Association of Kidney Cysts With Progressive CKD After Radical Nephrectomy.

RATIONALE & OBJECTIVE: Simple kidney cysts, which are common and usually considered of limited clinical relevance, are associated with older age and lower glomerular filtration rate (GFR), but little has been known of their association with progressive chronic kidney disease (CKD). STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: Patients with presurgical computed tomography or magnetic resonance imaging who underwent a radical nephrectomy for a tumor; we reviewed the retained kidney images to characterize parenchymal cysts at least 5mm in diameter according to size and location. EXPOSURE: Parenchymal cysts at least 5mm in diameter in the retained kidney. Cyst characteristics were correlated with microstructural findings on kidney histology. OUTCOME: Progressive CKD defined by dialysis, kidney transplantation, a sustained≥40% decline in eGFR for at least 3 months, or an eGFR<10mL/min/1.73m2 that was at least 5mL/min/1.73m2 below the postnephrectomy baseline for at least 3 months. ANALYTICAL APPROACH: Cox models assessed the risk of progressive CKD. Models adjusted for baseline age, sex, body mass index, hypertension, diabetes, eGFR, proteinuria, and tumor volume. Nonparametric Spearman's correlations were used to examine the association of the number and size of the cysts with clinical characteristics, kidney function, and kidney volumes. RESULTS: There were 1,195 patients with 50 progressive CKD events over a median 4.4 years of follow-up evaluation. On baseline imaging, 38% had at least 1 cyst, 34% had at least 1 cortical cyst, and 8.7% had at least 1 medullary cyst. A higher number of cysts was associated with progressive CKD and was modestly correlated with larger nephrons and more nephrosclerosis on kidney histology. The number of medullary cysts was more strongly associated with progressive CKD than the number of cortical cysts. LIMITATIONS: Patients who undergo a radical nephrectomy may differ from the general population. A radical nephrectomy may accelerate the risk of progressive CKD. Genetic testing was not performed. CONCLUSIONS: Cysts in the kidney, particularly the medulla, should be further examined as a potentially useful imaging biomarker of progressive CKD beyond the current clinical evaluation of kidney function and common CKD risk factors. PLAIN-LANGUAGE SUMMARY: Kidney cysts are common and often are considered of limited clinical relevance despite being associated with lower glomerular filtration rate. We studied a large cohort of patients who had a kidney removed due to a tumor to determine whether cysts in the retained kidney were associated with kidney health in the future. We found that more cysts in the kidney and, in particular, cysts in the deepest tissue of the kidney (the medulla) were associated with progressive kidney disease, including kidney failure where dialysis or a kidney transplantation is needed. Patients with cysts in the kidney medulla may benefit from closer monitoring.

Acquired cystic kidney disease in patients on maintenance hemodialysis, prevalence and associated factors: a cross-sectional study.

Introduction: Acquired Cystic Kidney Disease (ACKD) is a known complication in patients on maintenance hemodialysis, and it is associated with a high risk of malignant transformation. There is a paucity of data on ACKD in sub-Saharan Africa. Objectives: To determine the prevalence and factors associated with acquired cystic kidney disease in patients on maintenance hemodialysis. Methods: patients on maintenance hemodialysis were screened for ACKD. Patients with hereditary cystic kidney disease were excluded. Renal ultrasounds were performed by two radiologists. ACKD was defined as 3 or more bilateral renal cysts in a small or normal size kidney. Associated factors were determined using logistic regression. A p-value <0.05 was significant. Results: a total of 158 participants were enrolled and 61.4% (97) were male. Their mean (SD) age was 45.8 (14.9) years. The median dialysis vintage was 33.5 [10.7-63.2] months. The mean (SD) length of the kidneys was 85.1 (17.5) mm on the left and 81.2 (17.1) mm on the right. The prevalence of ACKD was 31.6% (n=50). Septated cysts (4), calcification of the wall of the cysts (2), irregular thick calcified wall (1), septated cysts with calcification (1) and hemorrhagic cyst (1) cysts were also observed. Dialysis vintage > 36 months (OR 7.1, 95% CI: 3.3 - 15.5) and male sex (OR 2.6, 95% CI: 1.2-5.6) were independently associated with ACKD. Conclusion: the prevalence of ACKD is high in a population of Cameroonians on maintenance. This result calls for the implementation of strategies to screen for the condition and its complications.

Atypical histological abnormalities in an adult patient with nephronophthisis harboring NPHP1 deletion: a case report.

BACKGROUND: Nephronophthisis (NPHP) is a chronic tubular interstitial disorder that exhibits an autosomal recessive genetic form and causes progressive renal failure in children. Patients with NPHP rarely show urinary abnormalities, edema, or hypertension. Thus, NPHP is often detected only when renal failure becomes advanced. NPHP can be divided into three types based on the age of end-stage renal failure, i.e., infant type (approximately 5 years old), juvenile type (approximately 13-14 years old), and adolescent type (approximately 19 years old). Here, we report a case of NPHP diagnosed by genetic analysis at 26 years of age with atypical histological abnormalities. CASE PRESENTATION: A 26-year-old woman showed no growth disorders or urinary abnormalities in annual school physical examinations. However, at a check-up at 26 years old, she exhibited renal dysfunction (eGFR 26 mL/min/1.73 m2). Urine tests indicated low specific gravity of urine, but not proteinuria or microscopic hematuria. Urinary ß2-microglobulin was high (805 µg/L), and renal biopsy was performed for definitive diagnosis. Histological findings showed no significant findings in glomeruli. However, moderate fibrosis was observed in the interstitial area, and moderate atrophy was observed in the tubules. There were no significant findings in immunofluorescence analysis, and no electron dense deposits were detected by electron microscopy. Although cyst-like expansion of the tubules was unclear, tubular atrophy was dominantly found in the distal tubule by cytokeratin 7 staining. Genetic analysis of the NPHP1 gene showed complete deletion of this gene, leading to a definitive diagnosis of NPHP. CONCLUSIONS: NPHP is not merely a pediatric disease and is relatively high incidence in patients with adult onset end-stage of renal disease. In this case, typical histological abnormalities, such as cyst-like expansion of the tubular lesion, were not observed, and diagnosis was achieved by genetic analysis of the NPHP1 gene, which is responsible for the onset of NPHP. In patients with renal failure with tubular interstitial disease dominantly in the distal tubules, it is necessary to discriminate NPHP, even in adult cases.

Macrophage migration inhibitory factor is regulated by HIF-1α and cAMP and promotes renal cyst cell proliferation in a macrophage-independent manner.

Progressive cyst growth leads to decline of renal function in polycystic kidney disease. Macrophage migration inhibitory factor (MIF) was found to be upregulated in cyst-lining cells in a mouse model of polycystic kidney disease and to promote cyst growth. In addition, MIF can be secreted by tubular cells and may contribute to cyst growth in an autocrine manner. However, the underlying mechanisms leading to induction of MIF in cyst-lining cells remained elusive. Here, we demonstrate that hypoxia-inducible transcription factor (HIF) 1α upregulates MIF in cyst-lining cells in a tubule-specific PKD1 knockout mouse. Pharmacological stabilization of HIF-1α resulted in significant increase of MIF in cyst epithelial cells whereas tubule-specific knockout of HIF-1α prevented MIF upregulation. Identical regulation could be found for ABCA1, which has been shown to act as a transport protein for MIF. Furthermore, we show that MIF and ABCA1 are direct target genes of HIF-1α in human primary tubular cells. Next to HIF-1α and hypoxia, we found MIF being additionally regulated by cAMP which is a strong promotor of cyst growth. In line with these findings, HIF-1α- and cAMP-dependent in vitro cyst growth could be decreased by the MIF-inhibitor ISO-1 which resulted in reduced cyst cell proliferation. In conclusion, HIF-1α and cAMP regulate MIF in primary tubular cells and cyst-lining epithelial cells, and MIF promotes cyst growth in the absence of macrophages. In line with these findings, the MIF inhibitor ISO-1 attenuates HIF-1α- and cAMP-dependent in vitro cyst enlargement. KEY MESSAGES: • MIF is upregulated in cyst-lining cells in a polycystic kidney disease mouse model. • MIF upregulation is mediated by hypoxia-inducible transcription factor (HIF) 1α. • ABCA1, transport protein for MIF, is also regulated by HIF-1α in vitro and in vivo. • MIF is additionally regulated by cAMP, a strong promotor of cyst growth. • MIF-inhibitor ISO-1 reduces HIF-1α- and cAMP-dependent cyst growth.

Novel biallelic loss-of-function variants in CEP290 cause Joubert syndrome in two siblings.

BACKGROUND: Joubert syndrome (JS) is a rare genetic disorder, which can be defined by brain stem malformation, cerebellar vermis hypoplasia, and consequent "molar tooth sign" (MTS). JS always shares variety of phenotypes in development defects. With the development of next-generation sequencing, dozens of causative genes have been identified to JS so far. Here, we investigated two male siblings with JS and uncovered a novel pathogenesis through combined methods. RESULTS: The siblings shared similar features of nystagmus, disorders of intellectual development, typical MTS, and abnormal morphology in fourth ventricle. Whole-exome sequencing (WES) and chromosome comparative genomic hybridization (CGH) were then performed on the proband. Strikingly, a maternal inherited nonsense variant (NM_025114.3: c.5953G>T [p.E1985*]) in CEP290 gene and a paternal inherited deletion in 12q21.32 including exons 1 to 10 of CEP290 gene were identified in the two affected siblings. We further confirmed the two variants by in vitro experiments: quantitative PCR and PCR sequencing. CONCLUSIONS: In this study, we first reported a novel causative mechanism of Joubert syndrome: a copy number variation (CNV) combined with a single-nucleotide variant in CEP290 gene, which can be helpful in the genetic diagnosis of this disease.

Tissue-Resident Macrophages Promote Renal Cystic Disease.

BACKGROUND: Mutations affecting cilia proteins have an established role in renal cyst formation. In mice, the rate of cystogenesis is influenced by the age at which cilia dysfunction occurs and whether the kidney has been injured. Disruption of cilia function before postnatal day 12-14 results in rapid cyst formation; however, cyst formation is slower when cilia dysfunction is induced after postnatal day 14. Rapid cyst formation can also be induced in conditional adult cilia mutant mice by introducing renal injury. Previous studies indicate that macrophages are involved in cyst formation, however the specific role and type of macrophages responsible has not been clarified. METHODS: We analyzed resident macrophage number and subtypes during postnatal renal maturation and after renal injury in control and conditional Ift88 cilia mutant mice. We also used a pharmacological inhibitor of resident macrophage proliferation and accumulation to determine the importance of these cells during rapid cyst formation. RESULTS: Our data show that renal resident macrophages undergo a phenotypic switch from R2b (CD11clo) to R2a (CD11chi) during postnatal renal maturation. The timing of this switch correlates with the period in which cyst formation transitions from rapid to slow following induction of cilia dysfunction. Renal injury induces the reaccumulation of juvenile-like R2b resident macrophages in cilia mutant mice and restores rapid cystogenesis. Loss of primary cilia in injured conditional Ift88 mice results in enhanced epithelial production of membrane-bound CSF1, a cytokine that promotes resident macrophage proliferation. Inhibiting CSF1/CSF1-receptor signaling with a CSF1R kinase inhibitor reduces resident macrophage proliferation, R2b resident macrophage accumulation, and renal cyst formation in two mouse models of cystic disease. CONCLUSIONS: These data uncover an important pathogenic role for resident macrophages during rapid cyst progression.

Unexpected Activities in Regulating Ciliation Contribute to Off-target Effects of Targeted Drugs.

PURPOSE: For many tumors, signaling exchanges between cancer cells and other cells in their microenvironment influence overall tumor signaling. Some of these exchanges depend on expression of the primary cilium on nontransformed cell populations, as extracellular ligands including Sonic Hedgehog (SHH), PDGFRα, and others function through receptors spatially localized to cilia. Cell ciliation is regulated by proteins that are themselves therapeutic targets. We investigated whether kinase inhibitors of clinical interest influence ciliation and signaling by proteins with ciliary receptors in cancer and other cilia-relevant disorders, such as polycystic kidney disease (PKD). EXPERIMENTAL DESIGN: We screened a library of clinical and preclinical kinase inhibitors, identifying drugs that either prevented or induced ciliary disassembly. Specific bioactive protein targets of the drugs were identified by mRNA depletion. Mechanism of action was defined, and activity of select compounds investigated. RESULTS: We identified multiple kinase inhibitors not previously linked to control of ciliation, including sunitinib, erlotinib, and an inhibitor of the innate immune pathway kinase, IRAK4. For all compounds, activity was mediated through regulation of Aurora-A (AURKA) activity. Drugs targeting cilia influenced proximal cellular responses to SHH and PDGFRα. In vivo, sunitinib durably limited ciliation and cilia-related biological activities in renal cells, renal carcinoma cells, and PKD cysts. Extended analysis of IRAK4 defined a subset of innate immune signaling effectors potently affecting ciliation. CONCLUSIONS: These results suggest a paradigm by which targeted drugs may have unexpected off-target effects in heterogeneous cell populations in vivo via control of a physical platform for receipt of extracellular ligands.

Prevalence of extramedullary hematopoiesis, renal cysts, splenic and hepatic lesions, and vertebral hemangiomas among thalassemic patients: a retrospective study from the Myocardial Iron Overload in Thalassemia (MIOT) network.

We determined the prevalence of incidental extracardiac findings (IEF) at Magnetic Resonance Imaging (MRI) potentially related to anemia and hypoxia in age- and sex-matched populations (N = 318) with thalassemia major (TM) and thalassemia intermedia (TI) enrolled in the Myocardial Iron Overload in Thalassemia network. Overall, IEFs were detected in 33.3% and 25.8% of patients with TI and TM, respectively (P = 0.114). TI and TM patients had elevated but comparable prevalence of renal, splenic and liver cysts, and vertebral hemangiomas while TI patients had a significant higher frequency of extramedullary hematopoiesis (EMH) (15.1% vs 4.4%; P = 0.002). The prevalence of total IEFs increased with advancing age. TI non-transfusion-dependent patients had a significantly lower frequency of renal cysts than TI transfusion-dependent patients (8.8% vs 26.4%; P = 0.005). The prevalence of renal cysts in the thalassemic population was significantly higher than that in the general population (19.2% vs 1.9%; P < 0.0001). Our data on renal cysts indicate a significant higher prevalence of these IEFs compared to the general population, suggesting the role of the inappropriate activation of the hypoxia-inducible factor system linked to the chronic hypoxia. The significant prevalence of IEF in thalassemia patients undergoing MRI for iron quantification should prompt the discussion of the inclusion of IEF in the MRI report.

Bilateral kidneys involvement of collecting duct carcinoma with cystic change: A case report.

RATIONALE: Collecting duct carcinoma (CDC) is a rare neoplasm arising from the collecting duct and should be distinguished from other renal cell carcinomas that mostly originated from the proximal tubular epithelium and tumors originated from the urothelium. It usually occurs in unilateral kidney, sometimes found with cystic change. PATIENT CONCERNS: We present the case of a 53-year-old male suffering from repeated bilateral flank pain for 6 months, increased pain with dysuria for 5 days. DIAGNOSIS: Ultrasound showed 2 similar hybrid echo masses in bilateral kidneys with enlarged lymph nodes surrounded, which accords with magnetic resonance imaging (MRI), and intraoperative biopsy reported malignancy. INTERVENTIONS: An exploratory operation was performed and the mass on the left kidney was removed, but pathological result reported collecting duct carcinoma according to the morphological features and immunohistochemical tests. Also postsurgery positron emission tomography-computed tomography (PET-CT) confirmed the mass on the left kidney is also a lesion of CDC. OUTCOMES: The patient refused chemotherapy and had an overall survival of 7 months. LESSONS: We presented a case of CDC involving bilateral kidneys with cystic change; this is the first case of bilateral renal occurrence with cystic change to our knowledge. Because of CDC's rapid growth and the lack of effective adjuvant treatment after surgery, the prognosis is poor and the diagnosis should be made carefully.

Renal cystic disease in the Fbn1C1039G/+ Marfan mouse is associated with enhanced aortic aneurysm formation.

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 gene (FBN1), resulting in aortic aneurysm formation and dissections. Interestingly, variable aortopathy is observed even within MFS families with the same mutation. Thus, additional risk factors determine disease severity. Here, we describe a case of a 2-month-old Fbn1C1039G/+ MFS mouse with extreme aortic dilatation and increased vascular inflammation, when compared to MFS siblings, which coincided with unilateral renal cystic disease. In addition, this mouse presented with increased serum levels of creatinine, angiotensin-converting enzyme, corticosterone, macrophage chemoattractant protein-1, and interleukin-6, which may have contributed to the vascular pathology. Possibly, cystic kidney disease is associated with aneurysm progression in MFS patients. Therefore, we propose that close monitoring of the presence of renal cysts in MFS patients, during regular vascular imaging of the whole aorta trajectory, may provide insight in the frequency of cystic kidney disease and its potential as a novel indicator of aneurysm progression in MFS patients.

Renal manifestation of tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a tumor predisposition syndrome with significant renal cystic and solid tumor disease. It commonly causes several types of cystic disease and benign tumors (angiomyolipomata) in the kidneys that can both lead to significant premature loss of glomerular filtration rate. The main risks of angiomyolipomata, severe bleeding, loss of renal function, and pulmonary lymphangioleiomyomatosis, can be ameliorated by active surveillance and preemptive therapy with mTOR inhibitors. The cystogenic mechanism may involve primary cilia, but also appears to also involve a majority of normal tubular cells and may be driven by a minority of cells with mutations inactivating both their TSC1 or TSC2 genes. Malignant tumors are rare.

Acquired cystic disease-associated renal cell carcinoma is the most common subtype in long-term dialyzed patients: Central pathology results according to the 2016 WHO classification in a multi-institutional study.

New pathological subtypes of renal cell carcinoma (RCC) were designated in the 2016 World Health Organization (WHO) classification corresponding to the features commonly seen in patients with end-stage renal disease (ESRD). To determine the clinicopathological findings of new subtypes, we reanalyzed all sections from 315 kidneys in 291 ESRD patients bearing RCC tumors surgically resected in three Japanese institutes by the central pathologist. Clear cell RCC was diagnosed in 144 kidneys (45.7%), acquired cystic disease (ACD)-associated RCC in 100 (31.7%), papillary RCC in 41 (13.0%), and other minor subtypes in 30 (9.52%). Multivariate analysis showed that longer duration of dialysis, young age, and male sex were independent prognostic clinical factors for the occurrence of ACD-associated RCC. ACD-associated RCC included more WHO/International Society of Urologic Pathology (ISUP) grade 3/4 cases compared to other RCCs. In contrast, other unfavorable findings were less frequent in ACD-associated RCC, including the presence of a sarcomatoid component, lymphovascular invasion, and necrosis. In conclusion, ACD-associated RCC is a common histology in Japanese patients with ESRD. In addition, ACD-associated RCC showed more cases with a higher WHO/ISUP grade, but fewer cases with other unfavorable pathological features, suggesting a favorable prognosis of ACD-associated RCC.

Acquired cystic kidney disease and renal tumor.

Immunosuppression is a well-known risk factor for malignancy. Renal transplant patients are at high risk for cancer in the native kidneys especially in the presence of acquired cystic disease. We report a case highlighting the importance of screening for renal malignancy in renal transplant patients.

17q12 Deletion Syndrome as a Rare Cause for Diabetes Mellitus Type MODY5.

Context: Maturity-onset diabetes of the young type 5 (MODY5) is caused by mutations of the hepatocyte nuclear factor 1 homeobox ß gene (HNF1B). Although clinical characteristics and therapeutic management of MODY5 are increasingly better defined, adequate consideration of the frequent association of MODY5 with 17q12 deletion syndrome is often missing. Evidence Acquisition: We report two cases of patients with 17q12 deletion syndrome who presented to our clinic. Furthermore, we reviewed the existing literature to improve systematic diagnostic and therapeutic approaches. A PubMed search using the terms 17q12 deletion syndrome, diabetes mellitus type MODY5, and/or HNF1B was performed. Evidence Synthesis: Three hundred sixty-one cases of postnatal 17q12 deletion syndrome were assessed, and details on clinical manifestations, diagnostic approaches, and therapeutic management were reviewed and compared with the two cases at our clinic. Furthermore, data on pathogenic mechanisms and their clinical implications were evaluated. Conclusion: The 17q12 deletion syndrome usually comprises MODY5, structural or functional abnormalities of the kidneys, and neurodevelopmental or neuropsychiatric disorders. A complete deletion of HNF1B can be found in about 50% of patients with MODY5. A wide variety of additional clinical features, including genital and brain malformations, has been reported. Because HNF1B deletions are virtually always part of a 17q12 deletion syndrome and common genetic analyses for evaluation of MODY5 are unable to detect the deletion of a 1.4-Mb chromosomal region, initial attention to the syndromal features at the stage of diagnosis is of considerable importance for establishing correct diagnosis, subsequent therapy, and interdisciplinary patient care.