A Low-Protein, Plant-Dominant Gluten-Free Diet for Immunoglobulin A Nephropathy and Focal Segmental Glomerulosclerosis.

Immunoglobulin A nephropathy is the most common glomerulonephritis syndrome in the world, yet there is currently no cure. While blood pressure control, renin-angiotensin-aldosterone system inhibition, and immunosuppression may slow disease progression, low-protein diets, defined as a daily dietary protein intake of 0.6 to 0.8 g/kg body weight, may also decrease immune complex deposition and disease severity, as evidenced in animal models. The link between secondary immunoglobulin A nephropathy and celiac disease has also led to the rise of gluten-free diets and zinc supplementation as potential lifestyle modifications to help manage common immunoglobulin A nephropathy symptoms such as proteinuria and hematuria. In addition, case reports and prospective studies suggest that patients with focal segmental glomerulosclerosis, which manifests as steroid-resistant nephrotic syndrome may also benefit from a gluten-free diet. We highlight the example of a gluten-free, plant-dominant low-protein diet (a different type of low-protein diet that addresses both protein quantity and quality) for patients with immunoglobulin A nephropathy or focal segmental glomerulosclerosis.

A broad clinical spectrum of PLCε1-related kidney disease and intrafamilial variability.

BACKGROUND: The phenotypic and genotypic spectrum and kidney outcome of PLCε1-related kidney disease are not well known. We attempted to study 25 genetically confirmed cases of PLCε1-related kidney disease from 11 centers to expand the clinical spectrum and to determine the relationship between phenotypic and genotypic features, kidney outcome, and the impact of treatment on outcome. METHODS: Data regarding demographics, clinical and laboratory characteristics, histopathological and genetic test results, and treatments were evaluated retrospectively. RESULTS: Of 25 patients, 36% presented with isolated proteinuria, 28% with nephrotic syndrome, and 36% with chronic kidney disease stage 5. Twenty patients underwent kidney biopsy, 13 (65%) showed focal segmental glomerulosclerosis (FSGS), and 7 (35%) showed diffuse mesangial sclerosis (DMS). Of the mutations identified, 80% had non-missense, and 20% had missense; ten were novel. No clear genotype-phenotype correlation was observed; however, significant intrafamilial variations were observed in three families. Patients with isolated proteinuria had significantly better kidney survival than patients with nephrotic syndrome at onset (p = 0.0004). Patients with FSGS had significantly better kidney survival than patients with DMS (p = 0.007). Patients who presented with nephrotic syndrome did not respond to any immunosuppressive therapy; however, 4/9 children who presented with isolated proteinuria showed a decrease in proteinuria with steroids and/or calcineurin inhibitors. CONCLUSION: PLCε1-related kidney disease may occur in a wide clinical spectrum, and genetic variations are not associated with clinical presentation or disease course. However, clinical presentation and histopathology appear to be important determinants for prognosis. Immunosuppressive medications in addition to angiotensin-converting enzyme inhibitors may be beneficial for selected patients. "A higher resolution version of the Graphical abstract is available as Supplementary information".

Coexistence of Interstitial Nephritis and the Cellular Variant of Focal Segmental Glomerulosclerosis Secondary to Anabolic Steroid Abuse.

Anabolic-androgenic steroids (AAS) have been widely used by young people to enhance performance and increase muscle mass. The use of AAS can affect the kidneys and lead to a myriad of presentations, ranging from mildly elevated serum creatinine and blood urea nitrogen to irreversible chronic kidney disease and focal segmental glomerulosclerosis (FSGS). To the best of our knowledge, the coexistence of interstitial nephritis and the cellular variant of FSGS [Immunoglobulin M (IgM)] secondary to AAS abuse has not been previously reported in the literature. Here, we report the case of a 40-year-old bodybuilder who developed simultaneous interstitial nephritis and the cellular variant of FSGS (IgM) after short-term use of AAS and other dietary supplements.

Pregnancy, Proteinuria, Plant-Based Supplemented Diets and Focal Segmental Glomerulosclerosis: A Report on Three Cases and Critical Appraisal of the Literature.

Chronic kidney disease (CKD) is increasingly recognized in pregnant patients. Three characteristics are associated with a risk of preterm delivery or small for gestational age babies; kidney function reduction, hypertension, and proteinuria. In pregnancy, the anti-proteinuric agents (ACE-angiotensin converting enzyme-inhibitors or ARBS -angiotensin receptor blockers) have to be discontinued for their potential teratogenicity, and there is no validated approach to control proteinuria. Furthermore, proteinuria usually increases as an effect of therapeutic changes and pregnancy-induced hyperfiltration. Based on a favourable effect of low-protein diets on proteinuria and advanced CKD, our group developed a moderately protein-restricted vegan-vegetarian diet tsupplemented with ketoacids and aminoacids for pregnant patients. This report describes the results obtained in three pregnant patients with normal renal function, nephrotic or sub-nephrotic proteinuria, and biopsy proven diagnosis of focal segmental glomerulosclerosis, a renal lesion in which hyperfiltration is considered of pivotal importance (case 1: GFR (glomerular filtration rate): 103 mL/min; proteinuria 2.1 g/day; albumin 3.2 g/dL; case 2: GFR 86 mL/min, proteinuria 3.03 g/day, albumin 3.4 g/dL; case 3: GFR 142 mL/min, proteinuria 6.3 g/day, albumin 3.23 g/dL). The moderately restricted diet allowed a stabilisation of proteinuria in two cases and a decrease in one. No significant changes in serum creatinine and serum albumin were observed. The three babies were born at term (38 weeks + 3 days, female, weight 3180 g-62th centile; 38 weeks + 2 days, female, weight 3300 g-75th centile; male, 38 weeks + 1 day; 2770 g-8th centile), thus reassuring us of the safety of the diet. In summary, based on these three cases studies and a review of the literature, we suggest that a moderately protein-restricted, supplemented, plant-based diet might contribute to controlling proteinuria in pregnant CKD women with focal segmental glomerulosclerosis. However further studies are warranted to confirm the potential value of such a treatment strategy.

COQ6 Mutations in Children With Steroid-Resistant Focal Segmental Glomerulosclerosis and Sensorineural Hearing Loss.

The phenotypic combination of steroid-resistant focal segmental glomerulosclerosis (SR-FSGS) and sensorineural hearing loss has been mainly reported in patients with mitochondrial cytopathies, including primary coenzyme Q10 (CoQ10) deficiency. In this report of 10 children with SR-FSGS and sensorineural hearing loss, we found 6 patients with biallelic COQ6 mutations. Median age at the onset of nephrotic syndrome was 29 (range, 15-47) months. All patients progressed to end-stage renal disease within a median of 13 (range, 1-27) months after the onset. Kidney biopsy revealed abnormal mitochondrial proliferation in podocytes in all 6 patients. None of the 5 patients who underwent kidney transplantation developed recurrence of FSGS. Primary CoQ10 deficiency due to COQ6 mutations should be considered in children presenting with both SR-FSGS and sensorineural hearing loss. An early diagnosis of COQ6 mutations is essential because the condition is treatable when CoQ10 supplementation is started at the early stage. We recommend early kidney biopsy because detection of abnormal mitochondrial proliferation in podocytes might provide an earlier diagnostic clue.

Clinicopathological features and prognosis of Kimura's disease with renal involvement in Chinese patients.

AIMS: Kimura's disease (KD) with renal involvement is a rare disease. Optimal treatments are still not well established. It is necessary to analyze clinicopathological features, treatment responses, and prognosis for improving KD diagnosis and treatment. MATERIALS AND METHODS: Clinicopathological data, treatment responses, and prognosis were collected and analyzed retrospectively. RESULTS: The patients consisted of 27 males and 2 females, with an average age of 35.5 ± 15.1 (13 - 61) years. 27 exhibited proteinuria ranging from 0.730 to 14.1 g/24 h (5.98 ± 3.40 g/24 h). Hypertension, renal insufficiency (serum creatinine (Scr) > 1.24 mg/dL), and microhematuria occurred in 4 (13.8%), 11 (37.9%), and 13 (44.8%) cases, respectively. Light microscopy (LM) identified mesangium proliferation, minimal change, focal and segmental glomerulosclerosis (FSGS), membranous glomerulonephritis, membranoproliferative glomerulonephritis (MPGN), and acute tubular necrosis in 14, 8, 3, 2, 1, and 1 cases, respectively. All were treated with Tripterygium wilfordii (TW), prednisone, leflunomide (LEF), tacrolimus (FK506), myophenolate mofetil (MMF), or renin-angiotensin system blockers (RASI). 26 patients were followed up for 1.60 - 108.7 months (39.6 ± 28.7). After treatments, urinary red blood cells (RBC) decreased in all. The amount of 24-hour urinary protein (24-hUPE) decreased in 24 patients. 22 reached complete remission (CR), 4 partial remissions (PR). The patients who did not relapse were younger than those who relapsed. CONCLUSIONS: KD with renal involvement occurs predominantly among 35 - 50 year old Chinese patients with male predilection. The most common features are proteinuria, hypertension, micro hematuria with minimal change, and mesangial proliferative glomerulonephritis. Most were responsive to treatment, but could relapse. Gender, age, and hypertension are associated with KD recurrence. The prognosis is good mostly.

Inhibition of calcium(2+)/calmodulin-dependent protein kinase type IV ameliorates experimental nephrotic syndrome.

OBJECTIVE: Evidence has demonstrated that Ca(2+)/calmodulin-dependent protein kinase type IV (CaMKIV) contributes to altered cytokine production by promoting the production of inflammatory cytokines. This study aimed to explore the protective role and underlying mechanisms of CaMKIV inhibition in experimental nephrotic syndrome. METHODS: BALB/c mice received single intravenous injections of adriamycin (10 mg/kg) then were sacrificed at two, four and six weeks. In the second study, treatment with KN-93, a CaMKIV inhibitor, or vehicle administered via intraperitoneal injection was started five days after adriamycin injection. Functional and pathologic parameters, the presence of inflammatory infiltration and the expressions of pro-inflammatory cytokines were assessed. RESULTS: The CaMKIV protein expression levels were upregulated in the mice with adriamycin nephropathy, which was significantly inhibited by KN-93 (p<0.01). As compared with the vehicle-treated controls, KN-93 treatment resulted in marked suppression of proteinuria and serum creatinine at week 6 (p<0.01), but not at two weeks after induction of the disease. KN-93 inhibited glomerulosclerosis and the development of tubulointerstitial lesions. The renal alpha-smooth muscle actin (α-SMA) expression was also significantly suppressed by KN-93 treatment at week 6 (p<0.01). Moreover, KN-93 inhibited the renal monocyte chemoattractant protein-1 (MCP-1) expression, paralleled by a reduction in the interstitial infiltration of macrophages and T-cells (p<0.01). CONCLUSION: Our findings suggest that activation of CaMKIV signaling is involved in the progression of glomerular diseases with a proteinuric state. Our data therefore justify the development of small molecule CaMKIV inhibitors for the treatment of clinical nephrotic syndrome.

Vitamin D down-regulates TRPC6 expression in podocyte injury and proteinuric glomerular disease.

The transient receptor potential cation channel C6 (TRPC6) is a slit diaphragm protein expressed by podocytes. TRPC6 gain-of-function mutations cause autosomal dominant focal segmental glomerulosclerosis. In acquired proteinuric renal disease, glomerular TRPC6 expression is increased. We previously demonstrated that acquired increased TRPC6 expression is ameliorated by antiproteinuric angiotensin receptor blockers and angiotensin-converting enzyme inhibitors. Vitamin D also has an antiproteinuric effect. We hypothesized that vitamin D reduces proteinuria by affecting TRPC6 expression in podocytes. Adriamycin-induced nephropathy increased TRPC6 mRNA and protein expression and induced proteinuria in rats. Treatment with 1,25-dihydroxyvitamin D3 (1,25-D3) normalized TRPC6 expression and reduced proteinuria. In vitro, podocyte injury induced by adriamycin exposure in cultured podocytes increased TRPC6 expression. Treatment of injured podocytes with 1,25-D3 dose dependently reduced adriamycin-induced TRPC6 expression. Chromatin immunoprecipitation analysis demonstrated that the vitamin D receptor directly binds to the TRPC6 promoter. Moreover, 1,25-D3 reduced TRPC6 promoter activity in a luciferase reporter assay. In 1,25-D3-deficient 25-hydroxy-1α-hydroxylase knockout mice, TRPC6 expression was increased, accompanied by podocyte foot process effacement and proteinuria. 1,25-D3 supplementation normalized TRPC6 expression, podocyte morphology, and proteinuria in these mice. These results demonstrate that vitamin D down-regulates the enhanced TRPC6 expression in in vivo and in vitro podocyte injury, possibly through a direct effect on TRPC6 promoter activity. This TRPC6 down-regulation could contribute to the antiproteinuric effect of vitamin D.

Focal segmental glomerulosclerosis in association with Gitelman syndrome.

Gitelman syndrome (GS) is an autosomal recessive disorder characterized by hypokalemia, metabolic alkalosis, hypomagnesemia and hypocalciuria. Glomerulonephritis associated with GS is rarely documented in the literature. We present an adult patient with GS whose renal biopsy revealed focal segmental glomerulosclerosis.

Evaluation and management of steroid-unresponsive nephrotic syndrome.

PURPOSE OF REVIEW: Idiopathic nephrotic syndrome in children is commonly associated with minimal change disease and response to steroid therapy. Steroid-unresponsive nephrotic syndrome is often characterized by persistent proteinuria and progression to chronic kidney disease. Focal segmental glomerulosclerosis is the leading cause of steroid-unresponsive nephrotic syndrome in childhood. There is no uniformed consensus as to the treatment of steroid-unresponsive nephrotic syndrome. Advances in the pathogenesis, genetics and biomarkers or surrogate markers may be useful for the diagnosis and identification of patients with steroid-unresponsive nephrotic syndrome, severity of disease, progression and response to therapy. RECENT FINDINGS: This review is intended to describe some of the recent changes in the epidemiology of steroid-unresponsive nephrotic syndrome, in particular focal segmental glomerulosclerosis, its pathogenesis and alternative therapies. SUMMARY: Recent studies in both children and adults have shown an increase in the incidence of focal segmental sclerosis as a cause of steroid-unresponsive nephrotic syndrome. Advances in the pathogenesis and noninvasive methods of diagnosis may allow for the identification of steroid-responsive patients.

Low-dose therapy with the long-acting erythropoietin analogue darbepoetin alpha persistently activates endothelial Akt and attenuates progressive organ failure.

BACKGROUND: The hematopoietic cytokine erythropoietin has cytoprotective effects in endothelial cells in vitro that are mediated through direct activation of the pro-survival Akt tyrosine kinase signaling pathway. We tested the hypothesis that low-dose therapy with the long-acting recombinant human erythropoietin analogue darbepoetin alpha protects vascular endothelium in vivo in a classic remnant kidney rat model characterized by severe endothelial damage, progressive vascular sclerosis, and ischemia-induced tissue fibrosis. METHODS AND RESULTS: Using a parallel group study design, we randomly assigned animals after 5/6 nephrectomy to treatment with either saline (n=36) or 0.1 microg/kg body wt darbepoetin (n=24) subcutaneously once weekly. We monitored hematocrit, blood pressure, and serum creatinine regularly and obtained renal tissue 6 weeks after nephrectomy for morphological and immunohistochemical analysis. Darbepoetin-treated animals had significantly improved survival compared with saline-treated controls (63% versus 33%; P<0.05), although hematocrit levels were similar in both groups. Darbepoetin treatment ameliorated endothelial damage; attenuated the composite tissue injury score (saline 1.9+/-0.4; darbepoetin 0.4+/-0.2; P<0.001), which included vascular sclerosis, glomerulosclerosis, and tubulointerstitial damage; and preserved renal function. We found persistent activation of the pro-survival Akt signaling pathway in endothelial and epithelial glomerular cells in darbepoetin-treated animals, accompanied by a significant reduction of apoptotic cell death in renal tissue. CONCLUSIONS: Low-dose darbepoetin treatment confers vascular and tissue protection that is associated with persistent stimulation of the pro-survival Akt signaling pathway. The use of recombinant human erythropoietin or analogues may have utility in preventing ischemia-related progressive vascular injury and organ failure.

Long-term dietary L-arginine supplementation attenuates proteinuria and focal glomerulosclerosis in experimental chronic renal transplant failure.

Glomerular endothelial nitric oxide synthase expression is decreased in humans during acute rejection and chronic renal transplant failure (CRTF). This may contribute to vascular damage through changes in the renal hemodynamics and enhanced endothelial adhesion of leukocytes and platelets. Dietary supplementation of L-arginine may increase endothelial NO production, thereby protecting the vascular wall and improving renal hemodynamics. We tested the hypothesis that long-term L-arginine supplementation attenuates the development of CRTF in an experimental model for renal transplantation. In the Fisher 344 to Lewis rat model for renal transplantation, renal function and histology of untreated rats was compared with rats receiving L-arginine in the drinking water (10g/L), starting 2 days before transplantation. Every 4 weeks systolic blood pressure was measured and serum and urine were collected for measurement of nitrite and nitrate (NO(x)), creatinine, and proteinuria. At 34 weeks the histological renal damage was assessed by scoring focal glomerulosclerosis and measurement of alpha-smooth muscle actin (alpha-SMA) expression. Urinary NO(x) was significantly increased in treated animals. Proteinuria was significantly lower in L-arginine-treated animals from week 24 onward (p<0.05). Plasma creatinine and creatinine clearance did not differ between the groups. The focal and segmental glomerulosclerosis (FGS) score (max 400) at week 34 was also significantly lower in treated rats arbitrary U (20+/-21 vs 61+/-67 arbitrary U; p<0.05). The expression of alpha-SMA was lower in L-arginine-treated rats than in untreated rats (1.93+/-0.8% area surface vs 3.64+/-2.5% area surface). In conclusion, in this experimental model for CRTF, L-arginine administration significantly reduced FGS and proteinuria, without affecting renal function. Our data suggest that dietary L-arginine supplementation attenuates progression of CRTF and may therefore be an additional therapeutic option in human renal allograft recipients.

Calciphylaxis in chronic renal failure.

Calciphylaxis is a rare and life-threatening complication that is estimated to occur in 1% of patients with ESRD each year. Typically, extensive microvascular calcification and occlusion/thrombosis leads to violaceous skin lesions, which progress to nonhealing ulcers and sepsis. Secondary infection of skin lesions is common, often leading to sepsis and death. The lower extremities are predominantly involved (roughly 90% of patients). Patients with skin involvement over the trunk or proximal extremities have a poorer prognosis. Although most calciphylaxis patients have abnormalities of the calcium:phosphate axis or elevated levels of parathyroid hormone, these abnormalities do not appear to be fundamental to the pathophysiology of the disorder, and the etiology of calciphylaxis remains unclear. Recently, functional protein C deficiency has been hypothesized to cause a hypercoagulable state that could induce thrombosis in small vessels, with resulting skin ischemia, necrosis, and gangrene. The lack of understanding of the pathophysiology of the disease results in treatments that are equally unsatisfactory. Patients who undergo parathyroidectomy have a tendency to improve, but the prognosis for the disease is poor and mortality remains high.

Fish oil ameliorates renal injury and hyperlipidemia in the Milan normotensive rat model of focal glomerulosclerosis.

Rats of the Milan normotensive rat strain (MNS) spontaneously develop severe proteinuria and excessive glomerular thromboxane (Tx)A2 production at a young age. These abnormalities are accompanied by podocyte alterations, progressive focal glomerulosclerosis (FGS), and interstitial fibrosis, resembling human FGS. Since it has been shown that pharmacologic Tx-synthase inhibition protects MNS rats from these changes, it was hypothesized that a fish oil (FO) enriched diet, by enhancing TxA3 production instead of TxA2, might afford similar protection, compared with diets enriched in safflower oil (SO) or lard (LD). Rats were pair-fed 11% fat diets from age of 1 to 11 months. Glomerular TxA2 at 11 months was significantly lower in PO-fed rats than in SO- and LD-fed rats (11 +/- 3.0, 69 +/- 3.0, 59 +/- 19.0 nanograms per min/mg, respectively; P < 0.001). At 3 months, urinary albumin excretion was similar among the groups. Over the course of the study, rats fed FO developed significantly less albuminuria than the SO and LD groups (P < 0.001 by analysis of variance for repeated measures), such that the values at 11 months were 25 +/- 5.8, 49 +/- 8.7, and 68 +/- 13.0 mg/24h, respectively. Serum cholesterol and triglycerides were also significantly lower in FO-fed rats than in SO- and LD-fed rats. The extent of FGS was similar in the three groups, but FO-fed rats had less interstitial injury than the other groups. It was observed that a fish-oil diet substantially alleviated albuminuria, normalized nephrotic hyperlipidemia, and reduced interstitial injury, but did not prevent the development of FGS in the MNS model.

A transplant of real life.

A case of steroid-resistant nephrotic syndrome with focal segmental glomerulosclerosis leading to renal failure in a 4-year-old girl is described by her mother, with special emphasis on the problems resulting from recurrence of this disease, with graft loss in three successive kidney transplants. This report chronicles the gradual evolution from a family's initial heavy dependence upon medical solutions to their ultimate primary emphasis upon spiritual values, with medicine seen as the support toward achieving the child's psychological well-being and spiritual growth. The physician's role in balancing medical decision making, non-medical alternatives, and demands on limited and precious resources in such difficult cases is discussed.