Familial collapsing focal segmental glomerulosclerosis.

The majority of patients with non-HIV-related collapsing focal segmental glomerular sclerosis (FSGS) have idiopathic disease. Only a few genetic forms associated with rare syndromes have been described in families. Here we report two families with multiple members who have collapsing FSGS with no clear associated secondary etiology. Genetic analysis revealed a defect in the TRPC6 gene in one family, but excluded all known common inherited podocyte defects in the other family. The course and response to treatment differed dramatically among members of the same family.

Recurrent focal segmental glomerulosclerosis in the renal allograft: single center experience in the era of modern immunosuppression.

FSGS is an important cause of ESRD and tends to recur in allografts (rFSGS). Older series suggest recurrence rates of 30-60%. In the modern era of transplant immunosuppression, recurrence rates are unknown. There are also few data regarding prevalence of known genetic mutations in adult FSGS patients who undergo transplantation. Recently, FSGS has been subdivided into histological variants, which may predict renal outcomes; there is little information on patterns of recurrence and outcomes in these variants. Finally, treatment for rFSGS relies upon up-titrating calcineurin inhibitors and plasmapheresis. Insufficient information exists on the use of these regimens for rFSGS in the era of modern immunosuppression. We conducted a retrospective chart review involving all renal transplant recipients at Columbia University Medical Center from December 1999 to March 2007. Those with biopsy confirmed primary FSGS were included and information regarding baseline characteristics, histologic variants, genetics, treatment, and clinical outcomes were collected. FSGS recurred in 23% of patients. Those with collapsing histology on native kidney biopsy, tended to recur with the same histology. No known genetic mutations were identified among those with recurrence. Plasmapheresis resulted in complete or partial remission in 75% of those with recurrence. Recurrent FSGS resulted in a trend toward the combined outcome of ESRD or death compared to those without recurrence (27% vs. 12%). Modern immunosuppression does not reduce the rate of rFSGS, known genetic mutations are uncommon in such adult patients, collapsing FSGS tends to recur with the same histology, and plasmapheresis may be helpful in the treatment of recurrence.

The treatment of acute interstitial nephritis: More data at last.

Acute interstitial nephritis (AIN) is an uncommon form of acute renal failure that is usually medication related. Although the clinical features and renal histopathology are well recognized, therapy beyond discontinuing the offending drug has been a challenge. The use of corticosteroids, although supported by numerous small retrospective studies and anecdotal case reports, has been controversial. The study by González et al., although it has limitations, provides solid support for the early use of corticosteroids in the treatment of drug-related AIN.

Detection and management of early diabetic nephropathy.

It has proven difficult to alter the progression of diabetic nephropathy once overt proteinuria is established. The presence of microalbuminuria reflects an early renal lesion that may be more amenable to therapeutic intervention. Dietary protein restriction, improved glycemic control, and aggressive treatment of high blood pressure all have shown beneficial effects in some patients. Angiotensin-converting enzyme inhibitor therapy may offer specific advantages in terms of its renal protective effects.

Primary hyperparathyroidism and benign monoclonal gammopathy.

Three patients had primary hyperparathyroidism and monoclonal serum immunoglobulins. Although multiple myeloma was suspected in each case, subsequent evaluation was consistent with a "benign monoclonal gammopathy". Parathyroid adenomas were removed from two patients. The three patients are presented and compared to the four other cases that have been reported previously. The association between primary hyperparathyroidism and benign monoclonal gammopathy is discussed in terms of possible pathogenetic mechanisms. Primary hyperparathyroidism should be suspected in patients with hypercalcemia and benigh monoclonal gammopathy, as well as in other conditions, like multiple myeloma, that are known to be associated with hypercalcemia.

Acute interstitial nephritis associated with carbenicillin therapy.

Although acute interstitial nephritis has been documented during therapy with many antibiotics of the penicillin class, it has not previously been reported in association with carbenicillin therapy. We report here the case of a patient who developed the characteristic clinical features of this form of injury while receiving prolonged large doses of carbenicillin. Histologic examination confirmed the presence of a striking interstitial nephritis. Carbenicillin should be considered a potential cause of renal damage in patients who develop rash, eosinophilia, and microscopic hematuria in association with deterioration of renal function.

Kinetics of intravenous mezlocillin in chronic hemodialysis patients.

The kinetics of intravenous mezlocillin was studied in 8 patients with creatinine clearances under 7 ml/min who were undergoing chronic hemodialysis. Kinetic parameters were determined using a 2-compartment linear model. The mezlocillin serum half-life (t 1/2) in these patients ranged from 2.9 to 7.8 hr (mean, 5.4). The t 1/2 decreased to 1.57 +/- 0.09 hr during dialysis. Approximately 18% of the dose was recovered in the dialysate in 4 hr of dialysis. There was a 30% reduction per hour in serum concentration. The kinetics of mezlocillin, due to removal by nonrenal mechanisms, more closely resemble the kinetics of penicillin G and ampicillin than of carbenicillin and ticarcillin. A dosage schedule for use of intravenous mezlocillin in patients undergoing hemodialysis is presented.

Kinetics of intravenous amoxicillin in patients on long-term dialysis.

The kinetics of intravenous amoxicillin was studied in 8 patients with creatinine clearances of less than 7 ml/min who were on long-term hemodialysis. Kinetic parameters were determined using a 2-compartment linear model. The serum half-life (t1/2) of amoxicillin in these patients ranged from 7.5 to 21 hr. The t1/2 fell to 2.84 +/- 0.45 hr during dialysis. Approximately 30% of the dose was recovered in the dialysate during 4 hr of dialysis and there was a 25% reduction per hour in serum concentration. We present a dosage schedule for intravenous amoxicillin in patients with reduced renal function who are undergoing hemodialysis.

Aminoglycoside nephrotoxicity.

The high incidence of associated nephrotoxicity represents an important concern in the use of aminoglycoside antibiotics, which have been implicated as one of the primary causes of drug-induced acute renal failure. Several factors, including the underlying health of the patient, criteria used to define nephrotoxicity, and the specific aminoglycoside administered, may contribute to the nephrotoxic potential of these agents. The development of aminoglycoside-induced nephrotoxicity is a complex problem. These drugs appear to be only minimally metabolized within the body and undergo nearly exclusive renal excretion, primarily by glomerular filtration. Ultimately, reabsorption and accumulation within the kidney results in proximal tubular cell damage; several possible mechanisms have been proposed, both for the development of such cell damage and for its subsequent role in the evolution of nephrotoxicity. The pathology and the clinical pattern of aminoglycoside-induced kidney damage have been extensively studied in animal models and in humans. Although the data often conflict, many of these studies have attempted to identify some of the factors associated with a higher risk for aminoglycoside nephrotoxicity. Of the factors generally agreed upon to influence risk, correction of volume depletion and diminished renal perfusion, as well as dose adjustment for level of renal function, have been identified as critical measures for prevention of renal damage by aminoglycosides. Recent studies have indicated that newer agents, such as third-generation cephalosporins and aztreonam, often may be as therapeutic and cost-effective as the aminoglycosides without the nephrotoxicity associated with the latter agents.(ABSTRACT TRUNCATED AT 250 WORDS)

The syndrome of multiple endocrine gland insufficiency.

Addison's disease, when caused by idiopathic atrophy of the adrenal cortex, is frequently associated with other endocrine abnormalities. Primary hypothyroidism and hypogonadism have been reported in association with adrenal insufficiency; understandably, such cases may lead to diagnostic confusion with respect to possible pituitary disease. This case study concerns a woman who exhibited, in sequence and over a period of 17 years, hypogonadism, hypoadrenalism, diabetes mellitus and, finally, hypothyroidism. Originally misdiagnosed as having Sheehan's syndrome, she eventually became hyperpigmented. The true nature of her illness was then revealed to be primary insufficiency of multiple endocrine glands, with the demonstration of elevated levels of several pituitary hormones. Because multiple endocrine insufficiencies may coexist or develop with time, we suggest that a patient with a single documented endocrine deficiency be investigated initially and serially for additional glandular deficiencies.

The hyperlipidemia of the nephrotic syndrome.

Lipid abnormalities in patients with the nephrotic syndrome have long been recognized. However, the significance of these lipid abnormalities, the mechanisms producing them, and their potential treatment have all been a cause of debate. Recent data have helped clarify each of these areas of controversy. Studies of the lipoprotein abnormalities of patients with the uncomplicated nephrotic syndrome have shown that many will have elevated levels of total and low-density lipoprotein cholesterol, whereas only a few will have elevated levels of high-density lipoprotein cholesterol. If these lipid abnormalities have the same significance in this population as in other populations studied, then some patients with unremitting nephrotic syndrome will be at high risk for cardiovascular disease. The elevated cholesterol levels noted in the nephrotic syndrome are caused primarily by enhanced hepatic synthesis, with lesser contributions by decreased clearance and altered enzyme activities. The signal for enhanced hepatic lipogenesis may relate to changes in plasma albumin concentration, plasma oncotic pressure, a local effect of viscosity at the hepatic sinusoidal level, or a loss of urinary proteins or other liporegulatory substances. Recently, a number of short-term studies in nephrotic patients have documented the safety and efficacy of lipid-lowering drugs such as the bile acid-binding resins, probucol, and the HMGCoA (hydroxymethylglutaryl coenzyme A) reductase inhibitors.

Course and prognosis of human immunodeficiency virus-associated nephropathy.

PURPOSE: Patients infected with the human immunodeficiency virus (HIV) have been described to have an unusual form of renal disease known as HIV-associated nephropathy. This condition is characterized by severe proteinuria, rapid progression to renal insufficiency, and a morphologic pattern of focal segmental glomerulosclerosis (FSGS) on renal biopsy. Despite increasing awareness of this entity, the epidemiology and clinical course of HIV-associated nephropathy are not yet well defined. We therefore decided to study HIV-infected patients with this biopsy-proven pattern of focal sclerosis. PATIENTS AND METHODS: Using life-table analysis, we evaluated the clinical features and course of 26 patients with HIV infection and biopsy-proven FSGS and compared them with those in 24 subjects with HIV infection who had no glomerular disease at autopsy. RESULTS: The group with FSGS had a higher percentage of blacks (96% versus 46%) and intravenous drug abusers (42% versus 17%), and had a higher mean serum creatinine level (5.4 mg/dL versus 1.0 mg/dL) than the group of HIV-infected subjects without glomerular disease. At the time of diagnosis of FSGS, six patients had clinical acquired immunodeficiency syndrome (AIDS), eight had AIDS-related complex (ARC), and 12 patients had no evidence of AIDS or ARC. The progression to end-stage renal disease for all patients was rapid, with a median time to dialysis of 10.9 weeks. Duration of patient survival was dependent upon the stage of HIV infection at the time of diagnosis of renal disease. Patients who presented with AIDS had a median survival of 1.9 months, compared to a median survival of 3.6 months for those with ARC and 9.7 months for initially asymptomatic HIV carriers (p less than 0.05). Fifteen patients either presented with or developed AIDS during the course of the study, and all died as a consequence of their immunodeficiency. Survival curves from the diagnosis of AIDS to death were similar in the group with HIV-associated nephropathy (7.3 weeks) compared to the control AIDS group without renal disease (6.9 weeks). CONCLUSION: Our data indicate that FSGS associated with HIV infection can occur before other manifestations of AIDS, is more common in blacks and in intravenous drug abusers, and is rapidly progressive to uremia. Patient survival is dependent upon the stage of HIV infection. These findings may prove useful in devising more effective strategies for the care of this growing patient population.

Nephrotic syndrome and immune complex glomerulonephritis associated with chlorpropamide therapy.

Therapeutic drugs are well-recognized as a cause of the nephrotic syndrome in humans. However, documentation of the renal histopathologic features is lacking or incomplete in many cases. Even when accurate histopathologic information is available, there is little evidence to support a specific pathogenetic mechanism of renal injury in the vast majority of cases. We describe a patient with diabetes who had hepatitis and dermatitis in association with the use of chlorpropamide. In addition to these well-described toxic reactions to this drug, the nephrotic syndrome developed. Renal biopsy revealed the presence of a proliferative glomerulonephritis that was shown to be of an immune complex nature on immunofluorescence and electronmicroscopic study. Serial serum complement levels and circulating immune complex levels were consistent with an immunologically mediated reaction. Repeated renal biopsy documented resolution of the renal changes. Thus, in this patient, a drug-induced nephrotic syndrome was associated with a proliferative glomerulonephritis, probably due to the formation of immune complexes.

Acute renal failure in patients with multiple myeloma.

In the past, patients with multiple myeloma and acute renal failure have had a poor prognosis. Few patients recovered renal function and fewer still survived for prolonged time periods. This report describes the course of 10 patients with multiple myeloma and true acute renal failure treated during the decade 1970 to 1980, and reviews recent reports concerning this association. The use of radiographic contrast agents is no longer the primary predisposing factor to acute renal failure in the myeloma population. Rather, infection, hypercalcemia, and dehydration in the presence of light chain excretion are the major conditions precipitating the renal failure. Despite severe renal failure requiring dialysis, many patients may regain good renal function. Factors associated with a good or poor prognosis in this population are reviewed. The prognosis in patients with myeloma and acute renal failure has greatly improved in recent years, and prolonged survival may occur.

Long-term follow-up of patients with lupus nephritis. A study based on the classification of the World Health Organization.

The long-term course of 56 patients with systemic lupus erythematosus who had precisely defined renal histology and carefully assessed clinical status at the time of their initial renal biopsy prior to 1976 was evaluated and analyzed by life-table analysis. The average length of follow-up has now been greater than 10 years since initial biopsy. Patients with mesangial lesions (World Health Organization [WHO] classes IIA and IIB) had a more favorable renal and patient survival at five and 10 years than did patients in the other WHO classes (III, IV, and V). Individual renal histologic features of activity and chronicity when combined into an activity index and a chronicity index did not significantly predict renal survival in this population, nor did the presence of hypertension or renal dysfunction at the time of the initial renal biopsy significantly influence renal or patient survival. Patients with the nephrotic syndrome at initial biopsy had a poorer renal survival than did patients without the nephrotic syndrome. However, patients who experienced a remission of the nephrotic syndrome fared better in terms of both renal and patient survival than did those patients without a remission. By life-table analysis, patient survival was significantly better for patients in whom biopsy was performed after 1973 than for those in whom biopsy was performed prior to that time despite similar clinical features and WHO histology in each group interval. Our data suggest that improved survival for patients in recent studies may relate to better supportive care and more selective use of immunosuppressive therapy in patients with milder forms of lupus nephritis.

Use of mycophenolate mofetil in resistant membranous nephropathy.

Membranous nephropathy (MN) is a common cause of nephrotic syndrome. Optimal therapy for this disease is still debated. We report our experience using mycophenolate mofetil (MMF), an immunosuppressive agent widely used in transplant recipients, to treat 16 nephrotic patients with MN. All patients had biopsy-documented MN; secondary forms were ruled out. Fifteen patients had steroid-resistant disease; cytotoxic agents had failed in 6 patients and cyclosporine therapy had failed in 5 patients. Patients were treated with MMF (dose range, 500 to 2,000 mg) for a mean of 8 months. Six patients experienced a halving of proteinuria, which occurred after a mean duration of 6 months of therapy. Partial remissions occurred in 2 patients. There were no significant changes in mean values for serum creatinine, serum albumin, or proteinuria. Mean cholesterol levels were significantly less. Side effects of MMF were infrequent and generally mild. In summary, MMF appears to reduce proteinuria in some patients with idiopathic MN previously resistant to steroids, cytotoxic agents, or cyclosporine. Further trials with this agent are warranted.

Heavy chain deposition disease: the disease spectrum.

A 45-year-old white woman was found to have microscopic hematuria during her annual physical examination. After a negative urologic workup, she returned 5 months later with nephrotic syndrome, renal insufficiency, and hypocomplementemia. Renal biopsy showed a nodular sclerosing glomerulopathy that could not be further characterized because of inadequate tissue for immunofluorescence. The patient returned 8 months later with chronic renal failure. A repeat renal biopsy showed deposits composed of immunoglobulin G (IgG) heavy chain and complement components C3 and C1 along glomerular, tubular, and vascular basement membranes, with negativity for kappa and lambda light chains, findings consistent with heavy chain deposition disease (HCDD). The heavy chain subclass was exclusively IgG3. Staining with monoclonal antibodies to epitopes of the constant domains of IgG heavy chain showed a CH1 deletion, indicating a truncated heavy chain. On review of the previously reported cases of HCDD, common clinical presentations include nephrotic syndrome, renal insufficiency, hematuria, and, in some cases, hypocomplementemia. In most patients, the hematologic disorder is mild, without overt myeloma. Light microscopy shows a nodular sclerosing glomerulopathy, and heavy chain deposits are detectable within basement membranes throughout the kidney by immunofluorescence and electron microscopy. There is no effective treatment for this condition, and virtually all patients progress to chronic renal failure.

The renal and urologic complications of inflammatory bowel disease.

SUMMARY: : Extraintestinal manifestations of inflammatory bowel disease (IBD) are common. Clinically significant renal/urologic complications occur in 10-15% of patients with IBD. In this article, we review the incidence, pathogenesis, diagnosis, and management of the various renal/urologic complications. In general, renal/urologic complications in IBD may be directly related to the underlying intestinal disease process (acalculous hydronephrosis, fistula formation, abscess) related to metabolic consequences of the disease (urolithiasis) or to the medication used in the treatment of IBD. Less clearly understood complications include amyloidosis and glomerular disease. Renal/urologic complications of IBD represent a potential source of significant morbidity and mortality. Clinicians caring for patients with IBD should therefore be familiar with the various manifestations of these complications, as well as appropriate preventative measures and treatment.

Cyclosporine: nephrotoxic effects and guidelines for safe use in patients with rheumatoid arthritis.

Renal abnormalities occur frequently in patients with rheumatoid arthritis; they may be complications of the rheumatoid disease process itself (amyloidosis) or may result from various therapies including gold compounds, D-penicillamine, analgesics such as aspirin or phenacetin used long term, and nonsteroidal anti-inflammatory drugs. Cyclosporine, a highly effective immunosuppressive agent currently under investigation as a treatment for RA, is also known to produce renal dysfunction. Some forms of functional and structural tubular changes appear readily reversible. Others associated with renal vasculopathy and interstitial fibrosis can lead to irreversible nephrotoxicity. A clear understanding of the pharmacology, drug interactions, and types of renal side effects encountered with cyclosporine can lead to a reduction of adverse renal reactions. Similarly, an understanding of which patients are at high risk for renal dysfunction can lead to safer and more efficacious use of this potent immunosuppressive agent.

Renal pathology of human immunodeficiency virus infection.

Renal complications of HIV infection are clinically and morphologically diverse. These may affect the glomerular, tubulointerstitial, and vascular compartments. Tubulointerstitial injury predominates in most autopsy-based studies, whereas glomerular disease is most frequently identified in biopsy-based studies. The most common glomerular lesion is HIV-associated focal segmental glomerulosclerosis and related mesangiopathies (collectively termed HIV-associated nephropathy). Increasingly, a variety of immune complex-mediated glomerular diseases such as membranoproliferative glomerulonephritis, IgA nephropathy and lupus-like nephritis, as well as hemolytic uremic syndrome/thrombotic thrombocytopenic purpura have been reported. The spectrum of tubulointerstitial lesions includes acute tubular necrosis, interstitial nephritis, diffuse infiltrative lymphocytosis syndrome, renal infection, and neoplasms including lymphoma and Kaposi's sarcoma. The pathological features of these conditions are reviewed with emphasis on clinical-pathological correlations and pathogenesis.