scr increase was 1.35 times baseline (median Scr 117µmol/l, range 88 to 155 µmol/l, p&lt;0.0001 compared to baseline values), and 3 patients (18%) developed stage 1 KDIGO Acute Kidney Injury/Disease (Scr increase &gt; 1.5-2 fold baseline). None of the cases had biochemical signs of tubular or glomerular injury. Urinary creatinine clearance was higher than urinary clearance of 51Cr-EDTA, making interaction with tubular creatinine secretion unlikely. Kidney biopsy was performed in one patient who developed albuminuria. Microscopic examination identified mild tubular atrophy and interstitial fibrosis without inflammatory lesion Immunofluorescence analysis did not show immune deposits. Mesangiolysis was found in some glomeruli, typical of bevacizumab effects. Niraparib was interrupted in all but 1 patient (95%), because of haematological toxicity (n=7), tumoral progression (n=7) or gastro-intestinal toxicity (n=1). Average Scr level returned to baseline (82 µmol/l, range 62 to 107 µmol/l) over the 2 months following discontinuation. Conclusion Niraparib is associated with a systematic and significant increase in Scr (+35%) without obvious sign of tubular or glomerular injury. Renal dysfunction is mainly reversible after discontinuation. Decline of renal function under treatment may not be an incentive to stop treatment automatically. Physicians prescribing this agent should be aware of this complication.


1992 ◽  
Vol 2 (10) ◽  
pp. S206
Author(s):  
L G Fine ◽  
J T Norman

Knowledge of the control of cell growth and extracellular matrix deposition has assumed center stage in the understanding of how the diseased kidney responds to injury. After acute tubular injury, there may be reversible, partial depolarization of renal cells or cell necrosis. The latter requires a regenerative response, which could be under the control of growth factors such as epidermal growth factor (EGF). Up-regulation of EGF receptors on viable cells provides the cell with an enhanced growth response despite a reduction in EGF production by the kidney. Acute glomerular injury involves a highly complex network of cytokines and growth inhibitors, the most important of which appear to be platelet-derived growth factor as a mitogen and transforming growth factor beta as an activator of extracellular matrix deposition. The long-term growth responses of the kidney to injury, reflected by chronic renal diseases, include tubular hypertrophy in those nephrons which are less affected by the primary disease. Tubular cell enlargement appears to proceed along a pathway that is different from the growth in cell size which precedes cell division, at least as indicated by a fundamentally different pattern of early gene expression. This pattern is not suggestive of a classical growth factor-initiated process. Other chronic changes that seem to correlate well with the progression of human disease are tubular atrophy and interstitial fibrosis. Growth factors produced by tubular cells may cause proliferation and matrix deposition by adjacent interstitial fibroblasts. A scheme is proposed in which low-grade ischemic injury to tubular cells, secondary to microvascular injury, leads to tubular atrophy, the release of growth factors, interstitial fibrosis, and the obliteration of peritubular capillaries. This would aggravate primary glomerular injury by compromising the vascular outflow from the glomerulus and would account for the long-recognized association between tubulo-interstitial injury and the progression of a variety of renal diseases. The use of growth factors to stimulate specific growth responses, antibodies, or inhibitory molecules to inhibit scarring generated by cytokines and the potential for genetic manipulation of the kidney provide future avenues for manipulating the growth response of the diseased kidney.


Author(s):  
Johannes Philipp Kläger ◽  
Ahmad Al-Taleb ◽  
Mladen Pavlovic ◽  
Andrea Haitel ◽  
Eva Comperat ◽  
...  

Abstract Background Nephrectomy is the management of choice for the treatment of renal tumors. Surgical pathologists primarily focus on tumor diagnosis and investigations relating to prognosis or therapy. Pathological changes in non-neoplastic tissue may, however, be relevant for further management and should be thoroughly assessed. Methods Here, we examined the non-neoplastic renal parenchyma in 206 tumor nephrectomy specimens for the presence of glomerular, tubulo-interstitial, or vascular lesions, and correlated them with clinical parameters and outcome of renal function. Results We analyzed 188 malignant and 18 benign or pseudo-tumorous lesions. The most common tumor type was clear cell renal cell carcinoma (CCRCC, n = 106) followed by papillary or urothelial carcinomas (n = 25). Renal pathology examination revealed the presence of kidney disease in 39 cases (18.9%). Glomerulonephritis was found in 15 cases (7.3%), and the most frequent was IgA nephropathy (n = 6; 2.9%). Vasculitis was found in two cases (0.9%). In 15 cases we found tubulo-interstitial nephritis, and in 9 severe diabetic or hypertensive nephropathy. Partial nephrectomy was not linked to better eGFR at follow-up. Age, vascular nephropathy, glomerular scarring and interstitial fibrosis were the leading independent negative factors influencing eGFR at time of surgery, whereas proteinuria was associated with reduced eGFR at 1 year. Conclusion Our large study population indicates a high incidence of renal diseases potentially relevant for the postoperative management of patients with renal neoplasia. Consistent and systematic reporting of non-neoplastic renal pathology in tumor nephrectomy specimens should therefore be mandatory.


2021 ◽  
pp. 239936932110319
Author(s):  
Yihe Yang ◽  
Zachary Kozel ◽  
Purva Sharma ◽  
Oksana Yaskiv ◽  
Jose Torres ◽  
...  

Introduction: The prevalence of chronic kidney disease (CKD) is high among kidney neoplasm patients because of the overlapping risk factors. Our purpose is to identify kidney cancer survivors with higher CKD risk. Methods: We studied a retrospective cohort of 361 kidney tumor patients with partial or radical nephrectomy. Linear mixed model was performed. Results: Of patients with follow-up >3 months, 84% were identified retrospectively to fulfill criteria for CKD diagnosis, although CKD was documented in only 15%. Urinalysis was performed in 205 (57%) patients at the time of nephrectomy. Multivariate analysis showed interstitial fibrosis and tubular atrophy (IFTA) >25% ( p = 0.005), severe arteriolar sclerosis ( p = 0.013), female gender ( p = 0.024), older age ( p = 0.012), BMI ⩾ 25 kg/m2 ( p < 0.001), documented CKD ( p < 0.001), baseline eGFR ⩽ 60 ml/min/1.73 m2 ( p < 0.001), and radical nephrectomy ( p < 0.001) were independent risk factors of lower eGFR at baseline and during follow-up. Average eGFR decreased within 3 months post nephrectomy. However, patients with different risk levels showed different eGFR time trend pattern at longer follow-ups. Multivariate analysis of time × risk factor interaction showed BMI, radical nephrectomy and baseline eGFR had time-dependent impact. BMI ⩾ 25 kg/m2 and radical nephrectomy were associated with steeper eGFR decrease slope. In baseline eGFR > 90 ml/min/1.73 m2 group, eGFR rebounded to pre-nephrectomy levels during extended follow-up. In partial nephrectomy patients with baseline eGFR ⩾ 90 ml/min/1.73 m2 ( n = 61), proteinuria ( p < 0.001) and BMI ( p < 0.001) were independent risk factors of decreased eGFR during follow up. Conclusions: As have been suggested by others and confirmed by our study, proteinuria and CKD are greatly under-recognized. Although self-evident as a minimum workup for nephrectomy patients to include SCr, eGFR, urinalysis, and proteinuria, the need for uniform applications of this practice should be reinforced. Non-neoplastic histology evaluation is valuable and should include an estimate of global sclerosis% (GS) and IFTA%. Patients with any proteinuria and/or eGFR ⩽ 60 at the time of nephrectomy or in follow-up with urologists, and/or >25% GS or IFTA, should be referred for early nephrology consultation.


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