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Diabetic nephropathy is characterized by excessive deposition of extracellular matrix protein and disruption of the glomerular filtration barrier. Matrix metalloproteinases (MMPs) affect the breakdown and turnover of extracellular matrix protein, suggesting that altered expression of MMPs may contribute to diabetic nephropathy. Here we used an MMP-9 gene knockout mouse model, with in vitro experiments and clinical samples, to determine the possible role of MMP-9 in diabetic nephropathy. After 6 months of streptozotocin-induced diabetes, mice developed markedly increased albuminuria, glomerular and kidney hypertrophy, and thickening of the glomerular basement membrane. Gelatin zymographic analysis and western blotting showed that there was enhanced MMP-9 protein production and activity in the glomeruli. However, MMP-9 knockout in diabetic mice significantly attenuated these nephropathy changes. In cultured podocytes, various cytokines related to diabetic nephropathy including TGF-β1, TNF-α, and VEGF stimulated MMP-9 secretion. Overexpression of endogenous MMP-9 induced podocyte dedifferentiation. MMP-9 also interrupted podocyte cell integrity, promoted podocyte monolayer permeability to albumin, and extracellular matrix protein synthesis. In diabetic patients, the upregulation of urinary MMP-9 concentrations occurred earlier than the onset of microalbuminuria. Thus, MMP-9 seems to play a role in the development of diabetic nephropathy.Kidney International advance online publication, 26 March 2014; doi:10.1038/ki.2014.67.

Heme oxygenase-1 (HO-1) is a rate-limiting enzyme in heme degradation, producing carbon monoxide (CO), which carries potent antiproliferative and anti-inflammatory effects in the vascular walls. Transcription of the HO-1 gene is regulated by the length polymorphism of dinucleotide guanosine thymine repeat (GT)(n) in the promoter region, which was measured in this study to determine its association with arteriovenous fistula (AVF) failure in Chinese hemodialysis (HD) patients in Taiwan. L allele means (GT)(n)or=30 and S allele means (GT)n30. Therefore, there are two L alleles for L/L genotype, one L and one S allele for L/S genotype, and two S alleles for S/S genotype. Among the 603 HD patients who were enrolled in this study, 178 patients had history of AVF failure, while 425 patients did not. Significant associations were found between AVF failure and the following factors (hazard ratio): longer HD duration (1.004 month), lower pump flow (0.993 ml/min), higher dynamic venous pressure (1.010 mmHg), location of AVF on the right side (1.587 vs left side) and upper arm (2.242 vs forearm), and L/L and L/S genotypes of HO-1 (2.040 vs S/S genotype). The proportion of AVF failure increased from 20.3% in S/S genotype and 31.0% in L/S genotype to 35.4% in L/L genotype (P=0.011). Relative incidences were 1/87.6 (1 episode per 87.6 patient-months), 1/129, and 1/224.9 for HD patients with L/L, L/S, and S/S genotypes, respectively (P0.002). The unassisted patency of AVF at 5 years decreased significantly from 83.8% (124/148) to 75.1% (223/297) and 69% (109/158) in S/S, L/S, and L/L genotypes, respectively (P0.0001). In comparison with HD patients with S/S genotype, those with L/L genotype had a higher prevalence of coronary artery disease (29.1 vs 14.2%; P=0.005). A longer length polymorphism with (GT)(n)or=30 in the HO-1 gene was associated with a higher frequency of access failure and a poorer patency of AVF in HD patients. The longer GT repeat in the HO-1 promoter might inhibit gene transcription, and consequently offset the CO-mediated protective effect against vascular injury.

Left ventricular mass and hemodynamic overload in normotensive hemodialysis patients. Background It remains uncertain whether the hemodynamic parameters are important determinants of left ventricular mass (LVM) in normotensive chronic hemodialysis (NTHD) patients, as has been found in their hypertensive counterparts. Methods Forty NTHD patients (mean age, 53.7 ± 14.4 years; male/female, 18/22) without the requirement of antihypertensive drugs for at least six months were studied. Controls were 41 hypertensive hemodialysis patients (HTHD) and 46 normotensive subjects with normal renal function (NTNR). The influence of anthropometrics, cardiovascular structure and function, and volume status on LVM (by two-dimensional echocardiography) was analyzed by steps of multiple linear regression. Results As compared with the NTNR and NTHD group, the HTHD group had obvious pressure and volume/flow overload, and greater LV wall thickness, chamber size and mass. In contrast, NTHD subjects had similar blood pressure, large artery function, LV chamber size and stroke volume as the NTNR subjects. However, the NTHD patients still had greater wall thickness and LVM, along with greater cardiac output, lower total peripheral resistance and lower end-systolic meridional stress to volume ratio (ESSV) than the NTNR group. LVM in the NTHD group was significantly positively related to averaged systolic blood pressure (SBPavg), body surface area, extracellular fluid (ECF), carotid intima-media thickness (IMT), aortic pulse wave velocity (PWV), and negatively related to ESSV and Kt/V. The independent significant noncardiac structural determinants of LVM in NTHD subjects were ESSV, SBPavg, PWV and SV (model r 2 = 0.617, P Conclusions The NTHD patients, without significant pressure and volume overload, still had increased LVM that was partially explained by the persistent flow overload and subclinical LV dysfunction.

Intravenous ascorbic acid as an adjuvant therapy for recombinant erythropoietin in hemodialysis patients with hyperferritinemia.BackgroundInadequate iron mobilization and defective iron utilization may cause recombinant erythropoietin (rEPO) hyporesponsiveness in hemodialysis (HD) patients with iron overload. We have demonstrated that intravenous ascorbic acid (IVAA), but not intravenous iron medication, can effectively circumvent the functional iron-deficient erythropoiesis associated with iron overload in HD patients. However, it is uncertain whether all HD patients with hyperferritinemia will consistently respond to IVAA and which index may indicate functional iron deficiency in the special entity. Therefore, a prospective study was conducted to establish the guidelines for IVAA adjuvant therapy.MethodsSixty-five HD patients with serum ferritin levels of more than 500 μg/liter were recruited and divided into the control (N = 19) and IVAA (N = 46) groups. IVAA patients with a hematocrit (Hct) of less than 30% received 300mg of ascorbic acid three times per week for eight weeks. Controls had a Hct of more than 30% and did not receive the adjuvant therapy. Red blood cell and reticulocyte counts, iron metabolism indices, erythrocyte zinc protoporphyrin (E-ZPP), and the concentrations of plasma ascorbate and oxalate were examined before and following the therapy.ResultsThirteen patients (four controls and nine IVAA patients) withdrew by the end of the study. Eighteen patients had a dramatic response to IVAA with a significant increase in their hemoglobin and reticulocyte index and a concomitant 24% reduction in rEPO dose after eight weeks. This paralleled a significant rise in serum iron and transferrin saturation (TS) and a fall in E-ZPP and serum ferritin (baselines vs. 8weeks, serum iron 68 ± 37 vs. 124 ± 64 μg/dl, TS 27 ± 10 vs. 48 ± 19%, E-ZPP 123 ± 44 vs. 70 ± 13 μmol/mol heme, and serum ferritin 816 ± 435 vs. 587 ± 323 μg/liter, P < 0.05). Compared with responders, mean values of hemoglobin, rEPO dose, iron metabolism parameters, and E-ZPP showed no significant changes in controls (N = 15) and in non-responders (N = 19). Thirty-seven patients (18 responders and 19 non-responders) were further analyzed by receiver operating characteristic curves to seek the criteria for prediction of a response to IVAA treatment. The results showed that E-ZPP at a cut-off level of more than 105 μmol/mol heme and TS at a level of less than 25% were more specific to confirm the status of functional iron deficiency in iron-overloaded patients. The two criterion values had the highest accuracy to predict a response to treatment.ConclusionsFunctional iron-deficient erythropoiesis plays a role in rEPO-hyporesponsive anemia in HD patients with hyperferritinemia. IVAA may be an adjuvant therapy for rEPO in these patients, and E-ZPP of more than 105 μmol/mol heme and TS of less than 25% should be used to guide the IVAA treatment.

Erythropoietin hyporesponsiveness: From iron deficiency to iron overload. Iron deficiency is the most frequently encountered cause of suboptimal response to recombinant human erythropoietin (rHuEPO). Carefully assessing iron status is of paramount importance in chronic renal failure patients prior to or during rHuEPO therapy. Because there is great need for iron in the EPO-stimulated erythroid progenitors, it is essential that serum ferritin and transferrin saturation levels should be maintained over 300 μg/liter and 30%, respectively. Investigators have shown that oral iron is unlikely to keep pace with the iron demand for an optimal rHuEPO response in uremics. Therefore, patients with iron deficiency will always require intravenous iron therapy. The early and prompt iron supplementation can lead to reductions in rHuEPO dose and hence cost. After the iron deficiency has been corrected or excluded, we must remember all of the possible causes of hyporespon-siveness in every rHuEPO-treated patient. As dose requirements vary, it is not clear which dose of rHuEPO causes this hyporesponsiveness. However, if the patient with iron repletion does not respond well after the induction period, the major causes blunting the response to rHuEPO should be investigated. Most factors are reversible and remediable, except resistant anemia associated with hemoglobinopathy or bone marrow fibrosis, which requires a further increase in the rHuEPO dose. By means of early detection and correction of the possible causes, the goal of increasing therapeutic efficacy can be achieved. Iron overload may lead to an enhanced risk for infection, cardiovascular complication, and cancer. Over-treatment with iron should be avoided in dialysis patients, despite the fact that the safe upper limit of serum ferritin to avoid iron overload is not clearly defined. On the other hand, functional iron deficiency may develop even when serum ferritin levels are increased. Controversy remains as to whether intravenous iron therapy can overcome this form of hyporesponsiveness in iron-overloaded patients. Moreover, a treatment option of iron supplementation is not warranted in these patients, as the potential hazards of iron overload will be worsened. We demonstrated that the mean hematocrit significantly increased from 25.1 ± 0.9% to 31 ± 1.2% after eight weeks of intravenous ascorbate therapy (300 mg three times a week) in 12 hemodialysis patients with serum ferritin levels of more than 500 μg/liter. The enhanced erythropoiesis paralleled with a rise in transferrin saturation (27.8 ± 2.5% vs. 44.8 ± 9.5%, P < 0.05) and reductions in erythrocyte zinc protoporphyrin (130 ± 32 vs. 72 ± 19 mmol/mol heme, P < 0.05) and monthly rHuEPO dose (24.2 ± 4.5 vs. 16.8 ± 3.4 3 103units, P < 0.05) at the end of study. It is speculated that ascorbate supplementation not only facilitates the iron release from storage sites and its delivery to hematopoietic tissues, but also increases iron utilization in ery-throid cells. Our study provides a more complete understanding of the pathogenesis of iron overload-related anemia and the development of an adjuvant therapy, intravenous ascorbic acid, to the existing treatments.

Tubular epithelial-myofibroblast transdifferentiation in progressive tubulointerstitial fibrosis in 5/6 nephrectomized rats. Background Tubulointerstitial fibrosis is the final common pathway to end-stage renal failure. The present study investigated the potential role of tubular epithelial cells (TEC) in progressive fibrosis in the rat remnant kidney model. Methods Rats underwent 5/6 nephrectomy or a sham operation (control), and groups of six animals were killed at weeks 1, 3, 5, 9, 13, 17 and 21. Results Immunohistochemistry staining and in situ hybridization at week 3 after nephrectomy demonstrated de novo expression of alpha-smooth muscle actin ( α -SMA)–a marker of smooth muscle cells and myofibroblasts–by TEC that was invariably associated with disruption of the tubular basement membrane (TBM). This phenotypic evidence of tubular epithelial-myofibroblast transdifferentiation was supported by ultrastructural studies identifying the presence of characteristic actin microfilaments and dense bodies within TEC with a transformed morphology. In the late stage of this apparent tubular epithelial-myofibroblast transdifferentiation, TEC lost apical-basal polarity and tight junctions, became elongated, detached from the TBM, separated from neighboring cells and appeared to migrate into the peritubular interstitium through the damaged basement membrane. Indeed, focal peritubular accumulation of α -SMA + myofibroblasts and local tubulointerstitial fibrosis was closely associated with α -SMA + tubules, suggesting a tubular epithelial origin for some of these cells. Quantitative analysis found a significant correlation between the number of α -SMA + TEC and the accumulation of interstitial α -SMA + myofibroblasts and the severity of tubulointerstitial fibrosis (both P Conclusions This study provides phenotypic and morphological evidence to support the hypothesis that TEC are pro-fibrogenitor cells capable of tubular epithelial-myofibroblast transdifferentiation in progressive renal fibrosis. In addition, we postulate that disruption of the TBM, which facilitates epithelial cell contact with the interstitial matrix, promotes this process of transdifferentiation.

Previous studies have shown that nonsteroidal anti-inflammatory drug (NSAID) use might be associated with a lower risk of developing cancer in the general population. Patients on dialysis have increased risk for cancer, but there are no studies to determine the relationship between NSAID use and cancer risk in these patients. To identify any association between NSAID use and cancer risk in patients with end-stage renal disease on dialysis, we used Taiwan's National Health Insurance database to conduct a nationwide population-based, propensity score–matched cohort study. All cancers between groups were compared by Cox proportional hazards models. Compared to nonuse of NSAIDs, the use of non-COX-2-selective inhibitors (hazard ratio 0.81, 95% confidence interval 0.67–0.97) or COX-2-selective inhibitors (0.78, 0.62–0.98) was associated with a lower risk of developing cancer. NSAID use reduced the risk of respiratory (0.39, 0.19–0.79), breast (0.41, 0.19–0.89), kidney (0.58, 0.38–0.88), digestive tract (0.64, 0.49–0.85), and bladder cancers (0.73, 0.55–0.96). NSAID use, however, significantly increased risk for upper gastrointestinal bleeding (odds ratio, 1.15, 1.07–1.23) but not adverse cardiac or cerebrovascular events. Thus, NSAID use was associated with a lower risk of developing cancer in chronic dialysis patients; however, they should still be used with caution due to the side effects of gastrointestinal bleeding.

A 41-year-old woman presented with hypokalemic paralysis with non-anion-gap metabolic acidosis and normotension. During the work-up of suspected renal tubular acidosis, a bicarbonate loading test was performed. During the test, the patient developed tetany with severe facial (Figure 1) and carpal spasm (Figure 2). Her venous pH at this time was 7.47 (venous bicarbonate 26 mequiv. per liter) from a baseline of 7.31 (venous bicarbonate 12.2 mequiv. per liter). The infusion was discontinued, and calcium gluconate (9.2 mequiv.) was administered intravenously with complete subsidence of symptoms. The serum ionized calcium level at this event was 0.68 mmol per liter, and the baseline serum total calcium level was 7.8 mg per dl with serum albumin of 3.5 g per dl. Rapid alkalization of plasma may induce acute hypocalcemia leading to tetany; other complications in this setting can include seizures, cardiac dysrhythmias (prolongation of the QT interval), decreased cardiac contractility, hypotension, and heart failure.

A 62-year-old woman presented with sudden onset of lower abdominal pain and lower limb weakness. She had a history of hypertension, hyperlipidemia, diff use atherosclerosis, and renal failure from nephrosclerosis, and had been on peritoneal dialysis for 10 years. A clinical diagnosis of spinal cord infarction with paraplegia was made, and an MRI was arranged. However, she rapidly went into shock with a limited response to intravenous fl uids and vasopressors. Rhabdomyolysis with elevated serum creatine phosphokinase (CK) up to 55,620 U/l was noted. Th e peritoneal dialysis (PD) effl uent, initially clear A B C D B C

Ho-Han Wu, Szu-Yuan Li and Wu-Chang Yang Division of Nephrology, Department of Internal Medicine, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan; Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, Taipei, Taiwan and Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

A 64-year-old man presented with progressive painless right lower leg swelling for 5 years. The patient had a history of surgical resection of similar lesions over his right forearm and abdominal wall 5 and 8 years ago, respectively. He had bilateral recurrent renal stones over the past 5 years. The physical examination was normal except for a painless stone-hard right lower leg swelling (Figure 1). He had no skin lesions or lymphadenopathy. His blood tests revealed a total white blood cell count of 4700/mm3 (78% neutrophils), hemoglobin 10.4 g/dL, blood urea nitrogen 57 mg/dL, creatinine 4.68 mg/dL, calcium 14.6 mg/dL (normal 8.4–10.6), and normal C-reactive protein and creatine kinase level. Serum electrophoresis was normal. He had a serum intact parathyroid hormone of 9.36 pg/dL (

To the Editor: In a recent issue of Kidney International, Ohtomo et al.1 showed that pioglitazone (PGZ), one of these currently used thiazolidinediones, could provide better renoprotection than insulin in an obese, hypertensive, type 2 diabetes mellitus rat model. However, a few questions should be considered for this animal study. First, many diabetic patients have insulin as their main treatment for glycemic control, as the author proved PGZ has better renoprotection, would combination treatment with insulin and PGZ be a better regimen for diabetic patients? If the answer is yes, why didn't the author add another group treated by both insulin and PGZ in their study design. Second, the glycemic control was not better in rats treated with PGZ than those with insulin. Is it possible that the dose of PGZ was too low to achieve a better glycemic status? Third, how could we explain the finding that insulin had a renoprotective effect in the first 8 weeks but it increased urine protein later gradually? According to Schena and Gesualdo,2 insulin can reduce oxidative stress with prevention of accumulation of toxic advanced glycation end products, which may provide renoprotection in the first 8 weeks. However, in the later period, insulin may induce production of matrix proliferation and results in glomerular sclerosis, thus renal function may decline with increased urine protein excretion.

To the Editor: We read with great interest the article by Santiago et al. The continuous renal replacement therapy (CRRT) device functioned correctly after connecting with the extracorporeal membrane oxygenation (ECMO) circuit in parallel, not in series. Previously we observed different problematic pressures in connecting the CRRT device with the ECMO circuit in adults and children. It is clear from this article that the low blood flow rate of the CRRT device drained from the ECMO circuit will trigger the ‘arterial line disconnection’ alarm, owing to the positive inlet pressure exceeding the normal range. How can we ignore a prior warning of the Food and Drug Administration in 2005 on the potential risk of fluid imbalance in a Prisma device by allowing the alarm to be silenced repeatedly? Therefore, the real fluid removal from the CRRT device should be measured to make sure an accurate balance. When we tried the same connection system in adults, the normal blood flow (150ml/min) of the CRRT device avoided alarm because of difficulty in blood extraction, but not in blood return. Actually, the high resistance within the ECMO circuit following the centrifugal pump hindered the outlet flow of the CRRT device. Again, the on-line monitoring of pressure became an obstacle. It is not recommended to override the alarm, owing to the potential risks of hemolysis and filter clotting. Difficulty in finding vascular access for renal replacement therapy is a common problem in critically ill patients, especially in children. Thus, the utility of the ECMO circuit might be an alternative solution. However, it is inappropriate to conclude that inclusion of the CRRT device in the ECMO circuit is safe and effective without any complications in all patients.

To the Editor: In a recent issue of Kidney International, Chen et al.1 suggested that patients with myeloperoxidase (MPO)-antineutrophil cytoplasmic autoantibodies (ANCA) positive Wegener's granulomatosis were not rare in Chinese, and the prevalence of elevated initial serum creatinine was significantly higher in patients with MPO-ANCA than that in patients with PR3-ANCA. However, the possible contributors for more prevalent elevated serum creatinine in patients with MPO-ANCA were not clarified. First, the common confounding factors associated with chronic kidney diseases (e.g. diabetes mellitus, hypertension, advanced age, nephrotoxic agents (e.g. non-steroid anti-inflammation drugs) use, etc.) and acute renal failure (e.g. prerenal and postrenal types) should be excluded in patients with elevated initial serum creatinine. Second, the serum ANCA titer, a plausible indicator of disease activity, might be further determined in both groups. Third, the significantly lower prevalence of extra-renal involvement (e.g. arthralgia, skin rash, ophthalmic, and ear involvement) in the MPO-ANCA group1 may lead to a longer insidious inflammation process, resulting in more severe renal damages with elevated serum creatinine. It was speculated that MPO-ANCA-positive Wegener's granulomatosis was somewhat more like microscopic polyangiitis, which was more likely to have a greater degree and severity of glomerulosclerosis, interstitial fibrosis, and tubular atrophy on initial renal biopsy.2 In addition, the differences in histopathology between MPO-ANCA and PR3-ANCA glomerulonephritis could be explained by the observation that in patients with MPO-ANCA, kidney biopsy was carried out late in the course of the disease, and diffuse chronic sclerotic lesions predominated.3

To the Editor: With the article by Tang et al.,1 recently published in Kidney International, we anticipate that the lamivudine-resistant mutation and hepatitis flares will occur in their patients with hepatitis B virus-associated membranous nephropathy under further long-term lamivudine treatment. Although, hepatitis B virus variants with mutations at the YMDD motif of DNA polymerase have not been observed in their cohort, the proportion of patients with a documented lamivudine-resistant mutation increased from 23% in year 1 to 65% in year 5 was reported by Chayama et al.2 and Lok et al.3

A report with consensus statements of the International Society of Nephrology 2004 Consensus Workshop on Prevention of Progression of Renal Disease, Hong Kong, June 29, 2004. This report summarizes the discussions of the International Society of Nephrology (ISN) 2004 Consensus Workshop on Prevention of Progression of Renal Disease, which was held in Hong Kong on June 29, 2004. Three key areas were discussed during the workshop: (1) screening for chronic kidney disease; (2) evaluation and estimating progression of chronic kidney disease; and (3) measures to prevent the progression of chronic kidney disease. Fifteen consensus statements were made in these three areas, as endorsed by the participants of the workshop. The ISN can make use of and take reference to these statements in formulating its policy for tackling chronic kidney disease, a disease with significant global impact.

A 71-year-old woman with end-stage kidney failure from diabetes, on hemodialysis for 20 years, presented tongue abnormalities. The surface of the tongue was covered with numerous mottled whitish-to-yellowish, cobblestone-like nodules (Figure 1). These nodules had gradually enlarged over the preceding 2 years. Contact bleeding was noted on occasion, and the patient complained of slurred speech. She also suffered from altered taste but denied any pain. An incisional biopsy of these nodules was performed, and the pathology showed no evidence of malignancy but a picture of mild chronic inflammation and deposition of sheets and globules of amorphous eosinophilic substance in submucosal and muscle layers. Congo red staining revealed typical apple-green birefringence under polarized light, which confirmed the diagnosis of amyloidosis (Figure 2). Serial survey for hematological malignancy showed negative findings, including peripheral blood smear, serum protein electrophoresis, and skeletal films. The patient’s serum β2-microglobulin result was 29,295 ng/ml (normal values 1000–2400 ng/ml). The patient was also previously diagnosed with bilateral carpal tunnel syndrome requiring surgical decompression.

A 66-year-old woman, with a 15-year history of type II diabetes and hypertension, was admitted for suspected coronary artery disease. She was clinically euvolemic without a history of diuretic use. Severe asymptomatic hyponatremia (121 mmol/l) with mild prerenal azotemia (blood urea nitrogen 34 mg per 100 ml and serum creatinine 1.4 mg per 100 ml) and hyperglycemia (350–475 mg per 100 ml) were noted. Her hemoglobin A1C was 11%. Her plasma was grossly milky (Figure 1) with severe hypertriglyceridemia (11,284 mg per 100 ml) and hypercholesterolemia (674 mg per 100 ml). Her plasma osmolality was normal (298 mosM/kg). There was no family history of hyperlipoproteinemia. The diagnosis of pseudohyponatremia due to severe secondary hyperlipidemia was made. Intensive insulin therapy and fenofibrate 200 mg twice daily were given, resulting in better control of hyperglycemia (200–275 mg per 100 ml) and hyperlipidemia (total cholesterol 319 mg per 100 ml and triglyceridemia 910 mg per 100 ml) after 4 days. The hyponatremia and prerenal azotemia also markedly improved (sodium 135 mmol/l, blood urea nitrogen 27 mg per 100 ml, and serum creatinine 1.2 mg per 100 ml), whereas the plasma osmolality remained unchanged (295 mosM/kg). Two weeks later, with continuing control of hyperglycemia, her hyponatremia and hyperlipidemia were completely resolved with normal appearance of the plasma. Fenofibrate was discontinued thereafter.