Averting the legacy of kidney disease - focus on childhood

World Kidney Day 2016 focuses on kidney disease in childhood and the antecedents of adult kidney disease that can begin in earliest childhood. Chronic kidney disease (CKD) in childhood differs from that in adults, in that the largest diagnostic group among children includes congenital anomalies and inherited disorders, with glomerulopathies and kidney disease as a consequence of diabetes being relatively uncommon. In addition, many children with acute kidney injury will ultimately develop sequelae that may lead to hypertension and CKD in later childhood or in adult life. Children born early or who are small-for-date newborns have relatively increased risk for the development of CKD later in life. Persons with a high-risk birth and early childhood history should be watched closely in order to help detect early signs of kidney disease in time to provide effective prevention or treatment. Successful therapy is feasible for advanced CKD in childhood; there is evidence that children fare better than adults, if they receive kidney replacement therapy including dialysis and transplantation, although only a minority of children may require this ultimate intervention. Because there are disparities in access to care, effort is needed so that children with kidney disease, wherever they live, may be treated effectively, irrespective of their geographic or economic circumstances. Our hope is that the World Kidney Day will inform the general public, policy makers and caregivers about the needs and possibilities surrounding kidney disease in childhood.

Early initiation of dialysis: mortality and renal function recovery in acute kidney injury patients

INTRODUCTION: The decision of when to start dialysis in Acute Kidney Injury (AKI) patients with overt uremia is strongly established, however, when blood urea nitrogen (BUN) levels is < 100 mg/dL the timing of initiation of dialysis remains uncertain. Purpose: The aim of this study was to assess mortality and renal function recovery AKI patients started on dialysis at different BUN levels. METHODS: This was a retrospective study performed at Medical School Hospital, São Paulo, Brazil, enrolling 86 patients underwent to dialysis. RESULTS: Dialysis was started when BUN < 75 mg/dl in 23 patients (Group I) and BUN > 75 mg/dl in 63 patients (Group II). Hypervolemia and mortality were higher in Group I than in Group II (65.2% vs. 14.3% - p < 0.05, 39.1% vs. 68.9%- p < 0.05, respectively). Among survivors, the rate of renal function recovery was higher in Group I (71.4% and 36.8%, respectively - p < 0.05). Multivariate analysis showed that sepsis, age > 60 years, peritoneal dialysis and BUN > 75 mg/dl at dialysis initiation were independently related with mortality. CONCLUSIONS: Lower mortality and higher renal function recovery rates were associated with early dialysis initiated at lower BUN leves in AKI patients.

Histopathological analysis of pre-implantation donor kidney biopsies: association with graft survival and function in one year post-transplantation

Introduction: Pre-implantation kidney biopsy is a decision-making tool when considering the use of grafts from deceased donors with expanded criteria, implanting one or two kidneys and comparing this to post-transplantation biopsies. The role of histopathological alterations in kidney compartments as a prognostic factor in graft survival and function has had conflicting results. Objective: This study evaluated the prevalence of chronic alterations in pre-implant biopsies of kidney grafts and the association of findings with graft function and survival in one year post-transplant. Methods: 110 biopsies were analyzed between 2006 and 2009 at Santa Casa de Porto Alegre, including live donors, ideal deceased donors and those with expanded criteria. The score was computed according to criteria suggested by Remuzzi. The glomerular filtration rate (GFR) was calculated using the abbreviated MDRD formula. Results: No statistical difference was found in the survival of donors stratified according to Remuzzi criteria. The GFR was significantly associated with the total scores in the groups with mild and moderate alterations, and in the kidney compartments alone, by univariate analysis. The multivariate model found an association with the presence of arteriosclerosis, glomerulosclerosis, acute rejection and delayed graft function. Conclusion: Pre-transplant chronic kidney alterations did not influence the post-transplantation one-year graft survival, but arteriosclerosis and glomerulosclerosis is predictive of a worse GFR. Delayed graft function and acute rejection are independent prognostic factors.

Five years results after intrafamilial kidney post-transplant in a case of familial hypomagnesemia due to a claudin-19 mutation

Introduction: Familial Hypomagnesaemia with hypercalciuria and nephrocalcinosis, with severe ocular impairment secondary to claudin-19 mutation, is a rare recessive autossomic disorder. Its spectrum includes renal Mg2+ wasting, medullary nephrocalcinosis and progressive chronic renal failure in young people. Objective: To report a case of kidney transplantation father to daughter in a familial occurrence of severe bilateral nephrocalcinosis associated with ocular impairment in a non-consanguineous Brazilian family, in which two daughters had nephrocalcinosis and severe retinopathy. Methods: The index case, a 19 years-old female, had long-lasting past medical history of recurrent urinary tract infections, and the abdominal X-ray revealed bilateral multiple renal calcifications as well as ureteral lithiasis, and she was under haemodialysis. She had the diagnosis of retinitis pigmentosa in the early neonatal period. The other daughter (13 years-old) had also nephrocalcinosis with preserved kidney function, retinopathy with severe visual impairment, and in addition, she exhibited hypomagnesaemia = 0.5 mg/dL and hypercalciuria. The other family members (mother, father and son) had no clinical disease manifestation. Mutation analysis at claudin-19 revealed two heterozygous missense mutations (P28L and G20D) in both affected daughters. The other family members exhibited mutant monoallelic status. In despite of that, the index case underwent intrafamilial living donor kidney transplantation (father). Conclusion: In conclusion, the disease was characterized by an autosomal recessive compound heterozygous status and, after five years of donation the renal graft function remained stable without recurrence of metabolic disturbances or nephrocalcinosis. Besides, donor single kidney Mg2+ and Ca2+ homeostasis associated to monoallelic status did not affect the safety and the usual living donor post-transplant clinical course.

Computerized Tomography Contrast Induced Nephropathy (CIN) among adult inpatients

Introduction: Contrast induced nephropathy (CIN) is one of the complications of the use of intravascular contrast agents, being defined as a reduction of the glomerular filtration rate caused by the iodinated contrast. Most CIN data derive from the cardiovascular literature, which identified as the most consistent risk factors pre-existing chronic renal insufficiency and diabetes mellitus. However, these studies limit their conclusions to a more specific patient population. Computerized tomography as a cause of CIN has been studied less often. Objective: To report on the incidence of computerized tomography contrast induced nephropathy (CIN) in an inpatient population of a tertiary general hospital, identifying potentially avoidable risk factors. Methods: We performed a prospective cohort study with inpatients admitted at a tertiary hospital requiring contrast-induced CT. The primary outcome was the development of CIN, measure by the alteration of serum creatinine or glomerular filtration rate in 48 or 72 hours. Through clinical interview, we verified possible risk factors and preventive measures instituted by the medical team and their association with development of CIN. Results: Of a total of 410 patients, 35 (8.5%) developed CIN. There was a positive correlation between CIN and the presence of diabetes mellitus (OR = 2.15; 95%CI 1.35-4.06; p = 0.02), heart failure (OR = 2.23; 95%CI 1.18-8.8; p = 0.022), and renal failure (OR = 3.36; 95%CI 1.57- 7.17; p = 0.002) Conclusion: Incidence of CIN varies according to the population. Diabetes mellitus, heart failure and renal failure were independent risk factors for the development of CT-associated CIN. Further studies are needed to better understand and treat CT-associated CIN.

Inverse association between serum creatinine and mortality in acute kidney injury

Introduction: Sepsis is a leading precipitant of Acute Kidney Injury (AKI) in intensive care unit (ICU) patients, and is associated with a high mortality rate. Objective: We aimed to evaluate the risk factors for dialysis and mortality in a cohort of AKI patients of predominantly septic etiology. Methods: Adult patients from an ICU for whom nephrology consultation was requested were included. End-stage chronic renal failure and kidney transplant patients were excluded. Results: 114 patients were followed. Most had sepsis (84%), AKIN stage 3 (69%) and oliguria (62%) at first consultation. Dialysis was performed in 66% and overall mortality was 70%. Median serum creatinine in survivors and non-survivors was 3.95 mg/dl (2.63 - 5.28) and 2.75 mg/dl (1.81 - 3.69), respectively. In the multivariable models, oliguria and serum urea were positively associated with dialysis; otherwise, a lower serum creatinine at first consultation was independently associated with higher mortality. Conclusion: In a cohort of septic AKI, oliguria and serum urea were the main indications for dialysis. We also described an inverse association between serum creatinine and mortality. Potential explanations for this finding include: delay in diagnosis, fluid overload with hemodilution of serum creatinine or poor nutritional status. This finding may also help to explain the low discriminative power of general severity scores - that assign higher risks to higher creatinine levels - in septic AKI patients.

The long-term outcome after acute kidney injury: a narrative review

This review will focus on long-term outcomes after acute kidney injury (AKI). Surviving AKI patients have a higher late mortality compared with those admitted without AKI. Recent studies have claimed that long-term mortality in patients after AKI varied from 15% to 74% and older age, presence of previous co-morbidities, and the incomplete recovery of renal function have been identified as risk factors for reduced survival. AKI is also associated with progression to chronic kidney (CKD) disease and the decline of renal function at hospital discharge and the number and severity of AKI episodes have been associated with progression to CKD. IN the most studies, recovery of renal function is defined as non-dependence on renal replacement therapy which is probably too simplistic and it is expected in 60-70% of survivors by 90 days. Further studies are needed to explore the long-term prognosis of AKI patients.

Pkd1 transgenic mice: Adult model of polycystic kidney disease with extrarenal and renal phenotypes

While high levels of Pkd1 expression are detected in tissues of patients with autosomal dominant polycystic kidney disease (ADPKD), it is unclear whether enhanced expression could be a pathogenetic mechanism for this systemic disorder. Three transgenic mouse lines were generated from a Pkd1-BAC modified by introducing a silent tag via homologous recombination to target a sustained wild type genomic Pkd1 expression within the native tissue and temporal regulation. These mice specifically overexpressed the Pkd1 transgene in extrarenal and renal tissues from approximately 2- to 15-fold over Pkd1 endogenous levels in a copy-dependent manner. All transgenic mice reproducibly developed tubular and glomerular cysts leading to renal insufficiency. Interestingly, Pkd1(TAG) mice also exhibited renal fibrosis and calcium deposits in papilla reminiscent of nephrolithiasis as frequently observed in ADPKD. Similar to human ADPKD, these mice consistently displayed hepatic fibrosis and approximately 15% intrahepatic cysts of the bile ducts affecting females preferentially. Moreover, a significant proportion of mice developed cardiac anomalies with severe left ventricular hypertrophy, marked aortic arch distention and/or valvular stenosis and calcification that had profound functional impact. Of significance, Pkd1(TAG) mice displayed occasional cerebral lesions with evidence of ruptured and unruptured cerebral aneurysms. This Pkd1(TAG) mouse model demonstrates that overexpression of wildtype Pkd1 can trigger the typical adult renal and extrarenal phenotypes resembling human ADPKD.

Identification de facteurs de risque d'insuffisance rénale en trauma

Contexte: la survenue d’IRA chez les patients ayant subi un traumatisme est une problématique qui a été peu étudiée jusqu’à ce jour. La présence de cette atteinte rénale a été démontrée comme étant associée à un risque accru de morbidités et de mortalité chez les sujets atteints. Objectifs: identifier les facteurs prédictifs d’insuffisance rénale ou plus récemment appelée atteinte rénale dans cette population particulière et tenter de trouver des facteurs qui peuvent être mesurés dans les premières heures de la prise en charge du patient. Aussi, nous avons cherché à savoir si l’injection de produit de contraste est associée à un risque accru d’insuffisance rénale aiguë dans cette population. Méthodes et résultats: la recherche a eu lieu à l’Hôpital du Sacré-Coeur de Montréal, un centre de traumatologie tertiaire en milieu urbain. Nous avons utilisé le registre des patients hospitalisés en traumatologie dans notre centre hospitalier entre 2002 et mars 2007 de même que les banques de données de laboratoire et de radiologie pour obtenir les données sur la créatinine et les examens avec produits de contraste. Finalement, une revue de dossiers structurée fut conduite pour recueillir le reste de l’information requise. L’incidence d’IRA dans la population étudiée est estimée à environ 5 %. Une analyse cas témoins fut conduite pour identifier les facteurs prédictifs d’IRA. Quarante-neuf cas d’IRA diagnostiqués par le médecin traitant et 101 témoins sélectionnés au hasard ont été analysés. Les facteurs prédictifs suivants ont été identifiés à l’analyse univariée : la première valeur de créatinine obtenue (p<0,001), l’instabilité hémodynamique (p<0,001), les antécédents d’insuffisance rénale chronique tels que notés dans le dossier par le médecin traitant (p=0,009), une maladie cardiaque (p=0,007), une chirurgie dans les 48 premières heures suivant le traumatisme (p=0,053), le niveau de gravité du traumatisme (Injury Severity Score) (p=0,046) et l’injection de produit de contraste au cours des 48 heures suivant le trauma (p=0,077). Parmi ces facteurs, deux ont été identifiés comme prédicteurs indépendants d’IRA à l’analyse multivariée. Une des valeurs était la première valeur de créatinine obtenue RC = 6,17 (p<0,001, IC95 % 2,81 – 13,53) pour chaque augmentation de 0.5mg/dL de créatinine. L’autre facteur était la présence d’instabilité hémodynamique RC 11,61 (p<0,001, IC95 % 3,71 – 36,29). Conclusion: des informations obtenues tôt dans la prise en charge du patient permettent de prédire le risque d’IRA chez ces patients. L’administration de contraste (intraveineuse ou intra-artérielle) ne s’est pas avérée un facteur indépendant de prédiction d’insuffisance rénale aiguë dans cette population dans le modèle multivarié.

Facteurs de risque d’insuffisance rénale chronique chez les greffés cardiaques : du phénotype aux tests pharmacogénomiques

L’insuffisance rénale chronique (IRC) est un problème majeur fréquemment rencontré chez les greffés cardiaques. Les inhibiteurs de la calcineurine, pierre angulaire de l’immunosuppression en transplantation d’organes solides, sont considérés comme une des principales causes de dysfonction rénale postgreffe. Plusieurs autres éléments tels que les caractéristiques démographiques, cliniques et génétiques du receveur contribuent également au phénomène, mais il demeure plutôt difficile de déterminer quels sont les patients les plus à risque de développer une IRC après la transplantation. Ainsi, la découverte de nouveaux marqueurs génétiques de dysfonction rénale pourrait un jour mener à l’individualisation de la thérapie immunosuppressive selon le profil génétique de chaque patient. Or, on ne connaît pas les opinions des greffés à l’égard des tests pharmacogénomiques et l’on ne sait pas si celles-ci diffèrent des opinions exprimées par les individus en bonne santé. Cette thèse de doctorat a donc pour objectifs : 1- De décrire l’évolution de la fonction rénale à très long terme après la transplantation et d’identifier les marqueurs démographiques et phénotypiques associés à l’IRC postgreffe cardiaque; 2- D’identifier les marqueurs génétiques associés à la néphrotoxicité induite par les inhibiteurs de la calcineurine; 3- D’évaluer et de comparer les attitudes des patients et des individus en bonne santé par rapport à l’intégration clinique potentielle des marqueurs pharmacogénomiques. Trois projets ont été réalisés pour répondre à ces questions. Le premier repose sur une analyse rétrospective de l’évolution de la fonction rénale chez les patients greffés au sein de notre établissement entre 1983 et 2008. Nous y avons découvert que le déclin de la fonction rénale se poursuit jusqu’à 20 ans après la transplantation cardiaque et que les facteurs de risque d’IRC incluent entre autres l’âge avancé, le sexe féminin, la dysfonction rénale prégreffe, l’hypertension, l’hyperglycémie et l’utilisation de la prednisone. Le deuxième projet est une étude pharmacogénomique s’intéressant aux déterminants génétiques de la néphrotoxicité induite par les inhibiteurs de la calcineurine. Elle nous a permis d’illustrer pour la première fois qu’un polymorphisme génétique lié à PRKCB (gène codant pour la protéine kinase C-β) est associé avec la fonction rénale des patients greffés cardiaques, alors que cela n’est probablement pas le cas pour les polymorphismes de TGFB1 (gène codant pour le transforming growth factor-β1). La troisième section de cette thèse rapporte les résultats d’un questionnaire dont le but était de comparer les attitudes envers les tests pharmacogénomiques parmi un groupe de personnes en bonne santé, de patients greffés cardiaques et de patients souffrant d’insuffisance cardiaque. Cette étude a démontré que, bien que l’enthousiasme pour la pharmacogénomique soit partagé par tous ces individus, les craintes liées à la confidentialité et aux répercussions potentielles sur l’emploi et les assurances sont plus prononcées chez les personnes en bonne santé. En résumé, les travaux issus de cette thèse ont révélé que l’identification précoce des patients greffés cardiaques les plus susceptibles de présenter une détérioration de la fonction rénale ainsi que l’adoption d’une approche thérapeutique individualisée reposant notamment sur les applications cliniques de la pharmacogénomique pourraient éventuellement permettre de freiner cette complication postgreffe.

Sociodemographic characteristics and clinical features of patients with adult polycystic kidney disease undergoing hemodialysis

Aims:To analyze the socio-demographic and clinical characteristics of patients with adult polycystic kidney disease admitted to hemodialysis services in Northwestern Paraná state,Brazil. Methods: This was an observational, descriptive and retrospective longitudinal study. Medical records of patients with polycystic kidneys who initiated hemodialysis between 1995 and 2012, in four centers that treat patients of the coverage area of the 15th Regional Health Region of Paraná state where analyzed. Results:We found that 10.3% of hemodialysis patients had polycystic kidney disease as a leading cause of stage 5 of chronic kidney disease. The mean age of patients was 54.9±9.4 years (ranging between 27 and 74 years), with equal gender distribution and Caucasian predominance (72.9%). The average age of dialysis initiation was 50±10.2 years. The most common comorbidity was systemic hypertension (66.7%). Liver cyst was the main extra-renal manifestation (10.4%). Twenty-five percent of the patients required renal transplantation, and (22.9%) undergone nephrectomy. The most widely used classes of antihypertensive drugs were β-blockers (41.7%) and drugs that act on the renin-angiotensin system (31.3%), while 56.3% of patients were treated with recombinant human erythropoietin. Conclusions:This is a pioneering epidemiological study in Northwestern Paraná state. We found in this population a sociodemographic and clinical profile of adult polycystic kidney disease similar to that of North America and Europe, probably because the ethnic constitution of the sample was predominantly of Euro-descendants.

Autosomal dominant polycystic kidney disease in hemodialysis patients in southern Brazil

Introduction: Autosomal dominant polycystic kidney disease is the most common hereditary renal disease in humans. Objective: To examine the prevalence, clinical and laboratory characteristics of patients with polycystic kidneys and relate disease manifestations by gender. Methods: This was an observational and retrospective study. All the medical records of patients with polycystic kidneys who initiated hemodialysis between 1995 and 2012, in four centers that treat patients of the coverage area of the 15th regional health Paraná (Brazil), were analyzed. Results: The study included 48 patients with polycystic kidneys, the primary cause of stage 5 CKD. Disease prevalence was one in 10,912 people. The average age of dialysis initiation was 50.7 years and the follow-up time on dialysis until transplantation (36.5 months) was lower among men. Hypertension was the most frequent diagnosis in 73% of patients, predominantly in women (51.4%). The liver cyst was the most frequent extrarenal manifestations in men (60.0%). The death occurred in 10.4% of patients using hemodialysis, and 60% of men. The class of antihypertensive drug used was that acts on the renin-angiotensin system with higher frequency of use among women (53.3%). The post-dialysis urea was significantly higher in men. Conclusion: The prevalence of the disease is low among hemodialysis patients in southern Brazil. The differences observed between genders, with the exception of the post-dialysis urea, were not significant. The findings are different from those reported in North America and Europe.

Characteristics of Acute Kidney Injury in Patients Infected with the 2009 Influenza A (H1N1) Virus

Background and objectives: There have been few studies investigating acute kidney injury (AKI) in patients infected with the 2009 pandemic influenza A (H1N1) virus. Therefore, the objective of this study was to identify the factors associated with AKI in H1N1-infected patients. Design, setting, participants, & measurements: This was a study of 47 consecutive critically ill adult patients with reverse transcriptase-PCR-confirmed H1N1 infection in Brazil. Outcome measures were AKI (as defined by the Risk, Injury, Failure, Loss, and End-stage renal failure [RIFLE] criteria) and in-hospital death. Results: AKI was identified in 25 (53%) of the 47 H1N1-infected patients. AKI was associated with vasopressor use, mechanical ventilation, high Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, and severe acidosis as well as with higher levels of C-reactive protein and lactic dehydrogenase upon intensive care unit (ICU) admission. A nephrology consultation was requested for 16 patients (64%), and 8 (50%) required dialysis. At ICU admission, 7 (15%) of the 25 AKI patients had not yet progressed to AKI. However, by 72 hours after ICU admission, no difference in RIFLE score was found between AKI survivors and nonsurvivors. Of the 47 patients, 9 (19%) died, all with AKI. Mortality was associated with mechanical ventilation, vasopressor use, dialysis, high APACHE II score, high bilirubin levels, and a low RIFLE score at ICU admission. Conclusions: Among critically ill H1N1-infected patients, the incidence of AKI is high. In such patients, AKI is mainly attributable to shock. Clin J Am Soc Nephrol 5: 1916-1921, 2010. doi: 10.2215/CJN.00840110

Functional and morphologic evaluation of kidney proximal tubuli and correlation with renal allograft prognosis

P>Renal transplant patients with stable graft function and proximal tubular dysfunction (PTD) have an increased risk for chronic allograft nephropathy (CAN). In this study, we investigated the histologic pattern associated with PTD and its correlation with graft outcome. Forty-nine transplant patients with stable graft function were submitted to a biopsy. Simultaneously, urinary retinol-binding protein (uRBP) was measured and creatinine clearance was also determined. Banff`s score and semi-quantitative histologic analyses were performed to assess tubulointerstitial alterations. Patients were followed for 24.0 +/- 7.8 months. At biopsy time, mean serum creatinine was 1.43 +/- 0.33 mg/dl. Twelve patients (24.5%) had uRBP >= 1 mg/l, indicating PTD and 67% of biopsies had some degree of tubulointerstitial injury. At the end of the study period, 18 (36.7%) patients had lost renal function. uRBP levels were not associated with morphologic findings of interstitial fibrosis and tubular atrophy (IF/TA), interstitial fibrosis measured by Sirius red or tubulointerstitial damage. However, in multivariate analysis, the only variable associated with the loss of renal function was uRBP level >= 1 mg/l, determining a risk of 5.290 of loss of renal function (P = 0.003). Renal transplant patients who present PTD have functional alteration, which is not associated with morphologic alteration. This functional alteration is associated to progressive decrease in renal function.

Mesenchymal Stem Cells Attenuate Renal Fibrosis Through Immune Modulation and Remodeling Properties in a Rat Remnant Kidney Model

Mesenchymal stem cells (MSCs) have regenerative properties in acute kidney injury, but their role in chronic kidney diseases is still unknown. More specifically, it is not known whether MSCs halt fibrosis. The purpose of this work was to investigate the role of MSCs in fibrogenesis using a model of chronic renal failure. MSCs were obtained from the tibias and femurs of male Wistar-EPM rats. Female Wistar rats were subjected to the remnant model, and 2 vertical bar x vertical bar 10(5) MSCs were intravenously administrated to each rat every other week for 8 weeks or only once and followed for 12 weeks. SRY gene expression was observed in female rats treated with male MSCs, and immune localization of CD73(+)CD90(+) cells at 8 weeks was also assessed. Serum and urine analyses showed an amelioration of functional parameters in MSC-treated animals at 8 weeks, but not at 12 weeks. Masson`s trichrome and Sirius red staining demonstrated reduced levels of fibrosis in MSC-treated animals. These results were corroborated by reduced vimentin, type I collagen, transforming growth factor beta, fibroblast specific protein 1 (FSP-1), monocyte chemoattractant protein 1, and Smad3 mRNA expression and alpha smooth muscle actin and FSP-1 protein expression. Renal interleukin (IL)-6 and tumor necrosis factor alpha mRNA expression levels were significantly decreased after MSC treatment, whereas IL-4 and IL-10 expression levels were increased. All serum cytokine expression levels were decreased in MSC-treated animals. Taken together, these results suggested that MSC therapy can indeed modulate the inflammatory response that follows the initial phase of a chronic renal injury. The immunosuppressive and remodeling properties of MSCs may be involved in the decreased fibrosis in the kidney. STEM CELLS 2009;27:3063-3073