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INTRODUCTION: Autologous cell-based therapies (CBT) to treat chronic kidney disease (CKD) with diabetes are novel and can potentially preserve renal function and decelerate disease progression. CBT dosing schedules are in early development and may benefit from individual bilateral organ dosing and kidney-dependent function to improve efficacy and durability. The objective of this open-label, phase 2 randomized controlled trial (RCT) is to evaluate participants' responses to rilparencel (Renal Autologous Cell Therapy-REACT®) following bilateral percutaneous kidney injections into the kidney cortex with a prescribed dosing schedule versus redosing based on biomarker triggers. METHODS: Eligible participants with type 1 or 2 diabetes and CKD, eGFR 20-50 mL/min/1.73 m2, urine albumin-to-creatinine ratio (UACR) 30-5,000 mg/g, hemoglobin >10 g/dL, and glycosylated hemoglobin <10% were enrolled. After a percutaneous kidney biopsy and bioprocessing ex vivo expansion of selected renal cells, participants were randomized 1:1 into two cohorts determined by the dosing scheme. Cohort 1 receives 2 cell injections, one in each kidney 3 months apart, and cohort 2 receives one injection and the second dose only if there is a sustained eGFR decline of ≥20 mL/min/1.73 m2 and/or UACR increase of ≥30% and ≥30 mg/g, confirmed by re-testing. CONCLUSION: The trial is fully enrolled with fifty-three participants. Cell injections and follow-up clinical visits are ongoing. This multicenter phase 2 RCT is designed to investigate the efficacy and safety of rilparencel with bilateral kidney dosing and compare two injection schedules with the potential of preserving or improving kidney function and delaying kidney disease progression among patients with stages 3a-4 CKD with diabetes.

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Rationale & Objective: Chronic kidney disease-associated pruritus (CKD-aP) in patients treated by hemodialysis (HD) impairs quality of life (QoL). Difelikefalin, a selective κ-opioid receptor agonist, decreased the intensity of CKD-aP in patients undergoing HD. This pooled analysis evaluated difelikefalin's efficacy and the itch-related QoL overall and in subgroups defined by demographics or disease characteristics. Study Design: In KALM-1 and KALM-2, participants were randomized (1:1) to receive intravenous difelikefalin or placebo 3 times/wk for 12 weeks, followed by a 52-week open-label extension. Setting & Participants: Adults with moderate to severe CKD-aP treated by HD in North America, Europe, and the Asia-Pacific region. Intervention: Intravenous difelikefalin at 0.5 mcg/kg or placebo. Outcomes: Itch intensity (Worst Itching Intensity Numerical Rating Scale [WI-NRS]) and itch-related QoL (Skindex-10 and 5-D Itch questionnaires). Results: 851 participants were randomized (difelikefalin, n = 426; placebo, n = 425). This pooled analysis demonstrated early     (week 1), sustained difelikefalin efficacy, with significantly greater achievement of ≥3-point WI-NRS reduction with difelikefalin (51.1%) versus placebo (35.2%; P < 0.001). Achievement of a ≥4-point WI-NRS reduction was significantly greater with difelikefalin (38.7%) versus placebo (23.4%; P < 0.001). Difelikefalin reduced itch intensity in subgroups based on age, sex, anti-itch medication use, the presence of specific medical conditions, and gabapentin or pregabalin use. More participants receiving difelikefalin versus placebo achieved clinically meaningful decreases of ≥15 points on the Skindex-10 scale (55.5% vs 40.5%, respectively; P < 0.001) and ≥5 points on the 5-D Itch scale (52.1% vs 42.3%, respectively; P = 0.01), with sustained 5-D Itch effects up to 64 weeks. Limitations: Subgroup samples were small. The WI-NRS, Skindex-10, and 5-D Itch are not used in routine clinical care of dialysis patients; therefore, findings may not reflect the real-world effectiveness of difelikefalin. Conclusions: Difelikefalin demonstrated rapid, sustained efficacy, with consistent results in diverse populations of patients treated by HD. Funding: Cara Therapeutics, Inc. Trial Registration: The KALM-1 trial is registered as NCT03422653 and the KALM-2 trial is registered as NCT03636269.

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Primary renal tubulointerstitial disease resulting from proximal tubule antigen-specific antibodies and immune complex formation has not been well characterized in humans. We report a cohort of patients with a distinct, underappreciated kidney disease characterized by kidney antibrush border antibodies and renal failure (ABBA disease). We identified ten patients with ABBA disease who had a combination of proximal tubule damage, IgG-positive immune deposits in the tubular basement membrane, and circulating antibodies reactive with normal human kidney proximal tubular brush border. All but one of the patients also had segmental glomerular deposits on renal biopsy specimen. Patients with ABBA disease were elderly and presented with AKI and subnephrotic proteinuria. Serum from all patients but not controls recognized a high molecular weight protein in renal tubular protein extracts that we identified as LDL receptor-related protein 2 (LRP2), also known as megalin, by immunoprecipitation and mass spectrometry. Immunostaining revealed that LRP2 specifically colocalized with IgG in the tubular immune deposits on the ABBA biopsy specimen but not the control specimen analyzed. Finally, ABBA serum samples but not control samples showed reactivity against recombinantly expressed N-terminal LRP2 fragments on Western blots and immunoprecipitated the recombinantly expressed N-terminal region of LRP2. This case series details the clinicopathologic findings of patients with ABBA disease and shows that the antigenic target of these autoantibodies is LRP2. Future studies are needed to determine the disease prevalence, stimulus for ABBA, and optimal treatment.

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Medications can cause a tubulointerstitial insult leading to acute kidney injury through multiple mechanisms. Acute tubular injury, a dose-dependent process, occurs due to direct toxicity on tubular cells. Acute interstitial nephritis characterized by interstitial inflammation and tubulitis develops from drugs that incite an allergic reaction. Other less common mechanisms include osmotic nephrosis and crystalline nephropathy. The latter complication is rare but has been associated with several drugs, such as sulfadiazine, indinavir, methotrexate, and ciprofloxacin. Triamterene crystalline nephropathy has been reported only rarely, and its histologic characteristics are not well characterized. We report 2 cases of triamterene crystalline nephropathy, one of which initially was misdiagnosed as 2,8-dihydroxyadenine crystalline nephropathy.

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PURPOSE: The incidence of parathyroid carcinoma is approximately 0.5% to 5% in patients with primary hyperparathyroidism. Recurrent parathyroid carcinoma is treated with surgical resection of all sites of disease to ameliorate systemic manifestations of hyperparathyroidism, primarily hypercalcemia. This study investigates the role of parathyroid scintigraphy and computed tomography (CT) imaging in recurrent parathyroid carcinoma. MATERIALS AND METHODS: A retrospective chart review was performed on 8 patients diagnosed with recurrent parathyroid carcinoma at our tertiary care institution between 1975 and 2001. Surgical reports, histopathology, parathyroid scintigraphy, and CT findings were recorded. Surgical reports and radiologic studies were compared for concordance of recurrence sites. RESULTS: There were 32 imaging studies before reoperation: 15 parathyroid scintigraphy and 17 CTs. Of 15 sites of recurrence potentially seen on scintigraphy, 10 were true-positive (67%). Of 17 sites of recurrence potentially seen on CT, 9 were true-positive (53%). Of the 8 false-negatives on CT, 7 of these recurrences were in the surgical bed (88%). There were 9 instances in which CT and scintigraphy were performed preoperatively for comparison and correlation. CT and scintigraphic findings were incongruent in 7 of 9 of these cases (78%). CONCLUSION: Successful surgical intervention for recurrent parathyroid carcinoma requires accurate preoperative localization studies and complete excision of metastases. Our data supports combined analysis of parathyroid scintigraphy and CT for patients with recurrent disease before reoperation. Additionally, our review suggests that sensitivity may be optimized with SPECT parathyroid scintigraphy and close correlation with CT.

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OBJECT: A zone of perilesional ischemia has been demonstrated around intracerebral hemorrhage (ICH) in numerous experimental models and in human studies. There is potential for perfusion recovery in the zone of perilesional oligemia around ICH. The authors sought to demonstrate, quantify, and study the chronological evolution of perilesional ischemic change in ICH in humans by measuring cerebral blood flow. METHODS: Eleven patients with spontaneous supratentorial ICH underwent two technetium-99m hexamethylpropyleneamine oxime single-photon emission computerized tomography (SPECT) scanning, one in the acute stage (within days of ictus) and the other in the late stage (6-9 months postictus). All patients in this study were treated nonsurgically. Methods of SPECT data analysis based on count differences in regions of interest can be difficult to apply to images with large space-occupying lesions such as ICH, because of the distortion of intracranial anatomy, midline shift, and alterations in the three-dimensional (3D) characteristics of the lesion over time (that is, absorption of the hematoma on the later studies). The authors used the following method: the late and early images were registered and aligned to a common 3D orientation and were normalized to maximal counts. The late images were then compared voxel by voxel with the early ones. The region-growing algorithm was used to discern the difference between the two images, outlining voxels in the perihematoma region, with a signal improvement of at least 15% on the late image. Discrete brain regions around the hematoma with at least a 15% improvement in radiotracer uptake (and hence perfusion) in the late images were observed in all cases. The mean volume of brain with a greater than 15% improvement in perfusion between the two studies was 34.8 cm3 (range 7.2-71.3 cm3). These volumes represent regions of the brain that were poorly perfused in the initial studies. This may represent a zone of reversible perilesional oligemia (penumbra) in ICH in humans. CONCLUSIONS: This is the first study in which it is documented that some of the perilesional hypoperfused tissue around human ICH regains its perfusion in the long term, leading the authors to suggest that there may be a penumbra in human ICH. Medical or surgical therapeutic interventions could increase the volume of perilesional brain that recovers after the initial insult. The results of this study therefore support the concept that intervention in ICH has the potential to reduce the ultimate neurological deficit and improve outcome.

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OBJECT: Spontaneous intracerebral hemorrhage (SICH) and traumatic intracerebral hemorrhage (TICH) are common disorders. The authors planned to study how these two types of hemorrhage behave pathologically and clinically to gain further insight into their causes, pathogeneses, indications for surgical intervention, and prognoses. METHODS: Prospectively filled databases of demographic, clinical, radiological, and outcome details have been maintained for all patients admitted to the Regional Neurosciences Centre with head injury since 1987 and with SICH since 1993. Of the 5686 patients whose case information was included in the head-injury database, 90 were found to suffer from an isolated intracerebral hemorrhage (ICH) as the only major abnormality observed on computerized tomography scans (subdural and extradural hematomas were excluded). Case details on these 90 patients and the 440 patients from the SICH database were extracted and analyzed using a statistical software program. The median age of patients with TICH was lower than the median age of patients with SICH (51 years compared with 65 years, respectively), but it was much higher than the median age of the entire head-injury group (21 years). Among patients younger than 45 years of age, 0.8% of patients who experienced trauma suffered from an ICH compared with 4.3% of patients older than 45 years of age. Irrespective of intervention, much better outcomes were achieved by patients with TICH compared with those with SICH (67% favorable outcomes compared with 24% in patients with SICH). Following trauma, there was no significant relationship between the severity of injury and the development of ICH. At presentation the median Glasgow Coma Scale (GCS) score for both groups was 13. Younger age and higher GCS score at presentation were strongly related to a favorable outcome for both types of hemorrhage. There was no significant difference in patient age, presenting GCS score, or outcomes of patients who underwent surgery compared with those who did not for either type of hemorrhage. No conclusions can be drawn about the efficacy of surgery from such observational studies. CONCLUSIONS: On the basis of these data the authors suggest that TICH and SICH have different features: TICH affects a slightly younger age group and carries a much better prognosis compared with SICH. In addition, indications for surgical intervention are not well defined for either type of hemorrhage. Practice is subjective and inconsistent. The International Surgical Trial in Intracerebral Haemorrhage may resolve the dilemma for SICH. A similar trial in which surgery is compared with conservative management should be considered for cases of TICH.

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