Lupus nephritis: an update.

Lupus nephritis (LN) is an inflammatory condition of the kidneys that encompasses various patterns of renal disease including glomerular and tubulointerstitial pathology. It is a major predictor of poor prognosis in patients with systemic lupus erythematosus (SLE). Genetic factors, including several predisposing loci, and environmental factors, such as EBV and ultraviolet light, have been implicated in the pathogenesis. It carries a high morbidity and mortality if left untreated. Renal biopsy findings are utilized to guide treatment. Optimizing risk factors such as proteinuria and hypertension with renin-angiotensin receptor blockade is crucial. Immunosuppressive therapy is recommended for patients with focal or diffuse proliferative lupus nephritis (Class III or IV) disease, and certain patients with membranous LN (Class V) disease. Over the past decade, immunosuppressive therapies have significantly improved long-term outcomes, but the optimal therapy for LN remains to be elucidated. Cyclophosphamide-based regimens, given concomitantly with corticosteroids, have improved survival significantly. Even though many patients achieve remission, the risk of relapse remains considerably high. Other treatments include hydroxychloroquine, mycofenolate mofetil, and biologic therapies such as Belimumab, Rituximab, and Abatacept. In this paper, we provide a review of LN, including pathogenesis, classification, and clinical manifestations. We will focus, though, on discussion of the established as well as emerging therapies for patients with proliferative and membranous lupus nephritis.

Collapsing glomerulopathy superimposed on diabetic nephropathy: insights into etiology of an under-recognized, severe pattern of glomerular injury.

BACKGROUND: Collapsing glomerulopathy (CG) represents severe podocyte injury with massive proteinuria, rapid progression and relative resistance to therapy. It is associated with multiple etiologies, including obliterative arteriopathy in transplants. However, its association with diabetic nephropathy (DN) has not been reported. METHODS: Renal biopsies performed in diabetic patients for either increasing proteinuria or deteriorating renal function, or both, were retrospectively reviewed. The clinicopathologic features and immunohistochemical staining of podocytes were analyzed. RESULTS: Of 534 patients with DN, 26 human immunodeficiency virus (HIV)-negative patients were found to have CG superimposed on DN (5% DN cases). At the time of biopsy, their mean serum creatinine was 3.8 mg/dL and proteinuria was 9.8 g/24 h. Renal biopsy showed CG in 2-30% (mean 16% of glomeruli), with segmental (2%) and global (33%) glomerulosclerosis. DN classification was Class IV-12, III-8, IIb-4 and IIa-2. Vascular sclerosis was moderate (44%) and severe (56%). Extensive arteriolar hyalinosis with >50% luminal stenosis was seen in 85% of cases. Markers of podocyte differentiation were lost, consistent with other types of CG. Cytokeratin was focally positive in 70% and VEGF overexpressed in 43%. Follow-up on 17 patients: 13 developed end-stage renal disease (ESRD) in 7 months from the time of biopsy. The development to ESRD in these patients was more rapid than diabetic controls without CG (P=0.005). The remaining four, 5-24 months follow-up, had an increase in creatinine with stable proteinuria. CONCLUSIONS: CG contributes to an increased level or new onset of proteinuria in DN which may be intractable. CG in DN with advanced vascular hyalinosis is presumably due to ischemic podocyte injury and is of prognostic significance.

Resistant hypertension: is renal denervation the current treatment of choice?

BACKGROUND: Resistant hypertension is simply defined as failure to control blood pressure <140/90 mmHg in an adherent non-diabetic patient with normal kidney function despite the use of optimal doses of three antihypertensive agents, including a diuretic. Also, control of blood pressure in any adherent patient with more than four antihypertensive agents defines resistant hypertension. In a patient with diabetes or chronic kidney disease, the goal blood pressure is <130/80 mmHg. One of the most important pathophysiological mechanisms of resistant hypertension is overactivity of the sympathetic nervous system (SNS). In selected patients with resistant hypertension, renal denervation has been shown to control blood pressure by suppressing SNS overactivity. SUMMARY: This review summarizes the results of the studies of renal denervation for resistant hypertension and suggests the use of this procedure in several other conditions that are associated with SNS overactivity. KEY MESSAGE: Renal denervation seems to control blood pressure in patients with resistant hypertension.

A patient with foot ulcer and severe metabolic alkalosis.

We report a case of triple acid-base disorder with metabolic alkalosis as the primary disorder in a 65-year-old man due to ingestion and application to leg ulcers of baking soda (calcium bicarbonate). The blood pH was 7.65 with hypochloremia, hypokalemia, and prerenal azotemia. He was treated with isotonic saline with K replacement, and the patient improved without any adverse clinical consequences. We discuss the causes, mechanisms, and management of Cl-responsive (depletion) metabolic alkalosis.

Contrast-Induced Acute Kidney Injury: Evidence in Support of Its Existence and a Review of Its Pathogenesis and Management.

The role of contrast-induced nephropathy (CIN) remains controversial. Many experts contend that CIN does not exist or is extremely rare. The diagnosis was previously made too frequently and inappropriately in the presence of coexisting and confounding comorbidities and risk factors making it difficult to singularly isolate the etiologic role of intravenous contrast media in acute kidney injury (AKI). It is probable that many patients were denied important diagnostic information from radiocontrast studies for fear of CIN. Recently, a new terminology for CIN was introduced, and the term CIN was replaced by two interrelated new terms: one is contrast-associated acute kidney injury (CA-AKI), and the second one is contrast-induced acute kidney injury (CI-AKI). CA-AKI occurs in association with risk factors or comorbidities, therefore, it is a correlative diagnosis. On the other hand, CI-AKI is a subtype of CA-AKI that results directly from iodinated contrast media. In this review, we present evidence from various studies that argue against CI-AKI and also those that suggest its existence but with much lower frequency. We will also provide the current status of the pathophysiology and management of CA-AKI/CI-AKI.

Administration of human umbilical cord blood cells delays the onset of prostate cancer and increases the lifespan of the TRAMP mouse.

Stem cell transplantation to improve the onset and survival of animals or humans with prostate cancer has not been studied adequately. In this study, we examined whether intravenous administration of human umbilical cord blood (HUCB) mononuclear cells into TRAMP (transgenic adenocarcinoma of the mouse prostate) mice can delay the onset of prostate cancer and improve survival of these mice before and after the development of cancer. Twenty TRAMP mice were randomly divided into 2 groups. One group of 10 mice received 200 x10(6) HUCB mononuclear cells retro-orbitally into the venous plexus at the age of 6 weeks. Another group of 10 mice did not receive HUCB cells and served as control mice. The presence of tumor was detected by abdominal palpation, which was confirmed by biopsy. When 4 of the 10 control mice developed the tumor, they were treated with the same dose of HUCB cells. Either at the time of death or sacrifice, various tissues were examined for the presence of HUCB cell total RNA by reverse transcriptase PCR. Also, the tissues were examined histologically for the presence of metastasis and carcinoma. Kaplan-Meier survival plots were used to assess the lifespan of the mice. The data show that the control mice developed the tumor much earlier than the treated mice (control vs treated: 238+/-38 vs 311+/-40 days; P<0.001). Also, transplantation of HUCB cells either before or after the development of tumor significantly increased the life span compared to that of control mice. Persistence of human RNA either in blood or spleen was associated with prolonged survival. No graft vs host disease was observed in any of the mice. In conclusion, transplantation of HUCB mononuclear cells via intravenous administration into TRAMP mice retards not only the development of prostate cancer but also increases the lifespan of these mice.

Administration of human umbilical cord blood to low birth weight infants may prevent the subsequent development of type 2 diabetes.

Both epidemiological and experimental studies have shown that impaired growth in utero due to maternal malnutrition, resulting in low birth weight, is associated with a high incidence of glucose intolerance, insulin resistance, and type 2 diabetes in adult life. Maternal malnutrition is a worldwide problem and unavoidable; therefore, prevention of type 2 diabetes in low birth weight infants who reach adulthood is difficult to achieve. Administration of human umbilical cord blood (HUCB) mononuclear cells into type 1 and type 2 diabetic mice has been shown to improve both their blood glucose levels and survival. It has also been shown that the progenitor cells derived from HUCB improve not only glycemia but also other disease conditions, including systemic lupus erythematosis, amyotrophic lateral sclerosis, Alzheimer's disease, stroke, brain damage in animals and certain malignancies in humans. Transfusion of unrelated HUCB, although abundantly available, is underutilized as a therapeutic agent. Therefore, we propose the hypothesis that transfusion of HUCB to low birth weight infants be considered a therapeutic modality to prevent the development of type 2 diabetes in their adulthood.

Albumin and Furosemide Combination for Management of Edema in Nephrotic Syndrome: A Review of Clinical Studies.

The treatment of edema in patients with nephrotic syndrome is generally managed by dietary sodium restriction and loop diuretics. However, edema does not improve in some patients despite adequate sodium restriction and maximal dose of diuretics. In such patients, combination of albumin and a loop diuretic may improve edema by diuresis and natriuresis. The response to this combination of albumin and a diuretic has not been observed in all studies. The purpose of this review is to discuss the physiology of diuresis and natriuresis of this combination therapy, and provide a brief summary of various studies that have used albumin and a loop diuretic to improve diuretic-resistant edema. Also, the review suggests various reasons for not observing similar results by various investigators.

Human umbilical cord blood cells and diabetes mellitus: recent advances.

Stem cell therapy for patients with diabetes is an area of great interest to both scientists and clinicians. Human umbilical cord blood cells (HUCBCs) are being increasingly used as a source of stem cells for cell-based therapy for diabetes because these cells can differentiate into pancreatic islet ß-cells. Administration of HUCBCs has been shown to lower blood glucose levels in diabetic animal models. The use of autologous HUCBC transfusion in type 1 diabetic children has not shown any benefit. However, "Stem Cell Educator" therapy has shown promise in long term lowering of blood glucose levels in both type 1 and type 2 diabetic patients. In this review, we will briefly discuss recent advances in HUCBC therapy in the treatment of diabetes and some of its complications.

Human umbilical cord blood as an emerging stem cell therapy for diabetes mellitus.

Cellular therapy for patients with diabetes is receiving great attention among scientists and clinicians. Bone marrow is considered one of the rich sources of stem cells. However, the limited availability of bone marrow donors precludes its use for all the suitable patients. Human umbilical cord blood (HUCB) is being increasingly used as an alternative source of stem cells for cell-based therapy for malignant and nonmalignant diseases. HUCB is preferred to bone marrow because of its easy availability, low potential for graft-versus-host disease and tumorigenicity as well as infectious complications. Furthermore, no immunosuppression is required. In vitro and in vivo studies have shown that HUCB-derived stem cells can differentiate into insulin-secreting ß-cells. Administration of HUCB cells has been shown to improve blood glucose levels in diabetic animals. The first use of autologous HUCB transfusion in type 1 diabetic children is showing promise in reducing the daily requirement of insulin dose and the maintenance of near normoglycemia over a short period of time. The time has come for more clinical trials using autologous and allogenic cord blood transfusion to treat diabetes mellitus.

Administration of human umbilical cord blood cells produces interleukin-10 (IL-10) in IL-10 deficient mice without immunosuppression.

Recent studies from our laboratory have shown that intravenous administration of human umbilical cord blood (HUCB) mononuclear cells to mice improved blood glucose levels, survival, atherosclerosis and prostate cancer. In this study, we examined the effect of HUCB cells on the production of IL-10 levels in IL-10 knockout mice. It has been proposed that administration of IL-10 may be beneficial in the treatment of inflammatory bowl disease. The results show that mice treated with HUCB cells (100 x 10(6)) produce IL-10, as demonstrated by both qualitative and quantitative analyses, and that the levels of this cytokine persisted until the mice were sacrificed (5.5 months after administration). Immunohistochemical staining of the intestine using HuNu antibody cocktail demonstrated the presence of HUCB cells in the knockout mouse. Although the mice did not receive any immunosuppression, there was no evidence of graft-versus-host disease. Our data suggest that HUCB cells are capable of producing IL-10, and the use of these cells or HUCB may be indicated in the treatment of certain human diseases.

Prevalence of elevated blood pressure in 563,704 adult patients with stroke presenting to the ED in the United States.

PURPOSE: The aim of this study was to estimate the prevalence of elevated blood pressure in adult patients with acute stroke in the United States (US). METHODS: Patients with stroke were classified by initial systolic blood pressure (SBP) into 4 categories using demographic, clinical, and treatment data from the National Hospital Ambulatory Medical Care Survey, the largest study of use and provision of emergency department (ED) services in the United States. We also compared the age-, sex-, and ethnicity-adjusted rates of elevated blood pressure strata, comparable with stages 1 and 2 hypertension in the US population. RESULTS: Of the 563704 patients with stroke evaluated, initial SBP was below 140 mm Hg in 173120 patients (31%), 140 to 184 mm Hg in 315207 (56%), 185 to 219 mm Hg in 74586 (13%), and 220 mm Hg or higher in 791 (0.1%). The mean time interval between presentation and evaluation was 40 +/- 55, 33 +/- 39, 25 +/- 27, and 5 +/- 1 minutes for increasing SBP strata (P = .009). A 3- and 8-fold higher rate of elevated blood pressure strata was observed in acute stroke than the existing rates of stages 1 and 2 hypertension in the US population. Labetalol and hydralazine were used in 6126 (1%) and 2262 (0.4%) patients, respectively. Thrombolytics were used in 1283 patients (0.4%), but only in those with SBP of 140 to 184 mm Hg. CONCLUSIONS: In a nationally representative large data set, elevated blood pressure was observed in over 60% of the patients presenting with stroke to the ED. Elevated blood pressure was associated with an earlier evaluation; however, the use of thrombolytics was restricted to patients with ischemic stroke with SBP below 185 mm Hg.

Prevention of atherosclerosis in LDL receptor-mutant mice by human umbilical cord blood cells.

Previous studies have shown that congenic bone marrow transplantation into apolipoprotein E-deficient mice prevented hypercholesterolemia and atherosclerosis. In this study, we examined the effect of intravenous administration of human umbilical cord blood (HUCB) mononuclear cells on the progression of atherosclerosis in male homozygous mice that had mutation in the low-density lipoprotein receptor (Ldlr(tm1Her) mutation mice). In addition, the effect of human breastmilk alone as well as the combination of HUCB cells and breastmilk was studied on the prevention of atherosclerosis in these mice. In all groups of mice, atherosclerosis was predominant in the ascending aorta, but the rest of the aorta had variable evidence of atherosclerosis. Treatment of mice with HUCB cells significantly ameliorated the development of atherosclerosis in the ascending aorta, as compared with untreated mice; whereas breastmilk alone did not have any significant effect. A similar beneficial effect was observed with the combination therapy, which could be attributed only to HUCB cell treatment. There was no beneficial effect of treatment on the thoracic and abdominal aorta. Thus, early administration of HUCB cells prevents the progression of atherosclerosis in the ascending aorta of mice that are prone to the development of atherosclerosis. This beneficial effect occurred without any immunosuppression and graft-vs-host disease.

Effect of human umbilical cord blood cells on glycemia and insulitis in type 1 diabetic mice.

Several studies have shown that transplantation of embryonic stem cells into diabetic animals either improved or normalized blood glucose levels. In this study, we examined the dose-dependent effect of early (prediabetic stage) intravenous administration of human umbilical cord blood (HUCB) mononuclear cells on blood glucose levels, survival, and insulitis in nonobese diabetic (NOD) mice with autoimmune type 1 diabetes. The results show that mice treated with HUCB cells significantly lowered their blood glucose levels and increased their lifespan, as compared with untreated mice. Also, a significant reduction in insulitis was observed in treated than in untreated mice. The mice that received the highest dosage (200 x 10(6)) of cells had greater reduction in blood glucose levels and the degree of insulitis than the mice that received lower dosage (100-150 x 10(6)) of cells. Prolonged lifespan in the former group of mice seems to be related to better control of blood glucose levels. Thus, administration of HUCB cells in the prediabetic stage without any immunosuppression improves type 1 diabetes by protecting the islets from insulitis in NOD mice.

Transplantation of human umbilical cord blood cells improves glycemia and glomerular hypertrophy in type 2 diabetic mice.

Recent in vitro and in vivo studies have shown that either animal- or human-derived embryonic stem cells can differentiate into insulin-secreting cells and lower blood glucose levels. However, studies utilizing human umbilical cord blood (HUCB) mononuclear cells to improve blood glucose levels in diabetic animals have received little attention. In this study, we examined the effect of transplanted HUCB mononuclear cells on blood glucose levels, survival, and renal pathology in obese mice with spontaneous development of type 2 diabetes. The results show that injection of HUCB mononuclear cells into orbital plexus of mice caused improvement not only in blood glucose levels and survival rate but also normalization of glomerular hypertrophy and tubular dilatation. Thus, transplantation of HUCB mononuclear cells appears to be another modality of stem cell therapy in diabetes mellitus.