Kidney function, blood pressure and proteinuria were associated with pregnancy outcomes of pregnant women with chronic kidney disease: a single-center, retrospective study in the Asian population.

BACKGROUND: Studies among pregnant Asian women with chronic kidney disease (CKD) have not been widely performed; therefore, clinical criteria for these patients have not been well established. METHODS: We conducted a retrospective study among pregnant women with CKD who received prenatal care at our institution for 8 consecutive years. Primary outcome was the development of severe adverse events (SAEs). We analyzed correlations between primary outcome and CKD parameters [age, body mass index (BMI), estimated glomerular filtration rate (eGFR), urinary protein-creatinine ratio (UP), systolic blood pressure (SBP), diastolic blood pressure (DBP), and not normal blood pressure (non-NBP)] at the time of referral. Secondary outcomes were low birth weight (LBW), preterm delivery (PreD), and small for gestational age (SGA). We divided into two categories, CKD stage G1, and G2 or higher according to eGFR, and proteinuria negative and proteinuria positive according to UP, respectively. RESULTS: We observed 89 pregnancies. SAE was observed in 28 pregnancies. In live birth cases, there were 28 PreD, 28 LBW and 13 SGA. Major SAEs included preeclampsia, superimposed preeclampsia, unscheduled cesarean section, neonatal intensive care unit admission, and fetal death. Stepwise logistic regression analysis selected eGFR (OR = 0.847, p = 0.026), SBP (OR = 1.897, p = 0.006) and proteinuria positive (OR = 2.96, p = 0.046) as the significant predictors of SAEs. There were no significant differences among the baseline characteristics stratified by SGA. CONCLUSIONS: This is the first study to report pregnancy outcomes among Japanese non-disease-oriented patients with CKD. In Asians, especially in the Japanese population, kidney function, blood pressure and proteinuria might affect pregnancy outcomes.

Questionnaire survey on the prescription of renal replacement therapy for acute phase patients on maintenance dialysis who developed cerebrovascular disease.

BACKGROUND: There is limited information about acute phase renal replacement therapy (RRT) for maintenance hemodialysis patients after the onset of cerebrovascular disease. This study aimed to investigate which modality of renal replacement therapy is currently selected in practice. METHODS: We conducted a mail-based survey in 317 dialysis facilities that were certified by three academic societies that focus on dialysis, neurology, and neurosurgery in Japan. RESULTS: We received responses from 103 facilities (32.5%). In cases of cerebral infarction (CI) and intracerebral hemorrhage (ICH), more than 80% of the facilities selected only intermittent RRT, and 22.3% (CI)/8.7% (ICH) of the facilities selected intermittent HD which is the same setting in normal conditions. Although continuous hemodiafiltration and peritoneal dialysis are recommended in the Japanese guidelines, these were selected in only a few facilities: 16.5% and 0% in CI, 16.5% and 1% in ICH, respectively. RRT on the day of onset tended to be avoided, irrespective of the duration following the last HD session. Furthermore, physicians preferred to modify anticoagulants and reduce dialysis performance in the acute phase. CONCLUSION: This questionnaire survey uncovered a gap between guidelines and actual practice, even in hospitals accredited as educational facility, which is a novel and important finding. Further studies with larger sample sizes are needed to determine the optimal modality of RRT for the acute phase of cerebrovascular disease.

Low-energy extracorporeal shock wave ameliorates ischemic acute kidney injury in rats.

BACKGROUND: Low-energy extracorporeal shock wave (SW) improves ventricular function in ischemic cardiomyopathy through the upregulation of vascular endothelial growth factor (VEGF). VEGF is known to play important roles in acute kidney injury (AKI), and the present study investigates the efficacy of SW for AKI by renal ischemia-reperfusion (I/R) injury. METHODS: Male 8-week-old Sprague-Dawley rats were divided into the following groups: SW-treated I/R group (I/R-SW), untreated I/R group (I/R), and Sham group. To induce I/R, the left renal pedicles were clamped for 45 min. The I/R-SW group was treated with SW to both kidneys on the immediate postoperative period (day 0), days 1, 2, 7, 8, 9, 14, 15, and 16. Rats were killed on day 2 and day 20 to determine histology, renal function, and Vegf family mRNA expression. RESULTS: Plasma creatinine on day 2 was significantly lower in the I/R-SW group than in the I/R group. Light microscopy revealed significantly lower tubular injury scores for the outer medulla in the I/R-SW group than in the I/R group. Podoplanin-positive lymphatic vessels were significantly increased in the left (affected side) outer medulla in the I/R-SW group on day 20. The expression levels of Vegf in the right (intact side) cortex were significantly higher in the I/R-SW group than in the I/R group on day 2. CONCLUSION: Shock wave ameliorated renal tubular injury and renal function in AKI model, through the stimulation of Vegf family expression and lymphangiogenesis. SW may be effective as a non-invasive treatment for ischemic AKI.

Amiodarone-induced syndrome of inappropriate antidiuresis with hepatic transaminitis.

A 72-year-old woman with hypertrophic cardiomyopathy was admitted to the hospital after an appropriate implantable cardioverter-defibrillator shock for ventricular fibrillation. She was discharged after the addition of amiodarone. Eight months after discharge, she was admitted to the hospital with a sign of somnolence. She had low levels of serum sodium and plasma osmolality, as well as hepatic transaminitis. She underwent a computed tomography scan, which detected high liver density. Amiodarone-induced syndrome of inappropriate antidiuresis with hepatic transaminitis was diagnosed, and amiodarone was discontinued. After discharge, her hepatic transaminitis improved, and there was no recurrence of hyponatremia with a sign of somnolence. Amiodarone is an important drug used to treat ventricular arrhythmias. However, it has a variety of adverse effects. Syndrome of inappropriate antidiuresis is a rare complication of amiodarone. If hyponatremia occurs after starting amiodarone, this complication should be considered. Learning objective: Amiodarone is an important drug used to treat ventricular arrhythmias, such as ventricular tachycardia and ventricular fibrillation. However, amiodarone has a variety of adverse effects. Syndrome of inappropriate antidiuresis is a rare complication of amiodarone. If hyponatremia occurs after starting amiodarone, this complication should be considered.

[The effects and new insights of ARB on CKD management].

Increasing number of patients suffer from chronic kidney disease (CKD) all over the world. CKD is a risk factor of cardiovascular disease as well as end-stage renal disease. The strategy to reduce CKD patients is pivotal for public health. The most useful treatment is to control blood pressure. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) are now recommended as the first choice. The recent clinical studies have provided more and more evidence that ARB is effective for CKD management. A part of mechanisms is beyond blood pressure lowering. Oxidative stress and inflammation may be involved in the mechanisms.

A Catastrophic Case of Idiopathic Cholesterol Crystal Embolism with Multiple Lethal Complications: A Labyrinth Underneath the Diagnosis of Skin Ulcers in Chronic Kidney Disease Patients.

A 66-year-old man was admitted to our hospital because of multiple refractory skin ulcers. Based on his severe systemic arterial calcification and severe calcium-phosphate imbalance due to severe kidney dysfunction, we initially considered calciphylaxis. However, a skin biopsy provided a diagnosis of cholesterol crystal embolization. Although we initiated hemodialysis, steroid treatment, and low-density lipoprotein-cholesterol apheresis, he died of multiple intestinal perforation. An autopsy showed cholesterol crystals occluding multiple organ arterioles. This case suggests that skin ulcers in patients with chronic kidney disease may be an important diagnostic hallmark and may be associated with several serious diseases.

(Pro)renin receptor is involved in mesangial fibrosis and matrix expansion.

(Pro)renin receptor [(P)RR] is expressed in the kidney and is involved in renal injury. Although (P)RR is activated by indoxyl sulfate (IS) and may be related to renal injury, the details remain unclear. We used mouse mesangial cell line SV40 MES13 to investigate the association of (P)RR with mesangial fibrosis or expansion. Furthermore, we examined the correlation between serum soluble (P)RR [s(P)RR] and various laboratory data including serum IS, a uremic toxin that induces renal fibrosis through (P)RR, and pathological indices in chronic kidney disease and particularly in IgA nephropathy patients. In vitro study using SV40 MES13 cells revealed that (P)RR expression significantly increased in the presence of IS. IS stimulated the fibrotic factors' expression, which was significantly suppressed by (P)RR knockdown. Moreover, it significantly increased the expression of matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 via the ERK1/2 pathway. In addition, the s(P)RR level significantly correlated with serum IS and mesangial injury markers in our patients. Our results suggest that (P)RR is associated with mesangial fibrosis and matrix expansion through the IS-(P)RR-ERK1/2 pathway. Clinically, s(P)RR may be a biomarker of mesangial fibrosis and matrix expansion.

Focal Segmental Glomerulosclerosis Associated with Chronic Progressive External Ophthalmoplegia and Mitochondrial DNA A3243G Mutation.

Focal segmental glomerulosclerosis (FSGS) is caused by various etiologies, with mitochondrial dysfunction being one of the causes. FSGS is known to be associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), which is a subclass of mitochondrial disease. However, it has rarely been reported in other mitochondrial disease subclasses. Here, we reported a 20-year-old man diagnosed with FSGS associated with chronic progressive external ophthalmoplegia (CPEO) due to mitochondrial DNA (mtDNA) 3243A>G mutation. He presented with left ptosis, short stature, mild sensorineural deafness, and cardiac conduction block. A renal biopsy sample showed segmental sclerosis and adhesions between capillaries and Bowman's capsule, indicating FSGS. Electron microscopy demonstrated abnormal aggregated mitochondria in podocytes, and the basement membrane and epithelial cells of Bowman's capsule. Skeletal muscle biopsy also showed accumulation of abnormal mitochondria. mtDNA analysis identified heteroplasmic mtDNA 3243A>G mutation with no large-scale deletions. From these findings, we diagnosed the case as CPEO with multi-organ involvement including FSGS. Our report demonstrates that CPEO, as well as MELAS, can be associated with FSGS. Because mitochondrial disease presents with a variety of clinical symptoms, atypical cases with non-classical manifestations are observed. Thus, mitochondrial disease should be considered as an underlying cause of FSGS with systemic manifestations even with atypical phenotypes.

Concurrent isolated IgG2-positive membranous nephropathy and malignant B-cell lymphoma.

A recent systematic review showed that hematological malignancy is often complicated by membranous nephropathy (MN). Histologically, the deposition of IgG subclasses other than IgG4 may imply secondary MN, such as malignancy-associated MN (M-MN). We describe a very rare case of concurrent isolated IgG2-positive MN and B-cell lymphoma. An 83-year-old woman was hospitalized at our institute for facial and lower extremity edema persisting for 2 months. Laboratory tests showed urinary protein level of 10.8 g/day, serum albumin level of 1.6 g/dl, and serum creatinine level of 2.34 mg/dl. Soon after diagnosis of nephrotic syndrome, treatment with corticosteroid was initiated, but it proved to be ineffective. Renal biopsy showed isolated IgG2-positive MN with highly infiltrated CD20-positive lymphoid cells in the kidney. Computed tomography revealed systemic lymphadenopathy, and aberrant B-cells with immunoglobulin light chain restriction were detected in peripheral blood and bone marrow, which led to the diagnosis of mature B-cell lymphoma. Although rituximab (375 mg/m2/week) was administered, the patient suddenly died from gastrointestinal bleeding on day 40 of hospitalization. It is, thus, necessary to consider hematological malignancy when a diagnosis of MN is made. Further studies are expected to elucidate the pathogenesis and to help establish the adequate treatment for this rare situation.

Marked recovery of severe renal lesions in POEMS syndrome with high-dose melphalan therapy supported by autologous blood stem cell transplantation.

POEMS syndrome is a rare plasma cell disorder, characterized by polyneuropathy, organomegaly, endocrinopathy, serum monoclonal protein, and skin lesions. Although not included in the acronym, renal lesions also are characteristic of this disease and sometimes require dialysis therapy. We treated a 61-year-old woman with POEMS syndrome with high-dose melphalan therapy (HDT) supported by autologous blood stem cell transplantation (SCT), and clinical remission was achieved. A repeated renal biopsy showed the striking effectiveness of this therapy on renal lesions. Pathological features of the renal lesions, such as membranoproliferative glomerulonephritis-like lesions, microangiopathic glomerulopathy, and mesangiolytic lesions with microcapillaries, almost completely disappeared. This treatment also markedly decreased serum levels of vascular endothelial growth factor (VEGF). These findings indicate that HDT with SCT is effective, even on renal lesions in patients with POEMS syndrome, and suggest that high serum VEGF concentrations are associated closely with the development of renal lesions in patients with this type of plasma cell disorder.

Synovitis in a Patient with IgG4-related Disease.

A 71-year-old man was admitted to our department due to arthralgia and renal dysfunction. A physical examination disclosed swelling of the right shoulder and left wrist joints. Laboratory tests showed elevated serum IgG4 and creatinine levels, and magnetic resonance imaging of the wrist revealed bone erosion and synovitis. In addition, fluorodeoxyglucose positron emission tomography showed uptake in the submandibular glands, pancreas, kidneys, and affected joints and a renal biopsy revealed tubulointerstitial nephritis with the infiltration of IgG4+ plasma cells. The patient was subsequently diagnosed with IgG4-related disease (IgG4-RD) and successfully treated with corticosteroid therapy. This case suggests that erosive arthritis may occur in patients with IgG4-RD.

Fabry's disease discovered with chance urinary mulberry cells: a case report.

Fabry's disease (FD) is a rare X-linked lysosomal storage disorder. Novel enzyme replacement therapy (ERT) at an early stage can slow the progression of cardiovascular and renal dysfunction. Urinary mulberry cells are occasionally found in renal FD. We report a case of variant FD in which detection of urinary mulberry cells led to an early diagnosis. A 36-year-old Japanese man was referred to our hospital because mulberry cells had been detected during urinalysis. Proteinuria and renal dysfunction were not observed. His plasma alpha-galactosidase activity was very low. Renal biopsy revealed typical foamy changes in the glomerular podocytes and tubular epithelial cells that are found in renal FD. Based on the detection of urinary mulberry cells, we successfully started ERT before the patient's renal function deteriorated. Clinical nephrologists and laboratory technicians should recognize the importance of screening for mulberry cells during urinalysis as this is a simple, inexpensive, and non-invasive method for diagnosing FD.

Losartan modulates muscular capillary density and reverses thiazide diuretic-exacerbated insulin resistance in fructose-fed rats.

The renin-angiotensin system (RAS) is involved in the pathogenesis of insulin sensitivity (IS). The role of RAS in insulin resistance and muscular circulation has yet to be elucidated. Therefore, this study sought to determine the mechanisms of angiotensin II receptor blockers (ARBs) and/or diuretics on IS and capillary density (CD) in fructose-fed rats (FFRs). Sprague-Dawley rats were fed either normal chow (control group) or fructose-rich chow for 8 weeks. For the last 4 weeks, FFRs were allocated to four groups: an FFR group and groups treated with the thiazide diuretic hydrochlorothiazide (HCTZ), with the ARB losartan, or both. IS was evaluated by the euglycemic hyperinsulinemic glucose clamp technique at week 8. In addition, CD in the extensor digitorum longus muscle was evaluated. Blood pressure was significantly higher in the FFRs than in the controls. HCTZ, losartan and their combination significantly lowered blood pressure. IS was significantly lower in the FFR group than in the controls and was even lower in the HCTZ group. Losartan alone or combined with HCTZ significantly increased IS. In all cases, IS was associated with muscular CD, but not with plasma adiponectin or lipids. These results indicate that losartan reverses HCTZ-exacerbated insulin resistance, which can be mediated through the modulation of muscular circulation in rats with impaired glucose metabolism.

Role of specific T-type calcium channel blocker R(-) efonidipine in the regulation of renal medullary circulation.

OBJECTIVES: Blockade of the T-type calcium channel (TCC), which is expressed in the renal efferent arterioles of the juxtamedullary nephron and vasa recta, has been shown to protect against renal injury. Studies were designed to determine the effects of a specific TCC blocker, R(-) efonidipine [R(-)EFO], on the regulation of renal circulation. METHODS AND RESULTS: Renal medullary blood flux (MBF) and cortical blood flux (CBF) were simultaneously monitored using laser-Doppler flowmetry in Sprague-Dawley rats. Responses were also determined in rats with angiotensin II (AngII) induced renal ischemia. Intravenous (i.v.) or renal interstitial (r.i.) infusion of R(-)EFO (0.25 mg/h, i.v. or r.i.) significantly increased MBF by 24.0 ± 7.0 and 21.0 ± 4.4%, respectively, but without changing CBF or mean arterial pressure. The nitric oxide (NO) synthase inhibitor NG-nitro-L-argininemethylester (L-NAME, 1 µg/kg per min, i.v. or r.i.) significantly attenuated R(-)EFO-induced increase in MBF. R(-)EFO inhibited the AngII-mediated (50 ng/kg per min, i.v.) reduction of MBF (28.4 ± 1.7%), which was associated with increased urinary NO(2) + NO(3) excretion and decreased urinary hydrogen peroxide (H(2)O(2)) excretion. Intracellular H(2)O(2) fluorescence (real-time fluorescence imaging) in the epithelial cells of isolated medullary thick ascending limb (mTAL) significantly increased following AngII stimulation (1 µmol/L, 235 ± 52 units), which was significantly inhibited by pre and coincubation with R(-)EFO. R(-)EFO stimulation also increased the intracellular NO concentration in the epithelial cells of mTAL (220 ± 62 units). CONCLUSION: These results suggest that TCC blockade with R(-)EFO selectively increases MBF, an effect that appears to be mediated by changes in renal NO and oxidative stress balance, which may protect against ischemic renal injury in the renal medullary region.

Characteristics of the antibodies of two patients who developed daytime hyperglycemia and morning hypoglycemia because of insulin antibodies.

We encountered two patients who developed daytime hyperglycemia and early morning hypoglycemia because of insulin antibody (IA) that the affinity was extremely lower and the capacity extremely higher than those of IA in the insulin autoimmune syndrome, after their insulin treatment were changed from human insulin to analog insulin.

Blockade of angiotensin II type-1 receptor increases salt sensitivity in Sprague-Dawley rats.

This study determined the role of angiotensin II type-1 (AT1) receptor in the salt sensitivity of blood pressure. The mean arterial blood pressure (MAP) of Sprague-Dawley rats was monitored by radio telemetry and, after baseline measurements, rats were treated either with (1) vehicle, (2) AT1 receptor blocker (ARB) olmesartan (OLM, 100 nmol kg(-1) h(-1), subcutaneously), (3) OLM with hydrochlorothiazide (HCTZ, 40 mg kg(-1) day(-1), orally), (4) angiotensin II (AngII, 100 ng kg(-1) min(-1), subcutaneously) or with (5) AngII with OLM. Rats were fed a 0.5% salt diet during the baseline and first 7 days of treatment period, and the diet was then switched to one containing 8% salt for another 7 days. Urinary samples were collected in a metabolic cage at the end of each period. MAP of the vehicle group did not change throughout the study. In AngII-infused rats, BP increased only when rats were fed an 8% salt diet. OLM and OLM with AngII significantly reduced MAP when rats were on a 0.5% salt diet, but not on an 8% salt diet, indicating an enhanced salt sensitivity by OLM. Co-treatment with HCTZ reduced the salt sensitivity of OLM. The urinary level of the oxidative stress marker was increased by an 8% salt diet and was not altered by either OLM alone or in combination with HCTZ. However, OLM attenuated the salt-induced renal NAD(P)H (nicotinamide adenine dinucleotide phosphate) oxidase activity. These results indicate that AT1 receptor blockade increases salt sensitivity, which is reversed by diuretics. We conclude that OLM and HCTZ could be a useful combination for reduction of blood pressure even under high salt intake without changes in urinary oxidative stress levels.