Miscarriage-Related Acute Kidney Injury: A Case Report.

Background: Pregnancy-related acute kidney injury (Pr-AKI) is associated with significant maternal and fetal morbidity and mortality, with a three- to four-fold increase in perinatal mortality. Pr-AKI can arise from various obstetric complications, such as hyperemesis gravidarum, septic abortion, hypertensive disorders of pregnancy, pyelonephritis, and antiphospholipid antibody syndrome. Therefore, early diagnosis and appropriate intervention, including the identification of the underlying etiology, are important to effectively manage Pr-AKI. Therefore, we report a case of Pr-AKI after early miscarriage in a patient without hyperemesis gravidarum or septic abortion whose renal function gradually improved postoperatively for miscarriage. Case Presentation: A 34-year-old primigravid woman was referred to us for perinatal management at 6 weeks of gestation. Unfortunately, she was diagnosed with miscarriage 1 week later. The patient had no history of hyperemesis gravidarum or septic abortion; however, she developed oliguria, and her serum creatinine and blood urea nitrogen levels were abnormally increased. Consequently, she underwent a renal biopsy to evaluate renal dysfunction, which indicated tubulointerstitial damage. The patient also underwent manual vacuum aspiration for a miscarriage. Postoperatively, her urine output increased, and her renal function improved. She was determined to have experienced Pr-AKI due to her miscarriage. Conclusion: Our patient had Pr-AKI after a miscarriage in the absence of other causes. This case report highlights the presence of unknown causes of Pr-AKI, warranting further research for the development of preventive interventions.

A report of three cases of patients with tubulointerstitial nephritis with IgM-positive plasma cells, treatment, and serum-IgM as a sensitive marker for relapse.

BACKGROUND: Tubulointerstitial nephritis with IgM-positive plasma cells (IgMPC-TIN) is a newer disease about which there are many unclear points. Glucocorticoid therapy is effective in many cases of IgMPC-TIN; however, relapse during glucocorticoid tapering has been reported. Relapse and its treatment are poorly defined. CASE PRESENTATION: Case 1 was a 61-year-old man with renal dysfunction and proteinuria. Tubulointerstitial nephritis and IgM-positive plasma cells were observed in a renal biopsy. He was diagnosed with IgMPC-TIN accompanied by Fanconi syndrome and distal renal tubular acidosis (d-RTA). Prednisolone (PSL; 30 mg daily, 0.45 mg/kg/day) treatment was highly effective, and PSL was gradually tapered and discontinued after 1 year. However, 1 month after PSL discontinuation, therapeutic markers were elevated. Therefore, PSL (10 mg daily, 0.15 mg/kg/day) was administered, and the markers indicated improvement. Case 2 was a 43-year-old woman referred for renal dysfunction and proteinuria. Laboratory data revealed that she had primary biliary cholangitis (PBC), d-RTA, and Fanconi syndrome. A renal biopsy showed accumulation of IgM-positive plasma cells in the tubulointerstitium without any glomerular changes. A diagnosis of IgMPC-TIN was made and the patient was started on PSL (35 mg daily, 0.6 mg/kg/day). Therapeutic markers decreased immediately and PSL was discontinued after 1 year. Three months later, the proteinuria and Fanconi syndrome worsened. PSL treatment was restarted (20 mg daily, 0.35 mg/kg/day) and markers indicated improvement. Case 3 was a 45-year-old woman with renal dysfunction and proteinuria. Tubulointerstitial nephritis and IgM-positive plasma cells were observed in a renal biopsy. The patient had PBC, Sjögren syndrome, d-RTA, and Fanconi syndrome, and the diagnosis of IgMPC-TIN was made. The patient was started on PSL (30 mg daily, 0.4 mg/kg/day) and disease markers decreased immediately. However, when PSL was tapered to 15 mg daily (0.2 mg/kg/day), the patient's serum IgM levels increased; therefore, we maintained the PSL at 15 mg daily (0.2 mg/kg/day). CONCLUSION: We report three cases of relapsed IgMPC-TIN associated with reduction or discontinuation of glucocorticoid therapy. In these cases, elevation of serum IgM preceded that of other markers such as urinary ß2-microglobulin, proteinuria, and glycosuria. We recommend monitoring serum IgM levels while tapering glucocorticoids; a maintenance dose of glucocorticoid should be considered if relapse is suspected or anticipated.

Changes in erythropoiesis-stimulating agent responsiveness after transfer to combined therapy with peritoneal dialysis and hemodialysis for patients on peritoneal dialysis: A prospective multicenter study in Japan.

INTRODUCTION: Inadequate dialysis and fluid overload are corrected after starting combined therapy with peritoneal dialysis (PD) and hemodialysis (HD). However, the effects on anemia management has not been elucidated. METHODS: We conducted a prospective, multicenter, observational cohort study of 40 PD patients (age, 60 ± 10 years; male, 88%; median PD duration, 28 months) starting combined therapy and investigated changes in several clinical parameters, including erythropoiesis-stimulating agent (ESA) resistance index (ERI). RESULTS: ERI decreased significantly during 6 months after switching to combined therapy (from 11.8 [IQR 8.0-20.4] units/week/kg/(g/dL) to 7.8 [IQR 3.9-18.6] units/week/kg/(g/dL), p = 0.047). Body weight, urinary volume, serum creatinine and the dialysate-to-plasma creatinine ratio (D/P Cr) decreased, whereas hemoglobin and serum albumin increased. In subgroup analysis, the changes in ERI were not affected by cause for starting combined therapy, PD holiday and D/P Cr. CONCLUSION: Although detailed mechanism was unclear, ESA responsiveness improved after switching from PD alone to combined therapy.

MiR-34a induces myofibroblast differentiation from renal fibroblasts.

BACKGROUND: Renal fibrosis is the common outcome of progressive kidney diseases. To avoid dialysis, the molecular mechanism of renal fibrosis must be explored further. MicroRNAs play key roles in renal fibrosis. MiR-34a is a transcriptional target of p53, which regulates the cell cycle and apoptosis. Previous studies demonstrated that miR-34a promotes renal fibrosis. However, the distinct roles of miR-34a in renal fibrosis have not been fully elucidated. Here, we identified the roles of miR-34a in renal fibrosis. METHOD: We first analyzed p53 and miR-34a expression in kidney tissues in s UUO (unilateral ureteral obstruction) mouse model. Then, to confirm the effects of miR-34a in vitro, we transfected a miR-34a mimic into a kidney fibroblast cell line (NRK-49F) and analyzed. RESULTS: We found that the expression of p53 and miR-34a was upregulated after UUO. Furthermore, after transfection of the miR-34a mimic into kidney fibroblasts, the expression of α-SMA was upregulated dramatically. In addition, α-SMA upregulation was greater upon transfection of the miR-34a mimic than upon treatment with TGF-ß1. Moreover, high expression of Acta2 was maintained despite sufficient removal of the miR-34a mimic by changing the medium 4 times during the 9-day culture. After transfection of the miR-34a mimic into kidney fibroblasts, we did not detect phospho-SMAD2/3 by immunoblotting analysis. CONCLUSION: Our study revealed that miR-34a induces myofibroblast differentiation from renal fibroblasts. Moreover, the miR-34a-induced upregulation of α-SMA was independent of the TGF-ß/SMAD signaling pathway. In conclusion, our study indicated that the p53/miR-34a axis promotes the development of renal fibrosis.

Structural changes in renal arterioles are closely associated with central hemodynamic parameters in patients with renal disease.

Although central hemodynamics are known to be closely associated with microvascular damage, their association with lesions in the small renal arteries has not yet been fully clarified. We focused on arterioles in renal biopsy specimens and analyzed whether their structural changes were associated with noninvasive vascular function parameters, including central blood pressure (BP) and brachial-ankle pulse wave velocity (baPWV). Forty-four nondiabetic patients (18-50 years of age) with preserved renal function underwent renal biopsy. Wall thickening of arterioles was analyzed based on the media/diameter ratio, and hyalinosis was analyzed by semiquantitative grading. Associations of these indexes (arteriolar wall remodeling grade index (RG index) and arteriolar hyalinosis index (Hyl index)) with clinical variables were analyzed. Multiple regression analyses demonstrated that the RG index was significantly associated with central systolic BP (ß = 0.97, p = 0.009), serum cystatin C-based estimated glomerular filtration rate (ß = -0.36, p = 0.04), and high-density lipoprotein cholesterol levels (ß = -0.37, p = 0.02). The Hyl index was significantly associated with baPWV (ß = 0.75, p = 0.01). Our results indicate that aortic stiffness and abnormal central hemodynamics are closely associated with renal microvascular damage in young to middle-aged, nondiabetic kidney disease patients with preserved renal function.

Glomerulonephritis Caused by Bartonella spp. Infective Endocarditis: The Difficulty and Importance of Differentiation from Anti-neutrophil Cytoplasmic Antibody-related Rapidly Progressive Glomerulonephritis.

A 65-year-old man with valvular disorder presented to his physician because of widespread purpura in both lower extremities. Blood tests showed elevated serum creatinine levels and proteinase 3-anti-neutrophil cytoplasmic antibody (ANCA) with hematuria, suggesting ANCA-related rapidly progressive glomerulonephritis (RPGN). Although multiple blood cultures were negative, transthoracic echocardiography revealed warts in the valves, and a renal biopsy also showed findings of glomerular infiltration by mononuclear leukocytes and C3 deposition in the glomeruli, suggesting infection-related glomerulonephritis. Later, Bartonella antibody turned positive. Antimicrobial treatment improved the purpura and renal function without any recurrence. ANCA-positive RPGN requires the exclusion of infective endocarditis, especially that induced by Bartonella spp.

Blood pressure management in patients receiving renal replacement therapy.

Hypertension is the most common complication of kidney disease, diabetes, and other cardiovascular diseases. In addition, it is a critical factor in the progression of these diseases, and hence, blood pressure management is highly recommended worldwide, in accordance with the major guidelines. However, there are two blind spots in the management system: one concerns patients with cancer, and the other concerns patients receiving renal replacement therapy. End-stage renal failure is the final stage of hypertension, and nephrologists usually treat hypertension in both nondialysis patients and dialysis patients. Nephrologists first attempt to manage the blood pressure of dialysis patients using the same method employed for nondialysis patients, i.e., by deciding on a target blood pressure at the clinic. However, this is exceedingly difficult because dialysis patients have lost their most important body-fluid autoregulatory mechanism and have varying body weights during the dialysis session. Moreover, numerous lines of evidence and clinicians' observations have suggested that hypotension during a dialysis session leads to an unfavorable prognosis. However, when the target blood pressure is increased to avoid hypotension during a dialysis session, the risk of atherosclerosis and bleeding complications will be increased. Many nephrologists may feel unsure of choosing a target blood pressure using traditional methods. Recently, home blood pressure and average blood pressure have become new indices of blood pressure management. We believe that further advancements of this old and important theme will be possible with new technologies and big-data analytical methods.

rAAV6-mediated miR-29b delivery suppresses renal fibrosis.

BACKGROUND: Previous studies showed that microRNA-29b (miR-29b) inhibits renal fibrosis. Therefore, miR-29b replacement therapy represents a promising approach for treating renal fibrosis. However, an efficient method of kidney-targeted miRNA delivery has yet to be established. Recombinant adeno-associated virus (rAAV) vectors have great potential for clinical application. For kidney-targeted gene delivery, the most suitable AAV serotype has yet to be established. Here, we identified the most suitable AAV serotype for kidney-targeted gene delivery and determined that AAV-mediated miR-29b delivery can suppress renal fibrosis in vivo. METHOD: To determine which AAV serotype is suitable for kidney cells, GFP-positive cells were identified by flow cytometry after the infection of rAAV serotype 1-9 vectors containing the EGFP gene. Next, we injected rAAV vectors into the renal pelvis to determine transduction efficiency in vivo. GFP expression was measured seven days after injecting rAAV serotype 1-9 vectors carrying the EGFP gene. Finally, we investigated whether rAAV6-mediated miR-29b delivery can suppress renal fibrosis in UUO mouse model. RESULTS: We found that rAAV6 vector is the most suitable for targeting kidney cells regardless of animal species in vitro and rAAV6 is the most suitable vector for kidney-targeted in vivo gene delivery in mice. Intra-renal pelvic injection of rAAV vectors can transduce genes into kidney TECs. Furthermore, rAAV6-mediated miR-29b delivery attenuated renal fibrosis in UUO model by suppressing Snail1 expression. CONCLUSION: Our study has revealed that rAAV6 is the most suitable serotype for kidney-targeted gene delivery and rAAV6-mediated miR-29b delivery into kidney TECs can suppress established renal fibrosis.

[Two cases of incidentally detected renal arteriovenous fistula over ten years after renal biopsy].

CASE 1: The case was a 66-year-old Japanese woman. A renal biopsy had been carried out at 53 years of age, and she was diagnosed as IgA nephropathy. Her renal function had been stable at around 0.7 mg/dL of serum creatinine. At 66 years of age, macrohematuria was found and she was admitted to hospital. Enhanced abdominal computed tomography showed left renal arteriovenous fistula (AVF) (21 mm x 10 mm), and hydronephrosis. Her renal AVF was successfully treated with coil embolization, and hydronephrosis was improved with stable renal function. Her AVF was cirsoid type, which is usually congenital, although it was not recognized before the renal biopsy. CASE 2: A 48-year-old Japanese woman was referred to a nephrologist for proteinuria and an elevated serum creatinine level. She had undergone two renal biopsies when she was 14 and 18 years of age and her condition had been diagnosed as chronic glomerulonephritis. However, she had not received any special treatment. Upon abdominal ultrasonography, a right renal AVF (18 mm x 23 mm) was detected. Her aneurysmal type AVF was successfully treated with coil embolization. In these 2 cases, renal biopsy might be a cause of renal AVF. Regular screening test using ultrasonography is recommended to avoid missing remote complications of renal biopsy.

Dietary intake in Japanese patients with kidney transplantation.

BACKGROUND: Kidney transplantation may release the patient receiving dialysis therapy in their life style, especially in restriction of dietary intake. However, their renal functions are not enough to take daily diet without any restriction. In Japan, we have neither standard of diet intake for them, nor data to build it. METHODS: Dietary intake and its satisfaction were surveyed in 62 outpatients who received kidney transplantation in Keio University Hospital using brief-type self-administered diet history questionnaire. RESULTS: Cross-sectional research was carried out in 2013. Estimated GFR of the object was 42 ± 16 ml/min/1.73 m2. One patient was CKD G1 stage, five in G2, 17 in G3a, 24 in G3b, 14 in G4, and one in G5. Urinary protein was shown in 30 % of patients. Their daily intake was 29 ± 8 kcal/kg of energy, 1.1 ± 0.4 g/kg of protein, 9.9 ± 3.6 g of salt. Protein and salt intakes were over comparing the respective standards for CKD in Japan. The patient who have dissatisfaction for their daily diet was significantly decreased from 79 to 4 % after their kidney transplantation. Attentions to overtake were significantly reduced after kidney transplantation from 56 to 8 % for potassium, 55 to 21 % for salt, 50 to 16 % for protein, 35 to 3 % for calcium/phosphate. CONCLUSIONS: Changes in daily diet of the patients with dialysis and kidney transplantation were recognized. The patients who received kidney transplantation would take daily diet according to their renal function although they do not have specific standards.

A new Classification of Diabetic Nephropathy 2014: a report from Joint Committee on Diabetic Nephropathy.

The Joint Committee on Diabetic Nephropathy has revised its Classification of Diabetic Nephropathy (Classification of Diabetic Nephropathy 2014) in line with the widespread use of key concepts, such as the estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD). In revising the Classification, the Committee carefully evaluated, as relevant to current revision, the report of a study conducted by the Research Group of Diabetic Nephropathy, Ministry of Health, Labor and Welfare of Japan. Major revisions to the Classification are summarized as follows: (i) eGFR is substituted for GFR in the Classification; (ii) the subdivisions A and B in stage 3 (overt nephropathy) have been reintegrated; (iii) stage 4 (kidney failure) has been redefined as a GFR <30 mL/min/1.73 m(2), regardless of the extent of albuminuria; and (iv) stress has been placed on the differential diagnosis of diabetic nephropathy versus non-diabetic kidney disease as being crucial in all stages of diabetic nephropathy.

Relationship between dietary protein intake and the changes in creatinine clearance and glomerular cross-sectional area in patients with IgA nephropathy.

BACKGROUND: Dietary protein intake (PI) induces glomerular hyperfiltration and reduced dietary PI can be effective in preserving kidney function. However, there is limited information regarding the relationship between dietary PI and glomerular histological changes in chronic kidney disease. We investigated the relationship between changes in dietary PI and both the changes in creatinine clearance and glomerular histomorphometry in adult patients with IgA nephropathy (IgAN). METHODS: A total of 24 consecutive adult patients with biopsy-confirmed IgAN were enrolled and glomerular histomorphometric variables and clinical variables were investigated. The main clinical variables were differences in creatinine clearance (Ccr) (dCcr) and in PI (dPI) which were calculated by subtracting PI and Ccr values in patients on a controlled diet during hospitalization for kidney biopsy from the respective values in patients on daily diets as outpatients. These values of PI were estimated from urinary urea excretion measured by 24-h urine collection. The main renal histomorphometric variable was glomerular tuft area (GTA) (µm(2)). RESULTS: dCcr positively correlated with dPI (r = 0.726, P < 0.001). GTA correlated positively with dPI (r = 0.556, P = 0.013). Multiple regression analysis showed that dPI was independently associated with both dCcr and GTA. Additionally, GTA positively correlated with dietary PI as outpatients (r = 0.457, P = 0.043). CONCLUSION: Changes in dietary PI were associated with the changes in glomerular filtration rate. Furthermore, histomorphometric findings suggested that a greater dietary PI can affect the glomerular size at the time of the initial diagnostic biopsy for IgAN.

A case-control study of calciphylaxis in Japanese end-stage renal disease patients.

BACKGROUND: Calciphylaxis, also called calcific uremic arteriolopathy, is a rare and often fatal complication of end-stage renal disease and is characterized by painful skin ulceration, necrosis, medial calcification and intimal proliferation of small arteries. Studies in western countries have reported incidences ranging from 1 to 4% in chronic hemodialysis patients. Since no systematic studies of calciphylaxis have ever been performed in Japan, we conducted a nationwide survey and a case-control study to identify the characteristics of calciphylaxis in the Japanese dialysis population. METHODS: Firstly, we sent a questionnaire to 3760 hemodialysis centers in Japan, asking whether calciphylaxis cases had been encountered in the past, and detailed clinical data regarding each case were then collected from the centers. In addition, two control dialysis patients matched for age and duration of hemodialysis to each calciphylaxis case were identified at the participating centers, and their data were analyzed to identify risk factors for calciphylaxis. RESULTS: Responses to the questionnaire were obtained from 1838 centers (48.3%), and 151 centers reported that a total of 249 cases had been encountered. Sixty-four centers agreed to participate in the case-control study, and detailed clinical data in regard to 67 cases were obtained. In 28 of the 67 cases, a definite diagnosis of calciphylaxis was made by our study group based on the clinical characteristics and skin biopsy findings. A univariate logistic regression model comparing them with 56-matched controls identified warfarin therapy [odds ratio (OR) 11.4, 95% confidence interval (CI)] 2.7-48.1, P=0.0009], each 1 g/dL decline in serum albumin level (OR 19.8, 95% CI 4.4-89.5, P=0.0001), each 100 mg/dL increment in plasma glucose level (OR 3.74, 95% CI 1.08-12.9, P=0.037) and each 1 mg/dL increment in adjusted serum calcium level (OR 3.2, 95% CI 1.63-6.30, P=0.0008) at the time of diagnosis as significantly associated with calciphylaxis, but no significant associations were found with female gender, vitamin D analog therapy, serum phosphate level, adjusted calcium-phosphate products or serum alkaline-phosphatase level. Warfarin therapy and lower serum albumin levels were still significant risk factors after a multivariate logistic regression model analysis. CONCLUSION: The results of this study showed that warfarin therapy and lower serum albumin levels are significant and strong risk factors for the development of calciphylaxis in chronic hemodialysis patients in Japan.

Acute kidney injury of non-septic origin requiring dialysis therapy.

Acute kidney injury (AKI) requiring dialysis occurs frequently, and its pathogenesis involves multiple pathways within which hemodynamic, inflammatory and nephrotoxic factors overlap. Several studies have tried to assess the risk factors leading to AKI, and found, among other factors, that preoperative renal dysfunction is important. Currently, it is uncertain when dialysis therapy should start. However, AKI after cardiac surgery should be treated early by continuous hemodialysis.

Close association of vascular and valvular calcification and prognosis of patients on continuous ambulatory peritoneal dialysis.

In the present study, we examined the association between vascular and valvular calcification and the prognosis of patients on continuous ambulatory peritoneal dialysis (CAPD). Data were collected from the records of patients introduced onto CAPD therapy during 1999 - 2006 at the Department of Nephrology, Saitama Medical University. At the start of CAPD, cardiac and vascular echography were used to examine 162 patients (average age: 56 +/- 5 years; 58 men, 104 women; 43 with and 119 without diabetes) for evaluation of vascular and valvular calcification. Both vascular and valvular calcification were found in 32 patients. Vascular calcification was found in 16, and valvular calcification in 11. Over 5 years, 11 patients suffered from cardiovascular disease (7 with stroke, 4 with myocardial infarction). All of these patients had vascular or valvular calcification at the start of CAPD therapy. We also used Cox hazard analysis to examine values for Ca, P, Ca x P, intact parathyroid hormone (iPTH), and lipids. None of these values were independent contributory factors for incidence of cardiovascular disease in patients on CAPD. These data suggest the importance of vascular and valvular echography to evaluate patients on CAPD, especially at the start of CAPD therapy. Vascular and valvular calcification are important factors for determining the prognosis of patients on CAPD.

Risk factors and cause of removal of peritoneal dialysis catheter in patients on continuous ambulatory peritoneal dialysis.

In the present study, we examined the risk factors and causes for removal of the peritoneal dialysis (PD) catheter in patients on continuous ambulatory PD (CAPD). Data were collected from the records of patients who received CAPD therapy from 1995 to 2007 in the Department of Nephrology, Saitama Medical University. During that time, 473 patients were introduced onto CAPD therapy and the PD catheter was removed from 63 patients. Catheters were removed in 30 patients (47%) because of peritoneal infection, in 11 (17%) because of dialysis failure, in 8 (13%) because of neoplasm of the gastrointestinal tract, in 6 (10%) because of perforation of the gastrointestinal tract, in 2 (3%) because of laceration of PD catheter, and in 3 each (5%) because of transplantation and home hemodialysis therapy. Duration of CAPD was 5.6 +/- 1.2 years. In patients who experienced peritoneal infection, causative organisms were Staphylococcus (mainly methicillin-resistant S. aureus), Candida, Pseudomonas, and non tuberculous Mycobacterium. Failure to continue PD therapy related to dialysis deficiency. All patients were examined for encapsulating peritoneal sclerosis (EPS) by computed tomography (CT) enhanced using contrast material. In 9 cases in which the CT findings indicated EPS, treatment with oral prednisolone (20 mg daily) was started; the dose was then gradually reduced over 1 year. After removal of the PD catheter, no patient developed EPS. All removed catheters were examined using electron microscopy. The catheters from patients who experienced PD peritonitis revealed biofilm formation; however, no biofilm formation was found in PD catheters removed from patients without infection. Despite appropriate antibiotic therapy, peritoneal infection remains the major cause of PD catheter removal. Biofilm formation might be an obstacle to PD continuation.

Poly(ADP-ribose) polymerase-1 enhances transcription of the profibrotic CCN2 gene.

In the fibrotic kidney, tubular epithelial cells express CCN2, formerly known as connective tissue growth factor. Because little is known about the transcriptional regulation of this profibrotic protein, this study investigated the mechanism underlying epithelial cell-selective upregulation of CCN2 in fibrosis. It was found that a previously unidentified cis-regulatory element located in the promoter of the murine CCN2 gene plays an essential role in basal and TGF-beta1-induced gene transcription in tubular epithelial cells; this element acts in conjunction with the Smad-binding element and the basal control element-1. By protein mass fingerprint analysis and de novo sequencing, poly(ADP-ribose) polymerase-1 (PARP-1) was identified as a trans-acting protein factor that binds to this promoter region, which we termed the PARP-1-binding element. In vivo, knockdown of PARP-1 in proximal tubular epithelial cells significantly reduced CCN2 mRNA levels and attenuated interstitial fibrosis in the obstructed kidney. Thus, the PARP-1/PARP-1 binding element complex functions as a nonspecific, fundamental enhancer of both basal and induced CCN2 gene transcription in tubular epithelial cells. This regulatory complex may be a promising target for antifibrotic therapy.

Short- and long-term prognosis of blood pressure and kidney disease in women with a past history of preeclampsia.

Little research has been conducted into the long-term effects of preeclampsia, despite its frequent occurrence. The aim of this review is to examine the association between preeclampsia and the development of hypertension and kidney diseases later in life. To achieve this aim, we evaluated three retrospective studies conducted in our department. In the first study, 52 women who suffered from preeclampsia during their first pregnancy were followed for 2 years after delivery for any long-term effects upon blood pressure. In the second study, we evaluated HOMA-R, pulse wave velocity and augmentation index in groups of 48 postmenopausal women with a past history of preeclampsia and 204 postmenopausal women without a past history of preeclampsia. In the third study, we examined the association between a past history of preeclampsia and chronic kidney disease based on biopsy in 127 postmenopausal women. From the first study, although there were no significant differences in age, blood pressure at the onset of preeclampsia, the levels of proteinuria and the birth weight of the child between women who remained hypertensive and those who became normotensive, body mass index was significantly larger in women who remained hypertensive compared to those who were normotensive. In the second study, we found that women with a past history of preeclampsia exhibited insulin resistance combined with reduced vascular elasticity. In the third study, of 32 patients with a past history of preeclampsia, 12 patients exhibited focal segmental glomerulosclerosis, 10 exhibited IgA nephropathy and 10 exhibited nephrosclerosis. In contrast, of the women without a past history of preeclampsia, 26 patients exhibited IgA nephropathy, 20 exhibited a minimal change in nephritic syndrome, 6 exhibited nephrosclerosis, 6 exhibited membranous nephropathy, 5 exhibited lupus nephritis, 5 exhibited diabetic nephropathy, and 27 exhibited various nephropathies. None of the women without a past history of preeclampsia exhibited focal segmental glomerulosclerosis. Taken together with previous results, these findings suggest that hypertension and chronic kidney disease in postmenopausal women are closely associated with a past history of preeclampsia.

Estrogen and angiotensin II interactions determine cardio-renal damage in Dahl salt-sensitive rats with heart failure.

UNLABELLED: In women, the role of estrogen in the interrelationship between the progression of kidney and cardiac diseases is not fully understood. The present study attempted to elucidate the relationship between the process of cardiac remodeling and nephrosclerosis in ovariectomized Dahl salt-sensitive (DSS) rats with myocardial infarction (MI). METHODS: 60 DSS rats with MI produced by ligation of the left coronary artery were divided into 5 groups as follows: group 1: MI rats without ovariectomy (OVX); group 2: MI rats with OVX; group 3: MI and OVX rats with estradiol (E) (17beta-estradiol 15 mg/pellet/90 days subcutaneous pellet) supplementation; group 4: MI rats with OVX administered an angiotensin receptor antagonist (ARB), olmesartan, (2.5 mg/kg b.w. per day), and group 5: MI and OVX rats with E supplementation and administration of ARB in combination. Two weeks after ligation of the left coronary artery, OVX was carried out; this marked the start of the experiment. Body weight, systolic blood pressure (SBP), and urinary protein excretion were measured every 2 weeks for 12 weeks. Transthoracic echocardiogram was performed under anesthesia at 12 weeks. Blood samples for measurement of plasma renin activity, angiotensin (Ang) II, and aldosterone were obtained. At the end of the study, the heart and the kidney tissues were collected for light microscopic examination and evaluations of the expression of mRNA of angiotensin-converting enzyme and endothelial nitric oxide synthase (ecNOS). RESULTS: SBP in female DSS rats with MI and with or without OVX transiently increased at week 4 and then gradually decreased toward the end of the study. Administration of ARB reduced SBP significantly (p < 0.05) in rats with OVX independently of E supplementation. OVX significantly (p < 0.05) increased and E supplementation further increased (p < 0.01) urinary protein excretion. E supplementation plus ARB administration significantly decreased urinary protein excretion. OVX increased activity in renin-angiotensin-aldosterone system (RAS) and both E and ARB supplementation suppressed RAS (p < 0.05). Expression of ecNOS was decreased in the rats with OVX and this was reversed by E supplementation in the heart but not in the kidneys, although combined administration with ARB reversed it in the kidney (p < 0.01). Transthoracic echocardiogram showed decreased ejection fraction by OVX and it was reversed by E supplementation and administration of ARB. Pathological changes of the kidney showed that E supplementation produced thrombotic microangiopathic lesions in the glomeruli. These changes were reversed by concomitant administration of ARB. CONCLUSION: Although estrogen appears to protect the development of cardiac remodeling and heart failure, it promotes microangiopathy in the kidney due to thrombosis. Concomitant administration of estrogen and ARB might be effective for protection of the heart and the kidney in OVX DSS rats with CHF.

Connexins 37 and 40 transduce purinergic signals mediating renal autoregulation.

Our previous data indicated that various subtypes of connexin (Cx) were expressed in the juxtaglomerular apparatus. Experiments were performed to characterize the effects on renal autoregulation of specific mimetic peptides that inhibit these Cx subtypes in Wistar-Kyoto rats. Intrarenal infusion of (Cx37,43)GAP27 increased autoregulatory index of renal plasma flow (0.06 +/- 0.05 to 0.47 +/- 0.06, n = 6, P < 0.05) and glomerular filtration rate (GFR; 0.01 +/- 0.07 to 0.49 +/- 0.07, P < 0.05). The additional administration of 8-cyclopentyl- 1,3-dipropylxanthine (CPX) produced a further elevation of autoregulatory index of RPF (0.86 +/- 0.07, P < 0.05) and GFR (0.88 +/- 0.09, P < 0.05), compared with (Cx37,43)GAP27 alone. However, the addition of pyridoxal-phosphate-6-azophenyl-2,4-disulfonic acid (PPADS) to (Cx37,43)GAP27 did not. Combined treatment with CPX and PPADS markedly worsened autoregulatory index of RPF (0.04 +/- 0.10 to 0.81 +/- 0.06, n = 6 P < 0.01) and GFR (0.05 +/- 0.08 to 0.79 +/- 0.05, P < 0.01). (Cx40)GAP27 induced similar changes to (Cx37,43)GAP27. Renal autoregulation was preserved in the presence of (Cx43)GAP26. Our results indicate that the inhibition of gap junction impaired renal autoregulation. Furthermore, the present data provide evidence that both adenosine and purinergic receptors contribute to glomerular autoregulation. Finally, our findings suggest that gap junctions, at least in part, transduce purinergic signals mediating renal autoregulation.