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Alport syndrome (AS) is a rare hereditary disease that presents with chronic kidney disease and sensorineural hearing loss, and is diagnosed by its clinical features, pathological features on renal tissue, and mode of inheritance. We report a woman in her 20 s who exhibited persistent haematuria with normal renal function and sensorineural hearing loss. Her family members exhibited the same clinical findings among three generations and were suspected of having autosomal dominant AS (ADAS). Renal biopsy showed minor glomerular abnormalities on light microscopy and extensive thinning of the glomerular basement membrane on electron microscopy. Whole-exome analysis revealed a known COL4A4 (type IV collagen α4) mutation (c. 2510 G > C: p. Gly837Ala). Two pedigrees with the same variant have been reported previously, one as ADAS and the other as autosomal recessive AS. However, these two cases exhibited no sensorineural hearing loss. The analysis in the present case revealed another missense variant in ESPN (Espin), an actin-bundling protein, which is a causative gene for sensorineural hearing loss. Although the pathophysiological significance of this novel missense variant needs to be clarified, computational analysis predicted that the variant creates a new phosphorylation site for protein kinase C. Our case suggests a possible association of hereditary sensorineural hearing loss with ADAS. Whole-exome analysis should be considered to diagnose hereditary and multiple-organ disorders.

A 28-year-old woman with systemic lupus erythematosus was referred to our hospital due to nephrotic-level proteinuria despite approximately 1 year of treatment with 50 to 60 mg/d of prednisolone and 100 to 150 mg/d of cyclosporine with methylprednisolone pulse therapy. Kidney biopsy showed diffuse global lupus nephritis (World Health Organization class 4-G A/C) with many intraglomerular foam cells containing cholesterol crystals. Surprisingly, proteinuria diminished after only 5 low-density lipoprotein (LDL) cholesterol apheresis sessions. This case demonstrated the potential of LDL apheresis to exhibit a remarkable effect on not only focal segmental glomerulosclerosis, but also other types of nephritis, particularly nephritis with intraglomerular foam cells.

Nephrosclerosis/ischemic nephropathy (NS/IN) ranks third among renal diseases requiring dialysis in Japan. Although it is an important renal disease in terms of frequency, its prevalence, new incidence, and risk factors are not fully elucidated. We analyzed the prevalence, incidence, concurrent diseases, and risk factors of NS/IN by using data from specific health checkups of Kumamoto citizens between 2008 and 2010. Although the prevalence of NS/IN was 1−2 % in people in their 40s, it increased sharply with age, reaching 17.6 % in people aged 70–74 years. The incidence of new NS/IN was 0.4−0.5 % per year. In multivariate logistic regression analysis, factors such as age, male gender, body mass index (BMI), hyperuricemia, hypertension, and dyslipidemia correlated with NS/IN. When risk factors associated with NS/IN progress were evaluated by multivariate logistic regression analysis, four factors—male gender, hypertension, BMI, and current smoking—significantly correlated. The analysis of Kumamoto citizens aged 40–74 years receiving specific health checkups showed that in addition to hypertension and age that were considered important, male gender and obesity are also risk factors for NS/IS independent from hypertension.

Data regarding renal disease in the elderly (age ≥65 years old) and very elderly (age ≥80 years old) Japanese are extremely limited. The aim of this study was to examine the causes of renal disease and their clinical presentations in elderly patients who underwent renal biopsy.From July 2007 to November 2011, all of the elderly native renal biopsy patients who had been registered in the Japan Renal Biopsy Registry (J-RBR; 2802 including 1596 males and 1206 females) were identified. Their data were compared with a control group of 7416 patients who ranged in age from 20 to 64 years old and were registered on the J-RBR over the same period. In addition, the clinical and pathological classifications of 276 very elderly patients were also analyzed.The indications for biopsy were nephrotic syndrome (NS) in 36.2 and 50.7 % of the elderly and the very elderly patients, chronic nephritic syndrome in 31.8 and 17.4 %, and acute kidney injury including rapidly progressive glomerulonephritis in 18.6 and 22.5 %, respectively. Primary glomerular disease was the most frequent diagnosis, followed by MPO-ANCA-positive nephritis, IgA nephropathy (IgAN), and diabetic nephropathy. In primary GN including IgAN, membranous nephropathy (MN) was the most frequent histological type, followed by IgAN and minor glomerular abnormalities. A comparison with the control group showed that MN, MPO-ANCA-positive nephritis, and amyloid nephropathy were more common in the elderly (P 0.001), and IgAN was less common (P 0.001). As for nephrotic syndrome in the elderly, MN was the most common histological type, followed by minimal change NS, diabetic nephropathy, amyloid nephropathy, and focal segmental glomerulosclerosis. There was a significant discrepancy between the urinary protein/creatinine ratio and daily proteinuria after the 7th decade of life.Renal biopsy is a valuable diagnostic tool, even in elderly and very elderly Japanese patients. In the future, modified clinical guidelines for elderly renal disease should be developed.

A 59-year-old woman with a 10-year history of hemodialysis was admitted to our hospital for painful skin ulcers on her right thigh, right calf, and left upper arm. A whole-body plain computed tomographic scan showed diffuse calcification of the uterus and marked calcification of the mitral valve. Skin biopsy specimens from the left thigh showed calcium deposition in numerous small blood vessels in the dermis and fat, leading to a diagnosis of calcific uremic arteriolopathy (CUA). Despite antibiotic therapy and aggressive wound care for 2 months, the skin ulcers enlarged and the patient's general condition worsened. Surprisingly, oral administration of etidronate disodium (200 mg/d) strikingly improved the focal infection and decreased the size of the skin ulcers within several days. She was discharged from the hospital 2 months later, when epithelialization of the ulcers was almost complete. We report a case of CUA that was improved dramatically by treatment with etidronate. Etidronate therapy should be considered for refractory CUA.

Hyperosmolality in the renal medullary interstitium is generated by the renal countercurrent multiplication system, in which the medullary thick ascending limb (MAL) and the outer medullary collecting duct (OMCD) primarily participate. Since arginine vasopressin (AVP) regulates Na-K-ATPase activity directly via protein kinase A and indirectly via hyperosmolality, we investigated the acute and chronic effects of hyperosmolality on Na-K-ATPase and AVP-dependent cAMP generation in the MAL and OMCD. Microdissected MAL and OMCD from control and dehydrated rats were used for the measurement of Na-K-ATPase activity, mRNA expression of alpha-1, beta-1, and beta-2 subunits of Na-K-ATPase, and AVP-dependent cAMP generation. Na-K-ATPase activity in the MAL from dehydrated rats, as measured in isotonic medium, was higher than that of control rats. Moreover, incubation of samples in hypertonic medium (490 mOsm/kg H2O) further increased Na-K-ATPase activity. Dehydration increased alpha-1, beta-1, and beta-2 mRNA expression in the MAL without changing that in the OMCD. Western blot analysis revealed that in the outer medulla, the expression of beta-1, but not that of alpha-1 or beta-2, was stimulated by dehydration. Incubation of MAL or OMCD in hypertonic medium increased AVP-dependent cAMP generation. Higher levels of AVP-dependent cAMP were generated in the MAL from dehydrated rats than that of controls, although incubation in hypertonic medium did not lead to additional increases in AVP-dependent cAMP accumulation. In contrast, AVP-dependent cAMP generation in the OMCD was stimulated by dehydration, and was further stimulated by incubation in hypertonic medium. These findings demonstrate that Na-K-ATPase is upregulated short- and long-term hyperosmolality in the MAL, but not in OMCD.

Early detection of cysteine rich protein 61 (CYR61, CCN1) in urine following renal ischemic reperfusion injury. Background Acute renal failure (ARF) has a high morbidity and mortality. Many therapies have worked in animals but were unsuccessful in clinical trials. The inability to diagnose ARF early may have impaired the success of these trials. Method We screened a subtraction library to search for potential disease markers that would be induced rapidly after renal injury. Mice and rats were subjected to 30 to 40 minutes of bilateral ischemia. Results mRNA for Cyr61 , a secreted growth factor-inducible immediate early gene, was markedly up-regulated at two hours in the kidney but not other organs following renal ischemia. In situ hybridization studies suggested Cyr61 was synthesized in the proximal straight tubule. Cyr61 protein was analyzed by capture with heparin beads followed by Western blotting. Induction of Cyr61 protein could be detected in the kidney within one hour, peaked at four to eight hours, and remained elevated for at least 24 hours following ischemia. Cyr61 protein was detected in urine at three to six hours and peaked at six to nine hours after renal injury. Cyr61 was not detected after volume depletion, which is often difficult to differentiate from ARF. Conclusions The secreted, cysteine-rich, heparin binding protein Cyr61 is rapidly induced in proximal straight tubules following renal ischemia, and excreted in the urine where it might serve as an early biomarker of renal injury.

Interleukin-10 inhibits ischemic and cisplatin-induced acute renal injury. Background Acute renal failure (ARF) is caused by ischemic and nephrotoxic insults acting alone or in combination. Anti-inflammatory agents have been shown to decrease renal ischemia-reperfusion and cisplatin-induced injury and leukocyte infiltration. Interleukin-10 (IL-10) is a potent anti-inflammatory cytokine that inhibits inflammatory and cytotoxic pathways implicated in acute renal injury. Therefore, we sought to determine if IL-10 inhibits acute renal injury. Methods The effects of IL-10 were studied in mice following cisplatin administration and bilateral renal ischemia-reperfusion, in a rat model of renal transplantation, and in cultured mouse cortical tubule cells. Results IL-10 significantly decreased renal injury following cisplatin administration and following renal ischemia/reperfusion. Delay of IL-10 treatment for one hour after cisplatin also significantly inhibited renal damage. IL-10 and α-melanocyte stimulating hormone (α-MSH) increased recovery following transplantation of a kidney subjected to warm ischemia. To explore the mechanism of action of IL-10, its effects were measured on mediators of leukocyte trafficking and inducible nitric oxide synthase (NOS-II). IL-10 inhibited cisplatin and ischemia-induced increases in mRNA for tumor necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), and NOS-II. IL-10 also inhibited staining for markers of apoptosis and cell cycle activity following cisplatin administration, and nitric oxide production in cultured mouse cortical tubules. Conclusions IL-10 protects against renal ischemic and cisplatin-induced injury. IL-10 may act, in part, by inhibiting the maladaptive activation of genes that cause leukocyte activation and adhesion, and induction of iNOS.

The Japan Renal Biopsy Registry (J-RBR) was started in 2007 and the Japan Kidney Disease Registry (J-KDR) was then started in 2009 by the Committee for Standardization of Renal Pathological Diagnosis and the Committee for the Kidney Disease Registry of the Japanese Society of Nephrology. The purpose of this report is to describe and summarize the registered data from 2009 and 2010. For the J-KDR, data were collected from 4,016 cases, including 3,336 (83.1 %) by the J-RBR and 680 (16.9 %) other cases from 59 centers in 2009, and from 4,681 cases including 4,106 J-RBR cases (87.7 %) and 575 other cases (12.3 %) from 94 centers in 2010, including the affiliate hospitals. In the J-RBR, 3,165 native kidneys (94.9 %) and 171 renal grafts (5.1 %) and 3,869 native kidneys (94.2 %) and 237 renal grafts (5.8 %) were registered in 2009 and 2010, respectively. Patients younger than 20 years of age comprised 12.1 % of the registered cases, and those 65 years and over comprised 24.5 % of the cases with native kidneys in 2009 and 2010. The most common clinical diagnosis was chronic nephritic syndrome (55.4 % and 50.0 % in 2009 and 2010, respectively), followed by nephrotic syndrome (22.4 % and 27.0 %); the most frequent pathological diagnosis as classified by the pathogenesis was IgA nephropathy (31.6 % and 30.4 %), followed by primary glomerular diseases (except IgA nephropathy) (27.2 % and 28.1 %). Among the primary glomerular diseases (except IgA nephropathy) in the patients with nephrotic syndrome, membranous nephropathy was the most common histopathology in 2009 (40.3 %) and minor glomerular abnormalities (50.0 %) were the most common in 2010 in native kidneys in the J-RBR. Five new secondary and longitudinal research studies by the J-KDR were started in 2009 and one was started in 2010.

The Committee for the Standardization of Renal Pathological Diagnosis and the Working Group for Renal Biopsy Database of the Japanese Society of Nephrology started the first nationwide, web-based, and prospective registry system, the Japan Renal Biopsy Registry (J-RBR), to record the pathological, clinical, and laboratory data of renal biopsies in 2007.The patient data including age, gender, laboratory data, and clinical and pathological diagnoses were recorded on the web page of the J-RBR, which utilizes the system of the Internet Data and Information Center for Medical Research in the University Hospital Medical Information Network. We analyzed the clinical and pathological diagnoses registered on the J-RBR in 2007 and 2008.Data were collected from 818 patients from 18 centers in 2007 and 1582 patients from 23 centers in 2008, including the affiliated hospitals. Renal biopsies were obtained from 726 native kidneys (88.8%) and 92 renal grafts (11.2%) in 2007, and 1400 native kidneys (88.5%) and 182 renal grafts (11.5%) in 2008. The most common clinical diagnosis was chronic nephritic syndrome (47.4%), followed by nephrotic syndrome (16.8%) and renal transplantation (11.2%) in 2007. A similar frequency of the clinical diagnoses was recognized in 2008. Of the native kidneys, the most frequent pathological diagnosis as classified by pathogenesis was immunoglobulin (Ig) A nephropathy (IgAN) both in 2007 (32.9%) and 2008 (30.2%). Among the primary glomerular diseases (except IgAN), membranous nephropathy (MN) was the most common disease both in 2007 (31.4%) and 2008 (25.7%).In a cross-sectional study, the J-RBR has shown IgAN to be the most common disease in renal biopsies in 2007 and 2008, consistent with previous Japanese studies. MN predominated in the primary glomerular diseases (except for IgAN). The frequency of the disease and the clinical and demographic correlations should be investigated in further analyses by the J-RBR.

Background/Aims: The blockade of the renin-angiotensin-aldosterone system is the major target of efforts to prevent the progression of chronic kidney disease (CKD). Dual blockade with angiotensin-converting enzyme (ACE) inhibitor and angiotensin II receptor blocker has been reported to show additive renoprotection. However, three types of insertion/deletion (I/D) polymorphism have been reported, and it is unclear whether the dual blockade is effective for all the ACE genotypes. Methods: We treated 93 CKD patients with or without dual blockade and analyzed the effects on blood pressure (BP), proteinuria, progression of CKD and the relationship to I/D ACE polymorphisms. Results: After long-term medication (average 33 ± 2 months), BP decreased in all the genotype groups. However, urinary protein excretion decreased only in the II and DI groups (II: –27.1%, DI: –20.5%, DD: +0.8%). In the II and DI groups, amelioration of the progression of renal failure was correlated with reductions in BP and urinary protein excretion. However, the progression rate of renal failure was not correlated with proteinuria in the DD group. Conclusion: Proteinuria and BP are key factors for the progression of CKD in II/DI patients, while controlling the BP rather than reducing the proteinuria appears to be crucial in DD patients.

Because most angiotensin-converting enzyme inhibitors are excreted into urine, any decrease in renal function increases the plasma levels of these drugs. This study was designed to investigate the appropriate doses of alacepril in patients with chronic renal failure. The total plasma concentration of captopril, an active metabolite of alacepril, was measured in 47 patients with chronic renal failure or normal renal function. Fifteen patients on chronic hemodialysis were also enrolled in this study. In patients treated with 12.5, 25 and 50 mg alacepril, the plasma concentration of captopril was linearly correlated with serum creatinine and creatinine clearance (Ccr). There was an approximately 40% decrease of the plasma captopril concentration after 4 h of hemodialysis. Among patients treated with 25 or 50 mg alacepril for 4.5 years, the plasma concentration of captopril gradually increased along with an increase in serum creatinine (from 2.0 to 5.8, and from 1.9 to 7.1 mg/dL, respectively). Although the plasma concentration of captopril was higher in the 50 mg group, the increase in serum creatinine during this period was not different between the two groups. The plasma aldosterone concentration did not increase during this period. These data suggest that alacepril should be reduced from 50 to 25 and 12.5 mg/day in patients with a serum creatinine level of greater than 2-3 and 4-6 mg/dL, respectively, in order to maintain a plasma level equivalent to that in subjects with normal renal function receiving 50 mg/day alacepril. For patients on chronic hemodialysis, 12.5 mg alacepril is the appropriate dose.

Angiotensin-converting enzyme inhibitors (ACE-I) have a renoprotective effect in patients with chronic renal failure. Prostaglandins (PGs) have also been shown to ameliorate renal impairment. Although these two have different mechanisms-ACE-I reduces intraglomerular pressure by dilating the efferent arterioles, while it is thought that PGs may increase intraglomerular pressure--coadministration of these drugs may have an additive effect. Administration of a PG with an ACE-I might have an additive effect on chronic renal failure. However, there have been no studies on the efficacy of such a combination therapy. This study was conducted to determine whether combination therapy with PGE1 and an ACE-I might have a long-term benefit on chronic renal failure. Sixty patients with chronic renal disease receiving an ACE-I in advance were assigned to receive an ACE-I alone or an ACE-I plus PGE1. Blood pressure, blood chemistry, urinary protein excretion, and the changes in the reciprocal of serum creatinine (delta1/Cr) were monitored once monthly for an average of 36.5 months. In patients treated only with an ACE-I, the progression of renal failure did not change with time. In contrast, the decline of renal function was significantly reduced with the combination therapy. The renoprotective effect of the combination therapy was not exerted by reduced proteinuria or by decreased blood pressure. PGE1 may reinforce the renoprotective effects of ACE-I to prevent the progression of chronic renal failure.

alpha-Melanocyte-stimulating hormone (MSH) is an endogenous anti-inflammatory cytokine that inhibits all major forms of inflammation, alpha-MSH level is increased at sites of inflammation in humans, and is produced in the pituitary and in macrophages. The effects of alpha-MSH are mediated by melanocortin receptors found on macrophages, neutrophils, and renal tubules. alpha-MSH inhibited ischemic acute renal failure in mice and rats, even when started 6 h after injury. alpha-MSH acts, in part, by inhibiting the maladaptive activation of genes that cause inflammatory and cytotoxic renal injury. However, alpha-MSH is effective even in the absence of neutrophils, suggesting that alpha-MSH also acts directly on renal tubules.

Amlal, Hassane, Sulaiman Sheriff, and Manoocher Soleimani. Upregulation of collecting duct aquaporin-2 by metabolic acidosis: role of vasopressin. Am J Physiol Cell Physiol 286: C1019–C1030, 2004. First published December 24, 2003; 10.1152/ajpcell.00394.2003.—Metabolic acidosis is associated

Dialysate contents of 17-hydroxycorticosteroids (17-OHCS) in hemodialysis patients were studied as a potential measure of adrenocortical function. Dialysate 17-OHCS contents after a 2-day interval of hemodialysis in 15 hemodialysis patients were determined. Dialysate 17-OHCS increased after intravenous injection of cortisol the evening prior to hemodialysis (n = 4). Dialysate 17-OHCS content was suppressed, as was plasma cortisol, after a standard dexamethasone (Dex) suppression test (n = 1). Their plasma cortisol was suppressible or nonsuppressible by an overnight Dex suppression test, as reported previously. However, basal dialysate 17-OHCS contents were not different between them, indicating that the nonsuppressible patients with overnight Dex seem not to have hypercortisolism. We conclude that determination of dialysate 17-OHCS seems a useful noninvasive technique for the evaluation of adrenocortical function in hemodialysis patients.