Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease.

Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney cysts, often resulting in end-stage renal disease (ESRD). This disorder is genetically heterogeneous with ∼7% of families genetically unresolved. We performed whole-exome sequencing (WES) in two multiplex ADPKD-like pedigrees, and we analyzed a further 591 genetically unresolved, phenotypically similar families by targeted next-generation sequencing of 65 candidate genes. WES identified a DNAJB11 missense variant (p.Pro54Arg) in two family members presenting with non-enlarged polycystic kidneys and a frameshifting change (c.166_167insTT) in a second family with small renal and liver cysts. DNAJB11 is a co-factor of BiP, a key chaperone in the endoplasmic reticulum controlling folding, trafficking, and degradation of secreted and membrane proteins. Five additional multigenerational families carrying DNAJB11 mutations were identified by the targeted analysis. The clinical phenotype was consistent in the 23 affected members, with non-enlarged cystic kidneys that often evolved to kidney atrophy; 7 subjects reached ESRD from 59 to 89 years. The lack of kidney enlargement, histologically evident interstitial fibrosis in non-cystic parenchyma, and recurring episodes of gout (one family) suggested partial phenotypic overlap with autosomal-dominant tubulointerstitial diseases (ADTKD). Characterization of DNAJB11-null cells and kidney samples from affected individuals revealed a pathogenesis associated with maturation and trafficking defects involving the ADPKD protein, PC1, and ADTKD proteins, such as UMOD. DNAJB11-associated disease is a phenotypic hybrid of ADPKD and ADTKD, characterized by normal-sized cystic kidneys and progressive interstitial fibrosis resulting in late-onset ESRD.

Serum IL-18 is closely associated with renal tubulointerstitial injury and predicts renal prognosis in IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) was thought to be benign but recently found it slowly progresses and leads to ESRD eventually. The aim of this research is to investigate the value of serum IL-18 level, a sensitive biomarker for proximal tubule injury, for assessing the histopathological severity and disease progression in IgAN. METHODS: Serum IL-18 levels in 76 IgAN patients and 36 healthy blood donors were measured by ELISA. We evaluated percentage of global and segmental sclerosis (GSS) and extent of tubulointerstitial damage (TID). The correlations between serum IL-18 levels with clinical, histopathological features and renal prognosis were evaluated. RESULTS: The patients were 38.85 ± 10.95 years old, presented with 2.61 (1.43∼4.08) g/day proteinuria. Serum IL-18 levels were significantly elevated in IgAN patients. Baseline serum IL-18 levels were significantly correlated with urinary protein excretion (r = 0.494, P = 0.002), Scr (r = 0.61, P < 0.001), and eGFR (r = -0.598, P < 0.001). TID scores showed a borderline significance with serum IL-18 levels (r = 0.355, P = 0.05). During follow-up, 26 patients (34.21%) had a declined renal function. Kaplan-Meier analysis found those patients with elevated IL-18 had a significant poor renal outcome (P = 0.03), and Cox analysis further confirmed that serum IL-18 levels were an independent predictor of renal prognosis (ß = 1.98, P = 0.003).

Change in cardiovascular disease status in peritoneal dialysis patients: a 5-year single-center experience.

BACKGROUND: We compared patient characteristics, atherosclerosis, left ventricular hypertrophy, and dialysis practice patterns of peritoneal dialysis (PD) patients with change in cardiovascular disease (CVD) status and no change in CVD status in Chinese PD center. METHODS: This study included all patients who started on PD between 1 January 2003 and 30 June 2009 at the Renji Hospital, Shanghai Jiaotong University School of Medicine, China. They were followed up from the date of PD initiation until new-onset CVD. RESULTS: The median follow-up time was 44.13 months. In patients with preexisting CVD, both high triglyceride (1.43 ± 0.89 mmol/L vs. 2.64 ± 1.58 mmol/L, p < 0.001) and the duration of dialysis (45.76 ± 13.28 months vs. 58.68 ± 13.74 months, p < 0.01) were independent predictors of CVD progression and the left atrial dimension, left ventricle septal thickness, left ventricle mass index (LVMI), and intima-media thickness (IMT) also had the difference. On the other hand, in patients without preexisting CVD, the dialysis adequacy and nutritional status are important during the follow-up. Serum albumin in CVD group was lower than in no CVD group (30.86 ± 4.77 g/L vs. 36.04 ± 6.40 g/L, p < 0.05). Creatinine clearance (CCr) and Kt/V in CVD group were lower than in no CVD group (CCr 57.24 ± 13.86 L/week vs. 71.06 ± 23.96 L/week, p < 0.05; Kt/V 1.82 ± 0.41 vs. 2.23 ± 0.57, p < 0.05). CONCLUSION: In patients with preexisting CVD, it is important to address traditional risk factors such as LVMI, IMT, and lipid profile. In patients without preexisting CVD, we should pay more attention to the nutritional status and PD prescription in order to lower the morbidity of CVD in these PD patients.

High-sensitivity C-reactive protein: an independent risk factor for left ventricular hypertrophy in patients with lupus nephritis.

OBJECTIVE: To determine the prevalence of left ventricular hypertrophy (LVH) and its associated risk factors in lupus nephritis (LN) patients. METHODS: 287 LN patients (age: 38.54 ± 13.31, 262 female) were recruited. Echocardiography and serum high-sensitivity C-reactive protein (hs-CRP) were measured. Their relationship was evaluated by univariate correlation analysis and multivariate regression analysis. RESULTS: The prevalence of LVH in this cohort was 21.25% (n = 61). Serum hs-CRP level was significantly elevated in patients with LVH compared to those without (8.03 (3.22-30.95) versus 3.93 (1.48-9.48) mg/L, P < .01), and correlated with left ventricular mass index (LVMI) (r = 0.314, P = .001). Multivariate regression analysis further confirmed that hs-CRP was an independent risk factor (ß = 0.338, P = .002) for LVH in patients with LN. CONCLUSIONS: Our findings demonstrated that serum hs-CRP level is independently correlated with LVMI and suggested that measurement of hs-CRP may provide important clinical information to investigate LVH in LN patients.

Hepatocyte growth factor ameliorates progression of interstitial injuries in tubular epithelial cells.

OBJECTIVE: Hepatocyte growth factor (HGF) and its c-met receptor comprise a signalling system that has been reported to prevent injury in several models of renal disease; however, whether HGF can also retard progression of chronic kidney disease is not known. The aim of the present study was to examine the effects of HGF on progression of chronic kidney disease in tubular epithelial cells. MATERIAL AND METHODS: Studies were performed in human tubular epithelial cells that underwent different glucose concentrations, and then receive HGF or vehicle. The cell apoptosis was tested by DAPI and TUNEL staining. The level of activity of HGF was examined at multiple time-points. The expression of HGF, transforming growth factor-beta(1) (TGF-beta(1)), plasminogen activator inhibitor-1 (PAI-1) and collagen IV were examined by reverse transcription-polymerase chain reaction, Western blot and enzyme-linked immunosorbent assay. RESULTS: HGF administration was associated with a reduction in TGF-beta(1). The beneficial effects of HGF were associated with reductions in the expression of TGF-beta(1), and in the extent of epithelial cell apoptosis. HGF appeared to induce fibrinolytic pathways by reducing the expression of collagen IV and decreasing levels of PAI-1. CONCLUSIONS: These findings suggest that HGF can retard progression of diabetic nephropathy, primarily by promoting matrix degradation, and that HGF is a potent antifibrogenic factor.

Prognostic Performance of Kidney Volume Measurement for Polycystic Kidney Disease: A Comparative Study of Ellipsoid vs. Manual Segmentation.

Total kidney volume (TKV) is a validated prognostic biomarker for risk assessment in autosomal dominant polycystic kidney disease (ADPKD). TKV by manual segmentation (MS) is the "gold standard" but is time-consuming and requires expertise. The purpose of this study was to compare TKV-based prognostic performance by ellipsoid (EL) vs. MS in a large cohort of patients. Cross-sectional study of 308 patients seen at a tertiary referral center; all had a standardized MRI with typical imaging of ADPKD. An experienced radiologist blinded to patient clinical results performed all TKV measurements by EL and MS. We assessed the agreement of TKV measurements by intraclass correlation(ICC) and Bland-Altman plot and also how the disagreement of the two methods impact the prognostic performance of the Mayo Clinic Imaging Classification (MCIC). We found a high ICC of TKV measurements (0.991, p < 0.001) between EL vs. MS; however, 5.5% of the cases displayed disagreement of TKV measurements >20%. We also found a high degree of agreement of the individual MCIC risk classes (i.e. 1A to 1E) with a Cohen's weighted-kappa of 0.89; but 42 cases (13.6%) were misclassified by EL with no misclassification spanning more than one risk class. The sensitivity and specificity of EL in distinguishing low-risk (1A-B) from high-risk (1C-E) MCIC prognostic grouping were 96.6% and 96.1%, respectively. Overall, we found an excellent agreement of TKV-based risk assessment between EL and MS. However, caution is warranted for patients with MCIC 1B and 1C, as misclassification can have therapeutic consequence.

Foam Sclerotherapy for Cyst Volume Reduction in Autosomal Dominant Polycystic Kidney Disease: A Prospective Cohort Study.

RATIONALE & OBJECTIVE: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder. Progressive increase in cyst number and size leads to kidney failure in a majority of patients. Large kidney cysts, although few, can be especially deleterious by impeding kidney blood flow and obstructing urine flow over a large region. Foam sclerotherapy is a minimally invasive procedure that may be used to ablate large cysts. We examined the effectiveness and safety of foam sclerotherapy for kidney volume reduction in patients with ADPKD. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Adults with ADPKD at a tertiary referral center in Toronto. PREDICTOR: Foam sclerotherapy. OUTCOMES: Volume of treated kidneys and adverse events. ANALYTICAL APPROACH: Treated and nontreated kidney volume, kidney function, tolerability, and symptoms were analyzed within each patient. RESULTS: We performed 77 foam sclerotherapy treatment sessions in 66 patients. Foam sclerotherapy was associated with a 21.8% volume reduction of the treated kidneys (n = 95; median, 1,138 [IQR, 801-1,582] mL before vs 891 [IQR, 548-1,450] mL after; P < 0.001), while the volume of the nontreated kidneys increased by 3.4% during the same time frame (n = 37; median, 655 [IQR, 352-998] mL before vs 677 [IQR, 371-1,164] mL after; P < 0.001). 4 (6%) patients had a higher measured creatinine clearance by at least 10 mL/min at least 12 months after foam sclerotherapy. 9 (14%) patients experienced self-limiting pain at the procedure site and 2 (3%) had cyst or urinary tract infection. Most patients with flank/back pain, abdominal pain, and abdominal distension had improvement in their symptoms. LIMITATIONS: Small sample, observational data. CONCLUSIONS: Foam sclerotherapy is a safe and effective procedure for kidney volume reduction and amelioration of compressive symptoms in select patients with ADPKD. Further studies are needed to assess its effects on kidney blood flow and kidney function and determine the subgroups of patients most likely to benefit.

Identification of mannose-binding lectin as a mechanism in progressive immunoglobulin A nephropathy.

Immunoglobulin A nephropathy (IgAN), the pathogenesis of which remained still unclear is one of the leading courses of end-stage renal disease in approximately 50% affected patients. On the basis of several researches, the activation of complement mannose-binding lectin (MBL) pathway might be the underlying mechanism in disease progress. In order to investigate the relationship between MBL pathway and IgAN, we discussed the MBL gene polymorphism as well as its expressed level in serum, urine and renal parenchymal, with renal outcome in IgAN patients. The significantly down-regulated expression of MBL was discovered, which may serve as a potential urinary biomarker in progressive IgAN according to the results of difference in gel electrophoresis and matrix-assisted laser desorption/ionization time of flight mass spectrometry. The single nucleotide polymorphisms of MBL gene in promoter and exon region were found and confirmed relating with the poor prognosis of progressive IgAN patients. As a result, the deficient activation of MBL pathway caused by the mutation of MBL accompanied with low expressed level of MBL in serum might be the potential inspiring regulation in IgAN, and will attract a promising insight in remedy of IgAN to inhibit further progress.

Urinary excretion of liver-type fatty acid-binding protein as a marker of progressive kidney function deterioration in patients with chronic glomerulonephritis.

BACKGROUND: To evaluate the value of basal urinary L-FABP (uL-FABP) excretion as a prognostic indicator of the progression of kidney function impairment in patients with chronic glomerulonephritis (CGN). METHODS: One hundred twenty-three patients with newly diagnosed, biopsy-proven primary CGN were included. In all patients, and in 28 healthy subjects, uL-FABP was measured using an ELISA. Risk factors of the progression of kidney function were evaluated. The patients were in follow-up for at least 5 years. RESULTS: uL-FABP in the patients with CGN (76.58±17.3 µg/g.cr) was greater than in the healthy subjects. A significant positive correlation between uL-FABP and proteinuria (R=0.501, P<0.01), serum creatinine (R=0.601, P<0.01) were found. Kaplan-Meier analysis revealed that uL-FABP >76.58 µg/g.cr predicts progression of renal function. The cut off values for L-FABP at 119.8 µg/g.cr was found to be more sensitive, area under the curve (AUC) was 0.95. CONCLUSION: Urinary L-FABP may be a useful clinical biomarker for monitoring chronic glomerular disease. Urinary L-FABP can help predict the progression of chronic glomerular disease.

Brain natriuretic peptide is related to carotid plaques and predicts atherosclerosis in pre-dialysis patients with chronic kidney disease.

BACKGROUND: Although brain natriuretic peptide (BNP) concentration has been associated with atherosclerosis and ischemic cardiovascular diseases (CVD) in the general population, less is known about this relationship in pre-dialysis chronic kidney disease (CKD) patients. METHODS: We prospectively analyzed 227 pre-dialysis patients with CKD [median estimated glomerular filtration rate (eGFR): 28.82 (11.65-48.20) ml/min/1.73 m(2)]. At enrollment, BNP concentrations, biochemical and echocardiographic parameters were measured, and carotid artery ultrasound was performed. Patients were prospectively followed for a mean 31.8 months (range 0.5-57.0 months). Ischemic CV events and patient outcomes were recorded. RESULTS: Median BNP concentration at enrollment was significantly higher in the CKD patients than in a control group [53.9 (16.2-181.0) pg/ml vs. 9.4 (7.0-15.3) pg/ml, P<0.01]. BNP concentration was positively related with the carotid intima-media thickness of the common carotid artery (CCA-IMT) and left ventricular mass index (LVMI) and was significantly higher in patients with than without carotid plaques (P<0.01). Logistic regression analysis confirmed that lgBNP concentration was independently correlated with carotid plaques. Thirty-two patients experienced ischemic cardiovascular (ICV) events during follow-up. Kaplan-Meier analysis showed that cumulative survival without new ICV events was better in patients with lower than with higher BNP concentrations (P<0.01). Cox regression analysis showed that BNP was an independent risk factor for ICV events (HR=3.167, 95%CI=1.398-7.171, P<0.01). CONCLUSIONS: Similar to findings in the general population, elevated BNP level is related to atherosclerosis and an increased risk of ICV events in pre-dialytic CKD patients.

Circulating levels of asymmetric dimethylarginine are an independent risk factor for left ventricular hypertrophy and predict cardiovascular events in pre-dialysis patients with chronic kidney disease.

BACKGROUND: Several studies have related the circulating level of asymmetric dimethylarginine (ADMA) to cardiac remodeling and cardiovascular (CV) events in end-stage renal disease (ESRD) patients. Studies investigating this relationship in patients with pre-dialysis chronic kidney disease (CKD) are lacking. METHODS: We enrolled 76 CKD patients (age, 46.7+/-14.3 years, 39 females) and 15 controls (age, 40.1+/-18.5 years, 6 females). Clinical parameters, blood biochemistry and echocardiographic findings were recorded, and plasma ADMA concentrations measured by high-performance liquid chromatography-mass spectrometry (HPLC-MS). Patients were prospectively followed up for a median of 15 (range, 6-24) months. RESULTS: Plasma ADMA was significantly elevated in CKD patients compared with controls (41.56+/-12.76 microg/mL vs 17.12+/-7.09 microg/mL, P<0.001), and correlated with the left ventricular mass index (LVMI) (r=0.597, P<0.001). During follow-up, 25 patients experienced new CV events and their plasma ADMA level was significantly elevated (48.27+/-13.70 vs 34.91+/-6.38 in CV event-free patients, P<0.001). Cox regression analysis further confirmed that ADMA was an independent risk factor for CVD (HR=1.175, 95%CI[1.070-1.290], P=0.001). CONCLUSION: Similar to findings in ESRD patients, elevated circulating levels of ADMA may increase the risk of LVH and CV events in pre-dialysis CKD patients.

Hepatocyte growth factor suppresses transforming growth factor-beta-1 and type III collagen in human primary renal fibroblasts.

Tubulointerstitial changes in the diabetic kidney correlate closely with renal fibrosis, and transforming growth factor-beta-1 (TGF-beta1) is thought to play a key role in this process. In contrast, hepatocyte growth factor (HGF) has shown therapeutic effects on injured renal tubules in animal models. This study was undertaken to test the hypothesis that the preventive effects of HGF may result from interventions in TGF-beta1-mediated signaling and collagen III secretion. We examined the expression of HGF/HGF receptor (c-Met) and TGF-beta1 in renal fibroblasts at multiple time points. The effects of recombinant human HGF on TGF-beta1 expression were studied by RT-PCR and Western blotting, and the levels of collagen III were measured by ELISA. In the high-glucose condition, the expression of HGF and c-Met in renal fibroblasts was detected as early as 6 hours following cell culture while the level of TGF-beta1 peaked at 96 hours. The addition of recombinant human HGF to the culture media dose-dependently inhibited TGF-beta1 mRNA expression and reduced collagen III secretion by 34%. These results indicate that, during hyperglycemia, HGF inhibits TGF-beta1 signaling and type III collagen activation in interstitial fibroblasts. Furthermore, we should recognize that changes in the balance between HGF and TGF-beta1 might be decisive in the pathogenesis of chronic renal fibrosis. Therefore, administration of HGF to restore this balance may offer a novel therapeutic intervention in managing renal fibrogenesis in diabetic nephropathy.