Jerome Lowenstein

Lupus nephritis: Clinical course as related to morphologic forms and their transitions

An intensive study of the course of lupus nephritis has been undertaken in 88 patients in whom strict morphologic criteria were utilized in classification. All were treated with steroid, and 17 received cytotoxic drugs in addition. Focal proliferative lupus nephritis generally follows a benign course except in the occasional instances when transition to the diffuse proliferative or membranous forms occurs. Membranous lupus nephritis, when characterized by persistent nephrotic syndrome, leads slowly to renal failure, but this progression is aborted in the one-third in whom remission of the nephrotic syndrome can be achieved. A fatal outcome occurs within five years in the majority of those with diffuse proliferative lupus nephritis and the nephrotic syndrome, often in association with necrotizing renal vasculitis, severe hypertension and accelerated renal failure. A small number with the diffuse proliferative form have a remission and then show only mesangial abnormalities, usually, however, with the appearance of glomerular sclerosis. Progressive glomerular sclerosis is observed in some patients and may be a sequel of the remission of the diffuse or focal proliferative lesions, or it may represent still another form of lupus nephritis. Mesangial immune deposits with or without proliferation, at times in the absence of clinical renal disease, are observed early in the course of systemic lupus erythematosus (SLE) and may proceed to the diffuse proliferative or membranous forms. The present observations serve to emphasize the importance of strict morphologic classification in the comparison of different treatment regimens for lupus nephritis. In view of the grave prognosis of established diffuse proliferative lupus nephritis, which probably evolves from a mesangial involvement common to all patients with SLE from its onset, early therapy may be the key to the management of lupus nephritis.

The clinical course of the proliferative and membranous forms of lupus nephritis.

Abstract By using histologic, immunofluorescent, and electron microscopic observations of 52 patients with systemic lupus erythematosus and renal involvement, three different forms of lupus nephrit...

Renal failure after open heart surgery.

One hundred fifty of 490 patients undergoing open heart surgery had renal failure attributable to cardiopulmonary bypass. In 69, serum creatinine concentrations did not exceed 2 mg/dl and returned to normal by the fourth postoperative day. In 60 patients, serum creatinine attained levels between 2 and 5 mg/dl, oliguria did not develop, and recovery of renal function occurred within 4 to 37 days. Serum creatinine increased to levels exceeding 5 mg/dl in 21 patients, 11 of whom were oliguric. Despite dialysis, 14 of these patients died from cardiac causes or sepsis. Prolonged cardiopulmonary bypass time, hypotension, oliguria, low output syndrome, and hemoglobinemia during open heart surgery correlated with the development of renal failure postoperatively. Although severe renal failure was an uncommon complication after open heart surgery, its occurrence carried a grave prognosis.

Renal failure in minimal change nephrotic syndrome

Renal insufficiency, with serum creatinines ranging from 2.3 to 13.4 mg/dl, was observed in 15 patients with the minimal change nephrotic syndrome. Recovery of renal function occurred in association with diuretic therapy in 13, eight of whom subsequently underwent steroid-induced remission of the nephrotic syndrome. Two patients failed to undergo diuresis or to have a remission of the nephrotic syndrome and died with persistent renal failure. Glomerular filtration rate (Cinulin) was reduced out of proportion to renal plasma flow (CPAH) as evidenced by remarkably low filtration fractions ranging from 0.03 to 0.095. The invariable association between diuresis and recovery of renal function, the recurrence of renal failure when fluid reaccumulated and the finding of markedly depressed filtration fractions lead us to postulate that renal failure in minimal change nephrotic syndrome may be due to a reversible alteration in glomerular hemodynamics which is related to fluid retention and associated intrarenal edema.

The kidney and uremic toxin removal: Glomerulus or tubule?

Chronic kidney disease (CKD) is a condition that affects approximately 10% of the adult population in developed countries. In patients with CKD adequate renal clearance is compromised, resulting in the accumulation of a plethora of uremic solutes. These uremic retention solutes, also known as uremic toxins, are a heterogeneous group of organic compounds, many are too large to be filtered (middle molecules) or are protein-bound. Tubular secretion shifts the binding and allows for active secretion of such solutes. To mediate urinary solute excretion, renal proximal tubules are equipped with a range of transporters that cooperate in basolateral uptake and luminal excretion. These putative uremic toxins are poorly filtered across dialysis membranes because they are protein bound and current dialysis therapy does not correct the full spectrum of uremic toxicity. Residual renal function, which may represent an important contribution of solutes secreted by the proximal tubule rather than unreabsorbed filtrate, is an important predictor of survival of CKD patients. Many of the transporters that mediate the renal excretion of uremic retention solutes were first recognized as mediators of drug trafficking and drug-drug interactions, and a considerable amount of literature concerning the actions of these transporters antedates the recognition of their importance in the proximal renal tubular transport of uremic retention solutes. These transporters include members belonging to the organic cation/anion/zwitterion solute carrier family, such as the organic anion transporters (OAT)1, OAT3, and OATP4C1, and to the adenosine triphosphate binding cassette superfamily of transmembrane transporters, including the multidrug resistance proteins and breast cancer resistance protein. This article draws on this body of information to describe the renal tubular clearance mechanisms for uremic toxins, as well as the intracellular events associated with their accumulation, involving activation of the aryl hydrocarbon receptor, disturbance of mitochondrial functioning, and competition with metabolizing enzymes.

Drugs Five Years Later: Clonidine

Clonidine represents the prototype of a new class of centrally acting antihypertensive agents, classed as partial alpha-adrenergic antagonists. Blood pressure reduction is characterized, hemodynamically, by reduced cardiac output with unchanged peripheral vascular resistance at rest. Reflex control of blood pressure during orthostasis and exercise appears to be unimpaired, and orthostatic hypotension is uncommon. As with most other antihypertensive agents, satisfactory reduction of blood pressure with clonidine given as a sole agent is limited to patients with relatively mild hypertension; an additive or synergistic effect of diuretic administration has been well documented. Abrupt withdrawal of clinidine has been reported to be followed, within 24 to 36 h, by rebound hypertension, tachycardia, cardiac arrhythmias, and other changes suggestive of sympathetic overactivity. The incidence and clinical significance of rebound hypertension after abrupt cessation of clonidine therapy, and indeed the profile of blood pressure responses to varying physical activity during therapy, remain to be evaluated.

Effects of prazosin and propranolol on serum lipids in patients with essential hypertension

The effects of prazosin and propranolol on total serum cholesterol concentration, low-density lipoprotein and high-density lipoprotein cholesterol fractions, and serum triglyceride concentration were compared in a crossover study in 29 patients with mild to moderate essential hypertension. All patients received polythiazide at a constant dose throughout control and drug treatment periods. Comparable blood pressure reduction was achieved with prazosin (9.3 +/- 7.1 mg per day) and propranolol (183.6 +/- 154.5 mg per day). Prazosin administration was associated with a significant reduction in the concentrations of total serum cholesterol (-5.5 percent), triglyceride (-20.0 percent), and low-density lipoprotein cholesterol (-10.1 percent). High-density lipoprotein cholesterol concentration increased (+8.0 percent) as did the ratio high-density lipoprotein: total cholesterol (+14.1 percent). No significant changes in any of the serum lipid fractions were observed during propranolol administration.

The Distribution of Intrarenal Blood Flow in Normal and Hypertensive Man

Observations were made on eight normotensive subjects and on 12 patients with essential hypertension to determine whether the intrarenal distribution of blood flow is altered in essential hypertension. Dye-dilution curves were recorded across the renal vascular bed and a set of integral transformations, developed by Gomez, was used to determine distribution of blood flow per unit renal blood volume across the renal vascular bed from dye-dilution curves. Observations also were made on two hypertensives and two normotensives during administration of norepinephrine. The distribution of specific blood flow and the functional renal blood volume in the right kidney of patients with essential hypertension were comparable to those in normal subjects, but the mean specific blood flow was reduced in essential hypertension. Failure to demonstrate altered distribution of specific blood flow in essential hypertension indicated an absence of focal reductions in renal blood flow and that blood flow is reduced uniformly throughout the renal vascular bed in essential hypertension. This reduction in specific renal blood flow is attributed to arteriolar vasoconstriction.

Differential Effects of an Angiotensin II Analogue on Pressor and Adrenal Receptors in the Rabbit

The 1-sarcosine-8-alanine analogue of angiotensin II (1-Sar-8-Ala-angiotensin II) was infused at 1 and 5 μg/kg min−1 into conscious rabbits on normal or sodium-deficient diets. Blood pressures during the control period were comparable in both groups; plasma renin activity, angiotensin II concentration, and aldosterone concentration were higher in the rabbits on the sodium-deficient diet than they were in the rabbits on the normal diet. The analogue caused a 6-mm Hg fall in mean arterial blood pressure in sodium-depleted rabbits. Plasma renin activity increased in both groups to eight to ten times the control values with the higher rate of infusion. Angiotensin II concentration paralleled plasma renin activity. Plasma aldosterone concentration increased after infusion of the analogue at 1 μg/kg min−1 to three to four times the control values but decreased from these high levels after an additional 90-minute infusion at 5 μg/kg min−1 to only one to two times the control values in both groups. Infusion of angiotensin II during the administration of the analogue caused a clear-cut increase in aldosterone concentration without a change in blood pressure. The persistence of elevated aldosterone levels during inhibitor blockade in the sodium-depleted rabbits does not prove that factors other than angiotensin participate in the aldosterone response to sodium deprivation. However, the data do indicate that 1-Sar-8-Ala-angiotensin II is a less effective antagonist of angiotensin II at the adrenal receptors than it is at the vascular smooth muscle receptors and suggest that the pressor and adrenal receptors differ.

Effects of prazosin, atenolol, and thiazide diuretic on plasma lipids in patients with essential hypertension

The effects of prazosin and atenolol monotherapy on plasma lipid concentrations were compared in 51 patients with mild to moderate essential hypertension. Prazosin monotherapy (mean dose 5.4 +/- 5.3 mg per day) resulted in a significant decrease in total and low-density lipoprotein cholesterol concentrations; these changes were evident at three months and at six to 12 months. Atenolol monotherapy (mean dose 66 +/- 23 mg per day) resulted in a significant increase in plasma triglyceride concentration that persisted during one year of treatment. The deletion of thiazide from the regimen of prazosin plus thiazide resulted in a small stepwise decrease in plasma triglyceride concentration over 12 months of observation. The addition of polythiazide (0.5 mg two to three times weekly) to the regimen of patients in whom acceptable blood pressure was not attained with prazosin or atenolol monotherapy resulted in a decrease in blood pressure, averaging 18.8 mm Hg for systolic and 10.3 mm Hg for diastolic, and a small, though significant, increase in the concentration of low-density lipoprotein cholesterol. It is suggested that the effects of prazosin on plasma lipid composition may be mediated, at least in part, by blocking an action of either the sympathetic nervous system or circulating catecholamines that normally modulate lipoprotein metabolism and might mediate the lipid alterations induced by thiazide diuretics.