Equivalent Efficacy and Decreased Rate of Overcorrection in Patients With Syndrome of Inappropriate Secretion of Antidiuretic Hormone Given Very Low-Dose Tolvaptan.

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

Diverse Clinical Presentations of C3 Dominant Glomerulonephritis.

C3 dominant immunofluorescence staining is present in a subset of patients with idiopathic immune complex membranoproliferative glomerulonephritis (iMPGN). It is increasingly recognized that iMPGN may be complement driven, as are cases of "typical" C3 glomerulopathy (C3G). In both iMPGN and C3G, a frequent membranoproliferative pattern of glomerular injury may indicate common pathogenic mechanisms via complement activation and endothelial cell damage. Dysregulation of the alternative complement pathway and mutations in certain regulatory factors are highly implicated in C3 glomerulopathy (which encompasses C3 glomerulonephritis, dense deposit disease, and cases of C3 dominant MPGN). We report three cases that demonstrate that an initial biopsy diagnosis of iMPGN does not exclude complement alterations similar to the ones observed in patients with a diagnosis of C3G. The first patient is a 39-year-old woman with iMPGN and C3 dominant staining, with persistently low C3 levels throughout her course. The second case is a 22-year-old woman with elevated anti-factor H antibodies and C3 dominant iMPGN findings on biopsy. The third case is a 25-year-old woman with C3 dominant iMPGN, dense deposit disease, and a crescentic glomerulonephritis on biopsy. We present the varied phenotypic variations of C3 dominant MPGN and review clinical course, complement profiles, genetic testing, treatment course, and peri-transplantation plans. Testing for complement involvement in iMPGN is important given emerging treatment options and transplant planning.

Intravitreal bevacizumab-induced exacerbation of proteinuria in diabetic nephropathy, and amelioration by switching to ranibizumab.

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

Three Patients with Lithium-Associated Hyperparathyroidism: Literature Review Regarding Medical and Surgical Management.

Lithium (Li) carbonate has been established as a mood stabilizer and an efficacious treatment for bipolar disorder since its discovery by Dr. John Cade in 1948. Li interacts significantly with organ systems and endocrine pathways. One of the most challenging side effects of Li to manage is its effect on the parathyroid glands. Dysregulation of parathyroid signaling due to Li results in hypercalcemia due to increased vitamin D3 generation, increased calcium absorption from the gut, and bone resorption, occasionally resulting in concomitant hypercalciuria. However, hypercalciuria is not a definitive feature for hyperparathyroidism, and normal calcium excretion might be seen in these patients. Hypercalcemia may also result from volume contraction and decreased renal clearance, which are commonly seen in these patients. Anatomically the parathyroid abnormalities can present as single or multiglandular disease. We report 3 cases where the patients developed multiple side effects of Li therapy as well as hypercalcemia due to hyperparathyroidism. The literature is reviewed with regard to medical and surgical management of Li-associated hyperparathyroidism in the context of these 3 presented cases.

Nephrotoxicity induced by intravitreal vascular endothelial growth factor inhibitors: emerging evidence.

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

Primary membranous nephropathy with concomitant IgA nephropathy.

Membranous nephropathy (MN), an autoimmune glomerulonephritis which can occur in primary and secondary forms, is one of the most common inflammatory glomerulopathies in elderly patients. The pathophysiology of the primary form is generally due to circulating immunoglobulin (IgG4) antibodies which often target phospholipase A2 receptors (anti-PLA2R) and Thrombospondin Type 1 Domain containing 7A (anti THSD7A). IgA nephropathy is one of the most common autoimmune glomerular diseases in the world and presents with a spectrum of disease ranging from asymptomatic mild hematuria and proteinuria to rapidly progressive crescentic glomerulonephritis. We present a rare case of concomitant IgA and primary MN in a single patient treated successfully with renin-angiotensin-aldosterone blockade, corticosteroids, and calcineurin inhibitors. The peak proteinuria was near 7.5-8 g protein/g creatinine by various measures. Serum creatinine remained normal, and anti-PLA2R was detectable and decreased with successful treatment. Clinicians should be aware of the possibility of two glomerular disorders in patients with glomerulonephritis and atypical presentations for any single disorder.

Three patients with injection of intravitreal vascular endothelial growth factor inhibitors and subsequent exacerbation of chronic proteinuria and hypertension.

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

Left ventricular assist device patient maintained on home hemodialysis: A novel class of patients to the home dialysis population.

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

Case Report: 52-Year-Old Male with Right Upper Quadrant Abdominal Pain.

Renal artery dissections (RADs) are lesions that disrupt vessels that primarily occur in patients with a known history of hypertension and caused by stenosis or enlargement of the renal artery typically due to underlying connective tissue disorders. However, RADs may occur spontaneously from trauma and no previous history of hypertension. Here, we report a rare case of bilateral isolated spontaneous RADs that characteristically occurs in healthy males. A 52-year-old male presented with left lower quadrant abdominal pain and renal insufficiency. Two years prior, he had experienced a similar episode of pain on the contralateral side, which was due to an infarct of the right kidney. On this admission, a computed tomography angiogram confirmed a new infarct of the left kidney, with dissection of a branch of the renal artery supplying the upper lobe. Work-up for cardiovascular, hematologic, radiographic or connective tissue causes was negative. We postulate that both RADs were potentially associated with the rapid twisting and turning of the abdominal area on a daily basis required for his occupation as an air traffic controller. The patient was treated with a renin angiotensin system inhibitor. After one year, both RADs had significantly improved and his renal function increased by ~23%. Isolated RAD may be associated with consistent or long-term activities that require rapid twisting and turning of the abdominal area. If left untreated, this may result in malignant hypertension, bilateral dissections, or renal ischemia. To avoid misdiagnosis; we provide a comprehensive review of the typical presentation and necessary assessment and management.

Patient with a total artificial heart maintained on outpatient dialysis while listed for combined organ transplant, a single center experience.

Advanced mechanical circulatory support is increasingly being used with more sophisticated devices that can deliver pulsatile rather than continuous flow. These devices are more portable as well, allowing patients to await cardiac transplantation in an outpatient setting. It is known that patients with renal failure are at increased risk for developing worsening acute kidney injury during implantation of a ventricular assist device (VAD) or more advanced modalities like a total artificial heart (TAH). Dealing with patients who have an implanted TAH who develop renal failure has been a challenge with the majority of such patients having to await a combined cardiac and renal transplant prior to transition to outpatient care. Protocols do exist for VAD implanted patients to be transitioned to outpatient dialysis care, but there are no reported cases of TAH patients with end stage renal disease (ESRD) being successfully transitioned to outpatient dialysis care. In this report, we identify a patient with a TAH and ESRD transitioned successfully to outpatient hemodialysis and maintained for more than 2 years, though he did not survive to transplant. It is hoped that this report will raise awareness of this possibility, and assist in the development of protocols for similar patients to be successfully transitioned to outpatient dialysis care.

Aminoacylase 3 binds to and cleaves the N-terminus of the hepatitis C virus core protein.

Aminoacylase 3 (AA3) mediates deacetylation of N-acetyl aromatic amino acids and mercapturic acids. Deacetylation of mercapturic acids of exo- and endobiotics are likely involved in their toxicity. AA3 is predominantly expressed in kidney, and to a lesser extent in liver, brain, and blood. AA3 has been recently reported to interact with the hepatitis C virus core protein (HCVCP) in the yeast two-hybrid system. Here we demonstrate that AA3 directly binds to HCVCP (K(d) ~10 µM) that may by implicated in HCV pathogenesis. AA3 also revealed a weak endopeptidase activity towards the N-terminus of HCVCP.