The humoral pattern recognition molecule PTX3 is a key component of innate immunity against urinary tract infection.

Immunity in the urinary tract has distinct and poorly understood pathophysiological characteristics and urinary tract infections (UTIs) are important causes of morbidity and mortality. We investigated the role of the soluble pattern recognition molecule pentraxin 3 (PTX3), a key component of the humoral arm of innate immunity, in UTIs. PTX3-deficient mice showed defective control of UTIs and exacerbated inflammation. Expression of PTX3 was induced in uroepithelial cells by uropathogenic Escherichia coli (UPEC) in a Toll-like receptor 4 (TLR4)- and MyD88-dependent manner. PTX3 enhanced UPEC phagocytosis and phagosome maturation by neutrophils. PTX3 was detected in urine of UTI patients and amounts correlated with disease severity. In cohorts of UTI-prone patients, PTX3 gene polymorphisms correlated with susceptibility to acute pyelonephritis and cystitis. These results suggest that PTX3 is an essential component of innate resistance against UTIs. Thus, the cellular and humoral arms of innate immunity exert complementary functions in mediating resistance against UTIs.

Erdheim-Chester disease: from palliative care to targeted treatment.

Erdheim-Chester disease (ECD) is a life-threatening multi-systemic non-Langerhans histiocytosis with cardiovascular complications as the leading cause of death. ECD affects the kidneys in up to 30% of cases, with fibrotic tissue deposition in the perirenal fat and renal hilum. Diagnosis is usually based on histological analysis of the pathologic tissue, which typically shows xanthogranulomatous infiltrates of foamy CD68+/CD1a- histiocytes surrounded by fibrosis. A consistent percentage of patients affected by ECD develop renal failure and hypertension as a consequence of renal artery stenosis and hydronephrosis. These conditions have been generally treated with the placement of stents and nephrostomies that frequently led to disappointing outcomes. Before the introduction of interferon-alpha (IFNα) treatment, the mortality rate was as high as 57% in the long term. Recent studies have granted new insights into the pathogenesis of ECD, which seems to bear a dual component of clonal and inflammatory disease. These advances led to use specific therapies targeting either the oncogenes (BRAF(V600E)) or the effectors of the immune response implicated in ECD (IL-1, TNFα). Drugs such as anakinra (recombinant human IL-1 receptor antagonist), infliximab (monoclonal antibody against TNFα) and vemurafenib (inhibitor of mutant BRAF) showed promising results in small single-centre series. Although larger trials will be needed to address the impact of these drugs on ECD prognosis and to select the most effective treatment, targeted therapies hold the premises to drastically change the outcome of this condition.

Education and counseling of renal transplant recipients.

A large number of factors can influence the clinical outcome of kidney transplant recipients, but the active role of the patient to prevent the possible complications related to transplant and its treatment is often neglected. Poor adherence to prescriptions is frequent in transplant recipients and represents a major contributor to the development of graft failure, cardiovascular disease, infection and/or malignancy. Smoking can render the patient more susceptible to cancer, cardiovascular disease and infection, and can also impair renal allograft function. The risk of malignancy is increased in transplant recipients. Therefore screening for cancer is of paramount importance. Measures that can enable prevention or early detection of cancer include self-exams and screening, physical activity, avoidance of smoking and sun exposure, and a diet rich in fruits and vegetables but limited in fats, red meats, salt and alcohol. Regular exercise can help to prevent cardiovascular disease, diabetes, obesity, osteoporosis and even some forms of cancer. Thus regular exercise is recommended. Yet, too many transplant patients remain sedentary. Weight gain is common in renal allograft recipients and may be associated with hypertension, hyperlipidemia and/or glucose intolerance or overt diabetes. To prevent these complications, patients should follow diet regimens based on low fat and normal/low caloric intake. Small amounts of alcohol may be permitted in view of its potential cardioprotective effect, but a large consumption of alcohol can be responsible for devastating side effects. Last but not least, abidance by hygienic measures may help in preventing cardiovascular and infectious complications.

Chyluria associated with nephrotic-range proteinuria: pathophysiology, clinical picture and therapeutic options.

Chyluria denotes the urinary excretion of chyle, which is a lymphatic fluid rich in chylomicrons. Chyle flows from the intestinal lacteals to the left subclavian vein through the thoracic duct. When an abnormal connection between these structures and the urinary tract develops, chyluria appears. The syndrome is often associated with a nephrotic-range proteinuria, and this could be a wrong indication to perform renal biopsy. Chyluria is classified as parasitic or nonparasitic, the former being induced by lymphatic filariasis, whereas the latter is caused by medical, traumatic or inherited diseases. The patient usually reports excretion of milky urines, monolateral flank pain, malnutrition, weight loss and weakness. Urinalysis demonstrates lymphocyturia associated with chylomicrons and triglycerides in the supernatant. The diagnostic approach is aimed to define the site of lymphourinary fistula. A selective ureteral catheterization allows to collect urine samples from each kidney, demonstrating a monolateral source of proteins and lipids and making renal biopsy superfluous. Other diagnostic tools include nuclear magnetic resonance urography and lymphoangiography. Many therapeutic options have been proposed. Sclerosing solution instillation into the renal pelvis and laparoscopic renal pedicle disconnection are the invasive procedures most commonly employed. Among the medical alternatives, a low-fat diet supplemented with medium-chain triglycerides is often followed by complete clinical and biochemical remission.

Looking at appearance of urine before performing a renal biopsy in nephrotic syndrome.

Chyluria results from an abnormal connection between lymphatic bed and urinary tract, causing lymph leakage into the urine. The clinical picture often begins with the appearance of cloudy, milky urines accompanied by monolateral flank pain, malnutrition, weight loss and weakness. We report a case of chyluria that occurred in a young woman who was referred to our unit for nephrotic-range proteinuria. Before performing a renal biopsy, we found that urine analysis demonstrated a massive lipiduria. Therefore, we collected urine samples from each kidney with a selective ureteral catheterization, demonstrating a monolateral source of lipids and proteins. We suspended the renal biopsy and performed a lymphography that showed an inherited lymphangioma on the left lumbar lymphatic bed. Sclerosing solution instillation, renal pedicle lymphatic disconnection or laser therapy are invasive therapeutical options that may cause severe adverse effects. Instead of these procedures, a conservative therapy based on a low-fat diet supplemented with medium-chain triglycerides was chosen. This dietetic schedule was followed by complete resolution of proteinuria and lipiduria. The patient progressively gained body weight and improved quality of life. No relapses were observed after 3 years of follow-up. This case emphasizes the possible role of a noninvasive therapeutical option for patients with chyluria.

CNS involvement and treatment with interferon-α are independent prognostic factors in Erdheim-Chester disease: a multicenter survival analysis of 53 patients.

Erdheim-Chester disease (ECD) is a rare form of non-Langerhans histiocytosis, with noncodified therapeutic management and high mortality. No treatment has yet been shown to improve survival in these patients. We conducted a multicenter prospective observational cohort study to assess whether extraskeletal manifestations and interferon-α treatment would influence survival in a large cohort of ECD patients. To achieve this goal, we thoroughly analyzed the clinical presentation of 53 patients with biopsy-proven ECD, and we performed a survival analysis using Cox proportional hazard model. Fifty-three patients (39 men and 14 women) with biopsy-proven ECD were followed up between November 1981 and November 2010. Forty-six patients (87%) received interferon-α and/or PEGylated interferon-α. Multivariate survival analysis using Cox proportional hazard model revealed that central nervous system involvement was an independent predictor of death (hazard ratio = 2.51; 95% confidence interval, 1.28-5.52; P = .006) in our cohort. Conversely, treatment with interferon-α was identified as an independent predictor of survival (hazard ratio = 0.32; 95% confidence interval, 0.14-0.70; P = .006). Although definitive confirmation would require a randomized controlled trial, these results suggest that interferon-α improves survival in ECD patients. This may be seen as a significant advance, as it is the first time a treatment is shown to improve survival in this multisystemic disease with high mortality.

Life-threatening hypercalcemia in patients with rhabdomyolysis-induced oliguric acute renal failure.

BACKGROUND: In a third of patients presenting with rhabdomyolysis-induced acute renal failure (ARF), a biphasic plasma calcium profile may occur. METHODS: We report a case of rhabdomyolysis-induced ARF presenting hypocalcemia during oliguria, followed by a severe hypercalcemia in the polyuric phase. A hypocalcemia-induced acute increase of plasma parathyroid hormone in the early stage of ARF was followed by a down-regulation of parathyroid hormone, 1,25(OH)2 vitamin D and 25(OH) vitamin D during the renal function recovery, associated with an acute hypercalcemia. The plasma calcium increase induced in our patient severe neurological disturbances, life-threatening short QT interval and Brugada-like syndrome at risk of malignant arrhythmias. This complication was treated by hemodialysis and pamidronic acid infusion. RESULTS: This case confirms that the pathogenesis of the biphasic calcium profile may be related to the massive calcium uptake in the ischemic muscle cells during oliguria, followed by a muscle calcium release later in the polyuric stage of ARF. Therefore, the behavior of calciotropic hormones may be the consequence rather than the cause of plasma calcium changes. CONCLUSIONS: We would like to emphasize the danger of sudden death that may occur in the recovery phase of rhabdomyolysis-induced ARF when the physician might be wrongly convinced that the major risks have disappeared.

Ureteral endometriosis: a rare and underdiagnosed cause of kidney dysfunction.

Little attention has been paid by the renal literature to ureteral endometriosis, a rare and silent disorder that can eventually lead to renal failure. In endometriosis, the ureteral involvement can be limited to a single ureter, more often the left one, or both ureters with consequent urine tract obstruction and ureterohydronephrosis. In most cases, the ureteral obstruction is caused by endometrial tissue surrounding the ureter (extrinsic ureteral endometriosis). In the remaining cases, endometrial cells are located within the ureter (intrinsic ureteral endometriosis). Progressive ureteral obstruction can be insidious in onset and can ultimately lead to renal failure if a correct diagnosis is missed. The true incidence of renal failure caused by endometriosis is completely unknown, although cases have been reported in the literature. The diagnosis of ureteral endometriosis is difficult since the disease may be clinically silent or associated with non-specific symptoms. Only a high index of suspicion and radiological support may help to obtain an early diagnosis. However, while renal imaging is useful in the cases of extrinsic endometriosis, the diagnosis of intrinsic endometriosis often requires ureteroscopy or laparoscopy. The prognosis of ureteral endometriosis depends on the time of diagnosis. In too many cases of bilateral obstruction, the patient is referred to the nephrologist because of an advanced, irreversible renal failure. Although some patients may benefit from progestin or anti-arotamase therapy, in most cases of ureteral endometriosis surgery is needed, laparoscopy surgery being preferred today to laparatomy.

Role of the kidney in plasma cytokine removal in sepsis syndrome: a pilot study.

BACKGROUND: At the onset of sepsis, endotoxins or other components of the gram-negative capsular wall stimulate the synthesis of pro-inflammatory cytokines by activating the monocyte-macrophage system. In this context, interleukin-1 beta (IL-1), tumor necrosis factor-alpha (TNF) and IL-6 are considered co-responsible for the clinical picture of sepsis syndrome. Many organs can be involved, and kidney dysfunction occurs early with a picture of non-oliguric acute renal failure (NOARF) or oliguric acute renal failure (OARF). This study aimed to investigate the role of the kidney in plasma removal of some pro-inflammatory cytokines in the first 24 hr after the diagnosis of sepsis syndrome, when, according to the peak concentration hypothesis, their plasma concentration is maximal. 18 septic patients, six patients with normal renal function (NRF), six with NOARF and six with OARF were selected for the study. We measured the plasma levels and urinary excretion of IL-1, TNF and IL-6 at the moment of sepsis diagnosis (base-line) and 24 hr later. Moreover, urinary excretion of IL-1 and IL-6 was done in the same interval by measuring the percentage of fractional excretion (FE%) of these cytokines. RESULTS: Multivariate analysis (ANOVA) showed no significant difference in plasma IL-1 levels at baseline in the NRF, NOARF and OARF patients (p=0.11), whereas a significant increase was found in OARF patients at 24 hr, p<0.023. OARF patients presented significantly higher IL-6 plasma levels compared with the other two groups, both at baseline (p<0.0002) and at 24 hr (p<0.0001). Plasma TNF levels were not significantly different at baseline (p=0.184), whereas the OARF group showed a significant increase at 24 hr, (p<0.05). The urinary FE of IL-1 was 1.2 +/- 0.6% in NRF, and 1.0 +/- 0.4% in NOARF (ns), the FE of IL-6 was 1.4 +/- 0.8% in NRF and 1.3 +/- 0.3% in NOARF (ns). A negative in-significant correlation was found between the plasma concentration and FE of IL-1 beta (r=-0.33, p<0.07). Urinary excretion of IL-6 was significantly related with urinary IL-1 beta, both expressed as pg/ml/mg of urinary creatinine (r=0.85, p<0.0001). No significant relation was found between IL-1 and IL-6 plasma concentrations or between plasma concentration and FE of IL-6. CONCLUSION: These results suggest that at disease onset, the kidney removes some pro-inflammatory cytokines from the plasma of septic patients until diuresis is preserved. As it has been demonstrated that NOARF patients have a better prognosis than OARF patients and their survival in sepsis syndrome seems to be inversely related to the plasma pro-inflammatory cytokine levels, diuresis maintenance by diuretic infusion can be important to improve patient prognosis.