Fertility Management in Cystinosis: A Clinical Perspective.

Cystinosis is a rare, inherited, lysosomal storage disorder characterized by the progressive accumulation of intralysosomal cystine and subsequent organ and tissue damage. The kidneys are the first and most severely impacted organ. Although cystinosis was once considered a fatal pediatric disease, patients with cystinosis are living well into adulthood with advances in medical care, including kidney transplant and early and continuous use of cysteamine therapy. This increase in life expectancy has revealed an extrarenal phenotype of cystinosis that emerges in adolescence and adulthood, affecting nearly all body systems, including the endocrine and reproductive systems. As individuals with cystinosis are planning for the future, reproductive health and fertility have become areas of increased focus. This narrative review aims to summarize the current understanding of reproductive health and fertility in patients with cystinosis and discuss practical considerations for monitoring and managing these complications.

Kidney Transplant Outcomes in Patients With Scleroderma an Experience at Northwestern Memorial Hospital, Chicago, Illinois.

BACKGROUND: Scleroderma renal crisis (SRC) is a devastating complication of diffuse cutaneous systemic sclerosis (dcSSc) that occurs in 5% to 20% of patients in this population. End-stage kidney disease develops in 25% to 40% of SRC, and mortality occurs in 50% at 5 years. Kidney transplantation (KT) is a viable option, but little data exist on outcomes. METHODS: We performed a retrospective study of all patients with dcSSc who underwent KT at Northwestern Hospital between 2000 and 2020. The objective of this study was to determine graft and patient survival at years 5 and 10 post-transplant. RESULTS: Both patient and graft survival were 78% and 100% at 5 and 10 years, respectively. Kidney transplantation is associated with favorable outcomes in patients and graft survival at 5 and 10 years in patients with dcSSc.

Characterization of Choriocapillaris and Choroidal Abnormalities in Alport Syndrome.

Purpose: To analyze the characteristics of the choriocapillaris and the choroid in patients with Alport syndrome (AS) and investigate their clinical and demographic associations. Methods: Multicenter, cross-sectional study. Forty-two eyes with AS were consecutively enrolled. A cohort of 33 healthy eyes was included as controls. Demographics and medical history were collected for each participant. Each eye underwent 3 × 3 swept-source optical coherence tomography angiography (PLEX Elite 9000 2.0; Carl Zeiss Meditec, Dublin, CA, USA) and spectral-domain OCT (Spectralis HRA2; Heidelberg Engineering, Heidelberg, Germany). Choriocapillaris flow deficit (FD) number, mean FD size, total FD area, FD density, subfoveal choroidal thickness (CT), total CT, and choroidal vascularity index (CVI) were compared between AS and control eyes. Factors associated with the FD density and the CVI in AS were explored with multivariable linear mixed models. Results: There was high intragroup variability in choriocapillaris and choroidal measurements in patients with AS. Choriocapillaris FD in patients with AS were more numerous compared to controls (P = 0.02). FD density in eyes with AS increased with older age (estimate = 0.31% for each year; 95% confidence interval [CI], 0.06-0.57; P = 0.02) and was higher in patients with a history of kidney transplant (estimate = 9.66% in case of positive history; 95% CI, 3.52-15.8; P = 0.006). The CVI was lower in eyes with dot maculopathy (estimate = -3.30% if present; 95% CI, -6.38 to -0.21; P = 0.04) and anterior lenticonus (estimate = -6.50% if present; 95% CI, -10.99 to -2.00; P = 0.006). Conclusions: Patients with AS with kidney involvement requiring transplant may present with more severe choriocapillaris impairment. Lower choroidal vascularity was found in the presence of other ocular structural abnormalities. Translational Relevance: An increased load of choriocapillaris flow deficits on optical coherence tomography angiography was found in patients with Alport syndrome who also had severe kidney disease requiring transplant.

THE SPECTRUM OF INTERNAL LIMITING MEMBRANE DISEASE IN ALPORT SYNDROME: A Multimodal Imaging Study.

PURPOSE: To characterize the spectrum of internal limiting membrane (ILM) disease in Alport syndrome using multimodal imaging, including widefield (WF) and ultra-widefield (UWF) modalities, and to report their relative prevalence according to the genetic pattern of inheritance. METHODS: Cross-sectional clinical study of patients diagnosed with Alport syndrome. All patients underwent UWF color photography and autofluorescence, WF-optical coherence tomography angiography and spectral-domain optical coherence tomography. Demographics, past medical and ophthalmic history, and genetic mutation history were collected. RESULTS: Forty-two eyes of 21 patients (11 men; age 36.6 ± 12.9 years) were included. Macular spectral-domain optical coherence tomography revealed ILM granularity, more frequent in X-linked Alport syndrome and corresponding to dot maculopathy on color fundus. Mid-peripheral spectral-domain optical coherence tomography scans revealed multilamellated ILM in eight eyes (19%), presumably progressive, which corresponded to a cavitary pattern on en-face OCT. En-face OCT revealed multiple areas of retinal nerve fiber layer dehiscence in the macula, overlapping with vascular lacunae on optical coherence tomography angiography, and a coarse arrangement of retinal nerve fiber layer above and below the temporal raphe in 20 eyes (52%). CONCLUSION: Multimodal imaging allowed for the detection/characterization of retinal findings (ILM granularity, progressive ILM lamellation, retinal nerve fiber layer dehiscence, vascular lacunae, and coarse arrangement of retinal nerve fiber layer toward the disc) as multifaceted manifestations of ILM disease in Alport syndrome.

Scleroderma renal crisis.

Scleroderma renal crisis (SRC) is a rare but life-threatening complication of systemic sclerosis (SSc) characterized by malignant hypertension and acute kidney injury. Historically, SRC was the leading cause of death in SSc. However, with the advent of angiotensin converting enzyme (ACE) inhibitors, mortality rates have decreased significantly. Nevertheless, one-year outcomes remain poor, with over 30% mortality and 25% of patients remaining dialysis-dependent. There is an urgent need to improve early recognition and treatment, and to identify novel treatments to improve outcomes of SRC. In this chapter, the clinical features, classification, pathophysiology, differential diagnosis, management and outcomes of SRC are presented. Specific issues relating to pregnancy, prophylactic ACE inhibition and management of essential hypertension are also discussed.

Variability in Kidney Function Estimates in Emerging Adults With Spina Bifida: Implications for Transitioning From Pediatric to Adult Care.

OBJECTIVE: To examine the variability of estimated glomerular filtration rate (eGFR) in emerging adults with spina bifida (SB) by comparing multiple equations across the transitional age period, hypothesizing that creatinine (Cr)-based equations show greater variability than cystatin-C (CysC)- or combination-based equations. METHODS: A retrospective cohort study was performed from 2012 to 2017 at a multidisciplinary SB clinic. Emerging adults were defined as patients ages 18-28 years old. Four pediatric, 3 adult, and 3 averaged eGFR equations were considered. Cross-sectional variability in eGFR data was assessed using coefficients of variation, chronic kidney disease (CKD) stage classification, and pairwise percent relative difference in eGFR between analogous pediatric and adult equations based on included lab values. Longitudinal changes in eGFR over time were compared across equations using a covariance pattern model accounting for repeated measures. RESULTS: Seventy-five emerging adults with SB (median age 21.8 years; 55% female; 83% with myelomeningocele) were included in cross-sectional analyses. Adult equations gave higher median eGFRs by 22%-27% and generally milder CKD stage classification than analogous pediatric equations. In longitudinal analyses (median follow-up of 22 months), all equations conferred negative eGFR changes over time (range -1.9 to -4.3 mL/min/1.73m2 per year) that were not significantly different. CONCLUSION: In emerging adults with SB, adult equations demonstrated higher median eGFRs by 22%-27% compared to analogous pediatric equations, even with Cystatin-C, and generally downstaged CKD stage classification. The same eGFR equation should be used for serial kidney function monitoring in emerging adults with SB who transition care from pediatric to adult services.

Assessing success in transitioning of young adults from pediatric to adult kidney practice.

BACKGROUND: Transfer from a pediatric to an adult medical setting is associated with many barriers. Additionally, there are little data on patients' assessment of the transition process itself. 3 years ago at Lurie Children's Hospital of Chicago, we established a kidney transition program with the help of an adult nephrologist, physician assistant (PA) and social worker (LCSW). After 18 months, we evaluated the patients' perception of the program as part of a continuous quality initiative process. METHODS: Patients who had transitioned from pediatric care and were seen at least once in the adult nephrology clinic were anonymized and asked to take an established 5-point Likert scale survey. Survey questions addressed readiness to transition, the transition process itself, and the perception of adult care. Surveys were followed with semi-structured interviews. 3 readers rated each response as either "negative," "neutral," or "positive." Average, standard deviation and reader reliability were calculated. The readers also selected a word that best depicted each response and those most-common words were counted by question and overall. RESULTS: 17 out of 42 patients (40%) completed the survey. Average age at transition (mean + SD) was 20 + 2 years; the majority of patients (82%) felt ready to transfer to adult care but only 59% felt they were consulted on the timing. 88% of patients felt having a transition appointment and meeting the adult care providers in the pediatric setting to be valuable. Although 94% of patients ultimately felt comfortable in the adult care environment, 18% experienced noticeable differences in treatment recommendations. 13 semi-structured interviews were conducted. Overall, the patients responded positively (3 + 0, 100% reader reliability) to the transition. But, when asked what could have improved the transition, the word the patients used most was, "earlier." CONCLUSION: Young adults (YA) transitioning to adult care often feel ready to transition earlier than their transfer of care date. They subjectively benefit from a transition program that outlines the process of transferring their care. Many YA patients would benefit from a transition program that bolsters patient independence during early adult care visits.

Practical Guide to Vaccination in All Stages of CKD, Including Patients Treated by Dialysis or Kidney Transplantation.

Infection is a major cause of morbidity and mortality in patients with chronic kidney disease (CKD), including those receiving maintenance dialysis or with a kidney transplant. Although responses to vaccines are impaired in these populations, immunizations remain an important component of preventative care due to their favorable safety profiles and the high rate of infection in these patients. Most guidelines for patients with CKD focus on the importance of the hepatitis B, influenza, and pneumococcal vaccines in addition to age-appropriate immunizations. More data are needed to determine the clinical efficacy of these immunizations and others in this population and define optimal dosing and timing for administration. Studies have suggested that there may be a benefit to immunization before the onset of dialysis or transplantation because patients with early-stage CKD generally have higher rates of seroconversion. Because nephrologists often serve as primary care physicians for patients with CKD, it is important to understand the role of vaccinations in the preventive care of this patient population.

Generation of a Core Set of Items to Develop Classification Criteria for Scleroderma Renal Crisis Using Consensus Methodology.

OBJECTIVE: To generate a core set of items to develop classification criteria for scleroderma renal crisis (SRC) using consensus methodology. METHODS: An international, multidisciplinary panel of experts was invited to participate in a 3-round Delphi exercise developed using a survey based on items identified by a scoping review. In round 1, participants were asked to identify omissions and clarify ambiguities regarding the items in the survey. In round 2, participants were asked to rate the validity and feasibility of the items using Likert-type scales ranging from 1 to 9 (where 1 = very invalid/unfeasible, 5 = uncertain, and 9 = very valid/feasible). In round 3, participants reviewed the results and comments from round 2 and were asked to provide final ratings. Items rated as highly valid and feasible (median scores ≥7 for each) in round 3 were selected as the provisional core set of items. A consensus meeting using a nominal group technique was conducted to further reduce the core set of items. RESULTS: Ninety-nine experts from 16 countries participated in the Delphi exercise. Of the 31 items in the survey, consensus was achieved on 13, in the categories hypertension, renal insufficiency, proteinuria, and hemolysis. Eleven experts took part in the nominal group technique discussion, where consensus was achieved in 5 domains: blood pressure, acute kidney injury, microangiopathic hemolytic anemia, target organ dysfunction, and renal histopathology. CONCLUSION: A core set of items that characterize SRC was identified using consensus methodology. This core set will be used in future data-driven phases of this project to develop classification criteria for SRC.

Eight unexpected cases of vancomycin associated acute kidney injury with contemporary dosing.

Vancomycin is one of the most commonly utilized antibiotics in US hospitals. It remains the drug of choice for the treatment of serious infections caused by methicillin-resistant Staphylococcus aureus. For many of these deep-seated infections, guidelines recommend achieving troughs of 15-20 mg/L for treatment efficacy. At our institution we observed a number of cases of presumed vancomycin-induced acute tubular necrosis clinically diagnosed by the nephrology service. We report eight cases of presumed vancomycin-induced acute tubular necrosis, three of which required hemodialysis before resolution of nephrotoxicity. Only three of the eight patients received nephrotoxins prior to development of nephrotoxicity. All eight patients ultimately recovered renal function following discontinuation.

Familial C3 glomerulonephritis caused by a novel CFHR5-CFHR2 fusion gene.

C3 glomerulopathy (C3G) is an ultra-rare complement-mediated renal disease characterized histologically by the predominance of C3 deposition within in the glomerulus. Familial cases of C3G are extremely uncommon and offer unique insight into the genetic drivers of complement dysregulation. In this report, we describe a patient who presented with C3G. Because a relative carried the same diagnosis, we sought an underlying genetic commonality to explain the phenotype. As part of a comprehension genetic screen, we completed multiplex ligation-dependent probe amplification across the complement factor H related region and identified amplification alterations consistent with a genomic rearrangement. Using comparative genomic hybridization, we narrowed and then cloned the rearrangement breakpoints thereby defining a novel fusion gene that is translated into a serum protein comprised of factor H related-5 (short consensus repeats 1 and 2) and factor H-related-2 (short consensus repeats 1-4). These data highlight the role of factor H related proteins in the control of complement activity and illustrate how perturbation of that control leads to C3G.

Recent Developments in the Classification, Evaluation, Pathophysiology, and Management of Scleroderma Renal Crisis.

Scleroderma renal crisis (SRC) is an uncommon complication of systemic sclerosis. Despite the advent of angiotensin-converting inhibitor therapy, SRC remains a life-threatening complication. Recent studies have contributed to a better understanding of SRC, but much remains unknown regarding its pathophysiology, risk factors, and optimal management. Genetic studies provide evidence that immune dysregulation might be a contributing factor, providing hope that further research in this direction might illuminate pathogenesis and provide novel predictors for this complication.

A randomized multicenter trial of paricalcitol versus calcitriol for secondary hyperparathyroidism in stages 3-4 CKD.

BACKGROUND AND OBJECTIVES: Calcitriol is used to treat secondary hyperparathyroidism in patients with CKD. Paricalcitol is less calcemic and phosphatemic in preclinical studies and in some trials in dialysis patients, but head-to-head comparisons in nondialysis patients are lacking. A large meta-analysis of trials concluded that these agents did not consistently reduce parathyroid hormone (PTH) and increased the risk of hypercalcemia and hyperphosphatemia. Therefore, the objective of this multicenter trial was to compare the rate of hypercalcemia between calcitriol and paricalcitol, while suppressing PTH 40%-60%. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients with stages 3-4 CKD (n=110) with a PTH level >120 pg/ml were recruited and randomized to 0.25 µg/d of calcitriol or 1 µg/d of paricalcitol between April 2009 and July 2011. Subsequent dose adjustments were by protocol to achieve 40%-60% PTH suppression below baseline. The primary endpoint was the rate of confirmed hypercalcemia of >10.5 mg/dl between groups. RESULTS: Forty-five patients in each group completed the 24 weeks of treatment. Both agents suppressed PTH effectively (-52% with paricalcitol and -46% with calcitriol; P=0.17), although the paricalcitol group reached a 40% reduction in PTH sooner at a median 8 weeks (interquartile range [IQR], 4, 12) versus 12 weeks (IQR, 8, 18; P=0.02) and had a lower pill burden of 240 (IQR, 180, 298) versus 292 (IQR, 231, 405; P=0.01). Confirmed hypercalcemia was very low in both groups (three with paricalcitol and one with calcitriol) and was not significantly different (P=0.36). Both groups had small increases in calcium and phosphorus levels (0.3-0.4 mg/dl in each electrolyte) and significant decreases in alkaline phosphatase, a marker of high bone turnover, with no significant differences between groups. CONCLUSIONS: These results show that both calcitriol and paricalcitol achieved sustained PTH and alkaline phosphatase suppression in stages 3-4 CKD, with small effects on serum calcium and phosphorus and a low incidence of hypercalcemia.

Management of digoxin therapy using pharmacokinetics in a patient undergoing continuous venovenous hemofiltration.

PURPOSE: The management of digoxin therapy using pharmacokinetics in a patient undergoing continuous venovenous hemofiltration (CVVH) is reported. SUMMARY: A 46-year-old African-American woman with New York Heart Association class IV, American College of Cardiology- American Heart Association stage D heart failure arrived from an outside facility with complaints of dyspnea after minimal exertion, orthopnea, and lower-extremity edema. A transthoracic echocardiogram revealed an estimated left ventricular ejection fraction of 15%. The patient subsequently required left ventricular assist device placement on hospital day 5 as a potential bridge to transplantation. A total digoxin loading dose of 500 µg i.v. (8.2 µg/kg) was given in two divided doses six hours apart. The next morning, the serum digoxin concentration was 1.9 ng/mL, and the patient was started on a maintenance digoxin dosage of 125 µg i.v. daily. On postoperative day (POD) 20, the patient developed acute kidney injury, and CVVH was initiated. The sieving coefficient (Sc), transmembrane clearance (CLtm), digoxin concentration in ultrafiltration fluid (Cuf), and need for supplemental digoxin were determined to account for CVVH- associated digoxin loss. After 14 days of CVVH, the patient's clinical condition improved, and CVVH was transitioned to intermittent hemodialysis. On POD 66, the patient was discharged to an extended-care facility without adverse reactions related to digoxin therapy. CONCLUSION: Analysis of serum digoxin concentration and digoxin Cuf values suggested that digoxin was cleared by CVVH, allowed calculation of Sc and CLtm values, and facilitated determination of digoxin requirements in a critically ill patient requiring CVVH.

Pharmacodynamic target attainment for various ceftazidime dosing schemes in high-flux hemodialysis.

Ceftazidime is a broad-spectrum cephalosporin with high-level activity against a variety of Gram-negative pathogens, including Pseudomonas aeruginosa. Improved outcomes are associated with cumulative percentages of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (%TMIC) of >45 to 70% of the dosing interval. Optimal dosing to achieve a 90% probability of target attainment (PTA) in patients receiving high-flux hemodialysis (HFHD) is unknown. We used existing data from six anephric adults receiving hemodialysis to construct a population model with the Pmetrics package for R. From the final model's joint probability density, we simulated the PTA for various ceftazidime dosing regimens, HFHD schedules, and organism MICs. For HFHD every 48 h and 1 g of ceftazidime given posthemodialysis, the PTA exceeds 90% for all isolates with MICs of ≤8 µg/ml, assuming a goal of 70%TMIC. For 72-h dialysis intervals, postdialysis dosing of 1 g is adequate for achievement of the 70%TMIC goal only for organisms with MICs of ≤4 µg/ml, while 2 g is adequate for organisms with MICs of ≤8 µg/ml. A dose of 500 mg once daily, regardless of HFHD schedule, has a 90% PTA for organisms with MICs of ≤16 µg/ml, while 1 g once daily may achieve 100% PTA even for resistant organisms with a MIC of 32 µg/ml. Therefore, to ensure maximal ceftazidime activity, once-daily dosing of 500 mg to 1 g ceftazidime in patients receiving HFHD may be preferable for critically ill patients when MIC data are unavailable and for more resistant organisms with ceftazidime MICs of 16 to 32 µg/ml.

Pharmacokinetic assessment of peramivir in a hospitalized adult undergoing continuous venovenous hemofiltration.

OBJECTIVE: To report a sieving coefficient for peramivir in a patient receiving continuous venovenous hemofiltration (CVVH). CASE SUMMARY: An 18-year-old male presented with chills, myalgias, and dyspnea and was hospitalized. Nasal secretions were positive for influenza by rapid antigen test at an outside facility and oseltamivir was commenced. Oral absorption was predicted to be unreliable, and intravenous peramivir was accessed as an emergency investigational new drug applicaiton (eIND). CVVH was initiated after the development of acute renal failure, with blood samples collected to determine peramivir concentrations. DISCUSSION: Peramivir, an intravenous investigational neuraminidase inhibitor with activity against influenza viruses, has limited data for dosing in the setting of CVVH. A single patient received 600 mg of peramivir intravenously and had blood and ultrafiltrate concentrations measured serially. A sieving coefficient of approximately 0.9 was identified. CONCLUSIONS: Peramivir is well cleared by CVVH, and drug exposure is potentially predictable based on flow rates. Further study is necessary.

Biopsy-Proven Acute Tubular Necrosis due to Vancomycin Toxicity.

Vancomycin (VAN) has been associated with acute kidney injury (AKI) since it has been put into clinical use in the 1950's. Early reports of AKI were likely linked to the impurities of the VAN preparation. With the advent of the more purified forms of VAN, the incidence of AKI related to VAN were limited to acute interstitial nephritis (AIN) or as a potentiating agent to other nephrotoxins such as Aminoglycosides. VAN as the sole etiologic factor for nephrotoxic acute tubular necrosis (ATN) has not been described. Here, we report a case of biopsy-proven ATN resulting from VAN.

High prevalence of cardiac autonomic dysfunction and T-wave alternans in dialysis patients.

BACKGROUND: Chronic hemodialysis (HD) patients have an elevated risk of sudden cardiac death (SCD), particularly in the 24 hours before the first HD of the week. Temporal changes in cardiac autonomic dysfunction, as characterized by abnormalities in heart rate variability (HRV) and heart rate turbulence (HRT), along with T-wave alternans (TWA), may contribute to this dispersion of risk. OBJECTIVE: This study sought to determine the prevalence of abnormal HRV, HRT, and TWA in HD patients and to compare their temporal distribution among periods of variable SCD risk. METHODS: HRV, HRT, and TWA were analyzed from 72-hour Holter monitors in HD patients, and results were compared among the 24-hour high-risk period before the first dialysis session of the week, the 24-hour intermediate-risk period beginning with the weeks' first dialysis, and the low-risk period the day after the first dialysis. Positive cut points were standard deviation of all normal R-R intervals ≤70 ms for HRV, onset ≥0% and/or slope ≤2.5 ms/R-R for HRT, and ≥53 µV for TWA. RESULTS: Of 41 enrollees, 28 (46% male, age 55 ± 12, ejection fraction 57% ± 11%) had sufficient data for analysis. Abnormalities were prevalent with 82%, 75%, and 96% of patients reaching threshold for HRV, HRT, and TWA in at least one 24-hour period, respectively. There was no significant difference in the prevalence of abnormal measures among dialytic intervals nor in the intraindividual distribution of abnormal measures (P >.05 for all). CONCLUSION: Abnormal HRV, HRT, and TWA are prevalent in HD patients and may indicate heightened SCD risk. No significant correlation was observed among these measures and recognized periods of variable risk.