Protocol for the nationwide registry of patients with polycystic kidney disease: japanese national registry of PKD (JRP).

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are major genetic polycystic kidney diseases that can progress to end-stage kidney disease (ESKD). Longitudinal data on the clinical characteristics associated with clinical outcomes in polycystic kidney disease (PKD), including the development of ESKD and cardiovascular disease (CVD) are lacking in Japan. To address this unmet need the authors are establishing a novel, web-based, Nationwide Cohort Registry Study-the Japanese Registry of PKD (JRP). METHODS: The JRP is a prospective cohort study for ADPKD (aim to recruit n = 1000 patients), and both a retrospective and prospective study for ARPKD (aim to recruit n = 100). In the prospective registry, patients will be followed-up for 10 years every 6 months and 12 months for patients with ADPKD and ARPKD, respectively. Data collection will be recorded on Research Electronic Data Capture (REDCap) starting on April 1, 2024, with recruitment ending on March 31, 2029. (jRCT 1030230618). RESULTS: Data to be collected include: baseline data, demographics, diagnostic and genetic information, radiological and laboratory findings, and therapeutic interventions. During follow-up, clinical events such as development of ESKD, hospitalization, occurrence of extra kidney complications including CVD events, and death will be recorded, as well as patient-reported health-related quality of life for patients with ADPKD. CONCLUSIONS: The JRP is the first nationwide registry study for patients with ADPKD and ARPKD in Japan, providing researchers with opportunities to advance knowledge and treatments for ADPKD and ARPKD, and to inform disease management and future clinical practice.

Public support for patients with intractable diseases in Japan: impact on clinical indicators from nationwide registries in patients with autosomal dominant polycystic kidney disease.

BACKGROUND: Clinical practice guidelines recommend antihypertensive and tolvaptan therapies for patients with autosomal dominant polycystic kidney disease (ADPKD) in Japan. However, tolvaptan therapy may pose an economic burden. The Japanese Ministry of Health, Labour and Welfare supports patients with intractable diseases. This study aimed to confirm the impact of the intractable disease system in Japan on the clinical treatment of ADPKD. METHODS: We analyzed the data of 3768 patients with ADPKD having a medical subsidy certificate from the Japanese Ministry of Health, Labour and Welfare in 2015-2016. The following quality indicators were use: the adherence rate to the 2014 clinical practice guideline for polycystic kidney disease (prescription rates of antihypertensive agents and tolvaptan in this cohort) and the number of Japanese patients with ADPKD nationwide started on renal replacement therapy in 2014 and 2020. RESULTS: Compared with new applications from 2015 to 2016, the prescription rates of antihypertensives and tolvaptan for the indicated patients at the 2017 renewal application increased by 2.0% (odds ratio = 1.41, p = 0.008) and 47.4% (odds ratio = 10.1, p > 0.001), respectively. These quality indicators improved with antihypertensive treatment, especially in patients with chronic kidney disease stages 1-2 (odds ratio = 1.79, p = 0.013) and in those aged < 50 years (odds ratio = 1.70, p = 0.003). The number of patients with ADPKD who were started on renal replacement therapy in Japan decreased from 999 in 2014 to 884 in 2020 in the nationwide database (odds ratio = 0.83, p < 0.001). CONCLUSIONS: The Japanese public intractable disease support system contributes to improvement of ADPKD treatment.

Factors predicting decline in renal function and kidney volume growth in autosomal dominant polycystic kidney disease: a prospective cohort study (Japanese Polycystic Kidney Disease registry: J-PKD).

BACKGROUND: Factors affecting decline in renal function and cyst growth in patients with autosomal polycystic kidney disease (ADPKD) are not fully described, particularly in Japan. METHODS: This was the first multi-facility, prospective, observational cohort study conducted in ADPKD patients at 14 centers in Japan. Patients in the J-PKD registry were assessed from December 2009 to June 2012 (follow-up until June 2017). Patients' data including estimated glomerular filtration rate (eGFR) and total kidney volume (TKV) were assessed initially and a maximum of five times annually. Contributing factors to eGFR decline and TKV growth were identified using multiple linear regression analysis. RESULTS: Of the 340 patients in the J-PKD registry, data analysis was performed for 192 patients in whom serial changes for both eGFR and TKV were obtained. eGFR slope, eGFR change, and TKV change values were as follows: - 2.7 (- 4.2 to - 1.5) (ml/min/1.73 m2/year), - 5.0 (- 9.6 to - 2.3) (%/year), and 4.78 (0.86-8.22) (%/year), respectively. Lower high-density lipoprotein (HDL) cholesterol was an independent predictor of eGFR decline, using both eGFR slope and change (P = 0.04, P = 0.02, respectively), whereas lower hemoglobin and higher uric acid were significantly associated with greater eGFR change only (P = 0.02, P = 0.002, respectively). Younger age and higher fasting blood sugar were independent predictors of greater TKV change (P = 0.01, P = 0.02, respectively). CONCLUSIONS: This real-world study in Japan identified risk factors for renal function decline in ADPKD patients. These included lower HDL cholesterol, lower hemoglobin and higher uric acid for eGFR decline, and youth and higher blood sugar levels for TKV growth.

Significance of kidney biopsy in autosomal dominant tubulointerstitial kidney disease-UMOD: is kidney biopsy truly nonspecific?

BACKGROUND: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare hereditary disease caused by a variety of genetic mutations. Carriers of a mutation in the responsible genes are at risk of reaching end-stage kidney disease typically in middle age. The frequency of this disease is assumed to be underestimated because of a lack of disease-specific signs. Pathological findings obtained from kidney of uromodulin related ADTKD (ADTKD-UMOD) patients are regarded as non-specific and less-informative for its diagnosis. This research was undertaken to evaluate the significance of kidney biopsy in ADTKD-UMOD patients. METHODS: Thirteen patients from 10 families with nine identified uromodulin (UMOD) gene mutations who underwent kidney biopsy in the past were studied. Their kidney tissues were stained with anti-UMOD antibody in addition to conventional methods such as PAS staining. When positive, the numbers of tubules with visible UMOD protein accumulations were calculated based on the total numbers of UMOD expressing tubules. Pathological findings such as tubulointerstitial fibrosis, atrophy, inflammation and glomerulosclerosis were also evaluated and analyzed. RESULTS: Interstitial fibrosis and tubular atrophy were present in all 13 patients. Most atrophic tubules with thickening and lamellation of tubular basement membranes showed negative UMOD staining. In all but two patients with C94F mutations, massive accumulation of UMOD proteins was observed in the renal endoplasmic reticulum. UMOD accumulations were also detectable by PAS staining as polymorphic unstructured materials in the 11 patients at frequencies of 2.6-53.4%. 80.4% of the UMOD accumulations were surrounded by halos. The detection rate of UMOD accumulations positively correlated with eGFR. Glomerulosclerosis was detected in 11/13 patients, with a frequency of 20.0 to 61.1%, while no cystic dilatations of glomeruli were detected. CONCLUSIONS: Massively accumulated UMOD proteins in ADTKD-UMOD kidneys are detectable not only by immunostaining using anti-UMOD antibody but also by conventional methods such as PAS staining, although their detection is not easy. These findings can provide important clues to the diagnosis of ADTKD-UMOD. Kidney biopsy in ADTKD-UMOD may be more informative than assumed previously.

Mutation analyses by next-generation sequencing and multiplex ligation-dependent probe amplification in Japanese autosomal dominant polycystic kidney disease patients.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD), one of the most common hereditary kidney diseases, causes gradual growth of cysts in the kidneys, leading to renal failure. Owing to the advanced technology of next-generation sequencing (NGS), genetic analyses of the causative genes PKD1 and PKD2 have been improved. METHODS: We performed genetic analyses of 111 Japanese ADPKD patients using hybridization-based NGS and long-range (LR)-PCR-based NGS. Additionally, genetic analyses in exon 1 of PKD1 using Sanger sequencing because of an extremely low coverage of NGS and those using multiplex ligation-dependent probe amplification (MLPA) were performed. RESULTS: The detection rate using NGS for 111 patients was 86.5%. One mutation in exon 1 of PKD1 and five deletions detected by MLPA were identified. When combined, the total detection rate was 91.9%. CONCLUSION: Although NGS is useful, we propose the addition of Sanger sequencing for exon 1 of PKD1 and MLPA as indispensable for identifying mutations not detected by NGS.

Elevation of the serum liver enzyme levels during tolvaptan treatment in patients with autosomal dominant polycystic kidney disease (ADPKD).

BACKGROUND: In 2014, tolvaptan, a vasopressin receptor antagonist, was approved for the treatment of autosomal dominant polycystic kidney disease (ADPKD) in Japan. Clinical trials of tolvaptan revealed frequent occurrence of the liver function abnormality. According to the package insert in Japan, liver function tests should be performed once a month in patients receiving tolvaptan. Furthermore, immediate discontinuation of tolvaptan is recommended in the appearance of liver function abnormalities. METHODS: Seven patients of ADPKD who was discontinued tolvaptan because of elevation of the serum liver enzyme levels were described in detail and analyzed. RESULTS: None of them fulfilled the criteria for applicability of Hy's law, which predicts a high risk of severe, potentially fatal, drug-induced liver injury (DILI). In our patients, the rate of increase of total kidney volume (TKV) significantly decreased during tolvaptan administration, but increased after discontinuation; in Cases 1-5, mean annual growth rate of TKV during administration was - 10.15%/year, and during discontinuation was + 23.72%/year. After the serum liver enzyme levels returned to normal range, tolvaptan was resumed in six patients with informed consent. Except one patient, tolvaptan has been continued without increase of the serum liver enzyme levels. CONCLUSION: In patients with mild elevation of the serum liver enzyme, as is less than three times the upper limit of normal (ULN), resumption of tolvaptan may be considered after the serum liver enzyme levels return to normal range.

Reduced Klotho expression level in kidney aggravates renal interstitial fibrosis.

Renal expression of the klotho gene is markedly suppressed in chronic kidney disease (CKD). Since renal fibrosis is the final common pathology of CKD, we tested whether decreased Klotho expression is a cause and/or a result of renal fibrosis in mice and cultured renal cell lines. We induced renal fibrosis by unilateral ureteral obstruction (UUO) in mice with reduced Klotho expression (kl/+ mice) and compared them with wild-type mice. The UUO kidneys from kl/+ mice expressed significantly higher levels of fibrosis markers such as α-smooth muscle actin (α-SMA), fibronectin, and transforming growth factor-ß(1) (TGF-ß(1)) than those from wild-type mice. In addition, in cultured renal fibroblast cells (NRK49F), the levels of α-SMA and PAI1 expression were significantly suppressed by addition of recombinant Klotho protein to the medium. The similar effects were observed by a TGF-ß(1) receptor inhibitor (ALK5 inhibitor). These observations suggest that low renal Klotho expression enhances TGF-ß(1) activity and is a cause of renal fibrosis. On the other hand, TGF-ß(1) reduced Klotho expression in renal cultured epithelial cells (inner medullary collecting duct and human renal proximal tubular epithelium), suggesting that low renal Klotho expression is a result of renal fibrosis. Taken together, renal fibrosis can trigger a deterioration spiral of Klotho expression, which may be involved in the pathophysiology of CKD progression.

Successful steroid treatment of a patient with autosomal dominant polycystic kidney disease complicated by sarcoidosis.

The patient was a 54-year-old woman with autosomal dominant polycystic kidney disease (ADPKD) who developed complicating systemic sarcoidosis. Hypercalcemia and an abrupt increase in serum creatinine levels were observed during the clinical course. Steroid therapy was initiated and produced a distinct improvement in renal function. A kidney biopsy was not feasible because ADPKD is a contraindication for renal needle biopsy. The clinical findings strongly suggested renal disorder secondary to tubulointerstitial nephritis caused by renal sarcoidosis with complicating hypercalcemia. In addition to controlling hypertension and improving the hypercalcemia and dehydration, steroid therapy also improved the renal function in this patient.

Effect of the antiplatelet agent cilostazol on endovascular inflammatory biochemical parameters and the clinical symptoms of peripheral artery disease and restless legs syndrome in hemodialysis patients.

BACKGROUND: Peripheral artery disease (PAD) is a common complication in patients receiving hemodialysis (HD). Cilostazol is used for the treatment of ischemic symptoms in patients with PAD, based on its antiplatelet and vasodilating effects. In addition to these beneficial effects on clinical symptoms in PAD patients, cilostazol has been proposed to have additional effects on clinical symptoms in patients with restless legs syndrome (RLS) via the upregulation of dopamine. We performed an observational, prospective study to evaluate the effect of cilostazol on several clinical and biochemical parameters in HD patients with PAD and RLS. METHODS: All the study patients received cilostazol treatment for 12 months. During the study period, several biochemical parameters, such as high-sensitivity CRP, von Willebrand antigen (VW-Ag), triglyceride (TG), high-density lipoprotein (HDL) and malondialdehyde-modified low-density lipoprotein, were monitored. A questionnaire on the physical status of PAD and RLS was also completed. 45 HD patients who received cilostazol were compared with a control group of 22 patients. RESULTS: The patients who continued cilostazol treatment exhibited a improvement in their serum inflammatory and biochemical parameters (VW-Ag, TG, HDL). Although PAD and RLS scores were not improved by multivariate analysis, several patients showed improvement of signs and symptoms which were included in the PAD or RLS scores. CONCLUSION: The treatment of HD patients with cilostazol improved some of the lipid-related and endovascular inflammatory biochemical parameters associated with PAD, and relieved the clinical symptoms and physical status of PAD in some cases.

Cyst formation and activation of the extracellular regulated kinase pathway after kidney specific inactivation of Pkd1.

Polycystic kidney disease (ADPKD) results from failure of the kidney to properly maintain three-dimensional structure after loss of either polycystin-1 or -2. Mice with kidney selective inactivation of Pkd1 during embryogenesis develop profound renal cystic disease and die from renal failure within 3 weeks of birth. In this model, cysts form exclusively from cells in which Cre recombinase is active, but the apparent pace of cyst expansion varies by segment and cell type. Intercalated cells do not participate in cyst expansion despite the presence of cilia up to at least postnatal day 21. Cystic segments show a persistent increase in proliferation as determined by bromodeoxyuridine (BrdU) incorporation; however, the absolute proliferative index is dependent on the underlying proliferative potential of kidney tubule cells. Components of the extracellular regulated kinase (MAPK/ERK) pathway from Ras through MEK1/2 and ERK1/2 to the effector P90(RSK) are activated in both perinatal Pkd1 and adult Pkd2 ortholgous gene disease models. The pattern of MAPK/ERK activation is focal and does not correlate with the pattern of active proliferation identified by BrdU uptake. The possibility of a causal relationship between ERK1/2 activation and cyst cell proliferation was assessed in vivo in the acute perinatal Pkd1 model of ADPKD using MEK1/2 inhibitor U0126. U0126 treatment had no effect on progression of cyst formation in this model at doses sufficient to reduce phospho-ERK1/2 in cystic kidneys. Cysts in ADPKD exhibit both increased proliferation and activation of MAPK/ERK, but cyst growth is not prevented by inhibition of ERK1/2 activation.

Recombinant human erythropoietin mitigates reductions in renal klotho expression.

BACKGROUND: Erythropoietin (EPO) and Klotho expression have both been detected in the kidney. Since a recent study suggested that both EPO and Klotho mitigate kidney damage, we explored the relation between EPO and Klotho in a doxorubicin hydrochloride (DXR)-induced rat nephropathy model treated with recombinant human erythropoietin (rhEPO). METHODS: Male Sprague-Dawley rats were subjected to DXR-induced nephropathy. The rhEPO group was intracutaneously injected with rhEPO twice weekly at 4-16 weeks after the DXR injection. The rats were sacrificed at 16 weeks after the DXR administration. Expression of renal Klotho, HSP70, alpha-smooth-muscle actin and E-cadherin were assessed using real-time PCR or western blotting. The hematocrit, plasma creatinine and phosphate levels were also determined. Immunohistochemical studies and Masson-trichrome staining were performed. RESULTS: The renal Klotho mRNA and Klotho protein expressions were significantly reduced in the DXR nephropathy group. Treatment with rhEPO improved the serum creatinine, phosphate level and histological changes observed in the DXR nephropathy group. The reduction in Klotho expression induced by DXR nephropathy was mitigated by rhEPO administration. CONCLUSION: rhEPO is involved in the pathophysiology of DXR nephropathy. rhEPO mitigated elevated plasma phosphate concentrations in an experimental model of chronic kidney disease via the expression of Klotho.

Klotho reduces apoptosis in experimental ischaemic acute kidney injury via HSP-70.

BACKGROUND: High Klotho expression has been detected in the kidney, and since the results of a recent study suggested that Klotho induction mitigates ischaemic damage in the kidney, in the present study we explored the mechanism by which Klotho expression reduces renal ischaemia-reperfusion injury (IRI). METHODS: Male mice were subjected to bilateral renal ischaemia for 30 min and reperfusion for 24 h, or to a sham operation. Both the IRI group and the sham group were intravenously injected with an adenovirus harbouring the mouse Klotho gene (ad-kl) before renal IRI. In addition, mIMCD3 cells induced to overexpress Klotho by transferring the Klotho gene with ad-kl were analysed by DNA microarray and real-time PCR. Renal expression of Klotho and several genes selected by DNA microarray were assessed by real-time PCR or Western blotting, and TUNEL staining was performed to assess apoptosis. RESULTS: Prior administration of ad-kl to the mice resulted in robust induction of Klotho mRNA in the kidney and liver. Ad-kl transfer improved the plasma creatinine values and mitigated the histological damage and apoptosis induced by IRI. Expression of several genes was altered in mIMCD3 cells as a result of the change in Klotho expression, and expression of heat shock protein 70 (HSP70), in particular, was up-regulated in ad-kl mouse kidneys and HK2 cells. CONCLUSION: The results suggest that Klotho is involved in the pathophysiology of IRI. Klotho mitigates apoptosis in experimental ischaemic acute kidney injury via expression of HSP70.

Clinical outcome and prognosis of anti-neutrophil cytoplasmic antibody-associated vasculitis in Japan.

BACKGROUND/AIMS: We conducted a broad survey of 99 patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and investigated both prognosis and outcomes. METHODS: Clinical data evaluated were age, sex, patient survival, renal survival, serum albumin, serum creatinine, urinary protein, hematuria, C-reactive protein (CRP), ANCA titer, IgG and the Birmingham Vasculitis Activity Score (BVAS). RESULTS: The patient survival rate at 6 months after onset was 84.8%, and that at 2 years after onset was 82.0%. Most deaths were within 6 months of onset. Infection accounted for 9 deaths (60.0%). Infection together with pulmonary involvement of active vasculitis accounted for 2 deaths (13.3%). Organ-specific involvement of active vasculitis alone caused 3 deaths (20.0%). Others died of cardiac events. At 1 and 3 months after onset, BVAS (p < 0.0001, p = 0.002), albumin (p = 0.006, p = 0.0004) and CRP (p = 0.04, p = 0.0002) were also associated with patient death. CONCLUSION: To improve the prognosis of those with ANCA-associated vasculitis, the intensity of initial treatment should be aimed at disease severity. Employing BVAS improved the ability to evaluate therapeutic responses. Finally, prescription with sulfamethoxazole-trimethoprim during the induction therapy with immunosuppressive agents may be advised.

Clinical effects of calcium channel blockers and renin-angiotensin-aldosterone system inhibitors on changes in the estimated glomerular filtration rate in patients with polycystic kidney disease.

BACKGROUND: In the tubular cells of patients with polycystic kidney disease (PKD), a reduced intracellular Ca(2+) level accelerates cell proliferation, resulting in cyst formation. Thus, whether calcium channel blockers (CCB) are useful for the treatment of hypertension in patients with PKD is questionable. METHODS: Thirty-two outpatients with autosomal dominant PKD (ADPKD) were treated at Tokyo Women's Medical University between 2003 and 2008; these patients were studied retrospectively. Periods during which the antihypertensive drug prescriptions for CCB and/or renin-angiotensin-aldosterone system inhibitors (RAAS-I; including angiotensin converting enzyme inhibitor and angiotensin II receptor blocker) had not been changed for at least 1 year and during which time a diuretic agent had not been prescribed were selected from among the clinical histories of the 32 outpatients. Consequently, 31 periods of 31 patients were analyzed, and mean treatment duration was 2.4 years in this study. The estimated glomerular filtration rate (eGFR) was used to evaluate renal function. To evaluate the influence of CCB and RAAS-I with respect to the decrease of the eGFR, analysis of covariance (ANCOVA), including confounding factors [baseline eGFR, mean systolic blood pressure (SBP), mean diastolic blood pressure (DBP)], was used. Only CCB significantly contributed to a reduction in ∆eGFR in both a univariable ANCOVA and a multivariable ANCOVA. None of the confounding factors, RAAS-I, the baseline eGFR, or blood pressure, contributed to reductions in ∆eGFR. CONCLUSION: These results suggest that from a renoprotective perspective, CCB should possibly be avoided in patients with PKD unless treatment for resistant hypertension is necessary.

High Serum Phosphate Level as a Risk Factor to Determine Renal Prognosis in Autosomal Dominant Polycystic Kidney Disease: A Retrospective Study.

Background: Serum phosphate levels, which are associated with the progression of renal dysfunction in chronic kidney disease, in patients with autosomal dominant polycystic kidney disease (ADPKD) are lower than those in patients with other kidney diseases. However, their role in ADPKD remains unclear. This study aimed to determine whether serum phosphate levels could have an association with renal prognoses among patients with ADPKD. Methods: In total, 55 patients with PKD1 or PKD2 mutations but not undergoing dialysis were evaluated. Data regarding serum phosphate levels were collected, and Cox regression analyses were used to calculate hazard ratios (HRs) with renal replacement therapy as the endpoint. Results: The median (quartile 1; quartile 3) serum phosphate concentration was 3.4 (3.1; 3.9) mg/dL, and the estimated glomerular filtration rate (eGFR) was 39.5 (17.6; 65.7) mL/min/1.73 m2. The multivariate analysis that included age, PKD1 mutation, eGFR, urinary protein excretion, hyperuricemia, and serum phosphate determined that eGFR (HR, 0.82; 95% confidence interval (CI), 0.74-0.90; p < 0.0001) and serum phosphate (HR, 6.78; 95% CI, 1.94-34.02; p = 0.0021) were independently associated with renal replacement therapy. Conclusions: We found that serum phosphate levels were significantly associated with poor renal prognoses in patients with ADPKD.

Prediction of Renal Prognosis in Patients with Autosomal Dominant Polycystic Kidney Disease Using PKD1/PKD2 Mutations.

Autosomal dominant polycystic kidney disease (ADPKD) patients with PKD1 mutations, particularly those with truncating mutations, show poor prognosis. However, the differences in disease progression with different mutation types are unclear. Here, a comparative study was conducted on the renal prognosis of patients with ADPKD who were categorized based on genotype (PKD1 versus PKD2 mutation), mutation type (truncating mutation: nonsense, frameshift, splicing mutation, and large deletion; non-truncating mutation: substitution and in-frame deletion), and mutation position. A total of 123 patients visiting our hospital were enrolled. Renal prognosis was poor for those with PKD1 splicing, PKD1 frameshift, and PKD2 splicing mutations. Despite the truncating mutation, the renal prognosis was relatively favorable for patients with nonsense mutations. Three out of five patients with PKD2 mutation required renal replacement therapy before 58 years of age. In conclusion, we showed that renal prognosis differs according to mutation types in both PKD1 and PKD2, and that it was favorable for those with nonsense mutations among patients with PKD1 truncating mutations. It was also confirmed that renal prognosis was not always favorable in patients with PKD2 mutations. A detailed assessment of mutation types may be useful for predicting the renal prognosis of patients with ADPKD.

Characteristics of dialysis-related amyloidosis in patients on haemodialysis therapy for more than 30 years.

BACKGROUND: Dialysis-related amyloidosis is one of the chronic the complications of haemodialysis. We conducted an investigation of dialysis-associated amyloidosis in extremely long-term survivors. METHODS: Twenty-one patients on haemodialysis for more than 30 years ('30+' group) and 13 patients on haemodialysis for 20-30 years ('20-30' group) at Sangenjaya Hospital were enrolled in this study. The frequencies of operations for conditions related to haemodialysis-related amyloidosis were examined. RESULTS: The mean age at the start of haemodialysis was younger in the '30+' group (29.1 +/- 7.3 years) than in the '20-30' group (40.5 +/- 8.2 years, P = 0.0003). Eighteen (85.7%) patients had undergone surgery for CTS, six (28.6%) had undergone surgery for trigger finger and six (28.6%) had undergone surgery for cervical destructive spondyloarthropathy (DSA) at 30 years after the start of haemodialysis therapy. Patients who were over the age of 30 years at the start of dialysis therapy more frequently underwent CTS operations (100%) than those who were under 30 years of age at the start of dialysis (76.9%; P = 0.025) in the '30+' group at 30 years after the start of haemodialysis. The frequencies of operations for CTS did not differ significantly between the '20-30' group and the '30+' group. CONCLUSIONS: Haemodialysis-associated amyloidosis was common in extremely long-term survivors. Even though the mean age at the start of haemodialysis was younger in the '30+' group than in the '20-30' group, the frequency of operations for CTS did not differ. This may be attributable to the recent advances in haemodialysis technologies.

ATF3 protects against renal ischemia-reperfusion injury.

Oxidative stress-induced cell death plays a major role in the progression of ischemic acute renal failure. Using microarrays, we sought to identify a stress-induced gene that may be a therapeutic candidate. Human proximal tubule (HK2) cells were treated with hydrogen peroxide (H2O2) and RNA was applied to an Affymetrix gene chip. Five genes were markedly induced in a parallel time-dependent manner by cluster analysis, including activating transcription factor 3 (ATF3), p21(WAF1/CiP1) (p21), CHOP/GADD153, dual-specificity protein phosphatase, and heme oxygenase-1. H2O2 rapidly induced ATF3 approximately 12-fold in HK2 cells and approximately 6.5-fold in a mouse model of renal ischemia-reperfusion injury. Adenovirus-mediated expression of ATF3 protected HK2 cells against H2O2-induced cell death, and this was associated with a decrease of p53 mRNA and an increase of p21 mRNA. Moreover, when ATF3 was overexpressed in mice via adenovirus-mediated gene transfer, ischemia-reperfusion injury was reduced. In conclusion, ATF3 plays a protective role in renal ischemia-reperfusion injury and the mechanism of the protection may involve suppression of p53 and induction of p21.