Homoarginine is an amino acid derivative mainly synthesized in the kidney. It is suggested to increase nitric oxide availability, enhance endothelial function and to protect against cardiovascular diseases. We aimed to investigate the relation between homoarginine, kidney function and progression of chronic kidney disease (CKD).We measured plasma homoarginine concentrations in baseline samples of the Mild to Moderate Kidney Disease (MMKD) Study, a prospective cohort study of 227 patients with CKD in Europe. Homoarginine concentrations were available in 182 of the baseline samples and in 139 of the prospectively-followed patients. We correlated homoarginine concentrations to parameters of kidney function. The association between homoarginine and progression of CKD was assessed during a follow-up of up to seven years (median 4.45 years, interquartile range 2.54-5.19) using Cox regression analysis. Progression of CKD was defined as doubling of baseline serum creatinine and/or end-stage renal disease.Study participants were at baseline on average 47±13 years old and 65% were male. Mean±standard deviation of homoarginine concentrations were 2.5±1.1 µmol/L and concentrations were incrementally lower at lower levels of GFR with mean concentrations of 2.90±1.02 µmol/L (GFR>90 ml/min), 2.64±1.06 µmol/L (GFR 60-90 ml/min), 2.52±1.24 µmol/L (GFR 30-60 ml/min) and 2.05±0.78 µmol/L (GFR<30 ml/min), respectively (p = 0.002). The age- and sex-adjusted risk to reach the renal endpoint was significantly higher by 62% with each decrease by one standard deviation (1.1 µmol/L) of homoarginine (HR 1.62, 95% CI 1.16-2.27, p = 0.005). This association was independent of proteinuria (HR 1.56, 95% CI 1.11-2.20, p = 0.01), and was slightly attenuated when adjusting for GFR (HR 1.40 (95% CI 0.98-1.98, p = 0.06).Homoarginine concentrations are directly correlated with kidney function and are significantly associated with the progression of CKD. Low homoarginine concentrations might be an early indicator of kidney failure and a potential target for the prevention of disease progression which needs further investigations.

Fabry's disease results from an inborn error of glycosphingolipid metabolism that is due to deficiency of the lysosomal hydrolase α-galactosidase A. This X-linked defect results in the accumulation of enzyme substrates with terminally α-glycosidically bound galactose, mainly the neutral glycosphingolipid Globotriaosylceramide (Gb3) in various tissues, including the kidneys. Although end-stage renal disease is one of the most common causes of death in hemizygous males with Fabry's disease, the pathophysiology leading to proteinuria, hematuria, hypertension, and kidney failure is not well understood. Histological studies suggest that the accumulation of Gb3 in podocytes plays an important role in the pathogenesis of glomerular damage. However, due to the lack of appropriate animal or cellular models, podocyte damage in Fabry's disease could not be directly studied yet. As murine models are insufficient, a human model is needed. Here, we developed a human podocyte model of Fabry's disease by combining RNA interference technology with lentiviral transduction of human podocytes. Knockdown of α-galactosidase A expression resulted in diminished enzymatic activity and slowly progressive accumulation of intracellular Gb3. Interestingly, these changes were accompanied by an increase in autophagosomes as indicated by an increased abundance of LC3-II and a loss of mTOR kinase activity, a negative regulator of the autophagic machinery. These data suggest that dysregulated autophagy in α-galactosidase A-deficient podocytes may be the result of deficient mTOR kinase activity. This finding links the lysosomal enzymatic defect in Fabry's disease to deregulated autophagy pathways and provides a promising new direction for further studies on the pathomechanism of glomerular injury in Fabry patients.

A retrospective study was performed using 53 client owned dogs with leishmaniasis to determine whether the degree of proteinuria, evaluated by the urine protein/creatinine ratio (UP/C), changes following treatment with meglumine antimoniate and allopurinol. Medical records of dogs with leishmaniasis in clinical stage C (according to the Canine Leishmaniasis Working Group staging system) and either proteinuric or borderline proteinuric (according to the International Renal Interest Society [IRIS] staging system) were reviewed. All dogs were treated with meglumine antimoniate and allopurinol for 4-8 wk. After treatment, UP/C, total protein, and total globulin significantly decreased and albumin and the albumin/globulin ratio (A/G) increased. After treatment, 7 of the 53 dogs (13.4%) became nonproteinuric following either a proteinuric or borderline proteinuric stage. Moreover, 12 of the 53 proteinuric dogs (22.6%) changed their stage to borderline proteinuric. The antileishmaniasis treatment with meglumine antimoniate in combination with allopurinol in dogs significantly reduced the degree of proteinuria in a short period of time. The results of the current study may be useful to the veterinary practitioner in the clinical management of canine leishmaniasis (CanL) in dogs with proteinuric chronic kidney disease.

In cardiorenal syndrome (CRS) type 2, chronic heart failure (HF) results in the onset or progression of chronic kidney disease (CKD). Examples of CRS type 2 (CRS2) include progressive CKD resulting from chronic HF in congenital or acquired heart disease or from repeated bouts of acute decompensated HF. Animal data and clinical studies indicate that extended periods of chronic HF result in altered renal hemodynamics followed by progressive renal pathology. Experimental and clinical data indicate that CRS2 is characterized by mild to moderate proteinuria, a progressive decline of glomerular filtration rate, and an elevated expression of renal injury biomarkers. Important pathophysiological triggers of renal disease progression include chronic increases in renal venous pressure, maladaptive activation of the renin-angiotensin-aldosterone axis and the sympathetic nervous system, as well as a chronic inflammatory state. Intrarenal oxidative stress and proinflammatory signaling precipitate structural injury, including glomerulosclerosis and tubulointerstitial fibrosis. Yet, clinical interventional trials that directly test the impact of renin-angiotensin system antagonists and β-blockers on the progression of CKD in CRS2 are lacking. Secondary analyses of trials designed to assess the impact of these agents on cardiovascular endpoints have failed to show a consistent benefit regarding renal functional parameters. In contrast, left ventricular assist device placement and cardiac resynchronization therapy in HF patients consistently improved renal function, suggesting a marked potential for reversibility in many cases of CRS2. Future research should be directed towards the evaluation of novel biomarkers to improve the diagnosis, severity grading as well as our understanding of the pathophysiology of CRS2. In addition, there is a need for interventional trials in HF patients to address long-term renal endpoints incorporating clinical information and measures of renal function as well as renal injury.

Background:

Mycophenolate (MF) is effective as a maintenance therapy after induction therapy in patients with lupus nephritis (LN). However, little is known about its role in patients with impaired renal function. The purpose of this study was to evaluate the efficacy and safety of MF as a maintenance therapy for LN and its association with renal function.

Methods:

Data were obtained for 56 Spanish patients who were receiving MF as a maintenance therapy for LN. Patients were classified into two groups according to renal function at the initiation of MF treatment: group 1 [estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73 m(2)] and group 2 (eGFR <60 ml/min/1.73 m(2)). The primary endpoints of the study were the rates of renal relapse and responses, and their relationship with baseline renal function. Secondary outcomes were the appearance of side effects during treatment.

Results:

At initiation of MF treatment, the only differences between the groups were for age, hemoglobin levels, anti-DNA antibody titer, proteinuria, and renal function. In group 1 (n = 38), the eGFR was 98 ± 34 ml/min/1.73 m(2) and in group 2 (n = 18) the eGFR was 43 ± 14 ml/min/1.73 m(2). Only 3 cases had an eGFR <30 ml/min/1.73 m(2). No significant differences were observed in the rate of relapse at 6 months (group 1: 20%; group 2: 23%) or at 12 months (group 1: 25%; group 2: 17%). Response rates were also similar in both groups. Side effects were unremarkable.

Conclusions:

MF is effective and safe as a maintenance therapy for LN both in patients with normal renal function and in those with renal impairment.

C3 glomerulopathy is a recent disease classification comprising several rare types of glomerulonephritis, including dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). The most common histological feature in these diseases is the presence of glomerular deposition of C3 within the mesangium and along the glomerular basement membrane (GBM) in the subendothelial area or within the GBM. The key role of complement alternative pathway (AP) in these disorders has been recently shown with the identification of acquired or genetic abnormalities. Low serum C3 level but normal C4 is a common finding. The acquired AP dysregulation in DDD and C3GN may be first induced by C3 nephritic factor (C3NeF). C3NeF activity is found in approximately 80% of patients with DDD and in 45% of patients with C3GN. The correlation with the complement is further supported by the detection of homozygous or heterozygous mutations in the regulatory complement proteins factor H (CFH), factor I (CFI), or C3. The genetic background of the patients may also influence the disease manifestation since common genetic variants including single nucleotide polymorphisms in the CFH, C3 and CFHR5 genes are associated with DDD and one at-risk MCP haplotype have been found to be significantly increased in C3GN. C3 glomerulopathies can present over a broad age range. DDD is more often diagnosed in children and age at diagnosis is significantly higher for patients with C3GN. Presenting features comprise any of proteinuria, hematuria, hypertension and renal failure. These glomerulonephritides are associated with chronic deterioration of renal function, leading to ESRD within 10 years of the diagnosis in 36-50% of patients. Outcomes of renal transplantation are characterized by histological recurrence which may contribute to increased rates of allograft failure. Administration of recombinant FH if it becomes available or replacement of FH via plasma exchange may be efficacious in the cases of FH deficiency. However, therapeutic inhibition of complement C3 and C5 is the main perspective.

Membranous nephropathy (MN) has been recognized as a distinct morphological entity for over 50 years, but it is only recently that the underlying pathogenesis of the primary form of the disorder has been elucidated. This brief overview catalogues recent advances in understanding the pathogenesis of MN, focused mainly on its primary form. These studies have enumerated and identified several autologous podocyte antigens that serve as targets of autoantibody responses in primary MN. The dominant autoantigen is M-type phospholipase A2 receptor protein (PLA2R1) expressed on the surface of native glomerular podocytes. Autoantibodies to PLA2R1, usually of IgG4 subclass, are found in about 80% of patients with primary MN. These autoantibodies bind to genetically determined, conformational epitopes on PLA2R1, form immune complexes in situ and induce proteinuria, mostly likely via local activation of complement via the mannose-binding lectin pathway. The autoimmune response is modulated by genes at the HLA-DQA1 locus. The level of autoantibody to PLA2R correlates with the severity of the clinical disease and may predict recurrences in renal allografts, at least in some patients. Most forms of secondary MN appear to be due to distinctly different pathogenetic mechanisms.

This study aimed to analyze the treatment, clinical outcomes, and risk factors that affect the prognosis of patients with primary focal segmental glomerulosclerosis (FSGS) and to provide theoretical evidence for various treatment options in these patients. The study reviewed the clinical, laboratory, and pathological data of 168 patients with primary FSGS treated at Ruijin Hospital between January 2002 and October 2011. Of these patients, 108 were male (64.3%) and 60 were female (35.7%). The median age of disease onset was 38 years (range 12-78 years). The median case history was 10 months (range 4 days to 30 years). The mean proteinuria level was 2.3 ± 0.6 g/day. 75 (44.6%) patients had nephrotic syndrome. The mean serum creatinine was 108.1 ± 8.9 μmol/l. Over a follow-up period of 25.3 ± 11.4 months, end-stage renal failure occurred in 4 patients, and all 4 survived. In the group treated with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, the following factors were identified as risk factors for experiencing a 50% increase in serum creatinine over the baseline: a baseline eGFR <60 ml/min, proteinuria >1 g/day during the follow-up period, glomerular sclerosis >grade 1, and tubulointerstitial lesions >stage 1. In the group treated with steroids, patients who achieved a stable remission had better preserved renal function and milder glomerular sclerosis than steroid-dependent patients (p < 0.01). Steroid-resistant FSGS patients had a worse histological severity of glomerular sclerosis than steroid-dependent patients (p < 0.01). The prognosis of FSGS was correlated with the amount of proteinuria, the level of serum creatinine, and the severity of glomerular sclerosis and tubulointerstitial lesions. Steroids may be more effective in those who have better preserved renal function and milder glomerular sclerosis.

Objective:

Focal segmental glomerular sclerosis (FSGS) is one of the most important causes of end-stage renal disease (ESRD). The pathogenesis, clinical manifestation, pathological changes and treatment of FSGS differ in patients with and without a family history of the disease. Few studies have compared familial FSGS (FFSGS) and sporadic FSGS (SFSGS). The aim of this study was to assess the clinical and pathological features and the prognosis of FSGS in patients with and without a family history of the disease.

Methods:

We enrolled 124 FFSGS patients and 124 age- and sex-matched SFSGS patients in the study. All patients underwent a renal biopsy to determine FSGS. The mean follow-up time was 28.3 ± 12.5 months for the FFSGS group and 26.5 ± 19.5 months for the SFSGS group (p > 0.05). Baseline clinical characteristics were recorded for all participants. The primary outcomes of the study were ESRD and remission of proteinuria (defined as a 50% reduction of the baseline urine protein level). The pathological changes were assessed by focal/global glomerulosclerosis and the tubulointerstitial lesion score.

Results:

There were no age or gender differences between the two groups. A total of 43.75% of the FFSGS patients and 35.16% of the SFSGS patients had high blood pressure, but the difference was not statistically significant (p = 0.079). In addition, patients in the FFSGS group had a lower urine protein excretion rate (1.4 ± 1.4 vs. 2.0 ± 1.8 g/24 h) and a higher serum albumin value (3.6 ± 6.2 vs. 3.0 ± 1.1 g/dl) than patients in the SFSGS group (p < 0.01). A total of 62.9% of the FFSGS patients and 22.9% of the SFSGS patients had hematuria, and the difference was statistically significant (p = 0.0001). Nephrotic syndrome occurred less frequently in the FFSGS group than in the SFSGS group (13.3 vs. 22.6%, p = 0.003). The baseline serum creatinine, uric acid and eGFR values were similar in the two groups. When pathological changes were examined, the FFSGS patients showed more severe global glomerulosclerosis and tubular interstitial injury than the SFSGS patients. During the follow-up period, the FFSGS group had a lower proteinuria remission rate (23.08 vs. 48.39%, p = 0.006) and a lower median renal survival time (96 vs. 72 months, p = 0.04) than the SFSGS group.

Conclusions:

Compared to SFSGS patients, FFSGS patients displayed distinct clinicopathological features that were associated with less response to treatment and worse renal outcomes.

Objectives:

Familial focal segmental glomerulosclerosis (FSGS) has been widely reported as having an underlining genetic component to its pathogenesis. Recently, mutations in TRPC6 and ACTN4 were identified to be associated with familial FSGS, however few studies have reported the mutation rates of these two genes in Chinese familial FSGS patients. The aim of this study was to determine the prevalence of TRPC6 and ACTN4 mutations in Chinese adult-onset familial FSGS.

Methods:

80 FSGS pedigrees with Chinese ancestry who were admitted to our hospital from September 1997 to January 2012 were screened for TRPC6 and ACTN4 mutations. There was at least one biopsy-proven FSGS in each family. An additional family member with renal function insufficiency, obvious proteinuria, or end-stage renal disease was required if there was only 1 biopsy-proven FSGS case in the family. FSGS secondary to systemic diseases, such as obesity, hypertension, diabetes, or virus infection, were excluded. Other hereditary renal diseases, such as Alport's disease and Fabry disease, were also excluded by related tests. Genomic DNA was extracted from peripheral blood cells, and Sanger sequencing was performed for all exons and exon-intron boundaries of TRPC6 and ACTN4 in the probands of all FSGS pedigrees enrolled in this study.

Results:

Of the total index patients, 33 were female and 47 were male. The median age at disease onset was 39 years (range 15-67). The median proteinuria level was 1,324 mg/day and the median serum creatinine level was 114.5 μmol/l (range 41-1,040) at diagnosis. A missense mutation (Q889K) of TRPC6 was found in two independent families. No mutation was found in ACTN4. Accordingly, the mutation rate of TRPC6 was 2.5% and of ACTN4 it was 0%.

Conclusion:

Mutations of TRPC6 and ACTN4 occur in only a minor portion of Chinese familial FSGS patients. Further genetic studies conducted in these patients will be helpful to increase our understanding of the pathogenesis of FSGS.