Paraneoplastic Glomerular Diseases.

Paraneoplastic glomerular disease (PGD) develops from tumor cell products, leading to renal dysfunction. Unlike direct tumor effects, PGD illustrates the complex association between cancer and diverse clinical presentations and outcomes. Initially detected in a Hodgkin's disease patient, current research has defined diagnostic criteria based on PGD symptoms and cancer progression. PGDs, although rare (found in <1% of adult cancer patients with overt renal manifestations), are crucial, as they can signal cancer onset and frequently resist standard glomerulonephritis treatments. The emerging field of onconephrology studies this relationship between kidney disorders and cancers. The exact cause of many PGD cases remains unknown. This review examines PGDs, their clinicopathological features, related cancers, and mechanisms, emphasizing the need for early diagnosis and tailored treatment for kidney disease and linked cancer.

Assessment of GFR in Patients with Cancer: A Statement from the American Society of Onco-Nephrology.

Accurate assessment of GFR is crucial to guiding drug eligibility, dosing of systemic therapy, and minimizing the risks of both undertreatment and toxicity in patients with cancer. Up to 32% of patients with cancer have baseline CKD, and both malignancy and treatment may cause kidney injury and subsequent CKD. To date, there has been lack of guidance to standardize approaches to GFR estimation in the cancer population. In this two-part statement from the American Society of Onco-Nephrology, we present key messages for estimation of GFR in patients with cancer, including the choice of GFR estimating equation, use of race and body surface area adjustment, and anticancer drug dose-adjustment in the setting of CKD. These key messages are based on a systematic review of studies assessing GFR estimating equations using serum creatinine and cystatin C in patients with cancer, against a measured GFR comparator. The preponderance of current data involving validated GFR estimating equations involves the CKD Epidemiology Collaboration (CKD-EPI) equations, with 2508 patients in whom CKD-EPI using serum creatinine and cystatin C was assessed (eight studies) and 15,349 in whom CKD-EPI with serum creatinine was assessed (22 studies). The former may have improved performance metrics and be less susceptible to shortfalls of eGFR using serum creatinine alone. Since included studies were moderate quality or lower, the American Society of Onco-Nephrology Position Committee rated the certainty of evidence as low. Additional studies are needed to assess the accuracy of other validated eGFR equations in patients with cancer. Given the importance of accurate and timely eGFR assessment, we advocate for the use of validated GFR estimating equations incorporating both serum creatinine and cystatin C in patients with cancer. Measurement of GFR via exogenous filtration markers should be considered in patients with cancer for whom eGFR results in borderline eligibility for therapies or clinical trials.

Onconephrology 2022: An Update.

Onconephrology is an upcoming and expanding subspecialty that deals with the intersections between hematology/oncology and nephrology. With the paradigm shift in the understanding of cancer immunobiology and mechanisms of oncotherapeutic drug toxicities, it is important for a nephrologist to have a sound understanding of this field. Over the last 5 years, there have been immense developments in our understanding of kidney-related adverse events from various targeted, immuno- and cellular-based therapies. Pathogenic mechanisms of electrolyte imbalance, hypertension (oncohypertension), and AKI from multiple forms of cancer therapies have been explored. Significant research has also been conducted in the field of transplant onconephrology. In this review, we have tried to assimilate the most recent updates in the last 2 years in this ever-growing and fascinating field.

Shorter versus longer corticosteroid duration and recurrent immune checkpoint inhibitor-associated AKI.

BACKGROUND: Corticosteroids are the mainstay of treatment for immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI), but the optimal duration of therapy has not been established. Prolonged use of corticosteroids can cause numerous adverse effects and may decrease progression-free survival among patients treated with ICPis. We sought to determine whether a shorter duration of corticosteroids was equally efficacious and safe as compared with a longer duration. METHODS: We used data from an international multicenter cohort study of patients diagnosed with ICPi-AKI from 29 centers across nine countries. We examined whether a shorter duration of corticosteroids (28 days or less) was associated with a higher rate of recurrent ICPi-AKI or death within 30 days following completion of corticosteroid treatment as compared with a longer duration (29-84 days). RESULTS: Of 165 patients treated with corticosteroids, 56 (34%) received a shorter duration of treatment and 109 (66%) received a longer duration. Patients in the shorter versus longer duration groups were similar with respect to baseline and ICPi-AKI characteristics. Five of 56 patients (8.9%) in the shorter duration group and 12 of 109 (11%) in the longer duration group developed recurrent ICPi-AKI or died (p=0.90). Nadir serum creatinine in the first 14, 28, and 90 days following completion of corticosteroid treatment was similar between groups (p=0.40, p=0.56, and p=0.89, respectively). CONCLUSION: A shorter duration of corticosteroids (28 days or less) may be safe for patients with ICPi-AKI. However, the findings may be susceptible to unmeasured confounding and further research from randomized clinical trials is needed.

Kidney Disease Following Hematopoietic Stem Cell Transplantation.

Hematopoietic stem cell transplantation (SCT) provides a curative option for the treatment of several malignancies. Its growing use is associated with an increased burden of kidney disease. Acute kidney injury is usually seen within the first 100 days of transplantation and has an incidence ranging between 12 and 73%, with the highest rate in myeloablative allogeneic SCT. A large subset of patients after SCT develop chronic kidney disease. They can be broadly classified into thrombotic microangiopathy, nephrotic syndrome, and calcineurin toxicity. Dialysis requirement after SCT is associated with mortality exceeding 80%. Given the higher morbidity and mortality related to development kidney disease, nephrologists need to be aware of the various causes and best treatment options.

Kidney transplantation in patients with multiple myeloma: narrative analysis and review of the last two decades.

There have been significant advances in the treatment of multiple myeloma in the last two decades. Approximately 25% of patients with newly diagnosed myeloma have some degree of kidney impairment. During the course of illness, nearly 50% of myeloma patients will develop kidney disease. Moreover, ∼10% of myeloma patients have advanced kidney disease requiring dialysis at presentation. Hemodialysis is associated with a significantly reduced overall survival (OS). In the setting of prolonged long-term OS due to the use of newer immunotherapeutic agents in the treatment of myeloma, patients with myeloma and advanced kidney disease may benefit from more aggressive management with kidney transplantation (KTx). Unfortunately, most data regarding outcomes of KTx in patients with myeloma come from single-center case series. With the advent of novel treatment choices, it remains unclear if outcomes of kidney transplant recipients with myeloma have improved in recent years. In this descriptive systematic review, we coalesced published patient data over the last 20 years to help inform clinicians and patients on expected hematologic and KTx outcomes in this complex population. We further discuss the future of KTx in patients with paraproteinemia.

Immune checkpoint inhibitor-associated hypercalcaemia.

Immune checkpoint inhibitors (CPIs) have recently become a cornerstone for the treatment of different advanced cancers. These drugs have the ability to reactivate the immune system against tumour cells but can also trigger a myriad of side effects, termed immune-related adverse events (irAEs). Although there are numerous reports of CPI-related endocrinopathies, hypercalcaemia as a suspected irAE is not well documented. The mechanisms of CPI hypercalcaemia are not clearly established. However, in our review, four distinct causes emerged: endocrine disease-related, sarcoid-like granuloma, humoral hypercalcaemia due to parathyroid-related hormone and hyperprogressive disease following CPI initiation. Prompt recognition of hypercalcaemia and the institution of therapy can be lifesaving, affording the opportunity to address the underlying aetiology. In this review we discuss the incidence, diagnosis and management of immune-related hypercalcaemia in oncological patients receiving CPI agents.

Acute kidney injury in patients treated with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer. METHODS: We 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. RESULTS: ICPi-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. CONCLUSIONS: Patients 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.

Immune checkpoint inhibitor use in patients with end-stage kidney disease: an analysis of reported cases and literature review.

Immune checkpoint inhibitors (ICIs), immunomodulatory antibodies that are used to enhance the immune system, have substantially improved the prognosis of patients with advanced malignancy. As the use of ICI therapy becomes increasingly widespread across different types of cancer, their use in patients receiving dialysis is likely to increase. In this review we summarize the current literature on the use of ICIs in end-stage kidney disease (ESKD) patients and provide aggregate data from reported cases and series. Based on available pharmacological information, ICIs require no dosing adjustment in ESKD patients. Analysis of the reported cases in the literature demonstrates a similar incidence of immune-related adverse events in patients with ESKD receiving dialysis as compared with the general population (49%). Severe reactions graded as 3 and 4 have been seen in 15 patients (16%). As such, it is important that these patients are monitored very closely for immune-related adverse events; however, the risk of these adverse events should not preclude patients on dialysis from receiving these therapies. Cancer remission (complete and partial) was seen in close to 30% of patients, stable disease was seen in 28% and progression of disease in ∼36%. One-third of the patients died. Urothelial and renal cell cancer represented approximately half of all treated cancers and accounted for ∼50% of all deaths reported. Additional data in the dialysis population with the use of ICIs and involvement in prospective studies are needed to better assess outcomes, particularly within specific cancer types.

A Systematic Review of Immune Checkpoint Inhibitor-Associated Glomerular Disease.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) are increasingly used to treat cancers. Kidney immune-related adverse events (IRAEs) are now well recognized, with the incidence of IRAEs ranging from 2% to 5%. Most of the initial data related to kidney IRAEs have focused on acute interstitial nephritis (AIN). There are minimal data on the types and relative frequencies of glomerular diseases associated with ICIs, their treatment, and outcomes. METHODS: We performed a systematic review and meta-analysis of all biopsy-proven published cases/series of glomerular pathology associated with ICIs. We searched the MEDLINE, EMBASE, and Cochrane databases from inception to February 2020. We abstracted patient-level data, including demographics, cancer and ICI therapy details, and characteristics of kidney injury. RESULTS: After screening, 27 articles with 45 cases of biopsy-confirmed ICI-associated glomerular disease were identified. Several lesion types were observed, with the most frequent being pauci-immune glomerulonephritis (GN) and renal vasculitis (27%), podocytopathies (24%), and complement 3 GN (C3GN; 11%). Concomitant AIN was reported in 41%. Most patients had ICIs discontinued (88%), and nearly all received corticosteroid treatment (98%). Renal replacement therapy (RRT) was required in 25%. Most patients had full (31%) or partial (42%) recovery from acute kidney injury (AKI), although 19% remained dialysis-dependent, and approximately one-third died. Complete or partial remission of proteinuria was achieved in 45% and 38%, respectively. CONCLUSION: Multiple forms of ICI-associated glomerular disease have been described. Pauci-immune GN, podocytopathies, and C3GN are the most frequently reported lesions. ICI-associated glomerular disease may be associated with poor kidney and mortality outcomes. Oncologists and nephrologists must be aware of glomerular pathologies associated with ICIs and consider obtaining a kidney biopsy specimen when features atypical for AIN are present.

Chronic Kidney Disease in Cancer Survivors.

As breakthroughs in cancer care are leading to improved long-term outcomes in a subset of advanced cancers, there is a growing population of long-term cancer survivors that are at risk of long-term complications. In this review, we summarize what is known about chronic kidney disease in cancer survivors, focusing on the following high-risk groups: survivors of childhood cancers, stem cell transplant recipients, patients with renal cell carcinoma, patients exposed to cisplatin and other nephrotoxic chemotherapies, and patients receiving immunotherapy for cancer. As new anticancer therapies are developed, more research is needed to understand the long-term risks of kidney function decline and to devise methods to prevent chronic kidney disease.

Lorlatinib induced proteinuria: A case report.

INTRODUCTION: Lorlatinib is an oral anaplastic lymphoma kinase (ALK) and C-ros oncogene (ROS1) tyrosine kinase inhibitor with excellent central nervous system (CNS) penetrability. It is currently approved for use as second line therapy for those with ALK positive non-small cell lung cancer (NSCLC). Given its CNS penetrating effects, lorlatinib has shown to cause CNS adverse events such as seizures, hallucinations, and changes in cognitive function. To our knowledge proteinuria has not been previously described with this medication. CASE REPORT: We report a case lorlatinib induced proteinuria in a patient receiving lorlatinib as second line treatment for ROS1 rearranged NSCLC.Management & Outcome: The patient's dose was reduced from 100 mg to 75 mg and further down to to 50 mg daily. At that point the proteinuria improved. Other adverse events attributable to the medication, specifically hallucinations and peripheral neuropathy also improved. DISCUSSION: Our case demonstrates objective evidence for proteinuria induced by lorlatinib, which may also be dose dependent.

A multi-center study on safety and efficacy of immune checkpoint inhibitors in cancer patients with kidney transplant.

Immune checkpoint inhibitors (ICIs) are widely used for various malignancies. However, their safety and efficacy in patients with a kidney transplant have not been defined. To delineate this, we conducted a multicenter retrospective study of 69 patients with a kidney transplant receiving ICIs between January 2010 and May 2020. For safety, we assessed the incidence, timing, and risk factors of acute graft rejection. For efficacy, objective response rate and overall survival were assessed in cutaneous squamous cell carcinoma and melanoma, the most common cancers in our cohort, and compared with stage-matched 23 patients with squamous cell carcinoma and 14 with melanoma with a kidney transplant not receiving ICIs. Following ICI treatment, 29 out of 69 (42%) patients developed acute rejection, 19 of whom lost their allograft, compared with an acute rejection rate of 5.4% in the non-ICI cohort. Median time from ICI initiation to rejection was 24 days. Factors associated with a lower risk of rejection were mTOR inhibitor use (odds ratio 0.26; 95% confidence interval, 0.09-0.72) and triple-agent immunosuppression (0.67, 0.48-0.92). The objective response ratio was 36.4% and 40% in the squamous cell carcinoma and melanoma subgroups, respectively. In the squamous cell carcinoma subgroup, overall survival was significantly longer in patients treated with ICIs (median overall survival 19.8 months vs. 10.6 months), whereas in the melanoma subgroup, overall survival did not differ between groups. Thus, ICIs were associated with a high risk of rejection in patients with kidney transplants but may lead to improved cancer outcomes. Prospective studies are needed to determine optimal immunosuppression strategies to improve patient outcomes.

COVID-19-Associated Kidney Injury: A Case Series of Kidney Biopsy Findings.

BACKGROUND: Reports show that AKI is a common complication of severe coronavirus disease 2019 (COVID-19) in hospitalized patients. Studies have also observed proteinuria and microscopic hematuria in such patients. Although a recent autopsy series of patients who died with severe COVID-19 in China found acute tubular necrosis in the kidney, a few patient reports have also described collapsing glomerulopathy in COVID-19. METHODS: We evaluated biopsied kidney samples from ten patients at our institution who had COVID-19 and clinical features of AKI, including proteinuria with or without hematuria. We documented clinical features, pathologic findings, and outcomes. RESULTS: Our analysis included ten patients who underwent kidney biopsy (mean age: 65 years); five patients were black, three were Hispanic, and two were white. All patients had proteinuria. Eight patients had severe AKI, necessitating RRT. All biopsy samples showed varying degrees of acute tubular necrosis, and one patient had associated widespread myoglobin casts. In addition, two patients had findings of thrombotic microangiopathy, one had pauci-immune crescentic GN, and another had global as well as segmental glomerulosclerosis with features of healed collapsing glomerulopathy. Interestingly, although the patients had confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by RT-PCR, immunohistochemical staining of kidney biopsy samples for SARS-CoV-2 was negative in all ten patients. Also, ultrastructural examination by electron microscopy showed no evidence of viral particles in the biopsy samples. CONCLUSIONS: The most common finding in our kidney biopsy samples from ten hospitalized patients with AKI and COVID-19 was acute tubular necrosis. There was no evidence of SARS-CoV-2 in the biopsied kidney tissue.

Kidney oxalate crystal deposition in adult patients: A relatively common finding
.

AIMS: We aim to describe the clinical and histological findings in patients with the finding of any tubular oxalate deposits in kidney biopsy specimens. BACKGROUND: The prevalence, manifestation, and outcome of secondary oxalate nephropathy have not been extensively studied. MATERIALS AND METHODS: In this retrospective cohort study, we analyzed the clinical and histological findings in all patients with the finding of any tubular oxalate deposits in kidney biopsy specimens between July 1, 2017, and December 31, 2018, at Northwell Health Pathology Department (Manhasset, NY, USA). RESULTS: The prevalence of oxalate deposition on a kidney biopsy was 4.07% (25/615), and in 88% of cases was a major finding. Prior to biopsy, oxalate was anticipated in only 1 case. The etiology of oxalosis was clarified retrospectively in 14 cases, most commonly due to GI surgery (n = 10) and increased oxalate intake (n = 4). In 11 cases, etiology remained unknown, although at least 3 cases were exposed to antibiotics associated with secondary oxalosis. There was no significant clinical/pathological or survival difference between known vs. unknown cause groups. The overall 3-month renal survival rate was 76.0 ± 8.5%. Multivariate Cox regression showed that creatinine at the time of biopsy (HR: 1.79, 95% CI: 0.71 - 4.51), background histological chronicity change (HR: 1.82, 95% CI: 0.70 - 4.72) and oxalate density (HR: 2.27, 95% CI: 0.49 - 10.55) are associated with end-stage kidney disease. CONCLUSION: Oxalate deposition is common but rarely anticipated biopsy finding. Nephrologists need to consider surgical history and other secondary causes of oxalosis as causes of acute kidney injury and chronic kidney disease.