京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13376号 / 論医博第2210号 / 新制||医||1047(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 森田 智視, 教授 川上 浩司, 教授 佐藤 俊哉 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Acute kidney injury (AKI) is a major public health concern, which contributes to serious hospital complications, chronic kidney disease (CKD) and even death. Renal ischemia- reperfusion injury (IRI) remains a leading cause of AKI.IRI combines major cell stress, significant burst of free radicals, and strong inflammatory responses leading to extensive cell injury, necrosis, and late interstitial fibrosis. Moreover, IRI- induced AKI releases pro-inflammatory cytokines (e.g. IL-1β, TNF-α, IL-6) that induce a systemic inflammatory response, resulting in pro-inflammatory cells recruitment and remote organ damage. AKI is associated with poor outcomes, particularly when extrarenal complications or distant organ injuries occur.The stress-responsive enzyme, heme oxygenase-1 (HO-1) mediates protection against renal IRI and may be preventively induced using hemin prior to renal insult. This HO-1 induction pathway called hemin preconditioning is largely known in the literature to be effective.We first confirmed that hemin-induced HO-1 improved renal outcomes after IRI (i.e. fewer renal damage, renal inflammation and oxidative stress). We then demonstrated that this protective pathway mitigated AKI-induced ALI, a major extrarenal complication after renal IRI, through modulation of systemic and lung inflammation.Afterwards, we focused on the specific contribution of myeloid HO-1 to renal IRI, which remains poorly characterized. We therefore investigated the contribution of myeloid HO-1 to renal IRI using mice with myeloid-restricted deletion of HO-1 (HO-1M-KO). We observed that myeloid HO-1 appeared to be a critical regulator of the earliest phases of IRI (i.e. higher plasma creatinine, tubular damage, and renal inflammation/oxidative stress in HO-1M-KO mice).As a link between the severity of renal injury and the risk maladaptive repair leading to CKD has been established, we thereby decided to focus on tubular repair and fibrosis deposition upon IRI. We identified that myeloid HO-1 prevented maladaptive repair and subsequent CKD through modulation of cell-cycle and autophagy regulatory proteins.We then showed that hemin-mediated protection requires specific expression of HO-1 within myeloid cells. We therefore identified CD11b+ F4/80lo macrophages as the main protective myeloid source of HO-1 upon renal IRI. Interestingly, we observed this myeloid cell sub- population in the kidney and spleen, suggesting that protective effects might be provided by both tissue-resident and infiltrating/circulating HO-1+ myeloid cells.Based on its promising cytoprotective effects when giving preemptively, we investigated the use of hemin-induced myeloid HO-1 as a strategy to mitigate established AKI. However, due to its chemical structure and oxidative properties, hemin worsened IRI-induced AKI. We thereby identified that hemin had a dual effect on renal IRI, protective or deleterious, depending on the timing of its administration.Altogether, this work suggests that myeloid HO-1 plays a critical role in the modulation of IRI- induced AKI by improving short- and long-term functional outcomes after renal IRI. We conclude that hemin-induced myeloid HO-1 pathway might be an efficient preventive strategy in many renal IRI situations with predictable AKI such as renal transplantation or partial nephrectomy. / Doctorat en Sciences médicales (Médecine) / info:eu-repo/semantics/nonPublished

Introduction Acute interstitial nephritis (AIN), also called tubulointerstitial nephritis, is a renal pathology that can cause a significant decline in kidney function. Drug-induced AIN accounts for 70% of all cases and is often due to non-steroidal anti-inflammatory drugs (NSAIDs), antimicrobials, and proton pump inhibitors. However, there have been isolated reports of other drugs being responsible for AIN. We hereby report a case of furosemide-induced AIN. Case Presentation A 68-year-old caucasian male with a medical history significant for chronic kidney disease (CKD) stage 3 due to hypertensive nephrosclerosis with a baseline serum creatinine (Cr) of 1.3-1.5, hypertension, hyperlipidemia, atrial fibrillation, heart failure with preserved ejection fraction (HFpEF), and hypogonadism was admitted for evaluation of worsening renal failure. At initial evaluation, the patient had nonspecific symptoms like malaise, nausea, and vomiting but denied any other complaints. Physical examination was unremarkable, without any rashes or abdominal bruit. The patient’s creatinine progressively trended up from his baseline to 3.5 over three months. Pre-renal pathology was suspected initially, and the patient's furosemide was held on admission with concurrent fluid resuscitation. However, this did not improve his kidney function as repeat lab work showed a worsening Cr level of 4.4, along with a blood urea nitrogen (BUN) of 72. Further evaluation showed a complete blood count significant for mild eosinophilia with urinalysis revealing hematuria, pyuria with eosinophiluria but no protein, WBC casts, or RBC casts. Renal ultrasound and abdominal CT scan were unremarkable. The patient had no known drug allergies until that point and was on a stable medication regimen for his chronic conditions for several years, except for a daily dose of furosemide started three months ago for fluid retention and elevated BNP. Ultrasound-guided renal biopsy revealed findings consistent with acute interstitial nephritis on top of chronic tubulointerstitial fibrosis plus underlying moderate arterial sclerosis from hypertension. Other extensive workup was negative for any autoimmune process, IgG4 related disease, sarcoidosis, or infection, thus favoring the diagnosis of drug-induced acute interstitial nephritis. Given the temporal relationship between the initiation of furosemide in this patient and his worsening kidney function makes it the likely offending agent. He was observed off furosemide without any immunosuppressant treatment. The patient’s creatinine level gradually trended down and ultimately returned to his baseline at a one-month follow-up. Discussion Furosemide is a loop diuretic, often used in patients to prevent volume overload. Therefore, furosemide is often implicated as a cause of pre-renal acute kidney injury (AKI) secondary to volume depletion. However, interstitial inflammation as a mechanism of furosemide-induced kidney injury is uncommon and can often be overlooked as a potential cause, especially in patients with long medication lists. In such patients, a causal link can be established by correlating the onset of decline in kidney function with the time of initiation of a new drug and resolution of AKI after discontinuation of the drug.

Untreated human immunodeficiency virus (HIV) can be complicated by opportunistic infections, including disseminated histoplasmosis (DH). Although endemic to portions of the United States and usually benign, DH can rarely act as an opportunistic infection in immunocompromised patients presenting with uncommon complications such as acute kidney injury and idiopathic thrombocytopenic purpura. We report a rare presentation of DH presenting with acute kidney injury and immune thrombocytopenic purpura in an immunocompromised patient with HIV.

Acute kidney injury (AKI) is a major complication in hospitalized patients and is associated with elevated mortality rates. Numerous recent studies indicate that AKI also significantly increases the risk of chronic kidney disease (CKD), end-stage renal disease (ESRD), hypertension, cardiovascular disease, and mortality in those patients who survive AKI. Moreover, the risk of ESRD and mortality after AKI is substantially higher in patients with preexisting CKD. However, the underlying mechanisms by which AKI and CKD interact to promote ESRD remain poorly understood. The recently developed models that superimpose AKI on rodents with preexisting CKD have provided new insights into the pathogenic mechanisms mediating the deleterious interactions between AKI and CKD. These studies show that preexisting CKD impairs recovery from AKI and promotes the development of mechanisms of CKD progression. Specifically, preexisting CKD exacerbates microvascular rarefaction, failed tubular redifferentiation, disruption of cell cycle regulation, hypertension, and proteinuria after AKI. The purpose of this review is to discuss the potential mechanisms by which microvascular rarefaction and hypertension contribute to impaired recovery from AKI and the subsequent progression of renal disease in preexisting CKD states.

Introduction Severe hypercalcemia from chronic gout is a rare phenomenon seen after the advent of newer drugs for its treatment. The hypercalcemia is secondary to either granuloma formation around the tophi or chronic immobilization from severe gouty arthritis. We present a patient with chronic tophaceous gout presenting with severe hypercalcemia and acute kidney injury. Case presentation A 63-year-old male patient with a past medical history of hypertension and chronic gout presented to the office with chronic, severe left knee pain. Initial evaluation of the knee with X-rays revealed destruction of the knee joint with cystic changes, and subsequent MRI with contrast showed soft tissue mass in the suprapatellar pouch with intraosseous extension and involvement of medial and lateral collateral ligament involvement. After interdisciplinary evaluation between radiology, orthopedic surgery, and oncology, this was concerning for highly aggressive pigmented villonodular synovitis of the knee, and a decision was made for the patient to undergo complete knee replacement. Perioperative workup was significant for severe hypercalcemia with a total calcium level of 13.2 mg/dl with ionized calcium of 7.2 mg/dl. Further evaluation into the cause of hypercalcemia revealed a low normal intact parathyroid hormone (PTH) level with normal phosphorus, calcidiol, and calcitriol levels. Other etiologies of hypercalcemia such as multiple myeloma, malignancies, metastatic disease, autoimmune, granulomatous, and infectious processes are excluded with extensive workup. The hypercalcemia is treated with fluids, diuretics, and bisphosphonates, eventually normalizing the calcium levels. The patient underwent total left knee replacement, and the mass identified was sent for biopsy. Biopsy revealed a prominent granulomatous reaction to amorphous crystals containing birefringent crystals under polarised light. Uniquely during our evaluation, vitamin D metabolites, uric acid, and PTH levels were normal despite the biopsy findings. The patient's calcium continued to be normal (8.4 to 10.4 mg/dl) over six months after the surgery. Thus, the scenario is supportive of hypercalcemia secondary to granulomatous inflammation around the large tophi. Conclusion Although rare, the knee joint is a site of severe tophaceous gout, and deposition of uric acid crystals can invoke a granulomatous reaction presenting with severe hypercalcemia as in our patient. Unique to our case, the patient can have benign lab findings on evaluation of hypercalcemia. Only a few case reports are illustrated in the literature, making our case and patient presentation unique.

Acute Kidney Injury (AKI) is a prevalent systemic disorder that has an extremely high rate of mortality even after detection. Historically, the diagnosis and treatment of AKI was marred by the lack of universally accepted criteria defining AKI. Therefore, reports of incidence and mortality varied widely depending on location and the criteria used at the time, but all reports indicated a poor prognosis for the patient. Until recently, the only modes of detecting AKI were primarily through measurements of three clinical findings: serum creatinine concentration, blood urea nitrogen concentration, and urine output. While these measurements are still widely used as standard practice, they have limitations in their utility because their values can fluctuate depending on a person's age, gender, race, diet, and other comorbid conditions. Nevertheless, as these were the only universally accepted units of measurement for kidney function, the Acute Dialysis Quality Initiative (ADQI) used them to create the Risk, Injury, Failure, Loss, and End stage kidney disease (RIFLE) criteria to classify the severity of kidney injury across clinical settings. Eventually, modifications were made by the Acute Kidney Injury Network (AKIN) to increase the sensitivity of AKI diagnosis. It was not until the last decade that new biomarkers of kidney injury began to be researched that provided earlier detection of physical kidney injury before functional manifestations would present themselves. Some of these new biomarkers include cystatin C, kidney injury molecule-1 (KIM-1), and neutrophil gelatinase associated lipocalin (NGAL). This study will investigate how the properties of these new biomarkers are superior when compared to those of serum creatinine in early detection of AKI and specification as to the local site of injury within the nephron. The conclusion is that cystatin C has the potential to indicate damage to glomerular filtration while KIM-1 and NGAL have the ability to indicate damage to the proximal tubule. Along with the ability to provide information as to the specific site of renal injury, the levels of cystatin C, KIM-1, and NGAL increase much more rapidly and to a much higher value than serum creatinine once physical renal damage has occurred. These characteristics along with future research will allow for earlier detection of AKI, more personalized treatment plans, and an overall better prognosis for the patient.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20246号 / 医博第4205号 / 新制||医||1020(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 長船 健二, 教授 杉田 昌彦, 教授 髙折 晃史 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21008号 / 医博第4354号 / 新制||医||1028(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 長船 健二, 教授 小川 修, 教授 横出 正之 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21678号 / 医博第4484号 / 新制||医||1036(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 柳田 素子, 教授 福原 俊一, 教授 今中 雄一 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM