Multiple Serial Casting for Recurrent Clubfoot in Arthrogryposis Corrects Deformity With Diminishing Returns.

PURPOSE: Arthrogryposis multiplex congenita (AMC) consists of more than 400 conditions involving severe joint contractures of at least two or more body regions. Management of clubfoot in patients with AMC is notoriously challenging, with a higher likelihood of recurrence than idiopathic clubfoot, which can be treated using the Ponseti technique to avoid or delay more invasive procedures. The purpose of this study is to determine the utility of multiple serial casting as a treatment of clubfoot in AMC using Pirani scores as an objective measure of deformity. METHODS: Pirani scores were retrospectively collected from 17 AMC patients with a total of 30 clubfeet and two years follow-up from initiation of treatment. Patients with a minimum of three casting series were included. Pre-treatment and post-treatment deformity scores were examined across casting series using analysis of variance (ANOVA) statistical analysis. RESULTS: The first series pre-treatment Pirani score improved from 4.80±1.54 to 1.68±1.48 (p<0.001). The second series improved from 4.23±1.03 to 2.72±0.916 (p<0.001). The third series had the smallest improvement from 3.87±1.07 to 2.82±1.02 (p<0.001). Change in Pirani scores showed a significant decrease from the first series to the second (p=0.001) and third (p<0.001). In addition, the number of casting days was found to significantly affect the change in scores during the third series (p=0.038). CONCLUSIONS: The Ponseti technique can improve clubfoot in AMC as measured by the Pirani score. Data shows that early intervention yields better results, with a diminished yet effective ability to elicit change over time.

Predicting Success of Deformity Correction With Tension Band Plating in Early-Onset Tibia Vara.

BACKGROUND: Angular deformity correction with tension band plating has not been as successful in early-onset tibia vara (EOTV) as it has been in other conditions. Our hypothesis is that perioperative factors can predict the success of lateral tibial tension band plating (LTTBP) in patients with EOTV. METHODS: A retrospective review was performed at 7 centers evaluating radiographic outcomes of LTTBP in patients with EOTV (onset <7 y of age). Single-event tibial LTTBP outcome was assessed through medial proximal tibial angle (MPTA). The final limb alignment following comprehensive limb growth modulation (CLGM), which could include multiple procedures, was assessed by mechanical axis zone (MAZone), mechanical tibio-femoral angle (mTFA), and mechanical axis deviation (MAD). Preoperative age, weight, deformity severity, medial physeal slope, and Langenskiöld classification +/- modification were investigated as predictors of outcome. Success was defined as the correction or overcorrection to normal age-adjusted alignment. The minimum follow-up was 2 years except when deformity correction, skeletal maturity, or additional surgery occurred. RESULTS: Fifty-two patients with 80 limbs underwent 115 tibial LTTBP procedures at a mean age of 5.3 y, including 78 primary, 21 implant revisions, and 15 reimplantations for recurrence. Tibial LTTBP resulted in a mean change of +8.6 o in MPTA and corrected 53% of tibias. CLGM resulted in MAD correction for 54% of limbs.Univariate analysis showed that success was best predicted by preoperative age, weight, MPTA, and MAD. Multivariate analysis identified that preoperative-MPTA/MAD and preoperative-weight<70 kg were predictive of MPTA and MAD correction, respectively. The probability of success tables are presented for reference. CONCLUSION: Successful correction of MPTA to age-adjusted norms following a single-event LTTBP occurred in 53% of tibias and was best predicted by preoperative-MPTA and preoperative body weight <70 kg. Comprehensive growth modulation corrected limbs in 54%. The probability of correction to age-adjusted MAD is best estimated by preoperative-MAZone 1 or 2 (MAD ≤40 mm). Limbs with preoperative-MAD>80 mm improved, but ultimately all failed to correct completely with CLGM. Osteotomy may need to be considered with these severe deformities. While modified Langenskiöld classification and medial physeal slope have been shown to predict the outcome of osteotomy, they were not predictive for LTTBP. Change in MPTA was common after physeal untethering. LEVEL OF EVIDENCE: Level-III.

Predicting Deformity Correction of Growth Modulation in Late-onset Tibia Vara.

BACKGROUND: Growth modulation in late-onset tibia vara (LOTV) has been reported to yield variable results. We hypothesized that parameters of deformity severity, skeletal maturity, and body weight could predict the odds of a successful outcome. METHODS: A retrospective review of tension band growth modulation for LOTV (onset ≥8 y) was performed at 7 centers. Tibial/overall limb deformity and hip/knee physeal maturity were assessed on preoperative anteroposterior standing lower-extremity digital radiographs. Tibial deformity change with first-time lateral tibial tension band plating (first LTTBP) was assessed by medial proximal tibia angle (MPTA). Effects of a growth modulation series (GMS) on overall limb alignment were assessed by mechanical tibiofemoral angle (mTFA) and included changes from implant removal, revision, reimplantation, subsequent growth, and femoral procedures during the study period. The successful outcome was defined as radiographic resolution of varus deformity or valgus overcorrection. Patient demographics, characteristics, maturity, deformity, and implant selections were assessed as outcome predictors using multiple logistic regression. RESULTS: Fifty-four patients (76 limbs) had 84 LTTBP procedures and 29 femoral tension band procedures. For each 1-degree decrease in preoperative MPTA or 1-degree increase in preoperative mTFA the odds of their successful correction decreased by 26% in the first LTTBP and 6% by GMS, respectively, controlling for maturity. The change in odds of success for GMS assessed by mTFA was similar when controlling for weight. Closure of a proximal femoral physis decreased the odds of success for postoperative-MPTA by 91% with first LTTBP and for final-mTFA by 90% with GMS, controlling for preoperative deformity. Preoperative weight ≥100 kg decreased the odds of success for final-mTFA with GMS by 82%, controlling for preoperative mTFA. Age, sex, race/ethnicity, type of implant, and knee center peak value adjusted age (a method for bone age) were not predictive of outcome. CONCLUSIONS: Resolution of varus alignment in LOTV using first LTTBP and GMS, as quantified by MPTA and mTFA, respectively, is negatively impacted by deformity magnitude, hip physeal closure, and/or body weight ≥100 kg. The presented table, utilizing these variables, is helpful in the prediction of the outcome of the first LTTBP and GMS. Even if complete correction is not predicted, growth modulation may still be appropriate to reduce deformity in high-risk patients. LEVEL OF EVIDENCE: Level III.

Femoral Deformity in Tibia Vara and Its Response to Growth Modulation.

BACKGROUND: While tibia vara is a disorder of the proximal tibial physis, femoral deformity frequently contributes to the overall limb malalignment. Our purpose was to determine how femoral varus deformity in tibia vara responds to growth modulation, with/without lateral tension band plating (LTBP) to the femur. METHODS: One-hundred twenty-seven limbs undergoing LTBP for tibia vara were reviewed. All had tibial LTBP and 35 limbs also had femoral LTBP for varus. Radiographs were measured for correction of the mechanical lateral distal femoral angle (mLDFA) and mechanical axis deviation (MAD). Preoperative-femoral varus was defined with an age-adjusted guide: mLDFA >95 degrees for 2 to below 4 years and mLDFA >90 degrees for 4 to 18 years. The 35 limbs having femoral LTBP were compared with 50 limbs with femoral varus and no femoral LTBP. In addition, 42 limbs that did not have preoperative-femoral varus were followed. Patients with early-onset (below 7 y) tibia vara were compared with those with late-onset (≥8 y). Outcome success was based on published age-adjusted mLDFA and MAD norms. RESULTS: Following femoral LTBP, the mean mLDFA decreased from 98.0 to 87.1 degrees. All femurs had some improvement, with 28/35 femurs (80%) achieving complete correction. One limb, with late follow-up, overcorrected, requiring reverse (medial) femoral tension band plating.For the 50 limbs with femoral varus and only tibial LTBP, 16/22 limbs (73%) with early-onset and 11/28 limbs (39%) with late-onset completely corrected their femoral deformities. If the limb had preoperative-femoral varus, femoral LTBP statistically correlated with successful mLDFA correction and improvement of MAD, only in the late-onset group.Forty-two limbs, without preoperative-femoral varus, had no change in their mean mLDFA of 87 degrees. However, 4 femurs (10%) ended with posttreatment varus. CONCLUSIONS: Femoral LTBP is effective in correcting femoral varus deformity in the tibia vara. For femoral varus associated with late-onset tibia vara, femoral LTBP should be considered. Those that had femoral LTBP had statistically more successful femoral and overall limb varus correction. However, in early-onset tibia vara, with associated femoral varus, observation is warranted because 73% of femurs are corrected without femoral intervention. This study was underpowered to show additional improvement with femoral LTBP in the early-onset group. Even limbs with normal femoral alignment, should be observed closely for the development of femoral varus, during tibial LTBP treatment for tibia vara. LEVEL OF EVIDENCE: Level III.

Guided Growth for Varus Deformity Following Early Tibial Osteotomy in Infantile Tibia Vara-A Multi-Center Study.

BACKGROUND: Despite early osteotomy, many patients with infantile tibia vara (ITV) have persistent or recurrent varus deformity and disordered growth at the medial proximal tibial physis. Our hypothesis was that lateral tibial tension band plating (LTTBP) could guide correction. METHODS: A retrospective review at 6 centers of 15 patients (16 extremities) was performed of LTTBP for varus deformity following early osteotomy in ITV, diagnosed≤4years of age. Correction of deformity parameters on digital standing anteroposterior lower extremity radiographs determined outcome. RESULTS: Twenty-two LTTBP procedures were performed at mean age of 7.5 years, including 4 revisions for implant failure and 2 reimplantations for recurrence. Single event LLTBP, improved the medial proximal tibial angle with a mean change of 13.4 degrees (0.39 degrees/month). Eleven limbs had preoperative mechanical lateral distal femoral angle (mLDFA)>90 degrees. While n degree femoral procedures were performed, at study end, 11 femurs had mechanical lateral distal femoral angle≤90°. Pretreatment, 13 extremities had mechanical axis zone (MAZone) III varus (81%) and 3 had MAZone II varus (19%). LTTBP's were able to initially correct 13 limbs to MAZone I or valgus but 4 limbs rebounded to MAZone II varus after implant removal. Final limb alignment, after all surgeries and rebound, included 9 in MAZone I, 5 in MAZone II varus and 2 in MAZone III varus. Average follow-up was 3.0 years at mean 10.7 years of age. Fifteen procedures resulted in improvement in MAZone and 7 had no change. On average, those that improved were younger (7.3 vs. 8.0 y), weighed less (45.5 kg with body mass index 26.5 kg/m 2 vs. 67.8 kg and body mass index 35.7 kg/m 2 ), had lower mechanical axis deviation (37.1 mm vs. 43.9 mm), lower medial physeal slope (61.7 vs. 68.7 degrees) and had a higher percentage of open triradiate phases (87 vs. 57%). CONCLUSIONS: LTTBP for residual varus, after initial osteotomy in ITV, resulted in 81% of limbs initially achieving MAZone I or valgus with implant failure revisions and femoral remodeling. Rebound after implant removal reduced the corrected rate to 56%. Ninety-four percent avoided osteotomy during the study period. LEVEL OF EVIDENCE: IV.

Proximal Femoral Focal Deficiency/Congenital Femoral Deficiency: Evaluation and Management.

Proximal focal femoral deficiency is a congenital transverse deficiency in which the femur is globally smaller with a typical proximal deformity at the hip that may include distal involvement of knees, leg, and feet. Congenital femoral deficiency (CFD) describes a broader spectrum of longitudinal deficiency inclusive of proximal focal femoral deficiency. CFD may also include lateral distal femoral hypoplasia, knee cruciate ligament deficiency, rotational instability, patellar dislocation, fibular hemimelia, ray absence, and contralateral limb involvement. Treatment intends to maximize function by limb equalization and deformity correction ranging from nonsurgical management using prosthetics to amputation and may include lengthening, shortening, and complex limb reconstruction. Management decisions depend on overall severity and the patient and family's preferences and priorities. Owing to its complexity, CFD is best treated by clinicians with considerable deformity treatment experience who can help guide decision making and embark on a treatment course that will maximize the functional outcome.

Guided Growth Procedures: Broken Tension Band Implants in Patients With Blount Disease.

BACKGROUND: Tension band plate and screw implants (TBI) are frequently used for temporary hemiepiphyseodeses to manage angular deformity in growing children. The reported implant breakage rate, when TBI is used for deformities in patients with Blount disease, is much higher than when used in other diagnoses. Our hypothesis is that perioperative factors can identify risks for TBI breakage. METHODS: A retrospective case-control study was performed of 246 TBI procedures in 113 patients with Blount disease at 8 tertiary pediatric orthopaedic centers from 2008 to 2018. Patient demographics, age at diagnosis, weight, body mass index (BMI), radiographic deformity severity measures, location, and types of implants were studied. The outcome of implant breakage was compared with these perioperative factors using univariate logistic regression with Bonferroni correction for multiplicity to significance tests. RESULTS: There were 30 broken implants (12%), failing at mean 1.6 years following implantation. Most failures involved the metaphyseal screws. Increased BMI was associated with increased implant breakage. Increased varus deformity was directly associated with greater implant breakage and may be a more important factor in failure for those below 7 years compared with those 8 years or above at diagnosis. There was a 50% breakage rate for TBI with solid 3.5 mm screws in Blount disease with onset 8 years or above of age. No demographic or implant factors were found to be significant. CONCLUSIONS: Breakage of TBI was associated with increased BMI and varus deformity in patients with Blount disease. Larger studies are required to determine the relative contribution and limits of each parameter. Solid 3.5 mm screws should be used with caution in TBI for late-onset Blount disease. LEVEL OF EVIDENCE: Level III.

Does ventilator use status correlate with quality of life in patients with early-onset scoliosis treated with rib-based growing system implantation?

PURPOSE: Pulmonary function and quality of life (QOL) are important outcome measures for patients with early-onset scoliosis (EOS) undergoing rib-based growing system (RBGS) implantation. The Assisted Ventilation Rating (AVR) measures ventilator requirements in this population. A higher, more severe, score implies negative changes in QOL. The EOS Questionnaire (EOSQ) is a validated outcome measure. Paired measurements for both ratings were compared to clarify correlation between ventilator status and QOL. Secondary analysis aimed at defining QOL between more broad subgroups defined by ventilator use. METHODS: AVR and EOSQ scores were extracted from the Pediatric Spine Study Group database for patients 10 years of age and under. Instances were excluded if the time between AVR and EOSQ assessment was greater than 6 months. Scores were compared using Spearman correlation coefficient. Subgroup analysis included control for age, gender, and etiology. Secondary analysis was performed for broad functional grouping using ranked analysis of variance for repeated measures using median scores. RESULTS: Two thousand five hundred and forty-two instances of paired EOSQ and AVR in 329 patients were analyzed. A statistically significant weak correlation between AVR and EOSQ was identified in Child's Health Related QOL and Family Impact sections, in nine subsets. Subgroup analysis showed little variation, except increased correlation in female patients to near moderate level. Analysis of variance for demonstrated decreased medians for all subdomains when comparing those mechanically ventilated to patients who did not require ventilation. CONCLUSION: Ventilator status tracks with QOL were measured by EOSQ. A more severe AVR is negatively correlated with most domains of the EOSQ for patients with EOS who have undergone RBGS implantation. The strength of this correlation is weak, and so AVR alone may be insufficient to precisely determine QOL in this population. LEVEL OF EVIDENCE: Level-III, Retrospective.

Three-dimensional classification of the Lenke 1 adolescent idiopathic scoliosis using coronal and lateral spinal radiographs.

BACKGROUND: Classification of the spinal deformity in adolescent idiopathic scoliosis (AIS) remains two-dimensional (2D) as the spinal radiographs remain the mainstay in clinical evaluation of the disease. 3D classification systems are proposed, however are time consuming. We here aim to evaluate the clinical application of a 3D classification system by the use of only posterior-anterior and lateral radiographs in Lenke 1 adolescent idiopathic scoliosis (AIS). METHODS: Forty Lenke 1 AIS were classified by five observers following a three-step flowchart, developed based on our previous 3D classification system. This 3D classification characterizes the curve in the frontal and sagittal views and infers the third dimension with rules based on prior data to determine the 3D subtypes of the curve. Repeated rating was performed for 20 randomly selected patients in the same cohort. In addition to the classification by the raters, the 3D model of the spines were generated to determine the actual curve subtype based on the algorithm that was originally used to develop the 3D classification system. The interobserver and intraobserver reliability and the classification accuracy were determined for both 3D and axial classifications of the cohort. RESULTS: The interobserver reliability was moderate to strong with a kappa value between 0.61-0.89 for 3D and axial classifications. Comparing the mathematical classification and the raters' classification, the classification accuracy among all raters ranged between 56 and 89%. CONCLUSION: We evaluated the reliability of a previously developed 3D classification system for Lenke 1 AIS patients when only two-view spinal radiographs are available. Radiologists and orthopedic surgeons were able to identify the 3D subtypes of Lenke 1 AIS from the patients' radiographs with moderate to strong reliability. The new 3D classification has the potential to identify the subtypes of the Lenke 1 AIS without a need for quantitative 3D image post-processing.

Management of Pediatric Type I Open Fractures in the Emergency Department or Operating Room: A Multicenter Perspective.

BACKGROUND: The management of pediatric type I open fractures remains controversial. The aim of this study is to compare outcomes in type I open fractures managed with superficial wound debridement and antibiotics in the emergency department (ED) (nonoperative management) to patients managed with operative debridement and antibiotics (operative management). METHODS: A multicenter retrospective review was performed of all pediatric type I open forearm, wrist, and tibia fractures treated at 4 high volume pediatric centers between 2000 and 2015. Patients with multiple traumatic injuries, immunocompromised patients, or those without final radiographs indicating healing were excluded. RESULTS: In total, 219 patients met inclusion criteria. A total of 170 fractures were treated operatively (77.6%), 49 fractures were treated nonoperatively (22.4%). There was 1 infection in the nonoperative group (2.0% infection rate), and no infections in the operatively managed group (P=0.062). Cefazolin was the most commonly administered antibiotic (88.1% of patients). Duration of hospital-administered antibiotics was significantly different, with a mean of 10.9 hours in the nonoperative group and 41.6 hours in the operative group (P<0.001). Length of stay averaged 16.3 hours for nonoperative patients and 48.6 hours for the operatively treated patients (P<0.001). In the nonoperative group, 44/49 had documented superficial wound debridement in the ED utilizing, on an average, 1500 mL of irrigant. There were 10 other complications, 9 in the operative group (5.4%) and 2 in the nonoperative group (4.1%, P=0.107), including 2 compartment syndromes and 1 acute carpal tunnel syndrome all requiring immediate surgical release (1.8%) in the operative group. CONCLUSIONS: There was no significant difference in infection rate or complication rate in those managed with antibiotics and operative debridement versus those managed with superficial wound debridement and antibiotics in the ED. Consideration should be given to the similar safety profiles for these 2 treatment modalities when managing pediatric patients with type I open fractures. LEVEL OF EVIDENCE: Level III.

VEPTR: Are We Reducing Respiratory Assistance Requirements?

BACKGROUND: The assisted ventilation rating (AVR) indicates the degree of external respiratory support required in children with thoracic insufficiency syndrome (TIS) and early onset scoliosis. For skeletally immature patients with TIS, the vertical expandable prosthetic titanium rib (VEPTR) device can be used to improve lung volume and growth. We hypothesized that patients who underwent early thoracic reconstruction by VEPTR treatment had an improved respiratory status. METHODS: Preoperative and postoperative AVR ratings were prospectively collected in a multicenter study group and compared to determine change after VEPTR treatment. Patients under 10 years of age at initial implant with minimum of 2-year follow-up data were included. Patients were excluded if there were incomplete data or if initial AVR was normal (breathing on room air). Statistical analysis was performed on groups which had stable, declined, and improved AVR at final follow-up. RESULTS: Database search yielded 77 patients with initial abnormal AVR. Average follow-up was 5.6 years. The most frequent primary diagnoses were congenital scoliosis (n=14) and spinal muscular atrophy (n=14). In total, 19 (24%) demonstrated improvement, 9 (12%) patients deteriorated, and 49 (64%) remained at the same level. The average preoperative major curve in those with improvement (58.4 degrees) and those with no change (63.5 degrees) was less than in those with deterioration (85.5 degrees) (P=0.014). The average age in years at implant of those with improvement (4) was less than those declined (6.7) and those with no change (5.5). In total, 16 (84.2%) of those that improved had a normal AVR and did not require respiratory support at last follow-up. CONCLUSIONS: There is evidence that a subset of patients with early onset scoliosis and TIS who received early thoracic reconstruction with VEPTR treatment show complete resolution of pulmonary support at final follow-up. In total, 89% of 79 patients did not experience respiratory deterioration. A total of 24% (n=19) had a positive change with over 84% (n=16) of this group no longer requiring support. LEVEL OF EVIDENCE: Level III-prognostic.

Qualitative Assessment and Quantitative Analysis of the Long Head of the Biceps Tendon in Relation to the Pectoralis Major Tendon Humeral Insertion: An Anatomic Study.

PURPOSE: To qualitatively assess and to quantitatively analyze the long head of the biceps tendon (LHBT) in the region of the pectoralis major (PM). METHODS: From 11 fresh cadaveric donors, 20 cadaveric shoulders without operative scars were dissected-mean age, 76.9 years (range, 61 to 93 years); male, 75%; left-sided, 55%; mean height, 67.8 inches (range, 61 to 71 inches); mean weight, 148.1 pounds (range, 106 to 176 pounds). Two specimens with discovered ruptures were excluded. The LHBT circumference was measured at the anterior edge of supraspinatus, suprapectorally, midpectorally, and subpectorally. The muscle was then removed from the LHBT and the circumference was again measured at the supra-, mid-, and subpectoral levels. These data were used to calculate the area of the tendon. All measurements were performed by 2 independent observers. Statistical analysis was performed to assess reliability of data and the difference between serial measurements. RESULTS: The mean calculated percentage tendon decreased from 86.7% at the superior edge of the PM to 49.8% at the midpoint of the PM and to 17.5% at the inferior edge of the PM. CONCLUSIONS: Distal to the PM, the LHBT was composed of a small percentage of tendon to muscle, which may have implications for the mechanical strength of fixation of tenodesis. The anatomic location of the musculotendinous junction of the LHBT began proximal to the superior edge of the PM tendon, which implies that restoration of anatomic tensioning may require a more proximal docking site than previously described. Tenodesis performed between the midpoint of the PM insertion and more distal points involves a significant portion of muscle, which may not be optimal. CLINICAL RELEVANCE: Tenodesis performed between the midpoint of the PM insertion and more distal points involves a significant portion of muscle, which may affect the mechanical strength or optimal choice of fixation location.

Biologic augmentation of tendon-to-bone healing: scaffolds, mechanical load, vitamin D, and diabetes.

Biologic and synthetic scaffolds, mechanical loads, vitamin D, and diabetes can affect tendon and tendon-to-bone healing, muscle recovery, and growth in the perioperative period. Despite important advances in technical approaches to achieve surgical repair of soft tissues in a minimally invasive fashion, structural healing after tendon-to-bone repair remains a formidable challenge that is complicated by our incomplete knowledge of complex natural biologic processes and a diverse patient population with various comorbidities and deficiencies. Scientific research has led to promising strategies for promoting a structural repair that recapitulates the native anatomy of the tendon or enthesis. Augmentation with scaffolds may reinforce the initial repair biomechanically and can be coupled with growth factors to promote a favorable biologic environment for healing. Careful consideration of the implications of postoperative rehabilitation and endocrine and nutritional deficiencies on structural healing and muscle recovery are also critical to optimize patient outcomes.

Lack of both bradykinin B1 and B2 receptors enhances nephropathy, neuropathy, and bone mineral loss in Akita diabetic mice.

An insertion polymorphism of the angiotensin-I converting enzyme gene (ACE) is common in humans and the higher expressing allele is associated with an increased risk of diabetic complications. The ACE polymorphism does not significantly affect blood pressure or angiotensin II levels, suggesting that the kallikrein-kinin system partly mediates the effects of the polymorphism. We have therefore explored the influence of lack of both bradykinin receptors (B1R and B2R) on diabetic nephropathy, neuropathy, and osteopathy in male mice heterozygous for the Akita diabetogenic mutation in the insulin 2 gene (Ins2). We find that all of the detrimental phenotypes observed in Akita diabetes are enhanced by lack of both B1R and B2R, including urinary albumin excretion, glomerulosclerosis, glomerular basement membrane thickening, mitochondrial DNA deletions, reduction of nerve conduction velocities and of heat sensation, and bone mineral loss. Absence of the bradykinin receptors also enhances the diabetes-associated increases in plasma thiobarbituric acid-reactive substances, mitochondrial DNA deletions, and renal expression of fibrogenic genes, including transforming growth factor beta1, connective tissue growth factor, and endothelin-1. Thus, lack of B1R and B2R exacerbates diabetic complications. The enhanced renal injury in diabetic mice caused by lack of B1R and B2R may be mediated by a combination of increases in oxidative stress, mitochondrial DNA damage and over expression of fibrogenic genes.