Chronic Kidney Disease of Undetermined Etiology around the World.

BACKGROUND: Epidemics of chronic kidney disease of uncertain etiology (CKDu) are occurring on the Pacific coast of Central America, in Sri Lankan and Indian agricultural communities, and in other hotspots around the world. CKDu primarily affects male agricultural workers, and traditional risk factors such as diabetes and hypertension are not involved in the pathogenesis. Although a causal factor has not yet been identified, culprits include repeated volume depletion-induced kidney injury, as well as exposure to agrichemicals, heavy metals and nephrotoxins contained in drugs, beverages, and traditional medications. Multiple risk factors may interact in a synergistic fashion thus resulting in chronic kidney damage. The absence of undefined protective factors may amplify the risk. SUMMARY: This review focuses on the current understanding of CKDu by analyzing epidemiology, potential risk factors, and clinical and pathological features as well as geographical peculiarities of each disease. We also focus our attention on the etiology of these conditions in which multiple factors may synergistically contribute to the development and progression of the disease. The last part of the manuscript is dedicated to the research agenda and practical recommendations. Key Messages: Since renal replacement therapy is not extensively available in areas where CKDu is widespread, prevention by avoiding all known potential risk factors is crucial. Innovative healthcare solutions and social policies in endemic areas along with collaborative clinical research projects are needed to better identify factors involved in disease promotion and progression.

Protective role of DJ-1 in endotoxin-induced acute kidney injury.

Acute kidney injury (AKI) is a frequent complication of sepsis and an important cause of morbidity and mortality worldwide. A cornerstone of sepsis-associated AKI is dysregulated inflammation, leading to increased tissue oxidative stress and free radical formation, which leads to multiple forms of cell death. DJ-1 is a peroxiredoxin protein with multiple functions, including its ability to control cellular oxidative stress. Although DJ-1 is expressed prominently by renal tubules, its role in AKI has not been investigated. In the present study, we examined the effect of DJ-1 deficiency in a murine model of endotoxin-induced AKI. Endotoxemia induced greater kidney injury in DJ-1-deficient mice. Furthermore, DJ-1 deficiency increased renal oxidative stress associated with increased renal tubular apoptosis and with expression of death domain-associated protein (DAXX). Similar to the in vivo model, in vitro experiments using a medullary collecting duct cell line (mIMCD3) and cytotoxic serum showed that serum obtained from wild-type mice resulted in increased expression of s100A8/s100A9, DAXX, and apoptosis in DJ-1-deficient mIMCD3 cells. Our findings demonstrate a novel renal protective role for renal tubular DJ-1 during endotoxemia through control of oxidative stress, renal inflammation, and DAXX-dependent apoptosis.

Modulation of iron homeostasis with hepcidin ameliorates spontaneous murine lupus nephritis.

Lupus nephritis is the end organ manifestation of systemic lupus erythematosus. Iron metabolism and its master regulator, hepcidin, are known to regulate cell proliferation and inflammation, but their direct role in the pathophysiology of lupus nephritis remains under-investigated. Exogenous hepcidin reduced the severity of lupus nephritis in MRL/lpr mice, a preclinical model of spontaneous systemic lupus erythematosus without worsening anemia of inflammation. Hepcidin treatment reduced renal iron accumulation, systemic and intrarenal cytokines, and renal immune cell infiltration, independent of glomerular immune complex deposits and circulating autoantibodies. Hepcidin increased renal H-ferritin (a ferroxidase), reduced expression of free iron dependent DNA synthesis enzymes, Ribonucleotide Reductase 1 and 2, and intra-renal macrophage proliferation. These findings were recapitulated in vitro upon treatment of macrophages with hepcidin and murine colony stimulation factor-1. Furthermore, hepcidin-treated macrophages secreted less IL-1ß and IL-6 upon stimulation with the TLR3 agonist polyinosine-polycytidylic acid. Of clinical relevance, hepcidin reduced progression and severity of nephritis in old mice with established systemic autoimmunity and overt proteinuria, highlighting its therapeutic potential. Thus, our findings provide a proof-of-concept that targeting cellular iron metabolism with hepcidin represents a promising therapeutic strategy in lupus nephritis.

Pregnancy outcomes after kidney graft in Italy: are the changes over time the result of different therapies or of different policies? A nationwide survey (1978-2013).

BACKGROUND: Kidney transplantation is the treatment of choice to restore fertility to women on renal replacement therapy. Over time, immunosuppressive, support therapies and approaches towards high-risk pregnancies have changed. The aim of this study was to analyse maternal-foetal outcomes in two cohorts of transplanted women who delivered a live-born baby in Italy in 1978-2013, dichotomized into delivery before and after January 2000. METHODS: A survey involving all the Italian transplant centres was carried out, gathering data on all pregnancies recorded since the start of activity at each centre; the estimated nationwide coverage was 75%. Data on cause of ESRD, dialysis, living/cadaveric transplantation, drug therapy, comorbidity, and the main maternal-foetal outcomes were recorded and reviewed. Data were compared with a low-risk cohort of pregnancies from two large Italian centres (2000-14; Torino and Cagliari Observational Study cohort). RESULTS: The database consists of 222 pregnancies with live-born babies after transplantation (83 before 2000 and 139 in 2000-13; 68 and 121 with baseline and birth data, respectively), and 1418 low-risk controls. The age of the patients significantly increased over time (1978-99: age 30.7 ± 3.7 versus 34.1 ± 3.7 in 2000-13; P < 0.001). Azathioprine, steroids and cyclosporine A were the main drugs employed in the first time period, while tacrolimus emerged in the second. The prevalence of early preterm babies increased from 13.4% in the first to 27.1% in the second period (P = 0.049), while late-preterm babies non-significantly decreased (38.8 versus 33.1%), thus leaving the prevalence of all preterm babies almost unchanged (52.2 and 60.2%; P = 0.372). Babies below the 5th percentile decreased over time (22.2 versus 9.6%; P = 0.036). In spite of high prematurity rates, no neonatal deaths occurred after 2000. The results in kidney transplant patients are significantly different from controls both considering all cases [preterm delivery: 57.3 versus 6.3%; early preterm: 22.2 versus 0.9%; small for gestational age (SGA): 14 versus 4.5%; P < 0.001] and considering only transplant patients with normal kidney function [preterm delivery: 35 versus 6.3%; early preterm: 10 versus 0.9%; SGA: 23.7 versus 4.5% (P < 0.001); risks increase across CKD stages]. Kidney function remained stable in most of the patients up to 6 months after delivery. Multiple regression analysis performed on the transplant cohort highlights a higher risk of preterm delivery in later CKD stages, an increase in preterm delivery and a decrease in SGA across periods. CONCLUSIONS: Pregnancy after transplantation has a higher risk of adverse outcomes compared with the general population. Over time, the incidence of SGA babies decreased while the incidence of 'early preterm' babies increased. Although acknowledging the differences in therapy (cyclosporine versus tacrolimus) and in maternal age (significantly increased), the decrease in SGA and the increase in prematurity may be explained by an obstetric policy favouring earlier delivery against the risk of foetal growth restriction.

Hypertension in CKD Pregnancy: a Question of Cause and Effect (Cause or Effect? This Is the Question).

Chronic kidney disease (CKD) is increasingly encountered in pregnancy, and hypertension is frequently concomitant. In pregnancy, the prevalence of CKD is estimated to be about 3%, while the prevalence of chronic hypertension is about 5-8%. The prevalence of hypertension and CKD in pregnancy is unknown. Both are independently related to adverse pregnancy outcomes, and the clinical picture merges with pregnancy-induced hypertension and preeclampsia. Precise risk quantification is not available, but risks linked to CKD stage, hypertension, and proteinuria are probably multiplicative, each at least doubling the rates of preterm and early preterm delivery, small for gestational age babies, and related outcomes. Differential diagnosis (based upon utero-placental flows, fetal growth, and supported by serum biomarkers) is important for clinical management. In the absence of guidelines for hypertension in CKD pregnancies, the ideal blood pressure goal has not been established; we support a tailored approach, depending on compliance, baseline control, and CKD stages, with strict blood pressure monitoring. The choice of antihypertensive drugs and the use of diuretics and of erythropoiesis-stimulating agents (ESAs) are still open questions which only future studies may clarify.

Compliance, illiteracy and low-protein diet: multiple challenges in CKD and a case of self-empowerment.

BACKGROUND: Low-protein diets (LPD) are an important means of delaying the need for dialysis and attaining a stable metabolic balance in chronic kidney disease (CKD). Many authors consider a low educational level and illiteracy to be adverse features for a good dietary compliance. CASE PRESENTATION: We report the case of a 77-year old woman, illiterate, affected by advanced CKD (stage 4 according to KDIGO guidelines). She was initially ashamed of her problem and did not declare it, leading to an overzealous reduction in protein intake. However, with her daughter's help, who translated the dietary prescription into images, she overcame the barrier represented by illiteracy and was able to correctly follow the prescriptions, attaining good kidney function stability and preserving an adequate nutritional status. CONCLUSIONS: The case underlines the importance of a personalized approach to dietary prescriptions and suggests that it is possible to achieve a good compliance to the dietary treatment of CKD also in patients with relevant cultural barriers.

Vegan-vegetarian low-protein supplemented diets in pregnant CKD patients: fifteen years of experience.

BACKGROUND: Pregnancy in women with advanced CKD becoming increasingly common. However, experience with low-protein diets in CKD patients in pregnancy is still limited. Aim of this study is to review the results obtained over the last 15 years with moderately restricted low-protein diets in pregnant CKD women (combining: CKD stages 3-5, proteinuria: nephrotic at any time, or > =1 g/24 at start or referral; nephrotic in previous pregnancy). CKD patients on unrestricted diets were employed for comparison. STUDY PERIOD: January, 2000 to September, 2015: 36 on-diet pregnancies (31 singleton deliveries, 3 twin deliveries, 1 pregnancy termination, 1 miscarriage); 47 controls (42 singleton deliveries, 5 miscarriages). The diet is basically vegan; since occasional milk and yoghurt are allowed, we defined it vegan-vegetarian; protein intake (0.6-0.8 g/Kg/day), keto-acid supplementation, protein-unrestricted meals (1-3/week) are prescribed according to CKD stage and nutritional status. Statistical analysis was performed as implemented on SPSS. RESULTS: Patients and controls were similar (p: ns) at baseline with regard to age (33 vs 33.5), referral week (7 vs 9), kidney function (CKD 3-5: 48.4 % vs 64.3 %); prevalence of hypertension (51.6 % vs 40.5 %) and proteinuria >3 g/24 h (16.1 % vs 12.2 %). There were more diabetic nephropathies in on-diet patients (on diet: 31.0 % vs controls 5.3 %; p 0.007 (Fisher)) while lupus nephropathies were non-significantly higher in controls (on diet: 10.3 % vs controls 23.7 %; p 0.28 (Fisher)). The incidence of preterm delivery was similar (<37 weeks: on-diet singletons 77.4 %; controls: 71.4 %). The incidence of other adverse pregnancy related outcomes was non-significantly lower in on-diet patients (early preterm delivery: on diet: 32.3 % vs controls 35.7 %; birth-weight = <1.500 g: on diet: 9.7 % vs controls 23.8 %). None of the singletons in the on-diet series died, while two perinatal deaths occurred among the controls (p = 0.505). The incidence of small for gestational age (SGA <10th centile) and/or extremely preterm babies (<28th week) was significantly lower in singletons from on-diet mothers than in controls (on diet: 12.9 % vs controls: 33.3 %; p: 0.04 (Fisher)). CONCLUSION: Moderate protein restriction in the context of a vegan-vegetarian supplemented diet is confirmed as a safe option in the management of pregnant CKD patients.

The children of dialysis: live-born babies from on-dialysis mothers in Italy--an epidemiological perspective comparing dialysis, kidney transplantation and the overall population.

BACKGROUND: A successful pregnancy is an exceptional event on dialysis. Few data are available comparing pregnancy rates on dialysis, transplantation and the overall population. The aim of the study was to assess the incidence of live births from mothers on chronic dialysis compared with the overall population and with kidney transplant patients. METHODS: The setting of the study is in Italy between 2000-12. Data on dialysis was aquired by phone inquiries that were carried out between June and September, 2013, involving all the public dialysis centres in Italy; the result was a 100% response rate. The date included was end-stage renal disease, type of dialysis, residual glomerular filtration rate, changes in dialysis and therapy, hospitalization; week of birth, birth weight, centile; and outcome of mother and child. Information on transplantation was acquired by inquiry by the kidney and pregnancy study group who were contacted by phone or e-mail; the result was a 60% response rate. Data concerning prevalence of women in childbearing age (20-45) were obtained from the Italian Dialysis and Transplant Registries (2010-11 update). Official site of the Italian Ministry of Health. RESULTS: During the study period, 23 women on dialysis (three on peritoneal dialysis) delivered live-born babies and one woman delivered twins (24 babies). Three babies died in the first weeks-months of life (including one twin); 19 of 21 singletons with available data were pre-term (33.3% <34 weeks); the prevalence of children <10th gestational age-adjusted centile was 33.3%. Birth weight and gestational age were lower in children from on-dialysis mothers as compared with 110 pregnancies following kidney graft, (weight: 1200 versus 2500 g; gestational age: 30 versus 36 weeks; P < 0.001). Incidence of live-born babies was inferred as 0.7-1.1 per 1000 female dialysis patients aged 20-45 and 5.5-8.3 per 1000 grafted patients in the same age range (Italian live-birth rates: 72.5 per 1000 women aged 20-45 years). CONCLUSIONS: Having a baby while on dialysis is rare but not impossible, though early mortality remains high. There is a 'scale of probability' estimating that women on dialysis have a 10-fold lower probability of delivering a live-born baby than those who have undergone renal transplantation, who in turn have a 10-fold lower probability of delivering a live-born baby as compared with the overall population.

Protective Role of Hepcidin in Polymicrobial Sepsis and Acute Kidney Injury.

Background: Acute kidney injury (AKI) portends worse prognosis following sepsis, with limited available interventions. Host iron acquisition by pathogens and systemic inflammatory response are key events in the pathogenesis of sepsis. In sepsis, hepcidin induces iron sequestration to limit iron availability to pathogens. Hepcidin is also known to limit inflammation. Since its role in pathophysiology of sepsis-associated AKI is unknown, we investigated the effect of exogenous hepcidin in endotoxin- and peritonitis-induced pathology and AKI. Methods: C57BL/6 mice were treated with saline or 50-100 µg of hepcidin, pre- and post-LPS injection, or cecal ligation and puncture (CLP, model of peritonitis). Splenectomized mice were challenged with LPS, with and without hepcidin. Mice were euthanized at 24 h after LPS injection and at different time points after CLP. Systemic inflammation and renal injury markers were assessed. Direct effect of hepcidin on renal tubular and endothelial cells was evaluated using endotoxin-induced cytotoxic serum. Role of heavy chain ferritin (H-ferritin) in mediating hepcidin-induced anti-inflammatory effect on LPS stimulated macrophages was evaluated with siRNA studies. Results: Twenty-four hours pretreatment with hepcidin significantly reduced LPS-induced AKI. Hepcidin ameliorated LPS-induced increase in serum TNFα and renal Cox-2, and prevented loss in PGC1α and cytochrome c oxidase activity. This was associated with reduced glomerular injury and preserved mitochondrial structure. Hepcidin did not exert direct protection on the renal parenchymal cells but reduced endotoxin-induced serum cytotoxicity to mitigate renal injury. Splenectomy reduced LPS-induced early inflammation and AKI, independent of hepcidin, indicating the importance of systemic inflammation. Higher splenic H-ferritin in hepcidin-treated animals was associated with reduced splenocytes apoptosis and inflammation. Hepcidin reduced LPS-induced IL-6 secretion in macrophages in H-ferritin dependent manner. Hepcidin significantly reduced CLP-induced AKI, and mortality (20% hepcidin treated vs 80% PBS treated). Importantly hepcidin reduced bacteremia and AKI even when administered after onset of sepsis. Conclusion: We demonstrate a protective role of hepcidin in endotoxin- and peritonitis-induced pathologies and AKI, exerted primarily through its anti-inflammatory effects, and antibacterial property. Macrophage H-ferritin plays an important role in hepcidin-mediated protection against endotoxin-induced inflammation. We uncover a novel prophylactic and therapeutic role of hepcidin in sepsis-associated bacteremia, AKI, and mortality.

Entropy of human leukocyte antigen and killer-cell immunoglobulin-like receptor systems in immune-mediated disorders: A pilot study on multiple sclerosis.

BACKGROUND: Entropy is a thermodynamic variable statistically correlated with the disorder of a system. The hypothesis that entropy can be used to identify potentially unhealthy conditions was first suggested by Schrödinger, one of the founding fathers of quantum mechanics. Shannon later defined entropy as the quantity of information stored in a system. Shannon's entropy has the advantage of being adaptable across a variety of disciplines, including genetic studies on complex immunogenetic systems such as the human leukocyte antigen (HLA) and killer-cell immunoglobulin-like receptor (KIR) systems. METHODS: In our study, entropy associated to the HLA and KIR systems was compared between a cohort of 619 Sardinian healthy controls and a group of 270 patients affected by multiple sclerosis (MS), the latter stratified into 81 patients with primary progressive multiple sclerosis (PPMS) and 189 patients with relapsing remitting multiple sclerosis (RRMS). RESULTS: The entropy associated to HLA four-loci haplotypes (A, B, C, DR) and combinations of two inhibitory KIR genes was significantly higher in patients affected by RRMS than in healthy controls. No significant differences were observed for patients with PPMS. By calculating the total HLA and KIR entropy ratio in each subject, it was possible to determine the individual risk of developing MS, particularly RRMS. CONCLUSIONS: In addition to the standard statistical methods used to evaluate immunogenetic parameters associated to immune-mediated disease, the analysis of entropy measures the global disorder status deriving from these parameters. This innovative approach may represent a useful complementary tool to the risk assessment of immune-mediated disorders. Improved risk assessment is particularly important for family members of patients with MS. However, further investigation is warranted to confirm our findings and to evaluate the validity of the entropy-based method in other types of immune-mediated disorders.

Drug-Induced Kidney Injury in the Elderly.

The incidence of acute kidney injury in the elderly has grown over the past decade. One of the primary drivers is drug-induced nephrotoxicity, which is the result of a combination of the unique susceptibilities to kidney injury and the increased use of medications in the elderly population. Specific drug classes are associated with increased rates of kidney injury including agents that block the renin angiotensin system, antimicrobials, and chemotherapeutic agents. Mechanistically, injury may be due to hemodynamic effects, tubular or glomerular toxicity, and interstitial nephritis. Early recognition of nephrotoxicity is critical, as are preventative steps when applicable. Unfortunately, treatment for established drug-induced kidney injury is limited and supportive care is required. Limiting exposure to nephrotoxic drugs is critical in decreasing the incidence of acute kidney injury in the elderly patient.

Exercise-Associated Hyponatremia: 2017 Update.

Exercise-associated hyponatremia (EAH) was initially described in the 1980s in endurance athletes, and work done since then has conclusively identified that overdrinking beyond thirst and non-osmotic arginine vasopressin release are the most common etiologic factors. In recent years, EAH has been described in a broader variety of athletic events and also has been linked to the development of rhabdomyolysis. The potential role of volume and sodium depletion in a subset of athletes has also been described. This review focuses on the most recent literature in the field of EAH and summarizes key new findings in the epidemiology, pathophysiology, treatment, and prevention of this condition.

KIR and their HLA Class I ligands: Two more pieces towards completing the puzzle of chronic rejection and graft loss in kidney transplantation.

BACKGROUND: Kidney transplantation is a life-saving treatment for patients with end-stage renal disease. However, despite progress in surgical techniques and patient management, immunological rejection continues to have a negative impact on graft function and overall survival. Incompatibility between donors and recipients for human leukocyte antigens (HLA) of the major histocompatibility complex (MHC) generates a series of complex cellular and humoral immune response mechanisms that are largely responsible for rejection and loss of graft function. Within this context, a growing amount of evidence shows that alloreactive natural killer (NK) cells play a critical role in the immune response mechanisms elicited by the allograft. Killer immunoglobulin-like receptors (KIRs) are prominent mediators of NK cell alloreactivity. METHODS AND FINDINGS: A cohort of 174 first cadaveric kidney allograft recipients and their donors were selected from a total cohort of 657 transplanted patients for retrospective immunogenetic analyses. Patients with HLA Class II mismatches were excluded. HLA Class I allele frequencies were compared among patients with chronic rejection, patients with stable graft function and a group of 2388 healthy controls. Activating and inhibitory KIR gene frequencies, KIR haplotypes, KIR-HLA ligand matches/mismatches and combinations of recipient KIRs and donor HLA Class I ligands were compared among patients with and without chronic rejection and a group of 221 healthy controls. Patients transplanted from donors homozygous for HLA-C1 antigens had a significantly higher risk for chronic rejection than patients transplanted from donors homozygous or heterozygous for HLA-C2 antigens or with epitopes belonging to the HLA-Bw4 ligand group. The Kaplan-Meier curves obtained by dividing the patients into 3 groups according to the presence or absence of one or both of the combinations of recipient KIRs and donor HLA ligands (rKIR2DL1/dHLA-C2 and rKIR3DL1/dHLA-Bw4) showed a significantly higher cumulative incidence of chronic rejection in the group of patients completely lacking these functional units. These patients showed a progressively stronger decline in modification of diet in renal disease-estimated glomerular filtration rate. CONCLUSIONS: KIR genotyping should be performed at the time of enrolment of patients on the waiting list for organ transplantation. In our study, a significantly higher risk of chronic rejection after kidney transplantation was observed when recipient (r) and donor (d) pairs completely lacked the two functional rKIR-dHLA ligand combinations rKIR2DL1/dHLA-C2 and rKIR3DL1/dHLA-Bw4. This immunogenetic profile corresponds to low levels of NK cell inhibition. Therefore, patients with this high risk profile could benefit from immunosuppressive therapy aimed at reducing NK-cell cytotoxicity.

Outcomes of Pregnancies After Kidney Transplantation: Lessons Learned From CKD. A Comparison of Transplanted, Nontransplanted Chronic Kidney Disease Patients and Low-Risk Pregnancies: A Multicenter Nationwide Analysis.

BACKGROUND: Kidney transplantation (KT) may restore fertility in chronic kidney disease (CKD). The reasons why maternofetal outcomes are still inferior to the overall population are only partially known. Comparison with the CKD population may offer some useful insights for management and counselling.Aim of this study was to analyse the outcomes of pregnancy after KT, compared with a large population of nontransplanted CKD patients and with low-risk control pregnancies, observed in Italy the new millennium. METHODS: We selected 121 live-born singletons after KT (Italian study group of kidney in pregnancy, national coverage about 75%), 610 live-born singletons in CKD, and 1418 low-risk controls recruited in 2 large Italian Units in the same period (2000-2014). The following outcomes were considered: maternal and fetal death; malformations; preterm delivery; small for gestational age (SGA) baby; need for the neonatal intensive care unit; doubling of serum creatinine or increase in CKD stage. Data were analyzed according to kidney diseases, renal function (staging according to CKD-epidemiology collaboration), hypertension, maternal age, parity, ethnicity. RESULTS: Maternofetal outcomes are less favourable in CKD and KT as compared with the low-risk population. CKD stage and hypertension are important determinants of results. Kidney transplantation patients with estimated glomerular filtration rate greater than 90 have worse outcomes compared with CKD stage 1 patients; the differences level off when only CKD patients affected by glomerulonephritis or systemic diseases ("progressive CKD") are compared with KT. In the multivariate analysis, risk for preterm and early-preterm delivery was linked to CKD stage (2-5 vs 1: relative risk 3.42 and 3.78) and hypertension (RR 3.68 and 3.16) while no difference was associated with being a KT or a CKD patient. CONCLUSIONS: The maternofetal outcomes in patients with kidney transplantation are comparable with those of nontransplanted CKD patients with similar levels of kidney function impairment and progressive and/or immunologic kidney disease.

Low-Protein Diets in Diabetic Chronic Kidney Disease (CKD) Patients: Are They Feasible and Worth the Effort?

Low-protein diets (LPDs) are often considered as contraindicated in diabetic patients, and are seldom studied. The aim of this observational study was to provide new data on this issue. It involved 149 diabetic and 300 non-diabetic patients who followed a LPD, with a personalized approach aimed at moderate protein restriction (0.6 g/day). Survival analysis was performed according to Kaplan-Meier, and multivariate analysis with Cox model. Diabetic versus non-diabetic patients were of similar age (median 70 years) and creatinine levels at the start of the diet (2.78 mg/dL vs. 2.80 mg/dL). There was higher prevalence of nephrotic proteinuria in diabetic patients (27.52% vs. 13.67%, p = 0.002) as well as comorbidity (median Charlson index 8 vs. 6 p = 0.002). Patient survival was lower in diabetic patients, but differences levelled off considering only cases with Charlson index > 7, the only relevant covariate in Cox analysis. Dialysis-free survival was superimposable in the setting of good compliance (Mitch formula: 0.47 g/kg/day in both groups): about 50% of the cases remained dialysis-free 2 years after the first finding of e-GFR (estimated glomerular filtration rate) < 15 mL/min, and 1 year after reaching e-GFR < 10 mL/min. In patients with type 2 diabetes, higher proteinuria was associated with mortality and initiation of dialysis. In conclusion, moderately restricted LPDs allow similar results in diabetic and non non-diabetic patients with similar comorbidity.

A best practice position statement on pregnancy in chronic kidney disease: the Italian Study Group on Kidney and Pregnancy.

Pregnancy is increasingly undertaken in patients with chronic kidney disease (CKD) and, conversely, CKD is increasingly diagnosed in pregnancy: up to 3 % of pregnancies are estimated to be complicated by CKD. The heterogeneity of CKD (accounting for stage, hypertension and proteinuria) and the rarity of several kidney diseases make risk assessment difficult and therapeutic strategies are often based upon scattered experiences and small series. In this setting, the aim of this position statement of the Kidney and Pregnancy Study Group of the Italian Society of Nephrology is to review the literature, and discuss the experience in the clinical management of CKD in pregnancy. CKD is associated with an increased risk for adverse pregnancy-related outcomes since its early stage, also in the absence of hypertension and proteinuria, thus supporting the need for a multidisciplinary follow-up in all CKD patients. CKD stage, hypertension and proteinuria are interrelated, but they are also independent risk factors for adverse pregnancy-related outcomes. Among the different kidney diseases, patients with glomerulonephritis and immunologic diseases are at higher risk of developing or increasing proteinuria and hypertension, a picture often difficult to differentiate from preeclampsia. The risk is higher in active immunologic diseases, and in those cases that are detected or flare up during pregnancy. Referral to tertiary care centres for multidisciplinary follow-up and tailored approaches are warranted. The risk of maternal death is, almost exclusively, reported in systemic lupus erythematosus and vasculitis, which share with diabetic nephropathy an increased risk for perinatal death of the babies. Conversely, patients with kidney malformation, autosomal-dominant polycystic kidney disease, stone disease, and previous upper urinary tract infections are at higher risk for urinary tract infections, in turn associated with prematurity. No risk for malformations other than those related to familiar urinary tract malformations is reported in CKD patients, with the possible exception of diabetic nephropathy. Risks of worsening of the renal function are differently reported, but are higher in advanced CKD. Strict follow-up is needed, also to identify the best balance between maternal and foetal risks. The need for further multicentre studies is underlined.

Diabetic Kidney Disease: A Syndrome Rather Than a Single Disease.

The term "diabetic kidney" has recently been proposed to encompass the various lesions, involving all kidney structures that characterize protean kidney damage in patients with diabetes. While glomerular diseases may follow the stepwise progression that was described several decades ago, the tenet that proteinuria identifies diabetic nephropathy is disputed today and should be limited to glomerular lesions. Improvements in glycemic control may have contributed to a decrease in the prevalence of glomerular lesions, initially described as hallmarks of diabetic nephropathy, and revealed other types of renal damage, mainly related to vasculature and interstitium, and these types usually present with little or no proteinuria. Whilst glomerular damage is the hallmark of microvascular lesions, ischemic nephropathies, renal infarction, and cholesterol emboli syndrome are the result of macrovascular involvement, and the presence of underlying renal damage sets the stage for acute infections and drug-induced kidney injuries. Impairment of the phagocytic response can cause severe and unusual forms of acute and chronic pyelonephritis. It is thus concluded that screening for albuminuria, which is useful for detecting "glomerular diabetic nephropathy", does not identify all potential nephropathies in diabetes patients. As diabetes is a risk factor for all forms of kidney disease, diagnosis in diabetic patients should include the same combination of biochemical, clinical, and imaging tests as employed in non-diabetic subjects, but with the specific consideration that chronic kidney disease (CKD) may develop more rapidly and severely in diabetic patients.

Role of human leukocyte antigen-G 14-base pair polymorphism in kidney transplantation outcomes.

BACKGROUND: Both the membrane-bound and soluble forms of human leukocyte antigen-G (HLA-G) molecules exhibit a multitude of immunomodulatory properties that can potentially obviate or delay graft rejection. The 14-base pair (14-bp) polymorphism in the 3'-untranslated region of the HLA-G gene is thought to have a role in soluble HLA-G (sHLA-G) expression. METHODS: In this study, we retrospectively investigated a large cohort of 418 kidney transplant recipients with the aim of establishing whether the HLA-G 14-bp insertion/deletion polymorphism could serve as an effective genetic risk marker for acute and/or chronic deterioration of transplanted kidney function. RESULTS: A statistically significant higher incidence of chronic kidney dysfunction leading to allograft loss was observed in transplant recipients homozygous for the HLA-G 14-bp deletion polymorphism. This difference increased over time and was confirmed by progressive decline in the glomerular filtration rate. CONCLUSIONS: These results suggest that alongside other factors previously consolidated in clinical practice, recipient HLA-G 14-bp genotype may serve as an adjuvant independent predictor of long-term outcome of kidney transplantation.