Fibulin7 aggravates calcium oxalate-induced acute kidney injury by binding to calcium oxalate crystals.

Fibulin7 (Fbln7) is a matricellular protein that is structurally similar to short fibulins but does not possess elastogenic abilities. Fbln7 is localized on the cell surface of the renal tubular epithelium in the adult kidney. We previously reported that Fbln7 binds artificial calcium phosphate particles in vitro, and that heparin counteracts this binding by releasing Fbln7 from the cell surface. Fbln7 gene (Fbln7) deletion in vivo decreased interstitial fibrosis and improved renal function in a high phosphate diet-induced chronic kidney disease mouse model. However, the contribution of Fbln7 during acute injury response remains largely unknown. We hypothesized that Fbln7 serves as an exacerbating factor in acute kidney injury (AKI). We employed three AKI models in vivo and in vitro, including unilateral ureteral obstruction (UUO), cisplatin-induced AKI, and calcium oxalate (CaOx)-induced AKI. Here, we report that Fbln7KO mice were protected from kidney damage in a CaOx-induced AKI model. Using HEK293T cells, we found that Fbln7 overexpression enhanced the CaOx-induced upregulation of EGR1 and LAMB3, and that heparin treatment canceled this effect. Interestingly, the protective function observed in Fbln7KO kidneys was limited to the CaOx-induced AKI model, while Fbln7KO mice were not protected against UUO-induced renal fibrosis or cisplatin-induced renal tubular damage. Taken together, our study indicates that Fbln7 mediates the local deposition of CaOx and damages the renal tubular epithelium. Releasing Fbln7 from the cell surface via heparin/heparin derivatives or Fbln7 inhibitory antibodies may provide a general strategy to mitigate calcium crystal-induced kidney injuries.

Citric acid-based bicarbonate dialysate attenuates aortic arch calcification in maintenance hemodialysis patients: a retrospective observational study.

BACKGROUND: Progression of aortic calcification is associated with all-cause and cardiovascular mortality in hemodialysis patients. Blood calciprotein particle (CPP) levels are associated with coronary artery calcification and were reported to be inhibited when using citric acid-based bicarbonate dialysate (CD). Therefore, this study aimed to examine the effect of CD on the progression of the aortic arch calcification score (AoACS) and blood CPP levels in hemodialysis patients. METHODS: A 12-month retrospective observational study of 262 hemodialysis patients was conducted. AoACS was evaluated by calculating the number of calcifications in 16 segments of the aortic arch on chest X-ray (minimum score is 0; maximum score is 16 points). The patients were divided into the following groups according to their baseline AoACS: grade 0, AoACS = 0 points; grade 1, AoACS 1-4 points; grade 2, AoACS 5-8 points; grade 3, AoACS 9 points or higher. Patients on bisphosphonates or warfarin or with AoACS grade 3 were excluded. Progression, defined as ΔAoACS (12-month score - baseline score) > 0 points, was compared between the CD and acetic acid-based bicarbonate dialysate (AD) groups before and after adjusting the background using propensity score matching. RESULTS: The AoACS progression rate was significantly lower in the CD group than in the AD group (before matching: P = 0.020, after matching: P = 0.002). Multivariate logistic regression analysis showed that CD was significantly associated with AoACS progression (odds ratio 0.52, 95% confidence interval 0.29‒0.92, P = 0.025). CONCLUSION: CD may slow the progression of vascular calcification in hemodialysis patients.

Risk factors for cytomegalovirus reactivation in patients with kidney disease under immunosuppressive therapy.

BACKGROUND: Cytomegalovirus (CMV) is a herpes virus that causes latent infections, and its reactivation due to immunosuppression can cause fatal complications. CMV reactivation is a complication frequently occurring in patients with kidney disease who require immunosuppressive therapy, and, therefore, this study retrospectively examined its risk factors. METHODS: Patients who received immunosuppressive therapy and underwent the CMV antigenemia test (CMV antigenemia: C7-HRP) for the treatment of primary nephritis (minimal change disease, membranous nephropathy, membranoproliferative glomerulonephritis, focal glomerulosclerosis, and IgA nephropathy) and anti-neutrophil cytoplasmic autoantibody (ANCA)-associated nephritis diagnosed at Saiseikai Kurihashi Hospital from January 2014 to December 2019 were recruited as study participants. Risk factors of CMV reactivation were examined using univariable and multivariable analyses. RESULTS: Among the 64 patients (36 men and 28 women; median age, 72 years) included, 34 had primary nephritis (20 minimal disease changes, 10 membranous nephropathy, 1 membranoproliferative glomerulonephritis, 1 focal glomerulosclerosis, and 2 IgA nephropathy) and 30 had ANCA-associated nephritis. Regarding glucocorticoid (GC), 43 patients received oral GC therapy, whereas 21 received GC pulse therapy. CMV reactivation participants showed significant differences in age, ANCA-associated nephritis, hemoglobin level, lymphocyte count, maximum GC dosage, and hemodialysis in univariable analysis. Multivariate analysis showed significantly lower lymphocyte counts in CMV-reactivated patients, but no significant difference in other factors. CONCLUSION: In patients with kidney disease, who require immunosuppressive therapy, CMV reactivation risk is high in patients with low lymphocyte count, and monitoring CMV during the treatment course could lead to early diagnosis and treatment of CMV disease.

Late-Onset Neutropenia after Rituximab Treatment for Adult-Onset Nephrotic Syndrome.

A 41-year-old woman developed nephrotic syndrome at the age of 32 and was diagnosed with minimal change nephrotic syndrome based on a renal biopsy. Although remission was achieved with administration of prednisolone (PSL) and cyclosporine, the nephrotic syndrome recurred. She was also started on rituximab (RTX). She developed late-onset neutropenia after RTX treatment (R-LON) and improved 17 days later. Although the majority of R-LON cases undergo spontaneous remission, cases of death have been reported. This report is intended to warn about R-LON, since the use of RTX for adult-onset nephrotic syndrome is expected to increase in the future.

Fibulin-7, a heparin binding matricellular protein, promotes renal tubular calcification in mice.

Ectopic calcification occurs during development of chronic kidney disease and has a negative impact on long-term prognosis. The precise molecular mechanism and prevention strategies, however, are not established. Fibulin-7 (Fbln7) is a matricellular protein structurally similar to elastogenic short fibulins, shown to bind dental mesenchymal cells and heparin. Here, we report that Fbln7 is highly expressed in renal tubular epithelium in the adult kidney and mediates renal calcification in mice. In vitro analysis revealed that Fbln7 bound heparin at the N-terminal coiled-coil domain. In Fbln7-expressing CHO-K1 cells, exogenous heparin increased the release of Fbln7 into conditioned media in a dose-dependent manner. This heparin-induced Fbln7 release was abrogated in CHO-745 cells lacking heparan sulfate proteoglycan or in CHO-K1 cells expressing the Fbln7 mutant lacking the N-terminal coiled-coil domain, suggesting that Fbln7 was tethered to pericellular matrix via this domain. Interestingly, Fbln7 knockout (Fbln7-/-) mice were protected from renal tubular calcification induced by high phosphate diet. Mechanistically, Fbln7 bound artificial calcium phosphate particles (aCPP) implicated in calcification and renal inflammation. Binding was decreased significantly in Fbln7-/- primary kidney cells relative to wild-type cells. Further, overexpression of Fbln7 increased binding to aCPP. Addition of heparin reduced binding between aCPP and wild-type cells to levels of Fbln7-/- cells. Taken together, our study suggests that Fbln7 is a local mediator of calcium deposition and that releasing Fbln7 from the cell surface by heparin/heparin derivatives or Fbln7 inhibitory antibodies may provide a novel strategy to prevent ectopic calcification in vivo.

Fibroblast growth factor 23 is upregulated in the kidney in a chronic kidney disease rat model.

The hormone fibroblast growth factor 23 (FGF23) is secreted from bone and is involved in phosphorus (P) metabolism. FGF23 mainly binds the FGF receptor, which interacts with αKlotho in the kidney or parathyroid and regulates Na-dependent phosphate co-transporter type IIa (NaPi-IIa) and type IIc (NaPi-IIc) expression, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) activity, and parathyroid hormone (PTH) secretion. In this study, we utilized hemi-nephrectomized rats fed a high-P diet (HP Nx), rats subjected to a partial nephrectomy (PN) and rats with doxorubicin-induced renal failure (DXR) as chronic kidney disease (CKD) animal models and analyzed the P metabolism and FGF23 expression in the kidneys in each CKD model. We cultured HK2 cells with a high level of P, 1,25(OH)2D3 or transforming growth factor-ß1 (TGFß1) to investigate the FGF23 expression mechanism. In both the HP Nx and PN rats, the blood FGF23 and PTH levels were increased. However, the 1,25(OH)2D3 level was increased in the HP Nx rats and decreased in the PN rats. In all three animal models, the mRNA expression of αKlotho, NaPi-IIa and NaPi-IIc was decreased, and the mRNA expression of TGFß1, collagen1a1, osteopontin and FGF23 was elevated in the kidney. FGF23 protein and mRNA were expressed at high levels in the extended tubule epithelium, which was an osteopontin-positive region in the HP and PN rats. FGF23 and osteopontin mRNAs were expressed in HK2 cells incubated with TGFß1; however, these levels were not altered in HK2 cells incubated with 1,25(OH)2D3 and high P levels in vitro. Altogether, FGF23 is expressed in the kidneys in CKD model rats. Following stimulation with TGFß1, the injured renal tubular epithelial cells are strongly suspected to express both FGF23 and osteopontin. FGF23 produced in the kidney might contribute to P metabolism in subjects with CKD.

A case of medullary cystic kidney disease with rapid progressive renal dysfunction and kidney enlargement.

Medullary cystic kidney disease (MCKD) is usually associated with slowly progressive kidney injury. However, we encountered a case of MCKD with rapidly progressive kidney injury and irreversible renal dysfunction. A 63-year-old woman presented with a 4-month history of hypertension and rapidly progressive renal dysfunction. On admission, her blood pressure was slightly elevated (158/85 mmHg). The scrum creatinine (11.57 mg/dL) was markedly elevated. Urinalysis showed occult hematuria and proteinuria(1.06 g/gCr). /ß2- microglobulin 45,000 µg/ L, N-acetyl-/ß-D-glucosaminidase 5.6 U/L. Neither ultrasonography nor computed tomography revealed any evidence of renal medullary cysts. Both kidneys showed an irregular surface and enlargement. Microscopic evaluation of the renal biopsy revealed extensive tubular dilatation and atrophy with interstitial fibrosis. Often glomeruli, one had global sclerosis and the others were normal. The tubular dilatation was more marked in the distal than in the proximal tubules, according to the immunohistochemical findings of positivity for epithelial membrane antigen (EMA), a marker of distal tubules, and negativity for CD 10, a marker of proximal tubules. No immunoglobulin or complement deposition was detected in either the glomeruli or the tubules. Electron microscopy revealed disintegration of the tubular basement membrane with fragile thinning and lamination of the membrane. These pathological findings were compatible with MCKD. This was a case of MCKD diagnosed incidentally in an elderly patient who presented with rapidly progressive kidney injury accompanied by hypertension. Renal biopsy was necessary for the diagnosis.

Combined IgG4κ and IgG1λ deposition in the glomerular and tubular basement membrane accompanied by autoimmune neutropenia (AIN) and immune thrombocytopenia (ITP).

A 48-year-old male was admitted to our hospital with nephrotic syndrome. Light-microscopic examination of a renal biopsy specimen showed almost normal glomerular appearance, however, immunofluorescence examination revealed linear and granular IgG deposits on the glomerular basement membrane (GBM), accompanied by slight IgG deposition in the tubular basement membrane (TBM). Further investigation of the IgG subclass and light chain staining revealed that the glomerular deposits were composed of IgG1 and IgG4, with both κ and λ light chains, while the tubular deposits were composed of only IgG4 and κ light chains. The electron-microscopic findings of small granular deposits in the GBM and TBM closely resembled those of light and heavy chain deposition disease (LHCDD). Immunoelectron microscopy confirmed the presence of κ and λ chains in the GBM and TBM, however, only significant κ chain deposition was found in the TBM. There was no evidence of monoclonal gammopathy. Clinically, the patient subsequently developed neutropenia and thrombocytopenia associated with the presence of anti-neutrophil antibody and anti-GPIIb/IIIa antibody-producing B cells in the blood. Oral steroid administration was initiated, which led to amelioration of the neutropenia, thrombocytopenia and proteinuria. This may be a very rare case of combined IgG4κ and IgG1λ deposition disease accompanied by autoimmune neutropenia (AIN) and immune thrombocytopenia (ITP) suggestive of biclonal immunoglobulin deposition disease (BIDD). Investigation of the IgG subclass and of the light chains was useful for recognizing the clonality of the immunoglobulin deposits in the kidney.

Sphingosine-1-phosphate acts as a key molecule in the direct mediation of renal fibrosis.

The major sphingolipid metabolite, sphingosine-1-phosphate (S1P), has important biological functions. S1P serves as a ligand for a family of five G-protein-coupled receptors with distinct signaling pathways regulating important biological pathways. S1P induces renal fibrosis through an inflammatory pathway. However, its direct fibrosis-inducing effect on the kidney has not been shown. The role of S1P as a direct mediator of renal fibrosis was investigated in normal rat kidney interstitial fibroblast (NRK-49F) cells (in vitro) and kidneys of a unilateral ureteral obstruction (UUO) mouse model (in vivo). To clarify the role of S1P in renal fibrosis, we adopted nude UUO mice with immune response deficits. NRK-49F cells were stimulated with various concentrations of exogenous S1P and FTY720 (a S1P receptor agonist) or N,N-dimethylsphingosine (DMS; a sphingosine kinase inhibitor). C57BL6 and nude UUO mice were pretreated with FTY720, DMS, or saline. Expression levels of alpha-smooth muscle actin (a-SMA), E-cadherin, collagen type 1 (COL1), collagen type 4 (COL4), tissue inhibitor of matrix metalloproteinase-1 (TIMP1), and plasminogen activator inhibitor-1 (PAI1) were examined. S1P stimulated fibrosis in NRK-49F cells and UUO mice. Increased a-SMA, COL1, COL4, TIMP1, and PAI1 and decreased E-cadherin expression levels were observed in both the S1P-stimulated cells and UUO mice. Nude UUO mouse kidneys expressed fibrotic markers. Fibrotic changes were successfully induced in both UUO and nude UUO mice, evident through prominent fibronectin and COL1 staining. These S1P-induced fibrotic changes were suppressed by FTY720 and DMS both in vitro and in vivo. Thus, S1P essentially and directly mediates renal fibrosis.

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.

Beneficial effect of aliskiren combined with olmesartan in reducing urinary protein excretion in patients with chronic kidney disease.

BACKGROUND: Blockade of the renin-angiotensin-aldosterone system is a therapeutic mainstay in patients with chronic kidney disease (CKD). However, the renoprotective effect of the novel direct renin inhibitor aliskiren is unknown. MATERIALS AND METHODS: We performed a prospective study in 10 CKD patients. All 10 patients with persistent proteinuria (urinary protein-to-creatinin ratio 0.3-3.5 g/g), despite good blood pressure control (<130/80 mmHg) with olmesartan, were started on 150 mg/day aliskiren. Clinical parameters were examined before and after 4, 8, 12, and 16 weeks of treatment. RESULTS: Urinary protein-to-creatinine ratio significantly decreased by about 40% at 16 weeks from baseline (P = 0.0002), although estimated glomerular filtration rate and blood pressure did not change throughout the study period. Plasma renin activity also decreased significantly from baseline (P = 0.019), although plasma aldosterone concentration did not change. CONCLUSIONS: Aliskiren combined with olmesartan reduces proteinuria in CKD patients.

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.

Effect of single-dose rituximab on primary glomerular diseases.

BACKGROUND: A paradigm shift from such toxic 'nonspecific' therapies to selective immunomodulating regimens is necessary for glomerular diseases. Rituximab, which acts by inhibiting CD20-mediated B cell proliferation and differentiation, could be effective in the treatment of nephrotic syndrome as shown in recent reports. DESIGN: To assess the effects of rituximab in patients with primary glomerular diseases, including minimal-change disease, immunoglobulin A (IgA) nephropathy, focal segmental glomerulonephritis, membranous nephropathy and membranoproliferative glomerulonephritis, we performed a prospective trial of the effects of single-dose rituximab therapy in 24 patients. We prospectively evaluated the serum and urinary biochemical parameters before and after 6 months of therapy. RESULTS: In all of the patients studied, depletion of CD19 and CD20 cells was noted, with significant reduction in the degree of proteinuria from 3.7 ± 3.4 g/day at baseline to 1.3 ± 2.0 g/day at 6 months after the drug administration (p = 0.002). However, no significant changes of the serum creatinine, urinary RBC sediment, serum CD4/8 or serum IL-4 levels were observed at 6 months after the drug administration. In subjects with IgA nephropathy, while depletion of CD19 and CD20 cells was noted, no significant change in the severity of proteinuria was observed at 6 months after the drug administration as compared with the level at the baseline. CONCLUSION: For the treatment of primary glomerular diseases, the use of a single dose of rituximab is demonstrated with no serious adverse events. Further study of the mechanism of action of rituximab in successfully treated patients could encourage new perspectives in the treatment of primary glomerular diseases.

Three cases of late-onset oligomeganephronia.

Oligomeganephronia is classified as a subgroup of renal hypoplasia, characterized by histopathologic abnormalities which progress to end-stage renal disease (ESRD) by school age. We describe three adult cases of oligomeganephronia who have not yet developed ESRD. We performed a renal biopsy in all of them. The pathological features, consisting of a reduced number of enlarged glomeruli, were diagnostic of oligomeganephronia. It was assumed that the condition had not progressed to ESRD in the patients because the degree of loss of glomeruli may have been milder than that in typical cases of oligomeganephronia.

A case of pulmonary dialysis-related amyloidosis with reticular opacity of the lung in a patient undergoing long-term dialysis.

Dialysis-related amyloidosis (DRA) is one of the most important complications in long-term dialysis patients. Pulmonary involvement in patients with DRA has been rarely described, and lung radiographic findings have not yet been reported. The most common chronic lung disease process in chronic dialysis patients is interstitial fibrosis. This is the first case report of DRA presenting in the lung in a manner resembling interstitial pneumonia. This case study suggests that interstitial pneumonia as a result of DRA should be considered when dyspnoea and reticular opacity of the lung are observed in patients undergoing long-term dialysis.

Association between clinical characteristics and AL amyloid deposition in the kidney.

Renal involvement is very common in AL amyloidosis. Our aim was to investigate associations between the clinical characteristics and renal pathology of patients with AL amyloidosis. The data of 11 adult Japanese patients with AL amyloidosis and renal involvement were analyzed retrospectively. To assess the difference based on the pattern of distribution of amyloid deposition, we divided the patients into a group with the capillary form and a group with the small vessel form, and compared the clinical characteristics of the two groups. Concerning AL amyloidosis, the small vessel form group was associated with cardiac involvement and left ventricular thickening compared with the capillary form group (p = 0.03). There were no significant differences between the groups in the rates of patient survival and renal survival. There was a negative correlation between grade of amyloid deposition and renal survival duration (p = 0.04, r² = 0.66). The degree of amyloid deposition was not correlated with the extent of proteinuria or renal function. These findings suggest that the vascular deposition pattern of amyloid in the kidney is important for determining patient survival and renal outcome.

Risedronate therapy for the prevention of steroid-induced osteoporosis in patients with minimal-change nephrotic syndrome.

BACKGROUND: Minimal-change nephrotic syndrome (MCNS) is treated by the administration of prednisolone (PSL) at high doses. Steroid-induced osteoporosis is a serious adverse effect of this drug. METHODS: Patients with MCNS were randomly assigned to two groups, the risedronate (2.5 mg/day) + alfacalcidol (0.25 µg/day) group (n=20) and the alfacalcidol (0.25 µg/day)-alone group (n=20). All the patients had received PSL and the clinical characteristics were compared between the two groups at baseline and at 12 months. RESULTS: A significant decrease of the mean bone mineral density (BMD) of the lumbar spine from 0.710±0.162 (g/cm(2)) to 0.588±0.125 was observed in the alfacalcidol-alone group (p=0.02), while no such decrease of the bone mineral density was found in the risedronate + alfacalcidol group (0.663±0.169 at baseline and 0.626±0.129 at 12 months). No significant differences in the results of other biochemical tests performed at the baseline and at 12 months were observed between the two groups. The likelihood of development of steroid-induced osteoporosis was influenced by the cumulative dose of PSL, the mean BMD at the baseline, occurrence of disease relapse, and risedronate therapy. CONCLUSION: Risedronate appears to be effective in preventing steroid-induced osteoporosis. It is necessary to use bisphosphonates to maintain the BMD in patients with MCNS receiving prolonged steroid therapy.

[Case of MMF monotherapy for membranous nephropathy].

We report the case of a 58-year-old male patient who visited our hospital for the management of edema and proteinuria. He was diagnosed as having nephrotic syndrome, with serum total protein and albumin levels of 4.6 g/dL and 2.1 g/dL, respectively, and a urinary protein excretion level of 6.0 g/day. A percutaneous renal biopsy showed features of membranous glomerulonephritis, with capillary-wall granular deposits of IgG and C3 on immunofluorescence and subepithelial immune complex deposits on electron microscopy. No other secondary cause of membranous glomerulopathy was found even after extensive investigations. The patient was started on mycophenolate mofetil (MMF) monotherapy (1,500 mg/day), and 18 months after the start of this therapy, the proteinuria decreased to 0.5 g/day, with return to a normal serum albumin level. No digestive symptoms, kidney function worsening or increase in blood pressure were noted during treatment. These findings suggest that MMF monotherapy is effective and safe for the treatment of membranous nephropathy.

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.