Disseminated Ureaplasma polyarthritis in a renal transplant recipient.

BACKGROUND: The risk of infection following kidney transplant increases substantially in the setting of hypogammaglobulinemia and T-cell-depleting therapy. Ureaplasma has been described to cause invasive disease in immunocompromised hosts with humoral immunodeficiency. We describe a kidney transplant recipient with history of antineutrophil cytoplasmic autoantibody (ANCA) vasculitis remotely treated with rituximab who developed Ureaplasma polyarthritis following transplant. The purpose of this report is to highlight the unique risks that kidney transplant patients face particularly if hypogammaglobulinemic. CASE REPORT: Patient is a 16-year-old female with history of granulomatosis with polyangiitis (GPA) treated with maintenance dose of rituximab 13 months prior to transplant. Patient underwent deceased donor kidney transplant with thymoglobulin induction. IgG was 332 mg/dL and CD20 was zero at the time of transplant. One month posttransplant, the patient developed polyarticular arthritis without fever, pyuria, or evidence of GPA reactivation. MRI had diffuse tenosynovitis, myositis, fasciitis, cellulitis, and effusions of three involved joints. Bacterial, fungal, and AFB cultures remained negative, but 16 s ribosomal PCR testing from joint aspirates detected Ureaplasma parvum. The patient was treated with levofloxacin for 12 weeks with the resolution of symptoms. CONCLUSIONS: Ureaplasma infection is an under-recognized pathogen in kidney transplant patients. A high index of clinical suspicion should be employed to identify Ureaplasma infection, especially in those with secondary hypogammaglobulinemia, as this is often missed due to its lack of growth on standard media and the need for molecular testing. In patients with prior B-cell depletion, routine monitoring for B-cell recovery to identify risk factors for opportunistic infections is indicated.

Pregnancy History and Kidney Disease Progression Among Women Enrolled in Cure Glomerulonephropathy.

Introduction: Preeclampsia increases the risk for future chronic kidney disease (CKD). Among those diagnosed with CKD, it is unclear whether a prior history of preeclampsia, or other complications in pregnancy, negatively impact kidney disease progression. In this longitudinal analysis, we assessed kidney disease progression among women with glomerular disease with and without a history of a complicated pregnancy. Methods: Adult women enrolled in the Cure Glomerulonephropathy study (CureGN) were classified based on a history of a complicated pregnancy (defined by presence of worsening kidney function, proteinuria, or blood pressure; or a diagnosis of preeclampsia, eclampsia, or hemolysis, elevated liver enzymes, and low platelets [HELLP] syndrome), pregnancy without these complications, or no pregnancy history at CureGN enrollment. Linear mixed models were used to assess estimated glomerular filtration rate (eGFR) trajectories and urine protein-to-creatinine ratios (UPCRs) from enrollment. Results: Over a median follow-up period of 36 months, the adjusted decline in eGFR was greater in women with a history of a complicated pregnancy compared to those with uncomplicated or no pregnancies (-1.96 [-2.67, -1.26] vs. -0.80 [-1.19, -0.42] and -0.64 [-1.17, -0.11] ml/min per 1.73 m2 per year, P = 0.007). Proteinuria did not differ significantly over time. Among those with a complicated pregnancy history, eGFR slope did not differ by timing of first complicated pregnancy relative to glomerular disease diagnosis. Conclusions: A history of complicated pregnancy was associated with greater eGFR decline in the years following glomerulonephropathy (GN) diagnosis. A detailed obstetric history may inform counseling regarding disease progression in women with glomerular disease. Continued research is necessary to better understand pathophysiologic mechanisms by which complicated pregnancies contribute to glomerular disease progression.

Functional Validation of an Alpha-Actinin-4 Mutation as a Potential Cause of an Aggressive Presentation of Adolescent Focal Segmental Glomerulosclerosis: Implications for Genetic Testing.

Genetic testing in the clinic and research lab is becoming more routinely used to identify rare genetic variants. However, attributing these rare variants as the cause of disease in an individual patient remains challenging. Here, we report a patient who presented with nephrotic syndrome and focal segmental glomerulosclerosis (FSGS) with collapsing features at age 14. Despite treatment, her kidney disease progressed to end-stage within a year of diagnosis. Through genetic testing, an Y265H variant with unknown clinical significance in alpha-actinin-4 gene (ACTN4) was identified. This variant has not been seen previously in FSGS patients nor is it present in genetic databases. Her clinical presentation is different from previous descriptions of ACTN4 mediated FSGS, which is characterized by sub-nephrotic proteinuria and slow progression to end stage kidney disease. We performed in vitro and cellular assays to characterize this novel ACTN4 variant before attributing causation. We found that ACTN4 with either Y265H or K255E (a known disease-causing mutation) increased the actin bundling activity of ACTN4 in vitro, was associated with the formation of intracellular aggregates, and increased podocyte contractile force. Despite the absence of a familial pattern of inheritance, these similar biological changes caused by the Y265H and K255E amino acid substitutions suggest that this new variant is potentially the cause of FSGS in this patient. Our studies highlight that functional validation in complement with genetic testing may be required to confirm the etiology of rare disease, especially in the setting of unusual clinical presentations.

Kidney transplantation in children with decreased left ventricular systolic function: a Midwest Pediatric Nephrology Consortium study.

BACKGROUND: Left ventricular (LV) systolic dysfunction is a relatively uncommon but serious complication of pediatric chronic kidney disease, and may be related to uremia and uncontrolled hypertension. There is limited information on the strategy for managing these children. In some cases, combined heart-kidney transplant may be considered or kidney transplant delayed until cardiac function improves. It is unknown whether these patients are at increased risk for poor outcomes after kidney transplantation. METHODS: We conducted a retrospective, multicenter study on the outcomes of children with severe and symptomatic cardiomyopathy who underwent kidney transplantation. RESULTS: Eleven patients receiving maintenance dialysis with systolic dysfunction underwent kidney transplantation without simultaneous heart transplant. Nine patients had congestive heart failure in the pre-transplant period. There were no identified complications post-transplant related to the underlying cardiac dysfunction. LV systolic function normalized in all patients and the mean shortening fraction increased from 19.0 ± 4.6 % to 32.0 ± 4.4 % (p < 0.0001). CONCLUSIONS: Kidney transplantation should be considered for children receiving maintenance dialysis with severe LV dysfunction.

Rasburicase improves hyperuricemia in infants with acute kidney injury.

Recent data suggest that elevated levels of uric acid (UA) might contribute to the progression of renal disease. Rasburicase, recombinant urate oxidase, is a highly safe and efficacious hypo-uricosuric agent for treatment of elevated UA levels from tumor lysis. We adopted the use of rasburicase for management of hyperuricemia in infants with acute kidney injury (AKI) and, herein, report our experience. We conducted a retrospective chart review of infants with hyperuricemia (UA > 8 mg/dl) secondary to AKI (serum creatinine > 1.5 mg/dl) treated with rasburicase. Seven infants (mean age 34 +/- 55 days, six male), with a mean weight of 3.2 +/- 1.2 kg, were identified. Rasburicase was administered intravenously as a single, onetime, bolus of 0.17 +/- 0.04 mg/kg body weight. Within 24 h, serum UA had decreased from 13.6 +/- 4.5 mg/dl to 0.9 +/- 0.6 mg/dl (P < 0.05), creatinine had decreased from 3.2 +/- 2.0 mg/dl to 2.0 +/- 1.2 mg/dl (P < 0.05), and urinary output had increased from 2.4 +/- 1.2 ml/kg per hour to 5.9 +/- 1.8 ml/kg per hour (P < 0.05). Continued improvements in UA, creatinine, and urinary output were observed in the week following administration of rasburicase, without rebound of the UA. We observed no treatment-related side effects. All patients demonstrated a normalization of uric acid level without need of renal replacement therapy. In conclusion, a single intravenously administered bolus of rasburicase appears to be a novel treatment for hyperuricemia in infants with AKI.

The natural progression of kidney injury in young type 1 diabetic patients.

Diabetes is the most common cause of end-stage renal disease in industrialized countries. This article describes the structural changes in early diabetic nephropathy and the relationship with renal functional parameters, blood pressure, and albumin excretion. The detrimental influence of sustained hyperglycemia and/or glycemic fluctuations on renal structural change has been well documented. Tight glycemic control is paramount to preventing the development, and even the regression, of renal lesions. As much of the renal injury from diabetes occurs in clinical silence before symptoms or laboratory findings of renal injury are evident, finding early markers of risk is imperative so that nephropathy can be prevented. Currently, the only clinical surrogate marker of diabetic renal injury available is microalbuminuria. However, given the reports of regression of microalbuminuria back to normoalbuminuria, the reliability of this tool as an indicator of risk has been questioned. The need for alternative, noninvasive surrogate markers is described in this report.

Lessons learned from studies of the natural history of diabetic nephropathy in young type 1 diabetic patients.

Diabetic Nephropathy (DN) remains the leading cause of end stage renal disease (ESRD) in the Western world, responsible for nearly half of all new ESRD cases in the USA (1). DN develops in 20-25% of patients with type 1 diabetes (T1DM) (2) and, although risk of DN is clearly related to glycemic control (3,4), other variables including genetic propensity (5) are needed to explain why only a minority T1 DN patients progress to ESRD. The clinical manifestations of DN including increasing levels of urinary albumin excretion (AER), rising blood pressure (BP) and falling glomerular filtration rates (GFR) are closely related to renal structural abnormalities of DN (5,6). These glomerular, tubular, vascular and interstitial lesions are strongly correlated with these functional abnormalities especially when non-linear analysis models are used (6,7). This is because DN's natural history is one of clinical silence for years to decades during which time serious underlying renal lesions may be developing. Once the clinical manifestations, including the development of persistent microalbuminuria [(MA); (AER 20-200 microg/min)] are present, the structural injury is often far advanced (8). Moreover the nature of the renal lesions changes following the development of overt proteinuria so that the further decline in GFR is now associated with focal and global glomerular sclerosis and tubulo-interstitial injury which probably accelerates the GFR decline towards ESRD (7). Since interventions at these late stages of disease may only slow but not completely arrest the inexorable progression towards renal failure (9), understanding early natural history becomes important. Since DN structurally and functionally is a progressive disease; it is reasonable to presume that patients that either do not develop the earlier lesions of DN or develop them very slowly will not progress within their lifetime to stages of advanced renal structural injury and ESRD. We therefore considered it important to understand the early natural history of diabetic nephropathy and formed the International Diabetic Nephropathy Study Group (IDNSG) in order to investigate the early stages of DN in young T1DM volunteers. The design of the Natural History Study (NHS) (9) has been reported. The IDNSG participating institutions included 3 university centers (McGill University, Montreal, Canada with affiliations with the University of Sherbrooke, Sherbrooke, Canada, the Ottawa Civic Hospital, and the Childrens Hospital of Eastern Ontario; the Department of Pediatrics, University of Minnesota Medical School with affiliations at St Paul Children's Hospital and the International Diabetes Center in Minneapolis; the Robert Debré Höpital in Paris with affiliations with Höpital Saint Louis). The data coordinating center for the NHS was in the Department of Epidemiology and Biostatistics at McGill University and light microscopy readings were carried out at INSERM Unité 192 at the Höpital Necker-Enfants Malades in Paris. Patients could be included if they had type 1 diabetes for 2-20 years, had onset of diabetes before age 31, had AER less than 100 mug/min and GFR > or = 90 ml/min/ 1.73m2 (9). Patients also had to be normotensive for their age and sex and have no other significant renal or systemic disease. Quarterly studies included measurements of blood pressure, (BP), urinary albumin excretion rate (AER), hemoglobin A1C (HbA1C), GFR, and renal plasma flow (RPF). Renal biopsies were performed at baseline and after 5 years in the study. The primary goal of the study was to determine the clinical predictors of the baseline biopsy and baseline clinical and renal structural predictors of the changes between the baseline and the 5 year biopsy. The longitudinal structural studies are still in analysis and this paper will mainly review the cross sectional studies that have been completed to date.

The early natural history of nephropathy in Type 1 Diabetes: III. Predictors of 5-year urinary albumin excretion rate patterns in initially normoalbuminuric patients.

Predictors of albumin excretion rate (AER) abnormalities could provide earlier indicators of diabetic nephropathy risk. Data from the Natural History Study, a prospective 5-year observation of renal structure and function in young type 1 diabetic patients, were examined for predictors of AER patterns in normoalbuminuric type 1 diabetic patients. Included were 170 patients (96 females) (aged 16.7 +/- 5.9 years, duration of diabetes 8.0 +/- 4.3 years) with normal blood pressure, normoalbuminuria (AER <20 microg/min), and eight or more follow-up visits over 5 years. AER, blood pressure, and HbA1c (A1C) were determined quarterly and glomerular filtration rate (GFR) annually. Persistent microalbuminuria (PMA) was defined as 20-200 microg/min in two of three consecutive values within 6-12 months. Four different AER patterns were identified. Group 1 (n = 99): all values <20 microg/min. Group 2 (n = 49): intermittent levels >20 microg/min but not meeting microalbuminuria criteria. Group 3 (n = 14): PMA during follow-up but normoalbuminuria at study exit. Group 4 (n = 8): microalbuminuria at study exit. Group 4 (497 +/- 95 nm, P < 0.01) and group 3 (464 +/- 113 nm, P = 0.03) patients had greater baseline glomerular basement membrane (GBM) width versus group 1 (418 +/- 67 nm). Baseline GFR in group 4 (163 +/- 37 ml.min(-1). 1.73 m(-2)) was higher than group 1 (143 +/- 28 ml.min(-1) . 1.73 m(-2), P = 0.04). A1C was higher in group 2 (9.0 +/- 1.2%) than group 1 (8.4 +/- 1.1%, P = 0.008). Thus, greater increases in GBM width and GFR were predictors of PMA. Since 64% of the patients that developed microalbuminuria reverted to normoalbuminuria, the risk of diabetic nephropathy as defined by current microalbuminuria criteria is unclear.