Results of untargeted analysis using the SOMAscan proteomics platform indicates novel associations of circulating proteins with risk of progression to kidney failure in diabetes.

This study applies a large proteomics panel to search for new circulating biomarkers associated with progression to kidney failure in individuals with diabetic kidney disease. Four independent cohorts encompassing 754 individuals with type 1 and type 2 diabetes and early and late diabetic kidney disease were followed to ascertain progression to kidney failure. During ten years of follow-up, 227 of 754 individuals progressed to kidney failure. Using the SOMAscan proteomics platform, we measured baseline concentration of 1129 circulating proteins. In our previous publications, we analyzed 334 of these proteins that were members of specific candidate pathways involved in diabetic kidney disease and found 35 proteins strongly associated with risk of progression to kidney failure. Here, we examined the remaining 795 proteins using an untargeted approach. Of these remaining proteins, 11 were significantly associated with progression to kidney failure. Biological processes previously reported for these proteins were related to neuron development (DLL1, MATN2, NRX1B, KLK8, RTN4R and ROR1) and were implicated in the development of kidney fibrosis (LAYN, DLL1, MAPK11, MATN2, endostatin, and ROR1) in cellular and animal studies. Specific mechanisms that underlie involvement of these proteins in progression of diabetic kidney disease must be further investigated to assess their value as targets for kidney-protective therapies. Using multivariable LASSO regression analysis, five proteins (LAYN, ESAM, DLL1, MAPK11 and endostatin) were found independently associated with risk of progression to kidney failure. Thus, our study identified proteins that may be considered as new candidate prognostic biomarkers to predict risk of progression to kidney failure in diabetic kidney disease. Furthermore, three of these proteins (DLL1, ESAM, and MAPK11) were selected as candidate biomarkers when all SOMAscan results were evaluated.

Comprehensive Search for Novel Circulating miRNAs and Axon Guidance Pathway Proteins Associated with Risk of ESKD in Diabetes.

BACKGROUND: Mechanisms underlying the pro gression of diabetic kidney disease to ESKD are not fully understood. METHODS: We performed global microRNA (miRNA) analysis on plasma from two cohorts consisting of 375 individuals with type 1 and type 2 diabetes with late diabetic kidney disease, and targeted proteomics analysis on plasma from four cohorts consisting of 746 individuals with late and early diabetic kidney disease. We examined structural lesions in kidney biopsy specimens from the 105 individuals with early diabetic kidney disease. Human umbilical vein endothelial cells were used to assess the effects of miRNA mimics or inhibitors on regulation of candidate proteins. RESULTS: In the late diabetic kidney disease cohorts, we identified 17 circulating miRNAs, represented by four exemplars (miR-1287-5p, miR-197-5p, miR-339-5p, and miR-328-3p), that were strongly associated with 10-year risk of ESKD. These miRNAs targeted proteins in the axon guidance pathway. Circulating levels of six of these proteins-most notably, EFNA4 and EPHA2-were strongly associated with 10-year risk of ESKD in all cohorts. Furthermore, circulating levels of these proteins correlated with severity of structural lesions in kidney biopsy specimens. In contrast, expression levels of genes encoding these proteins had no apparent effects on the lesions. In in vitro experiments, mimics of miR-1287-5p and miR-197-5p and inhibitors of miR-339-5p and miR-328-3p upregulated concentrations of EPHA2 in either cell lysate, supernatant, or both. CONCLUSIONS: This study reveals novel mechanisms involved in progression to ESKD and points to the importance of systemic factors in the development of diabetic kidney disease. Some circulating miRNAs and axon guidance pathway proteins represent potential targets for new therapies to prevent and treat this condition.

A profile of multiple circulating tumor necrosis factor receptors associated with early progressive kidney decline in Type 1 Diabetes is similar to profiles in autoimmune disorders.

This study comprehensively evaluated the association between known circulating tumor necrosis factor (TNF) superfamily ligands and receptors and the development of early progressive kidney decline (PKD) leading to end-stage kidney disease (ESKD) in Type 1 diabetes. Participants for the study were from the Macro-Albuminuria Study (198 individuals), and the Micro-Albuminuria Study (148 individuals) of the Joslin Kidney Study. All individuals initially had normal kidney function and were followed for seven-fifteen years to determine the slope of the estimate glomerular filtration rate and to ascertain onset of ESKD. Plasma concentrations of 25 TNF superfamily proteins were measured using proximity extension assay applied in the OLINK proteomics platform. In the both studies risk of early PKD, determined as estimated glomerular filtration rate loss greater than or equal to three ml/min/1.73m2/year, was associated with elevated circulating levels of 13 of 19 TNF receptors examined. In the Macro-Albuminuria Study, we obtained similar findings for risk of progression to ESKD. These receptors comprised: TNF-R1A, -R1B, -R3, -R4, -R6, -R6B, -R7, -R10A, -R10B, -R11A, -R14, -R21, and -R27. Serial measurements showed that circulating levels of these TNF receptors had increased before the onset of PKD. In contrast, none of the six measured TNF ligands showed association with risk of early PKD. Of significance, the disease process that underlies PKD leading to ESKD in Type 1 diabetes has a profile also seen in autoimmune disorders. The mechanisms of this enrichment may be causally related to the development of PKD in Type 1 diabetes and must be investigated further. Thus, some of these receptors may be used as new risk predictors of ESKD.

Predictors of withdrawal from renal replacement therapy among patients with acute kidney injury requiring renal replacement therapy.

BACKGROUND: Although recovery of renal function after an episode of acute kidney injury (AKI) is an important clinical measure of morbidity, predictors of withdrawal from renal replacement therapy (RRT) among AKI patients remain unclear. METHODS: In this single-center retrospective cohort study, we examined the clinical records of AKI patients requiring RRT who were hospitalized in the ICU or general wards at our hospital from January 2010 to December 2013. A priori-determined covariates of age, sex, cardiovascular disease, chronic kidney disease (CKD), mean arterial pressure (MAP), sepsis, nephrotoxic agents, and hypoalbuminemia were assessed in Cox hazard models to estimate hazard ratio (HR). RESULTS: A total of 334 patients were enrolled (median age, 68 years; interquartile range [IQR], 57-77 years; male, 71.6%). During follow-up 157 (47.0%) patients achieved RRT withdrawal. Multivariable Cox regression analysis revealed that CKD, MAP between 95 and 105 mmHg and MAP ≥ 105 mmHg, compared with MAP between 65 and 75 mmHg, ventilator use and hypoalbuminemia, were significantly associated with RRT withdrawal. CONCLUSION: Among patients with AKI requiring RRT, CKD, ventilator use, hypoalbuminemia, and high MAP were associated with RRT withdrawal. Furthermore, keeping a higher MAP at RRT initiation can potentially lead to dependence on RRT.

Frailty, multimorbidity and polypharmacy: exploratory analyses of the effects of empagliflozin from the EMPA-KIDNEY trial.

BACKGROUND: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are recommended treatment for adults with chronic kidney disease (CKD), but uncertainty exists regarding their use in patients with frailty and/or multimorbidity, among whom polypharmacy is common. We derived a multivariable logistic regression model to predict hospitalization (reflecting frailty) and assessed empagliflozin's risk-benefit profile in a post-hoc analysis of the double-blind, placebo-controlled EMPA-KIDNEY trial. METHODS: The EMPA-KIDNEY trial randomized 6609 patients with CKD (estimated glomerular filtration rate [eGFR] ≥20<45 mL/min/1.73m2, or ≥45<90 mL/min/1.73m2 with urinary albumin-to-creatinine ratio ≥200 mg/g) to receive either empagliflozin 10 mg daily or matching placebo and followed for two years (median). Additional characteristics analysed in subgroups were multimorbidity, polypharmacy and health-related quality of life (HRQoL) at baseline. Cox regression analyses were performed with subgroups defined by approximate thirds of each variable. RESULTS: The strongest predictors of hospitalization were N-terminal prohormone of brain natriuretic peptide, poor mobility and diabetes; then eGFR and other comorbidities. Empagliflozin was generally well-tolerated independent of predicted risk of hospitalization. In relative terms, allocation to empagliflozin reduced the risk of the primary outcome of kidney disease progression or cardiovascular death by 28% (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.64-0.82); and all-cause hospitalization by 14% (HR 0.86, 95% CI 0.78-0.95); with broadly consistent effects across subgroups of predicted risk of hospitalization, multimorbidity, polypharmacy or HRQoL. In absolute terms, the estimated benefits of empagliflozin were greater in those at highest predicted risk of hospitalization (reflecting frailty) and outweighed potential serious harms. CONCLUSIONS: These findings support the use of SGLT2 inhibitors in CKD, irrespective of frailty, multimorbidity or polypharmacy.

[A case of combination therapy with MMF and steroids for idiopathic membranoproliferative glomerulonephritis].

A 26-year-old man diagnosed with nephrotic syndrome was administered steroid monotherapy. Urinary protein excretion was 2-3 g/day despite the therapy. Percutaneous renal biopsy revealed Type I idiopathic membranoproliferative glomerulonephritis (IMPGN). Although intravenous steroid therapy at the dose of 1,000 mg/day for 3 days was administered, proteinuria persisted at the level of 1 g/day. Renal dysfunction (cystatin C, 1.33 mg/L) was evident. Strong inflammation was suggested by occult blood (3+) and urinary (red blood cells: 30-50/high power field) sediment. We considered steroid monotherapy to be ineffective, and initiated combina-tion therapy with mycophenolate mofetil (MMF) and steroids. Consequently, urinary protein excretion moderately decreased to 0.34 g/day without adverse events or worsening of the renal function. The steroid quantity could be reduced without relapse. Subsequently, we were able to reduce the dose of MMF gradually, then terminated the medication. IMPGN is a rare disease with a poor renal prognosis. Recently, MMF therapies for IMPGN have been attempted, but there are few cases in Japan. Our case suggests that combination therapy with MMF and steroids is effective and safe for treating IMPGN.

Neuroblastoma suppressor of tumorigenicity 1 is a circulating protein associated with progression to end-stage kidney disease in diabetes.

Circulating proteins associated with transforming growth factor-ß (TGF-ß) signaling are implicated in the development of diabetic kidney disease (DKD). It remains to be comprehensively examined which of these proteins are involved in the pathogenesis of DKD and its progression to end-stage kidney disease (ESKD) in humans. Using the SOMAscan proteomic platform, we measured concentrations of 25 TGF-ß signaling family proteins in four different cohorts composed in total of 754 Caucasian or Pima Indian individuals with type 1 or type 2 diabetes. Of these 25 circulating proteins, we identified neuroblastoma suppressor of tumorigenicity 1 (NBL1, aliases DAN and DAND1), a small secreted protein known to inhibit members of the bone morphogenic protein family, to be most strongly and independently associated with progression to ESKD during 10-year follow-up in all cohorts. The extent of damage to podocytes and other glomerular structures measured morphometrically in 105 research kidney biopsies correlated strongly with circulating NBL1 concentrations. Also, in vitro exposure to NBL1 induced apoptosis in podocytes. In conclusion, circulating NBL1 may be involved in the disease process underlying progression to ESKD, and its concentration in circulation may identify subjects with diabetes at increased risk of progression to ESKD.

Minimal change disease concurrent with acute interstitial nephritis after long-term use of sorafenib in a patient with renal cell carcinoma.

Sorafenib is one of the multi-targeted tyrosine kinase inhibitors (TKI), mainly used for treating advanced renal cell carcinoma. Accumulated evidence indicates a minority of patients develop nephrotic syndrome (NS) as a high-grade nephrotoxic injury; however, evidence of NS after long-term use of sorafenib remains unclear. A 64-year-old man developed NS following 2-year use of sorafenib and his NS persisted even after sorafenib use was discontinued. Renal biopsy disclosed minimal change disease (MCD) concurrent with acute tubulointerstitial nephritis, indicating secondary MCD with which sorafenib may be involved. To prevent permanent renal insufficiency, we administered glucocorticoid and succeeded in achieving complete remission from NS. Nephrotoxic injuries could occur at any time with variable onset after sorafenib. Renal biopsy should be pursued in the case of NS associated with TKI therapy. To facilitate recovery of renal dysfunction, administration of prednisolone should be considered, particularly when NS does not disappear after cessation of TKIs.

Circulating proteins protect against renal decline and progression to end-stage renal disease in patients with diabetes.

Diabetic kidney disease (DKD) and its major clinical manifestation, progressive renal decline that leads to end-stage renal disease (ESRD), are a major health burden for individuals with diabetes. The disease process that underlies progressive renal decline comprises factors that increase risk as well as factors that protect against this outcome. Using untargeted proteomic profiling of circulating proteins from individuals in two independent cohorts with type 1 and type 2 diabetes and varying stages of DKD followed for 7 to 15 years, we identified three elevated plasma proteins-fibroblast growth factor 20 (OR, 0.69; 95% CI, 0.54 to 0.88), angiopoietin-1 (OR, 0.72; 95% CI, 0.57 to 0.91), and tumor necrosis factor ligand superfamily member 12 (OR, 0.75; 95% CI, 0.59 to 0.95)-that were associated with protection against progressive renal decline and progression to ESRD. The combined effect of these three protective proteins was demonstrated by very low cumulative risk of ESRD in those who had baseline concentrations above median for all three proteins, whereas the cumulative risk of ESRD was high in those with concentrations below median for these proteins at the beginning of follow-up. This protective effect was shown to be independent from circulating inflammatory proteins and clinical covariates and was confirmed in a third cohort of diabetic individuals with normal renal function. These three protective proteins may serve as biomarkers to stratify diabetic individuals according to risk of progression to ESRD and might also be investigated as potential therapeutics to delay or prevent the onset of ESRD.

Profibrotic Circulating Proteins and Risk of Early Progressive Renal Decline in Patients With Type 2 Diabetes With and Without Albuminuria.

OBJECTIVE: The role of fibrosis in early progressive renal decline in type 2 diabetes is unknown. Circulating WFDC2 (WAP four-disulfide core domain protein 2) and matrix metalloproteinase 7 (MMP-7; Matrilysin) are postulated to be biomarkers of renal fibrosis. This study examined an association of circulating levels of these proteins with early progressive renal decline. RESEARCH DESIGN AND METHODS: Individuals with type 2 diabetes enrolled in the Joslin Kidney Study with an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 were monitored for 6-12 years to ascertain fast early progressive renal decline, defined as eGFR loss ≥5 mL/min/1.73 m2/year. RESULTS: A total of 1,181 individuals were studied: 681 without and 500 with albuminuria. Median eGFR and albumin-to-creatinine ratio (ACR) at baseline were 97 mL/min/1.73 m2 and 24 mg/g, respectively. During follow-up, 152 individuals experienced fast early progressive renal decline: 6.9% in those with normoalbuminuria and 21% with albuminuria. In both subgroups, the risk of renal decline increased with increasing baseline levels of WFDC2 (P < 0.0001) and MMP-7 (P < 0.0001). After adjustment for relevant clinical characteristics and known biomarkers, an increase by one quartile in the fibrosis index (combination of levels of WFDC2 and MMP-7) was associated with higher risk of renal decline (odds ratio 1.63; 95% CI 1.30-2.04). The association was similar and statistically significant among patients with and without albuminuria. CONCLUSIONS: Elevation of circulating profibrotic proteins is associated with the development of early progressive renal decline in type 2 diabetes. This association is independent from albuminuria status and points to the importance of the fibrotic process in the development of early renal decline.

Microscopic polyangiitis associated with subarachnoid hemorrhage.

Microscopic polyangiitis (MPA), an anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, is a systemic disease that damages all organs through predominantly affecting small vessels. However, few cases of MPA are related to aneurysms on medium-sized muscular vessels, and whether subarachnoid hemorrhage (SAH) is associated with MPA is still unclear. An 85-year-old woman with rapid progressive glomerular nephritis caused by MPA complained of sudden severe headache due to SAH 2 days after admission and subsequently underwent surgery. Cerebrovascular disease occurring simultaneously with MPA might result in poor prognosis, and the complications exacerbate the condition and lead to high mortality; thus, physicians should pay more attention to cerebral aneurysms concurrent with MPA. Among patients with MPA, it is important to identify priority cases and investigate the intracranial vessel environment. To the best of our knowledge, this is a rare report about SAH associated with MPA. We recommend that the presence of cerebrovascular disease should be considered in patients with MPA to improve their prognosis.

Risk of Heparin-induced Immediate-type Hypersensitivity during Arteriovenous Fistula Placement.

Heparin is commonly used to prevent clotting; however, severe hypersensitivity reactions during vascular access (VA) placement are rarely but occasionally reported. A 49-year-old man experienced a heparin-induced hypersensitivity reaction during VA placement. Severe side effects may occur even while placing the VA; therefore, we reconsidered the routine use of heparin, as the side effects are unpredictable. Physicians should be aware of the risk of heparin-induced hypersensitivity and be ready to effectively manage it during VA placement.

Infective endocarditis in a patient with lupus nephritis who was undergoing immunosuppressive therapy: A case of survival.

Systemic lupus erythematosus is an autoimmune disease associated with mild valvular regurgitation. However, there have been no detailed reports of infective endocarditis in patients with systemic lupus erythematosus. Here, we describe a case of a 55-year-old woman without any cardiac abnormalities who was diagnosed with lupus nephritis by renal biopsy; she contracted infective endocarditis while receiving immunosuppressive therapy. Our case emphasizes that special consideration of the occurrence of infective endocarditis, and its early diagnosis and treatment are mandatory for patient survival. We propose that echocardiography should be performed before treating patients with systemic lupus erythematosus who have an uncertain cardiac status.

Acquired Gitelman Syndrome in an Anti-SSA Antibody-positive Patient with a SLC12A3 Heterozygous Mutation.

A 36-year-old woman developed hypokalemic metabolic alkalosis after anti SS-A antibody was found to be positive. Diuretic loading test results were compatible with Gitelman syndrome (GS). The patient had a heterozygous mutation in SLC12A3, which encodes for thiazide-sensitive NaCl cotransporter (NCCT). While the mutation may be responsible for a latent hypofunction of NCCTs, the underlying anti-SSA antibody-associated autoimmunity induced the manifestation of its hypofunction. To the best of our knowledge, this is the first report to demonstrate that anti SS-A antibody-associated autoimmunity may induce GS in a patient with a SLC12A3 heterozygous mutation.

Successful recovery from an acute kidney injury due to amniotic fluid embolism.

A 33-year-old Japanese woman at 40 weeks gestation visited the maternity hospital after imminent labor had begun. After the delivery, persistent bleeding developed resulting in hemorrhagic shock. Although the hemorrhage was eventually controlled, hepatic and renal dysfunction occurred, leading to acute kidney injury (AKI). The patient's clinical presentation was suggestive of amniotic fluid embolism (AFE). We subsequently initiated continuous renal replacement therapy (RRT) for AKI. The patient's condition improved, she discontinued RRT, and her renal function recovered. We herein report a patient who successfully recovered from AKI caused by AFE.

Hepatic cyst infection in an autosomal dominant polycystic kidney disease patient diagnosed by right pleural effusion.

A 64-year-old Japanese man with renal dysfunction caused by autosomal dominant polycystic kidney disease (ADPKD) was admitted to our hospital for evaluation of right back pain, fever, inflammation, and pleural effusion. Diagnostic investigations for tuberculous pleuritis were all negative. Although no radiographic abnormality suggesting hepatic cyst infection was detected by computed tomography, hepatic cyst drainage demonstrated purulent contents indicative of cyst infection. Conglutination of the cyst by minocycline 100 mg was performed five times in addition to drainage. After drainage, the symptoms of inflammation, right back pain and right pleural effusion subsided. Renal function and anemia, which had been resistant to darbepoetin treatment, also improved after the procedure. These results suggested that the infected hepatic cyst was associated with the patient's symptoms, exacerbation of renal dysfunction and anemia. The pleural effusion was due to the propagation of inflammation from the cyst infection. This is the first report of an infected hepatic cyst in an ADPKD patient presenting with and diagnosed by right pleural effusion.