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BackgroundImmune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer.MethodsWe collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI.ResultsICPi-AKI occurred at a median of 16 weeks (IQR 8–32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3–10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI.ConclusionsPatients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery.

Background Atypical hemolytic uremic syndrome is a rare group of disorders that have in common underlying complement amplifying conditions. These conditions can accelerate complement activation that results in a positive feedback cycle. The known triggers for complement activation can be diverse and include, infection, autoimmune disease, and malignancy. Recent reports suggest that certain autoimmune and rheumatological triggers of complement activation may result in atypical hemolytic uremic syndrome that does not resolve despite treating the underlying disorder. Specifically, patients with systemic lupus erythematosus and microangiopathic hemolysis may not respond to treatment of their underlying rheumatological trigger but responded to complement blockade. Case presentations We report two patients with inflammatory bowel disease complicated by development of atypical hemolytic uremic syndrome. In both cases, patients were on treatment for inflammatory bowel disease, that was not well controlled/flaring at the time. The first patient is a male who developed Crohn’s disease and microangiopathic hemolysis at age 5 and was treated with eculizumab successfully. Discontinuation of the medication led to multiple relapses, and the patient currently is being treated with eculizumab and has normal hematological and stable renal parameters. The second patient is a 49-year-old female with Ulcerative Colitis treated with 6-Mercaptopurine. She developed acute kidney injury and microangiopathic hemolysis. Prompt diagnosis and treatment with eculizumab resulted in the recovery of kidney injury along with a complete hematological response. Conclusions These two cases are the fifth and sixth patients to be published in the literature with atypical hemolytic uremic syndrome and inflammatory bowel disease treated with complement blockade. This confirms that C5 complement blockade is effective in treating complement mediated thrombotic microangiopathy/atypical hemolytic uremic syndrome when it is triggered in patients with inflammatory bowel disease.

Recent evidence suggests that renal dysfunction may be a direct consequence of primary myelofibrosis (PMF). We performed a retrospective analysis of 100 patients with previously untreated PMF, receiving frontline treatment with single agent ruxolitinib, and compared them to 105 patients, receiving frontline treatment with a non-ruxolitinib-based therapy, matched by age, sex, DIPSS plus, and estimated glomerular filtration rate (eGFR). Use of ruxolitinib associated with a significantly higher rate of renal improvement (RI) 10% (73% vs 50%, p = 0.01) confirmed on multivariate analysis (MVA) [odds ratio 3, 95% confidence interval (CI) 1.6-5.5, p 0.001]. After a median follow-up of 41 months (range, 1-159 months), median failure-free survival (FFS) was 14 months (range, 1-117 months). Achievement of a RI 10% maintained its independent association with prolonged FFS on MVA (hazard ratio 1.4, 95% CI 1.1-2, p = 0.02). Ruxolitinib can significantly improve renal function in patients with PMF, significantly impacting failure-free survival.

Rationale & Objective The approved therapeutic indication for immune checkpoint inhibitors (CPIs) are rapidly expanding including treatment in the adjuvant setting, the immune related toxicities associated with CPI can limit the efficacy of these agents. The literature on the nephrotoxicity of CPI is limited. Here, we present cases of biopsy proven acute tubulointerstitial nephritis (ATIN) and glomerulonephritis (GN) induced by CPIs and discuss potential mechanisms of these adverse effects. Study design, setting, & participants We retrospectively reviewed all cancer patients from 2008 to 2018 who were treated with a CPI and subsequently underwent a kidney biopsy at The University of Texas MD Anderson Cancer Center. Results We identified 16 cases diagnosed with advanced solid or hematologic malignancy; 12 patients were male, and the median age was 64 (range 38 to 77 years). The median time to developing acute kidney injury (AKI) from starting CPIs was 14 weeks (range 6–56 weeks). The average time from AKI diagnosis to obtaining renal biopsy was 16 days (range from 1 to 46 days). Fifteen cases occurred post anti-PD-1based therapy. ATIN was the most common pathologic finding on biopsy (14 of 16) and presented in almost all cases as either the major microscopic finding or as a mild form of interstitial inflammation in association with other glomerular pathologies (pauci-immune glomerulonephritis, membranous glomerulonephritis, C3 glomerulonephritis, immunoglobulin A (IgA) nephropathy, or amyloid A (AA) amyloidosis). CPIs were discontinued in 15 out of 16 cases. Steroids and further immunosuppression were used in most cases as indicated for treatment of ATIN and glomerulonephritis (14 of 16), with the majority achieving complete to partial renal recovery. Conclusions Our data demonstrate that CPI related AKI occurs relatively late after CPI therapy. Our biopsy data demonstrate that ATIN is the most common pathological finding; however it can frequently co-occur with other glomerular pathologies, which may require immune suppressive therapy beyond corticosteroids. In the lack of predictive blood or urine biomarker, we recommend obtaining kidney biopsy for CPI related AKI.

Transplant patients are at risk for hemodynamic injury and glomerular diseases such as focal segmental glomerulosclerosis (FSGS) and thrombotic microangiopathy (TMA). Calcineurin inhibitors (CNI) can cause various patterns of acute kidney injury (AKI) in transplant patients and their effects must be differentiated from kidney injury due to other agents. Transplant populations are also at risk for atypical infections and malignancies. These conditions and the agents that are used to treat them can then induce their own set of glomerular diseases. We report a patient with hepatitis C who had received an orthotopic liver transplant and then developed recurrent hepatocellular carcinoma, which was treated with the oral tyrosine kinase inhibitor (TKI) sorafenib. In a manner temporally related to the initiation of the TKI, progressive AKI and high-grade rising proteinuria were noted. A biopsy disclosed FSGS and concomitant TMA. Despite the discontinuation of the TKI and high-dose steroid treatment, the patient developed end-stage renal disease and was initiated on hemodialysis. After determining the TKI as the probable culprit, as opposed to CNIs, the patient successfully received a living related renal transplant. CNIs are used to maintain renal and hepatic allografts without the development of hematuria, significant proteinuria, or significant impairment of renal function. It is noted that the pathologic phenotype observed in this case is only the second reported case of concomitant TMA and FSGS in a sorafenib-treated patient.

Background: The incidence of renal immune-related adverse events (irAEs) is reported to be 3.8%, with varied definitions of acute kidney injury (AKI). This study reports a 10-year experience at MD Anderson Cancer Center of patients diagnosed with melanoma and treated with immune checkpoint inhibitors (ICIs) and evaluated the incidence of AKI, associated factors, and its association with overall survival. Methods: A retrospective chart review (2010–2019) of all patients with melanoma treated with ipilimumab, nivolumab, pembrolizumab, or atezolizumab was performed. All available serum creatinine data were extracted and used to calculate the estimated GFR (eGFR) using the CKD Epi equation, and to diagnose AKI using the two KDIGO (Kidney Disease: Improving Global Outcomes) criteria for defining stage I AKI in 1664 unique patients. Cumulative incidence rates of AKI after initiation of ICIs were calculated in the presence of death as a competing risk. The effects of covariates on the cumulative incidence function of AKI were evaluated in a univariant and multivariable analysis. Overall survival was estimated by Kaplan–Meier method in accordance to the occurrence of AKI. Results: The incidence of AKI by definitions 1a and 1b were 3.49% and 3.33%, respectively. After adjudication, AKI attributable to ICI was 58% and 65% of the overall incidence of AKI in each definition respectively. Increasing age was associated with decreased risk of AKI. Asian race was associated with a higher risk of AKI. Comorbidities were not associated with increased risk of AKI while use of proton pump inhibitors (PPI), ipilimumab or ICI combinations were significantly associated with AKI. AKI was not significantly associated with overall survival. Immune-related adverse events (irAEs) occurred in 30% of patients with AKI but their incidence was not different in patients with AKI attributable to ICI versus other AKI. Conclusions: In a large population of patients with melanoma treated with ICIs, an accurate documentation of AKI in setting of ICI use and predictors associated is presented. AKI following ICI use is infrequent, not associated with mortality, and associated with the use of ipilimumab, ICI combinations and PPIs.

Acute tubular interstitial nephritis (ATIN) is the most frequently reported pathology in patients with checkpoint inhibitor (CPI) induced acute kidney injury (AKI). Glucocorticoid (GC) therapy and discontinuation of CPI are the mainstay of treatment to prevent permanent renal dysfunction and dialysis. However, less than 50% of patients have complete kidney recovery and relapse of ATIN can occur. Infliximab is effective in treating other immune-related adverse events but its use for the treatment of CPI-ATIN is not well established. We report the first retrospective study examining the steroid-sparing potential of infliximab in achieving durable and complete renal recovery for patients with CPI-ATIN. Data were collected from medical records of patients diagnosed with CPI-AKI with a kidney biopsy or clinical diagnosis of ATIN that was managed with GC and infliximab. Infliximab-containing regimens were used to treat 10 patients with CPI-ATIN. Four patients relapsing after GC therapy achieved durable and complete renal recovery, four patients experienced partial renal recovery, and two patients showed no improvement in kidney function. This is the first study evaluating clinical outcomes using an infliximab-containing regimen for treatment of relapsed CPI-ATIN in patients or patients failing to achieve complete response after primary therapy. Our data suggest that infliximab may be a treatment option for achieving durable and complete renal recovery in this patient population and represents a potential steroid-sparing strategy in challenging cases of CPI-ATIN. Rigorous clinical studies are warranted to evaluate the risk-benefit analysis for infliximab usage in CPI-ATIN patients.

Certain diabetic and hypertensive patients started on intravitreal vascular endothelial growth factor inhibition for diabetic retinopathy may experience worsening of hypertension and proteinuria. The etiology of this is the newly recognized absorption of intravitreally injected vascular endothelial growth factor inhibitors, and the susceptibility of patients with pre-existing renal disease to exacerbations depends on the degree of systemic absorption. There are eighteen reported cases of worsening hypertension, woresening proteinuria, worsening renal function, thrombotic microangiopathy, and glomerular disease noted after initiation of intravitreal vascular endothelial growth factor blockade. This nineteenth case demonstrates worsening hypertension and proteinuria with the start of bevacizumab. Both blood pressure and proteinuria parameters showed overall improvement with switching to the less absorbed and lower potency agent ranibizumab. There was a slight rise in serum creatinine after bevacizumab therapy, which stabilized at a new baseline, and the serum creatinine remained stable on ranibizumab. There were no other nephrotoxic exposures that explained the mild rise in serum creatinine. Because of improvement in renal function and proteinuria, a renal biopsy was deferred for the time. This case re-demonstrates the risk of worsening proteinuria with vascular endothelial growth factor inhibitors when given intravitreally in some patients. The demonstration of improvement in blood pressure and proteinuria with the use of lower potency agents like ranibizumab is novel and an important concept confirming observations from pharmacokinetic studies. The switch to ranibizumab offers a therapeutic option when proteinuria worsens with intravitreal vascular endothelial growth factor blockade, and the patient requires ongoing intravitreal therapy for treatment of diabetic retinopathy.

Rationale & Objective Euvolemic hyponatremia often occurs due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Vasopressin 2 receptor antagonists may be used to treat SIADH. Several of the major trials used 15 mg of tolvaptan as the lowest effective dose in euvolemic and hypervolemic hyponatremia. However, a recent observational study suggested an elevated risk for serum sodium level overcorrection with 15 mg of tolvaptan in patients with SIADH. Study Design A retrospective chart review study comparing outcomes in patients with SIADH treated with 15 versus 7.5 mg of tolvaptan. Settings & Participants Patients with SIADH who were treated with a very low dose of tolvaptan (7.5 mg) at a single center compared with patients using a 15-mg dose from patient-level data from the observational study described previously. Predictors Tolvaptan dose of 7.5 versus 15 mg daily. Outcomes Appropriate response to tolvaptan, defined as an initial increase in serum sodium level > 3 mEq/L, and overcorrection of serum sodium level (>8 mEq/L per day, and >10 mEq/L per day in sensitivity analyses). Analytical Approach Descriptive study with additional outcomes compared using t tests and F-tests (Fischer's Exact χ2 Test). Results Among 18 patients receiving 7.5 mg of tolvaptan, the mean rate of correction was 5.6 ± 3.1 mEq/L per day and 2 (11.1%) patients corrected their serum sodium levels by >8 mEq/L per day, with 1 of these increasing by >12 mEq/L per day. Of those receiving tolvaptan 7.5 mg, 14 had efficacy, with increases ≥ 3 mEq/L; similar results were seen with the 15-mg dose (21 of 28). There was a statistically significant higher chance of overcorrection with the use of 15 versus 7.5 mg of tolvaptan (11 of 28 vs 2 of 18; P = 0.05; and 10 of 28 vs 1 of 18; P = 0.03, for >8 mEq/L per day and >10 mEq/L per day, respectively). Limitations Small sample size, retrospective, and nonrandomized. Conclusions Tolvaptan, 7.5 mg, daily corrects hyponatremia with similar efficacy and less risk for overcorrection in patients with SIADH versus 15 mg of tolvaptan., Graphical abstract

Dysnatremias are common electrolyte abnormalities noted in a cancer patient, with hyponatremia being the most common. Hyponatremia has been linked to poor prognosis and prolonged hospital stays, poor performance status, and increased mortality. Although hypernatremia has not been as extensively studied in the cancer population as hyponatremia, it also has been associated with increased incidences of morbidity, mortality and prolonged hospital stays. The use of normal saline as a resuscitative measure, in the majority of our cancer patients who are admitted, can lead to hospital acquired hypernatremia, as seen in many reports, with half of the intensive care unit patients with sepsis can develop hypernatremia. With the cancer patients having increased co-morbidities because of their underlying treatments and malignancy, dysnatremia would pose a challenge where there is a delay in their cancer care. We will discuss in this chapter the etiologies and management of dysnatremias and the uniqueness of the abnormality in the cancer population.

Circulating antineutrophil cytoplasmic antibodies (ANCAs) are the central pathogenic mechanism for a group of systemic and renal syndromes called the ANCA-associated vasculitis (AAV). The nomenclature has changed from eponymous labeling to granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, and microscopic polyangiitis. These syndromes predominantly affect the pulmonary and renal systems. We also review the molecular pathology behind ANCAs and associated antigens and infections. Various clinical presentations, the multiple target organs affected, and diagnostic challenges involved in identifying these diseases are discussed. Treatment updates are also provided with regard to new studies and the now standard use of anti-CD-20 monoclonal antibodies as first-line therapy in all but the most aggressive presentations of this disease. Maintenance regimens and monitoring strategies for relapse of vasculitis and associated systemic complications are discussed.

Rationale & Objectives Lower 25-hydroxyvitamin D concentrations have been associated with risk for kidney function decline, heart failure, and mortality. However, 25-hydroxyvitamin D requires conversion to its active metabolite, calcitriol, for most biological effects. The associations of calcitriol concentrations with clinical events have not been well explored. Study Design Case-cohort study. Setting & Participants Well-functioning community-living older adults aged 70 to 79 years at inception who participated in the Health, Aging, and Body Composition (Health ABC) Study. Predictor Serum calcitriol measured using positive ion electrospray ionization-tandem mass spectrometry. Outcomes Major kidney function decline (≥30% decline in estimated glomerular filtration rate from baseline), incident heart failure (HF), and all-cause mortality during 10 years of follow-up. Analytic Approach Baseline calcitriol concentrations were measured in a random subcohort of 479 participants and also in cases with major kidney function decline [n=397]) and incident HF (n=207) during 10 years of follow-up. Associations of serum calcitriol concentrations with these end points were evaluated using weighted Cox regression to account for the case-cohort design, while associations with mortality were assessed in the subcohort alone using unweighted Cox regression. Results During 8.6 years of mean follow-up, 212 (44%) subcohort participants died. In fully adjusted models, each 1–standard deviation lower calcitriol concentration was associated with 30% higher risk for major kidney function decline (95% CI, 1.03-1.65; P=0.03). Calcitriol was not significantly associated with incident HF (HR, 1.16; 95% CI, 0.94-1.47) or mortality (HR, 1.01; 95% CI, 0.81-1.26). We observed no significant interactions between calcitriol concentrations and chronic kidney disease status, baseline intact parathyroid or fibroblast factor 23 concentrations. Limitations Observational study design, calcitriol measurements at a single time point, selective study population of older adults only of white or black race. Conclusions Lower calcitriol concentrations are independently associated with kidney function decline in community-living older adults. Future studies will be needed to clarify whether these associations reflect lower calcitriol concentrations resulting from abnormal kidney tubule dysfunction or direct mechanisms relating lower calcitriol concentrations to more rapid loss of kidney function.

Pembrolizumab is an immune checkpoint inhibitor that targets the programmed cell death protein 1 (PD-1) antigen and induces an immune response against tumor tissues. It has been successful in inducing remission in patients with severe metastatic disease, often refractory to other chemotherapeutic agents. The risk of injury of other organ systems has been noted with reported cases of glomerular disease and endocrine disease. In addition, hypophysitis as well as dermatological and gastroenterological side effects have been reported. Renal injury with immune checkpoint inhibitors like nivolumab and pembrolizumab is usually mediated via interstitial nephritis, though glomerular disease presentations like anti-neutrophil cytoplasmic antibody-associated vasculitis, immune complex disease, and thrombotic microangiopathy have also been reported. We report a 70-year-old Caucasian male who underwent treatment with pembrolizumab for adenocarcinoma of the lung. He developed acute adrenal insufficiency and concomitant severe hypotension upon presentation. He did not require renal replacement therapy, rather his severe acute kidney injury resolved with hydration, normalization of blood pressures with vasopressors, and treatment with high-dose corticosteroids. His urinary indices (fractional excretion of urea, FEUrea) and clinical course were highly suspicious for acute tubular necrosis that resolved quickly after treating his underlying adrenalitis. The urinary sediment, proteinuria, and clinical course were not typical for the usually expected renal lesion of interstitial nephritis in patients treated with immune checkpoint inhibitors.

Hepatitis C (HCV) infection has a prevalence of 3 million infected individuals in the United States, according to recent Center for Disease Control reports, and can have various renal manifestations. Cryoglobulins, antibodies that precipitate at colder temperatures in vitro, are a relatively common cause of renal disease in HCV infection. The cryoglobulin proteins can form occlusive aggregates in small glomerular capillary lumina or deposit in other areas of the glomerulus, resulting in hypocomplementemia, proteinuria, hematuria, and renal injury. The typical biopsy pattern is that of membranoproliferative glomerulonephritis (MPGN). There are, however, other HCV-related patterns of glomerular injury. Anti-neutrophil cytoplasmic antibodies (ANCA) are known to exist in HCV-infected patients. In many reported cases, ANCA serologic testing may appear positive due to cross-reactivity of the immune assays; however, the biopsy findings do not support ANCA-associated crescentic glomerulonephritis (GN)/vasculitis as the primary cause of glomerular injury. There are rare reports of microscopic polyangiitis (MPA) p-ANCA vasculitis, in patients with HCV infection. In comparison with the MPGN pattern of cryoglobulinemic glomerular injury, biopsies from these HCV-infected patients with concomitant MPA revealed a crescentic GN, associated with normal serum complement levels. We present a case of HCV-associated glomerular disease with the surprising biopsy finding of necrotizing and crescentic p-ANCA GN, with a background, low-grade mesangial immune complex GN. Thus, p-ANCA disease should also be considered in HCV-infected patients, in addition to the more typical lesions of MPGN or cryoglobulinemic GN.

Primary myelofibrosis (PMF) is a disease of the elderly, with a median age at diagnosis of 71 years. As a consequence, many patients present with comorbid health conditions, including diabetes and ...

An exciting era in the diagnosis and treatment of cancer has emerged in the last 2 decades. What was once an often deadly disease has, for many patients, become a chronic disease with longer surviv...

Severe heart failure is increasingly being managed by cardiac transplantation, and in some cases mechanical support devices serve as destination therapies. Left ventricular assist devices (LVADs) were approved for destination therapy for end stage heart failure patients before the more advanced total artificial heart modality became available. One common complication of mechanical assist device placement is acute kidney injury. Historically, patients with mechanical support devices have had to have inpatient hemodialysis until combined heart kidney transplant. Though, some units have started accepting LVAD patients in outpatient dialysis clinics. The cost of in center hemodialysis remains high and home dialysis modalities are becoming increasingly popular. We report the first patient with an LVAD to undergo training and successful home hemodialysis while awaiting combined heart kidney transplantation.

Ruxolitinib is a targeted agent that inhibits Janus 2 Kinase and is approved for use in Polycythemia Vera and Primary Myelofibrosis. Its mechanism of action involves inhibition of cellular proliferation via the Janus kinase/signal transducer and activator of transcription proteins pathway. Ruxolitinib has different immune modulating effects that result in functional immunosuppression, leading to an increased susceptibility to certain infections. Klebsiella pneumoniae infections, in particular, were common among the reported pathogens contracted by ruxolitinib users. We report a 75-year-old male patient who had recurrent K. pneumoniae urinary tract infections while on ruxolitinib for Polycythemia Vera. This case is reported to add to the literature describing an increased susceptibility of patients to this often-resistant bacteria and to raise awareness about the immune modulating effects of JAK inhibitors.

Membranous glomerulonephritis is the most common glomerular disease in adults. Its primary form has been characterized with formation of phospholipase A2 receptor antibodies. Malignancy, infections, and autoimmune disorders are the most common causes of secondary membranous glomerulonephritis. We present a case of a 55-year-old African American female who presented with nephrotic range proteinuria and diagnosed with secondary membranous glomerulonephritis based on distinct pathological features on kidney biopsy and absence of serum phospholipase A2 receptor antibodies. She initially underwent extensive workup for malignancies, infections, and common autoimmune disorders which were all negative. Her proteinuria remained resistant to steroid treatment and she was treated with subcutaneous adrenocorticotropic hormone injections. Meanwhile, she was also diagnosed with the anti-muscle specific kinase antibody variant of myasthenia gravis. In literature, there are few case reports of myasthenia gravis as a cause of secondary membranous glomerulonephritis. In our case, the lack of other inciting factors also suggested this association.

Chemotherapeutic agents have toxicities that extend beyond their therapeutic effect on malignant cells, and the kidneys are involved in the metabolism of these agents. Kidney toxicity delay the elimination of anticancer drugs from the body and increase the risk of systemic toxicity. Conventional chemotherapeutics generally cause direct renal tubular injury and electrolyte wasting syndromes. Newer cancer treatments include targeted therapy and immunotherapy. Targeted therapy, especially the drugs that target vascular endothelial growth factor, disrupt the crosstalk between podocytes and endothelial cells of the glomerulus resulting in a spectrum of glomerular diseases. On the other hand, immune checkpoint inhibitors release the break on the immune system and can cause immune-mediated tubulointerstitial nephritis and glomerulonephritis similar to autoimmune diseases. This chapter summarizes nephrotoxicity profiles of some of the common conventional chemotherapeutics as well as newer anticancer agents.

Vascular endothelial growth factor (VEGF) inhibitors have emerged as powerful tools to treat malignant neoplasms and ocular diseases by virtue of their ability to inhibit angiogenesis. Recent data indicate that intravitreal injections of VEGF inhibitors can lead to significant systemic absorption as well as a measurable reduction of plasma VEGF activity. There is increasing evidence showing that vitreal absorption of these drugs is associated with cases of accelerated hypertension, worsening proteinuria, glomerular disease, thrombotic microangiopathy, and possible chronic renal function decline. In this review, the 3 most commonly used anti-VEGF agents—bevacizumab, ranibizumab, and aflibercept—are discussed, highlighting their intravitreal absorption and associated effects on the kidney as a target organ system. We provide clinical suggestions for clinicians to both better manage patients receiving anti-VEGF agents intravitreally and detect any putative systemic renal effects of these agents. While acknowledging the risks of aberrant retinal angiogenesis, it is important for clinicians to be aware of the potential for adverse renal risks with use of these agents.

KDIGO guidelines recommend dietary phosphate restriction to lower serum phosphate levels in CKD stage 3-5. Recent studies suggest that dietary phosphate intake is only weakly linked to its serum concentration, and the relationship of phosphate intake with adverse outcomes is uncertain. To further evaluate this, we used Cox proportional hazards models to assess associations of baseline 24 hour urine phosphate excretion with risk of end stage renal disease (ESRD), all-cause mortality, and mortality subtypes (cardiovascular disease (CVD) and non-CVD) using the Modification of Diet in Renal Disease data. Models were adjusted for demographics, CVD risk factors, iothalamate GFR, and urine protein and nitrogen excretion. Phosphate excretion was modestly inversely correlated with serum phosphate concentrations. There was no association of 24 hour urinary phosphate excretion with risk of ESRD, CVD-, non-CVD- or all-cause mortality. For comparison, higher serum phosphate concentrations were associated with all-cause mortality (hazard ratio per 0.7 mg/dL higher, 1.15 [95% CI 1.01, 1.30]). Thus, phosphate intake is not tightly linked with serum phosphate concentrations in CKD stage 3-5, and there was no evidence that greater phosphate intake, assessed by 24 hour phosphate excretion, is associated with ESRD, CVD-, non CVD-, or all-cause mortality in CKD stage 3-5. Hence, factors other than dietary intake may be key determinants of serum phosphate concentrations and require additional investigation.

The percentage of patients with cancer eligible for checkpoint inhibitor (CPI) therapy has increased rapidly over the past few years and approaches 45%. As a result, more cases of CPI-related nephrotoxicity, including a rare subset with vasculitis, are being reported. To elucidate the clinical presentation of CPI-associated renal vasculitis and its possible mechanisms, treatment options and prognosis, we describe cases from a comprehensive cancer center and reviewed the literature for similar cases. We retrospectively reviewed the charts of all patients with cancer from 2014 to 2020 who were diagnosed with CPI-related nephrotoxicity and underwent a kidney biopsy. We identified five cases of renal vasculitis: three patients were diagnosed with seronegative antineutrophil cytoplasm antibody (ANCA)-associated vasculitis, one case with seropositive ANCA-associated vasculitis and one case was diagnosed with IgA vasculitis. Of these cases, four patients were receiving nivolumab, and one patient was receiving tremelimumab. All patients had microscopic hematuria, four out of five patients had negative ANCA serology, one patient had concurrent lung involvement and positive ANCA serology, and all had severe acute kidney injury with creatinine >4.50 mg/dL on diagnosis. All patients were treated by discontinuing CPI and initiating corticosteroids and rituximab. Three patients received plasmapheresis; two of these required renal replacement therapy including the patient with lung involvement. All patients after rituximab had a partial or complete renal response. Two patients died within 8 months of diagnosis due to malignancy progression. None of the patients had a relapse of vasculitis. We demonstrated that CPI can be associated with different types of renal vasculitis that are predominantly ANCA negative and manifest as severe acute kidney injury. Despite the lack of strong evidence, treatment similar to treatment of primary seropositive ANCA-associated vasculitis with corticosteroids and rituximab is well tolerated with favorable renal outcomes.

e15145 Background: As the percentage of cancer patients eligible for checkpoint inhibitor therapy (CPI) is increasing rapidly over the past couple years and approaching 45%, more cases of CPI related nephrotoxicity, including a rare subset with vasculitis, are reported. To learn more about the clinical presentation of CPI associated renal vasculitis, its mechanism, treatment options, and prognosis, we describe cases from our institution and reviewed the literature for related cases. Methods: We retrospectively reviewed the charts of all cancer patients from 2014 to 2020 who were diagnosed with CPI related nephrotoxicity and underwent a kidney biopsy. Results: We identified 6 cases of renal vasculitis reach with different malignancy, 4 had pauci-immune GN and one of which had IgA vasculitis. 4 of the patients were on nivolumab and 4 of the patients had negative ANCA serology. All patients had microscopic hematuria and severe acute kidney injury (AKI) with Creatinine > 4.5 mg/dl upon diagnosis and 2 patients requiring renal replacement therapy (RRT). One patient had concurrent lung involvement. All patients were treated by discontinuing CPI and initiating corticosteroids and rituximab. 3 patients received plasmapheresis who required RRT or had lung involvement. 2 patients died within 8 months of diagnosis due to malignancy progression and none of the cases had a relapse of vasculitis. Conclusions: We demonstrated that CPI can be associated with different types of renal vasculitis that is predominantly ANCA negative and manifest as severe kidney. Despite the lack of strong evidence, treatment as primary ANCA vasculitis with corticosteroids and rituximab is well tolerated with favorable renal outcome.

Drug-induced lupus erythematosus has features distinct from primary systemic lupus erythematosus. It can occur with a wide variety of agents that result in the generation of anti-histone or other types of antibodies. Systemic manifestations of drug-induced systemic lupus erythematosus may include renal dysfunction due to circulating immune complexes or due to other immune reactions to the culprit medication(s). Acute interstitial nephritis occurs due to DNA–drug or protein–drug complexes that trigger an allergic immune response. We report a patient who developed acute kidney injury, rash, and drug-induced systemic lupus diagnosed by serologies after starting chlorthalidone and amiodarone. A renal biopsy showed acute interstitial nephritis and not lupus-induced glomerulonephritis. It is important to note that systemic lupus erythematosus and acute interstitial nephritis can occur together, and this report highlights the role of the kidney biopsy in ascertaining the pathological diagnosis and outlining therapy in drug-induced lupus erythematosus.

Vascular endothelial growth factor (VEGF) receptor inhibition is a commonly used tool to prevent vascular proliferation in tumors and retinal diseases. The antiangiogenic effects of these drugs have made them potent adjunct therapies when given systemically for malignancies. They are also useful tools to ameliorate diminishing eyesight in retinopathy. Hypertension and proteinuria have been observed in systemic VEGF inhibitor therapy, with rarer presentations involving nephrotic-range proteinuria due to glomerulopathies. Pharmacokinetic studies have shown detectable blood levels of anti-VEGF inhibitors up to 30 days postintravitreal injection. Animal studies have also demonstrated binding of VEGF inhibitors in simian glomeruli 1 week after a single intravitreal injection. We report three patients who received intravitreal bevacizumab and/or aflibercept with worsening hypertension, proteinuria and renal injury. Data regarding emerging evidence of VEGF inhibitor nephrotoxicity after intravitreal injections are also presented. The clinical data and the existing literature are reviewed to support the hypothesis that intravitreal anti-VEGF agents may be unrecognized nephrotoxins. These agents are given to vulnerable patients with diabetes, hypertension and preexisting nephropathy and proteinuria. This case series is reported to spur further study of the systemic effects of intravitreal VEGF inhibitors.

Monoclonal gammopathy is a premalignant condition associated with an abnormal circulating immunoglobulin indicative of an expanded B cell clone. Apart from monitoring, no other intensive management is prescribed in these cases. Periodic bone marrow biopsies when free light chain imbalances are detected are used to spot incidental cases of multiple myeloma. New reports have suggested the existence of a monoclonal gammopathy of renal significance where a circulating antibody and normal bone marrow biopsy results may be associated with proteinuric renal disease due to monoclonal immunoglobulin deposition. We report a case of a 65-year-old male with an immunoglobulin G kappa monoclonal gammopathy of undetermined significance, chronic kidney disease, proteinuria, and an initial inconclusive renal biopsy. His chronic kidney disease worsened with persistence of 0.5 g of proteinuria. Given the finding of ongoing Bence Jones proteinuria, a repeat renal biopsy was done revealing monoclonal immunoglobulin G kappa deposition disease. Bone marrow biopsy showed 20% plasma cells that could be consistent with smoldering myeloma. The patient’s renal disease has stabilized after starting treatment for the monoclonal gammopathy of renal significance. This case illustrates the importance of renal biopsy in making the diagnosis of monoclonal immune deposition disease and monoclonal gammopathy of renal significance.

Introduction. Renal dysfunction is commonly observed in patients with primary myelofibrosis (PMF), but its etiology remains largely unknown. Recent evidence suggests that in many cases it may be a direct consequence of PMF, rather than simply reflecting individual aging. Glomerulopathy, in fact, can be observed in PMF, presenting with mesangial proliferation and hypercellularity, likely as a consequence of abnormal cytokine expression, and case reports show that the use of ruxolitinib may improve its outcome. Methods. We performed a retrospective analysis of 100 patients with previously untreated PMF, receiving frontline treatment with single agent ruxolitinib at our institution between 07/2004 and 11/2013. Creatinine clearance (CrCl) values were calculated by Cockcroft-Gault equation at baseline and serially during treatment. Renal improvement was defined as best percentage change in CrCl during treatment as compared to baseline value. A group of 105 patients with PMF, receiving frontline treatment with a non-ruxolitinib-based therapy on protocol during the same time range, and matched by age, sex and CrCl, was used as control. Results. Baseline characteristics of 100 patients with previously untreated PMF receiving frontline ruxolitinib are shown in the Table. Eighty-one (81%) patients in the ruxolitinib group had an increase in CrCl while on treatment (as compared to baseline) vs 61 (58%) in the control group (p The association between baseline patient characteristics and achievement of a RI ≥ 10% was evaluated among all patients. On univariate analysis (UVA), factors associated with a RI ≥ 10% were non-Caucasian race (99% vs 88%, p=0.006), elevated baseline serum creatinine (1 mg/dL vs 0.9 mg/dL, p=0.05), low baseline CrCl (66 ml/min vs 78 mL/min, p After a median follow-up of 41 months (range, 1-159 months), all patients failed frontline treatment, and median failure-free survival (FFS) was 14 months (range, 1-117 months). Factors associated with prolonged FFS on UVA were intermediate-1 DIPSS plus score as compared to intermediate-2 and high score (53 months vs 24 months and 6 months, p Discussion This is the first study showing that the use of ruxolitinib is associated with improved renal function in patients with PMF. Similarly to what is done in other hematological malignancies, routine kidney biopsies in patients with PMF and unexplained renal dysfunction may shed light on its etiology and help assess the efficacy on ruxolitinib for the treatment of PMF-related glomerulopathy. Figure. Figure. Disclosures Verstovsek: Incyte: Consultancy; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

e15083Background: Immune checkpoint (ICP) inhibitors, anti-CTLA-4 (Ipilimumab) and anti-PD-1 (Nivolumab and Pembrolizumab) have revolutionized treatment options for many types of cancers. Adverse e...