Renal Disease in Metabolic Syndrome: the Hidden Role of Intrarenal Ischemia.

Introduction: The pathogenesis of renal disease in obesity and metabolic syndrome (MS) is mostly unknown. This is in part because of the limited information about renal morphological changes in these conditions. We evaluated renal histology in subjects with MS and those without MS, who are participants in the European Nephrectomy Biobank (ENBiBA) project. Methods: MS was defined with at least 3 of the following criteria: (i) body mass index (BMI) ≥27 kg/m2; (ii) prediabetes: fasting glucose of 100-125 mg/dl or HbA1c >5.7%; (iii) systolic or diastolic blood pressure >140/90 mm Hg or the use of medications; and (iv) triglycerides >150 mg/dl or high-density lipoprotein cholesterol <40 (in men) or 50 mg/dl (in women). The absence of these criteria defined patients without MS. Exclusion criteria were diabetes or known causes of renal disease. Results: A total of 157 cases were evaluated: 49 without and 108 with MS. Those with MS were older (54 ± 16 vs. 66 ± 11, P < 0.0001), had more prevalent chronic kidney disease (CKD, estimated glomerular filtration rate [eGFR] <60 ml/min): 24% (23%) versus 4% (8%) (P = 0.02), and had higher albumin-to-creatinine ratio (10 [4-68] vs. 4.45 [0-27], P = 0.05) than those without MS. Global sclerosis (3% [1-7] vs. 7% [3-13], P < 0.0001), nodular sclerosis, mesangial expansion, glomerulomegaly; moderate + severe hyalinosis, and arteriosclerosis were more frequent in those with MS than in those without (88 [82] vs. 29 [59]; 83 [77] vs. 30 [61]; P < 0.05). These vascular changes were independent of differences in age. Conclusion: In MS, ischemic renal disease may play a role in renal disease. In addition, some patients may develop lesions compatible with diabetic nephropathy such as increased mesangial expansion and nodular sclerosis. Further analyses are needed to study the consequences of the pandemic of obesity on renal health.

Cystic phenotype and chronic kidney disease in autosomal dominant Alport syndrome.

BACKGROUND AND HYPOTHESIS: Autosomal Dominant Alport Syndrome (ADAS), also known as Thin Basement Membrane Disease (TBMD), is caused by pathogenic variants in COL4A3 and COL4A4 genes. A cystic phenotype has been described in some patients with TBMD, but no genetic studies were performed. We conducted a genetic and radiologic investigation in a cohort of ADAS patients to analyze the prevalence of multicystic kidney disease (MKD) and its association with Chronic Kidney Disease (CKD). METHODS: Retrospective single-center cohort study. Thirty-one patients showing pathogenic or likely pathogenic variants in COL4A3 or COL4A4 from a cohort of 79 patients with persistent microscopic hematuria were included. Mean follow-up was 9.4±9.6 years. The primary objective of the study was to determine the prevalence of MKD in the cohort of ADAS patients. Secondary objectives were to determine risk factors associated with an eGFR<45 ml/min/1.73m2 at the time of genetic and radiologic evaluation and to investigate the coexistence of other genetic abnormalities associated with familial hematuria and cystic kidney disease. RESULTS: MKD was found in 16 patients (52%). Mean number of cysts per kidney was 12.7±5.5. No genetic abnormalities were found in a panel of 101 other genes related to familial hematuria, focal segmental glomerulosclerosis and cystic kidney disease. A greater number of patients with MKD had an eGFR<45 ml/min/1.73m2 (63% vs 7%, p=0.006) and more advanced CKD than patients without MKD. The annual rate of eGFR decline was greater in patients with MKD: -1.8 vs 0.06 ml/min/1.73m2/year (p=0.009). By multivariable linear regression analysis, the main determinants of eGFR change per year were time-averaged proteinuria (p=0.002) and MKD (p=0.02). CONCLUSION: MKD is commonly found in ADAS and is associated with a worse kidney outcome. No pathogenic variants were found in genes other than COL4A3/COL4A4.

Facing the Challenge of Drug-Induced Acute Interstitial Nephritis.

BACKGROUND: Acute interstitial nephritis (AIN) is one of the chief causes of acute kidney injury (AKI). AIN might be produced by drugs, infections, autoimmune diseases, or can be idiopathic. Among these etiologies, drug-induced AIN (DI-AIN) is the dominant one in many countries. Even when DI-AIN is suspected, identification of the putative drug is challenging. SUMMARY: DI-AIN is an increasingly common cause of AKI. Diagnosis continues to pose a challenge for physicians due to nonspecific clinical symptoms, and the fact that it can be triggered by a wide variety of medications. Furthermore, the gold standard for the diagnosis is kidney biopsy. All these aspects render the diagnosis more difficult. The withdrawal of the causative drug of DI-AIN is the centerpiece of the treatment, and if early restoration of original kidney function is not obtained, several studies support the treatment with steroids especially when they are started quickly. KEY MESSAGES: Almost all drugs have the potential to produce drug-induced acute interstitial nephritis (DI-AIN); however, antibiotics, nonsteroidal anti-inflammatory agents, and proton pump inhibitors account for the majority of the reported cases. DI-AIN is produced by an idiosyncratic delayed type IV hypersensitivity reaction, but the precise pathophysiological mechanism remains to be elucidated. DI-AIN symptoms are nonspecific, and most of the patients will present mild symptoms including malaise, nausea, and vomiting. The classical triad, associating fever, rash, and eosinophilia, is seldom present. Nonoliguric acute kidney injury is the main renal manifestation of DI-AIN. Tubular nonnephrotic range proteinuria is usually present. Diagnosis of DI-AIN relies on maintaining a high index of suspicion in those patients at greater risk, but kidney biopsy is required to confirm diagnosis. Histologically, AIN is characterized by the presence of an extensive interstitial infiltrate, mainly composed of lymphocytes and monocytes, but eosinophils, plasma cells, histiocytes, and polymorphonuclear cells can also be found. The withdrawal of the presumed causative drug of DI-AIN is the mainstay of the treatment. When there is no evidence of kidney function recovery after an interval of 5-7 days since interrupting the treatment with the suspected drug, several studies support the treatment with steroids, especially when they are promptly started. Early corticosteroids would decrease the inflammatory infiltrates of the kidney interstitium, thus preventing the risk of subsequent fibrosis.

Humoral Response Following Triple Dose of mRNA Vaccines Against SARS-CoV-2 in Hemodialysis Patients: Results After 1 Year of Follow-Up.

Introduction: COVID-19 is associated with an increased mortality in hemodialysis patients. Therefore, achieving a long-lasting effective immune response to SARS-CoV-2 vaccines is essential. This study describes the humoral immune response in hemodialysis patients following three doses of mRNA vaccines against SARS-CoV-2, and explores the factors associated with a sustained immune response. Materials and Methods: We analyzed the monthly serological evolution of SARS-CoV-2 anti-S(RBD) antibodies for 1 year in 178 chronic hemodialysis patients who received three doses of SARS-CoV-2 mRNA vaccines. The primary outcome was sustained effective humoral response defined as anti-S(RBD) levels > 1,000 AU/ml after 4 months from the third dose. Multivariate logistic regression analyses were used to identify features associated with a sustained humoral immune response. Results: After the initial two SARS-CoV-2 mRNA vaccine doses, 77.8% of patients showed an immediate effective humoral response, decreasing to 52.5% after 4 months. Antibody levels were significantly higher in COVID-exposed patients and HBV vaccine responders. After the third dose, 97% of patients showed an effective humoral response, and remained in 91.7% after 4 months. The mean monthly rate of antibody titer decline decreased from 33 ± 14.5 to 25 ± 16.7%. Multivariate regression analysis showed that previous exposure to COVID-19 and response to HBV vaccines were associated with an effective sustained humoral immune response. Conclusion: Immunization with SARS-CoV-2 mRNA vaccines elicits an effective immediate humoral immune response in hemodialysis patients, with a progressive waning in antibody levels. A third booster dose enhances the immune response with significantly higher antibody levels and more sustained humoral immune response. COVID-naïve patients and patients without previous response to HBV vaccines are likely to benefit from receiving more booster doses to maintain an effective immune response.

Vitamin K antagonist-associated microscopic hematuria.

BACKGROUND: Vitamin K antagonists (VKA) are the most widely used anticoagulants for the prevention of thrombotic events. Several renal adverse effects have been associated with the use of VKA. The main aim of our study was to explore the association between international normalized ratio (INR) levels and microscopic hematuria in patients with VKA. METHODS: We performed a cross-sectional study of patients treated with VKA that attended the outpatient clinic for routine INR control. A simple urinalysis was performed on the day of the INR control and the precise number of red cells in the urine sediment was quantified. Demographic data, kidney function tests, comorbidities, anticoagulant dose and concomitant treatment were registered. RESULTS: A total of 337 patients were included with median INR levels of 2.6 (IQR 2.1-3.3). 11.9% of the patients presented microscopic hematuria (≥14 RBCs/µl). There was a significant correlation between INR levels and the number of red blood cells in the urine sediment (r = 0.201, p = 0.024). In the univariate analysis, microscopic hematuria was associated with having an INR >3.5 (19% vs. 10.2%, p = 0.046), bacteriuria (15.2% vs. 3.6%, p = 0.015), leukocyturia (14.8% vs. 6.6%, p =  0.026), hypertension (16.2% vs. 9.5%, p = 0.053), and the use of renin-angiotensin system (RAS) blockers (6.9% vs. 17.2%, p = 0.004). Multivariate logistic regression showed an association between microscopic hematuria and RAS blockade (OR 0.38, CI 95% 0.163-0.886, p = 0.025), independent from INR levels, hypertension, leukocyturia or bacteriuria. CONCLUSIONS: INR overdose was significantly associated with the presence of microscopic hematuria. RAS blockade is an independent protective factor for the presence of microscopic hematuria in anticoagulated patients.

Serum interleukin-6 levels predict kidney disease progression in diabetic nephropathy.

BACKGROUND: Inflammation is a main mechanism for the pathogenesis and progression of diabetic kidney disease (DKD). Interleukin-6 (IL-6) is an important inflammatory mediator that is suggested to be involved in the pathogenesis of DKD. The aim of our study was to evaluate the association between IL-6 levels and progression of DKD in patients with type 2 diabetes mellitus. Materials an methods: IL-6 levels were measured at baseline and after 4 and 12 months in 70 patients included in a multi-center, randomized controlled clinical trial designed to compare the effect of RAS blockers in monotherapy to dual blockade for slowing the progression of DKD. The primary composite endpoint was > 50% increase in baseline serum creatinine, end-stage kidney disease (ESKD), or death. RESULTS: The median follow-up was 36 months, during which 27 patients (38.6%) reached the primary endpoint. Baseline IL-6 levels correlated with TNF-α, C-reactive protein, and PTH levels. Survival analysis showed that patients with the highest IL-6 levels (> 4.84 pg/mL) reached the primary endpoint faster than the other two groups. Multivariate Cox regression analysis showed that baseline IL-6 levels > 4.84 pg/mL (HR 4.10, 95% CI 1.36 - 12.31) were a risk factor for reaching the primary endpoint adjusted for eGFR and proteinuria. Generalized linear mixed model analysis showed no effect on subsequent IL-6 levels either with RAS blockade monotherapy or dual blockade. CONCLUSION: These results suggest that treatment with RAS blockade does not influence IL-6 levels. IL-6 is independently associated with an increased risk for progression of DKD.

The Role of Vascular Lesions in Diabetes Across a Spectrum of Clinical Kidney Disease.

INTRODUCTION: The clinical-histologic correlation in diabetic nephropathy is not completely known. METHODS: We analyzed nephrectomy specimens from 90 patients with diabetes and diverse degrees of proteinuria and glomerular filtration rate (GFR). RESULTS: Thirty-six (40%) subjects had normoalbuminuria, 33 (37%) microalbuminuria, and 21 (23%) non-nephrotic proteinuria. Mean estimated GFR (eGFR) was 65±23 (40% <60 ml/min per 1.73 m2). About 170 glomeruli per patient were analyzed, and all samples included vascular tissue. Six subjects (7%) were classified in diabetic nephropathy class I, 61 (68%) in class II-a, 13 (14%) in class II-b, 9 (10%) class III, and 1 (1%) in class IV. Eighty percent to 90% of those with normoalbuminuria or microalbuminuria were classified in class II-a or II-b and <10% in class III; 52% of those with proteinuria were in class II-a, 15% in class II-b, and 19% in class III. Nodular sclerosis (57%) and mesangial expansion (15%) were more frequent in cases with proteinuria than in normoalbuminuria (28% and 8%; P = 0.028 and 0.017). About 20% to 30% of all cases, regardless the level of albuminuria or proteinuria or the histologic class had tubular atrophy, interstitial fibrosis, or inflammation in >10% to 20% of the sample. Moderate hyalinosis and arteriolar sclerosis were observed in 80% to 100% of cases with normoalbuminuria, microalbuminuria, proteinuria, as well as in class I, II, or III. CONCLUSIONS: Weak correspondence between analytical parameters and kidney histology was found. Thus, disease may progress undetected from the early clinical stages of the disease. Finally, vascular damage was a very common finding, which highlights the role of ischemic intrarenal disease in diabetes.

Urinary Dickkopf-3: a new biomarker for CKD progression and mortality.

BACKGROUND: Kidney fibrosis has been reported to be a prognostic factor in chronic kidney disease (CKD) progression. Previous studies have shown that the assessment of urinary Dickkopf-3 (uDKK3), a stress-induced tubular epithelial-derived profibrotic glycoprotein, might be a potential tubulointerstitial fibrosis biomarker and might identify patients at short-term risk of glomerular filtration rate loss. We aim to evaluate uDKK3 as a potential biomarker for progression of CKD in a cohort with various aetiologies of CKD and subsequently in an overt diabetic nephropathy cohort. METHODS: We prospectively studied two independent cohorts comprising a total of 351 patients with Stages 2 and 3 CKD. Combined primary outcome consisted of a 50% increase in serum creatinine, end-stage kidney disease or death. The Progreser cohort included patients with heterogeneous aetiologies and the Pronedi cohort (101 patients) with overt diabetic nephropathy. The median follow-up time was 36 months [interquartile range (IQR) 30-39] and 36 (16-48), respectively. RESULTS: At baseline, median uDKK3 was 2200 pg/mg (IQR 671-7617) in the Progreser cohort and 3042 pg/mg (IQR 661-9747) in the Pronedi cohort. There were no statistically significant differences in the uDKK3 ratio between both cohorts nor between CKD aetiologies. Baseline uDKK3 was significantly higher in patients who reached the primary outcome. In the Cox proportional hazards model, the highest levels of uDKK3 were found to be an independent factor for renal progression in the Progreser cohort {hazard ratio [HR] 1.91 [95% confidence interval (CI) 1.04-3.52]} and in the Pronedi cohort [HR 3.03 (95% CI 1.03-8.92)]. uDKK3 gradually increased in the following months, especially in patients with higher proteinuria. Treatment with renin-angiotensin-aldosterone system blockers did not modify uDKK3 after 4 or 12 months of treatment. CONCLUSIONS: uDKK3 identifies patients at high risk of CKD progression regardless of the cause of kidney injury. uDKK3 might serve as a useful biomarker for kidney disease progression and therefore could be used by clinicians to optimize staging for renal progression and monitor the response to potential treatments.

Late thrombotic complications after SARS-CoV-2 infection in hemodialysis patients.

INTRODUCTION: There is an increased risk of thrombotic complications in patients with COVID-19. Hemodialysis patients are already at an increased risk for thromboembolic events such as stroke and pulmonary embolism. The aim of our study was to determine the incidence of late thrombotic complications (deep vein thrombosis, pulmonary embolism, stroke, new-onset vascular access thrombosis) in maintenance hemodialysis patients after recovery from COVID-19. METHODS: We performed a retrospective cohort study of 200 prevalent hemodialysis patients in our center at the start of the pandemic. We excluded incident patients after the cohort entry date and those who required hemodialysis for acute kidney injury, and excluded patients with less than 1 month follow-up due to kidney transplantation or death from non-thrombotic causes. FINDINGS: One-hundred and eighty five prevalent hemodialysis patients finally met the inclusion criteria; 37 patients (17.6%) had SARS-CoV-2 infection, out of which 10 (27%) died during the acute phase of disease without evidence of thrombotic events. There was an increased risk of thrombotic events in COVID-19 survivors compared to the non-infected cohort (18.5% vs. 1.9%, p = 0.002) after a median follow-up of 7 months. Multivariate regression analysis showed that COVID-19 infection increased risk for late thrombotic events adjusted for age, sex, hypertension, diabetes, antithrombotic treatment, and previous thrombotic events (Odds Ratio (OR) 26.4, 95% confidence interval 2.5-280.6, p = 0.01). Clinical and laboratory markers did not predict thrombotic events. CONCLUSIONS: There is an increased risk of late thrombotic complications in hemodialysis patients after infection with COVID-19. Further studies should evaluate the benefit of prolonged prophylactic anticoagulation in hemodialysis patients after recovery from COVID-19.

Therapeutic Insights in Chronic Kidney Disease Progression.

Chronic kidney disease (CKD) has been recognized as a leading public health problem worldwide. Through its effect on cardiovascular risk and end-stage kidney disease, CKD directly affects the global burden of morbidity and mortality. Classical optimal management of CKD includes blood pressure control, treatment of albuminuria with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, avoidance of potential nephrotoxins and obesity, drug dosing adjustments, and cardiovascular risk reduction. Diabetes might account for more than half of CKD burden, and obesity is the most important prompted factor for this disease. New antihyperglycemic drugs, such as sodium-glucose-cotransporter 2 inhibitors have shown to slow the decline of GFR, bringing additional benefit in weight reduction, cardiovascular, and other kidney outcomes. On the other hand, a new generation of non-steroidal mineralocorticoid receptor antagonist has recently been developed to obtain a selective receptor inhibition reducing side effects like hyperkalemia and thereby making the drugs suitable for administration to CKD patients. Moreover, two new potassium-lowering therapies have shown to improve tolerance, allowing for higher dosage of renin-angiotensin system inhibitors and therefore enhancing their nephroprotective effect. Regardless of its cause, CKD is characterized by reduced renal regeneration capacity, microvascular damage, oxidative stress and inflammation, resulting in fibrosis and progressive, and irreversible nephron loss. Therefore, a holistic approach should be taken targeting the diverse processes and biological contexts that are associated with CKD progression. To date, therapeutic interventions when tubulointerstitial fibrosis is already established have proved to be insufficient, thus research effort should focus on unraveling early disease mechanisms. An array of novel therapeutic approaches targeting epigenetic regulators are now undergoing phase II or phase III trials and might provide a simultaneous regulatory activity that coordinately regulate different aspects of CKD progression.

Direct-acting antiviral therapy improves kidney survival in hepatitis C virus-associated cryoglobulinaemia: the RENALCRYOGLOBULINEMIC study.

BACKGROUND: Direct-acting antiviral agents (DAAs) have shown high rates of sustained virological response in chronic hepatitis C virus (HCV) infection. However, the influence of DAAs on the course of kidney involvement in HCV-associated mixed cryoglobulinaemia (HCV-MC) has been little studied. The aim of this study was to analyse the effects of antiviral treatment on kidney prognosis and evolution in patients diagnosed with HCV-MC. METHODS: The RENALCRYOGLOBULINEMIC study is an observational multicentre cohort study of 139 patients with HCV-MC from 14 Spanish centres. Clinical and laboratory parameters were measured before and after antiviral treatment. Primary endpoints were kidney survival and mortality after HCV-MC diagnosis. Secondary endpoints were clinical, immunological and virological responses after antiviral treatment. RESULTS: Patients were divided into three groups based on the treatment received: treatment with DAAs (n = 100) treatment with interferon (IFN) and ribavirin (RBV) (n = 24) and no treatment (n = 15). Patients were followed up for a median duration of 138 months (interquartile range 70-251. DAA treatment reduced overall mortality {hazard ratio [HR] 0.12 [95% confidence interval (CI) 0.04-0.40]; P < 0.001} and improved kidney survival [HR 0.10 ( 95% CI 0.04-0.33); P < 0.001]. CONCLUSIONS: Results from the RENALCRYOGLOBULINEMIC study indicated that DAA treatment in patients with HCV-MC improves kidney survival and reduces mortality.

Fulminant Emphysematous Pyelonephritis by Candida glabrata in a Kidney Allograft.

Emphysematous pyelonephritis (EPN) is a rare and serious necrotizing infection that is potentially life-threatening. It has been seldom reported in kidney grafts and is usually caused by Gram-negative bacteria, with some case reports caused by anaerobic bacteria, and has been closely associated with poorly controlled diabetes mellitus (DM) and urinary tract structural abnormalities. There are no reports of EPN of fungal etiology in kidney grafts. We present a case of a 53-year-old kidney transplant recipient with a history of DM, active vesicoureteral reflux, and recurrent urinary tract infections who developed EPN in the kidney allograft caused by Candida glabrata, 3 weeks after starting treatment with empagliflozin, with an aggressive course that required urgent transplant nephrectomy.

Nuevos retos en las nefritis tubulointersticiales inducidas por fármacos / New challenges in tubulointerstitial nephritis induced by drugs

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