Piyanuch Radinahamed

Renal Phosphate Loss in Long-Term Kidney Transplantation

BACKGROUND AND OBJECTIVES Renal phosphate wasting occurs early postkidney transplantation as a result of an accumulation of parathyroid hormone and fibroblast growth factor 23 from the CKD period. Serum phosphate, parathyroid hormone, and fibroblast growth factor 23 return to baseline 1 year postkidney transplantation. What happens beyond this period is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Mineral parameters were obtained from 229 kidney transplant recipients at least 1 year posttransplantation; 46 normal subjects and 202 CKD patients with similar GFR served as controls. Factors associated with phosphate metabolism were analyzed. RESULTS Despite the reduced graft function, most kidney transplant recipients had lower serum phosphate than normal subjects accompanied by renal phosphate loss. Fibroblast growth factor 23 was mostly lower or comparable with normal subjects, whereas parathyroid hormone was elevated in most patients. Hyperparathyroidism is also more common among kidney transplant recipients compared with CKD patients. Both parathyroid hormone and fibroblast growth factor 23 showed relationships with renal phosphate excretion, but only parathyroid hormone displayed an independent association. Parathyroid hormone showed the highest area under the curve in predicting renal phosphate leak. When patients were categorized according to parathyroid hormone and fibroblast growth factor 23 levels, only subset of patients with high parathyroid hormone had an increased renal phosphate excretion. CONCLUSIONS Relatively low serum phosphate from renal phosphate leak continued to present in long-term kidney transplantation. Both parathyroid hormone and fibroblast growth factor 23 participated in renal tubular phosphate handling, but persistent hyperparathyroidism seemed to have a greater influence in this setting.

Urine Epidermal Growth Factor, Monocyte Chemoattractant Protein-1 or Their Ratio as Biomarkers for Interstitial Fibrosis and Tubular Atrophy in Primary Glomerulonephritis

Background/Aims: The degree of tubular atrophy and interstitial fibrosis (IFTA) is an important prognostic factor in glomerulonephritis. Imbalance between pro-inflammatory cytokines such as monocyte chemoattractant protein- 1 (MCP-1) and protective cytokines such as epidermal growth factor (EGF) likely determine IFTA severity. In separate studies, elevated MCP-1 and decreased EGF have been shown to be associated with IFTA severity. In this study, we aim to evaluate the predictive value of urinary EGF/MCP-1 ratio compared to each biomarker individually for moderate to severe IFTA in primary glomerulonephritis (GN). Methods: Urine samples were collected at biopsy from primary GN (IgA nephropathy, focal and segmental glomerulosclerosis, minimal change disease, membranous nephropathy). MCP-1 and EGF were analyzed by enzyme-linked immunosorbent assay. Results: EGF, MCP-1 and EGF/MCP-1 ratio from primary GN, all correlated with IFTA (n=58). By univariate analysis, glomerular filtration rate, EGF, and EGF/MCP-1 ratio were associated with IFTA. By multivariate analysis, only EGF/MCP-1 ratio was independently associated with IFTA. EGF/MCP-1 ratio had a sensitivity of 88% and specificity of 74 % for IFTA. EGF/MCP-1 had good discrimination for IFTA (AUC=0.85), but the improvement over EGF alone was not significant. Conclusion: EGF/MCP-1 ratio is independently associated IFTA severity in primary glomerulonephritis, but the ability of EGF/MCP-1 ratio to discriminate moderate to severe IFTA may not be much better than EGF alone.

Metabolic acidosis lowers circulating adiponectin through inhibition of adiponectin gene transcription

BACKGROUND Metabolic acidosis (MA) adversely affects protein and lipid metabolism as well as endocrine function. Adipose tissue communicates with the rest of the body through synthesis and release adipokines, such as leptin, adiponectin and TNF-alpha. Adiponectin enhances insulin sensitivity and possesses anti-atherogenic and anti-inflammatory properties. Circulating adiponectin correlates inversely with cardiovascular events. It is possible that MA negatively regulates adiponectin contributing to poor patient outcome. The present study investigates the effect of MA on adiponectin in vivo and in vitro. METHODS Twenty healthy female volunteers underwent a 7-day course of oral ammonium chloride (NH4Cl)-induced acidosis. Serum adiponectin was determined before and after NH4Cl ingestion. Adipocytes were differentiated from their precursors, human mesenchymal stem cells (hMSCs), in culture. Concentrated HCl was added to the media to lower pH. Adiponectin mRNA and protein were determined at 48 and 96 h by real-time RT-PCR and ELISA, respectively. RESULTS After a 7-day course of NH4Cl, serum bicarbonate decreased significantly associated with the increase in urine ammonium and titratable acid. Adiponectin decreased significantly from 10,623 to 9723 pg/mL (P<0.005). MA suppressed adiponectin mRNA in hMSC-derived adipocytes at 48 and 96 h (P<0.01). The amount of adiponectin released into the culture media declined corresponding to the mRNA levels (P<0.001). MA did not affect adipocyte triglyceride or protein content. CONCLUSIONS MA lowered circulating adiponectin through inhibition of adiponectin gene transcription in adipocytes.

Increased urine transforming growth factor β1 (TGF-β1) and serum uric acid are associated with an early decline of glomerular filtration rate in kidney transplant recipients.

BACKGROUND The renin-angiotensin system (RAS) and transforming growth factor β1 (TGF-β1) may play a role in the pathogenesis of fibrosis in kidney allografts. Experimental hyperuricemia shows activation of intrarenal RAS. However, the association between uric acid (UA), RAS, and TGF-β1 in allograft recipients has not been demonstrated. Therefore we investigated the association between serum UA levels, RAS, and TGF-β1 in kidney transplant recipients during the 1st year after transplantation. METHODS Sixty-two transplant recipients were included in the study. Serum UA level, plasma renin activity (PRA), and urine TGF-β1 concentration were studied at 3, 6, and 12 months after transplantation. Statistical correlation was demonstrated with the use of Spearman rank correlation coefficient. Receiver operating characteristic curve analysis and area under the curve were performed to assess the diagnostic performance to discriminate between estimated glomerular filtration rate (eGFR) <60 and ≥ 60 mL/min/1.73 m(2). RESULTS For all 62 patients, urine TGF-β1 and serum UA had a tendency to increase during the 1-year follow-up period, despite no statistically significant change in eGFR. We found that increased urine TGF-β1 was correlated with rising serum UA levels and a decrease of the eGFR (r = 0.27 [P = .01]; r = -0.38 [P = .0003]). In contrast, there was no significant change in PRA and it was not correlated with eGFR or TGF-β1 (r = -0.01; P = .93). CONCLUSIONS Increased urine TGF-β1 and serum UA level during the 1st year after transplantation correlated with a decline in eGFR. The evaluation of these parameters in the early post-transplantation period may identify patients at risk of allograft dysfunction.

Independent associations of urine neutrophil gelatinase–associated lipocalin and serum uric acid with interstitial fibrosis and tubular atrophy in primary glomerulonephritis

The degree of interstitial fibrosis and tubular atrophy (IFTA) is one of the strongest prognostic factors in glomerulonephritis (GN). In experimental models, high serum uric acid (UA) could contribute to IFTA through direct effects on the renal tubules, but the significance of this process has not been evaluated in patients. Urine neutrophil gelatinase–associated lipocalin (NGAL) is produced by renal tubules following acute or chronic damage. We investigated the relationship between UA and NGAL excretion in primary GN and tested whether these biomarkers are independently associated with IFTA. Urine and blood were collected from patients on the day of kidney biopsy. IFTA was assessed semi-quantitatively. Fifty-one patients with primary GN were enrolled. NGAL/creatinine correlated significantly with proteinuria but not with glomerular filtration rate (GFR). By contrast, UA correlated with GFR but not with proteinuria. NGAL/creatinine did not correlate with UA. Both NGAL/creatinine and UA increased with the severity of IFTA. By multivariate analysis, GFR, NGAL/creatinine, and UA were independently associated with moderate-to-severe IFTA. Combining UA and NGAL/creatinine with classical predictors (proteinuria and GFR) tended to improve discrimination for moderate-to-severe IFTA. Findings that UA was unrelated to urinary NGAL excretion suggest that the two biomarkers reflect different pathways related to the development of IFTA in primary GN. Both NGAL/creatinine and UA were independently associated with moderate-to-severe IFTA.

Urine epidermal growth factor, monocyte chemoattractant protein-1 or their ratio as predictors of complete remission in primary glomerulonephritis

Background: The balance of several cytokines likely influences the resolution of glomerulonephritis. Monocyte chemoattractant protein‐1(MCP‐1) is a chemokine that promotes renal inflammation whereas epidermal growth factor (EGF) stimulates protective responses. Previously, high urine MCP‐1(MCP‐1) and low urine EGF (EGF) levels were found to be associated with tubulointerstitial fibrosis, but there is limited information on the value of these mediators as predictors of therapeutic responses or long term outcome in primary glomerulonephritis. Objectives: To determine the performance of urine EGF, MCP‐1 or their ratio at baseline as biomarkers to predict complete remission, and the relationship of these mediators with subsequent renal function 24months later in primary glomerulonephritis. Methods: This is a prospective study of patients with biopsy‐proven primary glomerulonephritis. Baseline urine samples were collected at biopsy before therapy. MCP‐1 and EGF were analyzed by enzyme‐linked immunosorbent assays and expressed as a ratio to urine creatinine (ng/mgCr) or as EGF/MCP‐1 ratio (ng/ng). Proteinuria and estimated glomerular filtration rate (eGRF) were monitored after therapy. Complete remission (CR) was defined as proteinuria≤0.3g/gCr. Results: Median follow‐up was 20months. Of all patients (n=74), 38 patients (51.4%) subsequently achieved CR. Baseline urine EGF and EGF/MCP‐1 levels were significantly higher in CR compared to Not CR. By contrast, MCP‐1 was not different. High EGF (EGF>75ng/mgCr) was a significant predictor (OR 2.28) for CR by multivariate analysis after adjusting for proteinuria, blood pressure, baseline eGFR. In patients who completed 24months follow‐up (n=43), baseline EGF correlated inversely with proteinuria and positively with eGFR at 24months. Conclusion: High urine EGF level is a promising biomarker of CR. Baseline EGF levels correlated with kidney function at 2years. EGF/MCP‐1 was not superior to EGF alone. Further studies are necessary to determine the role of urine EGF as a guide to therapy in primary GN. HIGHLIGHTSUrine cytokines were assessed for ability to predict outcome in glomerulonephritis.High epidermal growth factor was a significant predictor of complete remission.Baseline epidermal growth factor correlated with kidney function at 24months.Levels of monocyte chemoattractant protein‐1 levels did not add useful information.

Urinary epidermal growth factor, monocyte chemoattractant protein-1 or their ratio as predictors for rapid loss of renal function in type 2 diabetic patients with diabetic kidney disease

BackgroundIncreased monocyte chemoattractant protein-1 (MCP-1) and decreased epidermal growth factor (EGF) are promising biomarkers to predict progressive decline in kidney function in non-diabetic kidney diseases. We aimed to evaluate the performance of urinary EGF, MCP-1 or their ratio in predicting rapid decline of GFR in a cohort of Type 2 diabetic patients (T2DM) with diabetic kidney disease (DKD).MethodsT2DM patients (n = 83) with DKD at high risk for renal progression were followed up prospectively. The baseline urine values of MCP-1 to creatinine ratio (UMCP-1), EGF to creatinine ratio (UEGF), EGF to MCP-1 ratio (UEGF/MCP-1) and albumin to creatinine ratio (UACR) were measured. The primary outcome was a decline in estimated glomerular filtration rate (GFR) of ≥25% yearly from baseline.ResultsDuring follow-up time of 23 months, patients with rapid decline in estimated GFR of ≥25% yearly from baseline had significantly higher baseline levels of UMCP-1, and UACR and lower UEGF and UEGF/MCP-1 ratio. All renal biomarkers predicted primary outcomes with ROC (95%CI) for UMCP-1=0.73 (0.62-0.84), UEGF=0.68 (0.57-0.80), UEGF/MCP-1=0.74 (0.63-0.85), and UACR =0.84 (0.75-0.93). By univariate analysis, blood pressure, GFR, UACR, UMCP-1, UEGF, and UEGF/MCP-1 were associated with rapid decline GFR. By multivariate analysis, UACR, systolic blood pressure, and UMCP-1 or UEGF/MCP-1 were independently associated with rapid GFR decline.ConclusionsUMCP-1 or UEGF/MCP-1 ratio were associated with rapid renal progression independent from conventional risk factors in DKD.

Propylthiouracil-associated rapidly progressive crescentic glomerulonephritis with double positive anti-glomerular basement membrane and antineutrophil cytoplasmic antibody: the first case report

We report a case of propylthiouracil (PTU)-induced double antineutrophil cytoplasmic antibody (ANCA) and anti-glomerular basement membrane antibody (anti-GBM antibody) disease causing pulmonary-renal syndrome in a 35-year-old Thai woman with 10-year history of PTU treatment for thyrotoxicosis. She developed clinical symptoms of vasculitis upon receiving long-term PTU treatment. Prednisolone treatment and the switching from PTU to methimazole resulted to short-term clinical improvement. Nevertheless following termination of steroid treatment, she developed recurrent pulmonary hemorrhage and rapidly progressive glomerulonephritis. The kidney biopsy showed crescentic glomerulonephritis with linear IgG deposit on the glomerular basement membrane although transbronchial lung biopsy showed no immune deposit along the alveolar basement membrane. Serum testing for p-ANCA was positive and western blot showed positive antibody to the alpha-3 chain of collagen type IV. Both ANCA and anti-GBM antibody may play a role in the development of end organ damage. To facilitate early and specific intervention, clinicians should be aware of the propensity of PTU to cause lupus-like syndromes with renal involvement. In patients with PTU-induced ANCA-associated glomerulonephritis, serum anti-GBM antibody test may be useful in the early diagnosis of double positive antibodies disease and plasmapheresis should be performed without delay.