Heavy Proteinuria Research Articles

Favorable therapeutic efficacy of low-density lipoprotein apheresis for nephrotic syndrome with impaired renal function.

Many reports have shown the therapeutic efficacy of LDL apheresis (LDL‐A) in drug‐resistant nephrotic syndrome (NS) for improvement of heavy proteinuria and severely impaired renal function. To obtain comprehensive results in a large number of cases, a post hoc analysis of the Prospective Observational survey on the Long‐Term Effects of the LDL‐Apheresis on the Drug Resistant Nephrotic Syndrome (POLARIS) study was performed by stratifying enrolled cases according to the pretreatment estimated glomerular filtration rate (eGFR) levels indicating normal (N) (≥60 ml/min/1.73 m2), moderately impaired (M) (≥30 to <60 ml/min/1.73 m2), and severely impaired (S) (<30 ml/min/1.73 m2) renal function. Significant improvements of proteinuria and renal function were found in Group N and, most interestingly, in Group M. A tendency for improvement in proteinuria was found in Group S. Most cases in all groups had not entered end‐stage renal disease at 2 years after LDL‐A treatment. These results suggest that LDL‐A has therapeutic efficacy even in cases in which renal function has declined to 30 ml/min/1.73 m2.

VEGF-VEGFR2 inhibitor-associated hyaline occlusive glomerular microangiopathy: a Japanese single-center experience.

Inhibitors of vascular endothelial growth factor (VEGF)-VEGF receptor 2 (VEGFR2) signaling, such as bevacizumab (Bmab), are used for the treatment of various advanced cancers. However, these inhibitors induce renal thrombotic microangiopathy (TMA). Recently, two European cohort studies showed a distinctive histopathological pseudothrombotic pattern different from TMA in Bmab-treated patients. We analyzed 9 renal biopsies from proteinuric cancer patients treated with VEGF-VEGFR2 inhibitors in our Japanese cohort. Clinical and laboratory features were also assessed in these patients. All 9 patients had moderate to heavy proteinuria with normal or slightly elevated serum creatinine levels. On light microscopy, a patchy pattern of hemispherical/spherical lesions along glomerular capillary walls was a characteristic finding. On immunofluorescence microscopy, staining for immunoglobulins (IgM dominant) at varying intensities was observed mainly along glomerular capillary walls. Especially, hemispherical/spherical positive staining for immunoglobulins was a characteristic pattern. Immunohistochemical studies showed positive staining for immunoglobulins and negative staining for CD61-positive platelets in capillary hemispherical/spherical lesions and positive VEGF staining in podocytes. On electron microscopy, variably electron-dense material in dilated glomerular capillaries and partial effacement of podocyte foot processes were observed. After the withdrawal of VEGF-VEGFR2 inhibitors, proteinuria improved without any specific treatment in 8 patients. Histopathological findings in our patients treated with VEGF-VEGFR2 inhibitors were consistent with those observed in the recently described new form of Bmab-associated hyaline occlusive glomerular microangiopathy. This form should be considered in proteinuric cancer patients treated with VEGF-VEGFR2 inhibitors. Discontinuing VEGF-VEGFR2 inhibitors may lead to improvement of glomerular microangiopathy induced by these drugs.

A curious case of facial swelling

We present our case of a 16 year old boy presenting to us with shortness of breath and having features of both nephritic and nephrotic syndrome leading to intubation and ventilation due to pulmonary embolism. Nephrotic syndrome is characterised by heavy proteinuria (>3g/24hrs), hypertension, hypercholesterolemia, hypoalbuminemia, anasarca and microscopic hematuria whereas nephritic syndrome is characterised by the presence of proteinuria (1-2g/24hrs), hematuria, pyuria, hypertension, red blood cell casts, fluid retention, rise in serum creatinine with reduction in glomerular filtration rate. Both the diseases are separate entities however in certain cases, there can be overlapping of the components of both this syndrome.

MO523PATIENTS FROM COVID-19 MOSTLY RECOVER FROM TUBULAR PROTEINURIA AND ACUTE KIDNEY INJURY AFTER HOSPITAL DISCHARGE

Background and AimsProteinuria, hematuria and acute kidney injury (AKI) are frequently observed in hospitalized patients with COVID-19. However, few data are available on these parameters after hospital discharge.MethodThis retrospective, observational and monocentric study included 153 hospitalized patients, in whom urine total proteinuria and α1-microglobulin (a marker of tubular injury) were measured. Thirty patients died. Among the 123 survivors, follow-up urine and creatinine analyses were available for 72 patients (after a median of 51 [19;93] days following hospital discharge).ResultsThe median proteinuria at hospitalization and follow-up (n=72) was 419 [239; 748] and 79 [47; 129] mg/g, respectively (p<0.0001). The median concentrations of urinary α1-microglobulin (n=66) were 50 [25; 81] and 8 [0; 19] mg/g, respectively (p<0.0001). Estimating glomerular filtration rate (eGFR) was lower during the hospitalization compared to the follow-up: 81 [62; 92] versus 87 [66; 98] mL/min/1.73m² (p=0.0222). At follow-up, a decreased renal function was observed in 10/72 (14%) of patients, with 50% of them presenting decreased renal function before COVID-19 hospitalization and others developing severe AKI and/or proteinuria during hospitalization.ConclusionIn most hospitalized patients with COVID-19, proteinuria and eGFR significantly improved after hospital discharge. Only patients who developed severe AKI and/or heavy proteinuria will require a specific follow-up by nephrologists.Hospitalization (Hosp)Follow-up (F-U)Wilcoxon signed rank/ McNemar testCreatinine (mg/dL) (n=72)0.92 [0.80;1.09]0.87 [0.76;1.05]0.0488eGFR (mL/min/1.73m²)81 [62;92]87 [66;98]0.0222Decreased GFR (%) (age adapted definition)20.814nsDecreased GFR (KDIGO)2318nsProteinuria (mg/g) (n=72)419 [239 ;748]79 [47;129]<0.0001 Proteinuria Category 1 (%) Category 2 (%) Category 3 (%) 15 43 42 83 11 6Urine α1-microglobulin (mg/g) (n=66)50 [25;82]8 [0;19]<0.0001 Urine α1-microglobulin >15 mg/g (%)8829Urine β2-microglobulin (n=60) (mg/L)0.92 [0.41;4.52]0.00 [0.00;0.00]<0.0001Urine β2-microglobulin >0.19 mg/L (%)8213Hematuria (>10 per field) (%) (n=51)1912ns

MO313A CASE OF ALPORT SYNDROME WITH PREGNANCY-RELATED ATYPICAL HEMOLYTIC UREMIC SYNDROME, AND CRESCENTIC GLOMERULONEPHRITIS

Abstract Background Thrombotic microangiopathy (TMA) is one of the most important complications in pregnant patients with chronic kidney disease (CKD) causing clinical deterioration. However, little is known about the pregnancy course in women with Alport syndrome (AS). Case A 28-week pregnant, 22-year-old woman was admitted to our clinic because of widespread edema. Her medical history was notable only for hearing impairment. On examination, vital signs were normal except for the blood pressure (150/90 mmHg). There were diffuse crackles at the lung bases, and 3+ pitting edema in both legs. Lab results revealed heavy proteinuria with 11 gr/day and isomorphic erythrocytes with granular casts in microscopic urine examination. An emergency c-section was performed due to severe preeclampsia at 30 weeks’ gestation. After delivery, her edema did not improve, serum creatinine and lactate dehydrogenase levels elevated, anemia and thrombocytopenia developed (Table 1). Additional tests revealed negative Coombs test, schistocytes on peripheral smear and normal ADAMTS13 level. There was no pathology in serological studies. She received four sessions of plasmapheresis therapy, and with the diagnosis of aHUS, eculizumab therapy was started. Despite improving thrombocytopenia and anemia, serum creatinine levels continued to rise and her urine output decreased. A kidney biopsy was performed (Figure 1). In the light microscopy, 11 of 15 glomeruli had circumferential cellular crescents and 4 had partial cellular crescents. The sample had no findings consistent with TMA. No staining was seen with IgG, IgA, IgM, C3, C1q, κ and λ in immunofluorescence. Further evaluation of hearing impairment revealed bilateral sensorineural hearing loss. A homozygous mutation was identified on COLA4 gene, while homozygous polymorphism on complement factor H (CFH) c.1204C&amp;gt;T and heterozygotic polymorphisms on CFH c.2808G&amp;gt;T and c.3148A&amp;gt;T were revealed. After discharge, her kidney function remained poor requiring maintenance hemodialysis despite 6 months of eculizumab therapy. Discussion Alport syndrome is a genetic disease with the triad of hematuria, sensorineural hearing loss, and ocular symptoms due to the defect in the synthesis of α3, α4 and α5 chains of Type 4 collagen. The increase in proteinuria, hypertension and the presence of CKD are shown as poor prognostic factors for both maternal and fetal health in pregnant women with AS. However, crescentic glomerulonephritis is not the classical biopsy finding of AS. In a few studies, crescents in AS have been reported to correlate with rapid disease progression. There is increasing knowledge that the complement system is involved in the pathogenesis of pauci-immune crescentic GN. High plasma c3a, c5a, c5b-9, Bb and low plasma properdin levels were found to show alternative complement activation and correlate with disease activity in pauci-immune crescentic GN patients. Few reports show that anti-complement therapies might be an option in these cases. Although our case’s kidney functions did not improve on eculizumab, we conclude that the polymorphisms in the complement genes may have induced crescent formation in the presence of pregnancy and abnormal glomerular structure due to AS. Conclusion Here we presented a case with AS complicated by aHUS and crescentic GN. Given this complex combination of rare causes of acute kidney injury, detailed clinical evaluation is of great importance in the evaluation of acute kidney injury during pregnancy.

Characterization of a Rat Model of Myeloperoxidase-Anti-Neutrophil Cytoplasmic Antibody-Associated Crescentic Glomerulonephritis

Background/Aim: Necrotizing crescentic glomerulonephritis (GN) associated with anti-neutrophil cytoplasmic antibodies (ANCA) against myeloperoxidase (MPO) is a devastating disease that quickly progresses to kidney failure. Current therapies are broadly immunosuppressive and associated with adverse effects. We wanted to set up a model that could be suitable for testing narrowly targeted therapies. Methods: The model was constructed in male Wistar Kyoto rats through injections of human MPO (hMPO) and pertussis toxin, followed by a sub-nephritogenic dose of sheep anti-rat glomerular basement membrane (GBM) serum to boost the disease. Rats were monitored for 35 days. Rats given hMPO alone, saline, or human serum albumin with or without anti-GBM serum were also studied. Results: Rats receiving hMPO developed circulating anti-hMPO and anti-rat MPO antibodies. Challenging hMPO-immunized rats with the anti-GBM serum led to more glomerular neutrophil infiltration and MPO release, and severe haematuria, heavy proteinuria, and higher blood urea nitrogen than hMPO alone. Pauci-immune GN developed with crescents, affecting 25% of glomeruli. The majority of crescents were fibrocellular. Necrotizing lesions and Bowman capsule ruptures were detected. Cells double positive for claudin-1 (a marker of parietal epithelial cells [PECs]) and neural cell adhesion molecule (NCAM; progenitor PECs) were present in crescents. Double staining for NCAM and Ki-67 established proliferative status of progenitor PECs. Podocyte damage was associated with endothelial and GBM changes by electron microscopy. Monocyte/macrophages and CD4⁺ and CD8⁺ T cells accumulated in glomeruli and the surrounding area and in the tubulointerstitium. Lung haemorrhage also manifested. Conclusion: This model reflects histological lesions of human ANCA-associated rapidly progressive GN and may be useful for investigating new therapies.

Podocyte Sphingolipid Signaling in Nephrotic Syndrome.

Podocytes play a vital role in the pathogenesis of nephrotic syndrome (NS), which is clinically characterized by heavy proteinuria, hypoalbuminemia, hyperlipidemia, and peripheral edema. The pathogenesis of NS has evolved through several hypotheses ranging from immune dysregulation theory and increased glomerular permeability theory to the current concept of podocytopathy. Podocytopathy is characterized by dysfunction or depletion of podocytes, which may be caused by unknown permeability factor, genetic disorders, drugs, infections, systemic disorders, and hyperfiltration. Over the last two decades, numerous studies have been done to explore the molecular mechanisms of podocyte injuries or NS and to develop the novel therapeutic strategies targeting podocytopathy for treatment of NS. Recent studies have shown that normal sphingolipid metabolism is essential for structural and functional integrity of podocytes. As a basic component of the plasma membrane, sphingolipids not only support the assembly of signaling molecules and interaction of receptors and effectors, but also mediate various cellular activities, such as apoptosis, proliferation, stress responses, necrosis, inflammation, autophagy, senescence, and differentiation. This review briefly summarizes current evidence demonstrating the regulation of sphingolipid metabolism in podocytes and the canonical or noncanonical roles of podocyte sphingolipid signaling in the pathogenesis of NS and associated therapeutic strategies.

A novel mutation of congenital nephrotic syndrome in a Slovenian child eventually receiving a renal transplant

Congenital nephrotic syndrome (CNS) is a rare disease defined as heavy proteinuria, hypoalbuminemia, hyperlipidemia, and edema presenting in the first three months of life. It is most commonly caused by mutations in the NPHS1 gene associated with nephrotic syndrome type 1, also known as Finnish-type CNS, which is inherited in an autosomal recessive manner. Symptomatic treatment with intravenous albumins, vitamins, minerals, nutritional, and hormonal supplementation and treatment of complications are mandatory. Children refractory to the symptomatic treatment are recommended to undergo nephrectomy and renal replacement therapy, preferably renal transplantation. We report on a child with Finnish type CNS with a NPHS1 mutation, which is the first case confirmed by genetic study in Slovenia. We showed for the first time that homozygous mutation c.2928-3del in the NPHS1 gene caused exon 22 skipping, leading to a truncated protein and Fin-minor phenotype.

Role of distal nephron in the control of extracellular volume in physiology and in nephrotic syndrome

The kidney plays a major role to maintain the constancy of the "milieu intérieur" by adjusting the urinary excretion of water and solutes to the requirement of the body balance. This function is coordinated with elimination of waste products generated among others by the catabolism of proteins and nucleic acids. To cope with these two major functions, the human kidneys generate each day about 180 L of ultrafiltrate from plasma and reabsorbs the vast majority of filtered water and solutes to excrete daily about one-two liter(s) of urine containing concentrations of sodium, potassium and chloride ranging from 20 to 200 mM. The final adjustment of urine composition is finely tuned along the aldosterone-sensitive distal nephron (ASDN) which includes the distal convoluted tubule and the collecting system (connecting tubule and collecting duct). Sodium reabsorption is predominant along the distal tubule if potassium must be spared, or along the collecting system when large amounts of potassium must be secreted. Nephrotic syndrome is characterized by heavy proteinuria consecutive to a glomerular injury, associated with renal sodium and water retention taking initially place along ASDN and leading to edema.

Comparison the Serum Level of Paraoxonase Activity in Frequent Relapse and Infrequent Relapse Patients with Nephrotic Syndrome

Nephrotic syndrome (NS) is distinguished by heavy proteinuria (urine protein:creatinine ratio ?2000 mg/gor ?300 mg/dL, or 3+ protein on urine dipstick), hypoalbuminemia (?2.5 g/dL), and edema. Leakage ofmassive amounts of serum proteins into the urine leads to a hypercoagulable state, a higher rate of infectiousdisease, and the dysregulation of fluid balance. Idiopathic nephrotic syndrome (INS)is one of the most common renal problems in children encountered in day-to-day nephrology practices.The present study was aimed to evaluate the oxidant/ antioxidant status by measuring paraoxonase (PON)activities as well as total antioxidant capacity in steroid sensitive nephrotic syndrome (frequent and infrequentrelapse) and compares it with healthy control children . Paraoxonase activity by spectrophotometer in threegroups consisted of age and sex matched (30) patients with Frequent relapse nephrotic syndrome FRNS ,(30) patients with infrequent relapse nephrotic syndrome (IFRNS) and (30) healthy control children. Theserum level of paraoxonase activity in infrequent relapse group was 101.61±43.0 IU which far less thanfrequent relapse group (160.44±44.22 IU) or controls (228.35±32.35 IU) with highly significant differences.Of note, the difference between control group and frequent relapse group was highly significant.

Lowest nocturnal systolic blood pressure is related to heavy proteinuria and outcomes in elderly patients with chronic kidney disease

Ambulatory blood pressure monitoring (ABPM) can produce many variables, of which the lowest nocturnal systolic blood pressure (LNSBP) currently used in calculating morning surge is occasionally overlooked in recent kidney studies compared with other ABPM parameters. We explored the clinical effects of LNSBP in elderly patients with chronic kidney disease (CKD) in a multicenter, observational cohort study. A total of 356 elderly patients with CKD from 19 clinics were included in this analysis. We used multiple logistic regression and survival analyses to assess the associations between the lowest nocturnal systolic blood pressure and heavy proteinuria and kidney disease outcomes, respectively. The median age was 66 years, and 66.6% were men. The median eGFR was 49.2 ml/min/1.73 m2. Multivariate logistic regression analysis demonstrated that LNSBP (OR 1.24; 95% CI 1.10–1.39; P < 0.001; per 10 mmHg) was associated with heavy proteinuria. During the median follow-up of 23 months, 70 patients (19.7%) had a composite outcome; of these, 25 initiated dialysis, 25 had 40% eGFR loss, and 20 died. Cox analysis showed that the renal risk of LNSBP for CKD outcomes remained significant even after adjusting for background factors, including age, sex, medical history of hypertension and diabetes, smoking status, eGFR, 24-h proteinuria, and etiology of CKD (HR 1.18; 95% CI 1.06–1.32; P = 0.002; per 10 mmHg). Concentrating on LNSBP could be valuable in guiding antihypertensive treatment to control heavy proteinuria and improve renal prognosis in elderly CKD patients.

Associations among Heavy Metals and Proteinuria and Chronic Kidney Disease.

Background: The prevalence of chronic kidney disease (CKD) is increasing annually in Taiwan. In addition to traditional risk factors, heavy metals contribute to the development of CKD. The aim of this study was to investigate associations among heavy metals and proteinuria and CKD in the general population in Southern Taiwan. We also explored the interaction and synergetic effects among heavy metals on proteinuria. Methods: We conducted a health survey in the general population living in Southern Taiwan between June 2016 and September 2018. Seven heavy metals were measured: blood lead (Pb) and urine nickel (Ni), chromium (Cr), manganese (Mn), arsenic (As), copper (Cu), and cadmium (Cd). Proteinuria was measured using reagent strips. CKD was defined as an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2. Results: The mean age of the 2447 participants was 55.1 ± 13.2 years and included 977 males and 1470 females. Participants with high blood Pb and high urine Ni, Mn, Cu, and Cd were significantly associated with proteinuria. Interactions between blood Pb and urine Cr, and between urine Cd and Cu, had significant effects on proteinuria. The participants with high blood Pb and high urine Cu were significantly associated with an eGFR of <60 mL/min/1.73 m2. Conclusion: High blood Pb and high urine Cu may be associated with proteinuria and an eGFR of <60 mL/min/1.73 m2. High urine Ni, Mn, and Cd were significantly associated with proteinuria. Co-exposure to Cd and Cu, and Pb and Cr, may have synergistic effects on proteinuria.

Antithrombin III level in children with nephrotic syndrome, its correlation to thromboembolic complications, and serum albumin level.

Nephrotic syndrome (NS) is one of the most common pediatric diseases with many complications. Thromboembolic complication is the most serious complication. The aim of this study was to predict the possible risk of thromboembolic complication development in children with NS due to antithrombin III deficiency. This study was conducted in the Outpatient Nephrology Clinic of Children's Hospital in Fayoum University Hospital. It included 27 children with NS and 27 healthy children as a control group in an analytic study with cross-sectional comparative design. Laboratory investigations were done in the form of complete blood picture, serum levels of albumin, total protein, creatinine, urea, cholesterol, triglycerides, urine analysis, albumin/creatinine ratio, prothrombin time, and INR. The serum antithrombin III level was measured by double ELISA technique. Data analysis was performed using the Statistical Package for the Social Sciences software version 18. Student's t-test was used to compare measures of two independent groups of quantitative data. One-way ANOVA test was used to compare more than two independent groups of quantitative data. Kruskal-Wallis test was used in comparing more than two independent nonparametric groups. Bivariate Pearson correlation test was used to test the association between variables. The level P ≤0.05 was considered significant. There were significant decreases in antithrombin III, albumin, and total protein levels in the study group during relapse and improved after steroid. There were no thromboembolic complications detected among the study group. NS causes heavy proteinuria with loss of many important proteins as antithrombin III. Serum antithrombin III level is significantly decreased in children with NS, and it correlated with serum albumin. Although patients in the study have thrombocytosis, hypercholesterolemia, and decreased serum level of antithrombin III, none of the children in the the study showed thrombotic complication, so we conclude that, thromboembolism is uncommon in children with NS may be due to early diagnosis and proper treatment.

Immunofluorescence deposits in the mesangial area and glomerular capillary loops did not affect the prognosis of immunoglobulin a nephropathy except C1q:a single-center retrospective study

BackgroundImmunoglobulin A nephropathy (IgAN) is identified as mesangial IgA deposition and is usually accompanied by other immunofluorescence deposits. The impact of immunofluorescent features in IgAN patients, however, remains unclear.MethodsBaseline clinicopathologic parameters and renal outcomes of 337 patients diagnosed with IgAN between January 2009 and December 2015 were analyzed. We then categorized these patients into four groups: without immunofluorescence deposits, mesangial-only, mesangial and glomerular capillary loops (GCLs), and GCLs-only. The study endpoint was end-stage kidney disease (ESKD) or a ≥ 50% decline in the estimated glomerular filtration rate (eGFR). Kaplan–Meier and Cox regression analyses were performed to calculate renal survival.ResultsOf the 337 IgAN patients, women comprised 57.0%. Compared to patients with IgA deposition in the mesangial-only group, patients with IgA deposition in the mesangial +GCLs group were much heavier, and exhibited higher systolic blood pressure, lower serum IgG levels, and heavier proteinuria (all P < 0.05). Patients with IgG deposition in the mesangial +GCLs group presented with higher levels of cholesterol, heavier proteinuria than IgG deposition in the mesangial-only group (both P < 0.05). Compared with the mesangial-only group exhibiting C3 deposits, patients in the mesangial +GCLs group with C3 deposition had a higher systolic blood pressure (P = 0.028). A total of 38 patients (11.3%) continued to the study endpoint after a median follow-up time of 63.5 months (range,49.8–81.4). Kaplan–Meier analysis and Cox regression analysis showed that C1q deposition in the mesangial +GCLs group predicted a poor renal prognosis.ConclusionsIgA and IgG deposits in the mesangial region and GCLs were associated with more unfavorable clinical and histopathologic findings in IgAN patients. C1q deposition in the mesangial region and GCLs predicted a poor renal prognosis. However, the impact of the pattern of immunofluorescence deposits on renal outcomes remains to be proven by further investigation.

CKD and CKDu in northern Peru: a cross-sectional analysis under the DEGREE protocol

BackgroundThis study estimated the prevalence and risk factors for decreased estimated glomerular filtration rate (eGFR) in those without known hypertension, type 2 diabetes mellitus, or heavy proteinuria as a surrogate marker for chronic kidney disease of unknown cause (CKDu) among adults in the North of Peru.MethodsA cross-sectional study was conducted following the Disadvantaged Populations eGFR Epidemiology (DEGREE) Study protocol. Low eGFR was defined based on a single eGFR ≤60 mL/min/1.7m2 estimated using the CKD-EPI equation. Environmental conditions related to CKDu (i.e., work in agriculture or sugarcane, water source, heat intolerance, and pesticide exposure) were evaluated, in addition to traditional risk factors for CKD (i.e., smoking, heavy drinking, physical activity, hypertension, type 2 diabetes mellitus, urolithiasis, among others).ResultsA total of 1514 subjects were included in the study, mean age 45.1 (SD: 16.4), and 55.2% were females. Overall, only 26 cases (1.7%; 95%CI: 1.1–2.5%) had an eGFR < 60 mL/min/1.7m2 compatible with CKD definition; when those with hypertension and type-2 diabetes or heavy proteinuria were excluded, according to the DEGREE protocol, the estimate fell to 0.9% (95%CI: 0.4–1.5%). Low physical activity levels (OR = 1.99; 95%CI: 1.18–3.34), hypertension (OR = 2.07; 1.26–3.41), and urolithiasis (OR = 1.97; 95%CI: 1.18–3.27) were factors associated with low eGFR.ConclusionsA low population-based prevalence of low eGFR (as a surrogate for CKDu), both in rural and urban settings areas, in the Northern Peru, was found. Low physical activity levels, hypertension and urolithiasis were factors associated with low eGFR. Interventions to prevent CKD cases may be focused on well-known CV risk factors and urolithiasis.

Late intervention in the remnant kidney model attenuates proteinuria but not glomerular filtration rate decline.

The use of animal models to predict the response to new therapies in humans is a vexing issue in nephrology. Unlike patients with chronic kidney disease (CKD), few rodent models develop a progressive decline in glomerular filtration rate (GFR) so that experimental studies frequently report a reduction in proteinuria as the primary efficacy outcome. Moreover, while humans present with established kidney disease that continues to progress, many experimental studies investigate therapies in the prevention rather than in a therapeutic setting. We used the remnant kidney (subtotal nephrectomy [SNX]) rat model that develops a decline in GFR in conjunction with heavy proteinuria and hypertension along with the histological hallmarks of CKD in humans, glomerulosclerosis and tubulointerstitial fibrosis. Using agents that had been shown to improve GFR as well as proteinuria in the prevention setting, angiotensin-converting enzyme (ACE) inhibition with enalapril and SIRT1 activation with SRT3025, treatment was initiated 6 weeks after SNX. While enalapril reduced blood pressure, proteinuria and histological injury, it did not improve GFR, as measured by inulin clearance. SRT3025 improved neither GFR nor structural damage despite a reduction in proteinuria. These findings demonstrate that neither a reduction in proteinuria nor a reversal of structural damage in the kidney will necessarily translate to a restoration of kidney function.

The Level of Urine Dipstick Proteinuria and Its Relation to the Risk of Incident Cholelithiasis.

BackgroundPrevious studies have suggested the potential association between renal diseases and gallstone. The extent of proteinuria is recognized as a marker for the severity of chronic kidney disease. However, little data is available to identify the risk of incident gallstone according to the level of proteinuria.MethodsUsing a data of 207,356 Koreans registered in National Health Insurance Database, we evaluated the risk of gallstone according to the levels of urine dipstick proteinuria through an average follow-up of 4.36 years. Study subjects were divided into 3 groups by urine dipstick proteinuria (negative: 0, mild: 1+ and heavy: 2+ or greater). Multivariate Cox-proportional hazard model was used to assess the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident cholelithiasis according to urine dipstick proteinuria.ResultsThe group with higher urine dipstick proteinuria had worse metabolic, renal, and hepatic profiles than those without proteinuria, which were similarly observed in the group with incident cholelithiasis. The heavy proteinuria group had the greatest incidence of cholelithiasis (2.39%), followed by mild (1.54%) and negative proteinuria groups (1.39%). Analysis for multivariate Cox-proportional hazard model indicated that the heavy proteinuria group had higher risk of cholelithiasis than other groups (negative: reference, mild proteinuria: HR 0.97 [95% CI, 0.74–1.26], and heavy proteinuria: HR 1.46 [95% CI, 1.09–1.96]).ConclusionUrine dipstick proteinuria of 2+ or greater was significantly associated with increased risk for incident gallstone.

Clinicopathologic features and prognostic factors in older patients with biopsy-proven diabetic nephropathy.

The older population has increased sharply in China. However, renal clinical and histopathological data in this population are lacking. This study investigated the clinicopathologic features and the related risk factors for long-term renal survival in older patients with diabetic nephropathy (DN). In this retrospective observational study, 74 older patients (≥ 60years old) with type 2 diabetes mellitus and biopsy-proven DN from 2007 to 2019 were included. Clinical data were extracted from electronic records. Renal biopsy specimens were semiquantitatively evaluated using the Renal Pathology Society (RPS) classification system. Cox proportional hazard analysis was used to estimate hazard ratios (HRs) for progression to end-stage renal disease (ESRD). During the median follow-up period of 22months, 24 (32%) older patients progressed to ESRD. Older patients who progressed to ESRD had poorer renal function, lower hemoglobin and albumin concentrations, more severe glomerular lesions, and higher percentages of Kimmelstiel-Wilson lesions than those who did not progress to ESRD. After adjusting for age, sex, baseline renal function, and pathological parameters, multivariate Cox proportional hazard analysis showed that RPS glomerular classification (HR 2.49, 95% confidence interval [CI] 1.03-6.04), estimated glomerular filtration rate (eGFR) (HR 0.76, 95% CI 0.58-0.99), and proteinuria (HR 3.85, 95% CI 1.44-10.27) were independent risk factors for progression to ESRD. Lower eGFR, heavier proteinuria, and more severe RPS glomerular lesions were associated with ESRD in older patients with type 2 diabetes mellitus and DN.

Low-salt low-protein diet and blood pressure control in patients with advanced diabetic kidney disease and heavy proteinuria.

To assess the associations between effects of low salt, low protein diet supplemented with keto-analogues (sLPD)-on salt intake, blood pressure (BP) and cardiovascular events (CVEs) in patients with advanced diabetic kidney disease (DKD) and heavy proteinuria. Prospective, single-center study (total duration of 15months), enrolling 92 patients with advanced DKD (median eGFR 11.7ml/min) and heavy proteinuria (median 4.8g/g creatininuria). The intervention consisted in a low salt-low protein (0.6g/kg-day) diet (sLPD) under intensive nutritional counselling, and adjustment of antihypertensive therapy. The endpoints of this sub-analysis were a salt intake ≤ 5g/day, a mean blood pressure (MAP) ≤ 97mmHg, corresponding to KDIGO target of 130/80mmHg, and the rate of CVEs. Salt intake decreased with 2.5g/day and the proportion of patients reaching the salt intake endpoint increased with 58%. A salt intake ≤ 5g/day was associated with a reduced MAP, BMI, proteinuria, fractional excretion of sodium, and eGFR, suggesting a salt-related volume contraction but was not related to protein intake. Mean arterial pressure decreased with 13mmHg. MAP ≤ 97mmHg was associated with lower proteinuria, salt, and protein intake, but the contribution of salt intake cannot be differentiated from that of protein intake. CVEs occurred in 20% of patients and were independently related to a lower age and MAP, and increased comorbidities. eGFR only minimally declined and no renal adverse events were noted. sLPD was nutritionally safe. The multifactorial personalized intervention allowed a stable MAP reduction to KDIGO recommended levels (≤ 97mmHg), related to the decrease in salt and protein intake. However, BP lower than 130/80mmHg increased the cardiovascular but not the renal risk in heavy proteinuric patients with advanced DKD. 0341507433: NCT03415074. Registered 02/02/2015 in US National Library of Medicine, ClinicalTrials.gov (NCT).

The prognostic effect of immunosuppressive therapy in IgA nephropathy with stage 3 or 4 chronic kidney disease

Background It is debated whether patients with IgAN with heavy proteinuria and decreased eGFR benefit from aggressive treatment consisting of corticosteroids alone or combined with immunosuppressive agents. Methods A retrospective study was performed between January 2008 and December 2016 on patients with IgAN who had urinary protein excretion > 1.0 g/d and an eGFR between 15 and 59 mL/min/1.73 m2. These patients were assigned to receive supportive care alone or supportive care plus immunosuppressive therapy. The primary outcome was defined as the first occurrence of a 50% decrease in eGFR or the development of ESKD. Results All 208 included patients were followed for a median of 43 months, and 92 (44%) patients experienced the primary outcome. Cumulative kidney survival was better in the immunosuppression group than in the supportive care group (p < .001). The median annual rate of eGFR decline in the immunosuppression group was −2.0 (−7.3 to 4.2), compared with −8.4 (–18.9 to −4.1) mL/min/1.73 m2 in the supportive care group (p < .001). In multivariate Cox regression analyses, immunosuppressive therapy was associated with a lower risk of progression to ESKD, independent of age, sex, eGFR, proteinuria, MAP, kidney histologic findings and the use of RASi agents (HR = 0.335; 95% CI 0.209–0.601). Among the adverse events, infection requiring hospitalization occurred at similar rates in both groups (p = .471). Conclusion Immunosuppressive therapy attenuated the rate of eGFR decline and was associated with a favorable kidney outcome in IgAN patients with heavy proteinuria and decreased eGFR, and the side effects were tolerable.