Controversies and practical management of patients with gout and chronic kidney disease.

Uric acid is a toxin retained with advancing kidney disease. Clinical manifestations of hyperuricemia include gout and systemic inflammation that are associated with increased risk of cardiovascular mortality. As many as one-third of all patients with chronic kidney disease have a history of gout, yet <25% of these patients are effectively treated to target serum urate levels of ≤6 mg/dl. A major reason for ineffective management of gout and hyperuricemia is the complexity in managing these patients, with some medications contraindicated and others requiring special dosing, potential drug interactions, and other factors. Consequently, many nephrologists do not primarily manage gout despite it being a common complication of chronic kidney disease, leaving management to the primary physician or rheumatologist. We believe that kidney specialists should consider gout as a major complication of chronic kidney disease and actively manage it in their patients. Here, we present insights from nephrologists and rheumatologists for a team approach to gout management that includes the nephrologist.

Pegloticase efficacy and safety in kidney transplant recipients; results of the phase IV, open-label PROTECT clinical trial.

INTRODUCTION: Kidney transplant (KT) recipients have a high prevalence and severity of gout. Pegloticase (pegylated recombinant uricase) rapidly metabolizes serum uric acid (sUA), and its efficacy is not impacted by kidney function. METHODS: This open-label, Phase 4 trial (PROTECT NCT04087720) examined safety and efficacy of pegloticase in 20 participants with KT > 1 year prior to enrollment and with uncontrolled gout (sUA ≥7 mg/dL, intolerance/inefficacy to urate lowering therapy, and ≥1 of the following: tophi, chronic gouty arthritis, ≥2 flares in past year) and functioning KT (estimated glomerular filtration rate [eGFR] ≥15 mL/min/1.73 m2 ) on stable immunosuppression therapy. RESULTS: The primary endpoint was sUA response during month 6 (sUA < 6 mg/dL for ≥80% of time). The study enrolled 20 participants (mean ± SD); age: 53.9 ± 10.9 years, time since KT: 14.7 ± 6.9 years, sUA: 9.4 ± 1.5 mg/dL, gout duration: 8.4 ± 11.6 years; all on ≥2 stable doses of immunosuppression agents. Pegloticase (8 mg intravenous every 2 weeks) in KT recipients with uncontrolled gout showed a high response rate of 89% (16/18 responders). Two participants discontinued treatment solely due to COVID-19 concerns prior to month 6 were not included in the primary analysis. Pegloticase exposures were higher than those historically observed with pegloticase monotherapy, and no anaphylaxis or infusion reaction events occurred during the study. CONCLUSIONS: This improved response rate to pegloticase in the KT population reflects observations from other trials and reports on immunomodulation with pegloticase. As the KT population has a high prevalence of gout and limitations with oral urate lowering medication options, these findings suggest a potential option for uncontrolled gout therapy in KT participants.

Expert Opinion on Pegloticase with Concomitant Immunomodulatory Therapy in the Treatment of Uncontrolled Gout to Improve Efficacy, Safety, and Durability of Response.

PURPOSE OF REVIEW: Gout is a systemic disease from which some patients develop numerous painful tophi that adversely affect quality of life and functionality. Some patients treated with oral urate-lowering therapy are unable to maintain serum urate levels below 6 mg/dL, and these patients, thus classified as having refractory or uncontrolled gout, often require therapy with pegloticase to reduce symptoms and tophaceous burden. The objective of this expert opinion review is to summarize the available evidence supporting the use of concomitant immunomodulators with pegloticase to prevent development of anti-drug antibodies (ADAs) when treating patients with uncontrolled gout. RECENT FINDINGS: Emerging evidence suggests that adding an immunomodulator to pegloticase therapy can substantially increase response rates to double those observed in phase 3 randomized controlled trials. The combination of immunomodulation with pegloticase should be considered in routine clinical practice to improve durability of response, efficacy, and safety among patients with uncontrolled gout who otherwise have limited therapeutic options.

Management of gouty arthritis in patients with chronic kidney disease.

Chronic kidney disease (CKD) is a comorbid condition that affects, based on recent estimates, between 47% and 54% of patients with gouty arthritis. However, data from randomized controlled trials in patients with gouty arthritis and CKD are limited, and current gouty arthritis treatment guidelines do not address the challenges associated with managing this patient population. Nonsteroidal anti-inflammatory drugs and colchicine are recommended first-line treatments for acute gouty arthritis attacks. However, in patients with CKD, nonsteroidal anti-inflammatory drugs are not recommended because their use can exacerbate or cause acute kidney injury. Also, colchicine toxicity is increased in patients with CKD, and dosage reduction is required based on level of kidney function. Allopurinol, febuxostat, and pegloticase are all effective treatments for controlling elevated uric acid levels after the treatment of an acute attack. However, in patients with CKD, required allopurinol dosage reductions may limit efficacy; pegloticase requires further investigation in this population, and febuxostat has not been studied in patients with creatinine clearance<30 mL/min. This article reviews the risks and benefits associated with currently available pharmacologic agents for the management of acute and chronic gouty arthritis including urate-lowering therapy in patients with CKD. Challenges specific to primary care providers are addressed, including guidance to help them decide when to collaborate with, or refer patients to, rheumatology and nephrology specialists based on the severity of gout and CKD.

Acthar® Gel Treatment for Patients with Autoimmune and Inflammatory Diseases: An Historical Perspective and Characterization of Clinical Evidence.

Acthar® Gel (repository corticotropin injection) is a naturally sourced complex mixture of adrenocorticotropic hormone analogs and other pituitary peptides that is believed to have both steroidogenic and nonsteroidogenic immunomodulatory effects via activation of melanocortin receptors in various cells throughout the body. Since 1952, Acthar has been approved by the US Food and Drug Administration to treat a variety of autoimmune and inflammatory diseases. Since 2014, Mallinckrodt Pharmaceuticals has conducted a large number of preclinical, clinical, and real-world-evidence studies of Acthar for the treatment of rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis and polymyositis, multiple sclerosis relapse, ophthalmic disorders, sarcoidosis, and nephrotic syndrome. To date, Acthar has been the subject of more than 500 publications, many of which demonstrate the safety and efficacy of Acthar in patients with inflammatory diseases for whom standard treatments were ineffective or intolerable. Here, we review the history of Acthar and the findings of studies that have investigated the mechanism of action, safety, efficacy, and real-world effectiveness of Acthar for the treatment of inflammatory diseases.

Acthar^® Gel is an anti-inflammatory drug that directly affects the immune system in a manner that differs from other anti-inflammatory drugs, such as corticosteroids. Since 1952, Acthar has been approved by the U.S. Food and Drug Administration to treat a variety of diseases involving inflammation. The commercial rights to produce Acthar have changed hands several times over the years, beginning with Armour Pharmaceuticals and most recently ending with Mallinckrodt Pharmaceuticals in 2014. Since then, Mallinckrodt has conducted multiple studies in animals to demonstrate the function of Acthar compared with other anti-inflammatory drugs. Further, several clinical trials in humans and studies of hospital or clinical practice records have confirmed the safety and effectiveness of Acthar as a treatment for many inflammatory diseases. INFOGRAPHIC: A podcast discussion by the authors on Acthar^® Gel treatment for patients with autoimmune and inflammatory diseases, including their own personal reflections and experiences with Acthar^® Gel. For a transcript of the podcast see the electronic supplementary material. (MP4 177883 kb).

Retroperitoneal sarcoma presenting as acute renal failure, secondary to bilateral renal artery invasion.

Retroperitoneal sarcoma is a rare tumor accounting for 10 - 15% of all soft tissue malignancies with an incidence of 2.5 per million. Of those, liposarcoma is the most common type of retroperitoneal sarcoma accounting for 41% of cases. It usually presents late with vague symptoms such as abdominal discomfort or palpable mass. Vascular invasion is seen in 18% of retroperitoneal sarcomas but acute renal failure secondary to bilateral renal artery invasion/stenosis by these tumors has never been described yet. In this report, we describe the first case, to our knowledge, in the medical literature and discuss epidemiology, diagnosis, and management. Treatment is primarily surgical and the ability to completely resect the tumor is the most important predictor of survival. Active clinical trials are currently testing the use of adjunct chemotherapy and radiotherapy to improve morbidity and mortality.

Rabbit antithymocyte induction and dosing in deceased donor renal transplant recipients over 60 yr of age.

BACKGROUND: Antithymocyte globulin (rATG) is a commonly used induction agent in renal transplantation; however, data in older kidney recipients are limited. METHODS: We reviewed charts of 301 deceased donor renal transplants who received a protocol consisting of 3-7 doses of rATG and triple maintenance therapy. Outcomes of patients >60 yr of age (n = 45) were compared to those aged 18-59 yr (n = 256). RESULTS: Older recipients had more diabetics, were more likely to receive expanded criteria donor kidneys (p < 0.01), and over 30% were sensitized. Recipients >60 received less cumulative rATG (4.6 vs. 5.1 mg/kg; p < 0.01). Three-yr acute rejection was lower in the >60 group (2% vs. 16%, p < 0.01) although glomerular filtration rates were similar between groups. Actuarial graft survival was similar; however, patient survival in the >60 group at three yr was lower (80% vs. 95%; p = 0.02). Specifically, patients >60 with delayed graft function and rATG cumulative dosing >6 mg/kg had a survival of <50% by two yr. CONCLUSION: Recipients over 60 yr receiving rATG induction have acceptable renal function and a low risk of rejection; however, reduced survival was noted among those receiving >6 mg/kg. These data suggest that when used, lower cumulative dosages of rATG are preferable in the older recipient.

Pulmonary alveolar proteinosis in a kidney transplant: a rare complication of sirolimus.

Pulmonary alveolar proteinosis (PAP) has been associated with the immunosuppressant sirolimus in transplant patients. PAP is a progressive lung disease characterized by the accumulation of surfactant-like material in the lungs leading to decreased pulmonary function with shortness of breath and cough as common symptoms. We report a rare case of sirolimus-associated PAP in a kidney transplant recipient with a history of end-stage renal disease secondary to haemolytic uraemic syndrome (HUS) and review of the literature. Discontinuation of sirolimus and initiation of tacrolimus led to resolution of PAP without recurrence of HUS.

Osteonecrosis secondary to antiphospholipid syndrome: a case report, review of the literature, and treatment strategy.

Osteonecrosis is commonly present in patients with antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE). Treatment of this condition remains extremely controversial. We present a treatment strategy of avascular necrosis of the knee in a patient with catastrophic antiphospholipid syndrome with a history of SLE and APS. Aggressive treatment with 12 rounds of plasmapheresis, intravenous immunoglobulin, rituximab, and cyclophosphamide led to the patient's recovery with no recurrence of symptoms during 16 months of follow up. In this report, we further discuss the pathogenesis of osteonecrosis and current understanding of the treatment of this disease.

Catastrophic antiphospholipid syndrome presenting as ischemic pancreatitis in systemic lupus erythematosus.

CONTEXT: Antiphospholipid syndrome is often associated with systemic lupus erythematosus. Both syndromes have different clinical manifestations based on organ involvement. Antiphospholipid syndrome commonly causes spontaneous abortions, cerebral vascular occlusion, and deep venous thrombosis. Catastrophic antiphospholipid syndrome occurs when three or more organ systems are affected by thromboses in less than a week. CASE REPORT: We report a unique case of a young woman with a history of systemic lupus erythematosus and antiphospholipid syndrome who presented with recurrent ischemic pancreatitis. Pancreatitis was refractory to anticoagulation and low dose steroids. Secondary to recurrence of pancreatitis and other organ involvement, she was treated as a presumed case of catastrophic antiphospholipid syndrome. Aggressive treatment with plasmapheresis, corticosteroids, cyclophosphamide, and anticoagulation eventually led to her recovery. CONCLUSION: Awareness of this rare, rapidly fatal medical condition prompts vital, early intervention to improve patients' survival. This case report aims to add to the limited therapeutic data available as well as suggest a possible approach to treating this rare syndrome with very high morbidity and mortality.

Vitamin D deficiency plays an important role in cardiac disease and affects patient outcome: Still a myth or a fact that needs exploration?

There is increasing evidence that a low vitamin D status may be an important and hitherto neglected factor of cardiovascular disease. This review is an overview of the current body of literature, and presents evidence of the mechanisms through which vitamin D deficiency affects the cardiovascular system in general and the heart in particular. Available data indicate that the majority of congestive heart failure patients have 25-hydroxyvitamin D deficiency. Furthermore, the low serum 25-hydroxyvitamin D level has a higher impact on hypertension, coronary artery disease an on the occurrence of relevant cardiac events. A serum 25-hydroxyvitamin D level below 75 nmol/l (30 ng/l) is generally regarded as vitamin D insufficiency in both adults and children, while a level below 50 nmol/l (20 ng/l) is considered deficiency. Levels below 50 nmol/l (20 ng/l) are linked independently to cardiovascular morbidity and mortality.

Sodium hypochlorite-induced acute kidney injury.

Sodium hypochlorite (bleach) is commonly used as an irrigant during dental procedures as well as a topical antiseptic agent. Although it is generally safe when applied topically, reports of accidental injection of sodium hypochlorite into tissue have been reported. Local necrosis, pain and nerve damage have been described as a result of exposure, but sodium hypo-chlorite has never been implicated as a cause of an acute kidney injury (AKI). In this report, we describe the first case of accidental sodium hypochlorite injection into the infraorbital tissue during a dental procedure that precipitated the AKI. We speculate that oxidative species induced by sodium hypochlorite caused AKI secondary to the renal tubular injury, causing mild acute tubular necrosis.

Tubulointerstitial nephritis in systemic lupus erythematosus: innocent bystander or ominous presage.

SLE-associated tubulointerstitial injury (SLE TIN) is increasingly recognized in two forms, i.e., secondary and primary. The secondary form coexists with lupus glomerulonephritis, whereas the primary form develops against the background of no or mild glomerular or vascular involvement. Secondary SLE TIN is frequent, but its frequency and severity correlate with the class of the associated lupus glomerulonephritis (GN), being almost universal in Class IV lupus GN and less frequent in GN of other classes. Although the presence of underlying GN may mask its clinical manifestation, secondary SLE TIN has a major prognostic implication for the renal outcome. Yet, SLE TIN is not factored in the current therapy-focused International Society of Nephrology/Renal Pathology Society schema of renal lupus classification, and its management remains to be elucidated. The pathogenesis of secondary SLE TIN is either immunologic, i.e., the tubulointerstitial injury being mediated by SLE-related immunologic mechanisms akin to those responsible for lupus GN; or non-immunologic, i.e., a nonspecific tubulointerstitial injury secondary to any type of advanced glomerular lesion, regardless of etiology. Primary SLE TIN is rare with about 15 reported cases. It has a rather uniform and distinctive clinical manifestation including acute kidney injury with no or mild proteinuria. It responds well to steroid and usually carries a good prognosis. Its pathogenesis is almost certain immunologic, with immunoglobulin/complement deposits along the tubular basement membrane in each reported case. In spite of these profound clinical implications, the current review underlies a limited knowledge on the pathobiology of SLE TIN.

Profound nephrotic syndrome in a patient with ovarian teratoma.

The nephrotic syndrome (NS) has been associated with a variety of malignancies in a number of reports in the literature, but has been reported in only nine cases associated with ovarian neoplasms. Membranous nephropathy is the most common glomerular pathology causing the NS in patients with solid tumors. There has been only one report of an ovarian neoplasm associated with minimal change disease (MCD). We describe the case of a 36-year-old woman who presented with the NS secondary to biopsy-proven MCD, likely secondary to mature ovarian teratoma. Treatment by tumor removal and prednisone led to remission of the NS. To the best of our knowledge, this is the first report of an ovarian teratoma and the second report of an ovarian neoplasm associated with MCD.

The role of renin inhibition in treating the hypertensive patient with diabetes: a summary of preclinical and clinical evidence.

Comorbid hypertension and diabetes is common and associated with substantially greater cardiovascular and renal risk relative to hypertension alone. Tissue renin-angiotensin system (RAS) overactivity is a hallmark of diabetes and contributes to target organ damage. Treatment guidelines recommend angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) for reducing cardiorenal risk in patients with hypertension plus diabetes. However, these agents only partially prevent cardiovascular and renal morbidity/mortality. Further attempts to improve clinical outcomes have focused on the use of an ACE inhibitor plus an ARB, but this combination has not demonstrated a favorable risk-benefit profile. Direct renin inhibitors provide a more comprehensive blockade of the RAS compared with ACE inhibitors or ARBs, and may be of particular benefit in counteracting tissue RAS overactivity. In this article, the role of the RAS in diabetic hypertension and the preclinical and clinical effects of direct renin inhibitor therapy on target organs are reviewed.

Role of single-pill combination therapy in optimizing blood pressure control in high-risk hypertension patients and management of treatment-related adverse events.

Renin-angiotensin-aldosterone system (RAAS) inhibitors in combination with other antihypertensive drugs (eg, calcium channel blockers [CCBs] and/or diuretics) are a preferred treatment option for managing uncontrolled hypertension in high-risk patients with chronic kidney disease (CKD), diabetes, or heart failure because RAAS inhibitors provide cardiorenal benefits in addition to lowering blood pressure (BP). However, when prescribing antihypertensive therapies to high-risk patients, physicians must be aware of the risks of treatment-related adverse events of hyperkalemia and peripheral edema associated with RAAS inhibitors and CCBs, respectively. This review discusses the use of single-pill combination antihypertensive therapy to optimize BP control in high-risk patients with CKD, diabetes, and/or heart failure and provides strategies for preventing and managing hyperkalemia and peripheral edema in this group. Single-pill combination therapy can utilize different classes of antihypertensive drugs to reduce BP while mitigating the risks of treatment-related adverse events, reducing pill burden, lowering medical cost, and improving patient compliance.

Rituximab in the treatment of refractory lupus nephritis with vasculitis.

Dysfunction of the B lymphocyte, an important component of adaptive immunity, is thought to be important in the pathogenesis of lupus nephritis (LN). There are several novel strategies emerging including B-cell depletion by the monoclonal antibodies to B-cell markers, rituximab. We describe an unusual clinical response of a 22-year-old Hispanic woman with class IV LN with vasculitis while on dialysis to cyclophosphamide (CY) and adjunct rituximab. The patient had a history of class III/V LN and was treated with nine months of CY and maintenance therapy with mycophenolate mofetil (MMF) for three years. While on MMF, the patient developed class IV LN with vasculitis leading to end-stage renal disease (ESRD). While the patient was on peritoneal dialysis, the patient was treated with two doses of rituximab and six doses of intravenous CY. The patient responded to this regimen and recovered kidney function within four months. The kidney function remained stable nine months after discontinuing peritoneal dialysis.

Posterior reversible encephalopathy syndrome in a patient with lupus nephritis.

Posterior reversible encephalopathy syndrome (PRES) is characterized by acute onset of headache, nausea, focal neurological deficits or seizures along with radiological findings of white matter defects in the parietal and occipital lobes. Causes of PRES include uremia, hypertensive encephalopathy, eclampsia and immunosuppressive medications. Usually, the treatment of choice involves correcting the underlying abnormality. We describe an unusual case of recurrent PRES caused by uremia during a lupus flare in a patient with biopsy-proven Class IV Lupus Nephritis (LN) with vasculitis. PRES in systemic lupus erythematosis (SLE) is a rare clinical phenomenon and, when reported, it is associated with hypertensive encephalopathy. Our patient did not have hypertensive crisis, but had uremic encephalopathy. The patient's PRES-related symptoms resolved after initiation of hemodialysis. The temporal correlation of the correction of the uremia and the resolution of the symptoms of PRES show the etiology to be uremic encephalopathy, making this the first reported case of uremia-induced PRES in Class IV LN with vasculitis.