Molecular and cellular pathogenesis of autosomal recessive polycystic kidney disease

Autosomal recessive polycystic kidney disease (ARPKD) is an inherited disease characterized by a malformation complex which includes cystically dilated tubules in the kidneys and ductal plate malformation in the liver. The disorder is observed primarily in infancy and childhood, being responsible for significant pediatric morbidity and mortality. All typical forms of ARPKD are caused by mutations in a single gene, PKHD1 (polycystic kidney and hepatic disease 1). This gene has a minimum of 86 exons, assembled into multiple differentially spliced transcripts and has its highest level of expression in kidney, pancreas and liver. Mutational analyses revealed that all patients with both mutations associated with truncation of the longest open reading frame-encoded protein displayed the severe phenotype. This product, polyductin, is a 4,074-amino acid protein expressed in the cytoplasm, plasma membrane and primary apical cilia, a structure that has been implicated in the pathogenesis of different polycystic kidney diseases. In fact, cholangiocytes isolated from an ARPKD rat model develop shorter and dysmorphic cilia, suggesting polyductin to be important for normal ciliary morphology. Polyductin seems also to participate in tubule morphogenesis and cell mitotic orientation along the tubular axis. The recent advances in the understanding of in vitro and animal models of polycystic kidney diseases have shed light on the molecular and cellular mechanisms of cyst formation and progression, allowing the initiation of therapeutic strategy designing and promising perspectives for ARPKD patients. It is notable that vasopressin V2 receptor antagonists can inhibit/halt the renal cystic disease progression in an orthologous rat model of human ARPKD.

Renal and extrarenal manifestations of autosomal dominant polycystic kidney disease

The objective of the present study was to determine the frequency of the most common clinical features in patients with autosomal dominant polycystic kidney disease in a sample of the Brazilian population. The medical records of 92 patients with autosomal dominant polycystic kidney disease attended during the period from 1985 to 2003 were reviewed. The following data were recorded: age at diagnosis, gender, associated clinical manifestations, occurrence of stroke, age at loss of renal function (beginning of dialysis), and presence of a family history. The involvement of abdominal viscera was investigated by ultrasonography. Intracranial alterations were prospectively investigated by magnetic resonance angiography in 42 asymptomatic patients, and complemented with digital subtraction arteriography when indicated. Mean age at diagnosis was 35.1 ± 14.9 years, and mean serum creatinine at referral was 2.4 ± 2.8 mg/dL. The most frequent clinical manifestations during the disease were arterial hypertension (63.3%), lumbar pain (55.4%), an abdominal mass (47.8%), and urinary infection (35.8%). Loss of renal function occurred in 27 patients (mean age: 45.4 ± 9.5 years). The liver was the second organ most frequently affected (39.1%). Stroke occurred in 7.6% of the patients. Asymptomatic intracranial aneurysm was detected in 3 patients and arachnoid cysts in 3 other patients. In conclusion, the most common clinical features were lumbar pain, arterial hypertension, abdominal mass, and urinary infection, and the most serious complications were chronic renal failure and stroke. Both intracranial aneurysms and arachnoid cysts occurred in asymptomatic patients at a frequency of 7.14%.

Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common human life-threatening monogenic disorders. The disease is characterized by bilateral, progressive renal cystogenesis and cyst and kidney enlargement, often leading to end-stage renal disease, and may include extrarenal manifestations. ADPKD is caused by mutation in one of two genes, PKD1 and PKD2, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. PC2 is a non-selective cation channel permeable to Ca2+, while PC1 is thought to function as a membrane receptor. The cyst cell phenotype includes increased proliferation and apoptosis, dedifferentiation, defective planar polarity, and a secretory pattern associated with extracellular matrix remodeling. The two-hit model for cyst formation has been recently extended by the demonstration that early gene inactivation leads to rapid and diffuse development of renal cysts, while inactivation in adult life is followed by focal and late cyst formation. Renal ischemia/reperfusion, however, can function as a third hit, triggering rapid cyst development in kidneys with Pkd1 inactivation induced in adult life. The PC1-PC2 complex behaves as a sensor in the primary cilium, mediating signal transduction via Ca2+ signaling. The intracellular Ca2+ homeostasis is impaired in ADPKD, being apparently responsible for the cAMP accumulation and abnormal cell proliferative response to cAMP. Activated mammalian target for rapamycin (mTOR) and cell cycle dysregulation are also significant features of PKD. Based on the identification of pathways altered in PKD, a large number of preclinical studies have been performed and are underway, providing a basis for clinical trials in ADPKD and helping the design of future trials.

Caffeine intake by patients with autosomal dominant polycystic kidney disease

Because caffeine may induce cyst and kidney enlargement in autosomal dominant polycystic kidney disease (ADPKD), we evaluated caffeine intake and renal volume using renal ultrasound in ADPKD patients. Caffeine intake was estimated by the average of 24-h dietary recalls obtained on 3 nonconsecutive days in 102 ADPKD patients (68 females, 34 males; 39 ± 12 years) and compared to that of 102 healthy volunteers (74 females, 28 males; 38 ± 14 years). The awareness of the need for caffeine restriction was assessed. Clinical and laboratory data were obtained from the medical records of the patients. Mean caffeine intake was significantly lower in ADPKD patients versus controls (86 vs 134 mg/day), and 63% of the ADPKD patients had been previously aware of caffeine restriction. Caffeine intake did not correlate with renal volume in ADPKD patients. There were no significant differences between the renal volumes of patients in the highest and lowest tertiles of caffeine consumption. Finally, age-adjusted multiple linear regression revealed that renal volume was associated with hypertension, chronic kidney disease stage 3 and the time since diagnosis, but not with caffeine intake. The present small cross-sectional study indicated a low level of caffeine consumption by ADPKD patients when compared to healthy volunteers, which was most likely due to prior awareness of the need for caffeine restriction. Within the range of caffeine intake observed by ADPKD patients in this study (0-471 mg/day), the renal volume was not directly associated with caffeine intake.

Cyst infection in hospital-admitted autosomal dominant polycystic kidney disease patients is predominantly multifocal and associated with kidney and liver volume

Positron-emission tomography/computed tomography (PET/CT) has improved cyst infection (CI) management in autosomal dominant polycystic kidney disease (ADPKD). The determinants of kidney and/or liver involvement, however, remain uncertain. In this study, we evaluated clinical and imaging factors associated with CI in kidney (KCI) and liver (LCI) in ADPKD. A retrospective cohort study was performed in hospital-admitted ADPKD patients with suspected CI. Clinical, imaging and surgical data were analyzed. Features of infected cysts were evaluated by PET/CT. Total kidney (TKV) and liver (TLV) volumes were measured by CT-derived multiplanar reconstruction. CI was detected in 18 patients who experienced 24 episodes during an interval of 30 months (LCI in 12, KCI in 10 and concomitant infection in 2). Sensitivities of CT, magnetic resonance imaging and PET/CT were 25.0, 71.4, and 95.0%. Dysuria (P<0.05), positive urine culture (P<0.01), and previous hematuria (P<0.05) were associated with KCI. Weight loss (P<0.01) and increased C-reactive protein levels (P<0.05) were associated with LCI. PET/CT revealed that three or more infected cysts were present in 70% of the episodes. TKV was higher in kidney-affected than in LCI patients (AUC=0.91, P<0.05), with a cut-off of 2502 mL (72.7% sensitivity, 100.0% specificity). TLV was higher in liver-affected than in KCI patients (AUC=0.89, P<0.01) with a cut-off of 2815 mL (80.0% sensitivity, 87.5% specificity). A greater need for invasive procedures was observed in LCI (P<0.01), and the overall mortality was 20.8%. This study supports PET/CT as the most sensitive imaging method for diagnosis of cyst infection, confirms the multifocal nature of most hospital-admitted episodes, and reveals an association of kidney and liver volumes with this complication.

Pain determinants of pain in autosomal dominant polycystic kidney disease

Pain is the most common symptom reported by ADPKD patients, afflicting approximately 60% of cases and may result from renal hemorrhage, calculi, urinary tract infections, cyst rupture, or due to stretching of the capsule or traction of the renal pedicle. We have recently investigated pain patterns in AD-PKD patients using a translated version of a pain questionnaire specific for AD-PKD population. The questionnaire revealed that 67% patients with ADPKD exhibited some type of pain. The findings of that study emphasized that pain appeared early in the course of ADPKD, when patients still exhibited preserved renal function. In the present study, a multivariate logistic regression analysis disclosed that renal volume (9-fold increased risk) and nephrolithiasis (4-fold increased risk) were the most important determinant factors for pain in ADPKD patients with preserved renal function, after adjustments for the presence of hypertension and duration of the disease.

Schistosomal glomerulopathy and changes in the distribution of histological patterns of glomerular diseases in Bahia, Brazil

Distinct patterns of glomerular lesions, including membranoproliferative glomerulonephritis and focal segmental glomerulosclerosis, are associated with infection by Schistosoma mansoni or Schistosoma japonicum. Evidence suggests that immune complex deposition is the main mechanism underlying the different forms of schistosomal glomerulonephritis and that immune complex deposition may be intensified by portal hypertension. The relationship between focal segmental glomerulosclerosis and schistosomiasis remains poorly understood. A clinicopathologic classification of schistosomal glomerulopathies was proposed in 1992 by the African Association of Nephrology. In Brazil, mass treatment with oral medications has led to a decrease in the occurrence of schistosomal glomerulopathy. In a survey of renal biopsies performed in Salvador, Brazil, from 2003-2009, only 24 (4%) patients were identified as positive for S. mansoni infection. Among these patients, only one had the hepatosplenic form of the disease. Focal segmental glomerulosclerosis was found in seven patients and membranoproliferative glomerulonephritis was found in four patients. Although retrospective studies on the prevalence of renal diseases based on kidney biopsies may be influenced by many patient selection biases, a change in the distribution of glomerulopathies associated with nephrotic syndrome was observed along with a decline in the occurrence of severe forms of schistosomiasis.

Postmortem findings in collared peccaries raised in captivity in northeastern Brazil

This study is a retrospective examination of diseases in collared peccaries that were diagnosed by the Veterinary Pathology Laboratory, Universidade Federal Rural do Semiárido. Necropsy and histological examination were performed from 2005 to 2010. Of the 50 necropsied collared peccaries, 24% died due to restraint and capture myopathy; 18% died from trauma; and the remainder was diagnosed with splenic hemangioma (6%), enterolithiasis (6%), gastritis (6%), gastric ulcer (4%), intestinal volvulus (4%), gastric volvulus (2%), mammary carcinoma (2%), polycystic kidney disease (2%), pyometra (2%), and suppurative bronchopneumonia (2%). Twelve animals remained undiagnosed, seven of which (14%) were in advanced autolytic condition and five of which (10%) had no gross or microscopic lesions that were compatible with disease. This paper describes illnesses that have not been reported in the collared peccary, focusing on their clinical and pathological aspects.

Extracellular vesicles: structure, function, and potential clinical uses in renal diseases

Interest in the role of extracellular vesicles in various diseases including cancer has been increasing. Extracellular vesicles include microvesicles, exosomes, apoptotic bodies, and argosomes, and are classified by size, content, synthesis, and function. Currently, the best characterized are exosomes and microvesicles. Exosomes are small vesicles (40-100 nm) involved in intercellular communication regardless of the distance between them. They are found in various biological fluids such as plasma, serum, and breast milk, and are formed from multivesicular bodies through the inward budding of the endosome membrane. Microvesicles are 100-1000 nm vesicles released from the cell by the outward budding of the plasma membrane. The therapeutic potential of extracellular vesicles is very broad, with applications including a route of drug delivery and as biomarkers for diagnosis. Extracellular vesicles extracted from stem cells may be used for treatment of many diseases including kidney diseases. This review highlights mechanisms of synthesis and function, and the potential uses of well-characterized extracellular vesicles, mainly exosomes, with a special focus on renal functions and diseases.

Depressed cardiac autonomic modulation in patients with chronic kidney disease

Introduction: A dysfunctional autonomic nervous system (ANS) has also been recognized as an important mechanism contributing to the poor outcome in CKD patients, with several studies reporting a reduction in heart rate variability (HRV). Objective: Evaluate the sympathovagal balance in patients with chronic kidney disease on conservative treatment. Methods: In a cross-sectional study, patients with CKD stages 3, 4 and 5 not yet on dialysis (CKD group) and age-matched healthy subjects (CON group) underwent continuous heart rate recording during two twenty-minute periods in the supine position (pre-inclined), followed by passive postural inclination at 70° (inclined period). Power spectral analysis of the heart rate variability was used to assess the normalized low frequency (LFnu), indicative of sympathetic activity, and the normalized high frequency (HFnu), indicative of parasympathetic activity. The LFnu/HFnu ratio represented sympathovagal balance. Results: After tilting, CKD patients had lower sympathetic activity, higher parasympathetic activity, and lower sympathovagal balance than patients in the CON group. Compared to patients in stage 3, patients in stage 5 had a lower LFnu/HFnu ratio, suggesting a more pronounced impairment of sympathovagal balance as the disease progresses. Conclusion: CKD patients not yet on dialysis have reduced HRV, indicating cardiac autonomic dysfunction early in the course of CKD.

Prevalence of Chronic Kidney Disease in newly diagnosed patients with Human immunodeficiency virus in Ilorin, Nigeria

AbstractIntroduction:Human immunodeficiency virus (HIV) the causative agent of Acquired immunodeficiency syndrome (AIDS) is an important cause of renal diseases in sub-Saharan Africa. There is paucity of studies on the burden of chronic kidney disease (CKD) among patients with HIV/AIDS in the North-Central zone of Nigeria.Methods:This is a cross-sectional study of 227 newly-diagnosed, antiretroviral naïve patients with HIV/AIDS seen at the HIV clinic of the Medical Out-patient Department (MOPD) of University of Ilorin Teaching Hospital (UITH). They were matched with 108 control group. Laboratory investigations were performed for the participants. CKD was defined as estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2 and/or albumin creatinine ratio (ACR) > 30 mg/g.Results:There were 100 (44%) males among the patients and 47 (43.5%) among the control group. The mean ages of the patients and controls were 40.3 ± 10.3 years and 41.8 ± 9.5 years respectively. CKD was observed in 108 (47.6%) among the patients and 18 (16.7%) of the controls (p = 0.01). The median CD4 T-cell count was significantly lower in patients with CKD. Ninety-three (41.0%) of the patients had dipstick proteinuria of > 2 +. The median albumin creatinine ratio (ACR) was significantly higher among the HIV-positive patients (272.3 mg/g) compared with the HIV-negative controls (27.22 mg/g) p = 0.01. The CD4 T-cell count correlates positively with eGFR (r = 0.463, p = 0.001) and negatively with ACR (r = -0.806, p = 0.001).Conclusions:CKD is very common among patients with HIV/AIDS in Ilorin. Screening and early intervention for CKD should be part of the protocols in the management of these patients.

SEROLOGICAL MARKERS OF VIRAL, SYPHILITIC AND TOXOPLASMIC INFECTION IN CHILDREN AND TEENAGERS WITH NEPHROTIC SYNDROME: CASE SERIES FROM MATO GROSSO STATE, BRAZIL

Some infections can be the cause of secondary nephrotic syndrome. The aim of this study was to describe the experience of a Renal Disease Reference Clinic from Central Brazil, in which serological markers of some infectious agents are systematically screened in children with nephrotic syndrome. Data were obtained from the assessment of medical files of all children under fifteen years of age, who matched nephrotic syndrome criteria. Subjects were tested for IgG and IgM antibodies against T. gondii and cytomegalovirus; antibodies against Herpes simplex, hepatitis C virus and HIV; and surface antigen (HBsAg) of hepatitis B virus. The VDRL test was also performed. 169 cases were studied. The median age on the first visit was 44 months and 103 (60.9%) patients were male. Anti-CMV IgG and IgM were found in 70.4% and 4.1%, respectively. IgG and IgM against Toxoplasma gondii were present in 32.5% and 5.3%, respectively. Two patients were positive for HBsAg, but none showed markers for HIV, hepatitis C, or Treponema pallidum. IgG and IgM against herpes simplex virus were performed on 54 patients, of which 48.1% and 22.2% were positive. IgM antibodies in some children with clinical signs of recent infection suggest that these diseases may play a role in the genesis of nephrotic syndrome.

Acute kidney injury in a tropical country: a cohort study of 253 patients in an infectious diseases intensive care unit

Introduction: Acute kidney injury (AKI) is a frequent and potentially fatal complication in infectious diseases. The aim of this study was to investigate the clinical aspects of AKI associated with infectious diseases and the factors associated with mortality. Methods: This retrospective study was conducted in patients with AKI who were admitted to the intensive care unit (ICU) of a tertiary infectious diseases hospital from January 2003 to January 2012. The major underlying diseases and clinical and laboratory findings were evaluated. Results: A total of 253 cases were included. The mean age was 46±16 years, and 72% of the patients were male. The main diseases were human immunodeficiency virus (HIV) infection, HIV/acquired immunodeficiency syndrome (AIDS) (30%), tuberculosis (12%), leptospirosis (11%) and dengue (4%). Dialysis was performed in 70 cases (27.6%). The patients were classified as risk (4.4%), injury (63.6%) or failure (32%). The time between AKI diagnosis and dialysis was 3.6±4.7 days. Oliguria was observed in 112 cases (45.7%). The Acute Physiology and Chronic Health Evaluation (APACHE) II scores were higher in patients with HIV/AIDS (57±20, p-value=0.01) and dengue (68±11, p-value=0.01). Death occurred in 159 cases (62.8%). Mortality was higher in patients with HIV/AIDS (76.6%, p-value=0.02). A multivariate analysis identified the following independent risk factors for death: oliguria, metabolic acidosis, sepsis, hypovolemia, the need for vasoactive drugs, the need for mechanical ventilation and the APACHE II score. Conclusions: AKI is a common complication in infectious diseases, with high mortality. Mortality was higher in patients with HIV/AIDS, most likely due to the severity of immunosuppression and opportunistic diseases.

Atrial Fibrillation and Non-cardiovascular Diseases: A Systematic Review

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with an unfavorable prognosis, increasing the risk of stroke and death. Although traditionally associated with cardiovascular diseases, there is increasing evidence of high incidence of AF in patients with highly prevalent noncardiovascular diseases, such as cancer, sepsis, chronic obstructive pulmonary disease, obstructive sleep apnea and chronic kidney disease. Therefore, considerable number of patients has been affected by these comorbidities, leading to an increased risk of adverse outcomes.The authors performed a systematic review of the literature aiming to better elucidate the interaction between these conditions.Several mechanisms seem to contribute to the concomitant presence of AF and noncardiovascular diseases. Comorbidities, advanced age, autonomic dysfunction, electrolyte disturbance and inflammation are common to these conditions and may predispose to AF.The treatment of AF in these patients represents a clinical challenge, especially in terms of antithrombotic therapy, since the scores for stratification of thromboembolic risk, such as the CHADS2 and CHA2DS2VASc scores, and the scores for hemorrhagic risk, like the HAS-BLED score have limitations when applied in these conditions.The evidence in this area is still scarce and further investigations to elucidate aspects like epidemiology, pathogenesis, prevention and treatment of AF in noncardiovascular diseases are still needed.

Arterial hypertension and metabolic profile in patients with polycystic ovary syndrome

PURPOSE: To evaluate parameters related with arterial pressure and metabolic profile in women with polycystic ovary syndrome (POS). METHODS: This monocentric study at the University Hospital Endocrinology Section included 60 women aged 18-45 years, 42 being diagnosed with POS and acting as 18 controls. All women were subjected to transvaginal ultrasound and monitored for arterial pressure for 24 h in the ambulatory (MAP). Venous blood samples were taken between 07.00 and 09.00, after 12 h fasting. Basal (BG) and fasting glucose concentrations, total cholesterol and its fractions, triglycerides and insulin (to calculate the homeostatic assay insulin-resistance, HOMA-IR) were measured. Collected data were the mean arterial blood pressure (24-h awake/sleep cycle), arterial pressure nocturnal descensus, glycemia and fasting glucose for HOMA-IR, and lipid profile. The Student's t test was used to compare homogeneous variables; the Mann-Whitney test was used to compare non-homogeneous variables; the Pearson's correlation coefficient was used to search for correlation between the variables. The c² test was used for comparison of the absence of nocturnal descensus. Significance was taken as p<0.05. RESULTS: The mean age of the patients with POS was 27.4±5.5 (18-45 years, n=42) and the body mass index (BMI) was 30.2±6.5 kg/m² (18.3-54.9). In the Control Group, the mean age was 31.4±6.1 (18-45 years) and the BMI was 27.1±6.2 kg/m² (18.3-54.9, n=18). No difference in the metabolic parameters and insulin resistance was observed between the two groups. Comparison between these parameters and MAP showed that the only parameter with a correlation was the BMI, independent of the POS diagnosis. This was not seen in nocturnal descensus, which was uncorrelated with POS and any of the other studied parameters. CONCLUSION: POS women do not show higher arterial blood pressure, glycemia, HDL-col, TG, HOMA-IR and BMI compared to non-POS women. However, POS patients showed correlation between arterial pressure and BMI, suggesting that obesity is a primary factor involved in arterial pressure changes in these patients.