A critical view on autoantibodies in lupus nephritis: Concrete knowledge based on evidence.

Deposition of autoantibodies in glomeruli is a key factor in the development of lupus nephritis (LN). For a long time, anti-dsDNA and anti-C1q antibodies were thought to be the main cause of the kidney damage. However, recent studies have shown that the list of autoantibidies that have renal tropism and deposit in the kidney in LN is increasing and the link between anti-dsDNA and renal pathology is weak due to potential confounders. Aspecific bindings of dsDNA with cationic antibodies and of anti-dsDNA with several renal antigens such as actinin, laminin, entactin, and annexinA2 raised doubts about the specific target of these antibodies in the kidney. Moreover, the isotype of anti-dsDNA in SLE and LN has never received adequate interest until the recent observation that IgG2 are preponderant over IgG1, IgG3 and IgG4. Based on the above background, recent studies investigated the involvement of anti-dsDNA IgG2 and of other antibodies in LN. It was concluded that circulating anti-dsDNA IgG2 levels do not distinguish between LN versus non-renal SLE, and, in patients with LN, their levels do not change over time. Circulating levels of other antibodies such as anti-ENO1 and anti-H2 IgG2 were, instead, higher in LN vs non-renal SLE at the time of diagnosis and decreased following therapies. Finally, new classes of renal antibodies that potentially modify the anti-inflammatory response in the kidney are emerging as new co-actors in the pathogenetic scenario. They have been defined as 'second wave antibodies' for the link with detoxifying mechanisms limiting the oxidative stress in glomeruli that are classically stimulated in a second phase of inflammation. These findings have important clinical implications that may modify the laboratory approach to LN. Serum levels of anti-ENO1 and anti-H2 IgG2 should be measured in the follow up of patients for designing the length of therapies and identify those patients who respond to treatments. Anti-SOD2 could help to monitor and potentiate the anti-inflammatory response in the kidney.

ABCs of hemodiafiltration prescription: The Pisa style.

In end-stage kidney disease patients, hemodiafiltration, a mixed diffusive-convective technique, has shown beneficial effects in terms of improvement of anemia, inflammation, mineral bone disorders, malnutrition and cardiovascular stability. Greater convective volume exchange was also associated with improved overall and cardiovascular survival. However, absolute target threshold volume would be difficult to define and achieve in daily clinical practice, mainly because of differences in patient size. Convective volumes standardized for body surface area would appear to be the simplest approach in clinical practice. Several factors can affect achievement of optimal convective volume, with vascular access being the main limiting factor. Based on our own clinical experience, hemodiafiltration is a more effective and preferable dialysis technique but only when a target convective volume greater than 20 L can be achieved. Conversely, standard high flux hemodialysis or expanded hemodialysis may be helpful and valuable alternative dialysis techniques.

RAASi Therapy Attenuates the Association between 24-h Urinary Potassium Excretion and Dietary Potassium Intake in CKD Patients.

The aim of this study was to evaluate urinary potassium (K) excretion as a reliable marker of dietary K intake, in a cohort of CKD patients with or without Renin-Angiotensin-Aldosterone System (RAAS) inhibitor therapy. One hundred and thirty-eight consecutive out-patients (51 f and 87 m) aged 60 ± 13 years and affected by CKD stage 3-4, who were metabolically and nutritionally stable, entered the study between November 2021 and October 2022. No difference was observed between patients with (n = 85) or without (n = 53) RAAS inhibitor therapy, regarding dietary intakes, blood biochemistry, and 24-h urine excretion parameters. Considering all patients, urinary K showed a weak relationship with eGFR (r = 0.243, p < 0.01), and with dietary K intake (r = 0.184, p < 0.05). Serum K was not associated with dietary K intake, but an inverse relationship was observed with eGFR (r = -0.269, p < 0.01). When patients were examined depending on whether they were receiving RAAS inhibitor therapy, the weak inverse relationship between serum K and eGFR was maintained in both groups. Conversely, urinary K excretion remained positively associated with dietary K intake only in the no RAAS inhibitor group. In conclusion, 24-h urine K excretion may be used as a surrogate of K intake, but RAAS inhibitor therapy reduces the association between 24-h urine K excretion and dietary K intake in CKD patients.

Canagliflozin on top of dual renin-angiotensin system blockade in a woman with partial acquired lipodystrophy, type 2 diabetes and severely proteinuric chronic kidney disease: a case report.

Sodium glucose cotransporter 2 inhibitors have proven strong efficacy in reducing end-stage renal disease in patients with type 2 diabetes. We are presenting here the case of a 40-year-old woman with acquired partial lipodystrophy, type 2 diabetes and essential hypertension complicated by chronic kidney disease and proteinuria in the nephrotic range. She first came to our attention in 2012; estimated glomerular filtration rate (eGFR) was 41.5 ml/min/1.73 m2 and total proteinuria was 375 mg/24h; she was treated with dual renin angiotensin system blocking. Proteinuria significantly increased during the following years, reaching a nephrotic range (>5 g/day). A kidney biopsy revealed a tubule-interstitial involvement compatible with type 2 diabetes. Leptin replacement therapy, started in 2018, improved glycaemic control and lipid profile, also determining a reduction in insulin total daily dose. In 2019, after the publication of the CREDENCE study, canagliflozin was started on top of losartan and ramipril. After an initial, expected eGFR drop, kidney function stabilized, and albuminuria significantly reduced (from 4120 to 984 mg/24h), while serum potassium showed only minimal increase. At last follow-up (2022) total proteinuria was still reducing (510 mg/24h), while kidney function was substantially unchanged (eGFR 40 ml/min/1.73 m2). This case report suggests that, despite not recommended in international guidelines, the use of SGLT2i in combination with dual renin angiotensin system blockade should be considered in specific conditions and under close clinical monitoring.

Obesity, Hyperfiltration, and Early Kidney Damage: A New Formula for the Estimation of Creatinine Clearance.

CONTEXT: Glomerular hyperfiltration may represent a direct pathogenetic link between obesity and kidney disease. The most widely used methods to estimate creatine clearance such as Cockroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) have not been validated in subjects with obesity. OBJECTIVE: The performance of prediction formulas was compared with measured creatinine clearance (mCrCl) in subjects with obesity. METHODS: The study population included 342 patients with obesity (mean BMI 47.6 kg/m2) without primary kidney disease. A urine collection was performed over 24 hours for measurement of CrCl. RESULTS: mCrCl increased with body weight. The CG formula showed an overestimation at high CrCl, whereas an underestimation resulted from CKD-EPI and MDRD. To improve the accuracy of estimated CrCl (eCrCl), a new CG-based formula was developed:53+0.7×(140-Age)×Weight/(96xSCr)×(0.85iffemale)A cut-off point for BMI of 32 kg/m2 was identified, at which the new formula may be applied to improve eCrCl. CONCLUSION: In patients with obesity the glomerular filtration rate increases with body weight, and it is associated with the presence of albuminuria, suggesting an early kidney injury. We propose a novel formula that improves the accuracy of eCrCl to avoid missed diagnoses of hyperfiltration in patients with obesity.

Nutritional Treatment as a Synergic Intervention to Pharmacological Therapy in CKD Patients.

Nutritional and pharmacological therapies represent the basis for non-dialysis management of CKD patients. Both kinds of treatments have specific and unchangeable features and, in certain cases, they also have a synergic action. For instance, dietary sodium restriction enhances the anti-proteinuric and anti-hypertensive effects of RAAS inhibitors, low protein intake reduces insulin resistance and enhances responsiveness to epoetin therapy, and phosphate restriction cooperates with phosphate binders to reduce the net phosphate intake and its consequences on mineral metabolism. It can also be speculated that a reduction in either protein or salt intake can potentially amplify the anti-proteinuric and reno-protective effects of SGLT2 inhibitors. Therefore, the synergic use of nutritional therapy and medications optimizes CKD treatment. Quality of care management is improved and becomes more effective when compared to either treatment alone, with lower costs and fewer risks of unwanted side effects. This narrative review summarizes the established evidence of the synergistic action carried out by the combination of nutritional and pharmacological treatments, underlying how they are not alternative but complementary in CKD patient care.

Vitamin D and Calcium Supplementation and Urolithiasis: A Controversial and Multifaceted Relationship.

Patients with urolithiasis, and particularly those with hypercalciuria, frequently have a marked reduction of bone mineral content up to the levels of osteoporosis, with a significant increase in bone fracture risk. For these reasons, the indication to prescribe vitamin D and/or calcium supplementations is very frequent in such patients. On the other hand, both calcium supplementation, and even more vitamin D therapy, can worsen the risk of developing urolithiasis by increasing calcium, phosphate, and oxalate urinary excretion. Despite the clinical and practical relevance of this issue, the evidence on this topic is scarce and contradictory. Therefore, some concerns exist about how and whether to prescribe such supplements to a patient with a history of kidney stones. In this narrative review, we resume some pivotal pathophysiological concepts strictly related to the dealt topic, and we draw some considerations and personal opinions on the pros and cons of such prescriptions. Finally, we share with the reader our pragmatic algorithm for handling the urolithiasis risk in patients who have strong indications to be prescribed vitamin D and calcium supplementations.

Mediterranean Dietary Pattern Adjusted for CKD Patients: The MedRen Diet.

A number of studies in the general population showed that healthy dietary patterns, such as the Mediterranean Diet, can improve or prevent the development of several chronic diseases and are associated with a significant reduction in all-cause and cardiovascular mortality. The Mediterranean diet may also have favorable effects for the prevention of chronic kidney disease (CKD), but no evidence of renoprotection exists in CKD patients. The Mediterranean Renal (MedRen) diet is an adaptation of the Mediterranean diet recommendations comprising a quantitative reduction in the RDA values of protein, salt and phosphate intake for the general population. Hence, MedRen supplies 0.8 g/Kg of protein, 6 g of salt and less than 800 mg of phosphate daily. Obviously, there is a preference for products of plant origin, which contain more alkali, fibers, unsaturated fatty acids than animal-based food. The MedRen diet can be implemented easily in mild-to-moderate stages of CKD with good results, both in terms of adherence to prescriptions and metabolic compensation. In our opinion, it should be the first step of CKD stage 3 nutritional management. This paper describes the features and reports our experience in the implementation of the MedRen diet as an early nutritional approach to CKD.

A Clinical Workflow for Cost-Saving High-Rate Diagnosis of Genetic Kidney Diseases.

SIGNIFICANCE STATEMENT: To optimize the diagnosis of genetic kidney disorders in a cost-effective manner, we developed a workflow based on referral criteria for in-person evaluation at a tertiary center, whole-exome sequencing, reverse phenotyping, and multidisciplinary board analysis. This workflow reached a diagnostic rate of 67%, with 48% confirming and 19% modifying the suspected clinical diagnosis. We obtained a genetic diagnosis in 64% of children and 70% of adults. A modeled cost analysis demonstrated that early genetic testing saves 20% of costs per patient. Real cost analysis on a representative sample of 66 patients demonstrated an actual cost reduction of 41%. This workflow demonstrates feasibility, performance, and economic effect for the diagnosis of genetic kidney diseases in a real-world setting. BACKGROUND: Whole-exome sequencing (WES) increases the diagnostic rate of genetic kidney disorders, but accessibility, interpretation of results, and costs limit use in daily practice. METHODS: Univariable analysis of a historical cohort of 392 patients who underwent WES for kidney diseases showed that resistance to treatments, familial history of kidney disease, extrarenal involvement, congenital abnormalities of the kidney and urinary tract and CKD stage ≥G2, two or more cysts per kidney on ultrasound, persistent hyperechoic kidneys or nephrocalcinosis on ultrasound, and persistent metabolic abnormalities were most predictive for genetic diagnosis. We prospectively applied these criteria to select patients in a network of nephrology centers, followed by centralized genetic diagnosis by WES, reverse phenotyping, and multidisciplinary board discussion. RESULTS: We applied this multistep workflow to 476 patients with eight clinical categories (podocytopathies, collagenopathies, CKD of unknown origin, tubulopathies, ciliopathies, congenital anomalies of the kidney and urinary tract, syndromic CKD, metabolic kidney disorders), obtaining genetic diagnosis for 319 of 476 patients (67.0%) (95% in 21 patients with disease onset during the fetal period or at birth, 64% in 298 pediatric patients, and 70% in 156 adult patients). The suspected clinical diagnosis was confirmed in 48% of the 476 patients and modified in 19%. A modeled cost analysis showed that application of this workflow saved 20% of costs per patient when performed at the beginning of the diagnostic process. Real cost analysis of 66 patients randomly selected from all categories showed actual cost reduction of 41%. CONCLUSIONS: A diagnostic workflow for genetic kidney diseases that includes WES is cost-saving, especially if implemented early, and is feasible in a real-world setting.

Diagnosis, Prevalence and Significance of Obesity in a Cohort of CKD Patients.

BACKGROUND: data regarding the association between obesity and morbidity/mortality in patients with chronic kidney disease (CKD) are uncertain and sometimes contradictory. The aims of our study were to determine the associations among different measures of obesity and adiposity, and the risk of all-cause mortality or dialysis entry in stage 3-5 CKD patients. MATERIALS: this observational cohort study included 178 CKD patients followed for a median of 71 months. Biochemistry, anthropometric measures such as body mass index (BMI), waist-to-hip ratio, mid-arm muscle circumference (MAMC) and body composition by bioimpedance analysis were evaluated. RESULTS: we found a weak agreement between BMI and other measures of adiposity. In multivariable regression analysis, all measures of obesity such as BMI, waist circumference and waist-to-height ratio were not associated with dialysis entry and/or mortality. Instead, MAMC was associated with dialysis entry HR 0.82 [95% CI: 0.75-0.89] and high FM% with mortality HR 2.08 [95% CI: 1.04-4.18]. CONCLUSIONS: in our CKD population, lower MAMC was predictive of dialysis commencing, while a higher percentage of fatty mass was a predictor of mortality. Instead, obesity, as defined by BMI, is not associated with dialysis commencing or all-cause mortality.

Kidney Stone Prevention: Is There a Role for Complementary and Alternative Medicine?

Complementary and alternative medicine (CAM) is often implemented in kidney stone patients. It consists of preparations including different ingredients, such as herbs, probiotics, and vitamins, often together with alkali, that are classified within the dietary supplementation category. The majority of dietary supplements claiming to treat or prevent kidney stones contain ingredients with conflicting or no scientific evidence to support their claims. Clinicians should advise stone formers that the effects of most supplements are unknown or unstudied in humans and that the absence of evidence does not imply absence of potential harm. Unfortunately, the CAM preparation consists of a mix of different molecules, often including alkali, with different potential mechanisms of action and, even when favorable results are reported, the role of the single molecules cannot be assessed. Despite all these concerns, CAM products remain quite popular among kidney stone patients. The scarce knowledge in this field prevents one from recommending CAM products in daily clinical practice; only a weak suggestion for their use in kidney stone patients may be reasonable.

A Multisystem Mitochondrial Disease Caused by a Novel MT-TL1 mtDNA Variant: A Case Report.

BACKGROUND: Mitochondrial tRNA (MTT) genes are hotspot for mitochondrial DNA mutation and are responsible of half mitochondrial disease. MTT mutations are associated with a broad spectrum of phenotype often with complex multisystem involvement and complex genotype-phenotype correlations. MT-TL1 mutations, among which the m.3243A>G mutation is the most frequent, are associated with myopathy, maternal inherited diabetes and deafness, MELAS, cardiomyopathy, and focal segmental glomerulosclerosis. CASE STUDY: Here we report the case of an Italian 49-years old female presenting with encephalomyopathy, chronic proteinuric kidney disease and a new heteroplasmic m.3274_3275delAC MT-TL1 gene mutation. CONCLUSIONS: Our case demonstrates a systemic mitochondrial disease caused by the heteroplasmic m.3274_3275delAC MT-TL1 gene mutation, not yet described in the literature. A mitochondrial disease should be suspected in case of complex multisystem phenotypes, including steroid-resistant nephrotic syndrome with multisystemic involvement.

Idiopathic Retroperitoneal Fibrosis: What Is the Optimal Clinical Approach for Long-Term Preservation of Renal Function?

BACKGROUND: The aim of this study was to investigate the long-term effects of ureteral stenting and the exact timing of stent removal in favor of surgery in patients with idiopathic retroperitoneal fibrosis (IRF). SUMMARY: Medline research terms of "idiopathic retroperitoneal fibrosis" AND " medical therapy" OR "ureteral stenting" OR "surgical treatment" were done. Systematic reviews and observational and clinical studies were analyzed to obtain indication regarding the objective of the study for a narrative review. Ninety-two papers were analyzed. The treatment of IRF includes the monitoring of retroperitoneal fibrotic process spread and the prevention of abdominal organs entrapment. Treatment of ureteral obstruction includes medical therapy and ureteral stenting (US) or percutaneous nephrostomy (PNS) to overcome the worsening of renal function. Up to now, the timing of US or PNS removal is not yet clear, both for the complexity of evaluating the efficacy of the medical therapy and demonstrating the resolution of obstructive nephropathy. Moreover, it is not yet clear if the long-term ureteral stent placement or PNS is able to maintain an efficient renal function. Ureterolysis with a laparoscopic robot-assisted approach is now considered as an ultimate treatment for ureteral obstruction, limiting the progression of kidney impairment and improving the quality of life of patients, although nephrologists are generally abdicant regarding the potential switch toward the surgical approach. KEY MESSAGES: Prospective studies regarding the long-term effects of US on the renal function impairment in patients with IRF should be structured to obtain adequate information on the exact timing for the surgical approach.

The risks associated with percutaneous native kidney biopsies: a prospective study.

BACKGROUND: The known risks and benefits of native kidney biopsies are mainly based on the findings of retrospective studies. The aim of this multicentre prospective study was to evaluate the safety of percutaneous renal biopsies and quantify biopsy-related complication rates in Italy. METHODS: The study examined the results of native kidney biopsies performed in 54 Italian nephrology centres between 2012 and 2020. The primary outcome was the rate of major complications 1 day after the procedure, or for longer if it was necessary to evaluate the evolution of a complication. Centre and patient risk predictors were analysed using multivariate logistic regression. RESULTS: Analysis of 5304 biopsies of patients with a median age of 53.2 years revealed 400 major complication events in 273 patients (5.1%): the most frequent was a ≥2 g/dL decrease in haemoglobin levels (2.2%), followed by macrohaematuria (1.2%), blood transfusion (1.1%), gross haematoma (0.9%), artero-venous fistula (0.7%), invasive intervention (0.5%), pain (0.5%), symptomatic hypotension (0.3%), a rapid increase in serum creatinine levels (0.1%) and death (0.02%). The risk factors for major complications were higher plasma creatinine levels [odds ratio (OR) 1.12 for each mg/dL increase, 95% confidence interval (95% CI) 1.08-1.17], liver disease (OR 2.27, 95% CI 1.21-4.25) and a higher number of needle passes (OR for each pass 1.22, 95% CI 1.07-1.39), whereas higher proteinuria levels (OR for each g/day increase 0.95, 95% CI 0.92-0.99) were protective. CONCLUSIONS: This is the first multicentre prospective study showing that percutaneous native kidney biopsies are associated with a 5% risk of a major post-biopsy complication. Predictors of increased risk include higher plasma creatinine levels, liver disease and a higher number of needle passes.

The Impact of a Mediterranean-like Diet with Controlled Protein Intake on the Onco-Nephrological Scenario: Time for a New Perspective.

Chronic kidney disease (CKD) represents a frequent comorbidity in cancer patients, especially for patients affected by urological cancers. Unfortunately, impaired kidney function may limit the choice of adequate oncological treatments for their potential nephrotoxicity or due to contraindications in case of a low glomerular filtration rate. For these patients, tailored nephrological and nutritional management is mandatory. The K-DIGO guidelines do not define whether the nutritional management of CKD could be useful also in CKD patients affected by urological cancer. In fact, in clinical practice, oncological patients often receive high-protein diets to avoid malnutrition. In our study, we investigated the nutritional and nephrological impact of a Mediterranean-like diet with a controlled protein intake (MCPD) on a cohort of 82 stage III-IV CKD patients. We compared two cohorts: one of 31 non-oncological CKD patients and the other of 51 oncological patients with CKD. The use of an MCPD had a favorable impact on both the oncological and non-oncological CKD patients with an amelioration in all the investigated parameters and with a better quality of life, with no cases of malnutrition or AKI.

Processed Plant-Based Foods for CKD Patients: Good Choice, but Be Aware.

The beneficial effects of vegetarian diets are known in the general population and in patients with chronic kidney disease (CKD). In recent years, the market has developed a number of processed plant-based products because of several factors (lifestyle changes, ethical concerns, and sustainability). The composition in terms of nutrients, ingredients, and additives of 560 products available on the market and on online shopping sites was analyzed to understand the characteristics of these products. Processed plant-based meat substitutes have a higher content of salt (+467%), lipids (+26%), mostly unsaturated, and fiber with respect to regular animal-based ones. Protein content is lower (-40%) in plant-based products with respect to corresponding animal ones. Of the 49 additives on the label (on average 2 per product), 20 contain phosphorus, sodium, potassium, or nitrogen. Several plant-based processed products may contain elevated amounts of salt and additives, which make them not optimal for CKD patients. Although a plant-based diet remains a very important tool for CKD nutritional management, patients should be aware regarding the extra content of sodium and additives in processed plant-based products compared to animal-based processed food.

Interactions between Food and Drugs, and Nutritional Status in Renal Patients: A Narrative Review.

Drugs and food interact mutually: drugs may affect the nutritional status of the body, acting on senses, appetite, resting energy expenditure, and food intake; conversely, food or one of its components may affect bioavailability and half-life, circulating plasma concentrations of drugs resulting in an increased risk of toxicity and its adverse effects, or therapeutic failure. Therefore, the knowledge of these possible interactions is fundamental for the implementation of a nutritional treatment in the presence of a pharmacological therapy. This is the case of chronic kidney disease (CKD), for which the medication burden could be a problem, and nutritional therapy plays an important role in the patient's treatment. The aim of this paper was to review the interactions that take place between drugs and foods that can potentially be used in renal patients, and the changes in nutritional status induced by drugs. A proper definition of the amount of food/nutrient intake, an adequate definition of the timing of meal consumption, and a proper adjustment of the drug dosing schedule may avoid these interactions, safeguarding the quality of life of the patients and guaranteeing the effectiveness of drug therapy. Hence, a close collaboration between the nephrologist, the renal dietitian, and the patient is crucial. Dietitians should consider that food may interact with drugs and that drugs may affect nutritional status, in order to provide the patient with proper dietary suggestions, and to allow the maximum effectiveness and safety of drug therapy, while preserving/correcting the nutritional status.