Angiotensin Receptor-Neprilysin Inhibitor for Chronic Kidney Disease: Strategies for Renal Protection.

BACKGROUND: Chronic kidney disease (CKD) and hypertension are significant global health challenges that often coexist and aggravate each other. Renin-angiotensin system (RAS) inhibitors are important to the management of these conditions; however, their efficacy for advanced CKD remains uncertain. SUMMARY: Angiotensin receptor-neprilysin inhibitor (ARNI) have superior efficacy for heart failure (HF) management, as evidenced by landmark trials such as the PARADIGM-HF and PARAGON-HF, thus leading to its endorsement by various guidelines. Although direct evidence supporting the renal-protective effects of ARNI is lacking, post hoc analyses have suggested its potential to mitigate the decline of the estimated glomerular filtration rate and renal events, particularly in patients with HF with a relatively preserved ejection fraction. Mechanistically, ARNI augments the glomerular filtration rate by dilating glomerular arterioles, relaxing mesangial cells, and improving renal medullary blood flow, thereby mitigating interstitial fibrosis progression. ARNI also effectively addresses non-dipper hypertension, particularly in salt-sensitive individuals, thereby reducing the cardiovascular risk. KEY MESSAGES: Uncertainties regarding the efficacy and safety of ARNI for advanced renal failure (estimated glomerular filtration rate <30 mL/min) exist. Excessive hypotension associated with ARNI use may exacerbate the renal function decline, especially in older patients with comorbid HF with a reduced ejection fraction. Hence, vigilant blood pressure monitoring is essential to optimizing the renal benefits of ARNI and minimizing adverse effects. Evidence supporting the renal benefits of ARNI continues to evolve; therefore, ARNI could mitigate renal dysfunction in select patient populations. Further research should be performed to clarify the efficacy of ARNI for advanced renal failure and refine its therapeutic application for patients with concurrent HF and renal dysfunction.

NLRP3 Inflammasome Activation in Lung Vascular Endothelial Cells Contributes to Intestinal Ischemia/Reperfusion-Induced Acute Lung Injury.

Intestinal ischemia/reperfusion (I/R) injury is a life-threatening complication that leads to inflammation and remote organ damage. The NLRP3 inflammasome regulates the caspase-1-dependent release of IL-1ß, an early mediator of inflammation after I/R injury. In this study, we investigated the role of the NLRP3 inflammasome in mice with intestinal I/R injury. Deficiency of NLRP3, ASC, caspase-1/11, or IL-1ß prolonged survival after intestinal I/R injury, but neither NLRP3 nor caspase-1/11 deficiency affected intestinal inflammation. Intestinal I/R injury caused acute lung injury (ALI) characterized by inflammation, reactive oxygen species generation, and vascular permeability, which was markedly improved by NLRP3 deficiency. Bone marrow chimeric experiments showed that NLRP3 in non-bone marrow-derived cells was the main contributor to development of intestinal I/R-induced ALI. The NLRP3 inflammasome in lung vascular endothelial cells is thought to be important to lung vascular permeability. Using mass spectrometry, we identified intestinal I/R-derived lipid mediators that enhanced NLRP3 inflammasome activation in lung vascular endothelial cells. Finally, we confirmed that serum levels of these lipid mediators were elevated in patients with intestinal ischemia. To our knowledge, these findings provide new insights into the mechanism underlying intestinal I/R-induced ALI and suggest that endothelial NLRP3 inflammasome-driven IL-1ß is a novel potential target for treating and preventing this disorder.

Role of TLR5 in inflammation and tissue damage after intestinal ischemia-reperfusion injury.

BACKGROUND: Intestinal ischemia/reperfusion (I/R) injury is a life-threatening complication that leads to inflammation and remote organ damage. However, the underlying mechanism is not yet fully understood. Toll-like receptor 5 (TLR5) is highly expressed in mucosa and recognizes flagellin, the main component of the bacterial flagella. Here, we investigated the role of TLR5 in inflammation and tissue damage after intestinal I/R injury using TLR5-deficient mice. METHODS AND RESULTS: Intestinal levels of TLR5 mRNA and flagellin protein were elevated in wild-type mice subjected to intestinal I/R. Although TLR5 deficiency had no effect on intestinal flagellin levels, it significantly attenuated intestinal injury and inflammatory responses after intestinal I/R. TLR5 deficiency also markedly improved survival in mice after intestinal I/R injury. In wild-type mice, intestinal I/R injury induced remote organ damage, particularly in the lung, which was attenuated by TLR5 deficiency. Furthermore, TLR5 deficiency prevented lung inflammatory responses and vascular permeability after intestinal I/R injury. CONCLUSION: These findings demonstrate a novel role of TLR5 and provide new insights into the mechanism underlying inflammation and tissue damage after intestinal I/R injury.

Elucidating the complex interplay between chronic kidney disease and hypertension.

Chronic kidney disease (CKD) and hypertension share a complex relationship, each exacerbating the progression of the other. CKD contributes to hypertension by decreasing renal function, leading to fluid retention and increased plasma volume, whereas hypertension exacerbates CKD by increasing glomerular pressure and causing renal damage. This review examines the intertwined nature of CKD and hypertension, exploring the factors driving hypertension in CKD and how hypertension accelerates CKD progression. It discusses the role of the renin-angiotensin system and inflammatory cytokines in this relationship, as well as the potential of blood pressure management to slow renal decline. While studies suggest that meticulous blood pressure control can help attenuate CKD progression, optimal management strategies remain unclear and require further investigation. This review also evaluates the evidence surrounding strict antihypertensive therapy in patients with CKD, considering both diabetic and non-diabetic cases. It recommends blood pressure targets based on CKD stage and presence of diabetes, emphasizing the importance of individualized treatment approaches. Renin-angiotensin system inhibitors are highlighted as a key pharmacological intervention due to their renal protective effects, particularly in patients with CKD with proteinuria. However, evidence regarding their efficacy in patients with CKD but without proteinuria is inconclusive. This review underscores the need for comprehensive approaches to effectively address the intertwined nature of CKD and hypertension and calls for further research to optimize clinical management strategies in this complex interplay.

A 20-year follow-up study of identical twin sisters with immunoglobulin A nephropathy.

Immunoglobulin A nephropathy (IgAN) is characterized by diverse clinicopathological phenotypes. Herein we present a follow-up study of previously reported identical twin sisters with IgAN. The older sister exhibited more severe kidney histopathology and proteinuria and a lower birthweight than did her younger sister, and only the older sister experienced two childbirths. These raised concerns regarding her kidney outcomes. However, with timely multidisciplinary treatments, the older sister's kidney function remained preserved after 20 years of IgAN history. Our findings indicate the significant contribution of environmental/epigenetic factors to IgAN progression and the need for tailored medical care corresponding to life events.

Severe Acute Interstitial Nephritis Induced by α-glucosidase Inhibitor Miglitol in an Elderly Patient with Type 2 Diabetic Nephropathy.

A 79-year-old male patient with type 2 diabetic nephropathy and hypertension was admitted to our hospital because of acute kidney injury with significantly elevated serum creatinine (8.12 mg/dL) and urinary ß2-microglobulin (ß2MG, 31,748 µg/L) levels. α-glucosidase inhibitor (α-GI) miglitol, started two weeks prior to presentation, was discontinued because drug-induced acute interstitial nephritis (AIN) was suspected. Renal biopsy revealed AIN and diabetic nephropathy. The drug-induced lymphocyte stimulation test for miglitol was also positive. After the discontinuation of miglitol, the urinary ß2MG levels decreased to the normal range. This case raises the possibility that α-GI miglitol can worsen the renal function in patients with underlying renal dysfunction.

Acute Interstitial Nephritis with Glomerular Capillary IgA Deposition Following SARS-CoV-2 mRNA Vaccination.

We herein report a case of acute kidney injury (AKI) presenting as acute interstitial nephritis (AIN) after the first dose of the BNT162b2 mRNA vaccine against coronavirus disease 2019 (COVID-19). A 69-year-old man with a history of diabetes and hypertension presented with AKI 4 days after receiving the vaccine. Despite the administration of methylprednisolone pulse treatment, his renal function worsened, which prompted us to initiate temporal hemodialysis. His renal function subsequently improved, and a renal biopsy confirmed AIN and glomerular capillary IgA deposition without apparent crescents. The clinical history and histological findings suggest a relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination and AIN as a rare side effect.

Tubulointerstitial nephritis in antineutrophil cytoplasmic antibody-associated vasculitis with monoclonal gammopathy.

Isolated tubulointerstitial nephritis (TIN) without glomerular crescent formation is a rare manifestation of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Some patients with monoclonal gammopathy of undetermined significance present with renal complications due to serum monoclonal protein. Here, we present a case of TIN presumably attributable to AAV with monoclonal gammopathy. Laboratory data revealed acute kidney injury, elevated C-reactive protein (CRP) and ANCA titers, and elevated tubular injury markers. Renal biopsy revealed TIN with no apparent glomerular lesion. The findings of peritubular capillaritis and tubulitis indicated that AAV had contributed to the development of TIN. However, in situ hybridization for free light chains revealed kappa light chain restriction, indicating that the involvement of monoclonal gammopathy in the pathogenesis of TIN remains possible. The patient also developed ophthalmic neuropathy, probably caused by AAV. Oral prednisone (0.6 mg/kg/day) administration improved both the ocular symptoms and the laboratory parameters. Our case demonstrated that the concurrence of AAV and monoclonal gammopathy could pose a diagnostic dilemma in distinguishing the cause of TIN. Besides, some reports suggest an association between AAV and monoclonal gammopathy, although direct evidence is lacking. Further research is needed to establish this association.

Practical Strategy for Treating Chronic Kidney Disease (CKD)-Associated with Hypertension.

When renal function declines, blood pressure rises, which in turn causes the kidneys to deteriorate. In order to stop this vicious cycle, it is necessary to lower the blood pressure to a "moderate" level in patients who have chronic kidney disease (CKD)-associated hypertension. Such optimization is problematic, since tight control of blood pressure might worsen the prognosis in elderly patients with CKD, especially those with advanced arteriosclerosis. Although renin-angiotensin system (RAS) inhibitors, angiotensinogen converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are first-line drugs for hypertensive patients with diabetes, they should be used with caution depending on the patients' conditions. Recently, there has been a focus on the preventive effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors, anti-diabetic drugs that have been shown to have an impact, on heart and kidney complications. SGLT2 inhibitors increase the amount of sodium chloride delivered to the macular densa of the distal tubules and correct glomerular hyperfiltration by contraction of afferent arterioles via the tubule-glomerular feedback system. It might be one of the reasons why SGLT2 inhibitors show the renal- and cardio-protective effects; however, the mechanism behind their function remains to be elucidated.

GSDME-Dependent Incomplete Pyroptosis Permits Selective IL-1α Release under Caspase-1 Inhibition.

Pyroptosis is a form of regulated cell death that is characterized by gasdermin processing and increased membrane permeability. Caspase-1 and caspase-11 have been considered to be essential for gasdermin D processing associated with inflammasome activation. In the present study, we found that NLRP3 inflammasome activation induces delayed necrotic cell death via ASC in caspase-1/11-deficient macrophages. Furthermore, ASC-mediated caspase-8 activation and subsequent gasdermin E processing are necessary for caspase-1-independent necrotic cell death. We define this necrotic cell death as incomplete pyroptosis because IL-1ß release, a key feature of pyroptosis, is absent, whereas IL-1α release is induced. Notably, unprocessed pro-IL-1ß forms a molecular complex to be retained inside pyroptotic cells. Moreover, incomplete pyroptosis accompanied by IL-1α release is observed under the pharmacological inhibition of caspase-1 with VX765. These findings suggest that caspase-1 inhibition during NLRP3 inflammasome activation modulates forms of cell death and permits the release of IL-1α from dying cells.

Crucial Role of NLRP3 Inflammasome in the Development of Peritoneal Dialysis-related Peritoneal Fibrosis.

Long-term peritoneal dialysis (PD) therapy leads to peritoneal inflammation and fibrosis. However, the mechanism underlying PD-related peritoneal inflammation and fibrosis remains unclear. NLRP3 inflammasome regulates the caspase-1-dependent release of interleukin-1ß and mediates inflammation in various diseases. Here, we investigated the role of NLRP3 inflammasome in a murine model of PD-related peritoneal fibrosis induced by methylglyoxal (MGO). Inflammasome-related proteins were upregulated in the peritoneum of MGO-treated mice. MGO induced parietal and visceral peritoneal fibrosis in wild-type mice, which was significantly reduced in mice deficient in NLRP3, ASC, and interleukin-1ß (IL-1ß). ASC deficiency reduced the expression of inflammatory cytokines and fibrotic factors, and the infiltration of macrophages. However, myeloid cell-specific ASC deficiency failed to inhibit MGO-induced peritoneal fibrosis. MGO caused hemorrhagic ascites, fibrin deposition, and plasminogen activator inhibitor-1 upregulation, but all of these manifestations were inhibited by ASC deficiency. Furthermore, in vitro experiments showed that MGO induced cell death via the generation of reactive oxygen species in vascular endothelial cells, which was inhibited by ASC deficiency. Our results showed that endothelial NLRP3 inflammasome contributes to PD-related peritoneal inflammation and fibrosis, and provide new insights into the mechanisms underlying the pathogenesis of this disorder.

Valacyclovir Neurotoxicity and Nephrotoxicity in an Elderly Patient Complicated by Hyponatremia.

A 66-year-old women with no history of renal disease was admitted due to a coma and acute kidney injury with a serum creatinine level of 7.44 mg/dL which were ascribed to valacyclovir neurotoxicity and nephrotoxicity, respectively. She had received valacyclovir at a standard dosage for the treatment of herpes zoster and was finally discharged, having fully returned to her normal baseline mental status with a recovered serum creatinine level of 0.68 mg/dL. We feel that awareness of this pathology remains a challenge for physicians and therefore strongly recommend the further accumulation of experiences similar to our own. Our experience underscores the pitfalls of administering valacyclovir to elderly patients who barely appear to have a favorable renal function. Several concerns regarding the therapeutic management, including blood purification strategies, that emerged in this case are also discussed.

Retroperitoneal Bleeding: An Experience During Prophylactic Anticoagulation in a Patient With Nephrotic Syndrome.

The association between nephrotic syndrome (NS) and a hypercoagulable state has been demonstrated. Controlling the blood clotting activity may therefore be attractive for patients with nephrosis in terms of thromboembolism prophylaxis. We herein report a 75-year-old woman with minimal change disease who developed pains in the right back, groin, and thigh because of retroperitoneal bleeding during prophylactic anticoagulation with unfractionated heparin. Although this procedure has not been accepted as the standard of care for patients with nephrosis, pharmacologic prophylaxis may already be practiced empirically, as in the present patient. We believe that our experience highlights the pitfalls of such a management in patients with nephrosis, implying the need for a diagnostic strategy for identifying those patients with NS who can benefit from prophylactic anticoagulation. Several concerns that emerged in this case are also discussed.

Renal Failure Found during the Follow-up of Sarcoidosis: The Relevance of a Delay in the Diagnosis of Concurrent Hypercalcemia.

We herein present a case of relapsed sarcoidosis with a deteriorated renal function accompanied by hypercalcemia, nephrolithiasis, and a ureteral stone in a woman with a history of ocular sarcoidosis. The ocular involvement appeared to be well controlled for a long period of time with a topical ophthalmic steroid; however, we believe that the absence of apparent recrudescence could have led to the delay in our diagnosis of relapse of the disease during the follow-up period. The conundrums regarding longitudinal surveillance for both evaluating the disease activity and determining the necessity of therapeutics are also discussed.

Development of Acute Pericarditis Associated with New-onset Rheumatoid Arthritis in a Diabetic Patient with Renal Impairment: The Elusive Nature of Uremia.

Uremic patients may have a variety of organ involvement, however, the precise causality may be impossible to determine in some cases because the symptoms of uremia are also associated with other diseases. With an emphasis on the elusive nature of uremia, we herein describe a 53-year-old man with preexisting renal impairment who developed acute pericarditis with deterioration of his renal function. Hemodialysis was immediately initiated on the presumption of uremia, however, articular symptoms emerged approximately a month later and led to a final diagnosis of rheumatoid arthritis, followed by successful withdrawal of hemodialysis.