Thomas O. Pitts

Diabetic Nephropathy: Natural Course, Survivorship and Therapy

Diabetes mellitus is a disease with major social and economic consequences. End-stage renal disease (ESRD) due to diabetes occurs in as many as 30% of patients with juvenile diabetes, providing a large percentage (up to 33%) of all patients in need of therapy for ESRD. We have reviewed the natural course of the nephropathy in type I diabetes mellitus and the results of dialysis and transplantation therapy with particular regard to survival and morbidity. Comparisons of the survival of diabetic patients among peritoneal dialysis, hemodialysis, and transplantation are complicated by the lack of sufficient data for peritoneal dialysis and by the bias introduced by patient/treatment selection methods. Presently, it appears that transplantation with a living related donor graft offers the best survival for both graft and patient, with a definite reduction of morbidity associated with the complications of diabetes. Cadaveric transplantation is approximately the equivalent of hemodialysis in patient survival at 1 year and also appears to offer a somewhat diminished morbidity. Peritoneal dialysis data are sparse and skewed by patient selection. However, there is some emerging evidence that therapy with this modality may be associated with a delay in progression of retinopathy, when compared with hemodialysis.

Disorders of Divalent Ions and Vitamin D Metabolism in Chronic Alcoholism

This chapter reviews the pathogenesis of disordered divalent mineral and bone metabolism in alcoholism, emphasizing the role of impaired vitamin D physiology. Normally, vitamin D metabolites are derived principally from cholecalciferol, which is synthesized in the skin via the energy of sunlight. Most alcoholics have subnormal levels of 25-hydroxyvitamin D [25(OH)D]. Those with Laennecs cirrhosis also have low levels of vitamin D binding protein due to impaired hepatic protein synthesis and as a result, have low serum concentrations of total, but not free, 1,25-dihydroxyvitamin D. The causes of 25(OH)D deficiency in alcoholics include reduced hepatic 25-hydroxylase activity, lack of sun exposure, inadequate dietary intake, and malabsorption. Hypomagnesemia and hypophosphatemia, which are very common in hospitalized alcoholics, result from deficient intake, malabsorption, excessive renal losses, and cellular uptake of both ions. Hypocalcemia in alcoholics is caused primarily by hypoalbuminemia but can result also from deficient intake, malabsorption, hypomagnesemia, and renal calcium wastage. Low vitamin D activity may contribute significantly to the calcium and phosphate deficiencies. Osteoporosis is extremely common in alcoholics whereas osteomalacia is exceptional. However, both bone disorders respond well to vitamin D therapy. Thus, alcoholics should be screened periodically for vitamin D deficiency and osteopenia, and when either is detected they should receive vitamin D supplements.

Acute Renal Failure Due to High-Grade Obstruction Following Therapy With ϵ-Aminocaproic Acid

An 18-year-old man with mild factor VIII deficiency developed hematuria and, subsequently, acute renal failure due to high-grade urinary obstruction by clots during therapy with cryoprecipitate, ϵ-aminocaproic acid, and acetazolamide administered for ocular trauma. Discontinuation of therapy with the latter two agents and induction of a brisk diuresis with intravenous (IV) fluid therapy resulted in return of renal function concomitant with spontaneous clot passage. A review of previous literature suggests that hemophiliacs may be more susceptible than nonhemophiliacs to high-grade urinary obstruction due to clot formation when ϵ-aminocaproic acid is administered during episodes of hematuria. Acute flank pain, fever, and delayed dense nephrograms on IV pyelogram are characteristic of the syndrome and distinguish it from other forms of acute renal failure associated with ϵ-aminocaproic acid.

Inhibitory effects of volume expansion performed in vivo on transport in the isolated rabbit proximal tubule perfused in vitro.

To examine the renal tubular sites and mechanisms involved in the effects of hypooncotic volume expansion (VE) on renal electrolyte excretion, we performed clearance and isolated tubular perfusion studies using intact and thyroparathyroidectomized (TPTX) rabbits. We also examined the effect of VE on luminal brush border transport. In the microperfusion studies, proximal convoluted (PCT) and straight (PST) tubules were taken from rabbits without prior VE or after 30 min of 6% (body wt) VE. Acute VE increased the percentage excretion of Na, Ca, and P in TPTX animals and the percentage and absolute excretions of these ions in intact rabbits. In PST from VE animals, fluid flux (Jv) was depressed compared with Jv in PST from nonVE rabbits: Jv = 0.18 +/- 0.03, (VE) vs. 0.31 +/- 0.03 nl/mm.min, (nonVE) P less than 0.02. Phosphate transport (Jp) in the PST from VE animals was also depressed: JP = 1.58 +/- 0.10 (VE) vs. 2.62 +/- 0.47 pmol/mm.min, (nonVE) P less than 0.05. Similar results were obtained with TPTX animals. In the PCT from VE animals, Jv was decreased (0.49 +/- 0.10 (VE) vs. 0.97 +/- 0.14 nl/mm.min, (nonVE) P less than 0.02), but JP was not affected significantly. Transport inhibition was stable over approximately 90 min of perfusion. In the brush border vesicle studies, sodium-dependent phosphate transport was inhibited compared with that in control animals, at the 9-, 30-, and 60-s time points. These findings indicate that the inhibition of renal ionic transport by VE occurs in both PCT and PST and is, in part, the result of a direct effect of VE on tubular transport mechanisms.

Disorders of the Serum Electrolytes, Acid-Base Balance, and Renal Function in Alcoholism

This chapter reviews the disturbances of the serum sodium and potassium concentrations, acid-base imbalances, and acute renal dysfunction that are seen frequently in alcoholic patients. The hyponatremia common in decompensated cirrhotics is caused by an impairment of renal free water clearance and concomitant water ingestion. Excessive proximal renal tubular sodium reabsorption and nonosmotic vasopressin release underlie the defect in renal water excretion in cirrhosis. Restriction of water intake is the principal therapeutic measure for hyponatremia. Hypokalemia is common in alcoholics but when observed does not always represent true potassium depletion. Although most cirrhotics have a diminished total body potassium content, intracellular potassium concentration is usually normal. In some patients gastrointestinal and renal potassium losses and nutritional potassium deficiency may cause true potassium depletion. Respiratory and metabolic alkalosis are the acid-base disturbances seen most frequently in alcoholics. Acidosis is relatively uncommon and is usually due to renal insufficiency, lactic acid or keto-acid accumulation. Toxin ingestion (methanol, ethylene glycol, or isopropanol) may also cause severe acidosis. Rhabdomyolysis, common in severe alcoholism, may produce various electrolyte disturbances and acute renal failure. The prognosis for recovery is good although temporary dialysis may be necessary.

Urinary Tract Infections and Renal Papillary Necrosis in Alcoholism

An enhanced frequency and morbidity of urinary tract infections (UTI) have been observed in association with alcoholism and liver disease. The causes of these phenomena may relate, in part, to the defects in humoral and cellular immune mechanisms that occur in alcoholism. Urinary catheterization is the most common cause of UTI in hospitalized alcoholics. The severity of the sequelae of UTI in alcoholism is demonstrated by the unusually frequent occurrence of renal papillary necrosis (RPN) in conjunction with pyelonephritis in these patients. Indeed, in over 90% of the reported cases of RPN occurring with alcoholism or liver disease, pyelonephritis has been a contributing factor. The proclivity to medullary ischemia and RPN in this patient group may be, at least in part, a result of interstitial renal edema secondary both to infection and the effect of ethanol per se and to renal arterial vasoconstriction that occurs in cirrhosis. The frequency with which death due to sepsis or renal failure occurs in association with UTI in alcoholics obliges the physician to exercise caution in the prevention and treatment of UTI in these patients.

The Effects of Atrial Natriuretic Peptide on Whole-Kidney and Proximal Straight Tubular Function in the Rabbit

Abstract The mechanisms by which atrial natriuretic peptide (ANP) produces a diuresis and natriuresis remain unclear. It has been suggested that the major if not sole mediator of ANPs renal effects is a hemodynamically induced increase in glomerular filtration rate (GFR). Data from clearance studies in anesthetized rabbits demonstrate that ANP administration can produce a significant increase in absolute and percentage sodium excretion (42.0 ± 5.9 → 64.6 ± 10.2 μeq/min, P < 0.01, and 1.97 ± 0.28 → 3.12 ± 0.35%, P < 0.001, respectively) without increasing GFR (16.8 ± 2.1 → 16.1 ±2.5 cc/min, P > 0.30). The natriuresis occurred despite a fall in renal plasma flow (RPF) (56.7 ± 7.0 → 44.5 ± 9.4 cc/min, P < 0.01), a rise in filtration fraction (0.33 ± 0.01 → 0.46 ± 0.05, P < 0.01), and an unchanged filtered load of sodium (2.28 ± 0.27 → 2.16 ± 0.32 μeq/min, P > 0.10). Isolated tubular microperfusion studies demonstrated that ANP, present as a 10−9 M concentration in the solution bathing perfused proximal straight tubules (PST), did not affect fluid flux (J v) (0.38 ± 0.07 → 0.41 ± 0.07 nl/mm/min, P > 0.30) or phosphate reabsorption (J p) (1.50 ± 0.5 → 1.38 ± 0.36 pmole/mm/min, P > 0.50). When ANP was infused into rabbits prior to harvesting the PSTs for isolated tubular microperfusion and the results were compared to tubules taken from control animals, there was again no effect on J v (0.37 ± 0.05 vs 0.42 ± 0.05 nl/mm/min, P > 0.50) or J p (2.41 ± 0.27 vs 2.42 ± 0.44 pmole/mm/min, P > 0.90). These findings suggest that ANP can inhibit sodium transport without increasing whole-kidney GFR or RPF, but does not directly inhibit transport in the proximal straight tubule.

The pathogenesis of renal sodium retention and ascites formation in Laennec's cirrhosis.

This chapter critically reviews our current understanding of the pathogenesis, clinical syndrome, and therapy of the disturbances of renal sodium handling, renal perfusion, and glomerular filtration rate that occur in patients with Laennecs cirrhosis. Avid renal sodium reabsorption, a characteristic feature of cirrhosis, occurs independent of moderate changes in renal function and precedes the onset of ascites. The initiation of sodium retention may be a direct consequence of the hepatic disease process and may also result from defective intravascular filling. In the presence of ascites the most important sodium retaining signal is a defective intravascular volume. The principal effectors of renal sodium retention and vasoconstriction are stimulation of the renin-angiotensin-aldosterone axis and augmentation of renal sympathetic nerve activity. Deficient production of natriuretic hormone(s) and endogenous renal vasodilators, such as prostaglandins and kinins, also contributes to the sodium retention and renal hypoperfusion seen in cirrhosis. The hepatorenal syndrome is an extreme imbalance in these renal vasoconstrictor and vasodilator forces. In the therapy of ascites in Laennecs cirrhosis, abstention from alcohol, sodium restriction, and cautious diuresis are the principal therapeutic measures. A grave prognosis accompanies the diagnosis of the hepatorenal syndrome although recoveries have been reported.