IgG4-related kidney disease with systemic Epstein-Barr virus infection: A case report.

IgG4-related disease (IgG4-RD) is a newly recognized multi-organ fibro-inflammatory condition with characteristic histopathological findings of increased IgG4+ plasma cells in tissue and usually with increased IgG4 serum levels. Kidney involvement in IgG4-RD has been well described since 2006. Epstein-Barr virus (EBV) has reportedly been associated with nodal IgG4-RD, but not in extra-nodal disease. We report a case of renal IgG4-RD in the setting of acute EBV infection in a young healthy man, resulting in severe renal failure. Biopsy of kidney revealed IgG4+ plasma cell-rich tubulointerstitial nephritis, tissue eosinophilia, early-stage membranous nephropathy, and scattered EBV-positive cells. Oral prednisone and acyclovir only partially rescued his renal function.

Magnitude of the Difference Between Clinic and Ambulatory Blood Pressures and Risk of Adverse Outcomes in Patients With Chronic Kidney Disease.

Background Obtaining 24-hour ambulatory blood pressure ( BP ) is recommended for the detection of masked or white-coat hypertension. Our objective was to determine whether the magnitude of the difference between ambulatory and clinic BP s has prognostic implications. Methods and Results We included 610 participants of the AASK (African American Study of Kidney Disease and Hypertension) Cohort Study who had clinic and ambulatory BPs performed in close proximity in time. We used Cox models to determine the association between the absolute systolic BP ( SBP ) difference between clinic and awake ambulatory BPs (primary predictor) and death and end-stage renal disease. Of 610 AASK Cohort Study participants, 200 (32.8%) died during a median follow-up of 9.9 years; 178 (29.2%) developed end-stage renal disease. There was a U-shaped association between the clinic and ambulatory SBP difference with risk of death, but not end-stage renal disease. A 5- to <10-mm Hg higher clinic versus awake SBP (white-coat effect) was associated with a trend toward higher (adjusted) mortality risk (adjusted hazard ratio, 1.84; 95% CI, 0.94-3.56) compared with a 0- to <5-mm Hg clinic-awake SBP difference (reference group). A ≥10-mm Hg clinic-awake SBP difference was associated with even higher mortality risk (adjusted hazard ratio, 2.31; 95% CI, 1.27-4.22). A ≥-5-mm Hg clinic-awake SBP difference was also associated with higher mortality (adjusted hazard ratio, 1.82; 95% CI, 1.05-3.15) compared with the reference group. Conclusions A U-shaped association exists between the magnitude of the difference between clinic and ambulatory SBP and mortality. Higher clinic versus ambulatory BPs (as in white-coat effect) may be associated with higher risk of death in black patients with chronic kidney disease.

Skin Blood Flow and Vascular Endothelium Function in Uremia.

Prevalence of dermatological disorder in patients with end-stage kidney disease is estimated as 50% to 100% in various studies. Some of the skin lesions are specific for the diseases causing chronic kidney disease (CKD), some are associated with CKD, and still others are the dermatological manifestation of uremia. Microangiopathy was also found in both arterioles and venule in the skin biopsy of "normal looking" skin in patients with end-stage kidney disease. In a cross-sectional study in patients on dialysis, we measured skin blood flow (SBF) using laser Doppler device in a standardized way at various areas of lower extremities at 2 different local skin temperatures: 35°C and 44°C. Local heating increases skin perfusion by mechanisms dependent on nitric oxide (NO). SBF was impaired in CKD patients Stage 5 on HD, particularly in those with diabetes mellitus as a cause of CKD. The reduced response in the SBF to the heat in our patients may be due to decreased generation of NO in uremia. Endothelium-dependent vasodilatation in patients on dialysis and the response of the skin microcirculation to acetylcholine was diminished in hypertensive patients on dialysis. Similarly, patients with diabetes mellitus had decreased SBF during intradermal microdialysis with a NO synthase inhibitor. Multiple uremic toxins have been studied in vitro and show to cause various degree of endothelial cell dysfunction. Unfortunately, no clear benefit has been described in CKD patients to different intervention aimed to reduce uremic toxin effect on endothelium. There are no long-term data on the factors which can modify endothelium function in uremia, but non pharmacologic interventions, diet, and several pharmacologic approaches could be beneficial. Measurement of SBF can be useful in evaluation of vasculopathy in CKD population and can potentially be used for assessment of vascular response during specific clinical intervention.

William Osler and investigation on trench nephritis.

The first alarming reports about a new disease called "trench nephritis" affecting soldiers of the British Expeditionary Forces in Flanders appeared in British medical press in 1915th. Soon, the Medical Research Council initiated a special research investigation on trench nephritis at St. Bartholomews Hospital and the results of these studies were discussed during the Royal Society of Medicine meeting in February 1916. William Osler was invited as one of the four main speakers for this presentation. He had lived in England since 1906 and served as the Regius Professor of Medicine at Oxford. At the meeting, Osler summarizes the clinical presentation of trench nephritis as a sudden appearance of swelling with rare cases of anasarca. Fever was not a common early presentation in his experience. He found rapid improvement in most of the cases during hospitalization despite "persistence of a large amount of albumin, of blood, and of cast, with increasing high blood pressure, is an unusual combination in the nephritis of civil life, yet that has been common enough in these cases". He questioned the assumption of a good prognosis in trench nephritis especially in "Cases which are lasting from twelve to fourteen weeks, the chances are that it will become subacute or chronic".

Relationship between ambulatory BP and clinical outcomes in patients with hypertensive CKD.

BACKGROUND AND OBJECTIVES: Abnormal ambulatory BP (ABP) profiles are commonplace in CKD, yet the prognostic value of ABP for renal and cardiovascular outcomes is uncertain. This study assessed the relationship of baseline ABP profiles with CKD progression and subsequent cardiovascular outcomes to determine the prognostic value of ABP beyond that of clinic BP measurements. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Between 2002 and 2003, 617 African Americans with hypertensive CKD treated to a clinic BP goal of <130/80 mmHg were enrolled in this prospective, observational study. Participants were followed for a median of 5 years. Primary renal outcome was a composite of doubling of serum creatinine, ESRD, or death. The primary cardiovascular outcome was a composite of myocardial infarction, hospitalized congestive heart failure, stroke, revascularization procedures, cardiovascular death, and ESRD. RESULTS: Multivariable Cox proportional hazard analysis showed that higher 24-hour systolic BP (SBP), daytime, night-time, and clinic SBP were each associated with subsequent renal (hazard ratio, 1.17-1.28; P<0.001) and cardiovascular outcomes (hazard ratio, 1.22-1.32; P<0.001). After controlling for clinic SBP, ABP measures were predictive of renal outcomes in participants with clinic SBP <130 mmHg (P<0.05 for interaction). ABP predicted cardiovascular outcomes with no interaction based on clinic BP control. CONCLUSIONS: ABP provides additional information beyond that of multiple clinic BP measures in predicting renal and cardiovascular outcomes in African Americans with hypertensive CKD. The primary utility of ABP in these CKD patients was to identify high-risk individuals among those patients with controlled clinic BP.

Tadeusz Orlowski: founder of nephrology and kidney transplantation in Poland.

Modern nephrology in Poland and in the world owes much to the scientific, clinical and organizational activities of Prof. Tadeusz Orlowski. He was a pioneer in many fields of kidney disease. His pathophysiological work included studies on renal dysfunction in heart and liver diseases, function of the transplanted kidney and various aspects of the uremic syndrome. He was engaged in the development of hemodialysis and peritoneal dialysis in Warsaw. Together with surgeon Jan Nielubowicz, he initiated the transplant program in Poland and on January 26, 1966, successfully transplanted a kidney in a patient on chronic dialysis. This success was followed by establishment of the Transplantation Institute of the Warsaw Medical Academy in 1975, which facilitated the scientific and clinical growth of nephrology and transplantation in Poland. He also introduced and established scientific evidence for the use of immunosuppressive therapy for glomerular diseases. The heritage of Tadeusz Orlowski is broader than nephrology. His legacy will continue through the work of the many who learned from his example.

Intensive blood-pressure control in hypertensive chronic kidney disease.

BACKGROUND: In observational studies, the relationship between blood pressure and end-stage renal disease (ESRD) is direct and progressive. The burden of hypertension-related chronic kidney disease and ESRD is especially high among black patients. Yet few trials have tested whether intensive blood-pressure control retards the progression of chronic kidney disease among black patients. METHODS: We randomly assigned 1094 black patients with hypertensive chronic kidney disease to receive either intensive or standard blood-pressure control. After completing the trial phase, patients were invited to enroll in a cohort phase in which the blood-pressure target was less than 130/80 mm Hg. The primary clinical outcome in the cohort phase was the progression of chronic kidney disease, which was defined as a doubling of the serum creatinine level, a diagnosis of ESRD, or death. Follow-up ranged from 8.8 to 12.2 years. RESULTS: During the trial phase, the mean blood pressure was 130/78 mm Hg in the intensive-control group and 141/86 mm Hg in the standard-control group. During the cohort phase, corresponding mean blood pressures were 131/78 mm Hg and 134/78 mm Hg. In both phases, there was no significant between-group difference in the risk of the primary outcome (hazard ratio in the intensive-control group, 0.91; P=0.27). However, the effects differed according to the baseline level of proteinuria (P=0.02 for interaction), with a potential benefit in patients with a protein-to-creatinine ratio of more than 0.22 (hazard ratio, 0.73; P=0.01). CONCLUSIONS: In overall analyses, intensive blood-pressure control had no effect on kidney disease progression. However, there may be differential effects of intensive blood-pressure control in patients with and those without baseline proteinuria. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Center on Minority Health and Health Disparities, and others.)

Historical perspective on the role of the kidney in acid-base regulation.

Early observations on the acidity of normal urine by J. B. von Helmont (1527-1644) and on urine content of sulfate, phosphate and carbonate by J. J. Berzelius (1779-1848), followed by the studies of Bence Jones (1813-1878) on the connection between food, nutrition and urine acidity, pointed to the role of the kidney in regulation of acid-base status in humans and animals. The next important steps in this field of science were studies by F. Walter (1877) on decreased "alkali" in blood and increased ammonia in the urine of dogs after infusion into their blood of hydrochloric acid, and the observations of B. Naunyn (1939-1925) and O. Minkowski (1853-1931) on the presence of beta-hydroxybutyric acid in urine and on increased ammonia excretion in urine from patients with diabetic coma. Also it was found that patients with uremia had decreased titratable "alkali' in blood (R. von Jaksch 1855-1947) and reduced ability to excrete ammonia (W. W. Palmer and L. J. Henderson 1915). Finally, studies by R. F. Pitts (1908-1977) defined the role of the kidney in reabsorption of bicarbonate in the tubules and linked hydrogen secretion to sodium excretion in the urine.

Immunosuppressive therapy in glomerular diseases: major accomplishment of Tadeusz Orlowski and his school.

Glomerulopathies are the third most common cause of end-stage renal failure. Immunosuppressive treatment of glomerulonephritis in a systematic way was introduced in Poland by Professor Tadeusz Orlowski in the early 1960s. The studies were conducted at the First Department of Medicine and at the Transplantation Institute of the Medical Academy in Warsaw in the years 1962-1988. This paper critically reviews the results of studies on the use of combined, triple-drug (prednisone/chlorambucil/azathioprine), immunosuppressive protocol in various pathological forms of glomerulopathies. We conclude that immunosuppressive protocols pioneered by Tadeusz Orlowski continue to be the backbone of the treatment of glomerulonephritis, especially the one with nephrotic syndrome, progressive impairment of kidney function and poor prognosis.

Altered acetylcholine metabolism of brain in uremia: role of secondary hyperparathyroidism.

OBJECTIVE: Cholinergic system and its neurotransmitter, acetylcholine (ACh), play a major role in both behavior and motor function of the nervous system. Cholinergic neurons synthesize ACh from choline and acetyl-CoA by choline acetyltransferase in the nerve ending. The release of ACh in response to nerve impulses is dependent on the intracellular calcium ([Ca2+]i) concentration and its gradient. The regulation of a synthesis of ACh after depolarization and ACh release is controlled by mass-action effect on choline acetyltransferase equilibrium. Behavioral and motor changes in uremia may be due in part to derangements in ACh metabolism and such possible abnormalities may be related to the state of secondary hyperparathyroidism of chronic renal failure (CRF). DESIGN: We studied ACh and choline content, choline release, choline kinase activity in brain synaptosomes of CRF with and without secondary hyperparathyroidism and in CRF rats treated with verapamil which normalize [Ca2+]i in brain synaptosomes of CRF rats. RESULTS: The content of ACh of brain synaptosomes increased progressively with the duration of CRF from 3 to 6 weeks. ACh and choline release as well as choline uptake were significantly higher in CRF rats at all time intervals studied. CONCLUSION: Choline content and the activity of choline kinase of brain synaptosomes were deceased after 3 weeks of CRF and were significantly lower than in synaptosomes of normal. Normalization of ACh and choline content as well as ACh release and the activity of choline kinase by parathyroidectomy or treatment with verapamil but these maneuvers did not prevent the rise in choline uptake and choline release. Resting levels of cytosolic calcium of brain synaptosomes in rats with CRF were significantly higher (437 +/- 9 nM) as compared to normal rats (345 +/- 9 nM). This rise in [Ca2+]i was prevented either by parathyroidectomy prior induction of CRF or by treatment of CRF rats with calcium channel blocker verapamil.

Liver metabolism in CRF.

Alteration in liver function are not typically present in patients with uremic syndrome, but varying degrees of liver dysfunction were observed in animals with experimental uremia and, to a lesser degree, in patients with chronic renal failure. This article summarizes the data obtained during the last 2 decades on protein, carbohydrate, and lipid metabolism by the liver in uremia and molecular aspects of regulation of lipids and protein synthesis. Particular attention is given to the role of cytosolic calcium ([Ca(2+)](i)) regulation and calcium signal transduction in hepatocytes in chronic renal failure. It is proposed that the parathyroid hormone (PTH)-mediated increase in the [Ca(2+)](i) of hepatocytes in chronic renal failure is a major signal for the downregulation of hepatic receptors for PTH-PTHrP, vasopressin and angiotensin II as well as as hepatic lipase. It is possible that the mRNA of other hormone receptors and various proteins of the liver cells are affected similarly by the elevated basal levels of [Ca(2+)](i) in CRF.