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.

Monoallelic IFT140 pathogenic variants are an important cause of the autosomal dominant polycystic kidney-spectrum phenotype.

Autosomal dominant polycystic kidney disease (ADPKD), characterized by progressive cyst formation/expansion, results in enlarged kidneys and often end stage kidney disease. ADPKD is genetically heterogeneous; PKD1 and PKD2 are the common loci (∼78% and ∼15% of families) and GANAB, DNAJB11, and ALG9 are minor genes. PKD is a ciliary-associated disease, a ciliopathy, and many syndromic ciliopathies have a PKD phenotype. In a multi-cohort/-site collaboration, we screened ADPKD-diagnosed families that were naive to genetic testing (n = 834) or for whom no PKD1 and PKD2 pathogenic variants had been identified (n = 381) with a PKD targeted next-generation sequencing panel (tNGS; n = 1,186) or whole-exome sequencing (WES; n = 29). We identified monoallelic IFT140 loss-of-function (LoF) variants in 12 multiplex families and 26 singletons (1.9% of naive families). IFT140 is a core component of the intraflagellar transport-complex A, responsible for retrograde ciliary trafficking and ciliary entry of membrane proteins; bi-allelic IFT140 variants cause the syndromic ciliopathy, short-rib thoracic dysplasia (SRTD9). The distinctive monoallelic phenotype is mild PKD with large cysts, limited kidney insufficiency, and few liver cysts. Analyses of the cystic kidney disease probands of Genomics England 100K showed that 2.1% had IFT140 LoF variants. Analysis of the UK Biobank cystic kidney disease group showed probands with IFT140 LoF variants as the third most common group, after PKD1 and PKD2. The proximity of IFT140 to PKD1 (∼0.5 Mb) in 16p13.3 can cause diagnostic confusion, and PKD1 variants could modify the IFT140 phenotype. Importantly, our studies link a ciliary structural protein to the ADPKD spectrum.

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.

Detection and characterization of mosaicism in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited, progressive nephropathy accounting for 4-10% of end stage renal disease worldwide. PKD1 and PKD2 are the most common disease loci, but even accounting for other genetic causes, about 7% of families remain unresolved. Typically, these unsolved cases have relatively mild kidney disease and often have a negative family history. Mosaicism, due to de novo mutation in the early embryo, has rarely been identified by conventional genetic analysis of ADPKD families. Here we screened for mosaicism by employing two next generation sequencing screens, specific analysis of PKD1 and PKD2 employing long-range polymerase chain reaction, or targeted capture of cystogenes. We characterized mosaicism in 20 ADPKD families; the pathogenic variant was transmitted to the next generation in five families and sporadic in 15. The mosaic pathogenic variant was newly discovered by next generation sequencing in 13 families, and these methods precisely quantified the level of mosaicism in all. All of the mosaic cases had PKD1 mutations, 14 were deletions or insertions, and 16 occurred in females. Analysis of kidney size and function showed the mosaic cases had milder disease than a control PKD1 population, but only a few had clearly asymmetric disease. Thus, in a typical ADPKD population, readily detectable mosaicism by next generation sequencing accounts for about 1% of cases, and about 10% of genetically unresolved cases with an uncertain family history. Hence, identification of mosaicism is important to fully characterize ADPKD populations and provides informed prognostic information.

The Prognostic Value of Histopathologic Lesions in Native Kidney Biopsy Specimens: Results from the Boston Kidney Biopsy Cohort Study.

Background Few studies have evaluated whether histopathologic lesions on kidney biopsy provide prognostic information beyond clinical and laboratory data.Methods We enrolled 676 individuals undergoing native kidney biopsy at three tertiary care hospitals into a prospective, observational cohort study. Biopsy specimens were adjudicated for semiquantitative scores in 13 categories of histopathology by two experienced renal pathologists. Proportional hazards models tested the association between histopathologic lesions and risk of kidney disease progression (≥40% eGFR decline or RRT).Results Mean baseline eGFR was 57.5±36.0 ml/min per 1.73 m2 During follow-up (median, 34.3 months), 199 individuals suffered kidney disease progression. After adjustment for demographics, clinicopathologic diagnosis, and laboratory values, the following lesions (hazard ratio; 95% confidence interval) were independently associated with progression: inflammation in nonfibrosed interstitium (0.52; 0.32 to 0.83), moderate and severe versus minimal interstitial fibrosis/tubular atrophy (2.14; 1.24 to 3.69 and 3.42; 1.99 to 5.87, respectively), moderate and severe versus minimal global glomerulosclerosis (2.17; 1.36 to 3.45 and 3.31; 2.04 to 5.38, respectively), moderate and severe versus minimal arterial sclerosis (1.78; 1.15 to 2.74 and 1.64; 1.04 to 2.60, respectively), and moderate and severe versus minimal arteriolar sclerosis (1.63; 1.08 to 2.46 and 2.33; 1.42 to 3.83, respectively). An 11-point chronicity score derived from semiquantitative assessments of chronic lesions independently associated with higher risk of kidney disease progression (hazard ratio per one-point increase, 1.19; 95% confidence interval, 1.12 to 1.27).Conclusions Across a diverse group of kidney diseases, histopathologic lesions on kidney biopsy provide prognostic information, even after adjustment for proteinuria and eGFR.

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.

Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids.

Human-pluripotent-stem-cell-derived kidney cells (hPSC-KCs) have important potential for disease modelling and regeneration. Whether the hPSC-KCs can reconstitute tissue-specific phenotypes is currently unknown. Here we show that hPSC-KCs self-organize into kidney organoids that functionally recapitulate tissue-specific epithelial physiology, including disease phenotypes after genome editing. In three-dimensional cultures, epiblast-stage hPSCs form spheroids surrounding hollow, amniotic-like cavities. GSK3ß inhibition differentiates spheroids into segmented, nephron-like kidney organoids containing cell populations with characteristics of proximal tubules, podocytes and endothelium. Tubules accumulate dextran and methotrexate transport cargoes, and express kidney injury molecule-1 after nephrotoxic chemical injury. CRISPR/Cas9 knockout of podocalyxin causes junctional organization defects in podocyte-like cells. Knockout of the polycystic kidney disease genes PKD1 or PKD2 induces cyst formation from kidney tubules. All of these functional phenotypes are distinct from effects in epiblast spheroids, indicating that they are tissue specific. Our findings establish a reproducible, versatile three-dimensional framework for human epithelial disease modelling and regenerative medicine applications.

iPS cell technology: Future impact on renal care.

iPS cells from patients with kidney disease are a new tool with the potential to impact the future of renal care. They can be used in the laboratory to model the pathophysiology of human kidney disease, and have the potential to establish a new area of immunocompatible, on-demand renal transplantation. Critical challenges remain before the full potential of these cells can be accurately assessed. We need to understand whether the derived cell types are mature and can replace kidney function(s). To what extent can iPS cells model kidney disease in the simplified environment of cell culture? Ultimately, successful integration of these cells as autograft therapies will require demonstration of safety and efficacy equal or superior to the existing gold standards of kidney allograft transplantation and dialysis. Specific educational and infrastructural changes will be necessary if these specialized technologies are to be adopted as an accepted modalities in clinical medicine. Given these barriers, the first fruit of these labors is likely to be improved understanding of pathophysiological pathways in human IPS cell disease models, followed by drug discovery and testing. These experiments will lead naturally to improvements in differentiation and experiments in animal models testing function. The time course to achieve the desired goals remains unknown, but the ultimate hope is that new, more effective and less expensive modalities for renal replacement therapy will occur in the foreseeable future. A new standard of care for patients is anticipated that addresses limitations of currently available treatments.

Liver involvement in early autosomal-dominant polycystic kidney disease.

BACKGROUND & AIMS: Polycystic liver disease (PLD), the most common extrarenal manifestation of autosomal-dominant polycystic kidney disease (ADPKD), has become more prevalent as a result of increased life expectancy, improved renal survival, reduced cardiovascular mortality, and renal replacement therapy. No studies have fully characterized PLD in large cohorts. We investigated whether liver and cyst volumes are associated with volume of the hepatic parenchyma, results from liver laboratory tests, and patient-reported outcomes. METHODS: We performed a cross-sectional analysis of baseline liver volumes, measured by magnetic resonance imaging, and their association with demographics, results from liver laboratory and other tests, and quality of life. The data were collected from a randomized, placebo-controlled trial underway at 7 tertiary-care medical centers to determine whether the combination of an angiotensin I-converting enzyme inhibitor and angiotensin II-receptor blocker was superior to the inhibitor alone, and whether low blood pressure (<110/75 mm Hg) was superior to standard blood pressure (120-130/70-80 mm Hg), in delaying renal cystic progression in 558 patients with ADPKD, stages 1 and 2 chronic kidney disease, and hypertension (age, 15-49 y). RESULTS: We found hepatomegaly to be common among patients with ADPKD. Cysts and parenchyma contributed to hepatomegaly. Cysts were more common and liver and cyst volumes were greater in women, increasing with age. Patients with advanced disease had a relative loss of liver parenchyma. We observed small abnormalities in results from liver laboratory tests, and that splenomegaly and hypersplenism were associated with PLD severity. Higher liver volumes were associated with a lower quality of life. CONCLUSIONS: Hepatomegaly is common even in early stage ADPKD and is not accounted for by cysts alone. Parenchymal volumes were larger, compared with liver volumes of patients without ADPKD or with those predicted by standardized equations, even among patients without cysts. The severity of PLD was associated with altered biochemical and hematologic features, as well as quality of life. ClinicalTrials.gov identifier: NCT00283686.

Therapeutic advances in the treatment of polycystic kidney disease.

The spectrum of polycystic kidney disease (PKD) comprises a family of inherited syndromes defined by renal cyst formation and growth, progressive renal function loss and variable extrarenal manifestations. The most common form, autosomal-dominant PKD is caused by mutations in one of two genes, PKD1 or PKD2. Recent developments in genomic and proteomic medicine have resulted in the discovery of novel genes implicated in the wide variety of less frequent, recessive PKD syndromes. Cysts are the disease, and overall cystic burden, measured by MRI as total kidney volume, is being established as the best available biomarker of disease progression. Current state-of-the-art therapy is aimed at quality treatment for chronic renal insufficiency and cyst-related complications. Recent therapeutic studies have focused on mechanisms reducing intracellular cyclic AMP levels, blocking the renin-angiotensin-aldosterone system and inhibiting the mTOR-signaling pathway. PKD therapies with vasopressin antagonists and somatostatin analogues result in the reduction of intracellular cAMP levels and have shown limited clinical success, but side effects are prominent. Similarly, mTOR pathway inhibition has not shown significant therapeutic benefits. While the HALT-PKD study will answer questions by the end of 2014 about the utility of renin-angiotensin-aldosterone system blockade and aggressive blood pressure control, the next generation of PKD therapy studies targeting proliferative mechanisms of cyst expansion are already under way. Advances in research on the molecular mechanisms of cystogenesis will help design novel targeted PKD therapies in the future.

Polycystic kidney disease: a 2011 update.

PURPOSE OF REVIEW: The review will examine clinically relevant advances in the area of polycystic kidney disease (PKD), mainly focusing on autosomal dominant polycystic kidney disease (ADPKD). Discussion will focus on predicting the course of ADPKD, clinical trials and new research endeavors. RECENT FINDINGS: During the past several years PKD research has been one of the most prolific areas in investigative nephrology. Research endeavors have focused on decreasing cyst proliferation and cyst fluid formation based on an understanding of the pathophysiology of these processes. If cysts can be prevented from growing, kidney function can be better preserved. SUMMARY: Progression of this most common inherited kidney disorder can be altered by understanding that cysts are the disease in ADPKD. Assessing total kidney volume and noting its relationship to glomerular filtration rate is key in predicting the course of the disease and will aid in the evaluation of the new research initiatives that are designed to stop cyst proliferation and fluid secretion into the kidney cysts. The role of biomarkers is an advancement in predicting PKD progression and can potentially be used in evaluation of treatments for this disease. Complications of PKD alter the course and prognosis; hence management approaches will be addressed.

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.

Low and therapeutic doses of antidepressants are associated with similar response in the context of multimodal treatment of pain.

BACKGROUND: Antidepressants are prescribed in a wide range of doses to treat both depression and chronic pain, with optimal psychopharmacology individualized for each patient. In the past decade more antidepressants from different chemical classes have become available and are being used for the treatment of both chronic pain and depression. OBJECTIVE: To review the utilization pattern changes and compare response rates of different classes and doses of antidepressants for various pain conditions in the context of multimodal therapies. DESIGN: Chart review. METHODS: We reviewed 5,916 records at an outpatient multidisciplinary pain center. Of these, 379 records were for patients diagnosed with cancer pain. Because the mechanisms and treatment approaches to cancer pain can differ greatly from non-cancer chronic pain, these records were excluded from the analysis. We assessed 1,506 medical records for patients with chronic non-caner pain who had used at least one antidepressant, with the main outcome measure being the Numeric Rating Pain Scale, 0-10. RESULTS: Of the 5,916 charts reviewed, 1,506 (25.4%) chronic non-cancer pain charts recorded the prescription of at least one antidepressant. Most patients received a combination of medications and procedures. Of the 450 patients receiving secondary amines, favorable responses were recorded for 340 (76%) patients, while 103 (23%) did not respond and 7 had unknown responses. Of the 492 patients receiving tertiary amines, favorable responses were recorded for 375 (76%) patients, while 113 (23%) did not respond, and 4 had unknown responses. Of the 533 patients receiving SSRI/SNRIs, favorable responses were recorded for 382 (72%) patients, while 147 (28%) did not respond, and 4 had unknown responses. Of the 369 patients receiving atypical antidepressants, favorable responses were recorded for 272 (74%) patients, while 94 (25%) did not respond, and 3 had unknown responses. LIMITATIONS: A retrospective study design and the use of antidepressants as a part of multimodal treatment of pain. CONCLUSION: The data suggest that in the context of multimodal treatment for chronic pain, antidepressant therapy at both low and therapeutic doses demonstrates similar response rates. Tricyclic antidepressants (TCAs), which include secondary and tertiary amines, as well as SSRI/SNRIs and atypicals, all appear to show similar favorable response rates.

Hypercalcemia due to excess 1,25-dihydroxyvitamin D in Crohn's disease.

Hypercalcemia has been described in patients with a number of granulomatous diseases, including sarcoidosis and mycobacterial infection. Disordered vitamin D metabolism is the root cause for the elevated serum calcium levels. A similar mechanism of abnormal vitamin D metabolism explained the hypercalcemia occurring in patients with lymphoma. Crohn's disease is a granulomatous disorder that is more commonly associated with hypocalcemia caused by poor calcium intake and decreased intestinal calcium absorption related to vitamin D deficiency as a consequence of malabsorption. A man with Crohn's disease who presented with hypercalcemia and acute renal failure is described. Biochemical parameters showed an elevated 1,25-dihydroxyvitamin D level, with a low-normal 25-hydroxyvitamin D level and decreased parathyroid hormone level. Inflammatory bowel disease had been clinically active during the preceding 2 months. With resolution of gastrointestinal symptoms, serum calcium, vitamin D, and parathyroid hormone levels returned to normal. Serum creatinine levels decreased toward normal. Angiotensin-converting enzyme (ACE) levels have been reported to be elevated in patients with sarcoidosis, particularly in the setting of active disease with hypercalcemia. Controversy exists about ACE levels in the face of active Crohn's disease: 1 report noted elevated levels, whereas other publications reported depressed levels. Our patient had an elevated ACE level in the setting of active bowel disease and hypercalcemia, and ACE levels returned to normal with resolution of gastrointestinal symptoms.