Progressive Renal Dysfunction Research Articles

Iron homeostasis, recycling and vulnerability in the stressed kidney: A neglected dimension of iron-deficient heart failure.

The available evidence suggests that the kidney may contribute importantly to the development of an iron deficiency state in patients with heart failure and may be injured by therapeutic efforts to achieve iron repletion. The exceptional workload of the proximal renal tubule requires substantial quantities of iron for ATP synthesis, which it derives from Fe3+ bound to transferrin in the bloodstream. Following ferrireduction, Fe2+ is conveyed by divalent transporters (e.g. DMT1) out of the endosome of the proximal renal tubule, and highly reactive Fe2+ can be directed to the mitochondria, sequestered safely in a ferritin nanocage or exported through the actions of hepcidin-inhibitable ferroportin. The actions of ferroportin, together with transferrin endocytosis and DMT1-mediated transport, play a key role in the recycling of iron from the tubular fluid into the bloodstream and preventing the loss of filtered iron in the urine. Activation of endogenous neurohormonal systems and proinflammatory signalling in heart failure decrease megalin-mediated uptake and DMT1 expression, and increase hepcidin-mediated suppression of ferroportin, promoting the loss of iron in the urine and contributing to the development of an iron deficiency state. Furthermore, the failure of ferroportin-mediated efflux at the basolateral membrane heightens the susceptibility of the renal tubules to cytosolic excesses of Fe2+, causing lipid peroxidation and synchronized cell death (ferroptosis) through the iron-dependent free radical theft of electrons from lipids in the cell membrane. Ferroptosis is a central mechanism to most disorders that can cause acute and chronic kidney disease. Short-term bolus administration of intravenous iron can cause oxidative stress and is accompanied by markers of renal injury. Experimentally, long-term maintenance of an iron-replete state is accompanied by accelerated loss of nephrons, oxidative stress, inflammation and fibrosis. Intravenous iron therapy increases glomerular filtration rate rapidly in patients with heart failure (perhaps because of a haemodynamic effect) but not in patients with chronic kidney disease, and the effects of intravenous iron on the progression of renal dysfunction in the long-term trials - AFFIRM-AHF, IRONMAN and HEART-FID - have not yet been reported. Given the potential role of dysregulated renal iron homeostasis in the pathogenesis of iron deficiency and the known vulnerability of the kidney to intravenous iron, the appropriate level of iron repletion with respect to the risk of acute and chronic kidney injury in patients with heart failure requires further study.

ALBUMINURIA IS ASSOCIATED WITH LESS EFFORT TOLERANCE IN HYPERTENSION AND DIABETES

Introduction: The presence of albuminuria is an adverse marker of renal dysfunction progression. Hypertension and diabetes mellitus predispose to albuminuria. However, not all hypertensive and diabetic patients have albuminuria, so it is relevant to identify risk factors associated to this abnormality. The acute effect of intense physical activity may lead to transient albuminuria. On the other hand, physical inactivity is associated with risk factors for albuminuria Objective: To analyze the association between activity levels or physical performance and albuminuria in hypertensive and/or diabetic patients treated at basic health services. Methodology: A prospective cross-sectional study with hypertensives and/or diabetics subjects. The patients were evaluated in regard of albuminuria, clinical, laboratory and physical test performance variables. Results: There was no association between the degree of albuminuria and demographic, anthropometric, laboratory variables, functional capacity and level of physical activity. The degree of albuminuria was associated with systolic blood pressure, as well as the perception of effort, obtained by Borg Scale during the test in univariate analysis (odds ratio 4.11 with 95% confidence interval from 1.18 to 14.37, p = 0.027) and adjusted for systolic blood pressure and diabetes (odds ratio 3.02 with 95% confidence interval from 1.35 to 6.75; p = 0.007). Conclusion: there was association between albuminuria and perceived effort, as well with systolic blood pressure. There was not with association physical performance or level of activity. Further studies are needed to elucidate the association of albuminuria with Borg Scale.

A short treatment with resveratrol after a renal ischaemia-reperfusion injury prevents maladaptive repair and long-term chronic kidney disease in rats.

Acute kidney injury (AKI) often triggers physiological processes aimed at restoring renal function and architecture. However, this response can become maladaptive, leading to nephron loss and fibrosis. Although the therapeutic effects of resveratrol (RSV) are well established, its impact after AKI and for subsequent chronic kidney disease (CKD) remains unclear. This study assessed whether transient administration of RSV following ischaemia-reperfusion injury (IRI) could prevent the progression to CKD. Forty-one male Wistar rats were assigned randomly to sham surgery, bilateral renal ischaemia for 30min (IR) or IR+RSV. The RSV treatment commenced 24h after IRI and continued for 10days. The rats were studied for either 10days or 5months, after which kidney function and structure were evaluated. Mitochondrial homeostasis, oxidant defence and renal inflammation state were also evaluated. Despite having the same severity of AKI, rats receiving RSV for 10days after IRI exhibited significant improvement in kidney histological injury and reduced inflammation, although renal haemodynamic recovery was less pronounced. Resveratrol effectively prevented the elevation of tubular injury-related molecules and profibrotic signalling with reduced myofibroblast proliferation. Furthermore, RSV substantially improved the antioxidant response and mitochondrial homeostasis. After 5months, RSV prevented the transition to CKD, as evidenced by the prevention of progressive proteinuria, renal dysfunction and tubulointerstitial fibrosis. This study demonstrates that a brief treatment with RSV following IRI is enough to prevent maladaptive repair and the development of CKD. Our findings highlight the importance of the early days of reperfusion, indicating that maladaptive responses can be reduced effectively following severe AKI. KEY POINTS: Physiological processes activated after acute kidney injury (AKI) can lead to maladaptive responses, causing nephron loss and fibrosis. Prophylactic renoprotection with resveratrol (RSV) has been described in experimental AKI, but its impact after AKI and for subsequent chronic kidney disease (CKD) remains unclear. In this study, we found that histological tubular injury persists 10days after ischaemia-reperfusion injury and contributes to a failed repair phenotype in proximal tubular cells. Short-term RSV intervention influenced the post-ischaemic repair response and accelerated tubular recovery by reducing oxidative stress and mitochondrial damage. Furthermore, RSV targeted inflammation and profibrotic signalling during the maladaptive response, normalizing both processes. Resveratrol effectively prevented AKI-to-CKD transition even 5 months after the intervention. The study serves as a proof of concept, proposing RSV as a valuable candidate for further translational clinical studies to mitigate AKI-to-CKD transition.

Long-Term Effects of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: Predictors of Treatment Response and Safety over 6 Years of Continuous Therapy.

Tolvaptan, an oral vasopressin V2 receptor antagonist, reduces renal volume expansion and loss of renal function in patients with autosomal dominant polycystic kidney disease (ADPKD). Data for predictive factors indicating patients more likely to benefit from long-term tolvaptan are lacking. Data were retrospectively collected from 55 patients on tolvaptan for 6 years. Changes in renal function, progression of renal dysfunction (estimated glomerular filtration rate [eGFR], 1-year change in eGFR [ΔeGFR/year]), and renal volume (total kidney volume [TKV], percentage 1-year change in TKV [ΔTKV%/year]) were evaluated at 3-years pre-tolvaptan, at baseline, and at 6 years. In 76.4% of patients, ΔeGFR/year improved at 6 years. The average 6-year ΔeGFR/year (range) minus baseline ΔeGFR/year: 3.024 (-8.77-20.58 mL/min/1.73 m2). The increase in TKV was reduced for the first 3 years. A higher BMI was associated with less of an improvement in ΔeGFR (p = 0.027), and family history was associated with more of an improvement in ΔeGFR (p = 0.044). Hypernatremia was generally mild; 3 patients had moderate-to-severe hyponatremia due to prolonged, excessive water intake in response to water diuresis-a side effect of tolvaptan. Family history of ADPKD and baseline BMI were contributing factors for ΔeGFR/year improvement on tolvaptan. Hyponatremia should be monitored with long-term tolvaptan administration.

P-29 Metformin poisoning without lactic acidosis: Case report

Abstract Introduction Metformin is the most widely used oral antidiabetic, which belongs to the biguanide pharmacological group. Metformin-associated lactic acidosis (MALA) is a rare event with an incidence of approximately 19 cases per 100,000 patient-years. The risk of developing lactic acidosis, when taking metformin is enhanced by several factors such as: age > 65 years; concomitant diseases that have the ability to induce hypoxemia (chronic renal failure, congestive heart failure, cardiogenic shock, severe lung disease, sepsis, advanced liver disease, history of lactic acidosis); an excessive alcohol consumption; an administration of iodinated contrast agents. Clinical Case A 46-year-old man was urgently admitted with the following symptoms: drowsiness, repeated vomiting, lethargy, dizziness. The symptoms started after he administered outpatient and at own initiative 50 tablets of metformin, each tablet contains a dose of 500 mg (total dose 25g). Concomitant pathologies: diagnosed with Type 2 Diabetes for 8 years; Toxic liver cirrhosis, compensated Child-Pugh A (recently diagnosed); hypertension; CKD G3aA2 KDIGO. The patient's condition at admission was assessed as extremely serious, Glasgow scale - 11 points, mild hypertension, tachycardia, tachypnea. The paraclinical investigations revealed the presence of metabolic acidosis, but with lactate <5 mmol/l; the progressive renal dysfunction with creatinine values in the first 24 hours up to 1184 µmol/l, urea – 24.5 mmol/l; a severe hypoglycemia - 1.68 mmol/l; a moderate cytolytic syndrome; a cholestatic syndrome, an inflammatory and hepatoprive syndrome; coagulation disorders; a pancreatic dysfunction. In the context of the evident increase of urea and creatinine, the decision was made to initiate the intermittent hemodialysis, a total of 14 sessions were required during hospitalization. The particularity of this case is represented by the absence of lactic acidosis, despite metformin intoxication with altered neurological status, acute renal failure, developed due to chronic kidney disease, liver cirrhosis of toxic etiology and severe hypoglycemia. Conclusion Metformin should be administered with caution in patients with multiple comorbidities. Metformin intoxication can induce lactic acidosis with an increased risk of serious, potentially fatal adverse events. It is essential to identify metformin intoxication as early as possible, with prompt initiation of renal replacement measures and dynamic monitoring of biochemical parameters.

Safety and Tolerability of SGLT2 Inhibitors in Cardiac Amyloidosis-A Clinical Feasibility Study.

Sodium-glucose transport protein 2 inhibitors (SGLT2i) slow the progression of renal dysfunction and improve the prognosis of patients with heart failure. Amyloidosis constitutes an important subgroup for which evidence is lacking. Amyloidotic fibrils originating from misfolded transthyretin and light chains are the causal agents in ATTR and AL amyloidosis. In these most frequent subtypes, cardiac involvement is the most common organ manifestation. Because cardiac and renal function frequently deteriorate over time, even under best available treatment, SGLT2i emerge as a promising treatment option due to their reno- and cardioprotective properties. We retrospectively analyzed patients with cardiac amyloidosis, who received either dapagliflozin or empagliflozin. Out of 79 patients, 5.1% had urinary tract infections; 2 stopped SGLT2i therapy; and 2.5% died unrelated to the intake of SGLT2i. No genital mycotic infections were observed. As expected, a slight drop in the glomerular filtration rate was noted, while the NYHA functional status, cardiac and hepatic function, as well as the 6 min walk distance remained stable over time. These data provide a rationale for the use of SGLT2i in patients with amyloidosis and concomitant cardiac or renal dysfunction. Prospective randomized data are desired to confirm safety and to prove efficacy in this increasingly important group of patients.

Home Hospital Outcomes for Acute Decompensated Heart Failure and Factors Associated With Escalation of Care.

Overall outcomes and the escalation rate for home hospital admissions for heart failure (HF) are not known. We report overall outcomes, predict escalation, and describe care provided after escalation among patients admitted to home hospital for HF. Our retrospective analysis included all patients admitted for HF to 2 home hospital programs in Massachusetts between February 2020 and October 2022. Escalation of care was defined as transfer to an inpatient hospital setting (emergency department, inpatient medical unit) for at least 1 overnight stay. Unexpected mortality was defined as mortality excluding those who desired to pass away at home on admission or transitioned to hospice. We performed the least absolute shrinkage and selection operator logistic regression to predict escalation. We included 437 hospitalizations; patients had a median age of 80 (interquartile range, 69-89) years, 58.1% were women, and 64.8% were White. Of the cohort, 29.2% had reduced ejection fraction, 50.9% had chronic kidney disease, and 60.6% had atrial fibrillation. Median admission Get With The Guidelines HF score was 39 (interquartile range, 35-45; 1%-5% predicted inpatient mortality). Escalation occurred in 10.3% of hospitalizations. Thirty-day readmission occurred in 15.1%, 90-day readmission occurred in 33.8%, and 6-month mortality occurred in 11.5%. There was no unexpected mortality during home hospitalization. Patients who experienced escalation had significantly longer median length of stays (19 versus 7.5 days, P<0.001). The most common reason for escalation was progressive renal dysfunction (36.2%). A low mean arterial pressure at the time of admission to home hospital was the most significant predictor of escalation in the least absolute shrinkage and selection operator regression. About 1 in 10 home hospital patients with HF required escalation; none had unexpected mortality. Patients requiring escalation had longer length of stays. A low mean arterial pressure at the time of admission to home hospital was the most important predictor of escalation of care in the least absolute shrinkage and selection operator logistic regression model.

Successful treatment for life threatening recurrent non-traumatic rectus sheath hematoma in a case with microscopic polyangiitis with rapidly progressive glomerulonephritis.

A 68-year-old woman was admitted to our hospital because of a rapid progression of renal dysfunction with positive myeloperoxidase antineutrophil cytoplasmic antibody and was diagnosed with rapidly progressive glomerulonephritis associated with microscopic polyangiitis (MPA). Severe right rectus sheath hematoma (RSH) bleeding from the inferior epigastric artery developed after starting hemodialysis, which required 4 transarterial embolizations due to recurrent bleeding. After additional treatment with methylprednisolone pulse therapy and rituximab, no rebleeding occurred. Although the giant hematoma reached the pelvis, it shrank spontaneously without any intervention. Nontraumatic RSH should therefore be considered when treating patients with multiple risk factors.

A Rare Case of Sporadic Medullary Cystic Kidney Disease with Rapidly Progressive Renal Dysfunction and Renal Enlargement Complicated by Idiopathic Nodular Glomerulosclerosis.

An 81-year-old man with hypertension and a history of smoking presented with renal enlargement and progressive renal dysfunction despite no family history of kidney disease. A renal biopsy revealed diffuse tubular, dilated, and atrophic distal tubules with cystic formation and thin irregularities in the tubular basement membrane. Although no known genetic abnormalities were detected, the patient was diagnosed with medullary cystic kidney disease (MCKD). In addition, idiopathic nodular glomerulosclerosis, which is characterized by significant mesangial expansion and accentuated glomerular nodularity and is associated with hypertension and cigarette smoking, was identified as a complication of MCKD. We herein report a rare case of sporadic MCKD with idiopathic nodular glomerulosclerosis.

Chronic kidney disease in patients with long-term type 1 diabetes mellitus

BACKGROUND: Patients with type 1 diabetes mellitus (T1D) have an earlier age of onset and a longer course of the disease, already by middle age they have the development of microand macrovascular diabetic complications that reduce the quality and duration of life.AIM: To evaluate the prevalence of chronic kidney disease (CKD) and other late complications of T1D depending on renal dysfunction in the population of patients with T1D with disease duration of 20 and more years, who underwent examination and treatment in Endocrinology Research Centre.MATERIALS AND METHODS: A one-stage single-center epidemiological non-randomised study was conducted using the database of Endocrinology Research Centre with the study of 500 patients’medical histories with long-term T1D (20 years and mores), without kidney damage and with CKD at different stages (CKD C1–C5, C5D, after transplantation), examined and treated from 2011 to 2023.RESULTS: Normal renal function was observed in 10.8% of patients (n=54). Terminal stage of CKD was reached in 28.0% (n=140), of which 12.4% were on renal replacement therapy with program hemodialysis (RRT-HD), and 12.0% after isolated kidney transplantation or combined kidney and pancreas transplantation, the rest were at different stages of CKD. Normoalbuminuria was observed in 15.4% (n=77) among 500 patients. The prevalence of late complications of DM among the examined patients was high and increasing with the progression of renal dysfunction: diabetic retinopathy was diagnosed in 96% of patients, distal symmetrical polyneuropathy — in 97% of patients, various forms of autonomic neuropathy — in more than half of patients. About 60% of patients had diagnosed arterial atherosclerosis in the legs, about one third — atherosclerosis of brachiocephalic arteries, 23% — confirmed coronary heart disease, and suffered cardiovascular events (myocardial infarction, acute cerebral circulation disorder) — 19% of patients, about half of whom had CKD of different severity. Factors for increased risk of cardiovascular disease: estimated glomerular filtration rate (eGFR)&lt;60 mL/min/1.73m2, OR=7.1; 95% CI 3.6–8.4; p&lt;0.001), eGFR &lt;30 mL/min/1.73m2 OR=8.7; 95% CI 2.8–8.4; p&lt;0.001), eGFR &lt;15 mL/min/1.73m2 OR=14; 95% CI 6.3–31.3; p&lt;0.001); albuminuria &gt; 30 mg/g OR=2.4; 95% CI 1.6–3.6; p&lt;0.001), dialysis OR=14.1; 95% CI 6.2–32.1; p&lt;0.001), kidney transplant OR=11.7; 95% CI 5.4–24.9; p&lt;0.001). Manifestation of T1D between 1996–2002 reduced the risk of developing CKD by 10.75; 95% CI 4.37; 27.03) vs manifestation of T1D earlier. Age of T1D debut 6–17 years increased the risk of reaching terminal CKD vs age of debut &gt;18 years: OR=2.4; 95% CI 1.22; 5.022; p=0.012).CONCLUSION: Despite a significant reduction in the risk of developing CKD in individuals with T1D debut between 1996 and 2002, renal dysfunction is a frequent complication in patients with a long disease course, combining with other late complications and contributing to a high risk of terminal stage of CKD and cardiovascular events. Early age of T1D debut increases the risk of terminal CKD.

Identification of Messenger RNA Signatures in Age-Dependent Renal Impairment.

In general populations, age-dependent renal impairment contributes to the progression of renal dysfunction. It has not been known which molecules are involved in age-dependent renal impairment. Messenger RNA (mRNA) has been reported to modulate various renal diseases, and we therefore investigated mRNA signatures in age-dependent renal impairment. We performed an initial microarray-profiling analysis to screen mRNAs, the expression levels of which changed in the kidneys of 50-week-old senescence-accelerated prone (SAMP1) mice (which have accelerated age-dependent renal impairments) compared with those of 50 wk old senescence-accelerated-resistant (SAMR1) mice (which have normal aged kidneys) and with younger (10 wk old) SAMP1 and SAMR1 mice. We next assessed the expressions of mRNAs that were differentially expressed in the kidneys of SAMP1-50wk mice by conducting a quantitative real-time polymerase chain reaction (qRT-PCR) and compared the expressions among the SAMP1-10wk, SAMR1-10wk, and SAMR1-50wk mice. The results of the microarray together with the qRT-PCR analysis revealed five mRNAs whose expression levels were significantly altered in SAMP1-50wk mouse kidneys versus the control mice. The expression levels of the five mRNAs were increased in the kidneys of the mice with age-dependent renal impairment. Our findings indicate that the five mRNAs might be related and could become therapeutic targets for age-dependent renal impairment.

Impact of Ring Finger Protein 20 and Its Downstream Regulation on Renal Tubular Injury in a Unilateral Nephrectomy Mouse Model Fed a High-Fat Diet.

Abnormal lipid metabolism increases the relative risk of kidney disease in patients with a single kidney. Using transcriptome analysis, we investigated whether a high-fat diet leads to abnormalities in lipid metabolism and induces kidney cell-specific damage in unilateral nephrectomy mice. Mice with unilateral nephrectomy fed a high-fat diet for 12 weeks exhibited progressive renal dysfunction in proximal tubules, including lipid accumulation, vacuolization, and cell damage. Ring finger protein 20 (RNF20) is a ligase of nuclear receptor corepressor of peroxisome proliferator-activated receptors (PPARs). The transcriptome analysis revealed the involvement of RNF20-related transcriptome changes in PPAR signaling, lipid metabolism, and water transmembrane transporter under a high-fat diet and unilateral nephrectomy. In vitro treatment of proximal tubular cells with palmitic acid induced lipotoxicity by altering RNF20, PPARα, and ATP-binding cassette subfamily A member 1 (ABCA1) expression. PPARγ and aquaporin 2 (AQP2) expression decreased in collecting duct cells, regulating genetic changes in the water reabsorption process. In conclusion, a high-fat diet induces lipid accumulation under unilateral nephrectomy via altering RNF20-mediated regulation and causing functional damage to cells as a result of abnormal lipid metabolism, thereby leading to structural and functional kidney deterioration.

Tolerability and Outcomes of Bruton Tyrosine Kinase Inhibitors for Chronic Lymphocytic Leukemia in Patients with Severe Renal Dysfunction

Introduction: There is limited data on the outcomes and tolerability of Bruton Tyrosine Kinase (BTK) inhibitors for chronic lymphocytic leukemia (CLL) in patients with severe renal dysfunction, particularly older adults. The most commonly prescribed BTK inhibitor, ibrutinib, is believed to be safe for mild to moderate renal dysfunction. However, severe renal failure has been excluded from prospective studies, and there is no guidance on dosing under the FDA label. Furthermore, ibrutinib itself can cause kidney injury and worsen existing renal dysfunction. This national Veterans Affairs (VA) analysis aims to review the safety and tolerability of BTK inhibitors in severe renal impairment. Methods: An electronic query of the VA Corporate Data Warehouse and retrospective chart review were performed to identify patients with CLL treated with a BTK inhibitor between 2013-2022 and who had severe chronic kidney disease defined as an estimated glomerular filtration rate (eGFR) &amp;lt; 30 ml/min/1.73 m 2 overlapping with their treatment period. Isolated acute kidney injuries lasting &amp;lt; 1 month were excluded. Fisher's exact test was utilized to evaluate categorical variables, logistic regression for binary outcomes, and log-rank and Cox regression for time-to-event analyses. Results: A total of 115 patients across 68 VA medical centers received 124 lines of BTK inhibitors with an eGFR &amp;lt; 30 (Table 1). The median duration of follow-up from the start of therapy was 26 months (range, 0.5 - 94). The median age was 74, and 98% were male, reflecting the U.S. veteran population. 64% had an eGFR &amp;lt; 30 at the start of therapy, with 18% requiring dialysis, while the remaining 36% experienced progressive renal dysfunction during treatment. The oral BTK agents prescribed were ibrutinib ( n = 103), acalabrutinib ( n = 18), and zanubrutinib ( n = 3). Most BTK inhibitors (n = 94 of 124 lines, 76%) were initiated at the FDA-label dose. 46 (37%) later required dose reduction, primarily due to drug toxicity ( n = 37). The most common reasons for dose reduction were cytopenia ( n = 10), failure to thrive ( n = 6), bleeding ( n = 5), and worsening renal function ( n = 5). Discontinuation of therapy for toxicity occurred in 50% (ibrutinib), 39% (acalabrutinib), and 33% (zanubrutinib). The most common reasons for discontinuation were infection ( n = 15), bleeding ( n = 10), arrhythmia ( n = 9), and disease progression ( n = 9). Among patients who received ibrutinib ( n = 103), the median progression-free survival (PFS) and overall survival (OS) were 45 and 49 months, respectively. In multivariate Cox regression, covariates associated with shorter PFS included the baseline severity of renal failure (HR 1.85, 95% CI 1.21 - 2.88), cirrhosis (HR 6.36, 95% CI 1.45 - 19.76), and heart failure (HR 4.20, 95% CI 1.82 - 9.47). Younger age, dialysis, and absence of atrial fibrillation at the start of therapy were protective in univariate but not multivariate models. Heart failure and cirrhosis retained their prognostic impact on OS in multivariate modeling. Factors including race, rural residence, obesity, IGHV status, and TP53 deletion were not significantly associated with survival in this cohort. The median duration of therapy of ibrutinib was 33 months. Ibrutinib dose reductions at initiation or during treatment were associated with a longer duration of therapy (Figure 1). Of note, dose reductions did not significantly reduce the response rate to ibrutinib or worsen survival. Interestingly, 11 patients had CLL-related kidney dysfunction. However, kidney function did not improve after treatment with a BTK inhibitor in any of the 115 patients. Progression of renal impairment was observed in 51 patients (50%) on ibrutinib, 8 (44%) on acalabrutinib, and none on zanubrutinib. The etiology of worsening renal function was uncertain for the majority of patients. Conclusion: The clinical outcomes of BTK inhibitors in patients with CLL and severe renal dysfunction have not been well-described. In our real-world data analysis, these agents appear to be a reasonable therapeutic option in severe renal impairment, including in older adults and those on dialysis. Lab monitoring is needed, given the risk of worsening renal function. Dose modifications may help improve tolerability without reducing efficacy. Unfortunately, severe renal dysfunction is unlikely to improve with CLL treatment, even in CLL-related kidney failure.

SGLT2 inhibitors for heart and kidney

Sodium-glucose co-transporter 2 (SGLT2) inhibitors can block glucose reabsorption in the proximal tubule and thus play an important role in glycemic control in diabetes mellitus. In addition to glucosuric effects, surprisingly very extensive other positive effects were observed in chronic renal dysfunction and strong cardioprotective effects in heart failure. In the meantime, numerous mechanisms have been identified apart from the pure sugar-influencing effect of the SGLT2 inhibitors, which can have a direct positive influence heart and kidneys.In recent years there has been an extensive clinical study program, which has dealt with the effects of SGLT2 inhibitors on the progression of diabetic and non-diabetic chronic renal failure. It could be shown that patients with albuminuria have a significant benefit from the use of SGLT2 inhibitors. Therefore, the progression of renal dysfunction is slowed down significantly, while at the same time, positive cardiovascular endpoints could be influenced. Numerous studies have also been conducted in patients with and without diabetes or with heart failure, with and without, preserved ejection fraction. Impressive protection was also shown here, with the benefit of using SGLT2 inhibitors to reduce heart failure worsening.In a short period of 10 years, the use of SGLT2 inhibitors was established as an essential therapy for cardio-renal indications to inhibit the progression of renal failure as well as to protect against heart failure apart from pure diabetes therapy. In numerous guidelines (ESC heart failure, KDGIO diabetes, ESH hypertension), the early use of SGLT2 inhibitors is now recommended for protection against cardio-renal events and is an important first-line addition to the previously established therapies. Apart from diabetes therapy, it offers patients completely new options in cardio-renal protection.

Abstract 26 — Clinical Characteristics of Familial Mediterranean: Fever in Hemodialysis Patients

Introduction Familial Mediterranean fever (FMF) is an inherited genetic disorder characterized by recurrent episodes of fever, serositis, arthritis, and skin rash. Uncontrolled disease can lead to amyloid A disposition, nephrotic syndrome and progressive renal failure. Recurrence of AA amyloidosis post kidney transplantation has been reported. Long-term colchicine therapy will reduce the FMF attacks and risk of AA amyloidosis. Although there is high prevalence of FMF in MENA region, the data of end stage renal disease (ESRD) in FMF is limited. We report our center experience. Method A retrospective chart review study was conducted at Tawam Hospital over 12 years (January 2010 to January 2023). We included adult ESRD on hemodialysis with FMF disease and studied their management outcomes. Descriptive analysis was used. Results 1900 ESRD patients were on hemodialysis during study period, and only two patients were diagnosed with FMF and renal amyloidosis. Case 1: A 60-year-old male patient from Syria who is known to have FMF and polycystic kidney disease leading to ESRD. He underwent successful LRD kidney transplantation in 2009. He was on mycophenolic acid: 540 mg, BID, prednisolone: 5 mg, tacrolimus: 1 mg am, 0.5 mg and colchicine 0.5 mg BID. He developed progressive renal allograft dysfunction with evidence of nephrotic syndrome. The renal biopsy revealed recurrence of AA amyloidosis due to FMF in kidney allograft in 2018. He had decline in renal function over years was initiated on hemodialysis on 2022. He developed two attacks of FMF peritonitis while on hemodialysis that responded well to steroid/colchicine therapy. Case 2: 48 years old male, from Egypt, known to have irritable bowel syndrome. He presented to our hospital with bilateral lower limb edema, and progressive shortness of breath for one month. Investigations revealed heavy proteinuria (8.98 g/g Creat) and acute kidney injury. Serology and autoimmune workup were negative. Kidney biopsy showed renal amyloidosis, and chronic tubulointerstitial nephritis with severe interstitial fibrosis (60%). History taken again and was positive for FMF in his uncle. Genetic study and clinical confirmed the diagnosis of FMF. He was started on colchicine, but developed ESRD within 8 months and initiated on hemodialysis. He had attacks of FMF. Conclusion Renal amyloidosis in FMF patient leads to progressive renal failure despite colchicine therapy. In our dialysis cohort over 12 years, only two FMF patients were identified. Colchicine therapy is required in ESRD-FMF in order to managed FMF attacks and prevent other organ AA amyloidosis.

Clinical Characteristics of Retroperitoneal Fibrosis Patients at a Tertiary Hospital in Japan.

Retroperitoneal fibrosis (RPF) is a rare cause of hydronephrosis and progressive renal dysfunction with unidentified origin. RPF is categorized into idiopathic RPF with/without immunoglobulin G4 (IgG4)-related disease (IgG4-RD), and secondary RPF. Identifying the underlying cause is challenging and often associated with delayed diagnosis or therapeutic interventions. We investigated RPF's clinical characteristics based on different etiologies and factors that may help distinguish the underlying causes. We analyzed the cases of 49 patients with RPF that was radiographically diagnosed at our institution (2008-2022). The cohort was 77.6% males; 75.5% had idiopathic RPF and 24.5% had secondary RPF. Among the idiopathic patients, 54.1% had IgG4-RD. The patients were likely to have abdominal pain, lower back pain/lumbago, and constitutional symptoms including generalized fatigue and fever. The idiopathic patients were likely to have higher serum IgG4 and IgG levels and lower serum C3 levels compared to secondary RPF. The IgG4-RPF patients were likely to have higher serum IgG4 levels and lower serum C-reactive protein, ferritin, and C3 levels compared to the idiopathic RPF patients without IgG4-RD. These findings might reflect underlying systemic inflammatory responses. Comprehensive laboratory testing, including serum inflammatory markers and immunological panels, is recommended for radiologically diagnosed RPF patients.

Microbial-Derived Uremic Toxins: Role in the Pathogenesis of Comorbidities in Patients with Chronic Kidney Disease

Аim: to analyze the significance of microbial-derived uremic toxins (MDUT) in the pathogenesis of comorbidities in patients with chronic kidney disease (CKD).Key findings. Increased excretion of nitrogen metabolism products into the intestines of patients with CKD is associated with uremic dysbiosis; changes in the metabolic activity of the gut microbiota and the leaky gut syndrome; which largely cause the accumulation of MDUT in the internal environment of the body: indoxyl sulfate; p-cresyl sulfate; trimethylamine-N-oxide; etc. The results of recent studies allow to consider these metabolites as an independent risk factor for adverse outcomes in people with CKD due to the progression of renal dysfunction to the terminal stage; as well as frequent cardiovascular; neurological; bone mineral; nutritional and other complications.Conclusion. MDUT are one of the key modulators of the pathogenetic relationship between the gut and kidneys. Therapeutic manipulations with intestinal microbiota can be considered a promising strategy for preventing complications associated with uremia.

ПЕРСОНИФИЦИРОВАННЫЙ ПОДХОД К ОЦЕНКЕ РИСКА РАЗВИТИЯ ПОВТОРНЫХ СЕРДЕЧНО-СОСУДИСТЫХ СОБЫТИЙ И ХРОНИЧЕСКОЙ БОЛЕЗНИ ПОЧЕК У ПАЦИЕНТОВ С ИНФАРКТОМ МИОКАРДА И ОСТРЫМ ПОВРЕЖДЕНИЕМ ПОЧЕК

Introduction: AKI (acute kidney injury) is a common comorbid condition in patients with AMI (acute myocardial infarction), complicating its course and treatment. In the future, the prognosis of these patients after discharge from the hospital, as well as the incidence of recurrent cardiovascular events (CVS) and chronic kidney disease (CKD) are not known. The purpose of the study: to study the predictors of the development of recurrent cardiovascular events (CVS) in patients with myocardial infarction (MI) with acute kidney injury (AKI). Develop a calculator - a risk meter for repeated CCC. Materials and methods: the study was performed in the Altai Regional Cardiological Dispensary. 193 patients with MI and PCI (percutaneous coronary intervention) were included, divided into 2 groups: the first - 123 patients aged 62.8±1.1 years with MI and AKI, the second - 70 patients without AKI, age 61.3± 1.6 years. Upon admission and before discharge, the level of the KIM-1 molecule (Kidney Injury Molecule-1) and IL-18 (interleukin-18) was studied by ELISA in the urine. All patients underwent coronary angiography using low-osmolar contrast. One year after discharge, the frequency of development of repeated CCC was assessed. Statistical calculations were carried out using statistical packages STATISTICA 12.0. The level of statistical significance was taken equal to 0.05. Results. The level of KIM-1 (at admission) in the first group was statistically higher than in the second: 1998.9±147.6 versus 1289.8±126.1 pg/ml p=0.001, and IL-18 in the AKI group exceeded the corresponding parameter of the group without AKI: 179.0±12.9 versus 114.9±11.5 pg/ml p=0.007, respectively. A year later, it was found that the frequency of recurrent cardiovascular events was higher in the group with AMI and AKI: unstable angina was diagnosed in 26 (21.1%) patients in the group with AKI and 5 (7.1%) patients without AKI in history, p=0.010; 19 (15.4%) and 2 (2.8%) patients, p=0.006, 20 (16.2%) and 3 (4.2%), p=0.013 patients, respectively, had repeated myocardial infarction and progression of CHF in a year . Progression of renal dysfunction during the year was observed 5 times more often in patients with MI and AKI: CKD C2 was diagnosed in 49 (39.8%) patients of the first group and 16 (22.8%) of the second, p = 0.01; CKD C3a and C3b stages - in 34 (27.6%), p˂0.001 and 19 (15.4%) patients, p=0.002, respectively, CKD stage C4 was detected in 4 (3.2%) patients of the group with AMI and AKI in the early postinfarction period. As a result of constructing a multifactorial logistic regression model, predictors were identified that have a multiplicative effect on the development of recurrent CV events: BMI over 25 kg/m2 increases the risk of recurrent CV events by 0.91 [0.83; 0.99] times, p=0.028, history of prior MI in 3.32 [1.24; 9.86] times, p=0.022. Increase in CRP by 1.01 [1; 1.03] times, p=0.045, troponin I, 0.97 [0.94;1] times, p=0.037, and IMT-1, 1 [1;1] times, p=0.030. On the development of CKD: an increase in age is associated with an increase in the chances of developing CKD by 1.18 [1.1; 1.29], p ˂0.001; troponin I by 0.96 times [0.92; 1], p=0.030; systolic blood pressure in 1.03 [1; 1.07] times, p = 0.029. A calculator has been developed for risk stratification of the development of recurrent CV events and an algorithm for managing this category of patients after discharge from the hospital. Conclusions: thus, the identified predictors make it possible to calculate the risk of developing recurrent CV events and CKD using the developed calculator and allocate these patients to a separate group for personalized observation, taking appropriate measures of secondary prevention.

Microalbuminuria in Perinatally HIV-Infected Children and Adolescents in the United States.

The kidney is a common target for human immunodeficiency virus (HIV), making renal disease a common noninfectious complication of HIV. Microalbuminuria is an important marker that can detect early renal damage. Timely detection of microalbuminuria is important to initiate renal management and stop the progression of renal dysfunction in people with HIV. Limited data are available about renal abnormalities in people with perinatal HIV infection. The objective of this study was to determine the prevalence of microalbuminuria in a cohort of perinatally HIV-infected children and young adults receiving combination antiretroviral therapy and investigate correlations between microalbuminuria and clinical and laboratory findings. This was a retrospective study of 71 patients with HIV followed in an urban pediatric HIV clinic in Houston, Texas, between October 2007 and August 2016. Demographic, clinical, and laboratory data were compared between subjects with persistent microalbuminuria (PM) and those without. PM is defined as a microalbumin-to-creatinine ratio ≥30 mg/g on at least 2 occasions separated by at least 1 month. Sixteen of 71 patients (23%) met the definition of PM. In univariate analysis, patients with PM had significantly higher CD8+ T-cell activation and lower CD4+ T-cell nadir. Multivariate analysis demonstrated increased microalbuminuria to be independently associated with older age and CD8+ T-cell activation measured as CD8+HLA-DR+ T-cell percentage. Older age and increased activation of CD8+HLA-DR+ on T cells correlate with presence of microalbuminuria in this cohort of HIV-infected patients.

PKD1 Mutation Is a Biomarker for Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) occurs in 1 in 500-4000 people worldwide. Genetic mutation is a biomarker for predicting renal dysfunction in patients with ADPKD. In this study, we performed a genetic analysis of Japanese patients with ADPKD to investigate the prognostic utility of genetic mutations in predicting renal function outcomes. Patients clinically diagnosed with ADPKD underwent a panel genetic test for germline mutations in PKD1 and PKD2. This study was conducted with the approval of the Ethics Committee of Juntendo University (no. 2019107). Of 436 patients, 366 (83.9%) had genetic mutations. Notably, patients with PKD1 mutation had a significantly decreased ΔeGFR/year compared to patients with PKD2 mutation, indicating a progression of renal dysfunction (-3.50 vs. -2.04 mL/min/1.73 m2/year, p = 0.066). Furthermore, PKD1 truncated mutations had a significantly decreased ΔeGFR/year compared to PKD1 non-truncated mutations in the population aged over 65 years (-6.56 vs. -2.16 mL/min/1.73 m2/year, p = 0.049). Multivariate analysis showed that PKD1 mutation was a more significant risk factor than PKD2 mutation (odds ratio, 1.81; 95% confidence interval, 1.11-3.16; p = 0.020). The analysis of germline mutations can predict renal prognosis in Japanese patients with ADPKD, and PKD1 mutation is a biomarker of ADPKD.