Effects of chloride and extracellular fluid volume on bicarbonate reabsorption along the nephron in metabolic alkalosis in the rat. Reassessment of the classical hypothesis of the pathogenesis of metabolic alkalosis.

Volume expansion has been considered essential for the correction of chloride-depletion metabolic alkalosis (CDA). To examine the predictions of this hypothesis, rats dialyzed against 0.15 M NaHCO3 to produce CDA and controls, CON, dialyzed against Ringer-HCO3 were infused with either 6% albumin (VE) or 80 mM non-sodium chloride salts (CC) added to 5% dextrose (DX) and studied by micropuncture. CDA was maintained in rats infused with DX. VE expanded plasma volume (25%), maintained glomerular filtration rate (GFR), but did not correct CDA despite increased fractional delivery of total CO2 (tCO2) out of the proximal tubule (36 +/- 2%) as compared with VE/CON (24 +/- 4%; P less than 0.05). In contrast, CC corrected CDA despite volume contraction (-16%) and lower GFR than CC/CON; proximal tCO2 delivery in CC/CDA (29 +/- 4%) did not differ from VE/CDA. CC was associated with an increment in tCO2 excretion. The data strongly suggest that maintenance and correction of CDA are primarily dependent upon total body chloride and its influences on intrarenal mechanisms and not on the demands of sodium or fluid homeostasis.

Human complement protein D catabolism by the rat kidney.

Factor D (D) is an essential component of the alternative complement pathway. To determine whether D is catabolized by the kidney and, if so, at what site, we studied the renal handling of human D by in vivo nephron microperfusion and in vitro perfusion of rat kidneys. Human D was purified and labeled with 125I. Individual nephrons were perfused in vivo at varying rates with perfusate that contained 125I-D and [14C]inulin. When nephrons were perfused from proximal sites with perfusate 125I-D in a concentration of 3.0 micrograms/ml, urinary recovery of 125I-D increased (P less than 0.05) from 57.7 +/- 5.0 to 74.4 +/- 2.5% as tubule fluid flow rate was increased from 10 to 40 nl/min; recovery of 125I-D was less than (P less than 0.001) [14C]inulin recovery at all perfusion rates. At 20 nl/min, an increase in perfusate 125I-D concentration from 1.5 to 3.0 micrograms/ml was associated with an increase (P less than 0.001) in urinary 125I-D recovery (42.1 +/- 4.0 vs. 65.8 +/- 2.6%). Similarly, the addition of unlabeled D, 30 micrograms/ml, to 125I-D, 3.0 micrograms/ml, increased urinary 125I-D recovery (95.3 +/- 2.1%) at 20 nl/min. When nephrons were perfused from early distal segments at 10 nl/min, 125I-D recovery (91.2 +/- 4.3%) did not differ from [14C]inulin recovery (95.8 +/- 1.3%). In the isolated perfused filtering kidney, the concentration of intact 125I-D in the perfusate declined 60.3 +/- 14.6% over 1 h. 83.4 +/- 6.3% of the decrement in 125I-D was catabolized by the kidney; the remainder was excreted in the urine as intact D. When glomerular filtration was prevented by increasing perfusate albumin concentration to 16 g/dl, perfusate intact (125I-D) remained unchanged over 1 h. These data show that human D is catabolized by the kidney via glomerular filtration and reabsorption by the proximal nephron. Reabsorption of D appears to be a saturable process.

Segmental chloride and fluid handling during correction of chloride-depletion alkalosis without volume expansion in the rat.

To determine whether chloride-depletion metabolic alkalosis (CDA) can be corrected by provision of chloride without volume expansion or intranephronal redistribution of fluid reabsorption, CDA was produced in Sprague-Dawley rats by peritoneal dialysis against 0.15 M NaHCO3; controls (CON) were dialyzed against Ringer's bicarbonate. Animals were infused with isotonic solutions containing the same Cl and total CO2 (tCO2) concentrations as in postdialysis plasma at rates shown to be associated with slight but stable volume contraction. During the subsequent 6 h, serum Cl and tCO2 concentrations remained stable and normal in CON and corrected towards normal in CDA; urinary chloride excretion was less and bicarbonate excretion greater than those in CON during this period. Micropuncture and microinjection studies were performed in the 3rd h after dialysis. Plasma volumes determined by 125I-albumin were not different. Inulin clearance and fractional chloride excretion were lower (P less than 0.05) in CDA. Superficial nephron glomerular filtration rate determined from distal puncture sites was lower (P less than 0.02) in CDA (27.9 +/- 2.3 nl/min) compared with that in CON (37.9 +/- 2.6). Fractional fluid and chloride reabsorption in the proximal convoluted tubule and within the loop segment did not differ. Fractional chloride delivery to the early distal convolution did not differ but that out of this segment was less (P less than 0.01) in group CDA. Urinary recovery of 36Cl injected into the collecting duct segment was lower (P less than 0.01) in CDA (CON 74 +/- 3; CDA 34 +/- 4%). These data show that CDA can be corrected by the provision of chloride without volume expansion or alterations in the intranephronal distribution of fluid reabsorption. Enhanced chloride reabsorption in the collecting duct segment, and possibly in the distal convoluted tubule, contributes importantly to this correction.

Volume-independent reductions in glomerular filtration rate in acute chloride-depletion alkalosis in the rat. Evidence for mediation by tubuloglomerular feedback.

We have recently described reduced superficial nephron glomerular filtration rate (SNGFR) in chloride-depletion alkalosis (CDA) without volume depletion. To elucidate the mechanism of this phenomenon, we studied three degrees of increasing severity of CDA (groups CDA-1, 2, and 3) produced by one or two peritoneal dialyses against 0.15 M NaHCO3 and electrolyte infusions of different Cl and HCO3 content in Sprague-Dawley rats; control rats (CON) were dialyzed against and infused with Ringers-HCO3. Extracellular fluid (ECF) volume was assessed by blood pressure, hematocrit, plasma protein concentration, and 125I-albumin space; none of these variables differed among the four groups. Micropuncture of the latest proximal and earliest distal convolutions was carried out. As CDA intensified from CON to CDA-3 (plasma tCO2 25 +/- 1 to 43 +/- 1 meq/L; P less than 0.01), distally determined SNGFR declined progressively (40.9 +/- 1.7 to 28.3 +/- 1.8 nl/min; P less than 0.01), while in early distal tubule fluid, flow rate (8.6 +/- 0.7 to 3.4 +/- 0.6 nl/min) and Cl concentration (36 +/- 2 to 19 +/- 3 meq/L) decreased and osmolality (110 +/- 5 to 208 +/- 12 mosmol/kg) increased (P less than 0.01), and, in the loop segment, Cl reabsorption decreased progressively (2,009 +/- 112 to 765 +/- 128 peq/min; P less than 0.01). In early distal tubule fluid, Cl concentration correlated positively and osmolality negatively with distally determined SNGFR (P less than 0.05). Proximally determined SNGFRs did not differ among the four groups. Proximal tubule stop-flow pressure responses to increasing rates of orthograde perfusion of the loop segment from 0 to 40 nl/min did not differ between groups CON and CDA-2. We interpret these data to show that reductions in SNGFR in CDA in the rat can occur by tubuloglomerular feedback (TGF) in the absence of differences in ECF volume or of alterations in TGF sensitivity during metabolic alkalosis. Of the proposed signals for TGF sensed by the macula densa, distal tubule fluid osmolality or some related variable is the signal most compatible with our data.

Differential nephrotoxicity of low molecular weight proteins including Bence Jones proteins in the perfused rat nephron in vivo.

To investigate the pathogenetic mechanisms of tubule nephrotoxicity of low molecular weight proteins (LMWP), proximal tubules (PT) of rats were perfused in vivo with artificial tubule fluid (ATF) containing one of five LMWPs: three human Bence Jones proteins (BJP), beta-lactoglobulin (BLG), and rabbit myoglobin (MYG). Volume (JV), chloride (JCl) and glucose (JG) fluxes in these perfused PTs were compared with those determined using ATF alone. In separate experiments, perfused nephrons were examined with electron and immunoelectron microscopy. After exposure to BJP1 or BLG, JV, JCl, and JG were less (P less than 0.05) than corresponding control fluxes. Cell damage of these perfused PTs, along with cellular debris in the distal tubules, was prominent. The PT lysosomes often appeared atypical and contained crystals. In contrast, perfusion with BJP2, BJP3, or MYG did not alter JV, JCl, or JG. These findings were corroborated by the normal ultrastructure of these PTs despite immunohistochemical evidence of endocytosis of the BJPs. Isoelectric point, molecular form, and isotype were not factors associated with PT damage. In addition, proteins with pI less than 7.4 precipitated in the distal nephron, forming acellular casts. Thus, certain nephrotoxic LMWPs damaged the PT, while others precipitated in the distal tubule, obstructing the nephron. These two pathogenetic mechanisms may independently be responsible for tubulointerstitial nephropathy of LMWPs in humans.

Circulating immune complexes and immunoglobulin A rheumatoid factor in patients with mesangial immunoglobulin A nephropathies.

Circulating immune complexes (CIC) containing IgA and C3 were elevated in 48% of IgA nephropathy patients; IgA1 was the predominant subclass. IgA1-IgG CIC were detected in 44%, IgA2-IgG CIC in 7%, and IgM-IgA1 CIC in 16% of the patients. No IgM-IgA2 CIC were detectable. Sucrose gradient ultracentrifugation indicated that IgG-IgA1 CIC were predominantly of intermediate (13-19S) size whereas IgA1-C3 CIC sedimented from 11S to 19S. At acid pH, isolated CIC revealed the presence of substantial amounts of 7S IgA. One third of the patients had elevated serum IgA rheumatoid factor (RF) of both polymeric and monomeric forms despite normal levels of IgM-RF; 87% of patients with elevated IgA-RF had IgA1-IgG CIC. These results indicate that the IgA1 component of CIC in patients with IgA nephropathy is not necessarily of mucosal origin and suggest that a portion of these CIC consists of IgA RF immunologically complexed with autologous IgG.

Primary aldosteronism presenting as myoglobinuric acute renal failure.

Hypokalemia is an uncommon cause of rhabdomyolysis with acute tubular necrosis. We recently treated a patient in whom severe hypokalemia attributed to diuretic therapy antedated acute myoglobinuric renal failure by six months. After recovery, hypokalemia persisted and subsequent evaluation disclosed primary aldosteronism. This case is a unique presentation for primary aldosteronism and illustrates the importance of diagnosis before treatment in hypertension as well as the hazards of hypokalemia.

Renin and aldosterone in the cardiomyopathic hamster in congestive heart failure.

The renin-aldosterone system was studied in cardiomyopathic hamsters (CMH) before and after the onset of untreated clinical congestive heart failure. Age-matched random-bred hamsters (RB) served as controls. Before heart failure, there were no differences in body weight accretion, sodium balance, plasma renin activity or in vitro aldosterone production. After the onset of heart failure in CMH, body weight increased at a greater rate than in RB and positive sodium balance was nearly twice control levels. Although plasma renin activity was greater (P less than 0.005) in CMH than in RB (23.4+/-4.2 (mean+/-SEM) vs. 3.8+/-1.8 ng/ml/h), aldosterone production (101+/-15 vs. 95+/-16 ng/h) did not differ. Plasma aldosterone was low or undetectable in RB and in CMH in heart failure. In response to angiotensin stimulation, aldosterone production increased in both strains and did not differ. No difference in muscle potassium content, potassium balance or excretion was detected. Thus, in CMH, congestive heart failure is attended by increased plasma renin activity without a significant increase in aldosterone production, a dissociation which does not appear to be due to adrenal unresponsiveness to angiotensin II or to potassium depletion.

On the mechanism by which chloride corrects metabolic alkalosis in man.

To determine whether administration of chloride corrects chloride-depletion metabolic alkalosis (CDA) by correction of plasma volume contraction and restoration of glomerular filtration rate or by an independent effect of chloride repletion, CDA was produced in normal men by the administration of furosemide and maintained by restriction of dietary sodium chloride intake. Negative sodium balance (-112 +/- 16 meq) and reduced plasma volume (2.53 versus 2.93 liters, p less than 0.05) developed. The cumulative chloride deficit of 271 +/- 16 meq was then repleted by oral potassium chloride (267 +/- 19 meq) over 36 hours with continued serial measurements of glomerular filtration rate, effective renal plasma flow, plasma volume, body weight, and plasma renin and aldosterone levels. CDA was corrected, even though body weight, plasma volume, glomerular filtration rate, and renal plasma flow all remained reduced and plasma aldosterone was elevated; urinary bicarbonate excretion increased during correction. Administration of an identical potassium chloride load to similarly sodium-depleted but not chloride-depleted normal subjects produced no change in acid-base status. It is concluded that chloride repletion can correct CDA by a renal mechanism without restoring plasma volume or glomerular filtration rate or by altering sodium avidity.

Acute cryoglobulinemic renal failure after intravenous infusion of gamma globulin.

A 39-year-old woman had mixed IgM/IgG cryoglobulinemia, but was later found to have a lymphoma that produced an IgM kappa paraprotein with rheumatoid factor activity. With intermittent chlorambucil and prednisone therapy, the lymphoma was controlled for five years and she had no evidence of cryoglobulinemia. Because of the presence of intractable pulmonary infection and hypogammaglobulinemia G, she was given an intravenous infusion of gamma globulin. Within 72 hours, renal failure and a sustained decrease in serum concentrations of IgM and IgG began concurrently. A kidney biopsy specimen obtained five days after the infusion showed hyaline "thrombi" in numerous glomerular capillaries and glomerular necrosis, consistent with acute, severe mixed cryoglobulinemic nephropathy. Immunostaining showed strong positivity for IgM, IgG, and light chains in glomerular capillary lumina and subendothelial sites; immunostaining with a monoclonal antiidiotypic antibody specific for the patient's paraprotein established the presence of the rheumatoid factor paraprotein in the deposits. These observations strongly suggest that complexes consisting of IgM kappa rheumatoid factor, IgG, and complement initiated the renal damage. Therefore, demonstrable serum rheumatoid factor activity in patients with B cell neoplasms should be considered a contraindication to the administration of intravenous gamma globulin.

Goodpasture's syndrome in a patient with the Nail-Patella syndrome.

A patient with the nail-patella syndrome in whom end-stage renal failuure developed as the result of Goodpasture's syndrome is described. Lesions characteristic of both rare diseases were seen on renal morphology. It is postulated that the glomerular membrane alteration of the nail-patella syndrome predisposed to the development of antiglomerular basement membrane antibody and hence Goodpasture's syndrome. A review of the incidence of renal failure in the nail-patella syndrome suggests that renal involvement can no longer be regarded as benign and that immune mechanisms may be related to progressive renal disease in some cases.

Hemodialysis and kidney transplantation in a patient with glucose phosphate isomerase deficiency.

End stage failure in a patient with congenital hemolytic anemia attributable to glucose phosphate isomerase deficiency was treated successfully with maintenance hemodialysis and renal transplantation. Increased transfusion requirements, intolerance to immunosuppressive agents, and frequent infections were not encountered. Induction of the deficient erythrocyte enzyme by renal transplantation was not expected or realized.

Economics of an academic renal division: an approach.

Nephrology divisions work within the systems and constraints of a department of medicine in a college of medicine, and in an increasing number of cases, also within a larger health care delivery system. Key to the division's stability are a consistently applied practice pan, how the tenure and clinical track systems function, how teaching funds are distributed, mechanisms of incentive for the division, and its faculty and the ability to establish and maintain reasonable financial reserves, especially for investment in research. Dialysis, transplantation, hypertension, research, and the teaching of medical students, residents, and fellows are the key elements the divisional organization must address. Incentives for faculty performance should be included in all of these areas. The division director must recognize his or her control of earning capacity in the distribution of responsibilities; financial returns as compared with effort involved vary considerably. Three main problems confront the future of our divisions: manpower shortages in nephrology; the effects of managed care systems on nephrology practice; and the future existence and success of departments of internal medicine and academic health centers.

Malacoplakia of the kidney: apparent improvement following medical management.

Malacoplakia of the kidney is a rare histopathologic entity of unknown etiology. Patients may present with a renal mass or with urinary tract infection. The prognosis has been uniformly poor excepting in those patients with unilateral involvement treated by nephrectomy. A 31 year old woman presented with acute renal failure and pyelonephritis. Renal biopsy revealed an interstitial infiltrate of large histiocytic cells with intracytoplasmic PAS-positive granules and calcospherules, findings consistent with malacoplakia. Following antibiotic treatment and dialysis, the patient has had a gradual improvement in renal function.

Serum complement proteins in IgA nephropathy.

Immunohistologic studies in IgA nephropathy which have suggested activation of the alternative complement pathway prompted us to study serum complement components and control proteins in 28 patients with IgA nephropathy. Thirteen patients, 12 of whom were men, had or developed chronic renal failure (CRF) during 34 +/- 5 months of follow-up. These patients were more hypertensive and had heavier proteinuria than those with stable renal function. Their serum IgA concentrations were not different from patients with normal renal function. The prevalence of HLA antigens was similar to that for the reference population and BW35 was not associated with CRF. Serum C3, B, H and I concentrations in patients with stable normal renal function were higher than they were in patients with CRF. Four patients studied--two with normal renal function and two with CRF--had partial familial deficiencies of single complement proteins. Our data suggest that high serum levels of C3, B, H and I may be associated with stable normal glomerular filtration rate and that complement deficiencies are not infrequent in IgA nephropathy. How these findings relate to the pathogenesis and progression of IgA nephropathy requires further study. We also conclude that higher serum IgA concentrations and the presence of BW35 are not necessarily associated with progressive renal insufficiency in IgA nephropathy.

Prevalence of hypertension in a renal transplant population on alternate-day steroid therapy.

A study of the prevalence of hypertension in a group of renal transplant patients on alternate-day maintenance steroid therapy was conducted. Twenty-four percent of the transplant clinic population was hypertensive. The factors that were associated with a lower prevalence of hypertension were good graft function, bilateral nephrectomy of the patients' own diseased kidneys (although the majority of our patients without bilateral nephrectomy are normotensive), and use of a living related donor. We conclude that the prevalance of hypertension in transplant patients on alternate-day steroid therapy is low. In the presence of all these favorable factors, only 6% of allograft recipients were hypertensive.

Conservative management of chronic renal failure.

Failing kidneys can play havoc with other parts of the body. Specific treatment of these associated problems may help ward off uremia and preserve whatever renal function remains. Sodium levels may drop if too much water is mistakenly given to counteract kidney failure. Hyperkalemia can lead to cardiac arrest if potassium levels aren't reduced without delay. Acidosis also may reach life-threatening proportions, especially if diarrhea occurs. Almost all patients with chronic renal failure have a bleeding tendency and anemia, with the hematocrit dipping as low as 20 percent. Over half have decreased tolerance to carbohydrares, although severe hyperglycemia is rare. Disorders of calcium metabolism also are common, ranging from asymptomatic hypocalcemia to osteomalacia. The kidneys' impaired filtration ability should be kept in mind when drugs are prescribed. Dosages may need to be cut to avoid an adverse reaction.