Liver Disease-Associated Glomerulopathies.

Hepatitis B virus (HBV) and hepatitis C virus (HCV) infect a significant number of individuals globally and their extra-hepatic manifestations, including glomerular disease, are well established. Additionally, liver disease-associated IgA nephropathy is the leading cause of secondary IgA nephropathy with disease course varying from asymptomatic urinary abnormalities to progressive kidney injury. Herein we provide an updated review on the epidemiology, pathogenesis, clinical manifestations, and treatment of HBV- and HCV-related glomerulonephritis as well as IgA nephropathy in patients with liver disease. The most common HBV-related glomerulonephritis is membranous nephropathy, although membranoproliferative glomerulonephritis and podocytopathies have been described. The best described HCV-related glomerulonephritis is cryoglobulinemic glomerulonephritis occurring in about 30% of patients with mixed cryoglobulinemic vasculitis. The mainstay of treatment for HBV-GN and HCV-GN is antiviral therapy, with significant improvement in outcomes since the emergence of the direct-acting antivirals. However, cases with severe pathology and/or a more aggressive disease trajectory can be offered a course of immunosuppression, commonly anti-CD20 therapy, particularly in the case of cryoglobulinemic glomerulonephritis.

Association of Proton Pump Inhibitor Use and Immune Checkpoint Inhibitor Mediated Acute Kidney Injury: A Meta-Analysis and a Review of Related Outcomes.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. However, they pose the risk of immune-related adverse events, including ICI-mediated acute kidney injury (ICI-AKI). Recent studies have implicated proton pump inhibitors (PPIs) as potential contributors to ICI-AKI development. This meta-analysis examines the association between PPI use and ICI-AKI, exploring a potential modifiable risk factor in ICI therapy, while also reviewing the possible outcomes of ICI-AKI. METHODS: We conducted a comprehensive systematic review and meta-analysis of observational studies, assessing the risk of ICI-AKI in cancer patients concurrently using PPIs and potential outcomes. Odds ratios (ORs) were pooled using random-effects models. Subgroup analyses and sensitivity analyses were performed to evaluate heterogeneity and potential biases. RESULTS: A total of 14 studies involving 12,694 patients were included. In total, we analyzed 639 patients with all-cause AKI and 779 patients with ICI-AKI. The pooled OR for the overall incidence of AKI from all-cause was 1.57 (95% Confidence Interval (CI), 1.02 to 2.40) among patients on PPIs. Specifically, the risk of ICI-AKI associated with PPI use was significantly higher, with a pooled OR of 1.84 (95% CI 1.16 to 2.90). This indicates approximately 84% higher likelihood of developing ICI-AKI with concurrent use of PPIs. Additionally, among patients with ICI-AKI, 67% had complete or partial recovery of renal function, 32% progressed to chronic kidney disease (CKD) and about 36% died during a follow-up period of at least 3 months. CONCLUSION: This meta-analysis highlights the importance of cautious PPI prescription in cancer patients undergoing ICI therapy. Clinicians are advised to evaluate the risks and benefits of PPI use and consider alternative therapies when feasible.

Kidney Dysfunction in the Setting of Liver Failure: Core Curriculum 2024.

Individuals with liver disease are susceptible to pathophysiological derangements that lead to kidney dysfunction. Patients with advanced cirrhosis and acute liver failure (ALF) are at risk of developing acute kidney injury (AKI). Hepatorenal syndrome type 1 (HRS-1, also called HRS-AKI) constitutes a form of AKI unique to the state of cirrhosis and portal hypertension. Although HRS-1 is a condition primarily characterized by marked renal vasoconstriction and kidney hypoperfusion, other pathogenic processes, such as acute tubular injury and renal vein congestion, can overlap and further complicate the course of HRS-1. ALF can lead to AKI through mechanisms that involve systemic inflammation, direct drug toxicity, or bile acid-induced tubulopathy. In addition, the growing prevalence of nonalcoholic steatohepatitis is changing the spectrum of chronic kidney disease in cirrhosis. In this installment of AJKD's Core Curriculum in Nephrology, we explore the underpinnings of how cirrhosis, ALF, acute cholestasis, and post-liver transplantation can be associated with various forms of acute, subacute, or chronic kidney diseases. We navigate through the recommended therapies for each condition, including supportive care, pharmacological interventions, kidney replacement therapy, and organ transplantation. Finally, key acid-base and electrolyte disorders associated with hepatobiliary disease are also summarized.

Refractoriness of Hyperkalemia and Hyperphosphatemia in Dialysis-Dependent AKI Associated with COVID-19.

Background: Persistent hyperkalemia (hyperK) and hyperphosphatemia (hyperP) despite renal replacement therapy (RRT) was anecdotally reported in COVID-19 and acute kidney injury (AKI) requiring RRT (CoV-AKI-RRT). However, observation bias could have accounted for the reports. Thus, we systematically examined the rate and severity of hyperK and hyperP in patients with CoV-AKI-RRT in comparison with the pre-COVID-19 era. Methods: We identified patients with CoV-AKI-RRT treated with sustained low-efficiency dialysis (SLED) for ≥2 days in March-April 2020. As pre-COVID-19 control, we included patients with AKI treated with SLED in December 2019. We examined the rates of hyperK (serum potassium [sK] ≥5.5 mEq/L), severe hyperK (sK ≥6.5 mEq/L), hyperP (serum phosphate [sP] ≥4.5 mg/dl), and moderate or severe hyperP (sP ≥7-10 and >10 mg/dl, respectively) as %SLED-days with an event. Results: Along the duration of SLED, the incidence of hyperK was greater in CoV-AKI-RRT (n=64; mean 19%±2% versus 14%±3% SLED-days, P=0.002) compared with control (n=60). The proportion of patients with one or more event of severe hyperK was greater in CoV-AKI (33% versus 7%, P<0.001). The incidence of hyperP was similar between groups (mean 56%±4% versus 53%±5% SLED-days, P=0.49). However, the proportion of patients with one or more event of moderate and severe hyperP was greater in CoV-AKI-RRT (86% versus 60%, P=0.001, and 50% versus 18%, P<0.001, respectively). Among those with CoV-AKI-RRT, sK and sP correlated with lactate dehydrogenase (LDH; r=0.31, P=0.04, and r=0.31, P=0.04, respectively), whereas hyperP also correlated with shorter SLED runs (hours/run; r=-0.27, P=0.05). Conclusions: Refractory hyperK and hyperP were more frequent in CoV-AKI-RRT compared with the pre-COVID-19 era. Because of the correlation of sK and sP with higher LDH and sP with shorter SLED runs, intracellular ion release from cell injury due to cytokine storm and RRT interruptions may account for the findings.

Acute Kidney Injury in Patients with Liver Disease.

AKI is commonly encountered in patients with decompensated cirrhosis, and it is associated with unfavorable outcomes. Among factors specific to cirrhosis, hepatorenal syndrome type 1, also referred to as hepatorenal syndrome-AKI, is the most salient and unique etiology. Patients with cirrhosis are vulnerable to traditional causes of AKI, such as prerenal azotemia, acute tubular injury, and acute interstitial nephritis. In addition, other less common etiologies of AKI specifically related to chronic liver disease should be considered, including abdominal compartment syndrome, cardiorenal processes linked to cirrhotic cardiomyopathy and portopulmonary hypertension, and cholemic nephropathy. Furthermore, certain types of GN can cause AKI in cirrhosis, such as IgA nephropathy or viral hepatitis related. Therefore, a comprehensive diagnostic approach is needed to evaluate patients with cirrhosis presenting with AKI. Management should be tailored to the specific underlying etiology. Albumin-based volume resuscitation is recommended in prerenal AKI. Acute tubular injury and acute interstitial nephritis are managed with supportive care, withdrawal of the offending agent, and, potentially, corticosteroids in acute interstitial nephritis. Short of liver transplantation, vasoconstrictor therapy is the primary treatment for hepatorenal syndrome type 1. Timing of initiation of vasoconstrictors, the rise in mean arterial pressure, and the degree of cholestasis are among the factors that determine vasoconstrictor responsiveness. Large-volume paracentesis and diuretics are indicated to relieve intra-abdominal hypertension and renal vein congestion. Direct-acting antivirals with or without immunosuppression are used to treat hepatitis B/C-associated GN. In summary, AKI in cirrhosis requires careful consideration of multiple potentially pathogenic factors and the implementation of targeted therapeutic interventions.

Renal manifestations of hepatitis E among immunocompetent and solid organ transplant recipients.

Hepatitis E virus (HEV) infections are generally self-limited. Rare cases of hepatitis E induced fulminant liver failure requiring liver transplantation are reported in the literature. Even though HEV infection is generally encountered among developing countries, a recent uptrend is reported in developed countries. Consumption of unprocessed meat and zoonosis are considered to be the likely transmission modalities in developed countries. Renal involvement of HEV generally holds a benign and self-limited course. Although rare cases of cryoglobulinemia are reported in immunocompetent patients, glomerular manifestations of HEV infection are frequently encountered in immunocompromised and solid organ transplant recipients. The spectrum of renal manifestations of HEV infection include pre-renal failure, glomerular disorders, tubular and interstitial injury. Kidney biopsy is the gold standard diagnostic test that confirms the pattern of injury. Management predominantly includes conservative approach. Reduction of immunosuppressive medications and ribavirin (for 3-6 mo) is considered among patients with solid organ transplants. Here we review the clinical course, pathogenesis, renal manifestations, and management of HEV among immunocompetent and solid organ transplant recipients.

Improvement in Kidney Function after Discontinuation of Fenofibrate in Outpatient Nephrology Consultation for Chronic Kidney Disease.

BACKGROUND: It has been noted in observational and interventional studies that individuals exposed to fenofibrate can exhibit a rise in serum creatinine (sCr) concentration. However, it is not known to what extent this phenomenon impacts kidney function in patients who are referred to a nephrology clinic for consultation for chronic kidney disease (CKD). METHODS: We conducted a prospective observational study of patients referred to our nephrology clinic for a new evaluation of a rise in sCr or worsening CKD and who were on fenofibrate therapy. We examined the effect of discontinuation of fenofibrate on kidney function, change in sCr, and estimated glomerular filtration (eGFR) at 3, 6, and 12 months. RESULTS: A total of 22 patients (59% women, 86% White, 59% with type 2 diabetes, and 18% with peripheral arterial disease) were captured over 2.5 years. Median sCr at the time of fenofibrate discontinuation was 1.9 (1.1-3.3) mg/dL and eGFR, 32 (17-57) mL/min; proteinuria was absent in 17 (77%). Upon discontinuation of fenofibrate, median sCr decreased to 1.5 (0.9-2.4), 1.4 (1.0-2.5), and 1.4 (1.0-2.3) mg/dL at 3, 6, and 12 months, respectively (p < 0.05); whereas median eGFR increased to 44 (27-71), 45 (23-71), and 42 (21-71) mL/min, respectively (p < 0.05). A ≥30% rise in eGFR was observed in 59% of the patients at 3 months, and it persisted in 45% and 50% of patients at 6 and 12 months, respectively. CONCLUSION: Discontinuation of fenofibrate in patients referred for CKD evaluation can result in sustained reduction in sCr in about half of the patients and for up to 1 year. There is a need to raise awareness among primary practitioners about this phenomenon. Recognition of fenofibrate as a cause of rise in sCr could reduce unnecessary nephrology consultation and resource utilization.

Recovery after acute kidney injury requiring kidney replacement therapy in patients with left ventricular assist device: A meta-analysis.

BACKGROUND: Acute kidney injury (AKI) is a common and severe complication after left ventricular assist device (LVAD) implantation with an incidence of 37%; 13% of which require kidney replacement therapy (KRT). Severe AKI requiring KRT (AKI-KRT) in LVAD patients is associated with high short and long-term mortality compared with AKI without KRT. While kidney function recovery is associated with better outcomes, its incidence is unclear among LVAD patients with severe AKI requiring KRT. AIM: To identify studies evaluating the recovery rates from severe AKI-KRT after LVAD placement, which is defined by regained kidney function resulting in the discontinuation of KRT. Random-effects and generic inverse variance method of DerSimonian-Laird were used to combine the effect estimates obtained from individual studies. METHODS: A total of 268 patients from 14 cohort studies that reported severe AKI-KRT after LVAD were included. Follow-up time ranged anywhere from two weeks of LVAD implantation to 12 mo. Kidney recovery occurred in 78% of enrollees at the time of hospital discharge or within 30 d. Overall, the pooled estimated AKI recovery rate among patients with severe AKI-KRT was 50.5% (95%CI: 34.0%-67.0%) at 12 mo follow up. Majority (85%) of patients used continuous-flow LVAD. While the data on pulsatile-flow LVAD was limited, subgroup analysis of continuous-flow LVAD demonstrated that pooled estimated AKI recovery rate among patients with severe AKI-KRT was 52.1% (95%CI: 36.8%-67.0%). Meta-regression analysis did not show a significant association between study year and AKI recovery rate (P = 0.08). There was no publication bias as assessed by the funnel plot and Egger's regression asymmetry test in all analyses. RESULTS: A total of 268 patients from 14 cohort studies that reported severe AKI-KRT after LVAD were included. Follow-up time ranged anywhere from two weeks of LVAD implantation to 12 mo. Kidney recovery occurred in 78% of enrollees at the time of hospital discharge or within 30 d. Overall, the pooled estimated AKI recovery rate among patients with severe AKI-KRT was 50.5% (95%CI: 34.0%-67.0%) at 12 mo follow up. Majority (85%) of patients used continuous-flow LVAD. While the data on pulsatile-flow LVAD was limited, subgroup analysis of continuous-flow LVAD demonstrated that pooled estimated AKI recovery rate among patients with severe AKI-KRT was 52.1% (95%CI: 36.8%-67.0%). Meta-regression analysis did not show a significant association between study year and AKI recovery rate (P = 0.08). There was no publication bias as assessed by the funnel plot and Egger's regression asymmetry test in all analyses. CONCLUSION: Recovery from severe AKI-KRT after LVAD occurs approximately 50.5%, and it has not significantly changed over the years despite advances in medicine.

In-hospital mortality of hepatorenal syndrome in the United States: Nationwide inpatient sample.

BACKGROUND: Hepatorenal syndrome (HRS) is a life-threatening condition among patients with advanced liver disease. Data trends specific to hospital mortality and hospital admission resource utilization for HRS remain limited. AIM: To assess the temporal trend in mortality and identify the predictors for mortality among hospital admissions for HRS in the United States. METHODS: We used the National Inpatient Sample database to identify an unweighted sample of 4938 hospital admissions for HRS from 2005 to 2014 (weighted sample of 23973 admissions). The primary outcomes were temporal trends in mortality as well as predictors for hospital mortality. We estimated odds ratios from multi-level mixed effect logistic regression to identify patient characteristics and treatments associated with hospital mortality. RESULTS: Overall hospital mortality was 32%. Hospital mortality decreased from 44% in 2005 to 24% in 2014 (P < 0.001), while there was an increase in the rate of liver transplantation (P = 0.02), renal replacement therapy (P < 0.001), length of hospital stay (P < 0.001), and hospitalization cost (P < 0.001). On multivariable analysis, older age, alcohol use, coagulopathy, neurological disorder, and need for mechanical ventilation predicted higher hospital mortality, whereas liver transplantation, transjugular intrahepatic portosystemic shunt, and abdominal paracentesis were associated with lower hospital mortality. CONCLUSION: Although there was an increase in resource utilizations, hospital mortality among patients admitted for HRS significantly improved. Several predictors for hospital mortality were identified.

Industry Payments to Nephrologists in the United States.

Background Industry payments to physicians raise concerns about conflicts of interest that have the potential to impact patient care. In this study, we explored nonresearch and nonownership payments from industry to nephrologists to identify trends in compensation. Methodology Using data from the Centers for Medicare and Medicaid Services (CMS), we explored financial relationships between industry and US nephrologists from 2014 to 2018. We analyzed payment characteristics including payment categories, payment distribution among physicians, regional trends, and biomedical manufacturers. Results In this retrospective study, a total of $75,174,999 was paid to nephrologists in the United States during the study period (i.e., 2014-2018). The number of board-certified nephrologists receiving payment from the industry increased from 11,642 in 2014 to 13,297 in 2018. Among board-certified nephrologists, 56% to 63% received industry payments during the study period. The total payments to nephrologists increased from $13,113,512 in 2014 to $16,467,945 in 2017, with consulting fees (24%) and compensation for services other than consulting (35%) being the highest-paid categories. The top 10% of physician beneficiaries collected 90% of the total industry payments. Conclusions A small proportion of US nephrologists consistently received the majority of industry payments, the value of which grew over the study period.

Multiple Myeloma, Hyperviscosity, Hemodialysis Filter Clogging, and Antigen Excess Artifact: A Case Report.

Kidney involvement in multiple myeloma can result in kidney failure. Unlike Waldenström macroglobulinemia, hyperviscosity syndrome is a rare occurrence in multiple myeloma. Timely detection of hyperviscosity syndrome and initiation of plasma exchange to remove paraproteins can significantly alter the clinical course and be potentially lifesaving. We report a case of hospitalized patient with kidney failure due to multiple myeloma not in remission who experienced shortened hemodialysis sessions due to early dialysis filter failure due to hyperviscosity, which was later corrected with plasmapheresis. When confirmation of high levels of serum free light chains (sFLCs) was attempted, sFLC was initially reported as "not detectable." This false-negative result reflected a laboratory artifact caused by a high abundance of sFLCs, known as antigen excess or hook phenomenon. Manual serial dilutions led to unmasking of markedly elevated κ light chain levels. This case exemplifies that patients with multiple myeloma can exhibit clinically challenging kidney manifestations even after becoming dialysis dependent.

A Rare Case of Patiromer Induced Hypercalcemia.

Patiromer is a calcium (Ca)-potassium (K) exchange resin approved for the treatment of hyperkalemia. Disorders of Ca or acid base balance were not reported in pre-approval clinical trials. We present a case of a patient with chronic kidney disease (CKD) with an unusual picture of hypercalcemia, metabolic alkalosis and hypokalemia upon intensification of patiromer dosing. A 56-year-old white man with CKD stage 4 (baseline creatinine 2.8 mg/dL) due to type 1 diabetes mellitus, proteinuria (1.5 g/g) and persistently high serum potassium 5.9 mEq/L attributed to type 4 renal tubular acidosis was evaluated in clinic. Due to high risk of CKD progression, patiromer 8.4 g daily, followed by 16.8 g daily was prescribed to enable renin angiotensin aldosterone system (RAAS) inhibitor. After 5 months of being on patiromer 16.8 g daily, routine laboratory tests revealed serum potassium 2.5 mEq/L, serum calcium 12.8 mg/dL and carbon dioxide 34 mEq/L. Patiromer was discontinued and thorough investigation held was negative for other causes of hypercalcemia. Five days after patiromer discontinuation, serum calcium returned to normal. The role of secondary hyperparathyroidism in this case remains unclear. We, therefore recommend cautious vigilance of patients receiving patiromer and undergoing dose escalation.

A Case of Hypophosphatemia due to Oncogenic Osteomalacia in a Patient with Natural Killer T-Cell Lymphoma.

INTRODUCTION: Oncogenic osteomalacia (Onc-Ost) is a paraneoplastic phenomenon characterized by hypophosphatemia due to elevated fibroblast growth factor-23 (FGF-23). Onc-Ost has been previously reported in patients with germ line mesenchymal tumors and solid organ malignancies. This is the first report of aggressive natural killer (NK) T-cell lymphoma presenting as Onc-Ost. CASE DESCRIPTION: A 33-year-old Vietnamese female with active hepatitis B and Mycobacterium avium complex, on ongoing therapy with tenofovir disoproxil, azithromycin, and ethambutol, presented with persistent fevers and developed refractory hypophosphatemia. Workup confirmed severe renal phosphate wasting. Tenofovir disoproxil was initially suspected; however, presence of isolated phosphaturia without Fanconi syndrome and persistence of hypophosphatemia despite discontinuation of medication led to clinical suspicion of Onc-Ost. Elevated FGF-23 warranted further workup, leading to a definitive diagnosis of clinically subtle NK T-cell lymphoma. Chemotherapy was initiated; however, patient continued to deteriorate clinically and expired. CONCLUSION: Along with commonly reported germ line mesenchymal tumors and solid malignancies, NK T-cell lymphoma can also present as Onc-Ost. Timely detection of associated tumors and subsequent antitumor therapy would likely reverse hypophosphatemia and improve clinical outcomes.

Incidence and Characteristics of Kidney Stones in Patients on Ketogenic Diet: A Systematic Review and Meta-Analysis.

Very-low-carbohydrate diets or ketogenic diets are frequently used for weight loss in adults and as a therapy for epilepsy in children. The incidence and characteristics of kidney stones in patients on ketogenic diets are not well studied. Methods: A systematic literature search was performed, using MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews from the databases' inception through April 2020. Observational studies or clinical trials that provide data on the incidence and/or types of kidney stones in patients on ketogenic diets were included. We applied a random-effects model to estimate the incidence of kidney stones. Results: A total of 36 studies with 2795 patients on ketogenic diets were enrolled. The estimated pooled incidence of kidney stones was 5.9% (95% CI, 4.6-7.6%, I2 = 47%) in patients on ketogenic diets at a mean follow-up time of 3.7 +/- 2.9 years. Subgroup analyses demonstrated the estimated pooled incidence of kidney stones of 5.8% (95% CI, 4.4-7.5%, I2 = 49%) in children and 7.9% (95% CI, 2.8-20.1%, I2 = 29%) in adults, respectively. Within reported studies, 48.7% (95% CI, 33.2-64.6%) of kidney stones were uric stones, 36.5% (95% CI, 10.6-73.6%) were calcium-based (CaOx/CaP) stones, and 27.8% (95% CI, 12.1-51.9%) were mixed uric acid and calcium-based stones, respectively. Conclusions: The estimated incidence of kidney stones in patients on ketogenic diets is 5.9%. Its incidence is approximately 5.8% in children and 7.9% in adults. Uric acid stones are the most prevalent kidney stones in patients on ketogenic diets followed by calcium-based stones. These findings may impact the prevention and clinical management of kidney stones in patients on ketogenic diets.

Use and outcomes of kidneys from donors with renal angiomyolipoma: A systematic review.

BACKGROUND: Renal angiomyolipoma (AML) is the most frequent mesenchymal tumor of the kidney. Although there is a rare possibility of malignant transformation of AML, this risk has not been studied in immunosuppressed patients. The safety of donors with AML and their kidney transplant recipients has not been well established. METHODS: A literature search was conducted utilizing MEDLINE, EMBASE, and Cochrane databases from inception through May 15, 2018 (updated on October 2019). We included studies that reported the outcomes of kidney donors with AML or recipients of donor with AML. The protocol for this meta-analysis is registered with PROSPERO (International Prospective Register of Systematic Reviews; no. CRD42018095157). RESULTS: Fourteen studies with a total of 16 donors with AML were identified. None of the donors had a diagnosis of tuberous sclerosis complex (TSC), pulmonary lymphangioleiomyomatosis (LAM), or epithelioid variant of AML. Donor age ranged from 35 to 77 years, and recipient age ranged from 27 to 62 years. Ninety-two percent of the donors were female. Only 8% were deceased donor renal transplant. The majority underwent ex vivo resection (65%) before transplantation, followed by no resection (18%), and the remaining had in vivo resection. Tumor size varied from 0.4 cm to 7 cm, and the majority (87%) were localized in the right kidney. Follow-up time ranged from 1 to 107 months. Donor creatinine prenephrectomy ranged 0.89-1.1 mg/dL and postnephrectomy creatinine 1.0-1.17 mg/dL. In those who did not have resection of the AML, tumor size remained stable. None of the donors with AML had end-stage renal disease or died at last follow-up. None of the recipients had malignant transformation of AML. CONCLUSION: These findings are reassuring for the safety of donors with AML (without TSC or LAM) as well as their recipients without evidence of malignant transformation of AML. As such, this can also positively impact the donor pool by increasing the number of available kidneys.