Associations of dietary patterns with kidney cancer risk, kidney cancer-specific mortality and all-cause mortality among postmenopausal women.

BACKGROUND: The empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP) are novel measures of dietary quality associated with insulin hypersecretion or chronic inflammation, respectively, whereas the Healthy Eating Index (HEI-2015) measures adherence to the Dietary Guidelines for Americans (DGA). We evaluated associations of EDIH, EDIP and HEI-2015 on the risk of both kidney cancer development and mortality. METHODS: We calculated the dietary scores from baseline food frequency questionnaires among 115,830 participants aged 50-79 years in the Women's Health Initiative. Multivariable-adjusted Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (95%CI) for kidney cancer risk, kidney cancer-specific mortality and all-cause mortality, per 1-standard deviation increment in dietary pattern scores. RESULTS: Higher EDIH was associated with greater risk of kidney cancer development [HR, 1.12; 95%CI, (1.01,1.23)], kidney cancer-specific death [1.22(0.99,1.48)], and all-cause mortality, [1.05(1.02,1.08)]. Higher HEI-2015 was associated with lower risk of kidney cancer development, [0.85(0.77, 0.94)], kidney cancer-specific death, [0.84(0.69,1.03)] and all-cause mortality, [0.97(0.95,1.00)]. However, EDIP was not significantly associated with outcomes. Associations did not differ by BMI categories. CONCLUSIONS: Low-insulinemic dietary patterns and higher quality diets, are worthy of testing in dietary pattern intervention trials for kidney cancer prevention and improved survivorship.

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.

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.

Kidney toxicity of the BRAF-kinase inhibitor vemurafenib is driven by off-target ferrochelatase inhibition.

A multitude of disease and therapy related factors drive the frequent development of kidney disorders in cancer patients. Along with chemotherapy, the newer targeted therapeutics can also cause kidney dysfunction through on and off-target mechanisms. Interestingly, among the small molecule inhibitors approved for the treatment of cancers that harbor BRAF-kinase activating mutations, vemurafenib can trigger tubular damage and acute kidney injury. BRAF is a proto-oncogene involved in cell growth. To investigate the underlying mechanisms, we developed cell culture and mouse models of vemurafenib kidney toxicity. At clinically relevant concentrations vemurafenib induces cell-death in transformed and primary mouse and human kidney tubular epithelial cells. In mice, two weeks of daily vemurafenib treatment causes moderate acute kidney injury with histopathological characteristics of kidney tubular epithelial cells injury. Importantly, kidney tubular epithelial cell-specific BRAF gene deletion did not influence kidney function under normal conditions or alter the severity of vemurafenib-associated kidney impairment. Instead, we found that inhibition of ferrochelatase, an enzyme involved in heme biosynthesis contributes to vemurafenib kidney toxicity. Ferrochelatase overexpression protected kidney tubular epithelial cells and conversely ferrochelatase knockdown increased the sensitivity to vemurafenib-induced kidney toxicity. Thus, our studies suggest that vemurafenib-associated kidney tubular epithelial cell dysfunction and kidney toxicity is BRAF-independent and caused, in part, by off-target ferrochelatase inhibition.

AL amyloidosis: The effect of fluorescent in situ hybridization abnormalities on organ involvement and survival.

BACKGROUND: Systemic light chain (AL) amyloidosis is a clonal plasma-cell neoplasm that carries a poor prognosis. Although AL amyloidosis and Multiple Myeloma (MM) can co-exist and share various cytogenetic chromosomal abnormalities, little is known about Fluorescent in situ hybridization (FISH) and its prognostic relevance in AL amyloidosis. AIM: The study aims to evaluate the most prevalent FISH cytogenetic abnormalities in AL patients as independent prognostic factors, and assess the impact of cytogenetics on the survival of high-risk cardiac AL patients. MATERIALS & METHODS: This retrospective study reviewed 113 consecutive AL patients treated at The Ohio State University (OSU). Patients were divided into subgroups based on FISH data obtained within 90 days of diagnosis. Hyperdiploidy was defined as trisomies of at least 2 chromosomal loci. Primary endpoints were progression free survival (PFS) and overall survival (OS). Kaplan Meier curves were used to calculate PFS and OS. The log-rank test and Cox proportional hazard models were used to test the equality of survival functions and further evaluate the differences between groups. RESULTS: FISH abnormalities were detected in 76% of patients. Patients with abnormal FISH trended toward lower overall survival (OS) (p=0.06) and progression free survival (PFS) (p=0.06). The two most prevalent aberrations were translocation t(11;14) (39%) and hyperdiploidy-overall (38%). Hyperdiploidy-overall was associated with worsening PFS (p=0.018) and OS (p=0.03), confirmed in multivariable analysis. Patients with del 13q most frequently had cardiac involvement (p=0.006) and was associated with increased bone marrow plasmacytosis (p=0.02). Cardiac AL patients with no FISH abnormalities had much improved OS (p=0.012) and PFS (p=0.018) CONCLUSIONS: Our findings ultimately reveal the association of hyperdiploidy on survival in AL amyloidosis patients, including the high-risk cardiac AL population.

AL Amyloidosis: The Effect of Maintenance Therapy on Autologous Stem Cell Transplantation Outcomes.

BACKGROUND: Autologous stem cell transplantation (ASCT) remains an effective treatment option for many patients with systemic light chain (AL) amyloidosis. While maintenance post ASCT in multiple myeloma is now standard, the decision to utilize maintenance in AL amyloidosis remains largely unexplored. The present study aims to determine the prognostic significance of utilizing maintenance therapy following ASCT and assess the impact of fluorescent in situ hybridization (FISH) abnormalities, bone marrow plasma cell burden (BMPC), and degree of organ involvement on this decision. METHODS AND RESULTS: This is a retrospective analysis of fifty AL amyloidosis patients who underwent ASCT at The Ohio State University. Twenty-eight patients received maintenance and twenty-two did not. Kaplan-Meier survival analysis was used to compare the effect of maintenance therapy with no significant difference in PFS (p = 0.66) and OS (p = 0.32) between the two groups. There was no difference in survival based on maintenance when further categorized by FISH, PFS (p = 0.15), and OS (p = 0.65); BMPC ≥ 10%, PFS (p = 0.49), and OS (p = 0.32); or with 2 or more organs involved, PFS (p = 0.34) and OS (p = 0.80). CONCLUSION: Maintenance therapy post ASCT did not impact PFS or OS when categorized by FISH abnormalities, increasing BMPC, or ≥2 organs involved in AL amyloidosis patients.

Diffuse "background" monoclonal light chain staining on kidney biopsies in the absence of electron-dense deposits - putting it into perspective: A retrospective cohort study.

BACKGROUND: Pathologic diagnosis of monoclonal gammopathy (MIg)-associated kidney disease requires specific morphologic and immunofluorescence (IF) findings with deposits on electron microscopy. We have encountered kidney biopsies showing only diffuse "background" monoclonal light chain staining, without characteristic morphologic or ultrastructural findings. Such staining is often overlooked if weak, or over-diagnosed as MIg-associated kidney disease if strong, causing dilemma over the need for immediate clone-directed therapy. We performed a clinicopathologic study to better understand its significance. MATERIALS AND METHODS: Database search revealed 32 such cases over 12 years. Demographic, laboratory, and pathology data were retrieved along with a mean follow-up of 13 months. RESULTS: 15/32 (47%) patients did have active myeloma on hematologic testing (without myeloma casts) warranting immediate clone-directed therapy; but 11/32 (34%) did not develop active myeloma; 3/32 (9%) did not even have detectable paraprotein; 3/32 (9%) were lost to follow-up. Importantly, strong background light chain staining was seen even in some non-myeloma biopsies and conversely, weak staining was seen in some myeloma biopsies, complicating diagnosis. CONCLUSION: It is important to recognize and document this finding in the biopsy report, but by itself, it should not be classified as MIg-associated kidney disease even in the face of strong staining intensity. A thorough hematologic work-up is critically important to unmask underlying active myeloma, which many patients may have. But equally important is to avoid inadvertent clone-directed therapy in patients who do not have active myeloma despite the background monoclonal staining. A protocol for periodic monitoring with hematologic and renal parameters to watch for possible malignant transformation is recommend for timely implementation of therapy to minimize renal damage.

Revisiting medullary tophi: a link between uric acid and progressive chronic kidney disease?

BACKGROUND: It is well-established from autopsy studies that gouty tophi can form in the kidney, particularly in the renal medulla. Recently hyperuricemia has been identified as a risk factor for progression of chronic kidney disease (CKD). Because each collecting duct serves more than 2,000 nephrons, we postulated that obstruction or disruption of collecting ducts by medullary tophi may explain, at least in part, the association between hyperuricemia and progressive CKD. This work was done to determine the prevalence of medullary tophi in CKD patients. METHODS: We queried our nephropathology database over the last 10 years for native kidney biopsies that had medullary tophi. The presence or absence of CKD and uric acid levels around the time of biopsy were determined by chart review. RESULTS: Predominant medullary tissue was reported in 796 of 7,409 total biopsies, and 572 of these were from patients with established CKD. Medullary tophi were seen in 36 patients, 35 of whom had CKD, suggesting a minimum prevalence of tophi in CKD and no-CKD of 6.11 and 0.45%, respectively Medullary tophi occurred with and without hyperuricemia or a history of gout. CONCLUSION: Medullary tophi appear to be far more likely to occur in CKD compared to no-CKD patients. This cross-sectional study cannot determine whether medullary tophi are a cause or consequence of CKD. However, given their location and bulk, it is possible that medullary tophi contribute to progression of established CKD by causing upstream nephron damage.

Staphylococcus-related glomerulonephritis and poststreptococcal glomerulonephritis: why defining "post" is important in understanding and treating infection-related glomerulonephritis.

A spate of recent publications describes a newly recognized form of glomerulonephritis associated with active staphylococcal infection. The key kidney biopsy findings, glomerular immunoglobulin A (IgA) deposits dominant or codominant with IgG deposits, resemble those of IgA nephritis. Many authors describe this condition as "postinfectious" and have termed it "poststaphylococcal glomerulonephritis." However, viewed through the prism of poststreptococcal glomerulonephritis, the prefix "post" in poststaphylococcal glomerulonephritis is historically incorrect, illogical, and misleading with regard to choosing therapy. There are numerous reports describing the use of high-dose steroids to treat poststaphylococcal glomerulonephritis. The decision to use steroid therapy suggests that the treating physician believed that the dominant problem was a postinfectious glomerulonephritis, not the infection itself. Unfortunately, steroid therapy in staphylococcus-related glomerulonephritis can precipitate severe staphylococcal sepsis and even death and provides no observable benefits. Poststreptococcal glomerulonephritis is an authentic postinfectious glomerulonephritis; poststaphylococcal glomerulonephritis is not. Making this distinction is important from the perspective of history, pathogenesis, and clinical management.

Differential diagnosis of glomerular disease: a systematic and inclusive approach.

BACKGROUND: Glomerular disease is a complex and evolving topic. In evaluating a specific case it is not unusual for the clinician to ask: 'Am I missing something? Should I biopsy? When? Should I treat first, then biopsy?' This work, which is both evidence and experience based, is intended to address each of these concerns and many other issues relevant to the differential diagnosis of glomerular disease. SUMMARY: The central approach is the use of diagnostic algorithms that are based on quantitative measures routinely obtained early in the course of the diagnostic evaluation. The algorithms are designed to be easy to navigate, systematic, and inclusive. Also provided is a detailed and prioritized list of recommended diagnostic testing, and the rationale for each test. KEY MESSAGE: This work is intended to facilitate accurate diagnosis in the individual patient presenting with evidence of glomerular disease.

Cardiorenal syndrome and the role of ultrafiltration in heart failure.

Acute decompensated heart failure (ADHF) with associated volume overload is the most common cause of hospitalization in heart failure patients. When accompanied by worsening renal function, it is described as a cardiorenal syndrome and is a therapeutic challenge. Initial treatment commonly encompasses intravenous diuretics however, suboptimal results and high rehospitalization rates have led experts to search for alternative therapeutic strategies. Recent technological advances in extracorporeal therapies have made ultrafiltration a feasible option for treatment of hypervolemia in ADHF. Recent large randomized trials have compared the efficacy and safety of ultrafiltration with diuretics. Additionally, the benefits of novel pharmacologic approaches, including combining hypertonic saline with diuretics, have recently been studied. The aim of this review is to discuss the developments in both pharmacologic and extracorporeal methods for treating hypervolemia in ADHF and acute cardiorenal syndrome.

A composite urine biomarker reflects interstitial inflammation in lupus nephritis kidney biopsies.

The initial treatment of lupus nephritis is usually based on a renal biopsy. Subsequent disease flares, however, are often treated without the benefit of kidney pathology because repeat biopsies are infrequent. A noninvasive, real-time method to assess renal pathology would be useful to adjust treatment and improve outcome. To develop such a method we collected urine samples at or close to the time of 64 biopsies from 61 patients with lupus nephritis to identify potential biomarkers of tubulointerstitial inflammation and correlated these to biopsy parameters scored by a renal pathologist using a semiquantitative scale. Linear discriminant analysis was used to weight variables and derive composite biomarkers that identified the level of tubulointerstitial inflammation based on urine concentrations of monocyte chemotactic protein-1, hepcidin (a marker of active lupus), and liver fatty acid-binding protein. The discriminant function that described the most accurate composite biomarkers included urine monocyte chemotactic protein-1 and serum creatinine as the independent variables. This composite had sensitivity, specificity, positive predictive value, and negative predictive value of 100, 81, 67, and 100%, respectively. Only 14% of the biopsies were misclassified. Thus, specific renal pathologic lesions can be modeled by composite biomarkers to noninvasively follow and adjust the treatment of lupus nephritis reflecting renal injury.