Volume Progression and Imaging Classification of Polycystic Liver in Early Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND AND OBJECTIVES: The progression of polycystic liver disease is not well understood. The purpose of the study is to evaluate the associations of polycystic liver progression with other disease progression variables and classify liver progression on the basis of patient's age, height-adjusted liver cystic volume, and height-adjusted liver volume. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Prospective longitudinal magnetic resonance images from 670 patients with early autosomal dominant polycystic kidney disease for up to 14 years of follow-up were evaluated to measure height-adjusted liver cystic volume and height-adjusted liver volume. Among them, 245 patients with liver cyst volume >50 ml at baseline were included in the longitudinal analysis. Linear mixed models on log-transformed height-adjusted liver cystic volume and height-adjusted liver volume were fitted to approximate mean annual rate of change for each outcome. The association of sex, body mass index, genotype, baseline height-adjusted total kidney volume, and Mayo imaging class was assessed. We calculated height-adjusted liver cystic volume ranges for each specific age and divided them into five classes on the basis of annual percentage increase in height-adjusted liver cystic volume. RESULTS: The mean annual growth rate of height-adjusted liver cystic volume was 12% (95% confidence interval, 11.1% to 13.1%; P<0.001), whereas that for height-adjusted liver volume was 2% (95% confidence interval, 1.9% to 2.6%; P<0.001). Women had higher baseline height-adjusted liver cystic volume than men, but men had higher height-adjusted liver cystic volume growth rate than women by 2% (95% confidence interval, 0.4% to 4.5%; P=0.02). Whereas the height-adjusted liver cystic volume growth rate decreased in women after menopause, no decrease was observed in men at any age. Body mass index, genotype, and baseline height-adjusted total kidney volume were not associated with the growth rate of height-adjusted liver cystic volume or height-adjusted liver volume. According to the height-adjusted liver cystic volume growth rate, patients were classified into five classes (number of women, men in each class): A (24, six); B (44, 13); C (43, 48); D (28, 17); and E (13, nine). CONCLUSIONS: Compared with height-adjusted liver volume, the use of height-adjusted liver cystic volume showed greater separations in volumetric progression of polycystic liver disease. Similar to the Mayo imaging classification for the kidney, the progression of polycystic liver disease may be categorized on the basis of patient's age and height-adjusted liver cystic volume.

Continuous function of 80 primary renal allografts for 30-47 years with maintenance prednisone and azathioprine/mycophenolate mofetil therapy: A clinical mosaic of long-term successes.

Eighty primary renal allograft recipients, 61 living-related and 19 deceased donor, transplanted from 1963 through 1984 had continuous graft function for 30-47 years. They were treated with three different early immunosuppression programs (1963-1970: thymectomy, splenectomy, high oral prednisone; 1971-1979: divided-dose intravenous methylprednisolone; and 1980-1984: antilymphocyte globulin) each with maintenance prednisone and azathioprine, and no calcineurin inhibitor. Long-term treatment often included the anti-platelet medication, dipyridamole. Although both recipient and donor ages were young (27.2 ± 9.5 and 33.1 ± 12.0 years, respectively), six recipients with a parent donor had >40-year success. At 35 years, death-censored graft survival was 85.3% and death with a functioning graft 84.2%; overall graft survival was 69.5% (Kaplan-Meier estimate). Biopsy-documented early acute cellular and highly probable antibody-mediated rejections were reversed with divided-dose intravenous methylprednisolone. Complications are detailed in an integrated timeline. Hypogammaglobulinemia identified after 20 years doubled the infection rate. An association between a monoclonal gammopathy of undetermined significance and non-plasma-cell malignancies was identified. Twenty-seven azathioprine-treated patients tested after 37 years had extremely low levels of T1/T2 B lymphocytes representing a "low immunosuppression state of allograft acceptance (LISAA)". The lifetime achievements of these patients following a single renal allograft and low-dose maintenance immunosuppression are remarkable. Their success evolved as a clinical mosaic.

Expanded Imaging Classification of Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: The Mayo Clinic imaging classification of autosomal dominant polycystic kidney disease (ADPKD) uses height-adjusted total kidney volume (htTKV) and age to identify patients at highest risk for disease progression. However, this classification applies only to patients with typical diffuse cystic disease (class 1). Because htTKV poorly predicts eGFR decline for the 5%-10% of patients with atypical morphology (class 2), imaging-based risk modeling remains unresolved. METHODS: Of 558 adults with ADPKD in the HALT-A study, we identified 25 patients of class 2A with prominent exophytic cysts (class 2Ae) and 43 patients of class 1 with prominent exophytic cysts; we recalculated their htTKVs to exclude exophytic cysts. Using original and recalculated htTKVs in association with imaging classification in logistic and mixed linear models, we compared predictions for developing CKD stage 3 and for eGFR trajectory. RESULTS: Using recalculated htTKVs increased specificity for developing CKD stage 3 in all participants from 82.6% to 84.2% after adjustment for baseline age, eGFR, BMI, sex, and race. The predicted proportion of class 2Ae patients developing CKD stage 3 using a cutoff of 0.5 for predicting case status was better calibrated to the observed value of 13.0% with recalculated htTKVs (45.5%) versus original htTKVs (63.6%). Using recalculated htTKVs reduced the mean paired difference between predicted and observed eGFR from 17.6 (using original htTKVs) to 4.0 ml/min per 1.73 m2 for class 2Ae, and from -1.7 (using original htTKVs) to 0.1 ml/min per 1.73 m2 for class 1. CONCLUSIONS: Use of a recalculated htTKV measure that excludes prominent exophytic cysts facilitates inclusion of class 2 patients and reclassification of class 1 patients in the Mayo classification model.

Effect of Statin Therapy on the Progression of Autosomal Dominant Polycystic Kidney Disease. A Secondary Analysis of the HALT PKD Trials.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) commonly results in end-stage renal disease (ESRD), yet a long-term treatment that is well tolerated is still lacking. In a small randomized trial in children and adolescents pravastatin administration for 3 years was associated with reduced renal cyst growth, but no large trial has tested the effect of statins in adults. METHODS: We performed a post-hoc analysis of the HALT PKD trials to compare outcomes of participants who never used statins with those who used statin for at least 3 years. Because statins were not randomly allocated, we used propensity score models with inverse probability of treatment weighting to account for imbalances between the groups. For subjects in Study A (preserved renal function, n=438) relevant outcomes were percent change in total kidney and liver volume and the rate of decline in estimated glomerular filtration rate (eGFR); for those in Study B (reduced renal function, n=352) we compared time to the composite endpoint of death, ESRD or 50% decline in eGFR. Follow-up was 5-8 years. RESULTS: There was no difference in any outcome between the 2 groups. However, limitations of this analysis are the small number of statin users in Study A, different statin drugs and doses used, non-randomized allocation and advanced disease stage in Study B. CONCLUSION: Although this post-hoc analysis of the HALT PKD trials does not demonstrate a benefit of statin therapy, conclusions remain preliminary. A larger randomized trial in young people with ADPKD is necessary to answer the question whether statins can slow renal cyst growth and preserve kidney function.

Prognostic enrichment design in clinical trials for autosomal dominant polycystic kidney disease: the HALT-PKD clinical trial.

BACKGROUND: Patients with mild autosomal dominant polycystic kidney disease (ADPKD) are less likely to be informative in randomized clinical trials (RCTs). We previously developed an imaging classification of ADPKD (typical diffuse cyst distribution Class 1A-E and atypical cyst distribution Class 2) for prognostic enrichment design in RCTs. We investigated whether using this classification would have increased the power to detect a beneficial treatment effect of rigorous blood pressure (BP) control on HALT-PKD participants with early disease (Study A). METHODS: Post hoc analysis of the early disease HALT-PKD study, an RCT that studied the effect of rigorous versus standard BP control on rates of total kidney volume (TKV) increase and estimated glomerular filtration rate (eGFR) decline in ADPKD patients with eGFR >60 mL/min/1.73 m2. RESULTS: Five hundred and fifty-one patients were classified by two observers (98.2% agreement) into Class 1A (6.2%), 1B (20.3%), 1C (34.1%), 1D (22.1%), 1E (11.8%) and 2 (5.4%). The TKV increase and eGFR decline became steeper from Class 1A through 1E. Rigorous BP control had been shown to be associated with slower TKV increase, without a significant overall effect on the rate of eGFR decline (faster in the first 4 months and marginally slower thereafter). Merging Classes 1A and 2 (lowest severity), 1B and 1C (intermediate severity) and 1D and 1E (highest severity) detected stronger beneficial effects on TKV increase and eGFR decline in Class 1D and E with a smaller number of patients. CONCLUSIONS: Strategies for prognostic enrichment, such as image classification, should be used in the design of RCTs for ADPKD to increase their power and reduce their cost.

Predicted Mutation Strength of Nontruncating PKD1 Mutations Aids Genotype-Phenotype Correlations in Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) often results in ESRD but with a highly variable course. Mutations to PKD1 or PKD2 cause ADPKD; both loci have high levels of allelic heterogeneity. We evaluated genotype-phenotype correlations in 1119 patients (945 families) from the HALT Progression of PKD Study and the Consortium of Radiologic Imaging Study of PKD Study. The population was defined as: 77.7% PKD1, 14.7% PKD2, and 7.6% with no mutation detected (NMD). Phenotypic end points were sex, eGFR, height-adjusted total kidney volume (htTKV), and liver cyst volume. Analysis of the eGFR and htTKV measures showed that the PKD1 group had more severe disease than the PKD2 group, whereas the NMD group had a PKD2-like phenotype. In both the PKD1 and PKD2 populations, men had more severe renal disease, but women had larger liver cyst volumes. Compared with nontruncating PKD1 mutations, truncating PKD1 mutations associated with lower eGFR, but the mutation groups were not differentiated by htTKV. PKD1 nontruncating mutations were evaluated for conservation and chemical change and subdivided into strong (mutation strength group 2 [MSG2]) and weak (MSG3) mutation groups. Analysis of eGFR and htTKV measures showed that patients with MSG3 but not MSG2 mutations had significantly milder disease than patients with truncating cases (MSG1), an association especially evident in extreme decile populations. Overall, we have quantified the contribution of genic and PKD1 allelic effects and sex to the ADPKD phenotype. Intrafamilial correlation analysis showed that other factors shared by families influence htTKV, with these additional genetic/environmental factors significantly affecting the ADPKD phenotype.

Analysis of baseline parameters in the HALT polycystic kidney disease trials.

HALT PKD consists of two ongoing randomized trials with the largest cohort of systematically studied patients with autosomal dominant polycystic kidney disease to date. Study A will compare combined treatment with an angiotensin-converting inhibitor and receptor blocker to inhibitor alone and standard compared with low blood pressure targets in 558 early-stage disease patients with an eGFR over 60 ml/min per 1.73 m(2). Study B will compare inhibitor-blocker treatment to the inhibitor alone in 486 late-stage patients with eGFR 25-60 ml/min per 1.73 m(2). We used correlation and multiple regression cross-sectional analyses to determine associations of baseline parameters with total kidney, liver, or liver cyst volumes measured by MRI in Study A and eGFR in both studies. Lower eGFR and higher natural log-transformed urine albumin excretion were independently associated with a larger natural log-transformed total kidney volume adjusted for height (ln(HtTKV)). Higher body surface area was independently associated with a higher ln(HtTKV) and lower eGFR. Men had larger height-adjusted total kidney volume and smaller liver cyst volumes than women. A weak correlation was found between the ln(HtTKV) and natural log-transformed total liver volume adjusted for height or natural log liver cyst volume in women only. Women had higher urine aldosterone excretion and lower plasma potassium. Thus, our analysis (1) confirms a strong association between renal volume and functional parameters, (2) shows that gender and other factors differentially affect the development of polycystic disease in the kidney and liver, and (3) suggests an association between anthropomorphic measures reflecting prenatal and/or postnatal growth and disease severity.

Rapamycin for treatment of refractory dysthyroid compressive optic neuropathy.

We report a patient with dysthyroid optic neuropathy refractory to steroids and orbital decompression treated with rapamycin, a fibroblast and T cell inhibitor. Symptoms, visual acuity, color plate testing, and visual fields improved. Aside from hypercholesterolemia, no complication related to this therapy was observed. By addressing the pathogenesis of thyroid eye disease, rapamycin may represent an alternative when standard treatments fail. Further investigation of rapamycin for treatment of dysthyroid orbitopathy is warranted.

Donor factors influencing graft outcomes in live donor kidney transplantation.

Living donor renal allograft survival is superior to that achieved from deceased donors, although graft outcome is suboptimal in some of these patients. In an effort to identify the subset of patients at high risk for poor outcomes we studied donor risk factors in 248 living kidney donor-recipient pairs. Unadjusted donor (125)I-iothalamate GFR (iGFR), donor age more than 45 years, donor total cholesterol level less than 200 mg/dL, and donor systolic blood pressure (SBP) less than 120 mm Hg were correlated with allograft estimated glomerular filtration rate (eGFR), and incidence of acute rejection (AR), delayed graft function and/or graft loss at 2 years posttransplantation. Donor iGFR less than 110 mL/min (slope=-7.40, P<0.01), donors more than 45 years (slope=-8.76, P<0.01), donor total cholesterol levels more than 200 mg/dL (slope=-10.03, P<0.01), and SBP more than 120 mm Hg (slope=-5.60, P=0.03) were associated with lower eGFR. By multivariable linear regression analysis these variables remained independently associated with lower eGFR, and poorer outcomes. The increasing number of donor factors (age, iGFR, cholesterol, and blood pressure) was directly associated with worse posttransplant eGFR (P<0.01). In conclusion, our data suggest that routine assessment of living donor parameters could supplement the consideration of recipient characteristics in predicting posttransplant risk of graft injury/dysfunction.

Ultra-late antibody-mediated rejection 30 years after a living-related renal allograft.

Antibody-mediated renal allograft rejection has become increasingly recognized and more clearly defined through the use of flow cytometry cross-matching and the deposition of C4d in renal allograft biopsies. All of the cases reported thus far have developed an antibody within 10 years of transplantation, and many lacked HLA and/or donor specificity. The present patient developed an anti-HLA donor-specific antibody between the 22nd and 30th year after a living-related renal transplant. At the 30th year post-transplantation, she experienced a rise in the serum creatinine from 0.7 to 1.9 mg/dL associated with transplant biopsy C4d deposition in peritubular capillaries and glomeruli. After the replacement of azathioprine with mycophenolate mofetil, and six apheresis treatments followed by two infusions of IVIG, the renal function stabilized at 1.9 mg/dL, 33 years after transplantation. Antibody-mediated rejection must be considered as a possible cause or renal allograft dysfunction at all time periods after transplantation.

BK polyomavirus: a newly recognized threat to transplanted kidneys.

Reactivation of latent infection with BK polyomavirus is now being recognized as a cause of failure of renal allografts. An increasing serum creatinine concentration in a kidney transplant recipient should prompt a referral for reevaluation by the transplant center.